Compounds, compositions, and methods for protein degradation

Abstract

Disclosed herein are compounds that target SMARCA2, SMARCA4, or BRM and cause their degradation. Also disclosed herein are compositions and methods for use in treating related disorders and diseases.

Description

[Technical Field]

[0001] Related applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 975,529, filed on 12 February 2020, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Transcriptional abnormalities due to defects in chromatin remodeling activity have a significant impact on tumorigenesis. Tumor exome sequencing studies have shown that the multi-subunit SWI / SNF chromatin remodeling complex is mutated in approximately 20% of human cancers and contains one of two mutually exclusive ATPases, SMARCA2 or SMARCA4. Previous studies have revealed a synthetic lethal relationship between SMARCA2 and SMARCA4, with SMARCA2 being highly dependent in SMARCA4-deficient cancer cells. SMARCA4 mutations or loss of expression occur in many cancers, including non-small cell lung cancer. Furthermore, blocking SMARCA2 using biological methods such as knockout or knockdown is lethal to cancer cells. Therefore, targeted degradation of SMARCA2 or SMARCA4 is an attractive method for treating many cancers. However, to date, there are no small molecule treatments that target SMARCA2 or SMARCA4 and are approved for use in humans. [Overview of the project] [Means for solving the problem]

[0003] In one embodiment, the present disclosure relates to a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, [in the formula A is [ka] [Chemical] is; E is [Chemical] [Chemical] is; X 1 and X 2 are each independently selected from O, NR 3 and S; or X 1 or X 2 is attached to L to form a heterocyclyl or heteroaryl; or X 1 and X 2 both are attached to L to form a heterocyclyl or heteroaryl; X 3 is O, NR 3 or S; L is an alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene or heteroarylene chain containing 1 to 35 carbon atoms, or a combination thereof, for example, containing 1 to 35 -CH2- moieties, optionally, when L contains an alkylene containing 1 to 35 -CH2- moieties, at least one, but no more than 10, of the -CH2- moieties of L are independently replaced by a moiety selected from -C(=O)-, -C(=O)-NR 4 -, -NR 4 -C(=O)-, -C(=O)-O-, -O-C(=O)-, -NR 4 -C(=O)-NR 3 -, -O-C(=O)-NR 4 -, -NR 4 -C(=O)-O-, -O-, -S- and -NR 4 -, provided that the number of -CH2- moieties of L is the number of -C(=O)-, -C(=O)-NR 4 -, -NR 4 -C(=O)-, -C(=O)-O-, -O-C(=O)-, -NR 4-C(=O)-NR3-, -OC(=O)-NR 4 -, -NR 4 More than the sum of the -C(=O)-O-, -O-, -S- and -NR3- parts, except for each of the -C(=O)-, -C(=O)-NR3- parts of L. 4 -, -NR 4 -C(=O)-, -C(=O)-O-, -OC(=O)-, -NR 4 -C(=O)-NR3-, -OC(=O)-NR 4 -, -NR 4 -C(=O)-O-, -O-, -S-, and -NR 4 Between the segments, there is at least one -CH2-; R 1 and R 2 Each is independently selected from H, alkyl, halo, hydroxyl, hydroxyalkyl, carboxyl, acyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azide, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclylalkyl, heteroaralkyl, sulfonamide, aryl, heteroaryl, heterocyclyl, and aralkyl; R 3 and R 4 Each is independently selected from H and alkyl; n is provided to be 1 to 5, preferably 1.

[0004] In another embodiment, the disclosure provides a composition comprising a compound of formula I and at least one pharmaceutically acceptable excipient.

[0005] In further embodiments, the Disclosure provides a method for treating a disease or disorder (e.g., cancer) that involves administering a compound of Formula I to a subject that requires treatment of the disease or disorder (e.g., cancer). [Brief explanation of the drawing]

[0006] [Figure 1A]Figure 1A is a graph showing the activity of exemplary compounds of this disclosure against MV411 WT compared to a specific reference compound. [Figure 1B] Figure 1B is a graph showing the activity of the exemplary compounds of this disclosure against MV411 CRBN knockout compared to a specific reference compound. [Figure 2A] Figure 2A is a graph showing the activity of the exemplary compounds of this disclosure compared to a specific reference compound with respect to MV411 WT after 48 hours. [Figure 2B] Figure 2B is a graph showing the activity of the exemplary compounds of this disclosure compared to a specific reference compound against MV411 CRBN knockout after 48 hours. [Figure 3A] Figure 3A shows the structure of Cmp12. [Figure 3B] Figure 3B is a graph showing the activity of the exemplary compounds of this disclosure against MV411 compared to a specific reference compound. [Figure 3C] Figure 3C is a graph showing the activity of exemplary compounds of this disclosure against MOLM13 compared to a specific reference compound. [Figure 4A] Figure 4A is a graph showing the activity of the exemplary compounds of this disclosure compared to a specific reference compound with respect to MV411 after 48 hours. [Figure 4B] Figure 4B is a graph showing the activity of the exemplary compounds of this disclosure compared to a specific reference compound with respect to MV411 after 48 hours. [Figure 5A] Figure 5A is a graph showing the activity of the exemplary compounds of this disclosure compared to a specific reference compound with respect to MV411 after 48 hours. [Figure 5B] Figure 5B is a graph showing the activity of the exemplary compounds of this disclosure compared to a specific reference compound with respect to MOLM after 48 hours. [Figure 6A] Figure 6A shows the structure of Cmp14. [Figure 6B]Figure 6B is a graph showing the activity of the exemplary compounds of this disclosure compared to a specific reference compound with respect to MV411 WT after 48 hours. [Figure 6C] Figure 6C is a graph showing the activity of the exemplary compounds of this disclosure compared to a specific reference compound against MV411 CRBN knockout after 48 hours. [Figure 7A] Figure 7A is a Western blot of A549 cells treated with Example 4 at a concentration of 1 μM. The cells began to show proteolysis after 40 hours. [Figure 7B] Figure 7B is a Western blot of A549 cells treated with Example 2 at a concentration of 1 μM. The cells began to show proteolysis after 40 hours. [Figure 7C] Figure 7C is a Western blot of MOLM13 cells treated in Example 4. The cells began to show proteolysis after 16 hours. [Modes for carrying out the invention]

[0007] Proteolysis-targeting chimeras (PROTACs) are a class of drug molecules in which a target-binding ligand is covalently bound to an E3 ligase-binding ligand that can form a target-PROTAC-ligase ternary complex. The ternary complex directs the ubiquitin-proteasome system to degrade the target protein.

[0008] PROTACs exhibit higher selectivity for protein degradation than the target ligands themselves, and their degradation is not limited to protein domains functionally involved in disease; therefore, they extend the proteome, leading to the development of new drugs. This specification discloses PROTACS that interfere with the function of the SWI / SNF complex in cancer cells by targeting certain proteins, such as the core catalytic subunit SMARCA2.

[0009] Exemplary Compounds in this Disclosure In one embodiment, the present disclosure relates to a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, [in the formula A is [ka] and; E is [ka] [ka] and; X 1 and X 2 These are O and NR, respectively, independently. 3 and selected from S; or X 1 Or X 2 It combines with L to form a heterocycline or heteroaryl; or X 1 and X 2 Both combine with L to form a heterocycline or heteroaryl; X 3 O, NR 3 or S; L is an alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene, or heteroarylene chain containing 1 to 35 carbon atoms, or a combination thereof, for example, containing 1 to 35 -CH2- portions, optionally, If L contains alkylene with 1 to 35 -CH2- moieties, then at least one of L, with 10 or fewer -CH2- moieties, independently of -C(=O)- and -C(=O)-NR. 4 -, -NR 4 -C(=O)-, -C(=O)-O-, -OC(=O)-, -NR 4 -C(=O)-NR 3 -, -OC(=O)-NR 4 -, -NR 4 -C(=O)-O-, -O-, -S-, and -NR 4- is replaced by a portion selected from, however, the number of -CH2- portions of L is -C(=O)-, -C(=O)-NR of L. 4 -, -NR 4 -C(=O)-, -C(=O)-O-, -OC(=O)-, -NR 4 -C(=O)-NR3-, -OC(=O)-NR 4 -, -NR 4 More than the sum of the -C(=O)-O-, -O-, -S- and -NR3- parts, except for each of the -C(=O)-, -C(=O)-NR3- parts of L. 4 -, -NR 4 -C(=O)-, -C(=O)-O-, -OC(=O)-, -NR 4 -C(=O)-NR3-, -OC(=O)-NR 4 -, -NR 4 -C(=O)-O-, -O-, -S-, and -NR 4 Between the segments, there is at least one -CH2-; R 1 and R 2 Each is independently selected from H, alkyl, halo, hydroxyl, hydroxyalkyl, carboxyl, acyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azide, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclylalkyl, heteroaralkyl, sulfonamide, aryl, heteroaryl, heterocyclyl, and aralkyl; R 3 and R 4 Each is independently selected from H and alkyl; n is provided to be 1 to 5, preferably 1.

[0010] In one embodiment of formula I, R 1 is a halo. In one embodiment, R 1 is fluoro. In one preferred embodiment, R 1 It is chloroform.

[0011] In one embodiment of formula I, R 2is H or hydroxyalkyl. In certain preferred embodiments, R 2 H is H.

[0012] In one embodiment of formula I, R 1 and R 2 However, they cannot both be H.

[0013] In one embodiment of formula I, R 3 H is H.

[0014] In one embodiment of formula I, R 4 H is H.

[0015] In one embodiment of formula I, the compound is [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0016] In one embodiment of formula I, X 1 In other embodiments, X 1 teeth O .

[0017] In one embodiment of formula I, X 3 In other embodiments, X 3 teeth O .

[0018] In one embodiment of formula I, X 2 In other embodiments, X 2 teeth O In yet another embodiment, X 2 It combines with L to form a heterocycline (e.g., piperidinyl).

[0019] In one embodiment of formula I, L is a cycloalkylene (e.g., cyclohexyl). In another embodiment, L is an alkylene. In one embodiment, the alkylene contains 2 to 25 carbon atoms. In one embodiment, the alkylene contains 2 carbon atoms. In another embodiment, the alkylene contains 3 carbon atoms. In yet another embodiment, the alkylene contains 4 carbon atoms. In yet another embodiment, the alkylene contains 5 carbon atoms. In yet another embodiment, the alkylene contains 6 carbon atoms. In yet another embodiment, the alkylene contains 7 carbon atoms. In yet another embodiment, the alkylene contains 8 carbon atoms. In yet another embodiment, the alkylene contains 9 carbon atoms. In yet another embodiment, the alkylene contains 10 carbon atoms. In yet another embodiment, the alkylene contains 11 carbon atoms. In yet another embodiment, the alkylene contains 12 carbon atoms. In yet another embodiment, the alkylene contains 13 carbon atoms. In yet another embodiment, the alkylene contains 14 carbon atoms. In yet another embodiment, the alkylene contains 15 carbon atoms. In yet another embodiment, the alkylene contains 16 carbon atoms. In yet another embodiment, the alkylene contains 17 carbon atoms. In yet another embodiment, the alkylene contains 18 carbon atoms. In yet another embodiment, the alkylene contains 19 carbon atoms. In yet another embodiment, the alkylene contains 20 carbon atoms. In yet another embodiment, the alkylene contains 21 carbon atoms. In yet another embodiment, the alkylene contains 22 carbon atoms. In yet another embodiment, the alkylene contains 23 carbon atoms. In yet another embodiment, the alkylene contains 24 carbon atoms. In yet another embodiment, the alkylene contains 25 carbon atoms. In one embodiment, at least one, but no more than five, methylene portions of the alkylene are amide portions (e.g., [ka] ) is replaced by an amide moiety (for example, [ka] ) is replaced by two methylene moieties of the alkylene (for example, [ka] ) is replaced by three methylene moieties of the alkylene (for example, [ka] ) are replaced by one, two, three or six methylene moieties of the alkylene (for example, [ka] ) are replaced by. In some embodiments, the amide portions are not adjacent. In some embodiments, the amide portions are separated by at least one carbon atom. In some embodiments, the amide portions are separated by at least six carbon atoms. In some embodiments, at least one, but no more than 10, methylene portions of the alkylene are replaced by oxygen atoms. In some embodiments, at least one methylene portion of the alkylene is replaced by oxygen atoms. In some embodiments, at least two methylene portions of the alkylene are replaced by at least two oxygen atoms. In some embodiments, at least six methylene portions of the alkylene are replaced by at least six oxygen atoms. In some embodiments, one, two, or six methylene portions of the alkylene are replaced by oxygen atoms.

[0020] In a preferred embodiment of formula I, n is 1.

[0021] In one embodiment, the compound of formula I is [ka] [ka] [ka] or selected from pharmaceutically acceptable salts thereof.

[0022] Exemplary methods of this disclosure In one embodiment, the Disclosure provides a method for degrading SMARCA2, SMARCA4, or BRM, comprising contacting cells with a compound of the Disclosure or a pharmaceutically acceptable salt thereof. In one embodiment, the amount of compound used is an effective amount.

[0023] In another embodiment, the Disclosure provides a method for treating a disease or disorder, comprising administering a compound of the Disclosure to a subject that requires treatment of the disease or disorder. In one embodiment, the amount of compound used is a therapeutically effective dose.

[0024] In yet another embodiment, the Disclosure provides a method for treating a disease or disorder that benefits from the degradation of SMARCA2, SMARCA4, or BRM, comprising administering a compound of the Disclosure to a subject that requires treatment for a disease or disorder that benefits from the degradation of SMARCA2, SMARCA4, or BRM. In one embodiment, the amount of compound used is a therapeutically effective amount.

[0025] In some embodiments of the methods described herein, a disease or disorder benefits from the degradation of SMARCA2.

[0026] In some embodiments of the methods described herein, a disease or disorder benefits from the degradation of SMARCA4.

[0027] In some embodiments of the methods described herein, a disease or disorder benefits from the decomposition of the BRM.

[0028] In some embodiments of the methods described herein, the disease or disorder is cancer. In some embodiments, the cancer is selected from synovial sarcoma, lung cancer, ovarian cancer, brain cancer, kidney cancer, leukemia, non-small cell lung cancer, Burkitt lymphoma, pediatric medulloblastoma, pancreatic adenocarcinoma, ovarian clear cell carcinoma, renal cell carcinoma, endometrial carcinoma, and melanoma.

[0029] In some embodiments of the methods described herein, the administration of one or more additional chemotherapeutic agents is further included.

[0030] Pharmaceutical composition The compositions and methods of embodiments of the present invention may be used to treat individuals requiring the compositions and methods of embodiments of the present invention. In some embodiments, the individuals are mammals, such as humans or non-human mammals. When administered to animals such as humans, the compositions or compounds are preferably administered as a pharmaceutical composition comprising, for example, the compounds of the present invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions, such as water or physiologically buffered saline or other solvents or vehicles, such as glycols, glycerols, oils such as olive oil or injectable organic esters. In preferred embodiments, when such a pharmaceutical composition is for human administration, particularly for invasive administration routes (i.e., routes such as injection or implantation that avoid transport or diffusion across the epithelial barrier), the aqueous solution is pyrogenic or substantially pyrogenic. Excipients may be selected, for example, to result in delayed release of the active ingredient or to selectively target one or more cells, tissues or organs. Pharmaceutical compositions may be in the form of dosage units such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilized reconstituters, powders, solutions, syrups, suppositories, and injections. Compositions may also be present in transdermal delivery systems, such as skin patches. Compositions may also be present in solutions suitable for topical administration, such as lotions, creams, or ointments.

[0031] A pharmaceutically acceptable carrier may contain a physiologically acceptable active substance that acts to stabilize, increase the solubility of, or increase the absorption of a compound, such as the compound of the present invention. Examples of such physiologically acceptable active substances include carbohydrates such as glucose, sucrose, or dextran; antioxidants such as ascorbic acid or glutathione; chelating agents; low molecular weight proteins; or other stabilizers or excipients. The selection of a pharmaceutically acceptable carrier containing a physiologically acceptable active substance depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) may also be a liposome or other polymer matrix, which may incorporate, for example, the compound of the present invention. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers that are relatively easy to prepare and administer.

[0032] The phrase "pharmaceutically acceptable" is used herein to mean a compound, material, composition, and / or dosage form suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio, within the bounds of sound medical judgment.

[0033] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and is not harmful to the patient. Some examples of materials that can function as a pharmaceutically acceptable carrier include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose, and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, and corn oil. Examples include oils such as soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) water that does not contain pyrogens; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; and (21) other non-toxic, suitable substances used in pharmaceutical preparations.

[0034] Pharmaceutical compositions (preparations) can be administered to a subject by any of a number of routes of administration, including, for example, oral (e.g., aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingual); subcutaneous; transdermal (e.g., as a patch applied to the skin); and topical (e.g., as a cream, ointment, or spray applied to the skin). Compounds can also be formulated for inhalation. In some embodiments, compounds can be simply dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable for suitable routes of administration can be found, for example, in U.S. Patents 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, and the patents cited herein.

[0035] The formulations can be conveniently provided in unit dosage forms and can be prepared by any method well known in the field of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form varies depending on the host being treated and the specific mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally the amount of the compound that produces the therapeutic effect. Generally, out of 100%, this amount is in the range of about 1% to about 99%, preferably about 5% to about 70%, and most preferably about 10% to about 30% of the active ingredient.

[0036] Methods for preparing these formulations or compositions include the step of combining an active compound, such as the compound of the present invention, with a carrier and optionally one or more auxiliary components. Generally, formulations are prepared by uniformly and tightly combining the compound of the present invention with a liquid carrier, or a finely divided solid carrier, or both, and then optionally shaping the product.

[0037] Formulations of the present invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using flavored base ingredients, usually sucrose and gum arabic or tragacanth), lyophilized agents, powders, granules, or as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups, or as lozenges (using inert bases such as gelatin and glycerin, or sucrose and gum arabic), and / or as mouthwashes, etc., each containing a predetermined amount of the compound of the present invention as an active ingredient.

[0038] To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, sugar-coated tablets, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic; (3) water-retaining agents such as glycerol; (4) cold Disintegrants such as tallow, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) Dissolution retarders such as paraffin; (6) Absorption accelerators such as quaternary ammonium compounds; (7) Wetting agents such as cetyl alcohol and glycerol monostearate; (8) Absorbents such as kaolin and bentonite clay; (9) Lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; (10) Complexing agents such as modified and unmodified cyclodextrins; and (11) Colorants. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical composition may also include buffers. Similar types of solid compositions may also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose and high molecular weight polyethylene glycol.

[0039] Tablets may be prepared by compression or molding, with one or more optional auxiliary components. Compressed tablets may be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or crosslinked sodium carboxymethylcellulose), a surfactant, or a dispersant. Molded tablets may be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent using appropriate machinery.

[0040] Tablets, as well as other solid dosage forms of pharmaceutical compositions such as sugar-coated tablets, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be notched or prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation field. Tablets, as well as other solid dosage forms of pharmaceutical compositions such as sugar-coated tablets, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may also be formulated to provide delayed or controlled release of the active ingredient therein, for example, by using hydroxypropyl methylcellulose, other polymer matrices, liposomes and / or spheres in various proportions to provide a desired release profile. Tablets, as well as other solid dosage forms of pharmaceutical compositions such as sugar-coated tablets, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating a sterilizer in the form of a sterile solid composition that can be dissolved in sterile water or any other sterile injection medium immediately before use. These compositions may optionally contain an opacifier and may optionally release the active ingredient in a delayed manner, either only in or preferentially in a specific part of the gastrointestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient may also be in a microencapsulated form, as appropriate, together with one or more of the excipients.

[0041] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophilized products for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrins and their derivatives, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, as well as mixtures thereof.

[0042] In addition to inert diluents, oral compositions may also contain auxiliary agents such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents, colorants, fragrances and preservatives.

[0043] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof.

[0044] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0045] In addition to the active compound, ointments, pastes, creams, and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide or mixtures thereof.

[0046] In addition to the active compound, the powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powders or mixtures thereof. The sprays may further contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0047] Transdermal patches offer the further advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms can be prepared by dissolving or dispersing the active compound in a suitable medium. Absorption enhancers can also be used to increase the flow of the compound across the skin. The rate of such flow can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0048] As used herein, the terms “parenteral administration” and “administered parenterally” refer to modes of administration other than enteral and topical administration, typically by injection, and include, but are not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions. A pharmaceutical composition suitable for parenteral administration comprises one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted into a sterile injection solution or dispersion immediately before use, and may contain antioxidants, buffers, bacteriostatic agents, solutes that are isotonic with the blood of the recipient to whom the formulation is intended, or suspending agents or thickeners, and comprises one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted into a sterile injection solution or dispersion immediately before use.

[0049] Suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, and polyethylene glycol) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0050] These compositions may also contain auxiliary agents such as preservatives, humectants, emulsifiers, and dispersants. Prevention of microbial action can be ensured by including various antimicrobial and antifungal agents, such as parabens, chlorobutanol, and phenolsorbic acid. It may also be desirable to include isotonic agents such as sugars and sodium chloride in the composition. Furthermore, the inclusion of absorption-delaying agents such as aluminum monostearate and gelatin can lead to prolonged absorption of the pharmaceutical form for injection.

[0051] In some cases, it is desirable to delay the absorption of a drug from subcutaneous or intramuscular injection in order to prolong its effects. This can be achieved by using a liquid suspension of a crystalline or amorphous material with low water solubility. The rate of drug absorption depends on its dissolution rate, which may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oily vehicle.

[0052] Depot formulations for injection are prepared by forming a microencapsulated matrix of the subject compound within a biodegradable polymer such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot formulations for injection can also be prepared by encapsulating the drug in liposomes or microemulsions that conform to body tissues.

[0053] For use in the method of the present invention, the active compound can be provided either by itself or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0054] The method of delivery may also be provided by rechargeable or biodegradable devices. In recent years, various sustained-release polymeric devices have been developed and tested in vivo for the controlled delivery of drugs, including protein-based biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-biodegradable polymers, can be used to form implants for the sustained release of compounds at specific target sites.

[0055] The actual dose level of the active ingredient in a pharmaceutical composition can be varied to obtain an amount of the active ingredient that is not toxic to the patient and is effective in achieving the desired therapeutic response for a particular patient, composition, and mode of administration.

[0056] The selected dosage level depends on a variety of factors, including the activity of the specific compound or combination of compounds used, or its ester, salt, or amide; the route of administration; the time of administration; the rate of excretion of the specific compound used; the duration of treatment; other drugs, compounds, and / or materials used in combination with the specific compound used; the age, sex, weight, condition, overall health, and prior medical history of the patient being treated; and similar factors well known in the field of medicine.

[0057] A physician or veterinarian with ordinary art in the art can easily determine and prescribe the therapeutically effective dose of the required pharmaceutical composition. For example, a physician or veterinarian can start with a dose of the pharmaceutical composition or compound at a level lower than the level required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13th ed., 1814-1882, incorporated herein by reference).

[0058] Generally, the appropriate daily dose of the active compound used in the compositions and methods of the present invention is the amount of the compound that is the minimum effective dose to produce a therapeutic effect. Such an effective dose generally depends on the factors mentioned above.

[0059] If desired, the effective daily dose of the active compound may be administered in unit dosage form as one, two, three, four, five, six or more subdoses, administered separately at appropriate intervals throughout the day. In some embodiments of the present invention, the active compound may be administered two or three times a day. In preferred embodiments, the active compound is administered once a day.

[0060] Patients receiving this treatment include primates, especially humans; as well as other mammals such as horses, cattle, pigs, sheep, cats and dogs; poultry; and any animals in need, including pets in general.

[0061] In some embodiments, the compounds of the present invention may be used alone or administered in combination with other types of therapeutic agents.

[0062] In some embodiments, the present disclosure includes the use of pharmaceutically acceptable salts of the compounds of the present invention in compositions and methods of the present invention. In some embodiments, the salts intended for the present invention include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkylammonium salts. In some embodiments, the salts intended for the present invention include L-arginine, BenetaminThese salts include, but are not limited to, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydravamin, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In some embodiments, the salts intended for the present invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts. In one embodiment, the salts intended for use in the present invention include 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, l-ascorbic acid, l-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, and d-glucohep. Examples of acidic acids include, but are not limited to, tonic acid, d-gluconic acid, d-glucuronic acid, glutamic acid, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, l-malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, l-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, l-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid salts.

[0063] Pharmaceutically acceptable acid addition salts can also exist as various solvates with water, methanol, ethanol, dimethylformamide, and others. Mixtures of such solvates can also be prepared. The source of such solvates may be derived from the crystallization solvent, inherent in the preparation or crystallization solvent, or exogenous to such solvent.

[0064] Wetting agents such as sodium lauryl sulfate and magnesium stearate, emulsifiers and lubricants, as well as colorants, release agents, coating agents, sweeteners, flavoring agents and fragrances, preservatives and antioxidants may also be present in the composition.

[0065] Examples of pharmaceutically acceptable antioxidants include (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and alpha-tocopherol; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0066] definition Unless otherwise defined herein, scientific and technical terms used in this application shall have meanings that are generally understood by those skilled in the art. In general, the nomenclature and techniques used in relation to chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry described herein are well known and commonly used in the art.

[0067] The methods and techniques described herein are generally carried out in accordance with conventional methods well known in the art, unless otherwise specified, as described in the various general and more specific references cited and discussed herein. See, for example, “Principles of Neural Science”, McGraw-Hill Medical, New York, NY (2000); Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al., “Molecular Cell Biology, 4th ed.”, WH Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th ed.”, WH Freeman & Co., NY (1999); and Gilbert et al., “Developmental Biology, 6th ed.”, Sinauer Associates, Inc., Sunderland, MA (2000).

[0068] Chemical terms used herein, unless otherwise defined herein, are used in accordance with the common usage in the art, as exemplified by “The McGraw-Hill Dictionary of Chemical Terms”, Parker S., Ed. McGraw-Hill, San Francisco, CA (1985).

[0069] All of the foregoing, as well as any other publications, patents, and published patent applications cited herein, are incorporated herein by reference. In the event of any conflict, this Specified Version, including its specific definitions, shall prevail.

[0070] The term “active substance” is used herein to refer to chemical compounds (such as organic or inorganic compounds, mixtures of chemical compounds), biological macromolecules (such as nucleic acids, parts of antibodies and antibodies including humanized antibodies, chimeric antibodies and human antibodies and monoclonal antibodies, proteins or parts thereof, e.g., peptides, lipids, carbohydrates), or extracts made from biological materials such as cells or tissues of bacteria, plants, fungi, or animals (especially mammals). Examples of active substances include active substances whose structure is publicly known and active substances whose structure is unknown. The ability of such active substances to inhibit or promote AR degradation may make such active substances suitable as “therapeutic agents” in the methods and compositions of this disclosure.

[0071] The terms "patient," "subject," or "individual" are used interchangeably and refer to either a human or a non-human animal. These terms include mammals such as humans, primates, domesticated animals (including cattle and pigs), companion animals (e.g., canids and felines), and rodents (e.g., mice and rats).

[0072] To “treat” a symptom or patient means to take measures to obtain a beneficial or desired outcome, including clinical outcomes. As used herein and as is well understood in the art, “treatment” is an approach to obtain a beneficial or desired outcome, including clinical outcomes. Beneficial or desired clinical outcomes may include, but are not limited to, relief or improvement of one or more symptoms or symptoms, whether detectable or undetectable; reduction of disease severity; stabilization (i.e., non-exacerbating) of the disease; prevention of disease spread; delay or slowing of disease progression; improvement or relief of the disease state; and remission (whether partial or total). “Treatment” may also mean extending survival compared to the survival expected without treatment.

[0073] The term “prevent” is recognized and well understood in the art and, when used in relation to symptoms such as local recurrence (e.g., pain), diseases such as cancer, syndrome complexes such as heart failure, or any other medical symptoms, includes the administration of a composition that reduces the frequency of symptoms of a medical symptom in a subject or delays the onset of symptoms of a medical symptom compared to a subject that has not received the composition. Thus, cancer prevention includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving prophylactic treatment compared to an untreated control population, and / or delaying the appearance of detectable cancerous growths in the treated population by, for example, a statistically and / or clinically significant amount compared to an untreated control population.

[0074] "Administering" a substance, compound, or active agent to a subject, or "administering" a substance, compound, or active agent, can be done using one of the various methods known to those skilled in the art. For example, compounds or active agents can be administered intravenously, transarterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ophthalmally, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (e.g., by absorption through the skin canal). Compounds or active agents can also be appropriately introduced by rechargeable or biodegradable polymer devices or other devices, such as patches and pumps, or formulations, that provide sustained release, delayed release, or controlled release of the compound or active agent. Administration can also be done, for example, once, multiple times, and / or over one or more extended periods.

[0075] The appropriate method for administering a substance, compound, or active agent to a subject also depends, for example, on the subject's age and / or health condition, as well as the chemical and biological properties of the compound or active agent (e.g., solubility, digestibility, bioavailability, stability, and toxicity). In some embodiments, the compound or active agent is administered orally, for example, by ingestion. In some embodiments, the orally administered compound or active agent is a sustained-release or delayed-release formulation, or is administered using a device for such delayed-release or sustained-release.

[0076] As used herein, the term “conjoint administration” refers to any form of administration of two or more different therapeutic agents such that a second active agent is administered while a previously administered therapeutic agent is still effective in the body (for example, the two active agents are effective simultaneously in the patient, which may include a synergistic effect between the two active agents). For example, different therapeutic compounds may be administered simultaneously or sequentially, either in the same formulation or in separate formulations. Thus, an individual receiving such treatment may benefit from the combined effect of the different therapeutic agents.

[0077] The "therapeutic effective dose" of a drug or active substance is the amount of the drug or active substance that, when administered to a subject, produces the intended therapeutic effect. Complete prophylactic effect does not necessarily result from a single dose, but may only occur after a series of doses. Therefore, the therapeutic effective dose may be administered in one or more doses. The exact effective dose required for a subject depends, for example, on the subject's size, health condition and age, as well as the nature and severity of the condition being treated, such as cancer or MDS. A person skilled in the art can easily determine the effective dose for a given situation through routine experimentation.

[0078] As used herein, the terms “optional” or “optionally” mean that the event or situation described below may or may not occur, and that the description includes not only the cases in which the event or situation occurs, but also the cases in which it does not occur. For example, “optionally substituted alkyl” means not only that the alkyl may be substituted, but also that the alkyl is not substituted.

[0079] It will be understood that the substituents and substitution patterns on the compounds described herein can be selected by those skilled in the art to yield chemically stable compounds that can be readily synthesized from readily available starting materials by techniques known in the art and by the methods shown below. If the substituent itself is substituted with two or more groups, it will be understood that these groups may be on the same carbon or different carbons, as long as a stable structure is obtained.

[0080] As used herein, the term “optionally substituted” refers to the substitution of 1 to 6 hydrogen radicals in a given structure by radicals of certain substituents, including but not limited to hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2, or -CH2-OP(O)(O-alkyl)2. Preferably, “optionally substituted” refers to the substitution of 1 to 4 hydrogen radicals in a given structure by the substituents described above. More preferably, 1 to 3 hydrogen radicals are substituted by the substituents described above. It is understood that substituents may be further substituted.

[0081] As used herein, the term "alkyl" refers to C1-C 10 Linear alkyl groups or C1-C 10This refers to saturated aliphatic groups, including but not limited to branched alkyl groups. Preferably, the "alkyl" group refers to a C1-C6 linear alkyl group or a C1-C6 branched alkyl group. Most preferably, the "alkyl" group refers to a C1-C4 linear alkyl group or a C1-C4 branched alkyl group. Examples of "alkyl" include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl, or 4-octyl. The "alkyl" group may be optionally substituted.

[0082] The term "acyl" is recognized in the art and refers to a group represented by the general formula hydrocarbyl C(O)-, preferably alkyl C(O)-.

[0083] The term "acylamino" is recognized in the art and refers to an amino group substituted with an acyl group, which can be represented, for example, by the formula hydrocarbyl C(O)NH-.

[0084] The term "acyloxy" is recognized in the art and refers to a group represented by the general formula hydrocarbyl C(O)O-, preferably alkyl C(O)O-.

[0085] The term "alkoxy" refers to an alkyl group to which oxygen is bonded. Typical alkoxy groups include methoxy, ethoxy, propoxy, and tert-butoxy.

[0086] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and can be represented by the general formula alkyl-O-alkyl.

[0087] The term "alkyl" refers to saturated aliphatic groups, including linear alkyl groups, branched alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In preferred embodiments, linear or branched alkyl groups have 30 or fewer (for example, C in the case of a linear group) in their skeleton. 1~30 In the case of a branched chain, C 3~30 ), more preferably having 20 or fewer carbon atoms.

[0088] Furthermore, the term “alkyl” as used herein, in the examples and in the claims is intended to include both unsubstituted alkyl groups and substituted alkyl groups, the latter referring to alkyl moieties having substituents that replace hydrogens on one or more carbons of a hydrocarbon skeleton, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl.

[0089] "C x~y " or "C x ~C y The term "alkyl" means a group containing x to y carbon atoms in a chain, when used in combination with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy. C0 alkyl indicates hydrogen when the group is at the terminal position, and a bond when it is internal. 1~6 Alkyl groups, for example, contain 1 to 6 carbon atoms in their chain.

[0090] As used herein, the term "alkylamino" refers to an amino group substituted with at least one alkyl group.

[0091] As used herein, the term "alkylthio" refers to a thiol group substituted with an alkyl group, which may be represented by the general formula alkylS-.

[0092] The term "amide" as used herein refers to the base [ka] denotes, wherein R 9 and R 10 each independently represents hydrogen or a hydrocarbyl group, or R 9 and R 10 together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure.

[0093] The terms "amine" and "amino" are recognized in the art and include both unsubstituted and substituted amines and their salts, for example,

Chemical formula

[0094] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0095] As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group.

[0096] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings and at least one of the rings is aromatic; for example, the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Examples of aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0097] The term "carbamate" is recognized in the art and refers to the group

Chemical formula

[0098] As used herein, the term "carbocyclic alkyl" refers to an alkyl group substituted with a carbocyclic group.

[0099] The term "carbocyclic ring" includes monocyclic rings with 5 to 7 members and bicyclic rings with 8 to 12 members. Each ring in a bicyclic carbocyclic ring may be selected from saturated, unsaturated, and aromatic rings. A carbocyclic ring includes a bicyclic molecule in which one, two, three, or more atoms are shared between the two rings. The term "condensed carbocyclic ring" refers to a bicyclic carbocyclic ring in which each ring shares two adjacent atoms with the other ring. Each ring in a condensed carbocyclic ring may be selected from saturated, unsaturated, and aromatic rings. In exemplary embodiments, an aromatic ring, e.g., phenyl, may be condensed with a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of a carbocyclic ring, as long as the valence allows. Examples of “carbocyclic rings” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octo-3-ene, naphthalene, and adamantane. Examples of condensed carbocyclic rings include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. The “carbocyclic rings” can be substituted at any one or more positions where hydrogen atoms may be present.

[0100] As used herein, the term "carbocykrylalkyl" refers to an alkyl group substituted with a carbocyclic group.

[0101] The term "carbonate" is recognized in this technical field and refers to the group -OCO2-.

[0102] As used herein, the term "carboxyl" refers to the group represented by the formula -CO2H.

[0103] As used herein, the term "ester" refers to the group -C(O)OR 9 It refers to, and in the formula, R 9 This represents a hydrocarbyl group.

[0104] As used herein, the term “ether” refers to a hydrocarbyl group bonded to another hydrocarbyl group via oxygen. Therefore, the ether substituent of a hydrocarbyl group can be hydrocarbyl-O-. Ethers can be symmetric or asymmetric. Examples of ethers include, but are not limited to, heterocyclic-O-heterocyclic and aryl-O-heterocyclic groups. Ethers also include “alkoxyalkyl” groups, which can be represented by the general formula alkyl-O-alkyl.

[0105] As used herein, the terms "halo" and "halogen" mean halogens, including chloro, fluoro, bromo, and iodine.

[0106] As used herein, the terms “hetallalkyl” and “hetallalkyl” refer to alkyl groups substituted with hetalil groups.

[0107] The terms "hetalial" and "hetalial" include substituted or unsubstituted aromatic monocyclic structures whose ring structure contains at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms, preferably a 5 to 7-membered ring, more preferably a 5 to 6-membered ring. The terms "hetalial" and "hetalial" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, and at least one of the rings is heteroaromatic, for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl. Examples of heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine.

[0108] As used herein, the term “heteroatom” means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0109] As used herein, the term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclic group.

[0110] The terms “heterocyclyl,” “heterocyclic,” and “heterocyclic” refer to a substituted or unsubstituted non-aromatic ring structure whose ring structure contains at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms, preferably a 3 to 10-membered ring, more preferably a 3 to 7-membered ring. The terms “heterocyclyl” and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, and at least one of the rings is heterocyclic, for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Examples of heterocyclyl groups include piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, and the like.

[0111] As used herein, the term "hydrocarbyl" refers to a group that does not have =O or =S substituents and typically has at least one carbon-hydrogen bond and is primarily a carbon skeleton, but is bonded via a carbon atom that may optionally contain a heteroatom. Therefore, groups such as methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered hydrocarbyl in this application, but substituents such as acetyl (which has an =O substituent on the bonded carbon) and ethoxy (which is bonded via oxygen rather than carbon) are not hydrocarbyl. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclic, alkyl, alkenyl, alkynyl, and combinations thereof.

[0112] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl group.

[0113] When used in combination with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, the term “lower” means that the substituent contains 10 or fewer atoms, preferably 6 or fewer. “Lower alkyl” refers to an alkyl group containing, for example, 10 or fewer carbon atoms, preferably 6 or fewer. In some embodiments, the acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents as defined herein are lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy substituents, whether appearing alone or in combination with other substituents, such as in the notation hydroxyalkyl and aralkyl (in this case, for example, when counting the number of carbon atoms in the alkyl substituent, the number of atoms in the aryl group is not counted).

[0114] The terms “polycyclyl,” “polycyclic,” and “polycyclic formula” refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl) in which two or more atoms are common to two adjacent rings, for example, these rings are “fused rings.” Each of the rings in a polycyclic ring may be substituted or unsubstituted. In some embodiments, each ring in a polycyclic ring contains 3 to 10 atoms, preferably 5 to 7 atoms.

[0115] The term "sulfate" is recognized in the art and refers to the group -OSO3H or a pharmaceutically acceptable salt thereof.

[0116] The term "sulfonamide" is recognized in the art, and its general formula is [ka] This refers to the group represented by, in the formula, R 9 and R 10 This independently represents hydrogen or hydrocarbyl.

[0117] The term "sulfoxide" is recognized in this field and refers to the group -S(O)-.

[0118] The term "sulfonate" is recognized in the art and refers to the group SO3H or a pharmaceutically acceptable salt thereof.

[0119] The term "sulfone" is recognized in this technical field and refers to the group -S(O)2-.

[0120] The term “substituted” refers to a portion having substituents that replace hydrogens on one or more carbons of its skeleton. “Substituted” or “substituted with” will be understood to include the implicit condition that such substitution conforms to the acceptable valencies of the substituted atom and substituent, and that the substitution results in a stable compound that does not spontaneously undergo transformation, such as rearrangement, cyclization, or elimination. As used herein, the term “substituted” is assumed to include all acceptable substituents of an organic compound. In broad embodiments, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. Acceptable substituents may be one or more, identical or different, for a given organic compound. In the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any acceptable substituents of the organic compound described herein that satisfy the valency of the heteroatom. Substituents may include any substituents described herein, such as halogens, hydroxyls, carbonyls (carboxyls, alkoxycarbonyls, formyls, or acyls), thiocarbonyls (thioesters, thioacetates, or thioformates), alkoxyls, phosphoryls, phosphates, phosphonates, phosphinates, aminos, amides, amidines, imines, cyanos, nitros, azides, sulfhydryls, alkylthios, sulfates, sulfonates, sulfamoyls, sulfonamides, sulfonyls, heterocyclyls, aralkyls, or aromatic or heteroaromatic moieties. It will be understood by those skilled in the art that any substituted moieties on a hydrocarbon chain may be substituted themselves as appropriate.

[0121] As used herein, the term "thioalkyl" refers to an alkyl group substituted with a thiol group.

[0122] As used herein, the term "thioester" refers to the group -C(O)SR 9 or -SC(O)R 9 It refers to R 9 This represents hydrocarbyl.

[0123] As used herein, the term "thioether" is equivalent to an ether in which oxygen is replaced by sulfur.

[0124] The term "urea" is recognized in this field, and the general formula [ka] It can be expressed by, where R 9 and R 10 This independently represents hydrogen or hydrocarbyl.

[0125] As used herein, the term “modulate” includes inhibition or suppression of function or activity (such as cell proliferation) and enhancement of function or activity.

[0126] The phrase "pharmaceutically acceptable" is recognized in the art. In some embodiments, this term includes compositions, excipients, adjuvants, polymers, and other materials and / or dosage forms that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio, within the bounds of sound medical judgment.

[0127] "Pharmacologically acceptable salt" or "salt" is used herein to mean an acid addition salt or base addition salt that is suitable for or adapted to the treatment of a patient.

[0128] As used herein, the term “pharmaceutically acceptable acid addition salt” means any non-toxic organic or inorganic salt of any base compound represented by formula I. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as metal salts such as monohydrogen orthophosphate and potassium bisulfate. Exemplary organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, and salicylic acid, as well as sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid. They can form either mono or diate salts, and such salts may exist in hydrated, solvated, or substantially anhydrous forms. Generally, acid addition salts of compounds of formula I are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points compared to their free base forms. The selection of appropriate salts is known to those skilled in the art. Other pharmaceutically unacceptable salts, such as oxalates, may be used, for example, in the isolation of compounds of formula I for laboratory use, or for subsequent conversion to pharmaceutically acceptable acid addition salts.

[0129] As used herein, the term “pharmaceutically acceptable base addition salt” means any non-toxic organic or inorganic base addition salt of any acid compound represented by Formula I or any intermediate thereof. Exemplary inorganic bases that form suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or barium hydroxide. Exemplary organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine, and picoline or ammonia. The selection of suitable salts is known to those skilled in the art.

[0130] Many of the compounds useful in the methods and compositions of this disclosure have at least one chiral center in their structure. This chiral center may exist in an R or S configuration, and the R and S notations are used in accordance with the rules set out in Pure Appl. Chem. (1976), 45, 11-30. This disclosure intends all stereoisomeric forms, including enantiomers and diastereoisomers, of compounds, salts, prodrugs, or mixtures thereof (including all possible mixtures of stereoisomers). See, for example, International Publication No. 01 / 062726.

[0131] Furthermore, certain compounds containing alkenyl groups may exist as Z (tuzamen) or E (entgegen) isomers. In each example, the disclosure includes both mixtures and distinct individual isomers.

[0132] Some compounds may also exist in tautomeristic forms. Such forms, although not expressly shown in the formulas described herein, are intended to be included within the scope of this disclosure.

[0133] A “prodrug” or “pharmaceutically acceptable prodrug” refers to a compound that, after administration, is metabolized in the host, for example, by hydrolysis or oxidation, to form a compound described herein (e.g., a compound of formula I). ​​Typical examples of prodrugs include compounds having a biologically unstable or cleavable (protecting) group on the functional moiety of an active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce an active compound. Examples of prodrugs using esters or phosphoramides as biologically unstable or cleavable (protecting) groups are disclosed in U.S. Patents 6,875,751, 7,585,851, and 7,964,580, which are incorporated herein by reference. The prodrugs of this disclosure are metabolized to produce a compound of formula I. In certain embodiments, this disclosure includes, within its scope, prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of appropriate prodrugs are described, for example, in “Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985.

[0134] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filter, diluent, excipient, solvent, or encapsulating material, that is useful for formulating a drug for pharmaceutical or therapeutic use.

[0135] As used herein, the terms “Log,” “LogS,” or “logS” of solubility are used in the art to quantify the water solubility of a compound. The water solubility of a compound significantly affects its absorption and distribution characteristics. Low solubility is often associated with poor absorption. The LogS value is the logarithm (base 10) of the solubility measured in moles / liter, with the units removed. [Examples]

[0136] While the present invention is described in general terms here, it will be more readily understood by referring to the following examples, which are included solely for illustrative purposes of certain aspects and embodiments of the invention and are not intended to limit the invention.

[0137] Example A - Preparation of Exemplary Compounds [ka] General Procedure A Int1 (10 mg, 0.025 mmol, 1 equivalent) and HATU (19 mg, 0.05 mmol, 2 equivalents) were added to an 8 mL flask equipped with a stirring bar. Then, DMF (1 mL) was added to produce a colorless solution, followed by the addition of DIPEA (8.3 μL, 2 equivalents), and the resulting mixture was stirred at room temperature for 5 minutes. Subsequently, IMiDs-int (0.028 mmol, 1.1 equivalents) was added to the reaction flask. The reaction mixture was continued to stir at room temperature for 4 hours. The reaction mixture was then post-treated by adding 5 mL of water, and then extracted with ethyl acetate (2 mL x 3). The organic layers were combined, dried over Na2SO4, and then concentrated to obtain the residue. The residue was purified by ISCO (methanol / methylene chloride = 0-10%) to obtain the compounds of the example.

[0138] Example 1 [ka] A pale yellow powder was obtained according to general procedure A, 1.2 mg, yield: 6.0%. MS(ESI) calculated value for C43H41ClN8O8: 832.27, measured value: [M+1] 833.34, 834.29.

[0139] Example 2 [ka] Following general procedure A, yellow powder, 5 mg, yield: 26%. MS(ESI) calculated value for C41H39ClN8O6: 774.27, measured value: [M+1] 775.54, 777.14. 11H NMR (500 MHz, Acetone-d6) δ 9.76 (s, 1H), 9.44 (d, J = 17.2 Hz, 1H), 8.33 (d, J = 5.7 Hz, 1H), 8.07 (d, J = 5.6 Hz, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.86 - 7.74 (m, 3H), 7.66 - 7.58 (m, 2H), 7.48 - 7.37 (m, 3H), 7.30 (dd, J = 5.6, 2.0 Hz, 1H), 6.95 (d, J = 8.6 Hz, 1H), 6.88 (d, J = 7.0 Hz, 1H), 6.27 (d, J = 6.6 Hz, 1H), 4.96 - 4.91 (m, 1H), 3.30 (td, J = 7.1, 5.6 Hz, 2H), 3.25 - 3.23 (m, 2H), 2.84 - 2.79 (m, 2H), 2.69 - 2.61 (m, 4H), 2.07 (dddd, J = 16.5, 6.2, 5.2, 2.8 Hz, 2H), 1.54 (dq, J = 24.4, 7.1 Hz, 6H), 1.32 (s, 2H).

[0140] Example 3 [Chemical formula] According to General Procedure A, a yellow powder, 6.5 mg, yield: 33%. MS (ESI) calculated value for C39H35ClN8O8: 778.23, measured value: [M + 1] 779.34, 780.29, 782.31. 11H NMR (500 MHz, Acetone-d6) δ 9.95 (s, 1H), 9.09 (s, 1H), 9.00 (s, 1H), 8.45 (d, J = 5.6 Hz, 1H), 8.22 (d, J = 5.6 Hz, 1H), 8.08 (d, J = 1.9 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.87 (dd, J = 23.4, 4.0 Hz, 2H), 7.76 (d, J = 1.9 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.53 (dt, J = 18.9, 7.8 Hz, 2H), 7.45 (ddd, J = 14.4, 5.6, 2.1 Hz, 2H), 7.08 (d, J = 8.5 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.61 (t, J = 5.7 Hz, 1H), 5.08 (dd, J = 12.4, 5.4 Hz, 1H), 3.78 (t, J = 5.3 Hz, 2H), 3.71 (d, J = 5.8 Hz, 2H), 3.62 (t, J = 5.5 Hz, 2H), 3.53 (d, J = 5.2 Hz, 2H), 2.96 (ddt, J = 18.9, 14.8, 4.4 Hz, 2H), 2.79 - 2.75 (m, 2H), 2.21 (ddt, J = 13.3, 7.8, 3.8 Hz, 2H), 1.52 (d, J = 6.6 Hz, 2H).

[0141] Example 4 [Chemical formula] According to the general procedure A, a yellow powder, 4.2 mg, yield: 24%. Calculated value for MS (ESI) for C37H31ClN8O6: 718.21, measured value: [M+1] 719.34, 721.32. 1H NMR(500MHz,Acetone-d6)δ 9.76(s,1H),9.12(d,J=9.7Hz,1H),9.07(s,1H),8.33(d,J=5.7Hz,1H),8.08(d,J=5.6Hz,1H),7.96(d,J=1.8Hz,1H) ,7.90-7.75(m,3H),7.64-7.58(m,2H),7.42(dt,J=17.7,7.5Hz,2H),7.36(dd,J=5.6,2.1Hz,1H),7.30(dd,J=5.7,1. 9Hz,1H),6.99(d,J=8.6Hz,1H),6.88(d,J=7.1Hz,1H),6.32(d,J=6.0Hz,1H),4.93(dd,J=12.6,5.4Hz,1H),3.39(q,J =6.1Hz,2H),3.35-3.30(m,2H),2.82(q,J=2.9,2.3Hz,2H),2.66-2.59(m,2H),2.09-2.03(m,1H),1.74-1.62(m,4H).

[0142] Example 5 [ka] Following general procedure A, yellow powder, 2.76 mg, yield: 15%. MS(ESI) calculated value for C39H33ClN8O6: 744.22, measured value: [M+1] 745.41, 747.38.

[0143] Example 6 [ka] Int4 was obtained as a yellow gel according to general procedure A, 90 mg, yield: >99%. MS(ESI) calculated value for chemical formula: C25H28N6O7S: 556.17, measured value: [M+1] 557.27, 558.34.

[0144] Int4 (90 mg) was added to a 50 mL round-bottom flask and dissolved with ₹ (3 mL) to obtain a solution. Then, Pd / C (18 mg, 20 wt%) was added, and the resulting reaction mixture was purged three times with H2 and then stirred at room temperature for 16 minutes. After that, Pd / C was removed by filtration, and the solvent was removed under reduced pressure to obtain 80 mg of Int5, yield: 94%. Chemical formula: C25H30N6O5S MS(ESI) calculation value: 526.20, measured value: [M+OH] 543.33, 544.35. 1 H NMR(500MHz,Chloroform-d)δ 7.95(s,2H),7.58-7.38(m,2H),7.18-7.12(m,1H),7.05-6.97(m,2ldy H),6.84-6.78(m,1H),6.16(d,J=5.9Hz,1H),4.90-4.80(m,1H),3.43- 3.28(m,2H),3.22-3.13(m,2H),2.79(d,J=7.8Hz,2H),2.73-2.64(m,2H),2.11-1.92(m,2H),1.55(d,J=26.1Hz,4H),1.30(d,J=13.7Hz,6H).

[0145] In an 8 mL flask equipped with a stirring bar, Int5 (8 mg, 0.015 mmol, 1 equivalent) and Int6 (4.1 mg, 0.017 mmol, 1.1 equivalents), dissolved in DMF (2 mL), were added to obtain a solution. Next, LiHMDS (30 μL, 1 M, 2 equivalents) was added, and the resulting reaction mixture was stirred at room temperature for 1 hour. Then, 1 mL of MeOH was added to quench the reaction, and the mixture was purified by HPLC (water / acetonitrile = 95%~5%) to obtain Example 6, 1.2 mg, yield: 12%. MS(ESI) calculated value for chemical formula: C31H33ClN8O6S: 680.19, measured value: [M+1] 681.46, [M+OH] 697.34, 699.35.

[0146] Example 7 [ka] A typical sample, yellow powder, 7.4 mg, yield: 50%. MS (ESI) calculated value: 718.21, measured value: [M+1] 719.46, 721.47. ¹H NMR (500 MHz, Acetone-d6) δ 9.72(s,1H),9.12(s,1H),9.04(s,1H),8.31(d,J=5.6Hz,1H),8.07(d,J=5.6Hz,1H),7.95(t,J=1.7Hz,1H),7.88(ddd,J=7.6,3.1,1 .7Hz,1H),7.82(dt,J=7.9,1.5Hz,1H),7.77(d,J=2.1Hz,1H),7.63-7.58(m,2H),7.41(dd,J=8.1,2.5Hz,2H),7.35(dt,J=5.9,1.7Hz ,1H),7.30(dd,J=5.7,2.0Hz,1H),6.88(d,J=2.2Hz,1H),6.80(dd,J=8.4,2.2Hz,1H),6.28(t,J=5.4Hz,1H),4.90(dd,J=12.6,5.4H z,1H),3.38(q,J=6.1Hz,2H),3.27-3.19(m,2H),2.82(q,J=3.1Hz,2H),2.66-2.61(m,2H),2.06-2.01(m,1H),1.68(h,J=3.0Hz,4H).

[0147] Example 8

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[0148] Example 9 [Chemical formula] According to general procedure A, white powder, 10 mg, yield: 39%. Calculated MS(ESI) for C48H52ClN9O6S: 917.34, found: [M+1] 918.35. 11H NMR (500 MHz, Acetone-d6) δ 9.52 (s, 1H), 9.47 (s, 1H), 8.85 (s, 1H), 8.45 (d, J = 5.7 Hz, 1H), 8.21 (d, J = 5.6 Hz, 1H), 8.11 - 8.10 (m, 1H), 8.02 (q, J = 6.1 Hz, 1H), 7.96 (dt, J = 8.1, 1.3 Hz, 1H), 7.80 (d, J = 2.1 Hz, 1H), 7.76 (d, J = 1.9 Hz, 1H), 7.74 - 7.71 (m, 1H), 7.61 - 7.57 (m, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.42 (d, J = 6.3 Hz, 3H), 7.40 (d, J = 2.5 Hz, 1H), 4.72 (dd, J = 9.6, 7.5 Hz, 2H), 4.61 - 4.53 (m, 2H), 4.39 (dd, J = 15.4, 5.5 Hz, 1H), 4.03 (d, J = 15.5 Hz, 1H), 3.95 (d, J = 15.5 Hz, 1H), 3.91 - 3.85 (m, 1H), 3.82 (dd, J = 10.7, 4.0 Hz, 1H), 3.68 - 3.64 (m, 9H), 2.47 (s, 3H), 2.21 (dd, J = 5.2, 3.3 Hz, 1H), 1.03 (s, 9H).

[0149] Example 10 [Chemical formula] According to the general procedure A, a yellow powder, 12 mg, yield: 47%. Calculated value of MS (ESI) for C50H56ClN9O9S: 993.36, measured value: [M + 1] 994.69. 11H NMR (500 MHz, Acetone-d6) δ 11.67 (s, 1H), 11.55 (s, 1H), 8.80 (s, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.11 (dd, J = 5.5, 4.0 Hz, 1H), 8.06 (d, J = 1.8 Hz, 1H), 7.97 - 7.88 (m, 3H), 7.82 (t, J = 2.5 Hz, 1H), 7.69 (dt, J = 7.7, 1.4 Hz, 1H), 7.60 (dd, J = 5.6, 2.0 Hz, 1H), 7.52 - 7.46 (m, 2H), 7.44 - 7.39 (m, 2H), 7.38 - 7.33 (m, 2H), 7.05 (d, J = 9.1 Hz, 1H), 4.62 - 4.44 (m, 5H), 4.36 - 4.25 (m, 2H), 3.87 (d, J = 10.8 Hz, 1H), 3.70 (dd, J = 10.7, 4.1 Hz, 1H), 3.65 - 3.58 (m, 1H), 3.39 (q, J = 6.6 Hz, 2H), 3.30 (d, J = 7.1 Hz, 1H), 3.07 (d, J = 6.2 Hz, 2H), 2.42 (s, 3H), 2.25 (dt, J = 12.0, 7.3 Hz, 4H), 2.13 (ddt, J = 8.9, 3.1, 1.9 Hz, 2H), 0.94 (s, 9H).

[0150] Example 11 [Chemical formula] According to the general procedure A, a yellow powder, 3.2 mg, yield: 19%. Calculated value of MS (ESI) for C35H27ClN8O6: 690.17, measured value: [M / 2 + 1] 346.40, [M + 1] 691.41. 11H NMR (500 MHz, Acetone-d6) δ 8.46 (d, J = 5.6 Hz, 1H), 8.28 (s, 1H), 8.22 (d, J = 5.6 Hz, 1H), 8.10 (d, J = 1.8 Hz, 1H), 7.97 (dt, J = 7.9, 1.5 Hz, 1H), 7.92 (dd, J = 9.0, 2.1 Hz, 1H), 7.80 - 7.67 (m, 2H), 7.63 - 7.53 (m, 2H), 7.53 - 7.44 (m, 2H), 7.29 (d, J = 8.5 Hz, 1H), 7.06 (d, J = 7.0 Hz, 1H), 6.76 (d, J = 6.4 Hz, 1H), 5.13 - 5.00 (m, 1H), 3.78 - 3.60 (m, 4H), 3.07 - 2.92 (m, 2H), 2.74 (dd, J = 7.1, 3.3 Hz, 2H), 2.20 (ddd, J = 6.9, 4.4, 2.1 Hz, 1H).

[0151] Example 12 [Chemical formula] Following the general procedure A, a yellow powder, 20.2 mg, yield: 98%. Calculated MS (ESI) for C39H35ClN8O6: 746.24, found: [M / 2 + 1] 374.44, [M + 1] 747.54. 1H NMR (500 MHz, Acetone-d6) δ 9.93 (s, 1H), 9.16 (d, J = 37.6 Hz, 2H), 8.46 (d, J = 5.6 Hz, 1H), 8.22 (d, J = 5.6 Hz, 1H), 8.10 (t, J = 1.8 Hz, 1H), 7.97 (dt, J = 7.9, 1.5 Hz, 2H), 7.90 (d, J = 2.1 Hz, 1H), 7.78 - 7.71 (m, 2H), 7.60 - 7.52 (m, 2H), 7.50 - 7.43 (m, 2H), 7.09 (d, J = 8.5 Hz, 1H), 7.02 (d, J = 7.1 Hz, 1H), 6.43 (t, J = 5.8 Hz, 1H), 5.07 (dd, J = 12.6, 5.5 Hz, 1H), 4.10 - 3.93 (m, 2H), 3.88 - 3.64 (m, 2H), 3.49 - 3.44 (m, 2H), 3.39 (td, J = 6.3, 1.4 Hz, 2H), 2.97 - 2.94 (m, 2H), 2.80 - 2.75 (m, 2H), 2.25 - 2.18 (m, 1H), 1.71 (ddt, J = 14.3, 7.2, 3.6 Hz, 4H).

[0152] Example 13

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[0153] Example 14

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[0154] Example B - Cell proliferation ATP-lite assay using exemplary compounds of the present disclosure Human MV4;11WT, MV4;11 CRBN KO and MOLM13 cells were seeded in 384-well plates and treated with the indicated compounds for 48 hours. ATP levels were measured by ATPlite (PerkinElmer) according to the manufacturer's instructions. The experimental groups were measured in quadruplicate and the ATP levels were normalized to DMSO. IC 50 was analyzed using GraphPad Prism 7. Table 1: Activity of exemplary compounds of the present disclosure

Table 1

[0155] Example C - Immunoblot of SMARCA2 in A549 and MOLM13 cells Human A549 cells were seeded in 6-well plates and treated for 16, 24, and 40 hours according to Example 4 or Example 2. Human MOLM13 cells were seeded in 6-well plates and treated for 6, 10, 16, and 24 hours according to Example 4. After treatment, cells were collected and lysed in RIPA buffer (Thermo Scientific) containing Halt Protease and Phosphatase Inhibitor Cocktail (Thermo Scientific). Proteins were extracted and quantified using the BCA Protein Assay Kit (Pierce). Protein lysates were separated using NuPAGE 3-8% Tris-Acetate protein gel (Invitrogen) and detected by SMARCA2, PARP, and β-ACTIN antibodies (Cell Signaling Technology).

[0156] Inclusion by reference All publications and patents referenced herein are incorporated herein by whole reference as if each individual publication or patent were specifically and individually incorporated by way of reference. In the event of any conflict, the present application, including any definitions herein, shall prevail.

[0157] Equal parts While specific embodiments of the present invention have been discussed, the above specification is illustrative and not limiting. By examining this specification and the following claims, many variations of the present invention will become apparent to those skilled in the art. The full scope of the present invention should be determined by referring to the claims, combined with the full scope of their equivalents, and the specification, combined with such variations. The invention described in the original claims of this application is listed below. [1] Compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof [in the formula, A is

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[10] X 3 A compound described in any of [1] to [8], wherein the compound is O.

[11] X 2 A compound described in any of [1] to

[10] , wherein the compound is NH.

[12] X 2 A compound described in any of [1] to

[10] , wherein the compound is O.

[13] X 2 A compound according to any one of [1] to

[10] , which combines with L to form a heterocyclyl (e.g., piperidinyl).

[14] A compound according to any of [1] to

[12] , wherein L is a cycloalkylene (e.g., cyclohexylene).

[15] A compound according to any of [1] to

[12] , wherein L is alkylene.

[16] The compound according to

[15] , wherein the alkylene comprises 2 to 25 carbon atoms.

[17] The compound according to

[15] , wherein the alkylene comprises two carbon atoms.

[18] The compound according to

[15] , wherein the alkylene comprises three carbon atoms.

[19] The compound according to

[15] , wherein the alkylene comprises four carbon atoms.

[20] The compound according to

[15] , wherein the alkylene comprises five carbon atoms.

[21] The compound according to

[15] , wherein the alkylene comprises six carbon atoms.

[22] The compound according to

[15] , wherein the alkylene comprises seven carbon atoms.

[23] The compound according to

[15] , wherein the alkylene comprises eight carbon atoms.

[24] The compound according to

[15] , wherein the alkylene comprises nine carbon atoms.

[25] The compound according to

[15] , wherein the alkylene comprises 10 carbon atoms.

[26] The compound according to

[15] , wherein the alkylene comprises 11 carbon atoms.

[27] The compound according to

[15] , wherein the alkylene comprises 12 carbon atoms.

[28] The compound according to

[15] , wherein the alkylene comprises 13 carbon atoms.

[29] The compound according to

[15] , wherein the alkylene comprises 14 carbon atoms.

[30] The compound according to

[15] , wherein the alkylene comprises 15 carbon atoms.

[31] The compound according to

[15] , wherein the alkylene comprises 16 carbon atoms.

[32] The compound according to

[15] , wherein the alkylene comprises 17 carbon atoms.

[33] The compound according to

[15] , wherein the alkylene comprises 18 carbon atoms.

[34] The compound according to

[15] , wherein the alkylene comprises 19 carbon atoms.

[35] The compound according to

[15] , wherein the alkylene comprises 20 carbon atoms.

[36] The compound according to

[15] , wherein the alkylene comprises 21 carbon atoms.

[37] The compound according to

[15] , wherein the alkylene comprises 22 carbon atoms.

[38] The compound according to

[15] , wherein the alkylene comprises 23 carbon atoms.

[39] The compound according to

[15] , wherein the alkylene comprises 24 carbon atoms.

[40] The compound according to

[15] , wherein the alkylene comprises 25 carbon atoms.

[41] At least one of the alkylenes, but no more than five methylene portions, is an amide portion (for example,

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[15] to

[40] , which is replaced by ).

[42] At least one methylene portion of the alkylene is an amide portion (for example,

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[15] to

[40] , which is replaced by ).

[43] At least two methylene portions of the alkylene are two amide portions (for example,

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[15] to

[40] , which is replaced by ).

[44] At least three methylene portions of the alkylene are three amide portions (for example,

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[15] to

[40] , which is replaced by ).

[45] The 1, 2, 3 or 6 methylene portions of the alkylene are 1, 2, 3 or 6 amide portions (for example,

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[15] to

[40] , which is replaced by ).

[46] The compound according to any one of

[43] to

[45] , wherein the amide portion is not adjacent to the compound.

[47] The compound according to any one of

[43] to

[46] , wherein the amide portion is separated by at least one carbon atom.

[48] ​​The compound according to any one of

[43] to

[47] , wherein the amide portion is separated by at least six carbon atoms.

[49] The compound according to any one of

[15] to

[48] , wherein at least one methylene group of the alkylene, but no more than 10 methylene groups, is replaced by an oxygen atom.

[50] The compound according to any one of

[15] to

[49] , wherein at least one methylene group of the alkylene is replaced by an oxygen atom.

[51] The compound according to any one of

[15] to

[50] , wherein at least two methylene moieties of the alkylene are replaced by at least two oxygen atoms.

[52] The compound according to any one of

[15] to

[51] , wherein at least six methylene moieties of the alkylene are replaced by at least six oxygen atoms.

[53] The compound according to any one of

[15] to

[52] , wherein one, two, or six methylene moieties of the alkylene are replaced by oxygen atoms.

[54] The compound is

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[54] and at least one pharmaceutically acceptable excipient.

[56] A method for degrading SMARCA2, SMARCA4, or BRM, comprising contacting cells with any of the compounds described in [1] to

[54] or a pharmaceutically acceptable salt thereof.

[57] A method for treating a disease or disorder, comprising administering one of the compounds described in [1] to

[54] to a subject who requires treatment of the disease or disorder.

[58] A method for treating a disease or disorder that benefits from the degradation of SMARCA2, SMARCA4, or BRM, comprising administering one of the compounds described in [1] to

[54] to a subject who needs to be treated for a disease or disorder that benefits from the degradation of SMARCA2, SMARCA4, or BRM.

[59] A method by which the disease or disorder benefits from the degradation of SMARCA2

[58] .

[60] A method by which the disease or disorder benefits from the degradation of SMARCA4

[58] .

[61] A method by which the disease or disorder benefits from the breakdown of BRM

[58] .

[62] The method according to any one of

[57] to

[61] , wherein the disease or disorder is cancer.

[63] The method according to

[62] , wherein the cancer is selected from synovial sarcoma, lung cancer, ovarian cancer, brain cancer, kidney cancer, leukemia, non-small cell lung cancer, Burkitt lymphoma, pediatric medulloblastoma, pancreatic adenocarcinoma, ovarian clear cell carcinoma, renal cell carcinoma, endometrial carcinoma, and melanoma.

[64] The method according to any one of

[57] to

[63] , further comprising administering one or more additional chemotherapeutic agents in combination.

Claims

1. Compound of formula I: 【Chemistry 1】 or a pharmaceutically acceptable salt or stereoisomer thereof [in the formula, A is, 【Chemistry 2】 And; E is, 【Transformation 3】 And; X １ and X ２ These are O and NR, respectively, independently. ３ and selected from S; or X ２ It combines with L to form a 3- to 10-membered heterocyclyl or a 5- to 7-membered heteroaryl; L includes alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene, or heteroarylene chains containing 1 to 35 carbon atoms, or any combination thereof, and is optionally selected. When L contains an alkylene containing a -CH part where the value of L is from 1 to 35 ２ If at least one, but 10 or less, of the -CH parts of L ２ - parts are independently replaced by parts selected from -C(=O)-, -C(=O)-NR ４ -, -NR ４ -C(=O)-, -C(=O)-O-, -O-C(=O)-, -NR ４ -C(=O)-NR ３ -, -O-C(=O)-NR ４ -, -NR ４ -C(=O)-O-, -O-, -S- and -NR ４ -, provided that the number of -CH parts of L ２ - parts is more than the total number of -C(=O)-, -C(=O)-NR ４ -, -NR ４ -C(=O)-, -C(=O)-O-, -O-C(=O)-, -NR ４ -C(=O)-NR ３ -, -O-C(=O)-NR ４ -, -NR ４ -C(=O)-O-, -O-, -S- and -NR ３ - parts, provided that between each -C(=O)-, -C(=O)-NR ４ -, -NR ４ -C(=O)-, -C(=O)-O-, -O-C(=O)-, -NR ４ -C(=O)-NR ３ -, -O-C(=O)-NR ４ -, -NR ４ -C(=O)-O-, -O-, -S- and -NR ４ - parts, there is at least one -CH ２ - present; R １ It is a halo; R ２ is H; R ３ and R ４ These are H and (C) respectively, independently. １ -C １０ [Selected from alkyl groups].

2. R １ is a halo, and optionally the halo is fluoro or chloro; and / or R ２ H is; and / or R ３ H is; and / or R ４ The compound according to claim 1, wherein is H.

3. The aforementioned compound, 【Chemistry 4】 【Transformation 5】 The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof.

4. X １ The compound according to any one of claims 1 to 3, wherein is NH or O.

5. X ２ is NH or O, or X ２ The compound according to any one of claims 1 to 4, wherein L combines with the compound to form a 3- to 10-membered heterocycline, and optionally the heterocycline is piperidinyl.

6. The compound according to any one of claims 1 to 4, wherein L is alkylene or cycloalkylene, and optionally the cycloalkylene is cyclohexylene.

7. The compound according to claim 6, wherein the alkylene contains 2 to 25 carbon atoms.

8. The compound according to claim 7, wherein at least one, at least two, or at least three, but no more than five, methylene groups of the alkylene are replaced by amide groups.

9. The compound according to claim 7, wherein one, two, three or six methylene moieties of the alkylene are replaced by one, two, three or six amide moieties.

10. The compound according to claim 9, wherein the amide portion is separated by at least one carbon atom, or the amide portion is separated by at least six carbon atoms.

11. The compound according to claim 7, wherein at least one, at least two, at least six, but no more than 10 methylene groups of the alkylene are replaced by oxygen atoms.

12. The aforementioned compound, 【Transformation 6】 【Transformation 7】 【Transformation 8】 A compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, selected from the above.

13. A composition comprising a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

14. The composition according to claim 13 for use in a method of degrading SMARCA2 or SMARCA4, comprising contacting cells with a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt or stereoisomer thereof.

15. A composition according to claim 13 for use in a method of treating a disease or disorder that benefits from the breakdown of SMARCA2 or SMARCA4, The method comprises administering the composition to a subject who requires treatment for the disease or disorder, If the aforementioned disease or disorder is cancer, The cancer is optionally selected from synovial sarcoma, lung cancer, ovarian cancer, brain cancer, kidney cancer, leukemia, non-small cell lung cancer, Burkitt lymphoma, pediatric medulloblastoma, pancreatic adenocarcinoma, ovarian clear cell carcinoma, renal cell carcinoma, endometrial carcinoma, and melanoma, and The composition according to claim 13, wherein the composition may optionally be administered in combination with one or more further chemotherapeutic agents.

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