Amide GSPT1 degradation agent

Abstract

The invention relates to an amide compound used as a GSPT1 protein degradation agent or a pharmaceutically acceptable salt thereof. Specifically, the invention relates to a compound as shown in a general formula (I) and a pharmaceutically acceptable salt thereof. The invention also relates to a preparation method of the compound or the pharmaceutically acceptable salt thereof. The compound provided by the invention can be used for treating and / or preventing GSPT1-mediated diseases, especially tumors. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to amide compounds or pharmaceutically acceptable salts thereof as GSPT1 protein degradants. The present invention also relates to a method for preparing the compounds or pharmaceutically acceptable salts thereof. The present invention further relates to a method for treating and / or preventing GSPT1-mediated related diseases, especially tumors, using the compounds or pharmaceutically acceptable salts thereof. Background Art

[0002] Targeted protein degradation is a novel drug development strategy that promotes the interaction between the ubiquitin-proteasome system (UPS) and disease-related proteins (referred to as "new substrates") through small molecules (referred to as "molecular glues"), resulting in the degradation of the new substrates. A clinically validated class of molecular glues is glutarimide compounds, which can bind to cereblon (CRBN) of the CRL4 CRBN -E3 ubiquitin ligase complex, induce changes in the surface structure of the CRBN protein, promote the recruitment of new substrates that are usually not targetable by the E3 ligase, cause them to be ubiquitinated by E2, and ultimately be recognized and degraded by the 26S proteasome, thereby regulating the biological functions mediated by this new substrate, preventing the proliferation of abnormal cells and inducing their decomposition.

[0003] After different glutarimide molecular glues bind to the CRL4 CRBN -E3 ubiquitin ligase complex, they exhibit different specificities for the degradation of new substrate proteins and thus have different disease treatment indications. Lenalidomide and pomalidomide induce the degradation of transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) that play important roles in blood development and differentiation, and are used to treat multiple myeloma; however, lenalidomide also causes the degradation of protein kinase CK1α and can be used to treat myelodysplastic syndrome related to 5q deletion. In addition, CC-885 can promote the degradation of GSPT1 and is used to treat AML (acute myeloid leukemia), but because it also induces the degradation of Ikaros and Aiolos, etc., it brings toxic side effects. CC-90009 and MRT-2359 are molecular glues with high selectivity for the degradation of GSPT1 and are currently in clinical studies for the treatment of AML and solid tumors.

[0004] GSPT1 (G1 to S phase transition 1) is a translation termination factor that forms a complex with eukaryotic translation termination factor 1 (eFR1), mediates the recognition of stop codons and the release of nascent proteins from ribosomes, and plays a key role in protein synthesis. The degradation of GSPT1 blocks protein translation and leads to cell death. GSPT1 is overexpressed in a variety of tumor cells, and its targeted degradation has potential anti-tumor applications.

[0005] Although glutarimide compounds have similar chemical structures, they each have different mechanisms of action, clinical treatment effects, and toxic and side effects. Therefore, it is necessary to develop new GSPT1 degrading agents to meet different clinical needs.

[0006] Detailed Description of the Invention

[0007] Definition

[0008] Unless otherwise stated, the following terms used in this application have the following meanings.

[0009] “C x-y ” represents a range of carbon atom numbers, where x and y are both integers. For example, C 1-6 alkyl represents an alkyl group having 1 - 6 carbon atoms, that is, an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms; C 3-8 cycloalkyl represents a cycloalkyl group having 3 - 8 carbon atoms, that is, a cycloalkyl group having 3, 4, 5, 6, 7, or 8 carbon atoms. It should also be understood that “C 3-8 ” also includes any sub - ranges therein. For example, C 3-7 、C 3-6 、C 4-7 、C 4-6 、C 5-6 etc.

[0010] “Alkyl” refers to a saturated straight - chain or branched - chain hydrocarbon group containing 1 to 20 carbon atoms, such as 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Non - limiting examples of alkyl include methyl, ethyl, n - propyl, isopropyl, n - butyl, isobutyl, tert - butyl, sec - butyl, n - pentyl, 1,1 - dimethylpropyl, 1,2 - dimethylpropyl, 2,2 - dimethylpropyl, 1 - ethylpropyl, 2 - methylbutyl, 3 - methylbutyl, n - hexyl, 1 - ethyl - 2 - methylpropyl, 1,1,2 - trimethylpropyl, 1,1 - dimethylbutyl, 1,2 - dimethylbutyl, 2,2 - dimethylbutyl, 1,3 - dimethylbutyl, 2 - ethylbutyl, etc.

[0011] “Alkylene” refers to a divalent group of a straight - chain or branched - chain saturated hydrocarbon containing 1 to 20 carbon atoms, such as 1 to 6 carbon atoms or 1 to 4 carbon atoms. Non - limiting examples of alkylene include - CH2 -, - CH(CH3)-, - CH2CH2 -, - CH2CH2CH2 -, -(CH3)C(CH3)-, - CH2CH2CH2CH2 -, - CH2CH(CH3)CH2 -, etc.

[0012] "Cycloalkyl" refers to a saturated cyclic hydrocarbon group substituent containing 3 to 14 carbon ring atoms. The cycloalkyl group can be a monocyclic carbon ring, usually containing 3 to 8, 3 to 7, or 3 to 6 carbon ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The cycloalkyl group can also be a bicyclic or tricyclic group fused, bridged, or spiro-fused together, such as decahydronaphthyl, bicyclo[2.2.2]octane, spiro[3.3]heptane, etc.

[0013] "Heterocyclic group or heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic group, which contains 3 to 20 ring atoms, for example, it can be 3 to 14, 3 to 12, 3 to 10, 3 to 8, 3 to 6, or 5 to 6 ring atoms, and one or more of the ring atoms are selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it includes 3 to 12 ring atoms, 3 to 10 ring atoms, 4 to 7 ring atoms, 4 to 6 ring atoms, where 1 to 4 are heteroatoms, 1 to 3 are heteroatoms, or 1 to 2 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperazinyl, 1,4-oxazepinyl, pyrrolidinone, piperidone, 1,1-dioxothiomorpholinyl, etc. Polycyclic heterocyclic groups include fused, bridged, or spiro polycyclic heterocyclic groups, such as octahydrocyclopent[c]pyrrole, octahydropyrrolo[1,2-a]pyrazine, 3,8-diazabicyclo[3.2.1]octane, 5-azaspiro[2.4]heptane, 2-oxa-7-azaspiro[3.5]nonane, etc.

[0014] "Aryl or aromatic ring" refers to an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 membered, such as phenyl and naphthyl, more preferably phenyl. The aryl ring can be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, and the ring connected to the parent structure is the aryl ring. Non-limiting examples include:

[0015]

[0016] etc.

[0017] "Heteroaryl or heteroaromatic ring" refers to a heteroaromatic system containing 5 to 14 ring atoms, where 1 to 4 ring atoms are selected from heteroatoms including oxygen, sulfur, and nitrogen. The heteroaryl is preferably 5 to 10 membered, more preferably the heteroaryl is 5 membered or 6 membered, such as furyl, thienyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclic, or cycloalkyl ring. Non-limiting examples include:

[0018] etc.

[0019] "Halogen" means fluorine, chlorine, bromine or iodine.

[0020] "Cyano" means -CN.

[0021] "Optionally" means that the subsequent described event or circumstance may, but need not, occur. For example, the description "one or more hydrogens of phenyl are optionally substituted by halogen" includes the case where one or more hydrogens of phenyl are substituted by halogen and the case where they are not substituted by halogen.

[0022] "Substituted" means that one or more hydrogen atoms in a group, preferably 1 to 5, for example 1 to 3 hydrogen atoms, are independently substituted by a corresponding number of substituents. The substituents are only at the possible chemical positions understood by those skilled in the art. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene). Substituents include but are not limited to halogen, cyano, nitro, hydroxyl, amino, oxo, -SF5, C 1-4 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocyclic group, phenyl, 5- to 6-membered heteroaryl, etc.

[0023] "Isomer" means a compound having the same molecular formula but different bonding positions or spatial arrangements of its atoms. Isomers with different spatial arrangements of atoms are called "stereoisomers". Stereoisomers include optical isomers, geometric isomers and conformational isomers.

[0024] The compounds of the present invention may exist in the form of optical isomers. Optical isomers include enantiomers and diastereoisomers. Enantiomers are two stereoisomers that are non-superimposable on each other and are mirror images of each other. A racemic mixture or racemate is a mixture of chiral molecules having equal amounts of left-handed and right-handed enantiomers. Diastereoisomers are two stereoisomers that are non-superimposable on each other and are not mirror images of each other. When an optical isomer is a single isomer and its absolute configuration is determined, it is called an "R" or "S" isomer according to the configuration of the substituents on the chiral atom; when its absolute configuration is not determined, it is called a (+) or (-) isomer according to the measured optical rotation value. Methods for preparing and separating optical isomers are known in the art.

[0025] The compounds of the present invention may also have geometric isomers due to different distributions of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl or heterocyclic groups. Substituents around carbon-carbon double bonds or carbon-nitrogen bonds are designated as Z or E configurations, while substituents around cycloalkyl or heterocycles are designated as cis or trans configurations.

[0026] The compounds of the present invention may also exhibit tautomerism, such as keto-enol tautomerism.

[0027] It should be understood that the present invention encompasses any tautomeric or stereoisomeric forms and mixtures thereof, and is not limited to any one tautomeric or stereoisomeric form used in the naming or chemical structural formula of the compound.

[0028] "Isotope" refers to all isotopes of atoms present in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into the compounds of the present invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example but not limited to 2 H(D), 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F and 36 Cl. The isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples using appropriate isotopically labeled reagents in place of non-isotopically labeled reagents. Such compounds have various potential uses, such as standards and reagents in the determination of biological activity. In the case of stable isotopes, such as deuterium 2 H(D), 13 C and 15 N, compounds containing such isotopes have the potential to alter biological, pharmacological, or pharmacokinetic properties. Deuterium 2 H(D) is a preferred isotope of the present invention, for example, the hydrogen in methyl, methylene, or methine groups can be replaced by deuterium.

[0029] The compounds of the present invention can be administered in the form of prodrugs. "Prodrug" refers to derivatives of the bioactive compounds of the present invention that are converted in vivo under physiological conditions, such as by oxidation, reduction, hydrolysis, etc. (each of which utilizes enzymes or occurs without the participation of enzymes). Examples of prodrugs are compounds in which the amino group in the compounds of the present invention is acylated, alkylated, or phosphorylated, such as eicosanoylamino, alanyl amino, pivaloyloxymethyl amino, or in which the hydroxyl group is acylated, alkylated, phosphorylated, or converted into a borate, such as acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaroyloxy, alanyloxy, or in which the carboxyl group is esterified or amidated, or in which the mercapto group is conjugated with a carrier molecule that selectively delivers the drug to the target and / or to the cytosol of the cell. These compounds can be prepared from the compounds of the present invention according to known methods.

[0030] "Pharmaceutically acceptable salt" or "medicinally acceptable salt" means, in the case where the compounds of the present invention contain one or more acidic or basic groups, salts formed from pharmaceutically acceptable bases or acids, including inorganic and organic bases or acids. Thus, the compounds of the present invention containing acidic groups may exist in the form of salts, such as alkali metal salts, alkaline earth metal salts or ammonium salts. More specific examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine or amino acids. The compounds of the present invention containing basic groups may exist in the form of inorganic or organic acid salts. Examples of suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, aminosulfonic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid and other acids known to those skilled in the art. If the compounds of the present invention contain both acidic and basic groups in the molecule, the present invention also includes inner salts or inner ammonium salts in addition to the salt forms mentioned above. Each salt can be obtained by conventional methods known to those skilled in the art, such as by mixing the compound with an organic or inorganic acid or base in a solvent or dispersant or by anion or cation exchange with other salts.

[0031] "Pharmaceutical composition" refers to a mixture containing one or more compounds of the present invention or their pharmaceutically acceptable salts, stable isotope derivatives, isomers, prodrugs and mixtures thereof, as well as other components, such as pharmaceutically acceptable carriers and excipients.

[0032] Therefore, when referring to "compound", "compound of the present invention" or "compound described in the present invention" in this application, it includes all the said compound forms, such as their pharmaceutically acceptable salts, stable isotope derivatives, isomers, prodrugs and mixtures thereof.

[0033] "Therapeutically effective amount" refers to the amount of the compounds of the present invention that can effectively degrade GSPT1 and achieve the treatment or prevention of diseases mediated by it.

[0034] "Patient" refers to mammals, especially humans.

[0035] The present invention relates to compounds that can be used as GSPT1 degrading agents, the structures of which are shown in general formula (I), or their pharmaceutically acceptable salts, stable isotope derivatives, isomers and prodrugs:

[0036]

[0037] Wherein:

[0038] A is C 6-10 An aromatic ring or a 5-10 membered heteroaromatic ring;

[0039] R 1 is H, halogen, -OH, C 1-6 alkyl or -OC 1-6 alkyl;

[0040] R 2 is H, halogen, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, 4- to 8-membered heterocyclic group or -OR′, wherein one or more hydrogens of said alkyl, cycloalkyl and heterocyclic group are optionally substituted by D, halogen or C 1-6 alkyl;

[0041] R 3 is -C 1-6 alkylene-(OC 2-6 alkylene) m -R 4 、-(OC 2-6 alkylene) m -R 4 、-C 1-6 alkylene-NR′R 6 or -NR′R 7 ;

[0042] R 4 is -OR′ or -NR′R 5 ;

[0043] R′ is H, C 1-6 alkyl, C 3-8 cycloalkyl or 4- to 8-membered heterocyclic group, wherein one or more hydrogens of said alkyl, cycloalkyl and heterocyclic group are optionally substituted by D, halogen or C 1-6 alkyl; R 5 、R 6 and R 7 are each independently H, C 1-6 alkyl, C 3-8 cycloalkyl or -C(O)C 1-6 alkylene-OR′, wherein one or two hydrogens of said alkylene are optionally substituted by D, fluorine, C 1-6 alkyl, fluorinated C 1-6 alkyl or C 3-8 cycloalkyl, provided that when R′ is H, R 6 cannot be H, R 7 cannot be H or C 1-3 alkyl; when R′ is C 1-3 alkyl, R 7 cannot be H;

[0044] n is 0 or 1; and

[0045] m is an integer from 1 to 6.

[0046] In some embodiments, A is a benzene ring.

[0047] In some embodiments, R 1 is H, a halogen, or -OH.

[0048] In some embodiments, R 2 is H, a halogen, C 1-6 alkyl, fluoro C 1-6 alkyl, or C 3-8 cycloalkyl.

[0049] In some embodiments, R 3 is -C 1-6 alkylene-(OCH2CH2) m -R 4 、-(OCH2CH2) m -R 4 、-C 1-6 alkylene-NR′R 6 or -NR′R 7 .

[0050] In some embodiments, R 4 is -OH, -OC 1-6 alkyl, -NH2, -NH-C 1-6 alkyl, -NHC(O)C 1-6 alkylene-OH, or -N(C 1-6 alkyl)C(O)C 1-6 alkylene-OH, wherein one or two hydrogens of the alkylene are optionally substituted by D, fluorine, C 1-6 alkyl, fluoro C 1-6 alkyl, or C 3-8 cycloalkyl.

[0051] In some embodiments, R 4 is -OH, -NH2, -NH-C 1-6 alkyl, -NHC(O)CH2OH, or -N(CH3)C(O)CH2OH.

[0052] In some embodiments, R′ is H, and R 6 is C 1-6 alkyl, or -C(O)C 1-6 alkylene-OH, wherein one or two hydrogens of the alkylene are optionally substituted by D, fluorine, C 1-6 alkyl, fluoro C 1-6 alkyl, or C 3-8 cycloalkyl.

[0053] In some embodiments, R′ is H, and R 6 is C1-6 an alkyl group or -C(O)CH2OH.

[0054] In some embodiments, R′ is C 1-6 alkyl, and R 6 is H, C 1-6 alkyl or -C(O)C 1-6 alkylene-OH, wherein one or two hydrogens of said alkylene are optionally substituted by D, fluorine, C 1-6 alkyl, fluorinated C 1-6 alkyl or C 3-8 cycloalkyl.

[0055] In some embodiments, R′ is C 1-6 alkyl, and R 6 is H, C 1-6 alkyl or -C(O)CH2OH.

[0056] In some embodiments, R′ is H and R 7 is -C(O)C 1-6 alkylene-OH, wherein one or two hydrogens of said alkylene are optionally substituted by D, fluorine, C 1-6 alkyl, fluorinated C 1-6 alkyl or C 3-8 cycloalkyl.

[0057] In some embodiments, R′ is H and R 7 is -C(O)CH2OH.

[0058] In some embodiments, R′ is C 1-6 alkyl, and R 7 is C 1-6 alkyl or -C(O)C 1-6 alkylene-OH, wherein one or two hydrogens of said alkylene are optionally substituted by D, fluorine, C 1-6 alkyl, fluorinated C 1-6 alkyl or C 3-8 cycloalkyl.

[0059] In some embodiments, R′ is C 1-6 alkyl, and R 7 is C 1-6 alkyl or -C(O)CH2OH.

[0060] In some embodiments, n is 0.

[0061] In some embodiments, n is 1.

[0062] In some embodiments, m is 1 or 2.

[0063] In some embodiments, the compounds of the present invention are represented by the general formula (II):

[0064]

[0065] Wherein:

[0066] R 1 is H, halogen or -OH;

[0067] R 2 is H, halogen, cyano, C 1-6 alkyl, C 3-8 cycloalkyl or -OR′, wherein one or more hydrogens of the alkyl are optionally substituted by D or halogen;

[0068] R 3 is -C 1-6 alkylene-(OC 2-6 alkylene) m -R 4 、-(OC 2-6 alkylene) m -R 4 、-C 1-6 alkylene-NR′R 6 or -NR′R 7 ;

[0069] R 4 is -OR′ or -NR′R 5 ;

[0070] R 5 、R 6 and R 7 are each independently H, C 1-6 alkyl or -C(O)C 1-6 alkylene-OR′, wherein one or two hydrogens of the alkylene are optionally substituted by D, fluorine, C 1-6 alkyl, fluorinated C 1-6 alkyl or C 3-8 cycloalkyl, provided that when R′ is H, R 6 cannot be H, R 7 cannot be H or C 1-3 alkyl; when R′ is C 1-3 alkyl, R 7 cannot be H;

[0071] R′ is H or C 1-6 alkyl; and

[0072] m is an integer from 1 to 6.

[0073] In some embodiments, R 2 is H, halogen, C 1-6 alkyl, fluorinated C1-6 alkyl or C 3-8 cycloalkyl.

[0074] In some embodiments, R 3 is -C 1-6 alkylene-(OCH2CH2) m -R 4 、-(OCH2CH2) m -R 4 、-C 1-6 alkylene-NR′R 6 or -NR′R 7 .

[0075] In some embodiments, R 4 is -OH, -NH2, -NH-C 1-6 alkyl, -NHC(O)C 1-6 alkylene-OH or -N(C 1-6 alkyl)C(O)C 1-6 alkylene-OH, wherein one or two hydrogens of the alkylene are optionally substituted by D, fluorine, C 1-6 alkyl, fluorinated C 1-6 alkyl or C 3-8 cycloalkyl.

[0076] In some embodiments, R 4 is -OH, -NH2, -NH-C 1-6 alkyl, -NHC(O)CH2OH or -N(CH3)C(O)CH2OH.

[0077] In some embodiments, R′ is H, R 6 is C 1-6 alkyl or -C(O)C 1-6 alkylene-OH, wherein one or two hydrogens of the alkylene are optionally substituted by D, fluorine, C 1-6 alkyl, fluorinated C 1-6 alkyl or C 3-8 cycloalkyl.

[0078] In some embodiments, R′ is H, R 6 is C 1-6 alkyl or -C(O)CH2OH.

[0079] In some embodiments, R′ is C 1-6 alkyl, R 6 is H, C 1-6 alkyl or -C(O)C 1-6 alkylene-OH, wherein one or two hydrogens of the alkylene are optionally substituted by D, fluorine, C 1-6 alkyl, fluorinated C 1-6alkyl or C 3-8 substituted by cycloalkyl.

[0080] In some embodiments, R′ is C 1-6 alkyl, and R 6 is H, C 1-6 alkyl or -C(O)CH2OH.

[0081] In some embodiments, R′ is H and R 7 is -C(O)C 1-6 alkylene-OH, wherein one or two hydrogens of said alkylene are optionally substituted by D, fluorine, C 1-6 alkyl, fluorinated C 1-6 alkyl or C 3-8 substituted by cycloalkyl.

[0082] In some embodiments, R′ is H and R 7 is -C(O)CH2OH.

[0083] In some embodiments, R′ is C 1-6 alkyl, and R 7 is C 1-6 alkyl or -C(O)C 1-6 alkylene-OH, wherein one or two hydrogens of said alkylene are optionally substituted by D, fluorine, C 1-6 alkyl, fluorinated C 1-6 alkyl or C 3-8 substituted by cycloalkyl.

[0084] In some embodiments, R′ is C 1-6 alkyl, and R 7 is C 1-6 alkyl or -C(O)CH2OH.

[0085] In some embodiments, m is 1 or 2.

[0086] The present invention also relates to the following compounds 1-25, or pharmaceutically acceptable salts, stable isotope derivatives, isomers, prodrugs and mixtures thereof:

[0087]

[0088]

[0089]

[0090]

[0091]

[0092] The compounds of the present invention can effectively induce the degradation of GSPT1, and their DC50 Preferably less than 100 nM. The compounds of the present invention can also effectively inhibit the proliferation of SK-BR-3 cells, and their IC 50 Preferably less than 100 nM.

[0093] The present invention also relates to a pharmaceutical composition, which comprises a compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt, stable isotope derivative, isomer and prodrug thereof, and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition can induce the degradation of GSPT1 and affect its biological function, so as to achieve the effect of treating or preventing GSPT1-mediated diseases, including but not limited to hematological tumors, solid tumors, autoimmune diseases, inflammation, neurodegenerative diseases, skin diseases, etc.

[0094] The present invention also provides a method for treating or preventing GSPT1-mediated diseases, which comprises administering a therapeutically effective amount of a compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt, stable isotope derivative, isomer, prodrug thereof and its pharmaceutical composition to a patient in need, and the diseases include but not limited to hematological tumors, solid tumors, autoimmune diseases, inflammation, neurodegenerative diseases, skin diseases, etc.

[0095] The present invention also provides the use of the compounds of the present invention or their pharmaceutically acceptable salts, stable isotope derivatives, isomers, prodrugs and their pharmaceutical compositions in the preparation of GSPT1 degrading agents.

[0096] The present invention also provides the use of the compounds of the present invention or their pharmaceutically acceptable salts, stable isotope derivatives, isomers, prodrugs and their pharmaceutical compositions in the preparation of drugs for treating or preventing GSPT1-mediated diseases.

[0097] According to the present invention, the drug can be any pharmaceutical dosage form, including but not limited to tablets, capsules, solutions, lyophilized preparations, injections.

[0098] The pharmaceutical preparations of the present invention can be administered in dosage unit forms of a predetermined amount of the active ingredient. Such units contain 0.1 mg to 500 mg of the compounds of the present invention according to the disease to be treated, the method of administration and the age, weight and condition of the patient. In addition, the pharmaceutical preparations can be prepared by methods well known in the pharmaceutical field, such as by formulating the active ingredient with one or more excipients or one or more adjuvants.

[0099] The pharmaceutical preparations of the present invention are suitable for administration by any desired and appropriate method, such as by oral (including oral or sublingual), rectal, nasal, topical (including oral, sublingual or transdermal) or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods.

[0100] The present invention also provides a method for preparing the compound. The compound can also be synthesized by synthetic techniques known to those skilled in the art. The product obtained from each step of the reaction is obtained by separation techniques known in the art. The starting materials and chemical reagents required for the synthesis can be synthesized conventionally or purchased according to the literature (which can be queried from SciFinder).

[0101] The amide compound I of the general formula (I) of the present invention can be synthesized by amide condensation of an amine compound I-1 and a phenylacetic acid compound I-2 in the presence of a condensation reagent.

[0102]

[0103] The amide compound I of the general formula (I) of the present invention can also be synthesized according to the following route: Amide condensation occurs between an amine compound I-3 with a protecting group (PG) and a phenylacetic acid compound I-2 in the presence of a condensation reagent to generate I-4; I-4 undergoes deprotection to generate the compound I.

[0104]

[0105] The amide compound II of the general formula (I) of the present invention can also be synthesized by amide condensation of the compound I (where R 3″ is a group containing NH) and glycolic acid in the presence of a condensation reagent.

[0106]

[0107] The intermediate I-1 can be synthesized according to the following route: The phenylacetic acid compound J-1 undergoes a reduction reaction to generate J-2; J-2 undergoes m substitution reactions with tert-butyl 2-bromoacetate and reduction of the tert-butyl ester to generate J-4; J-4 undergoes a reduction reaction under suitable reduction conditions (for example, catalytic hydrogenation, iron powder and ammonium chloride solution, zinc powder and acetic acid) to generate the intermediate I-1.

[0108]

[0109] The intermediate I-3 can be synthesized according to the following route: K-1 is synthesized according to the route for synthesizing J-4, K-1 undergoes a substitution reaction with tert-butyl 2-bromoacetate under basic conditions to generate K-2; K-2 undergoes deprotection under acidic conditions to generate K-3; K-3 undergoes amide condensation with an amino reagent to generate K-4; K-4 undergoes a reduction reaction in the presence of a reducing reagent (for example, borane) to generate K-5; K-5 undergoes a protection reaction to generate K-6; When the X group is NO2, K-6 undergoes a reduction reaction to generate the intermediate I-3; When the X group is a halogen or a halogen analog, K-6 undergoes a coupling reaction to introduce a cyano group to generate K-7; K-7 undergoes a reduction reaction to generate the intermediate I-3.

[0110]

[0111] Intermediate I-3 can also be synthesized according to the route shown below: phenol compound L-1 undergoes substitution reaction with L-2 or L-3 (LG is a leaving group) under alkaline conditions to generate L-4 or L-5; L-4 or L-5 undergoes reduction reaction to generate intermediate I-3.

[0112]

[0113] Intermediate I-2 can be synthesized according to the following route: M-1 and M-2 undergo substitution ring closure under alkaline conditions to generate M-3; M-3 undergoes Negishi coupling with zinc reagent M-4 to generate M-5; M-5 is deprotected under acidic conditions to generate intermediate I-2.

[0114]

[0115] The following examples further illustrate the present invention. These examples are intended only to illustrate the present invention and should not be considered as limiting the scope of the present invention. Example

[0116] The starting materials of the present invention can be synthesized according to methods known in the art, or can be purchased from chemical companies such as Accela ChemBio Inc., Beijing Coupling, Bid Pharmaceutical, Zesheng Technology, and Shanghai Haohong Biopharmaceuticals.

[0117] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR measurements were performed using a Bruker ASCEND-400 nuclear magnetic spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDC13) or deuterated methanol (CD3OD) as the solvent, tetramethylsilane (TMS) as the internal standard, and chemical shifts at 10 -6 The unit is (ppm). MS was measured using an Agilent SQD (ESI) mass spectrometer (Agilent 6120).

[0118] HPLC was performed using an Agilent 1260DAD high pressure liquid chromatograph (Poroshell 120EC-C18, 50×3.0 mm, 2.7 μm column) or a Waters Arc high pressure liquid chromatograph (Sunfirc C18, 150×4.6 mm, 5 μm column).

[0119] Unless otherwise specified in the examples, the reaction temperature is room temperature (20°C-30°C).

[0120] Unless otherwise specified in the examples, the reactions were carried out under an argon or nitrogen atmosphere. An argon or nitrogen atmosphere means that the reaction flask was connected to an argon or nitrogen balloon with a volume of about 1 L.

[0121] A hydrogen atmosphere means that after the reaction flask was evacuated and then filled with hydrogen (repeated 3 times), it was connected to a hydrogen balloon with a volume of about 1 L.

[0122] The progress of the reactions in the examples was monitored using an Agilent liquid chromatography - mass spectrometry instrument (1260 / 6120), or thin - layer chromatography (TLC) could also be used. The thickness of the silica gel plate used was 0.15 - 0.2 mm (Qingdao Marine GF254).

[0123] The purification of the compounds was carried out by column chromatography or thin - layer chromatography. For column chromatography, 200 - 300 mesh silica gel from Qingdao Marine was used, and for thin - layer chromatography, a GF254 silica gel plate with a thickness of 0.4 - 0.5 mm from Qingdao Marine was used.

[0124] The developing solvent systems for column chromatography or thin - layer chromatography usually include a) dichloromethane and methanol system, b) petroleum ether and ethyl acetate system, or as shown in the examples. The volume ratio of the solvents was adjusted according to the polarity of the compounds, and a small amount of triethylamine, or other acidic or basic reagents could also be added for further adjustment.

[0125] The purification of the compounds was also carried out using a Waters mass - spectrometry - directed automatic preparation system (mass detector: SQD2). According to the polarity of the compounds, an appropriate acetonitrile / water (containing 0.1% trifluoroacetic acid or formic acid, or 0.05% ammonia water) gradient was used to elute a reversed - phase high - pressure column (XBridge - C18, 19×150 mm, 5 μm) at a flow rate of 20 mL / min.

[0126] The abbreviation DMA refers to N,N - dimethylacetamide.

[0127] The abbreviation DMSO refers to dimethyl sulfoxide.

[0128] The abbreviation DMF refers to N,N - dimethylformamide.

[0129] The abbreviation DCE refers to 1,2 - dichloroethane.

[0130] The abbreviation NMP refers to N - methylpyrrolidone.

[0131] The abbreviation DIPEA refers to N,N - diisopropylethylamine.

[0132] The abbreviation DMAP refers to 4 - dimethylaminopyridine.

[0133] The abbreviation TBSCl refers to tert - butyldimethylchlorosilane.

[0134] The abbreviation HATU refers to O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0135] The abbreviation NMI refers to N-methylimidazole.

[0136] The abbreviation TCFH refers to N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate.

[0137] The abbreviation PyBOP refers to 1H-benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate.

[0138] The abbreviation LiHMDS refers to lithium bis(trimethylsilyl)amide.

[0139] The abbreviation LDA refers to lithium diisopropylamide.

[0140] The abbreviation NBS refers to N-bromosuccinimide.

[0141] The abbreviation AIBN refers to azobisisobutyronitrile.

[0142] The abbreviation Pd2(dba)3 refers to tris(dibenzylideneacetone)dipalladium(0).

[0143] The abbreviation Pd(dppf)Cl2 refers to dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II).

[0144] The abbreviation Pd(dppf)Cl2·CH2Cl2 refers to dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane complex.

[0145] The abbreviation dppf refers to 1,1'-bis(diphenylphosphino)ferrocene.

[0146] The abbreviation X-Phos refers to 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0147] The abbreviation (Boc)2O refers to di-tert-butyl dicarbonate.

[0148] Example 1 - Synthesis of Intermediates

[0149] Intermediate A: 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetic acid

[0150]

[0151] First Step

[0152] (tert-Butoxycarbonyl)zinc(II) bromide (A-2)

[0153] To a mixture of zinc powder (6.25 g, 96.2 mmol) and DMA (16.5 mL), a mixture of trimethylchlorosilane and 1,2-dibromoethane (2.1 mL, v / v = 7 / 5) was added slowly. The reaction mixture was stirred at room temperature for 15 minutes. A DMA (24 mL) solution of tert-butyl 2-bromoacetate A-1 (15.0 g, 76.9 mmol) was added slowly, and the mixture was stirred at room temperature for 30 minutes to obtain a DMA solution (40.5 mL, 1.89 M) of the target product A-2. This product was used directly in the next reaction without further purification.

[0154] The second step

[0155] 3-(5-Bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (A-4)

[0156] To a solution of methyl 4-bromo-2-(bromomethyl)benzoate A-3 (20.0 g, 64.9 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (13.9 g, 84.4 mmol) in acetonitrile (200 mL) was added DIPEA (25.1 g, 194.8 mmol). The reaction mixture was stirred at 80 °C overnight. It was filtered, and the solid was washed with acetonitrile to obtain the target product A-4 (16.2 g, 78%).

[0157] MS m / z (ESI): 323 [M+1]

[0158] The third step

[0159] tert-Butyl 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetate (A-5)

[0160] To a solution of A-4 (5.0 g, 15.5 mmol) in tetrahydrofuran (60 mL) was added a tetrahydrofuran solution of LiHMDS (1.0 M, 17.1 mL, 17.1 mmol). The mixture was stirred at room temperature for 30 minutes. A-2 (32.7 mL, 62.1 mmol), Pd2(dba)3 (1.42 g, 1.55 mmol), and X-Phos (741 mg, 1.55 mmol) were added, and the mixture was stirred at 80 °C for 1 hour. It was cooled to room temperature, quenched with saturated ammonium chloride solution, and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 7) to obtain the target product A-5 (3.8 g, 68%).

[0161] MS m / z (ESI): 359 [M+1]

[0162] The fourth step

[0163] 2-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetic acid (A)

[0164] The reaction mixture A-5 (3.8 g, 10.6 mmol) and a 1,4-dioxane solution of hydrogen chloride (40 mL) were stirred at room temperature for 1 hour. Concentrated under reduced pressure, the residue was purified by trituration with ethyl acetate to give the target product A (3.0 g, 94%).

[0165] MS m / z (ESI): 303 [M+1]

[0166] Intermediate B: 2-(2-(2,6-Dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)acetic acid

[0167]

[0168] The first step

[0169] 4-Bromo-3-fluoro-2-methylbenzoic acid (B-2)

[0170] To a solution of B-1 (20.0 g, 91.3 mmol) in tetrahydrofuran (300 mL) at -70 °C was added LDA (2.0 M, 95.9 mL, 192 mmol), and the reaction mixture was stirred at -70 °C for 1 hour. Methyl iodide (38.9 g, 274 mmol) was added, and the reaction mixture was stirred at room temperature for 12 hours. Quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to give the target product B-2 (23.8 g, crude).

[0171] The second step

[0172] Methyl 4-bromo-3-fluoro-2-methylbenzoate (B-3)

[0173] To a solution of B-2 (crude, 23.8 g, 91.3 mmol) and cesium carbonate (66.9 g, 205 mmol) in DMF (250 mL) was added methyl iodide (17.5 g, 123 mmol), and the reaction mixture was stirred at room temperature for 4 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to give the target product B-3 (16.8 g, 74% yield over two steps).

[0174] The third step

[0175] Methyl 4-bromo-2-(bromomethyl)-3-fluorobenzoate (B-4)

[0176] To a solution of B-3 (10.0 g, 40.7 mmol) and NBS (10.8 g, 60.7 mmol) in DCE (150 mL) was added AIBN (667 mg, 4.1 mmol), and the reaction mixture was stirred overnight at 80 °C. It was cooled to room temperature, quenched with saturated sodium thiosulfate solution, and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to give the target product B-4 (10.0 g, 76%).

[0177] MS m / z(ESI): 327 [M+1]

[0178] Steps 4 to 6

[0179] 2-(2-(2,6-Dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)acetic acid (B)

[0180] Using B-4 in place of A-3, B was synthesized by referring to the operations in the second to fourth steps of Intermediate A.

[0181] MS m / z(ESI): 321 [M+1]

[0182] Intermediate C: 2-(2-(2,6-Dioxopiperidin-3-yl)-4-methoxy-1-oxoisoindolin-5-yl)acetic acid

[0183]

[0184] Step 1

[0185] Methyl 4-bromo-3-methoxy-2-methylbenzoate (C-2)

[0186] To a solution of methyl 4-bromo-3-hydroxy-2-methylbenzoate C-1 (2.0 g, 8.2 mmol) and methyl iodide (5.8 g, 40.8 mmol) in acetonitrile (20 mL) was added potassium carbonate (3.4 g, 24.5 mmol), and the reaction mixture was stirred at 50 °C for 12 hours. It was quenched by adding water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give the target product C-2 (2.1 g, 99%).

[0187] MS m / z(ESI): 259 [M+1]

[0188] Steps 2 to 5

[0189] 2-(2-(2,6-Dioxopiperidin-3-yl)-4-methoxy-1-oxoisoindolin-5-yl)acetic acid (C)

[0190] Replace B-3 with C-2 and synthesize C by referring to the operations in the third to sixth steps of Intermediate B.

[0191] MS m / z(ESI): 333 [M+1]

[0192] Example 2

[0193] 2-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-N-(2-fluoro-5-(2-hydroxyethoxy)phenyl)acetamide (Compound 1)

[0194]

[0195] The first step

[0196] 2-(4-Fluoro-3-nitrophenoxy)ethanol (1b)

[0197] To a solution of 4-fluoro-3-nitrophenol 1a (500 mg, 3.2 mmol) and 2-bromoethanol (644 mg, 5.2 mmol) in acetone (14 mL) was added potassium carbonate (880 mg, 6.4 mmol). The mixture was stirred at 70 °C overnight. After cooling to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 9 / 1) to obtain the target product 1b (30 mg, 47%).

[0198] MS m / z(ESI): 202 [M+1]

[0199] The second step

[0200] 2-(3-Amino-4-fluorophenoxy)ethanol (1c)

[0201] To a solution of 1b (300 mg, 1.5 mmol) in methanol (10 mL) was added palladium on carbon (10%, containing 55% water, 30 mg). The mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. After filtration, the filtrate was concentrated under reduced pressure to obtain the target product 1c (240 mg, 94%).

[0202] MS m / z(ESI): 172 [M+1]

[0203] The third step

[0204] 2-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-N-(2-fluoro-5-(2-hydroxyethoxy)phenyl)acetamide (1)

[0205] To a solution of 1c (42 mg, 0.25 mmol) and Intermediate A (50 mg, 0.17 mmol) in DMF (2 mL) were added DIPEA (64 mg, 0.50 mmol) and HATU (94 mg, 0.25 mmol). The mixture was stirred at room temperature for 2 hours. Purification by reversed-phase preparative high performance liquid chromatography gave the target product 1 (3 mg, 4%).

[0206] MS m / z (ESI): 456 [M+1]

[0207] 1 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 10.00 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.63–7.55 (m, 2H), 7.47 (d, J = 7.8 Hz, 1H), 7.15 (dd, J = 10.6, 9.1 Hz, 1H), 6.68 (dt, J = 8.9, 3.4 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.83 (s, 1H), 4.46 (d, J = 17.4 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 3.96–3.82 (m, 4H), 3.71–3.62 (m, 2H), 2.97–2.87 (m, 1H), 2.64–2.56 (m, 1H), 2.41 - 2.33 (m, 1H), 2.04–1.96 (m, 1H).

[0208] Example 3

[0209] 2-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-N-(4-(2-(2-(methylamino)ethoxy)ethyl)phenyl)acetamide (Compound 2)

[0210]

[0211] The first step

[0212] tert-Butyl 2-(4-nitrophenethoxy)acetate (2b)

[0213] To a solution of 2-(4-nitrophenyl)ethanol 2a (2.0 g, 12.0 mmol), tert-butyl 2-bromoacetate (18.7 g, 95.8 mmol) and tetrabutylammonium hydrogensulfate (3.26 g, 9.6 mmol) in toluene (6 mL) at 0 °C was added aqueous sodium hydroxide solution (5 M, 20 mL). The reaction mixture was stirred at room temperature for 2 hours. Extracted with ethyl acetate, the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the target product 2b (3.2 g, 94%).

[0214] MS m / z (ESI): 281 [M+1]

[0215] The second step

[0216] 2-(4-Nitrophenethoxy)acetic acid (2c)

[0217] Dissolve 2b (3.2 g, 11.4 mmol) and trifluoroacetic acid (8 mL) in dichloromethane (32 mL), and stir at room temperature for 1.5 hours. Concentrate under reduced pressure to obtain the target product 2c (2.4 g, crude product). This product was directly used in the next reaction without further purification.

[0218] MS m / z (ESI): 224 [M-1]

[0219] The third step

[0220] N-Methyl-2-(4-nitrophenethoxy)acetamide (2d)

[0221] Add HATU (5.1 g, 13.3 mmol) and DIPEA (5.1 g, 39.8 mmol) to a solution of 2c (2.0 g, 8.9 mmol) and methylamine hydrochloride (1.2 g, 17.8 mmol) in DMF (25 mL). Stir the mixture at room temperature for 2 hours. Add water and extract with ethyl acetate. Concentrate the organic phase under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the target product 2d (1.8 g, 86%).

[0222] MS m / z (ESI): 239 [M+1]

[0223] The fourth step

[0224] N-Methyl-2-(4-nitrophenethoxy)ethan-1-amine (2e)

[0225] Dissolve 2d (1.8 g, 7.6 mmol) and a tetrahydrofuran solution of borane (1.0 M, 7.6 mL, 7.6 mmol) in tetrahydrofuran (20 mL). Stir the mixture at 70 °C for 2 hours. Cool to room temperature, add methanol to quench the reaction, adjust to pH = 6 with dilute hydrochloric acid (1 N), and wash with ethyl acetate. Add saturated aqueous sodium bicarbonate solution to the aqueous phase to adjust to pH = 8, and extract with ethyl acetate. Concentrate the organic phase under reduced pressure to obtain the target product 2e (600 mg, crude product). This product was directly used in the next reaction without further purification.

[0226] MS m / z (ESI): 225 [M+1]

[0227] The fifth step

[0228] (2-(4-Nitrophenethoxy)ethyl)carbamic acid tert-butyl ester (2f)

[0229] To a solution of 2e (600 mg, 2.7 mmol) and triethylamine (541 mg, 5.4 mmol) in tetrahydrofuran (10 mL) was added (Boc)2O (876 mg, 4.0 mmol). The mixture was stirred at room temperature for 2 h. Concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give the target product 2f (600 mg, 69%).

[0230] MS m / z (ESI): 269 [M+1-56]

[0231] The sixth step

[0232] (2-(4-Aminophenethoxy)ethyl)(methyl)carbamic acid tert-butyl ester (2g)

[0233] To a solution of 2f (600 mg, 1.85 mmol) in methanol (10 mL) was added palladium on carbon (10%, containing 55% water, 60 mg). The mixture was stirred at room temperature for 1 h under a hydrogen atmosphere. Filtered, the filtrate was concentrated under reduced pressure to give the target product 2g (420 mg, 77%). This product was used directly in the next step without further purification.

[0234] MS m / z (ESI): 295.1 [M+1]

[0235] The seventh step

[0236] (2-(4-(2-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamido)phenethoxy)ethyl)(methyl)carbamic acid tert-butyl ester (2h)

[0237] To a solution of intermediate A (50 mg, 0.17 mmol) and 2g (58 mg, 0.20 mmol) in DMF (2 mL) were added HATU (94 mg, 0.25 mmol) and DIPEA (64 mg, 0.50 mmol). The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to give the target product 2h (25 mg, 26%).

[0238] MS m / z (ESI): 579 [M+1]

[0239] The eighth step

[0240] 2-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-N-(4-(2-(2-(methylamino)ethoxy)ethyl)phenyl)acetamide (2)

[0241] Dissolve 2h (25 mg, 0.043 mmol) and trifluoroacetic acid (0.5 mL) in dichloromethane (1 mL). The mixture was stirred at room temperature for 1 hour. Concentrate under reduced pressure, and the residue was purified by reverse-phase preparative high performance liquid chromatography to obtain the target product 2 (formate, 11 mg, 49%).

[0242] MS m / z (ESI): 479 [M+1]

[0243] 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (brs, 1H), 10.16 (s, 1H), 8.29 - 8.23 (m, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.50 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.1 Hz, 1H), 7.16 (d, J = 8.4 Hz, 2H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.45 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.4 Hz, 1H), 3.77 (s, 2H), 3.58 (t, J = 7.0 Hz, 2H), 3.52 (t, J = 5.3 Hz, 2H), 2.95–2.87 (m, 1H), 2.85–2.80 (m, 2H), 2.76 (t, J = 7.0 Hz, 2H), 2.60 (d, J = 17.6 Hz, 1H), 2.42–2.31 (m, 4H), 2.03–1.96 (m, 1H).

[0244] Example 4

[0245] N-(4-Chloro-2-fluoro-5-(2-hydroxyethoxy)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 3)

[0246]

[0247] The first step

[0248] 2-(2-Chloro-4-fluoro-5-nitrophenoxy)ethanol (3b)

[0249] To a solution of 2-chloro-4-fluoro-5-nitrophenol 3a (1.0 g, 5.2 mmol) and 2-bromoethanol (912 mg, 7.3 mmol) in DMF (5 mL) was added potassium carbonate (1.2 g, 8.4 mmol). The mixture was stirred at 80 °C for 4 h. It was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 85 / 15) to give the target product 3b (443 mg, 36%).

[0250] The second step

[0251] 2-(5-Amino-2-chloro-4-fluorophenoxy)ethanol (3c)

[0252] To a solution of 3b (443 mg, 1.88 mmol) in tetrahydrofuran (8 mL) was added iron powder (1.1 g, 18.8 mmol) and saturated aqueous ammonium chloride solution (8 mL). The mixture was stirred at 60 °C overnight. It was filtered, and the filtrate was diluted with ethyl acetate and washed with water. The organic phase was concentrated under reduced pressure to give the target product 3c (283 mg, 73%). This product was used directly in the next reaction without further purification.

[0253] MS m / z (ESI): 206 [M+1]

[0254] The third step

[0255] N-(4-Chloro-2-fluoro-5-(2-hydroxyethoxy)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (3)

[0256] To a solution of 3c (47 mg, 0.23 mmol) and intermediate A (69 mg, 0.23 mmol) in DMF (2 mL) were added NMI (65 mg, 0.80 mmol) and TCFH (77 mg, 0.27 mmol). The mixture was stirred at room temperature overnight. It was filtered, and the filtrate was purified by reversed-phase preparative high performance liquid chromatography to give the target product 3 (13.6 mg, 12%).

[0257] MS m / z (ESI): 490 [M+1]

[0258] 11H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 10.12 (s, 1H), 7.81 (d, J = 7.1 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.56 (s, 1H), 7.51–7.46 (m, 2H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 3.97 (t, J = 5.1 Hz, 2H), 3.90 (s, 2H), 3.70 (t, J = 5.1 Hz, 2H), 2.98–2.87 (m, 1H), 2.60 (d, J = 17.3 Hz, 1H), 2.45–2.34 (m, 1H), 2.05–1.96 (m, 1H).

[0259] Example 5

[0260] N-(3-chloro-4-(2-(2-(methylamino)ethoxy)ethyl)benzyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 4)

[0261]

[0262] The first step

[0263] 2-(4-bromo-2-chlorophenyl)ethanol (4b)

[0264] The reaction mixture 4a (6 g, 24.0 mmol), a tetrahydrofuran solution of borane (1.0 M, 48 mL) and tetrahydrofuran (60 mL) were stirred at 70 °C for 4 hours. Methanol was added to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the target product 4b (5 g, 89%).

[0265] The second to the sixth steps

[0266] (2-(4-bromo-2-chlorophenethoxy)ethyl)(methyl)carbamic acid tert-butyl ester (4g)

[0267] Using 4b instead of 2a, 4g was synthesized according to the operations of the first to the fifth steps in Compound 2.

[0268] MS m / z (ESI): 292 [M+1 - 100]

[0269] The seventh step

[0270] (2-(2-chloro-4-cyanophenethoxy)ethyl)(methyl)carbamic acid tert-butyl ester (4h)

[0271] To a solution of 4g (300 mg, 0.77 mmol) and zinc cyanide (180 mg, 1.54 mmol) in DMA (4.5 mL) was added Pd2(dba)3 (35 mg, 0.038 mmol) and dppf (21 mg, 0.038 mmol). The mixture was stirred at 120 °C for 4 h. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the target product 4h (170 mg, 66%).

[0272] MS m / z (ESI): 361 [M+23]

[0273] The eighth step

[0274] (2-(4-(Aminomethyl)-2-chlorophenethoxy)ethyl)(methyl)carbamic acid tert-butyl ester (4i)

[0275] To a solution of 4h (120 mg, 0.36 mmol) in methanol (10 mL) was added nickel (50 mg). The mixture was stirred at room temperature for 1 h under a hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the target product 4i (100 mg, 82%).

[0276] MS m / z (ESI): 365 [M+23]

[0277] The ninth step

[0278] (2-(2-Chloro-4-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamido)methyl)phenethoxy)ethyl)(methyl)carbamic acid tert-butyl ester (4j)

[0279] To a solution of intermediate A (50 mg, 0.17 mmol) and 4i (57 mg, 0.17 mmol) in NMP (2 mL) were added HATU (94 mg, 0.25 mmol) and DIPEA (64 mg, 0.50 mmol). The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 12 / 1) to give the target product 4j (50 mg, 48%).

[0280] MS m / z (ESI): 649 [M+23]

[0281] The tenth step

[0282] N-(3-Chloro-4-(2-(2-(methylamino)ethoxy)ethyl)benzyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (4)

[0283] Replace 2h with 4j, and synthesize 4 by referring to the operation in the eighth step of Compound 2.

[0284] MS m / z(ESI): 527 [M+1]

[0285] 1 H NMR(400 MHz, DMSO-d6) δ 8.63 (t, J = 5.9 Hz, 1H), 8.31 (s, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.22 (s, 1H), 7.12 (d, J = 6.5 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.44 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H), 4.24 (d, J = 5.9 Hz, 2H), 3.62 (s, 2H), 3.58 (t, J = 7.0 Hz, 2H), 3.52 (t, J = 5.4 Hz, 2H), 2.98–2.84 (m, 3H), 2.76 (t, J = 5.3 Hz, 2H), 2.62 (d, J = 2.4 Hz, 1H), 2.44–2.30 (m, 4H), 2.05–1.95 (m, 1H).

[0286] Example 6

[0287] N-(3-Chloro-4-(2-(2-(methylamino)ethoxy)ethyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 5)

[0288]

[0289] The first to the sixth steps

[0290] (2-(2-Chloro-4-nitrophenethoxy)ethyl)(methyl)carbamic acid tert-butyl ester (5 g)

[0291] Replace 4a with 5a, and synthesize 5g by referring to the operation in the first to the sixth steps of Compound 4.

[0292] MS m / z(ESI): 381 [M+23]

[0293] The seventh step

[0294] (2-(4-Amino-2-chlorophenethoxy)ethyl)(methyl)carbamic acid tert-butyl ester (5h)

[0295] To a mixture of 5g (0.35 g, 0.97 mmol), ammonium chloride (0.52 g, 9.75 mmol), ethanol (10 mL) and water (2 mL) was added iron powder (0.27 g, 4.9 mmol). The mixture was stirred at 80 °C for 2 h. It was cooled to room temperature, filtered, and the filter cake was washed with ethanol. The filtrate was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product 5h (305 mg, crude). This product was used directly in the next reaction without further purification.

[0296] MS m / z(ESI): 351 [M + 23]

[0297] Steps 8 to 9

[0298] N-(3-chloro-4-(2-(2-(methylamino)ethoxy)ethyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (5)

[0299] Using 5h instead of 2g, 5 was synthesized by referring to the operation in Steps 7 to 8 of Compound 2.

[0300] MS m / z(ESI): 513 [M + 1]

[0301] 1 H NMR(400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.26 (s, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.40 (dd, J = 8.4, 2.0 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.45 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 3.79 (s, 2H), 3.59 (t, J = 7.0 Hz, 2H), 3.54 (t, J = 5.3 Hz, 2H), 2.98–2.82 (m, 5H), 2.64–2.57 (m, 1H), 2.44–2.32 (m, 4H), 2.06–1.96 (m, 1H).

[0302] Example 7

[0303] N-(4-cyclopropyl-3-(2-hydroxyethoxy)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 6)

[0304]

[0305] The first step

[0306] 2-(2-Bromo-5-nitrophenoxy)ethanol (6b)

[0307] Cesium carbonate (4.5 g, 13.8 mmol) was added to a solution of 2-bromo-5-nitrophenol 6a (1.0 g, 4.59 mmol) and 2-bromoethanol (1.15 g, 9.2 mmol) in DMF (15 mL). The mixture was stirred overnight at 95 °C. After cooling to room temperature, it was diluted with water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain the target product 6b (790 mg, 66%).

[0308] MS m / z (ESI): 262 [M+1]

[0309] The second step

[0310] 2-(2-Cyclopropyl-5-nitrophenoxy)ethanol (6c)

[0311] Palladium acetate (68 mg, 0.30 mmol), potassium phosphate (1.28 g, 6.0 mmol) and tricyclohexylphosphine (84 mg, 0.30 mmol) were added to a mixture of 6b (790 mg, 3.0 mmol), cyclopropylboronic acid (519 mg, 6.0 mmol), toluene (12 mL) and water (3 mL). The mixture was stirred at 90 °C for 3 hours. After cooling to room temperature, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the target product 6c (650 mg, 97%).

[0312] MS m / z (ESI): 224 [M+1]

[0313] The third step

[0314] 2-(5-Amino-2-cyclopropylphenoxy)ethanol (6d)

[0315] Zinc powder (1.0 g) was added to a solution of 6c (650 mg, 2.9 mmol) and acetic acid (1 mL) in tetrahydrofuran (10 mL). The mixture was stirred at 0 °C for 2 hours. It was alkalized to pH = 7 with sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to obtain the target product 6d (450 mg, 80%). This product was used directly in the next reaction without further purification.

[0316] MS m / z (ESI): 194 [M+1]

[0317] The fourth step

[0318] N-(4-Cyclopropyl-3-(2-hydroxyethoxy)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (6)

[0319] Compound 6 was synthesized by replacing 2g with 6d and following the procedure of the seventh step in Reference Compound 2.

[0320] MS m / z (ESI): 478 [M+1]

[0321] 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.12 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 1.8 Hz, 1H), 7.07–6.99 (m, 1H), 6.70 (d, J = 8.3 Hz, 1H), 5.11 (dd, J = 13.1, 5.0 Hz, 1H), 4.88–4.75 (m, 1H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 3.93 (t, J = 5.1 Hz, 2H), 3.78–3.71 (m, 4H), 2.98–2.87 (m, 1H), 2.60 (d, J = 16.6 Hz, 1H), 2.44–2.33 (m, 1H), 2.15–2.08 (m, 1H), 2.03–1.96 (m, 1H), 0.88–0.71 (m, 2H), 0.59–0.55 (m, 2H).

[0322] Example 8

[0323] N-(4-Cyclopropyl-3-((2-hydroxyacetamido)methyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 7)

[0324]

[0325] The first step

[0326] 2-(2-Bromo-5-nitrobenzyl)isoindoline-1,3-dione (7b)

[0327] At 0 °C, 1-bromo-4-nitrobenzene 7a (3.0 g, 14.9 mmol) and 2-(hydroxymethyl)isoindoline-1,3-dione (1.3 g, 7.4 mmol) were added to trifluoromethanesulfonic acid (15 mL). The mixture was stirred overnight at room temperature. Water was added, and the mixture was extracted with dichloromethane. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 60) to obtain the target product 7b (2.2 g, 82%).

[0328] MS m / z(ESI): 383[M + 23]

[0329] The second step

[0330] (2-Bromo-5-nitrophenyl)methanamine (7c)

[0331] The reaction mixture of 7b (1.0 g, 2.76 mmol), hydrazine monohydrate (1.7 g, 13.8 mmol) and acetonitrile (50 mL) was stirred overnight at 80 °C. It was concentrated under reduced pressure, and the residue was purified by reverse-phase preparative high performance liquid chromatography to obtain the target product 7c (360 mg, 56%).

[0332] MS m / z(ESI): 231[M + 1]

[0333] The third step

[0334] (2-Bromo-5-nitrobenzyl) tert-butylcarbamate (7d)

[0335] The reaction mixture of 7c (360 mg, 1.56 mmol), (Boc)2O (1.0 g, 4.67 mmol), triethylamine (472 mg, 4.67 mmol) and dichloromethane (10 mL) was stirred at room temperature for 1 hour. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5) to obtain the target product 7d (320 mg, 62%).

[0336] MS m / z(ESI): 276[M + 1 - 56]

[0337] The fourth step

[0338] (2-Cyclopropyl-5-nitrobenzyl) tert-butylcarbamate (7e)

[0339] The reaction mixture 7d (320 mg, 0.97 mmol), cyclopropylboronic acid (166 mg, 1.9 mmol), potassium carbonate (399 mg, 2.9 mmol), Pd(dppf)Cl2·CH2Cl2 (79 mg, 0.097 mmol), 1,4-dioxane (10 mL) and water (3 mL) were stirred at 95 °C for 3 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 85 / 15) to give the target product 7e (240 mg, 85%).

[0340] MS m / z (ESI): 237 [M+1-56]

[0341] The fifth step

[0342] (tert-Butyl (5-amino-2-cyclopropylbenzyl)carbamate (7f)

[0343] The reaction mixture 7e (70 mg, 0.24 mmol), zinc powder (124 mg, 1.9 mmol), methanol (1 mL) and acetic acid (1 mL) were stirred at 0 °C for 1 h. Aqueous sodium carbonate solution was added until the pH of the solution reached 8 and the mixture was extracted with dichloromethane. The organic phase was concentrated under reduced pressure to give the target product 7f (85 mg, crude). This product was used directly in the next step without further purification.

[0344] MS m / z (ESI): 163 [M+1-100]

[0345] The sixth to seventh steps

[0346] N-(3-(Aminomethyl)-4-cyclopropylphenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (7h)

[0347] Using 7f instead of 2g, 7h was synthesized according to the procedures of the seventh to eighth steps in Compound 2.

[0348] MS m / z (ESI): 447 [M+1]

[0349] The eighth step

[0350] N-(4-Cyclopropyl-3-((2-hydroxyacetamido)methyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (7)

[0351] Using 7h instead of 2g and 2-hydroxyacetic acid instead of intermediate A, 7 was synthesized according to the procedure of the seventh step in Compound 2.

[0352] MS m / z (ESI): 505 [M+1]

[0353] 1 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.14 (s, 1H), 8.05 (t, J = 6.0 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.54 (s, 1H), 7.49 (dd, J = 8.4, 2.1 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.47–4.43 (m, 2H), 4.31 (d, J = 17.3 Hz, 1H), 3.88 (s, 2H), 3.75 (s, 4H), 2.95–2.85 (m, 1H), 2.60 (d, J = 16.5 Hz, 1H), 2.43–2.33 (m, 1H), 2.06–1.87 (m, 2H), 0.89–0.84 (m, 2H), 0.60–0.53 (m, 2H).

[0354] Example 9

[0355] N-(4-Cyclopropyl-3-(2-hydroxyacetamido)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 8)

[0356]

[0357] The first step

[0358] (2-Bromo-5-nitrophenyl)carbamic acid tert-butyl ester (8b)

[0359] The reaction mixture of 2-bromo-5-nitroaniline 8a (1.0 g, 4.6 mmol), (Boc)2O (2.0 g, 9.2 mmol), triethylamine (1.4 g, 13.8 mmol), DMAP (566 mg, 4.6 mmol) and dichloromethane (10 mL) was stirred at room temperature for 1 h. Concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 90 / 10) to obtain the target product 8b (1.6 g, 83%).

[0360] MS m / z (ESI): 339 [M + 23]

[0361] The second to the sixth steps

[0362] N-(4-Cyclopropyl-3-(2-hydroxyacetamido)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (8)

[0363] Compound 8 was synthesized by replacing 7d with 8b, referring to the operations in the fourth to eighth steps of Compound 7.

[0364] MS m / z (ESI): 491 [M+1]

[0365] 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.23 (s, 1H), 9.37 (s, 1H), 8.21 (d, J = 1.9 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.46 (d, J = 8.3 Hz, 2H), 7.04 (d, J = 8.4 Hz, 1H), 6.09 (brs, 1H), 5.10 (dd, J = 13.2, 5.1 Hz, 1H), 4.46 (d, J = 17.4 Hz, 1H), 4.32 (d, J = 17.4 Hz, 1H), 4.02 (s, 2H), 3.76 (s, 2H), 2.95–2.85 (m, 1H), 2.59 (d, J = 17.8 Hz, 1H), 2.42–2.32 (m, 1H), 2.04–1.95 (m, 1H), 1.79–1.74 (m, 1H), 0.93–0.86 (m, 2H), 0.58–0.53 (m, 2H).

[0366] Example 10

[0367] 2-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-N-(4-(2-(2-hydroxyacetamido)ethyl)phenyl)acetamide (Compound 9)

[0368]

[0369] The first step

[0370] (4-(2-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamido)phenethyl) tert-butyl carbamate (9b)

[0371] Compound 9b was synthesized by replacing 2g with (4-aminophenethyl) tert-butyl carbamate 9a, referring to the operation in the seventh step of Compound 2.

[0372] MS m / z (ESI): 543 [M+23]

[0373] The second step

[0374] N-(4-(2-Aminoethyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (9c)

[0375] The reaction mixture 9b (70 g, 0.13 mmol) and a 1,4-dioxane solution of hydrogen chloride (4.0 M, 5 mL) were stirred at room temperature for 2 h. Concentration under reduced pressure gave the title product 9c (60 mg, 98%).

[0376] MS m / z (ESI): 421 [M+1]

[0377] The third step

[0378] 2-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-N-(4-(2-(2-hydroxyacetamido)ethyl)phenyl)acetamide (9)

[0379] 9 was synthesized with reference to the operation in the seventh step of Compound 2, using 9c instead of 2 g and glycolic acid instead of Intermediate A.

[0380] MS m / z (ESI): 479 [M+1]

[0381] 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.15 (s, 1H), 7.71 - 7.68 (m, 2H), 7.55 (s, 1H), 7.50 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.5 Hz, 2H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.46 (d, J = 17.4 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 3.77–3.73 (m, 4H), 3.31–3.26 (m, 2H), 2.96–2.85 (m, 1H), 2.68 (t, J = 7.4 Hz, 2H), 2.60 (d, J = 16.8 Hz, 1H), 2.44–2.33 (m, 1H), 2.04–1.96 (m, 1H).

[0382] Example 11

[0383] N-(4-(2-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamido)phenethyl)-2-hydroxy-N-methylacetamide (Compound 10)

[0384]

[0385] The first step

[0386] (4-Nitrophenethyl)carbamic acid tert-butyl ester (10b)

[0387] Using 2-(4-nitrophenyl)ethan-1-amine 10a instead of 2e, 10b was synthesized by referring to the operation in the fifth step of Compound 2.

[0388] MS m / z (ESI): 289 [M+23]

[0389] Second step

[0390] (4-Nitrophenethyl)carbamic acid tert-butyl ester (10c)

[0391] To a solution of 10b (600 mg, 2.25 mmol) and methyl iodide (639 mg, 4.5 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (60%, 270 mg, 6.75 mmol). The mixture was stirred at room temperature for 3 hours. The reaction was quenched by adding water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to give the target product 10c (400 mg, 63%). This product was used directly in the next step without further purification.

[0392] MS m / z (ESI): 303 [M+23]

[0393] Third to fourth steps

[0394] (4-(2-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamido)phenethyl)(methyl)carbamic acid tert-butyl ester (10e)

[0395] Using 10c instead of 1b, 10e was synthesized by referring to the operation in the second to third steps of Compound 1.

[0396] MS m / z (ESI): 557 [M+23]

[0397] Fifth to sixth steps

[0398] N-(4-(2-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamido)phenethyl)-2-hydroxy-N-methylacetamide (10)

[0399] Using 10e instead of 9b, 10 was synthesized by referring to the operation in the second to third steps of Compound 9.

[0400] MS m / z (ESI): 493 [M+1]

[0401] 11H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.17 - 10.16 (m, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.51 (dd, J = 8.4, 2.8 Hz, 2H), 7.47 (d, J = 7.5 Hz, 1H), 7.17–7.12 (m, 2H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.46 (d, J = 17.4 Hz, 1H), 4.36–4.29 (m, 2H), 4.01 (d, J = 5.4 Hz, 1H), 3.82 (d, J = 5.3 Hz, 1H), 3.77 (s, 2H), 3.49–3.45 (m, 1H), 3.37–3.34 (m, 1H), 2.96–2.85 (m, 1H), 2.85–2.79 (m, 3H), 2.77–2.66 (m, 2H), 2.60 (d, J = 17.6 Hz, 1H), 2.42–2.33 (m, 1H), 2.04–1.97 (m, 1H).

[0402] Example 12

[0403] 2-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-N-(4-(2-hydroxyacetamido)phenyl)acetamide (Compound 11)

[0404]

[0405] The first step

[0406] (4-(2-Hydroxyacetamido)phenyl)carbamic acid tert-butyl ester (11b)

[0407] Using (4-aminophenyl)carbamic acid tert-butyl ester 11a instead of 2 g and glycolic acid instead of Intermediate A, 11b was synthesized according to the operation in the seventh step of Compound 2.

[0408] MS m / z (ESI): 289 [M + 23]

[0409] The second to the third steps

[0410] 2-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-N-(4-(2-hydroxyacetamido)phenyl)acetamide (11)

[0411] Using 11b instead of 9b and Intermediate A instead of glycolic acid, 11 was synthesized according to the operation in the second to the third steps of Compound 9.

[0412] MS m / z (ESI): 451 [M + 1]

[0413] 1 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.16 (s, 1H), 9.56 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 8.9 Hz, 2H), 7.56 (s, 1H), 7.51 (d, J = 9.0 Hz, 2H), 7.47 (d, J = 7.7 Hz, 1H), 5.61 (t, J = 5.9 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.4 Hz, 1H), 3.96 (d, J = 5.9 Hz, 2H), 3.76 (s, 2H), 2.95–2.86 (m, 1H), 2.60 (d, J = 17.9 Hz, 1H), 2.43–2.32 (m, 1H), 2.03–1.96 (m, 1H).

[0414] Compound 12 was prepared according to the experimental procedure of reference compound 11, but tert-butyl (4-(aminomethyl)phenyl)carbamate was used instead of 11a in the first step.

[0415]

[0416] The NMR data of compound 12 are as follows:

[0417]

[0418] Example 13

[0419] N-(4-chloro-2-((2-hydroxyacetylamino)methyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 13)

[0420]

[0421] The first step

[0422] (5-chloro-2-nitrophenyl)methanamine (13b)

[0423] To a solution of sodium borohydride (1.0 g, 27.4 mmol) and trifluoroacetic acid (3.1 g, 27.4 mmol) in tetrahydrofuran (10 mL) at 0 °C was added 5-chloro-2-nitrobenzonitrile 13a (1.0 g, 5.4 mmol). The mixture was stirred at room temperature overnight. Sodium hydroxide solution (2 M) was added to adjust the pH of the solution to 10, and the mixture was extracted with dichloromethane. The organic phase was concentrated under reduced pressure to obtain the target product 13b (crude). This product was used directly in the next step without further purification.

[0424] MS m / z (ESI): 170 [M + 1 - 17]

[0425] The second to fifth steps

[0426] N-(2-(Aminomethyl)-4-chlorophenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (13f)

[0427] Using 13b instead of 5f, referring to the operations of the sixth to ninth steps in Compound 5 to synthesize 13f.

[0428] MS m / z (ESI): 441 [M + 1]

[0429] The sixth step

[0430] N-(4-Chloro-2-((2-hydroxyacetylamino)methyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (13)

[0431] Using 13f instead of 2g, 2-hydroxyacetic acid instead of Intermediate A, referring to the operation of the seventh step in Compound 2 to synthesize 13.

[0432] MS m / z (ESI): 499 [M + 1]

[0433] 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 10.21 (s, 1H), 8.56 (t, J = 6.5 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.59 (s, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.29 (dd, J = 8.6, 2.5 Hz, 1H), 5.65 (t, J = 5.9 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.4 Hz, 1H), 4.27 (d, J = 6.4 Hz, 2H), 3.91 (d, J = 5.9 Hz, 2H), 3.84 (s, 2H), 2.97–2.86 (m, 1H), 2.64–2.55 (m, 1H), 2.44–2.32 (m, 1H), 2.06–1.95 (m, 1H).

[0434] Example 14

[0435] N-(4-Cyclopropyl-3-((methylamino)methyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 14)

[0436]

[0437] The first step

[0438] 1-(2-Bromo-5-nitrophenyl)-N-methylmethanamine (14b)

[0439] A mixture of 2-bromo-5-nitrobenzaldehyde 14a (500 mg, 2.17 mmol), an ethanolic solution of methylamine (33%, 612 mg, 6.52 mmol), and ethanol (10 mL) was stirred at room temperature for 1 h. Sodium borohydride (248 mg, 6.52 mmol) was added at 0 °C, and the reaction mixture was stirred at 0 °C for 1 h. Water was added, and the mixture was extracted with dichloromethane. The organic phase was concentrated under reduced pressure to give the target product 14b (crude). This product was used directly in the next step without further purification.

[0440] MS m / z (ESI): 245 [M+1]

[0441] The second to the sixth steps

[0442] N-(4-Cyclopropyl-3-((methylamino)methyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (14)

[0443] Compound 14 was synthesized by following the procedures of the third to the seventh steps in Compound 7, using 14b instead of 7c.

[0444] MS m / z (ESI): 461 [M+1]

[0445] 11H NMR (400 MHz, DMSO-d6) δ 10.98 (brs, 1H), 10.16 (s, 1H), 8.22 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.58 (s, 1H), 7.55 (s, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.42 (dd, J = 8.4, 2.0 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.45 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.4 Hz, 1H), 3.90 (s, 2H), 3.76 (s, 2H), 2.97–2.86 (m, 1H), 2.65–2.55 (m, 1H), 2.46–2.31 (m, 4H), 2.06–1.91 (m, 2H), 0.90–0.85 (m, 2H), 0.59–0.55 (m, 2H).

[0446] Example 15

[0447] N-(3-(2-Aminoethoxy)-4-chlorophenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 15)

[0448]

[0449] The first step

[0450] (2-(2-Chloro-5-nitrophenoxy)ethyl)carbamic acid tert-butyl ester (15b)

[0451] The reaction mixture of 2-chloro-5-nitrophenol 15a (1.0 g, 5.8 mmol), (2-bromoethyl)carbamic acid tert-butyl ester (1.9 g, 8.6 mmol), potassium carbonate (2.4 g, 17.2 mmol) and acetonitrile (20 mL) was stirred at 80 °C for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to give the title product 15b (1.2 g, 65%). This product was used directly in the next step without further purification.

[0452] MS m / z (ESI): 261 [M+1-56]

[0453] The second to the fourth steps

[0454] N-(3-(2-Aminoethoxy)-4-chlorophenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (15)

[0455] Replace 7e with 15b and synthesize 15 according to the operations in the fifth to seventh steps of Compound 7.

[0456] MS m / z(ESI): 471[M + 1]

[0457] 1 H NMR(400 MHz, DMSO - d6)δ10.43(s, 1H), 7.70(d, J = 7.8 Hz, 1H), 7.62–7.53(m, 2H), 7.47(d, J = 7.8 Hz, 1H), 7.35(d, J = 8.6 Hz, 1H), 7.15(d, J = 8.5 Hz, 1H), 5.11(dd, J = 13.2, 5.1 Hz, 1H), 4.46(d, J = 17.3 Hz, 1H), 4.32(d, J = 17.3 Hz, 1H), 4.12–4.03(m, 2H), 3.80(s, 2H), 3.16–3.06(m, 2H), 2.99–2.84(m, 1H), 2.66–2.56(m, 1H), 2.45–2.33(m, 1H), 2.05–1.95(m, 1H).

[0458] Example 16

[0459] 2-(2-(2,6 - Dioxopiperidin - 3 - yl)-1 - oxoisoindolin - 5 - yl)-N-(4-(2-(2-(methylamino)ethoxy)ethyl)-3-(trifluoromethyl)phenyl)acetamide (Compound 16)

[0460]

[0461] The first step

[0462] 2-(4 - Nitro - 2-(trifluoromethyl)phenyl)acetic acid (16b)

[0463] To a solution of 2-(4 - nitro - 2-(trifluoromethyl)phenyl)acetonitrile 16a (9.0 g, 48.6 mmol) in concentrated sulfuric acid (45 mL) at 0 °C, potassium nitrate (4.9 g, 48.6 mmol) was slowly added. The mixture was stirred at 0 °C for 1 hour. Ice (45 g) was added, and the reaction mixture was stirred at 110 °C overnight. It was cooled to room temperature, and ice - water (60 mL) was added dropwise and stirred for 30 minutes. It was filtered, and the filter cake was washed with water and dried to obtain the target product 16b (9.9 g, 82%).

[0464] The second step

[0465] 2-(4 - Nitro - 2-(trifluoromethyl)phenyl)ethanol 1 - ol (16c)

[0466] To a solution of 16b (2g, 8.0 mmol) in THF (8 mL) was added a solution of borane in THF (1.0 M, 11.2 mL). The reaction mixture was stirred at room temperature for 3 h. Methanol was added to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 96 / 4) to give the target product 16c (1.75 g, 93%).

[0467] MS m / z (ESI): 234 [M - 1]

[0468] The third step

[0469] tert-Butyl 2-(4-nitro-2-(trifluoromethyl)phenethoxy)acetate (16d)

[0470] Compound 16d was synthesized by following the procedure of the first step in Compound 2, using 16c instead of 2a.

[0471] MS m / z (ESI): 294 [M + 1 - 56]

[0472] The fourth step

[0473] 2-(4-Nitro-2-(trifluoromethyl)phenethoxy)acetic acid (16e)

[0474] To a solution of 16d (757 mg, 2.17 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure to give the target product 16e (crude). This product was used directly in the next step without further purification.

[0475] MS m / z (ESI): 292 [M - 1]

[0476] The fifth step

[0477] N-Methyl-2-(4-nitro-2-(trifluoromethyl)phenethoxy)acetamide (16f)

[0478] To a solution of 16e (crude, 2.17 mmol) in DMF (5 mL) were added methylamine hydrochloride (366 mg, 5.42 mmol), PyBOP (2.8 g, 5.42 mmol) and DIPEA (1.7 g, 13.0 mmol). The reaction mixture was stirred at room temperature overnight. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 90) to give the target product 16f (514 mg, 77%).

[0479] MS m / z (ESI): 307 [M + 1]

[0480] The sixth to ninth steps

[0481] (2-(4-(2-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamido)-2-(trifluoromethyl)phenethoxy)ethyl)(methyl)carbamic acid tert-butyl ester (16j)

[0482] 16j was synthesized by using 16f to replace 5e and referring to the operations in the fifth to eighth steps of Compound 5.

[0483] MS m / z (ESI): 547 [M+1 - 100]

[0484] Tenth step

[0485] 2-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-N-(4-(2-(2-(methylamino)ethoxy)ethyl)-3-(trifluoromethyl)benzene)acetamide (16)

[0486] 16 was synthesized by using 16j to replace 9b and referring to the operation in the second step of Compound 9.

[0487] MS m / z (ESI): 547 [M+1]

[0488] 1 H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.29 (s, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.77–7.72 (m, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.56 (s, 1H), 7.48–7.44 (m, 2H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.46 (d, J = 17.4 Hz, 1H), 4.32 (d, J = 17.4 Hz, 1H), 3.81 (s, 2H), 3.59 (t, J = 7.0 Hz, 2H), 3.52 (t, J = 5.4 Hz, 2H), 2.99–2.88 (m, 3H), 2.78 (d, J = 4.8 Hz, 2H), 2.60 (dd, J = 15.2, 2.3 Hz, 1H), 2.44–2.31 (m, 4H), 2.04–1.96 (m, 1H).

[0489] Example 17

[0490] N-(2-(4-(2-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamido)phenethoxy)ethyl)-2-hydroxy-N-methylacetamide (Compound 17)

[0491]

[0492] Replace 2g with 2, and replace intermediate A with glycolic acid. Refer to the operation in the seventh step of compound 2 to synthesize 17.

[0493] MS m / z(ESI):537[M+1]

[0494] 1 H NMR(400MHz,DMSO-d6)δ10.98(s,1H),10.15(s,1H),7.69(d,J=7.8Hz,1H),7.55(s,1H),7.50–7.45(m,3H),7.14(dd,J=8.3,5.7Hz,2H),5.11(dd,J=13.3,5.1Hz,1H),4.46(d,J=17.4Hz,1H),4.38–4.30(m,2H),4.07(d,J=5.4Hz,1H),4.02(d,J=5.4Hz,1H),3.77(s,2H),3.55(t,J=6.8Hz,2H),3.52–3.45(m,2H),3.43(d,J=4.7Hz,1H),3.35–3.32(m,1H),2.96–2.87(m,1H),2.82(s,3H),2.73(t,J=6.5Hz,2H),2.59(d,J=17.8Hz,1H),2.44–2.33(m,1H),2.05–1.95(m,1H).

[0495] For compounds 18 - 20, refer to the experimental procedure of compound 17, but replace 2 with different compounds.

[0496]

[0497] The NMR data of compounds 18 - 20 are as follows:

[0498]

[0499]

[0500] Example 18

[0501] N-(3-chloro-4-(2-(2-hydroxyethoxy)ethyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 21)

[0502]

[0503] The first step

[0504] 2-(2-chloro-4-nitrophenethoxy)ethanol (21a)

[0505] To a solution of 5c (100 mg, 0.32 mmol) in tetrahydrofuran (3 mL) was added a solution of lithium aluminum hydride in tetrahydrofuran (2.5 M, 0.14 mL, 0.35 mmol). The reaction mixture was stirred at 0 °C for 1 h. The reaction was quenched by adding water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the target product 21a (60 mg, 77%).

[0506] MS m / z (ESI): 246 [M+1]

[0507] The second step

[0508] tert-Butyl (2-(2-chloro-4-nitrophenethoxy)ethoxy)dimethylsilane (21b)

[0509] To a solution of 21a (60 mg, 0.24 mmol) and imidazole (49 mg, 0.72 mmol) in DMF (5 mL) was added TBSCl (54 mg, 0.36 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched by adding water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give the target product 21b (80 mg, 91%).

[0510] The third step

[0511] 4-(2-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)ethyl)-3-chloroaniline (21c)

[0512] Compound 21c was synthesized by referring to the operation of the second step in Compound 3, using 21b instead of 3b.

[0513] MS m / z (ESI): 352 [M+23]

[0514] The fourth to fifth steps

[0515] N-(3-Chloro-4-(2-(2-hydroxyethoxy)ethyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)acetamide (21)

[0516] Compound 21 was synthesized by referring to the operations of the first to second steps in Compound 9, using 21b instead of 9a.

[0517] MS m / z (ESI): 500 [M+1]

[0518] 11H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.34 (s, 1H), 7.79 (d, J = 1.9 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 5.11 (dd, J = 13.2, 5.0 Hz, 1H), 4.55 (t, J = 5.4 Hz, 1H), 4.45 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 3.79 (s, 2H), 3.57 (t, J = 7.1 Hz, 2H), 3.49–3.45 (m, 2H), 3.44–3.38 (m, 2H), 2.96–2.84 (m, 3H), 2.60 (d, J = 17.4 Hz, 1H), 2.42–2.33 (m, 1H), 2.05–1.96 (m, 1H).

[0519] Example 19

[0520] N-(3-Chloro-4-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 22)

[0521]

[0522] The first step

[0523] tert-Butyl 2-(2-(2-chloro-4-nitrophenethoxy)ethoxy)acetate (22a)

[0524] Compound 22a was synthesized by referring to the operation of the first step in Compound 2, using 21a instead of 2a.

[0525] MS m / z (ESI): 382 [M+23]

[0526] The second step

[0527] 2-(2-(2-Chloro-4-nitrophenethoxy)ethoxy)ethanol (22b)

[0528] Compound 22b was synthesized by referring to the operation of the first step in Compound 21, using 22a instead of 5c.

[0529] MS m / z (ESI): 290 [M+1]

[0530] The third step

[0531] 2-(2-(4-Amino-2-chlorophenethoxy)ethoxy)ethanol (22c)

[0532] Zinc powder (202 mg, 3.1 mmol) was added to a solution of 22b (180 mg, 0.62 mmol) in acetic acid (5 mL). The mixture was stirred at room temperature for 1 h. It was quenched with sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the target product 22c (50 mg, 31%).

[0533] MS m / z (ESI): 260 [M+1]

[0534] The fourth step

[0535] N-(3-Chloro-4-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (22)

[0536] 22 was synthesized by replacing methylamine hydrochloride with 22c and intermediate A with 16e, referring to the operation in the fifth step of compound 16.

[0537] MS m / z (ESI): 544 [M+1]

[0538] 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.34 (s, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.38 (dd, J = 8.4, 2.1 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.46 (d, J = 17.4 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 3.79 (s, 2H), 3.57 (t, J = 7.1 Hz, 2H), 3.51–3.45 (m, 6H), 3.41–3.38 (m, 2H), 2.96–2.83 (m, 3H), 2.60 (d, J = 16.8 Hz, 1H), 2.39 (ddd, J = 26.5, 13.3, 4.4 Hz, 1H), 2.05–1.96 (m, 1H).

[0539] Example 20

[0540] N-(3-chloro-4-(2-(2-hydroxyethoxy)ethyl)benzyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 23)

[0541]

[0542] The first step

[0543] 2-(4-bromo-2-chlorophenethoxy)ethanol (23a)

[0544] Compound 23a was synthesized by using 4c instead of 5c and referring to the operation of the first step in Compound 21.

[0545] The second step

[0546] (3-chloro-4-(2-(2-hydroxyethoxy)ethyl)benzyl)carbamic acid tert-butyl ester (23b)

[0547] To a solution of 23a (187 mg, 0.67 mmol) and potassium [(tert-butoxycarbonylamino)methyl]trifluoroborate (318 mg, 1.34 mmol) in 1,4-dioxane (10 mL) were added Pd(dppf)Cl2 (49 mg, 0.067 mmol), cesium carbonate (652 mg, 2.0 mmol) and water (1 mL). The reaction mixture was stirred at 90 °C for 3 hours. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 70 / 30) to obtain the target product 23b (108 mg, 49%).

[0548] MS m / z (ESI): 230 [M+1-100]

[0549] The third step

[0550] 2-(4-(aminomethyl)-2-chlorophenethoxy)ethanol (23c)

[0551] Compound 23c was synthesized by using 23b instead of 9b and referring to the operation of the second step in Compound 9.

[0552] MS m / z (ESI): 230 [M+1]

[0553] The fourth step

[0554] N-(3-chloro-4-(2-(2-hydroxyethoxy)ethyl)benzyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (23)

[0555] Compound 23 was synthesized by using 23c instead of 2g and referring to the operation of the seventh step in Compound 2.

[0556] MS m / z (ESI): 514 [M+1]

[0557] 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.61 (t, J = 6.0 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 1.5 Hz, 1H), 7.15–7.11 (m, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.44 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 4.24 (d, J = 5.9 Hz, 2H), 3.62 (s, 2H), 3.58 (t, J = 7.1 Hz, 2H), 3.49–3.45 (m, 2H), 3.44–3.41 (m, 2H), 2.98–2.84 (m, 3H), 2.60 (d, J = 17.7 Hz, 1H), 2.45–2.32 (m, 1H), 2.03–1.96 (m, 1H).

[0558] Example 21

[0559] N-(2-(2-Chloro-4-(2-(2-(2,6-dioxopiperidin-3-yl)-4-hydroxy-1-oxoisoindolin-5-yl)acetamido)phenethoxy)ethyl)-2-hydroxy-N-methylacetamide (Compound 24)

[0560]

[0561] The first step

[0562] (2-(2-Chloro-4-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methoxy-1-oxoisoindolin-5-yl)acetamido)phenethoxy)ethyl)(methyl)carbamic acid tert-butyl ester (24a)

[0563] Using 5h instead of 2g and Intermediate C instead of Intermediate A, 24a was synthesized by referring to the operation in the seventh step of Compound 2.

[0564] MS m / z (ESI): 543 [M+1 - 100]

[0565] The second step

[0566] N-(3-Chloro-4-(2-(2-(methylamino)ethoxy)ethyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-4-hydroxy-1-oxoisoindolin-5-yl)acetamide (24b)

[0567] To a solution of 24a (70 mg, 0.11 mmol) in dichloromethane (5 mL) was added boron tribromide (1 mL), and the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched by adding water, and the mixture was filtered. The desired product 24b (30 mg, 52%) was obtained after drying the filter cake.

[0568] MS m / z (ESI): 529 [M+1]

[0569] The third step

[0570] N-(2-(2-Chloro-4-(2-(2-(2,6-dioxopiperidin-3-yl)-4-hydroxy-1-oxoisoindolin-5-yl)acetamido)phenethoxy)ethyl)-2-hydroxy-N-methylethanamide (24)

[0571] Using 24b instead of 2g and glycolic acid instead of intermediate A, 24 was synthesized according to the procedure of the seventh step in Compound 2.

[0572] MS m / z (ESI): 587 [M+1]

[0573] 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 10.26 (s, 1H), 9.75 (s, 1H), 7.80 (s, 1H), 7.42–7.35 (m, 1H), 7.34–7.22 (m, 2H), 7.19 (d, J = 6.4 Hz, 1H), 5.10 (dd, J = 13.3, 4.9 Hz, 1H), 4.35 (d, J = 17.2 Hz, 1H), 4.24 (d, J = 17.2 Hz, 1H), 4.05 (d, J = 16.2 Hz, 2H), 3.76 (s, 2H), 3.61–3.55 (m, 2H), 3.54–3.43 (m, 4H), 2.96–2.77 (m, 6H), 2.60 (d, J = 17.0 Hz, 1H), 2.43–2.32 (m, 1H), 2.06–1.97 (m, 1H).

[0574] Example 22

[0575] N-(2-(2-Chloro-4-(2-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)acetamido)phenethoxy)ethyl)-2-hydroxy-N-methylethanamide (Compound 25)

[0576]

[0577] The first step

[0578] (2-(2-Chloro-4-(2-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)acetamido)phenethoxy)ethyl)(methyl)carbamic acid tert-butyl ester (25a)

[0579] Replace 2g with 5h, intermediate B with intermediate A, and synthesize 25a according to the operation in the seventh step of compound 2.

[0580] MS m / z(ESI): 531 [M+1-100]

[0581] Second step

[0582] N-(3-Chloro-4-(2-(2-(methylamino)ethoxy)ethyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)acetamide (25b)

[0583] Replace 9b with 25a, and synthesize 25b according to the operation in the second step of compound 9.

[0584] MS m / z(ESI): 531 [M+1]

[0585] Third step

[0586] N-(2-(2-Chloro-4-(2-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)acetamido)phenethoxy)ethyl)-2-hydroxy-N-methylacetamide (25)

[0587] Replace 2g with 25b, 2-hydroxyacetic acid with intermediate A, and synthesize 25 according to the operation in the seventh step of compound 2.

[0588] MS m / z(ESI): 589 [M+1]

[0589] 11H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.39 (s, 1H), 7.79 (s, 1H), 7.61–7.53 (m, 2H), 7.40–7.34 (m, 1H), 7.32–7.23 (m, 1H), 5.12 (dd, J=13.3, 5.1 Hz, 1H), 4.57 (d, J=17.4 Hz, 1H), 4.45–4.29 (m, 2H), 4.07–4.02 (m, 2H), 3.88 (s, 2H), 3.59–3.56 (m, 2H), 3.54–3.46 (m, 2H), 3.43 (t, J=5.5 Hz, 1H), 3.34–3.32 (m, 1H), 2.97–2.77 (m, 6H), 2.60 (d, J=17.0 Hz, 1H), 2.47–2.35 (m, 1H), 2.06–1.96 (m, 1H).

[0590] Example 23 - Biological Experiment

[0591] Determination of GSPT1 Degradation

[0592] The compound was dissolved in DMSO and diluted to 5 mM, and then serially diluted 4-fold with DMSO to 8 concentration points. Each concentration point was further diluted 50-fold with RPMI 1640 medium (Thermo Fisher, catalog number 72400-047). If the DC 50 value of the compound was low, the starting concentration of the compound could be reduced.

[0593] NB4 GSPT1-HiBiT cells were obtained by overexpressing GSPT1 fused to HiBiT at the C-terminus in NB4 cells (Shanghai Jihe, catalog number JH-H1370). The cells were cultured in RPMI 1640 complete medium [which contained 10% FBS (GIBCO, catalog number 10099-141) and a mixture of 100 units / mL penicillin-streptomycin (Thermo Fisher, catalog number 15140122)]. The cells (400,000 cells / mL) were seeded in 90 μL of complete medium in a 96-well plate. After culturing overnight, 10 μL of the compound solution was added to each well, and the cells were further cultured in an incubator at 37 °C and 5% CO2 for 4 hours. The cell culture plate was taken out and equilibrated to room temperature, and then according to Instructions for the HiBiT Lytic System kit (Promega, catalog number N3030): Add an equal volume of Nano-Glo reagent for sufficient lysis, incubate at room temperature for 30 minutes, and then read the luminescence signal using a microplate reader (EnVision, Perkin Elmer). Use the group containing 0.2% DMSO as the non-GSPT1 degradation control. % degradation rate = luminescence signal 化合物 / luminescence signal DMSO对照 × 100%. Use XLfit software (ID Business Solutions Ltd., UK) to plot the induction curve of compound-induced GSPT1 degradation and calculate its DC 50 value. The experimental results are shown in Table 1.

[0594] Determination of SK-BR-3 cell proliferation inhibition

[0595] Dissolve the compound in DMSO and dilute it to 10 mM, then perform a 5-fold serial dilution with DMSO to 8 concentration points, and further dilute each concentration point 50-fold with McCoy's 5A medium (Gibco, catalog number 12330031). If the IC 50 value of the compound is low, the starting concentration of the compound can be reduced.

[0596] SK-BR-3 cells (Nanjing Kebai Biotechnology Co., Ltd., catalog number CBP60413) were cultured in the same complete cell medium as above. The cells (12,500 cells / mL) were seeded in 36 μL of complete medium in a 384-well plate and cultured overnight. Then, 4 μL of the compound solution was added to each well, and the cells were further cultured in an incubator at 37 °C and 5% CO2 for 6 days. The cell culture plate was taken out and equilibrated to room temperature, and then operated according to the (CTG) kit (Promega, catalog number G7572) instructions, that is, add 20 μL of CTG reagent for sufficient lysis, let it stand at room temperature for 10 minutes, and then read the luminescence signal using a microplate reader (EnVision, Perkin Elmer). Use the group containing 0.2% DMSO as 0% inhibition, and the group treated with the control compound CC-885 (specific preparation refers to the synthesis of the compound in Example 5.76 of WO2008027542A2) as 100% inhibition. % inhibition rate = (luminescence signal 化合物 - luminescence signal 100％抑制 ) / (luminescence signal 0％抑制 - luminescence signal 100％抑制 ) × 100%. Use XLfit software (IDBusiness Solutions Ltd., UK) to plot the inhibition curve of compound-induced SK-BR-3 cell proliferation and calculate its inhibitory IC 50 value. The experimental results are shown in Table 1.

[0597] The structure of CC-885 is as follows:

[0598]

[0599] Table 1

[0600]

Claims

1. A compound represented by the general formula (I), or a pharmaceutically acceptable salt, stable isotope derivative, and isomer thereof: Wherein: A is C 6-10 an aromatic ring or a 5- to 10-membered heteroaromatic ring; R 1 is H, halogen, -OH, C 1-6 alkyl or -OC 1-6 alkyl; R 2 is H, halogen, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, 4- to 8-membered heterocyclic group or -OR′, wherein one or more hydrogens of said alkyl, cycloalkyl and heterocyclic group are optionally substituted by D, halogen or C 1-6 alkyl; R 3 is -C 1-6 alkylene-(OC 2-6 alkylene) m -R 4 、-(OC 2-6 alkylene) m -R 4 、-C 1-6 alkylene-NR′R 6 or -NR′R 7 ; R 4 is - OR' or - NR'R 5 ; R′ is H, C 1-6 alkyl, C 3-8 cycloalkyl or a 4- to 8-membered heterocyclic group, wherein one or more hydrogens of said alkyl, cycloalkyl and heterocyclic group are optionally substituted by D, halogen or C 1-6 alkyl; R 5 , R 6 and R 7 are each independently H, C 1-6 alkyl, C 3-8 cycloalkyl or -C(O)C 1-6 alkylene-OR′, wherein one or two hydrogens of said alkylene are optionally substituted by D, fluorine, C 1-6 alkyl, fluorinated C 1-6 alkyl or C 3-8 cycloalkyl, provided that when R′ is H, R 6 cannot be H, R 7 cannot be H or C 1-3 alkyl; when R′ is C 1-3 alkyl, R 7 cannot be H; n is 0 or 1; and m is an integer from 1 to 6.

2. The compound or a pharmaceutically acceptable salt, stable isotope derivative, and isomer thereof according to claim 1, wherein: A is a benzene ring; R 1 is H, a halogen or -OH; R 2 is H, halogen, C 1-6 alkyl, fluoro C 1-6 alkyl or C 3-8 cycloalkyl; R 3 is -C 1-6 alkylene-(OCH2CH2) m -R 4 、-(OCH2CH2) m -R 4 、-C 1-6 alkylene-NR′R 6 or -NR′R 7 ; R 4 is -OH, -OC 1-6 alkyl, -NH2, -NH-C 1-6 alkyl, -NHC(O)C 1-6 alkylene-OH or -N(C 1-6 alkyl)C(O)C 1-6 alkylene-OH, wherein one or two hydrogens of said alkylene are optionally substituted by D, fluorine, C 1-6 alkyl, fluorinated C 1-6 alkyl or C 3-8 cycloalkyl; R′ is H or C 1-6 alkyl; R 6 and R 7 are each independently H, C 1-6 alkyl or -C(O)C 1-6 alkylene-OH, wherein one or two hydrogens of the alkylene are optionally substituted by D, fluorine, C 1-6 alkyl, fluorinated C 1-6 alkyl or C 3-8 cycloalkyl, provided that when R′ is H, R 6 cannot be H, R 7 cannot be H or C 1-3 alkyl; when R′ is C 1-3 alkyl, R 7 cannot be H; n is 0 or 1; and m is an integer from 1 to 6.

3. The compound according to claim 1 or 2, which is a compound represented by the general formula (II) or a pharmaceutically acceptable salt, stable isotope derivative, and isomer thereof: Wherein: R 1 is H, a halogen or -OH; R 2 is H, halogen, cyano, C 1-6 alkyl, C 3-8 cycloalkyl or -OR′, wherein one or more hydrogens of said alkyl are optionally substituted by D or halogen; R 3 is -C 1-6 alkylene-(OC 2-6 alkylene) m -R 4 、-(OC 2-6 alkylene) m -R 4 、-C 1-6 alkylene-NR′R 6 or -NR′R 7 ; R 4 is -OR′ or -NR′R 5 ; R′ is H or C 1-6 alkyl; R 5 、R 6 and R 7 are each independently H, C 1-6 alkyl or -C(O)C 1-6 alkylene-OR′, wherein one or two hydrogens of said alkylene are optionally substituted by D, fluorine, C 1-6 alkyl, fluorinated C 1-6 alkyl or C 3-8 cycloalkyl, provided that when R′ is H, R 6 cannot be H, R 7 cannot be H or C 1-3 alkyl; when R′ is C 1-3 alkyl, R 7 cannot be H; and m is an integer from 1 to 6.

4. The compound or a pharmaceutically acceptable salt, stable isotope derivative, and isomer thereof according to any one of claims 1-3, wherein: R 1 is H, a halogen or -OH; R 2 is H, halogen, C 1-6 alkyl, fluoro C 1-6 alkyl or C 3-8 cycloalkyl; R 3 is -C 1-6 alkylene-(OCH2CH2) m -R 4 、-(OCH2CH2) m -R 4 、-C 1-6 alkylene-NR′R 6 or -NR′R 7 ; R 4 is -OH, -NH2, -NH-C 1-6 alkyl, -NHC(O)CH2OH or -N(CH3)C(O)CH2OH; R' is H or C 1-6 alkyl; R 6 and R 7 are each independently H, C 1-6 alkyl or -C(O)CH2-OH, provided that when R' is H, R 6 cannot be H, and R 7 cannot be H or C 1-3 alkyl; when R' is C 1-3 alkyl, R 7 cannot be H; and m is 1 or 2.

5. The compound or a pharmaceutically acceptable salt, stable isotope derivative, and isomer thereof according to any one of claims 1-4, having the following structure:

6. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt, stable isotope derivative, isomer, and pharmaceutically acceptable carrier or excipient according to any one of claims 1-5.

7. A method for treating or preventing GSPT1-mediated diseases, the method comprising administering to a patient in need a therapeutically effective amount of the compound or a pharmaceutically acceptable salt, stable isotope derivative, isomer, prodrug thereof according to any one of claims 1-5, or the pharmaceutical composition according to claim 6, wherein the GSPT1-mediated diseases include but are not limited to hematological tumors, solid tumors, autoimmune diseases, inflammation, neurodegenerative diseases, skin diseases, etc.

8. Use of the compound or a pharmaceutically acceptable salt, stable isotope derivative, isomer, prodrug thereof according to any one of claims 1-5, or the pharmaceutical composition according to claim 6 in the preparation of a GSPT1 degrader.

9. Use of the compound or a pharmaceutically acceptable salt, stable isotope derivative, isomer, prodrug thereof according to any one of claims 1-5, or the pharmaceutical composition according to claim 6 in the preparation of a drug for treating or preventing GSPT1-mediated diseases.

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