Amide GSPT1 degradation agent

Abstract

The present invention relates to an amide compound as a GSPT1 protein degradation agent or a pharmaceutically acceptable salt thereof. Specifically, the present invention relates to a compound as represented by general formula (I') and a pharmaceutically acceptable salt thereof. The present invention further relates to a method for preparing the compound or the pharmaceutically acceptable salt thereof. The compound of the present invention can be used for treating and / or preventing a GSPT1-mediated disease, especially tumor.

Description

Amide GSPT1 degraders Technical Field

[0001] The present invention relates to amide compounds or pharmaceutically acceptable salts thereof as GSPT1 protein degraders. The present invention also relates to methods for preparing the compounds or pharmaceutically acceptable salts thereof. The present invention further relates to methods for using the compounds or pharmaceutically acceptable salts thereof to treat and / or prevent GSPT1-mediated diseases, particularly tumors. Background Art

[0002] Targeted protein degradation is a new drug development strategy that uses small molecules (called "molecular glues") to promote the interaction between the ubiquitin-proteasome system (UPS) and disease-related proteins (called "new substrates"), resulting in the degradation of new substrates. One type of molecular glue that has been clinically validated is glutarimide compounds, which can bind to CRL4. CRBN -E3 ubiquitin ligase complex binds to cereblon (CRBN), inducing changes in the surface structure of the CRBN protein, prompting the E3 ligase to recruit new substrates that are usually not targeted, causing them to be ubiquitinated by E2 and ultimately 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] Different glutarimide molecular glues and CRL4 CRBN After binding to the E3 ubiquitin ligase complex, different agents exhibit different specificities for degrading new substrate proteins, resulting in different therapeutic indications. Lenalidomide and pomalidomide induce the degradation of Ikaros (IKZF1) and Aiolos (IKZF3), transcription factors important in blood development and differentiation, and are used to treat multiple myeloma. However, lenalidomide also causes degradation of the protein kinase CK1α and can be used to treat 5q deletion-associated myelodysplastic syndrome. Furthermore, CC-885 promotes the degradation of GSPT1 and is used to treat AML (acute myeloid leukemia), but because it also induces the degradation of Ikaros and Aiolos, it can cause toxic side effects. CC-90009 and MRT-2359 are molecular glues with high GSPT1 degradation selectivity 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), mediating the recognition of stop codons and the release of nascent proteins from the ribosome, playing a key role in protein synthesis. Degradation of GSPT1 blocks protein translation and leads to cell death. GSPT1 is overexpressed in various tumor cells, and its targeted degradation has potential anti-tumor applications.

[0005] Although glutarimides share similar chemical structures, they exhibit distinct mechanisms of action, clinical therapeutic effects, and toxic side effects. Therefore, the development of novel GSPT1 degraders is crucial to address diverse 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 the range of carbon atoms, where x and y are both integers, for example, C 1-6 Alkyl represents an alkyl group having 1 to 6 carbon atoms, ie an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms; C 3-8 Cycloalkyl means a cycloalkyl group having 3 to 8 carbon atoms, i.e. a cycloalkyl group having 3, 4, 5, 6, 7 or 8 carbon atoms. It is also understood that “C 3-8 " also includes any sub-ranges therein, such as C 3-7 、C 3-6 、C 4-7 、C 4-6 、C 5-6 wait.

[0010] "Alkyl" refers to a saturated, straight or branched hydrocarbon group containing 1 to 20 carbon atoms, for example, 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, and the like.

[0011] "Alkylene" refers to a divalent group of a straight or branched saturated hydrocarbon containing 1 to 20 carbon atoms, for example, 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-, and the like.

[0012] "Cycloalkyl" refers to a saturated cyclic hydrocarbon substituent containing 3 to 14 carbon ring atoms. A cycloalkyl can be a single carbon ring, typically containing 3 to 8, 3 to 7, or 3 to 6 carbon ring atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. A cycloalkyl can also be a bicyclic or tricyclic ring that is fused, bridged, or spiro-coupled, such as decahydronaphthyl, bicyclo[2.2.2]octane, spiro[3.3]heptane, and the like.

[0013] "Heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic ring group comprising 3 to 20 ring atoms, for example 3 to 14, 3 to 12, 3 to 10, 3 to 8, 3 to 6 or 5 to 6 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, the ring atoms include 3 to 12 ring atoms, 3 to 10 ring atoms, 4 to 7 ring atoms, 4 to 6 ring atoms, of which 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, pyrrolidonyl, piperidonyl, 1,1-dioxidothiomorpholinyl, and the like. Polycyclic heterocyclic groups include fused, bridged or spiro polycyclic heterocyclic groups, such as octahydrocyclopenta[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 and the like.

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

[0015] "Heteroaryl or heteroaromatic ring" refers to a heteroaromatic system containing 5 to 14 ring atoms, wherein 1 to 4 of the ring atoms are selected from heteroatoms including oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10-membered, and more preferably the heteroaryl group is 5-membered or 6-membered, for example, furyl, thienyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, isoindolyl and the like. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, and non-limiting examples include: wait.

[0016] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0017] "Cyano" refers to -CN.

[0018] "Optional" means that the subsequently described event or circumstances may but need not occur. For example, the description of "one or more hydrogen atoms of a phenyl group are optionally substituted with halogen" includes both situations in which the one or more hydrogen atoms of the phenyl group are substituted with halogen and situations in which the one or more hydrogen atoms of the phenyl group are not substituted with halogen.

[0019] "Substitution" means that one or more hydrogen atoms in a group, preferably 1 to 5, for example 1 to 3 hydrogen atoms, are independently replaced by a corresponding number of substituents. The substituents are only in possible chemical positions understood by those skilled in the art. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an olefin). Substituents include, but are not limited to, halogen, cyano, nitro, hydroxyl, amino, oxo, -SF5, C 1-4 Alkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, etc.

[0020] "Isomers" are compounds that have the same molecular formula but differ in the position or arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers include optical isomers, geometric isomers, and conformational isomers.

[0021] The compounds of the present invention may exist as optical isomers. Optical isomers include enantiomers and diastereomers. Enantiomers refer to two stereoisomers that are non-superimposable and mirror images of each other. A racemic mixture or racemate refers to a chiral molecular mixture with equal numbers of left-handed and right-handed enantiomers. Diastereomers refer to two stereoisomers that are non-superimposable and not mirror images of each other. When an optical isomer is a single isomer and its absolute configuration is determined, it is referred to as 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 referred to as a (+) or (-) isomer according to its measured optical rotation value. Methods for preparing and separating optical isomers are known in the art.

[0022] The compounds of the present invention may also have geometric isomers that differ by the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl groups, or heterocyclic groups. Substituents around carbon-carbon double bonds or carbon-nitrogen bonds are designated as Z or E configurations, while substituents around cycloalkyl groups or heterocyclic groups are designated as cis or trans configurations.

[0023] The compounds of the present invention may also exhibit tautomerism, such as keto-enol tautomerism.

[0024] It should be understood that the present invention encompasses any tautomeric or stereoisomeric forms and mixtures thereof and is not limited solely to any one tautomeric or stereoisomeric form used in the naming of the compound or chemical formula.

[0025] "Isotopes" 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, such as, 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 analogous to those described in the accompanying examples using appropriate isotopically labeled reagents instead of non-isotopically labeled reagents. Such compounds have a variety of potential uses, for example, as standards and reagents in assays for biological activity. With respect to stable isotopes, for example, deuterium 2 H(D), 13 C and 15 N, compounds containing this isotope have the potential to alter biological, pharmacological, or pharmacokinetic properties. 2 H (D) is a preferred isotope of the present invention. For example, the hydrogen in a methyl group, a methylene group or a methine group may be replaced by deuterium.

[0026] The compound of the present invention can be given in the form of a prodrug. "Prodrug" refers to a derivative of a bioactive compound of the present invention that is converted into a bioactive compound of the present invention under physiological conditions in vivo, for example, by oxidation, reduction, hydrolysis, etc. (each of which utilizes an enzyme or is carried out without enzyme participation). Examples of prodrugs include the following compounds: wherein the amino group in the compound of the present invention is acylated, alkylated, or phosphorylated, such as eicosanoylamino, alanylamino, pivaloyloxymethylamino, or wherein the hydroxyl group is acylated, alkylated, phosphorylated, or converted into borate, such as acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy, or wherein the carboxyl group is esterified or amidated, or wherein the sulfhydryl group is selectively delivered to the target and / or to the cytosol of the cell. These compounds can be prepared by the compound of the present invention according to known methods.

[0027] "Pharmaceutically acceptable salts" or "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids, when the compounds of the present invention contain one or more acidic or basic groups. Thus, compounds of the present invention containing acidic groups may exist in the form of salts, for example, 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. Compounds of the present invention containing basic groups may exist in the form of inorganic or organic acid salts. The example of suitable acid comprises 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, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid and other acid well known by persons skilled in the art.If compound of the present invention contains acidic and basic group simultaneously in molecule, the present invention also comprises inner salt or betaine except mentioned salt form.Each salt can be obtained by conventional methods well known by persons skilled in the art, for example, by making compound and organic or inorganic acid or alkali mix or by obtaining with the negatively charged ion of other salt or cation exchange in solvent or dispersant.

[0028] A "pharmaceutical composition" refers to a mixture containing one or more compounds of the present invention or pharmaceutically acceptable salts, stable isotopic derivatives, isomers, prodrugs and mixtures thereof, and other components such as pharmaceutically acceptable carriers and excipients.

[0029] Therefore, when referring to "a compound," "a compound of the present invention," or "the compound described herein," all forms of the compound, such as pharmaceutically acceptable salts, stable isotopic derivatives, isomers, prodrugs, and mixtures thereof, are included in this application.

[0030] "Therapeutically effective amount" refers to an amount of the compound of the present invention that can effectively degrade GSPT1 to achieve the treatment or prevention of diseases mediated by GSPT1.

[0031] "Patient" refers to a mammal, especially a human.

[0032] In one aspect, the present invention relates to a compound useful as a GSPT1 degrading agent, the structure of which is shown in the general formula (I'), or a pharmaceutically acceptable salt, stable isotope derivative, isomer, and prodrug thereof:

[0033] in:

[0034] A is C 6-10 Aromatic ring or 5-10 membered heteroaromatic ring;

[0035] R 1H, halogen, -OH, C 1-6 Alkyl or -OC 1-6 alkyl;

[0036] Each R 2 Each is independently H, halogen, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclyl or -OR', wherein one or more hydrogen atoms of the alkyl, cycloalkyl and heterocyclyl groups are optionally replaced by D, halogen or C 1-6 Alkyl substituted;

[0037] R 3 -C 1-6 Alkylene-(OC 2-6 alkylene) m -R 4 、-(OC 2-6 alkylene) m -R 4 、-C 1-6 Alkylene-(OC 2-6 alkylene) m1 -R 3′ -R 4 、-O(C 2-6 Alkylene O) m1 -R 3′ -R 4 、-C 1-6 Alkylene-NR′R 6 or -NR′R 7 ;

[0038] R 3′ is a 4-8 membered heterocyclic group;

[0039] R 4 -OH, -NR′R 5 or -C(O)C 1-6 Alkylene-OH;

[0040] R 5 、R 6 and R 7 Each is independently H or -C(O)C 1-6 Alkylene-OH, wherein one or two hydrogen atoms of the alkylene are optionally replaced by D, fluorine, C 1-6 Alkyl, fluorinated C 1-6 Alkyl or C 3-8 substituted by cycloalkyl;

[0041] R' is H, C 1-6 Alkyl, C 3-8 Cycloalkyl or 4-8 membered heterocyclyl, wherein one or more hydrogen atoms of the alkyl, cycloalkyl and heterocyclyl groups are optionally replaced by D, halogen or C 1-6alkyl, but when R' is H, R 6 and R 7 Each cannot be H; when R' is C 1-6 When alkyl, R 7 It cannot be H;

[0042] n is 0 or 1;

[0043] m is an integer from 1 to 6;

[0044] m1 is an integer from 0 to 6; and

[0045] p is an integer from 1 to 3.

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

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

[0048] In some embodiments, each R 2 Each is independently H, halogen, C 1-6 Alkyl, fluorinated C 1-6 Alkyl or C 3-8 Cycloalkyl.

[0049] In some embodiments, R 3 -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 3 -C 1-6 Alkylene-R 3′ -R 4 OR 3′ -R 4 .

[0051] In some embodiments, R 3′ It is a 4-8 membered heterocyclic group containing 1-2 nitrogen heteroatoms.

[0052] In some embodiments, R 4 -OH, -NH2, -NH-C 1-6 Alkyl, -NHC(O)C 1- 6-alkylene-OH, -C(O)C 1-6 Alkylene-OH or -N(C 1-6alkyl)C(O)C 1-6 Alkylene-OH.

[0053] In some embodiments, R 4 -OH, -NH2, -NH-C 1-6 Alkyl, -NHC(O)CH2OH, -C(O)CH2OH or -N(CH3)C(O)CH2OH.

[0054] In some embodiments, R′ is H, R 6 and R 7 Each is -C(O)C 1-6 Alkylene-OH, wherein one or two hydrogen atoms of the alkylene are optionally replaced by D, fluorine, C 1-6 Alkyl, fluorinated C 1-6 Alkyl or C 3-8 Substituted with a cycloalkyl group.

[0055] In some embodiments, R′ is H, R 6 and R 7 Each is -C(O)CH2OH.

[0056] In some embodiments, R' is C 1-6 Alkyl, R 6 H or -C(O)C 1-6 Alkylene-OH, wherein one or two hydrogen atoms of the alkylene are optionally replaced by D, fluorine, C 1-6 Alkyl, fluorinated C 1-6 Alkyl or C 3-8 Substituted with a cycloalkyl group.

[0057] In some embodiments, R' is C 1-6 Alkyl, R 6 It is H or -C(O)CH2OH.

[0058] In some embodiments, R' is C 1-6 Alkyl, R 7 -C(O)C 1-6 Alkylene-OH, wherein one or two hydrogen atoms of the alkylene are optionally replaced by D, fluorine, C 1-6 Alkyl, fluorinated C 1-6 Alkyl or C 3-8 Substituted with a cycloalkyl group.

[0059] In some embodiments, R' is C 1-6 Alkyl, R 7 It is -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 compound of the present invention is represented by the general formula (II'):

[0064] in:

[0065] R 1 is H, halogen or -OH;

[0066] Each R 2 Each is independently H, halogen, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl or -OR', wherein one or more hydrogen atoms of the alkyl group are optionally replaced by D or halogen;

[0067] R 3 -C 1-6 Alkylene-(OC 2-6 alkylene) m -R 4 、-(OC 2-6 alkylene) m -R 4 、-C 1-6 Alkylene-R 3′ -R 4 、-OR 3′ -R 4 、-C 1-6 Alkylene-NR′R 6 or -NR′R 7 ;

[0068] R 3′ It is a 4-8 membered heterocyclic group containing 1-2 nitrogen heteroatoms;

[0069] R 4 -OH, -NR′R 5 or -C(O)C 1-6 Alkylene-OH;

[0070] R 5 、R 6 and R 7 Each is independently H or -C(O)C 1-6 Alkylene-OH;

[0071] R' is H or C 1-6 Alkyl, but when R' is H, R 6 and R 7 Each cannot be H; when R' is C 1-6 When alkyl, R 7 It cannot be H;

[0072] m is an integer from 1 to 6; and

[0073] p is an integer from 1 to 3.

[0074] In some embodiments, each R 2 H, halogen, C 1-6 Alkyl, fluorinated C 1-6 Alkyl or C 3-8 Cycloalkyl.

[0075] In some embodiments, R 3 -C 1-6 Alkylene-(OCH2CH2) m -R 4 、-(OCH2CH2) m -R 4 、-C 1-6 Alkylene-NR′R 6 or -NR′R 7 .

[0076] In some embodiments, R 3 -C 1-6 Alkylene-R 3′ -R 4 OR 3′ -R 4 .

[0077] In some embodiments, R 4 -OH, -NH2, -NH-C 1-6 Alkyl, -NHC(O)C 1- 6-alkylene-OH, -C(O)C 1-6 Alkylene-OH or -N(C 1-6 alkyl)C(O)C 1-6 Alkylene-OH.

[0078] In some embodiments, R 4 -OH, -NH2, -NH-C 1-6 Alkyl, -NHC(O)CH2OH, -C(O)C 1-6 Alkylene -OH or -N(CH3)C(O)CH2OH.

[0079] In some embodiments, R′ is H, R 6 and R 7 Each is -C(O)C 1-6 Alkylene-OH.

[0080] In some embodiments, R′ is H, R 6 and R 7Each is -C(O)CH2OH.

[0081] In some embodiments, R' is C 1-6 Alkyl, R 6 H or -C(O)C 1-6 Alkylene-OH.

[0082] In some embodiments, R' is C 1-6 Alkyl, R 6 It is H or -C(O)CH2OH.

[0083] In some embodiments, R' is C 1-6 Alkyl, R 7 -C(O)C 1-6 Alkylene-OH.

[0084] In some embodiments, R' is C 1-6 Alkyl, R 7 It is -C(O)CH2OH.

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

[0086] In another aspect, the present invention relates to a compound useful as a GSPT1 degrading agent, the structure of which is shown in general formula (I), or a pharmaceutically acceptable salt, stable isotope derivative, isomer, and prodrug thereof:

[0087] in:

[0088] A is C 6-10 Aromatic ring or 5-10 membered heteroaromatic ring;

[0089] R 1 H, halogen, -OH, C 1-6 Alkyl or -OC 1-6 alkyl;

[0090] R 2 H, halogen, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclyl or -OR', wherein one or more hydrogen atoms of the alkyl, cycloalkyl and heterocyclyl groups are optionally replaced by D, halogen or C 1- 6 alkyl substituted;

[0091] R 3 -C 1-6 Alkylene-(OC 2-6 alkylene) m -R 4 、-(OC 2-6 alkylene) m -R 4 、-C1-6 Alkylene-NR′R 6 or -NR′R 7 ;

[0092] R 4 -OR′ or -NR′R 5 ;

[0093] R' is H, C 1-6 Alkyl, C 3-8 Cycloalkyl or 4-8 membered heterocyclyl, wherein one or more hydrogen atoms of the alkyl, cycloalkyl and heterocyclyl groups are optionally replaced by D, halogen or C 1-6 Alkyl substituted; R 5 、R 6 and R 7 Each is independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl or -C(O)C 1-6 Alkylene-OR', wherein one or two hydrogen atoms of the alkylene are optionally replaced by D, fluorine, C 1-6 Alkyl, fluorinated C 1-6 Alkyl or C 3-8 substituted by cycloalkyl, but 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 When alkyl, R 7 It cannot be H;

[0094] n is 0 or 1; and

[0095] m is an integer from 1 to 6.

[0096] In some embodiments, A is a benzene ring.

[0097] In some embodiments, R 1 is H, halogen or -OH.

[0098] In some embodiments, R 2 H, halogen, C 1-6 Alkyl, fluorinated C 1-6 Alkyl or C 3- 8-cycloalkyl.

[0099] In some embodiments, R 3 -C 1-6 Alkylene-(OCH2CH2) m -R 4 、-(OCH2CH2) m -R 4 、-C 1-6 Alkylene-NR′R 6 or -NR′R7 .

[0100] In some embodiments, R 4 -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 hydrogen atoms of the alkylene are optionally replaced by D, fluorine, C 1-6 Alkyl, fluorinated C 1-6 Alkyl or C 3-8 substituted with a cycloalkyl group.

[0101] In some embodiments, R 4 -OH, -NH2, -NH-C 1-6 Alkyl, -NHC(O)CH2OH or -N(CH3)C(O)CH2OH.

[0102] In some embodiments, R′ is H, R 6 C 1-6 Alkyl or -C(O)C 1-6 Alkylene-OH, wherein one or two hydrogen atoms of the alkylene are optionally replaced by D, fluorine, C 1-6 Alkyl, fluorinated C 1-6 Alkyl or C 3-8 substituted with a cycloalkyl group.

[0103] In some embodiments, R′ is H, R 6 C 1-6 Alkyl or -C(O)CH2OH.

[0104] In some embodiments, R' is C 1-6 Alkyl, R 6 H, C 1-6 Alkyl or -C(O)C 1-6 Alkylene-OH, wherein one or two hydrogen atoms of the alkylene are optionally replaced by D, fluorine, C 1-6 Alkyl, fluorinated C 1-6 Alkyl or C 3-8 Substituted with a cycloalkyl group.

[0105] In some embodiments, R' is C 1-6 Alkyl, R 6 H, C 1-6 Alkyl or -C(O)CH2OH.

[0106] In some embodiments, R′ is H, R 7 -C(O)C 1-6Alkylene-OH, wherein one or two hydrogen atoms of the alkylene are optionally replaced by D, fluorine, C 1-6 Alkyl, fluorinated C 1-6 Alkyl or C 3-8 Substituted with a cycloalkyl group.

[0107] In some embodiments, R′ is H, R 7 It is -C(O)CH2OH.

[0108] In some embodiments, R' is C 1-6 Alkyl, R 7 C 1-6 Alkyl or -C(O)C 1-6 Alkylene-OH, wherein one or two hydrogen atoms of the alkylene are optionally replaced by D, fluorine, C 1-6 Alkyl, fluorinated C 1-6 Alkyl or C 3-8 Substituted with a cycloalkyl group.

[0109] In some embodiments, R' is C 1-6 Alkyl, R 7 C 1-6 Alkyl or -C(O)CH2OH.

[0110] In some embodiments, n is 0.

[0111] In some embodiments, n is 1.

[0112] In some embodiments, m is 1 or 2.

[0113] In some embodiments, the compound of the present invention is represented by formula (II):

[0114] in:

[0115] R 1 is H, halogen or -OH;

[0116] R 2 H, halogen, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl or -OR', wherein one or more hydrogen atoms of the alkyl group are optionally replaced by D or halogen;

[0117] R 3 -C 1-6 Alkylene-(OC 2-6 alkylene) m -R 4 、-(OC 2-6 alkylene) m -R 4 、-C 1-6 Alkylene-NR′R6 or -NR′R 7 ;

[0118] R 4 -OR′ or -NR′R 5 ;

[0119] R 5 、R 6 and R 7 Each is independently H, C 1-6 Alkyl or -C(O)C 1-6 Alkylene-OR', wherein one or two hydrogen atoms of the alkylene are optionally replaced by D, fluorine, C 1-6 Alkyl, fluorinated C 1-6 Alkyl or C 3-8 substituted by cycloalkyl, but 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 When alkyl, R 7 It cannot be H;

[0120] R' is H or C 1-6 alkyl; and

[0121] m is an integer from 1 to 6.

[0122] In some embodiments, R 2 H, halogen, C 1-6 Alkyl, fluorinated C 1-6 Alkyl or C 3- 8-cycloalkyl.

[0123] In some embodiments, R 3 -C 1-6 Alkylene-(OCH2CH2) m -R 4 、-(OCH2CH2) m -R 4 、-C 1-6 Alkylene-NR′R 6 or -NR′R 7 .

[0124] In some embodiments, R 4 -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 hydrogen atoms of the alkylene are optionally replaced by D, fluorine, C 1-6 Alkyl, fluorinated C 1-6Alkyl or C 3-8 Substituted with a cycloalkyl group.

[0125] In some embodiments, R 4 -OH, -NH2, -NH-C 1-6 Alkyl, -NHC(O)CH2OH or -N(CH3)C(O)CH2OH.

[0126] In some embodiments, R′ is H, R 6 C 1-6 Alkyl or -C(O)C 1-6 Alkylene-OH, wherein one or two hydrogen atoms of the alkylene are optionally replaced by D, fluorine, C 1-6 Alkyl, fluorinated C 1-6 Alkyl or C 3-8 Substituted with a cycloalkyl group.

[0127] In some embodiments, R′ is H, R 6 C 1-6 Alkyl or -C(O)CH2OH.

[0128] In some embodiments, R' is C 1-6 Alkyl, R 6 H, C 1-6 Alkyl or -C(O)C 1-6 Alkylene-OH, wherein one or two hydrogen atoms of the alkylene are optionally replaced by D, fluorine, C 1-6 Alkyl, fluorinated C 1-6 Alkyl or C 3-8 Substituted with a cycloalkyl group.

[0129] In some embodiments, R' is C 1-6 Alkyl, R 6 H, C 1-6 Alkyl or -C(O)CH2OH.

[0130] In some embodiments, R′ is H, R 7 -C(O)C 1-6 Alkylene-OH, wherein one or two hydrogen atoms of the alkylene are optionally replaced by D, fluorine, C 1-6 Alkyl, fluorinated C 1-6 Alkyl or C 3-8 Substituted with a cycloalkyl group.

[0131] In some embodiments, R′ is H, R 7 It is -C(O)CH2OH.

[0132] In some embodiments, R' is C 1-6 Alkyl, R 7 C 1-6Alkyl or -C(O)C 1-6 Alkylene-OH, wherein one or two hydrogen atoms of the alkylene are optionally replaced by D, fluorine, C 1-6 Alkyl, fluorinated C 1-6 Alkyl or C 3-8 Substituted with a cycloalkyl group.

[0133] In some embodiments, R' is C 1-6 Alkyl, R 7 C 1-6 Alkyl or -C(O)CH2OH.

[0134] In some embodiments, m is 1 or 2.

[0135] The present invention also relates to the following compounds, or pharmaceutically acceptable salts, stable isotope derivatives, isomers, prodrugs and mixtures thereof:

[0136] The compounds of the present invention can effectively induce the degradation of GSPT1, and its DC 50 The compound of the present invention can also effectively inhibit the proliferation of SK-BR-3 and NB-4 cells, and its IC 50 Preferably, it is less than 100 nM.

[0137] The present invention also relates to pharmaceutical compositions comprising a compound represented by general formula (I') or (I), or a pharmaceutically acceptable salt, stable isotope derivative, isomer, or prodrug thereof, and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical compositions can induce the degradation of GSPT1, affecting its biological functions, thereby treating or preventing GSPT1-mediated diseases, including but not limited to hematologic malignancies, solid tumors, autoimmune diseases, inflammatory diseases, neurodegenerative diseases, and skin diseases.

[0138] The present invention also provides a method for treating or preventing GSPT1-mediated diseases, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by general formula (I′) or (I) or a pharmaceutically acceptable salt, stable isotope derivative, isomer, prodrug, and pharmaceutical composition thereof, wherein the diseases include but are not limited to hematologic malignancies, solid tumors, autoimmune diseases, inflammation, neurodegenerative diseases, skin diseases, and the like.

[0139] The present invention also provides a use of the compound of the present invention or its pharmaceutically acceptable salt, stable isotope derivative, isomer, prodrug and pharmaceutical composition thereof in the preparation of a GSPT1 degrader.

[0140] The present invention also provides a use of the compound of the present invention or its pharmaceutically acceptable salt, stable isotope derivative, isomer, prodrug and pharmaceutical composition thereof in the preparation of a drug for treating or preventing GSPT1-mediated diseases.

[0141] According to the present invention, the drug can be in any pharmaceutical dosage form, including but not limited to tablets, capsules, solutions, lyophilized preparations, and injections.

[0142] The pharmaceutical preparations of the present invention can be administered in dosage units containing a predetermined amount of the active ingredient. Depending on the condition being treated, the method of administration, and the age, weight, and condition of the patient, such units may contain from 0.1 mg to 500 mg of the compound of the present invention. In addition, the pharmaceutical preparations can be prepared using methods well known in the pharmaceutical art, for example, by formulating the active ingredient with one or more excipients or one or more adjuvants.

[0143] The pharmaceutical formulations of the invention may be adapted for administration by any desired suitable method, for example, by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal) or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) administration.

[0144] The present invention also provides methods for preparing the compounds. The compounds can also be synthesized using synthetic techniques known to those skilled in the art. The products obtained in each reaction step are obtained using separation techniques known in the art. The starting materials and chemical reagents required for the synthesis can be conventionally synthesized or purchased according to the literature (available for query on SciFinder).

[0145] 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.

[0146] The amide compound I of the general formula (I′) of the present invention can also be synthesized according to the following route: an amine compound I-3 with a protecting group (PG) and a phenylacetic acid compound I-2 undergo amide condensation in the presence of a condensation reagent to produce I-4; I-4 is then deprotected to produce compound I.

[0147] The amide compound II of the general formula (I') of the present invention can also be prepared from compound I (wherein R 3 " is a group containing NH) and 2-hydroxyacetic acid in the presence of a condensation reagent to undergo amide condensation to synthesize.

[0148] Intermediate I-1 can be synthesized according to the following route: phenylacetic acid compound J-1 undergoes a reduction reaction to produce J-2; J-2 undergoes m times of substitution reaction with tert-butyl 2-bromoacetate and reduction reaction of tert-butyl ester to produce J-4; J-4 undergoes a reduction reaction under suitable reducing conditions (e.g., catalytic hydrogenation, iron powder and ammonium chloride solution, zinc powder and acetic acid) to produce intermediate I-1.

[0149] Intermediate I-3 can be synthesized according to the route shown below: K-1 is synthesized according to the route for synthesizing J-4, K-1 undergoes a substitution reaction with tert-butyl 2-bromoacetate under alkaline conditions to produce K-2; K-2 undergoes deprotection under acidic conditions to produce K-3; K-3 undergoes amide condensation with an amino reagent to produce K-4; K-4 undergoes a reduction reaction in the presence of a reducing agent (e.g., borane) to produce K-5; K-5 undergoes a protection reaction to produce K-6; ​​when the X group is NO2, K-6 undergoes a reduction reaction to produce intermediate I-3; when the X group is a halogen or a halogen analogue, K-6 undergoes a coupling reaction to introduce a cyano group to produce K-7; K-7 undergoes a reduction reaction to produce intermediate I-3.

[0150] Intermediate I-3 can also be synthesized according to the following route: phenol compound L-1 undergoes a 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 a reduction reaction to generate intermediate I-3.

[0151] 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.

[0152] 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

[0153] 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 Biopharmaceutical.

[0154] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR measurements were performed using a Bruker ASCEND-400 nuclear magnetic spectrometer, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDC13), or deuterated methanol (CD3OD) as solvents, tetramethylsilane (TMS) as the internal standard, and chemical shifts in 10 -6 The unit is ppm. MS was measured using an Agilent SQD (ESI) mass spectrometer (Agilent 6120).

[0155] 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).

[0156] Unless otherwise specified in the examples, the reaction temperature is room temperature (20°C-30°C).

[0157] Unless otherwise specified in the examples, all reactions were carried out under an argon or nitrogen atmosphere, which means that the reaction flask was connected to an argon or nitrogen balloon with a volume of approximately 1 L.

[0158] Hydrogen atmosphere means that the reaction bottle is evacuated and then filled with hydrogen (repeated 3 times), and then connected to a hydrogen balloon with a capacity of about 1L.

[0159] The reaction progress in the examples was monitored using an Agilent liquid chromatography-mass spectrometer (1260 / 6120). Alternatively, thin layer chromatography (TLC) was used. The thickness of the silica gel plate used was 0.15-0.2 mm (Qingdao Ocean GF254).

[0160] The compound was purified by column chromatography or thin layer chromatography, wherein the column chromatography used 200-300 mesh silica gel from Qingdao Ocean, and the thin layer chromatography used GF254 silica gel plate with a thickness of 0.4-0.5 mm from Qingdao Ocean.

[0161] Column chromatography or thin-layer chromatography developing solvent systems typically include a) dichloromethane and methanol, b) petroleum ether and ethyl acetate, or as shown in the Examples. The volume ratio of the solvents is adjusted according to the polarity of the compound and can be further adjusted by adding a small amount of triethylamine or other acidic or basic reagents.

[0162] The compounds were purified using a Waters mass spectrometry-guided automated preparation system (mass spectrometry detector: SQD2). Depending on the polarity of the compounds, the compounds were eluted with an appropriate acetonitrile / water (containing 0.1% trifluoroacetic acid or formic acid, or 0.05% ammonia) gradient at a flow rate of 20 mL / min on a reversed-phase high-pressure column (XBridge-C18, 19×150 mm, 5 μm).

[0163] The abbreviation DMA refers to N,N-dimethylacetamide.

[0164] The abbreviation DMSO refers to dimethyl sulfoxide.

[0165] The abbreviation DMF refers to N,N-dimethylformamide.

[0166] The abbreviation DCE refers to 1,2-dichloroethane.

[0167] The abbreviation NMP refers to N-methylpyrrolidone.

[0168] The abbreviation DIPEA refers to N,N-diisopropylethylamine.

[0169] The abbreviation DMAP refers to 4-dimethylaminopyridine.

[0170] The abbreviation TBSCl refers to tert-butyldimethylsilyl chloride.

[0171] The abbreviation HATU refers to O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0172] The abbreviation NMI refers to N-methylimidazole.

[0173] The abbreviation TCFH refers to N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate.

[0174] The abbreviation PyBOP refers to 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate.

[0175] The abbreviation LiHMDS refers to lithium bis(trimethylsilyl)amide.

[0176] The abbreviation LDA refers to lithium diisopropylamide.

[0177] The abbreviation NBS refers to N-bromosuccinimide.

[0178] The abbreviation AIBN refers to azobisisobutyronitrile.

[0179] The abbreviation Pd2(dba)3 refers to tris(dibenzylideneacetone)dipalladium.

[0180] The abbreviation Pd(dppf)Cl2 refers to [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.

[0181] The abbreviation Pd(dppf)Cl2·CH2Cl2 refers to [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex.

[0182] The abbreviation dppf refers to 1,1'-bis(diphenylphosphino)ferrocene.

[0183] The abbreviation X-Phos refers to 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0184] The abbreviation (Boc)2O refers to di-tert-butyl dicarbonate.

[0185] The abbreviation Pd(PPh3)2Cl2 refers to bis(triphenylphosphine)palladium chloride.

[0186] Example 1 - Synthesis of intermediates

[0187] Intermediate A: 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetic acid

[0188] first step

[0189] (2-(tert-Butoxy)-2-oxoethyl)zinc(II) bromide (A-2)

[0190] To a mixture of zinc powder (6.25 g, 96.2 mmol) and DMA (16.5 mL) was slowly added a mixture of trimethylsilyl chloride and 1,2-dibromoethane (2.1 mL, v / v = 7 / 5). The reaction mixture was stirred at room temperature for 15 minutes. A solution of tert-butyl 2-bromoacetate A-1 (15.0 g, 76.9 mmol) in DMA (24 mL) was slowly added, and the mixture was stirred at room temperature for 30 minutes to obtain a DMA solution of the target product A-2 (40.5 mL, 1.89 M). This product was used directly in the next reaction without further purification.

[0191] Step 2

[0192] 3-(5-Bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (A-4)

[0193] 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), and the reaction mixture was stirred at 80° C. overnight. The mixture was filtered and the solid was washed with acetonitrile to obtain the desired product A-4 (16.2 g, 78%).

[0194] MS m / z(ESI):323[M+1]

[0195] Step 3

[0196] Tert-butyl 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetate (A-5)

[0197] To a solution of A-4 (5.0 g, 15.5 mmol) in tetrahydrofuran (60 mL) was added a solution of LiHMDS in tetrahydrofuran (1.0 M, 17.1 mL, 17.1 mmol), and 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. The mixture 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 desired product A-5 (3.8 g, 68%).

[0198] MS m / z(ESI):359[M+1]

[0199] Step 4

[0200] 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetic acid (A)

[0201] The reaction mixture A-5 (3.8 g, 10.6 mmol) and a solution of hydrogen chloride in 1,4-dioxane (40 mL) were stirred at room temperature for 1 hour, concentrated under reduced pressure, and the residue was purified by slurrying with ethyl acetate to obtain the target product A (3.0 g, 94%).

[0202] MS m / z(ESI):303[M+1]

[0203] Intermediate B: 2-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)acetic acid

[0204] first step

[0205] 4-Bromo-3-fluoro-2-methylbenzoic acid (B-2)

[0206] To a solution of B-1 (20.0 g, 91.3 mmol) in tetrahydrofuran (300 mL) was added LDA (2.0 M, 95.9 mL, 192 mmol) at -70°C, and the reaction mixture was stirred at -70°C for 1 hour. Iodomethane (38.9 g, 274 mmol) was added, and the reaction mixture was stirred at room temperature for 12 hours. The mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to obtain the target product B-2 (23.8 g, crude product).

[0207] Step 2

[0208] Methyl 4-bromo-3-fluoro-2-methylbenzoate (B-3)

[0209] To a solution of B-2 (crude product, 23.8 g, 91.3 mmol) and cesium carbonate (66.9 g, 205 mmol) in DMF (250 mL) was added iodomethane (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 obtain the target product B-3 (16.8 g, 74% yield over two steps).

[0210] Step 3

[0211] Methyl 4-bromo-2-(bromomethyl)-3-fluorobenzoate (B-4)

[0212] 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). The reaction mixture was stirred at 80°C overnight. The mixture 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 obtain the desired product B-4 (10.0 g, 76%).

[0213] MS m / z(ESI):327[M+1]

[0214] Steps 4 to 6

[0215] 2-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)acetic acid (B)

[0216] Substitute B-4 for A-3 and synthesize B by following the procedures of steps 2 to 4 in intermediate A.

[0217] MS m / z(ESI):321[M+1]

[0218] Intermediate C: 2-(2-(2,6-dioxopiperidin-3-yl)-4-methoxy-1-oxoisoindolin-5-yl)acetic acid

[0219] first step

[0220] Methyl 4-bromo-3-methoxy-2-methylbenzoate (C-2)

[0221] To a solution of methyl 4-bromo-3-hydroxy-2-methylbenzoate C-1 (2.0 g, 8.2 mmol) and iodomethane (5.8 g, 40.8 mmol) in acetonitrile (20 mL) was added potassium carbonate (3.4 g, 24.5 mmol). The reaction mixture was stirred at 50°C for 12 hours. The mixture was quenched 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 = 9 / 1) to obtain the desired product C-2 (2.1 g, 99%).

[0222] MS m / z(ESI):259[M+1]

[0223] Steps 2 to 5

[0224] 2-(2-(2,6-dioxopiperidin-3-yl)-4-methoxy-1-oxoisoindolin-5-yl)acetic acid (C)

[0225] Substitute C-2 for B-3 and follow the procedure from the third to the sixth step in intermediate B to synthesize C.

[0226] MS m / z(ESI):333[M+1]

[0227] Example 2

[0228] 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-N-(2-fluoro-5-(2-hydroxyethoxy)phenyl)acetamide (Compound 1)

[0229] first step

[0230] 2-(4-Fluoro-3-nitrophenoxy)1-ethanol (1b)

[0231] 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), and the mixture was stirred at 70° C. overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 9 / 1) to give the desired product 1b (30 mg, 47%).

[0232] MS m / z(ESI):202[M+1]

[0233] Step 2

[0234] 2-(3-Amino-4-fluorophenoxy)1-ethanol (1c)

[0235] 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), and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the desired product 1c (240 mg, 94%).

[0236] MS m / z(ESI):172[M+1]

[0237] Step 3

[0238] 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-N-(2-fluoro-5-(2-hydroxyethoxy)phenyl)acetamide (1)

[0239] 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), and the mixture was stirred at room temperature for 2 hours. Purification by reverse phase preparative HPLC afforded the desired product 1 (3 mg, 4%).

[0240] MS m / z(ESI):456[M+1]

[0241] 1 H NMR(400MHz, DMSO-d6)δ10.98(s,1H),10.00(s,1H),7.69(d,J=7.8Hz,1H),7.63–7.55(m,2H), 7.47(d,J=7.8Hz,1H),7.15(dd,J=10.6,9.1Hz,1H),6.68(dt,J=8.9,3.4Hz,1H),5.11(dd,J=13 .3,5.1Hz,1H),4.83(s,1H),4.46(d,J=17.4Hz,1H),4.32(d,J=17.3Hz,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).

[0242] Example 3

[0243] 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-N-(4-(2-(2-(methylamino)ethoxy)ethyl)phenyl)acetamide (Compound 2)

[0244] first step

[0245] tert-Butyl 2-(4-nitrophenylethoxy)acetate (2b)

[0246] To a solution of 2-(4-nitrophenyl)-1-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) was added aqueous sodium hydroxide solution (5 M, 20 mL) at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. The product was extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain the desired product 2b (3.2 g, 94%).

[0247] MS m / z(ESI):281[M+1]

[0248] Step 2

[0249] 2-(4-Nitrophenylethoxy)acetic acid (2c)

[0250] 2b (3.2 g, 11.4 mmol) and trifluoroacetic acid (8 mL) were dissolved in dichloromethane (32 mL) and stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure to give the target product 2c (2.4 g, crude product). This product was used directly in the next reaction without further purification.

[0251] MS m / z(ESI):224[M-1]

[0252] Step 3

[0253] N-Methyl-2-(4-nitrophenylethoxy)acetamide (2d)

[0254] To a solution of 2c (2.0 g, 8.9 mmol) and methylamine hydrochloride (1.2 g, 17.8 mmol) in DMF (25 mL) were added HATU (5.1 g, 13.3 mmol) and DIPEA (5.1 g, 39.8 mmol), and the mixture was stirred at room temperature for 2 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 = 3 / 1) to obtain the desired product 2d (1.8 g, 86%).

[0255] MS m / z(ESI):239[M+1]

[0256] Step 4

[0257] N-Methyl-2-(4-nitrophenylethoxy)ethan-1-amine (2e)

[0258] 2d (1.8 g, 7.6 mmol) and a tetrahydrofuran solution of borane (1.0 M, 7.6 mL, 7.6 mmol) were dissolved in tetrahydrofuran (20 mL), and the mixture was stirred at 70°C for 2 hours. After cooling to room temperature, the reaction was quenched by adding methanol, adjusted to pH 6 with dilute hydrochloric acid (1N), and washed with ethyl acetate. Saturated aqueous sodium bicarbonate was added to the aqueous phase to adjust to pH 8, and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to obtain the desired product 2e (600 mg, crude product). This product was used directly in the next reaction without further purification.

[0259] MS m / z(ESI):225[M+1]

[0260] Step 5

[0261] tert-Butyl (2-(4-nitrophenylethoxy)ethyl)carbamate (2f)

[0262] To a solution of 2e (600 mg, 2.7 mmol) and triethylamine (541 mg, 5.4 mmol) in tetrahydrofuran (10 mL) was added (Boc)O (876 mg, 4.0 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to obtain the desired product 2f (600 mg, 69%).

[0263] MS m / z(ESI):269[M+1-56]

[0264] Step 6

[0265] tert-Butyl (2-(4-aminophenethoxy)ethyl)(methyl)carbamate (2g)

[0266] 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 under a hydrogen atmosphere for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the desired product 2 g (420 mg, 77%). This product was used directly in the next reaction without further purification.

[0267] MS m / z(ESI):295.1[M+1]

[0268] Step 7

[0269] Tert-butyl (2-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamido)phenethoxy)ethyl)(methyl)carbamate (2h)

[0270] 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 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 (dichloromethane / methanol = 15 / 1) to obtain the desired product 2h (25 mg, 26%).

[0271] MS m / z(ESI):579[M+1]

[0272] Step 8

[0273] 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-N-(4-(2-(2-(methylamino)ethoxy)ethyl)phenyl)acetamide (2)

[0274] 2h (25 mg, 0.043 mmol) and trifluoroacetic acid (0.5 mL) were dissolved in dichloromethane (1 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by reverse phase preparative HPLC to obtain the desired product 2 (formate salt, 11 mg, 49%).

[0275] MS m / z(ESI):479[M+1]

[0276] 1H NMR (400MHz, DMSO-d6) δ10.97(brs,1H),10.16(s,1H),8.29-8.23(m,1H),7.69(d,J=7.8Hz,1H),7.55(s,1H) ,7.50(d,J=8.5Hz,2H),7.46(d,J=8.1Hz,1H),7.16(d,J=8.4Hz,2H),5.11(dd,J=13.3,5.1Hz,1H),4.45(d,J= 17.3Hz,1H),4.32(d,J=17.4Hz,1H),3.77(s,2H),3.58(t,J=7.0Hz,2H),3.52(t,J=5.3Hz,2H),2.95–2.87(m ,1H),2.85–2.80(m,2H),2.76(t,J=7.0Hz,2H),2.60(d,J=17.6Hz,1H),2.42–2.31(m,4H),2.03–1.96(m,1H).

[0277] Example 4

[0278] N-(4-chloro-2-fluoro-5-(2-hydroxyethoxy)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 3)

[0279] first step

[0280] 2-(2-Chloro-4-fluoro-5-nitrophenoxy)1-ethanol (3b)

[0281] 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), and the mixture was stirred at 80°C for 4 hours. The mixture 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 obtain the desired product 3b (443 mg, 36%).

[0282] Step 2

[0283] 2-(5-Amino-2-chloro-4-fluorophenoxy)-1-ethanol (3c)

[0284] To a solution of 3b (443 mg, 1.88 mmol) in tetrahydrofuran (8 mL) were added iron powder (1.1 g, 18.8 mmol) and saturated aqueous ammonium chloride (8 mL). The mixture was stirred at 60°C overnight. The mixture was filtered, and the filtrate was diluted with ethyl acetate and washed with water. The organic phase was concentrated under reduced pressure to afford the desired product 3c (283 mg, 73%). This product was used directly in the next reaction without further purification.

[0285] MS m / z(ESI):206[M+1]

[0286] Step 3

[0287] N-(4-chloro-2-fluoro-5-(2-hydroxyethoxy)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (3)

[0288] 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), and the mixture was stirred at room temperature overnight. The mixture was filtered, and the filtrate was purified by reverse-phase preparative HPLC to afford the desired product 3 (13.6 mg, 12%).

[0289] MS m / z(ESI):490[M+1]

[0290] 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),10.12(s,1H),7.81(d,J=7.1Hz,1H),7.69(d,J= 7.8Hz,1H),7.56(s,1H),7.51–7.46(m,2H),5.11(dd,J=13.3,5.1Hz,1H),4.46(d,J=17 .3Hz,1H),4.32(d,J=17.3Hz,1H),3.97(t,J=5.1Hz,2H),3.90(s,2H),3.70(t,J=5.1Hz ,2H),2.98–2.87(m,1H),2.60(d,J=17.3Hz,1H),2.45–2.34(m,1H),2.05–1.96(m,1H).

[0291] Example 5

[0292] N-(3-chloro-4-(2-(2-(methylamino)ethoxy)ethyl)benzyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 4)

[0293] first step

[0294] 2-(4-Bromo-2-chlorophenyl)-1-ethanol (4b)

[0295] The reaction mixture 4a (6 g, 24.0 mmol), a 1.0 M solution of borane in tetrahydrofuran (48 mL), and tetrahydrofuran (60 mL) were stirred at 70°C for 4 hours. Methanol was added to quench the mixture, 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 desired product 4b (5 g, 89%).

[0296] Steps 2 to 6

[0297] Tert-butyl (2-(4-bromo-2-chlorophenethoxy)ethyl)(methyl)carbamate (4g)

[0298] 4g was synthesized by replacing 2a with 4b and referring to the first to fifth steps of compound 2.

[0299] MS m / z(ESI):292[M+1-100]

[0300] Step 7

[0301] tert-Butyl (2-(2-chloro-4-cyanophenethoxy)ethyl)(methyl)carbamate (4h)

[0302] To a solution of 4 g (300 mg, 0.77 mmol) and zinc cyanide (180 mg, 1.54 mmol) in DMA (4.5 mL) were added Pd(dba) (35 mg, 0.038 mmol) and dppf (21 mg, 0.038 mmol), and the mixture was stirred at 120°C for 4 hours. The mixture was cooled to room temperature, water was added, and extraction was performed 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 obtain the desired product 4h (170 mg, 66%).

[0303] MS m / z(ESI):361[M+23]

[0304] Step 8

[0305] tert-Butyl (2-(4-(aminomethyl)-2-chlorophenethoxy)ethyl)(methyl)carbamate (4i)

[0306] To a solution of 4h (120 mg, 0.36 mmol) in methanol (10 mL) was added nickel (50 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour, filtered, and the filtrate was concentrated under reduced pressure to give the target product 4i (100 mg, 82%).

[0307] MS m / z(ESI):365[M+23]

[0308] Step 9

[0309] Tert-butyl (2-(2-chloro-4-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamido)methyl)phenethoxy)ethyl)(methyl)carbamate (4j)

[0310] 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 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 (dichloromethane / methanol = 12 / 1) to yield the desired product 4j (50 mg, 48%).

[0311] MS m / z(ESI):649[M+23]

[0312] Step 10

[0313] N-(3-chloro-4-(2-(2-(methylamino)ethoxy)ethyl)benzyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (4)

[0314] 4 was synthesized by replacing 2h with 4j according to the procedure of step 8 in compound 2.

[0315] MS m / z(ESI):527[M+1]

[0316] 1H NMR (400MHz, DMSO-d6) δ8.63(t,J=5.9Hz,1H),8.31(s,1H),7.67(d,J=7.8Hz,1H),7.51(s,1H),7.42(d,J=7. 8Hz,1H),7.31(d,J=7.8Hz,1H),7.22(s,1H),7.12(d,J=6.5Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.44(d,J=1 7.3Hz,1H),4.31(d,J=17.2Hz,1H),4.24(d,J=5.9Hz,2H),3.62(s,2H),3.58(t,J=7.0Hz,2H),3.52(t,J=5.4H z,2H),2.98–2.84(m,3H),2.76(t,J=5.3Hz,2H),2.62(d,J=2.4Hz,1H),2.44–2.30(m,4H),2.05–1.95(m,1H).

[0317] Example 6

[0318] N-(3-chloro-4-(2-(2-(methylamino)ethoxy)ethyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 5)

[0319] Steps 1 to 6

[0320] tert-Butyl (2-(2-chloro-4-nitrophenethoxy)ethyl)(methyl)carbamate (5g)

[0321] 5a was used to replace 4a, and 5g was synthesized by referring to the first to sixth steps of compound 4.

[0322] MS m / z(ESI):381[M+23]

[0323] Step 7

[0324] Tert-butyl (2-(4-amino-2-chlorophenethoxy)ethyl)(methyl)carbamate (5h)

[0325] To a mixture of 5g (0.35g, 0.97mmol), ammonium chloride (0.52g, 9.75mmol), ethanol (10mL) and water (2mL) was added iron powder (0.27g, 4.9mmol), and the mixture was stirred at 80°C for 2 hours. Cooled to room temperature, filtered, and the filter cake was washed with ethanol. The filtrate was concentrated under reduced pressure, water was added, and 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 (305mg, crude product). This product was used directly in the next reaction without further purification.

[0326] MS m / z(ESI):351[M+23]

[0327] Steps 8 to 9

[0328] N-(3-Chloro-4-(2-(2-(methylamino)ethoxy)ethyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (5)

[0329] 5h was used instead of 2g, and 5 was synthesized by referring to the procedures of steps 7 to 8 in compound 2.

[0330] MS m / z(ESI):513[M+1]

[0331] 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),8.26(s,1H),7.79(d,J=2.0Hz,1H),7.69(d,J=7.8Hz,1H),7. 55(s,1H),7.46(d,J=7.9Hz,1H),7.40(dd,J=8.4,2.0Hz,1H),7.31(d,J=8.4Hz,1H),5.11(dd,J=13 .3,5.1Hz,1H),4.45(d,J=17.3Hz,1H),4.32(d,J=17.3Hz,1H),3.79(s,2H),3.59(t,J=7.0Hz,2H), 3.54(t,J=5.3Hz,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).

[0332] Example 7

[0333] N-(4-cyclopropyl-3-(2-hydroxyethoxy)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 6)

[0334] first step

[0335] 2-(2-Bromo-5-nitrophenoxy)1-ethanol (6b)

[0336] 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) was added cesium carbonate (4.5 g, 13.8 mmol), and the mixture was stirred at 95°C overnight. The mixture was cooled to room temperature, 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 desired product 6b (790 mg, 66%).

[0337] MS m / z(ESI):262[M+1]

[0338] Step 2

[0339] 2-(2-Cyclopropyl-5-nitrophenoxy)1-ethanol (6c)

[0340] To a mixture of 6b (790 mg, 3.0 mmol), cyclopropylboronic acid (519 mg, 6.0 mmol), toluene (12 mL), and water (3 mL) were added palladium acetate (68 mg, 0.30 mmol), potassium phosphate (1.28 g, 6.0 mmol), and tricyclohexylphosphine (84 mg, 0.30 mmol), and the mixture was stirred at 90°C for 3 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the desired product 6c (650 mg, 97%).

[0341] MS m / z(ESI):224[M+1]

[0342] Step 3

[0343] 2-(5-Amino-2-cyclopropylphenoxy)1-ethanol (6d)

[0344] 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. The solution was basified with sodium bicarbonate solution to pH 7 and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to yield the desired product 6d (450 mg, 80%). This product was used directly in the next reaction without further purification.

[0345] MS m / z(ESI):194[M+1]

[0346] Step 4

[0347] N-(4-cyclopropyl-3-(2-hydroxyethoxy)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (6)

[0348] 6 was synthesized by replacing 2g with 6d according to the seventh step of compound 2.

[0349] MS m / z(ESI):478[M+1]

[0350] 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),10.12(s,1H),7.68(d,J=7.8Hz,1H),7.55(s,1H),7.46(d,J=7.6Hz,1H),7 .30(d,J=1.8Hz,1H),7.07–6.99(m,1H),6.70(d,J=8.3Hz,1H),5.11(dd,J=13.1,5.0Hz,1H),4.88–4.75(m,1H),4 .46(d,J=17.3Hz,1H),4.32(d,J=17.3Hz,1H),3.93(t,J=5.1Hz,2H),3.78–3.71(m,4H),2.98–2.87(m,1H),2.60( d,J=16.6Hz,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).

[0351] Example 8

[0352] N-(4-cyclopropyl-3-((2-hydroxyacetylamino)methyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 7)

[0353] first step

[0354] 2-(2-Bromo-5-nitrobenzyl)isoindoline-1,3-dione (7b)

[0355] 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) at 0°C, and 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 desired product 7b (2.2, 82%).

[0356] MS m / z(ESI):383[M+23]

[0357] Step 2

[0358] (2-Bromo-5-nitrophenyl)methanamine (7c)

[0359] The reaction mixture 7b (1.0 g, 2.76 mmol), hydrazine monohydrate (1.7 g, 13.8 mmol) and acetonitrile (50 mL) were stirred at 80°C overnight and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to give the target product 7c (360 mg, 56%).

[0360] MS m / z(ESI):231[M+1]

[0361] Step 3

[0362] Tert-butyl (2-bromo-5-nitrobenzyl)carbamate (7d)

[0363] The reaction mixture 7c (360 mg, 1.56 mmol), (Boc)2O (1.0 g, 4.67 mmol), triethylamine (472 mg, 4.67 mmol), and dichloromethane (10 mL) were stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5) to obtain the desired product 7d (320 mg, 62%).

[0364] MS m / z(ESI):276[M+1-56]

[0365] Step 4

[0366] tert-Butyl (2-cyclopropyl-5-nitrobenzyl)carbamate (7e)

[0367] 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 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 = 85 / 15) to obtain the desired product 7e (240 mg, 85%).

[0368] MS m / z(ESI):237[M+1-56]

[0369] Step 5

[0370] tert-Butyl (5-amino-2-cyclopropylbenzyl)carbamate (7f)

[0371] 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 hour. Aqueous sodium carbonate solution was added to the solution until the pH reached 8, and the solution was extracted with dichloromethane. The combined organic phases were concentrated under reduced pressure to afford the desired product 7f (85 mg, crude). This product was used directly in the next reaction without further purification.

[0372] MS m / z(ESI):163[M+1-100]

[0373] Steps 6 to 7

[0374] N-(3-(Aminomethyl)-4-cyclopropylphenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (7h)

[0375] 7f was used instead of 2g, and 7h was synthesized by referring to the procedures of steps 7 to 8 in compound 2.

[0376] MS m / z(ESI):447[M+1]

[0377] Step 8

[0378] N-(4-cyclopropyl-3-((2-hydroxyacetylamino)methyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (7)

[0379] 7 was synthesized by replacing 2g with 7h and intermediate A with 2-hydroxyacetic acid, following the procedure of step 7 in compound 2.

[0380] MS m / z(ESI):505[M+1]

[0381] 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),10.14(s,1H),8.05(t,J=6.0Hz,1H),7.68(d,J=7.8Hz,1H),7.54(s, 1H),7.49(dd,J=8.4,2.1Hz,1H),7.45(d,J=7.9Hz,1H),7.32(d,J=2.1Hz,1H),6.91(d,J=8.4Hz,1H),5.10 (dd,J=13.3,5.1Hz,1H),4.47–4.43(m,2H),4.31(d,J=17.3Hz,1H),3.88(s,2H),3.75(s,4H),2.95–2.85( m,1H),2.60(d,J=16.5Hz,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).

[0382] Example 9

[0383] N-(4-cyclopropyl-3-(2-hydroxyacetylamino)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 8)

[0384] first step

[0385] Tert-butyl (2-bromo-5-nitrophenyl)carbamate (8b)

[0386] 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 hour. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 90 / 10) to obtain the desired product 8b (1.6 g, 83%).

[0387] MS m / z(ESI):339[M+23]

[0388] Steps 2 to 6

[0389] N-(4-cyclopropyl-3-(2-hydroxyacetylamino)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (8)

[0390] 8 was synthesized by replacing 7d with 8b and referring to the fourth to eighth steps of compound 7.

[0391] MS m / z(ESI):491[M+1]

[0392] 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),10.23(s,1H),9.37(s,1H),8.21(d,J=1.9Hz,1H),7.68(d,J=7.8Hz, 1H),7.55(s,1H),7.46(d,J=8.3Hz,2H),7.04(d,J=8.4Hz,1H),6.09(brs,1H),5.10(dd,J=13.2,5.1Hz,1H) ,4.46(d,J=17.4Hz,1H),4.32(d,J=17.4Hz,1H),4.02(s,2H),3.76(s,2H),2.95–2.85(m,1H),2.59(d,J=1 7.8Hz,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).

[0393] Example 10

[0394] 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-N-(4-(2-(2-hydroxyacetylamino)ethyl)phenyl)acetamide (Compound 9)

[0395] first step

[0396] Tert-butyl (4-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamido)phenethyl)carbamate (9b)

[0397] 9b was synthesized by using tert-butyl (4-aminophenethyl)carbamate 9a instead of 2g and referring to the seventh step of Compound 2.

[0398] MS m / z(ESI):543[M+23]

[0399] Step 2

[0400] N-(4-(2-aminoethyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (9c)

[0401] The reaction mixture 9b (70 g, 0.13 mmol) and a solution of hydrogen chloride in 1,4-dioxane (4.0 M, 5 mL) were stirred at room temperature for 2 hours and concentrated under reduced pressure to obtain the target product 9c (60 mg, 98%).

[0402] MS m / z(ESI):421[M+1]

[0403] Step 3

[0404] 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-N-(4-(2-(2-hydroxyacetylamino)ethyl)phenyl)acetamide (9)

[0405] 9 was synthesized by replacing 2g with 9c and intermediate A with 2-hydroxyacetic acid, following the procedure of step 7 in compound 2.

[0406] MS m / z(ESI):479[M+1]

[0407] 1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H),10.15(s,1H),7.71-7.68(m,2H),7.55(s,1H),7.50(d, J=8.5Hz,2H),7.47(d,J=8.0Hz,1H),7.13(d,J=8.5Hz,2H),5.10(dd,J=13.3,5.1Hz,1H),4.4 6(d,J=17.4Hz,1H),4.32(d,J=17.3Hz,1H),3.77–3.73(m,4H),3.31–3.26(m,2H),2.96–2.85 (m,1H),2.68(t,J=7.4Hz,2H),2.60(d,J=16.8Hz,1H),2.44–2.33(m,1H),2.04–1.96(m,1H).

[0408] Example 11

[0409] N-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamido)phenethyl)-2-hydroxy-N-methylacetamide (Compound 10)

[0410] first step

[0411] Tert-butyl (4-nitrophenylethyl)carbamate (10b)

[0412] 10b was synthesized by using 2-(4-nitrophenyl)ethan-1-amine 10a instead of 2e and referring to the procedure of step 5 in compound 2.

[0413] MS m / z(ESI):289[M+23]

[0414] Step 2

[0415] Tert-butyl (4-nitrophenylethyl)carbamate (10c)

[0416] To a solution of 10b (600 mg, 2.25 mmol) and iodomethane (639 mg, 4.5 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (60%, 270 mg, 6.75 mmol), and the mixture was stirred at room temperature for 3 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to afford the desired product 10c (400 mg, 63%). This product was used directly in the next reaction without further purification.

[0417] MS m / z(ESI):303[M+23]

[0418] Steps 3 to 4

[0419] Tert-butyl (4-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamido)phenethyl)(methyl)carbamate (10e)

[0420] 10e was synthesized by replacing 1b with 10c and referring to the second to third steps of compound 1.

[0421] MS m / z(ESI):557[M+23]

[0422] Steps 5 to 6

[0423] N-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamido)phenethyl)-2-hydroxy-N-methylacetamide (10)

[0424] 10 was synthesized by replacing 9b with 10e and referring to the second to third steps of compound 9.

[0425] MS m / z(ESI):493[M+1]

[0426] 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),10.17-10.16(m,1H),7.68(d,J=7.8Hz,1H),7.55(s,1H),7.51(dd,J=8.4,2 .8Hz,2H),7.47(d,J=7.5Hz,1H),7.17–7.12(m,2H),5.10(dd,J=13.3,5.1Hz,1H),4.46(d,J=17.4Hz,1H),4.36–4 .29(m,2H),4.01(d,J=5.4Hz,1H),3.82(d,J=5.3Hz,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=17.6Hz,1H),2.42–2.33(m,1H),2.04–1.97(m,1H).

[0427] Example 12

[0428] 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-N-(4-(2-hydroxyacetylamino)phenyl)acetamide (Compound 11)

[0429] first step

[0430] Tert-butyl (4-(2-hydroxyacetylamino)phenyl)carbamate (11b)

[0431] 11b was synthesized by using tert-butyl (4-aminophenyl)carbamate 11a instead of 2g and 2-hydroxyacetic acid instead of intermediate A, referring to the seventh step of compound 2.

[0432] MS m / z(ESI):289[M+23]

[0433] Step 2 to Step 3

[0434] 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-N-(4-(2-hydroxyacetylamino)phenyl)acetamide (11)

[0435] 11 was synthesized by replacing 9b with 11b and 2-hydroxyacetic acid with intermediate A, following the procedures of the second to third steps in compound 9.

[0436] MS m / z(ESI):451[M+1]

[0437] 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),10.16(s,1H),9.56(s,1H),7.69(d,J=7.8Hz,1H),7.61(d, J=8.9Hz,2H),7.56(s,1H),7.51(d,J=9.0Hz,2H),7.47(d,J=7.7Hz,1H),5.61(t,J=5.9Hz,1H),5 .11(dd,J=13.3,5.1Hz,1H),4.46(d,J=17.3Hz,1H),4.32(d,J=17.4Hz,1H),3.96(d,J=5.9Hz,2H ),3.76(s,2H),2.95–2.86(m,1H),2.60(d,J=17.9Hz,1H),2.43–2.32(m,1H),2.03–1.96(m,1H).

[0438] Compound 12 was processed according to the experimental procedure of compound 11, except that tert-butyl (4-(aminomethyl)phenyl)carbamate was used instead of 11a in the first step.

[0439] The NMR data of compound 12 are as follows:

[0440] Example 13

[0441] N-(4-chloro-2-((2-hydroxyacetylamino)methyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 13)

[0442] first step

[0443] (5-Chloro-2-nitrophenyl)methanamine (13b)

[0444] 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) was added 5-chloro-2-nitrobenzonitrile 13a (1.0 g, 5.4 mmol) at 0°C, and the mixture was stirred overnight at room temperature. Sodium hydroxide solution (2 M) was added to a pH of 10, and the solution was extracted with dichloromethane. The organic phase was concentrated under reduced pressure to afford the desired product 13b (crude product). This product was used directly in the next reaction without further purification.

[0445] MS m / z(ESI):170[M+1-17]

[0446] Steps 2 to 5

[0447] N-(2-(Aminomethyl)-4-chlorophenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (13f)

[0448] 13f was synthesized by replacing 5f with 13b according to the procedures of steps 6 to 9 in compound 5.

[0449] MS m / z(ESI):441[M+1]

[0450] Step 6

[0451] N-(4-chloro-2-((2-hydroxyacetylamino)methyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (13)

[0452] 13 was synthesized by replacing 2g with 13f and intermediate A with 2-hydroxyacetic acid, following the procedure of step 7 in compound 2.

[0453] MS m / z(ESI):499[M+1]

[0454] 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),10.21(s,1H),8.56(t,J=6.5Hz,1H),7.69(d,J=7.9Hz,1H),7.66(d,J=8 .6Hz,1H),7.59(s,1H),7.50(d,J=7.2Hz,1H),7.33(d,J=2.5Hz,1H),7.29(dd,J=8.6,2.5Hz,1H),5.65(t,J=5. 9Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.46(d,J=17.3Hz,1H),4.32(d,J=17.4Hz,1H),4.27(d,J=6.4Hz,2H),3 .91(d,J=5.9Hz,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).

[0455] Example 14

[0456] N-(4-cyclopropyl-3-((methylamino)methyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 14)

[0457] first step

[0458] 1-(2-Bromo-5-nitrophenyl)-N-methylmethanamine (14b)

[0459] A mixture of 2-bromo-5-nitrobenzaldehyde 14a (500 mg, 2.17 mmol), methylamine in ethanol (33%, 612 mg, 6.52 mmol), and ethanol (10 mL) was stirred at room temperature for 1 hour. Sodium borohydride (248 mg, 6.52 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 1 hour. Water was added, and the mixture was extracted with dichloromethane. The organic phase was concentrated under reduced pressure to yield the desired product 14b (crude product). This product was used directly in the next reaction without further purification.

[0460] MS m / z(ESI):245[M+1]

[0461] Steps 2 to 6

[0462] N-(4-cyclopropyl-3-((methylamino)methyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (14)

[0463] 14 was synthesized by replacing 7c with 14b and referring to the procedures of steps 3 to 7 in compound 7.

[0464] MS m / z(ESI):461[M+1]

[0465] 1 H NMR (400MHz, DMSO-d6) δ10.98(brs,1H),10.16(s,1H),8.22(s,1H),7.69(d,J=7.8Hz,1H),7.58(s,1H ),7.55(s,1H),7.46(d,J=7.8Hz,1H),7.42(dd,J=8.4,2.0Hz,1H),6.91(d,J=8.4Hz,1H),5.10(dd,J=1 3.3,5.1Hz,1H),4.45(d,J=17.3Hz,1H),4.32(d,J=17.4Hz,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).

[0466] Example 15

[0467] N-(3-(2-aminoethoxy)-4-chlorophenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 15)

[0468] first step

[0469] Tert-butyl (2-(2-chloro-5-nitrophenoxy)ethyl)carbamate (15b)

[0470] The reaction mixture of 2-chloro-5-nitrophenol 15a (1.0 g, 5.8 mmol), tert-butyl (2-bromoethyl)carbamate (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 hour. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to afford the desired product 15b (1.2 g, 65%). This product was used directly in the next reaction without further purification.

[0471] MS m / z(ESI):261[M+1-56]

[0472] Steps 2 to 4

[0473] N-(3-(2-aminoethoxy)-4-chlorophenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (15)

[0474] 15 was synthesized by replacing 7e with 15b according to the procedures of steps 5 to 7 in compound 7.

[0475] MS m / z(ESI):471[M+1]

[0476] 1 H NMR(400MHz, DMSO-d6)δ10.43(s,1H),7.70(d,J=7.8Hz,1H),7.62–7.53(m,2H),7.47(d, J=7.8Hz,1H),7.35(d,J=8.6Hz,1H),7.15(d,J=8.5Hz,1H),5.11(dd,J=13.2,5.1Hz,1H) ,4.46(d,J=17.3Hz,1H),4.32(d,J=17.3Hz,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).

[0477] Example 16

[0478] 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-N-(4-(2-(2-(methylamino)ethoxy)ethyl)-3-(trifluoromethyl)benzene)acetamide (Compound 16)

[0479] first step

[0480] 2-(4-Nitro-2-(trifluoromethyl)phenyl)acetic acid (16b)

[0481] To a solution of 2-(4-nitro-2-(trifluoromethyl)phenyl)acetonitrile 16a (9.0 g, 48.6 mmol) in concentrated sulfuric acid (45 mL) was slowly added potassium nitrate (4.9 g, 48.6 mmol) at 0°C, and 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. The mixture was cooled to room temperature, and ice water (60 mL) was added dropwise, followed by stirring for 30 minutes. The mixture was filtered, and the filter cake was washed with water and dried to afford the desired product 16b (9.9 g, 82%).

[0482] Step 2

[0483] 2-(4-Nitro-2-(trifluoromethyl)phenyl)ethanol 1-ol (16c)

[0484] To a solution of 16b (2 g, 8.0 mmol) in tetrahydrofuran (8 mL) was added a solution of borane in tetrahydrofuran (1.0 M, 11.2 mL), and the reaction mixture was stirred at room temperature for 3 hours. Methanol was added to quench the mixture, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 96 / 4) to obtain the desired product 16c (1.75 g, 93%).

[0485] MS m / z(ESI):234[M-1]

[0486] Step 3

[0487] Tert-Butyl 2-(4-nitro-2-(trifluoromethyl)phenethoxy)acetate (16d)

[0488] 16d was synthesized by replacing 2a with 16c according to the first step of compound 2.

[0489] MS m / z(ESI):294[M+1-56]

[0490] Step 4

[0491] 2-(4-Nitro-2-(trifluoromethyl)phenethoxy)acetic acid (16e)

[0492] To a solution of 16d (757 mg, 2.17 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL), and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to afford the target product 16e (crude product). This product was used directly in the next reaction without further purification.

[0493] MS m / z(ESI):292[M-1]

[0494] Step 5

[0495] N-Methyl-2-(4-nitro-2-(trifluoromethyl)phenethoxy)acetamide (16f)

[0496] 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. The mixture was quenched 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 = 10 / 90) to afford the desired product 16f (514 mg, 77%).

[0497] MS m / z(ESI):307[M+1]

[0498] Steps 6 to 9

[0499] Tert-butyl (2-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamido)-2-(trifluoromethyl)phenethoxy)ethyl)(methyl)carbamate (16j)

[0500] 16j was synthesized by replacing 5e with 16f and following the procedures of steps 5 to 8 in compound 5.

[0501] MS m / z(ESI):547[M+1-100]

[0502] Step 10

[0503] 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-N-(4-(2-(2-(methylamino)ethoxy)ethyl)-3-(trifluoromethyl)phenyl)acetamide (16)

[0504] 16 was synthesized by replacing 9b with 16j according to the second step of compound 9.

[0505] MS m / z(ESI):547[M+1]

[0506] 1H NMR (400MHz, DMSO-d6) δ10.52(s,1H),8.29(s,1H),8.03(d,J=2.0Hz,1H),7.77–7.72(m,1H),7.69 (d,J=7.8Hz,1H),7.56(s,1H),7.48–7.44(m,2H),5.11(dd,J=13.2,5.1Hz,1H),4.46(d,J=17.4Hz, 1H),4.32(d,J=17.4Hz,1H),3.81(s,2H),3.59(t,J=7.0Hz,2H),3.52(t,J=5.4Hz,2H),2.99–2.88 (m,3H),2.78(d,J=4.8Hz,2H),2.60(dd,J=15.2,2.3Hz,1H),2.44–2.31(m,4H),2.04–1.96(m,1H).

[0507] Example 17

[0508] N-(2-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamido)phenethoxy)ethyl)-2-hydroxy-N-methylacetamide (Compound 17)

[0509] 17 was synthesized by replacing 2g with 2 and intermediate A with 2-hydroxyacetic acid, according to the seventh step of compound 2.

[0510] MS m / z(ESI):537[M+1]

[0511] 1H 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).

[0512] Compounds 18-20 were prepared by following the same experimental procedure as compound 17, except that different compounds were used instead of 2.

[0513] The NMR data of compounds 18-20 are as follows:

[0514] Example 18

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

[0516] first step

[0517] 2-(2-Chloro-4-nitrophenylethoxy)1-ethanol (21a)

[0518] To a solution of 5c (100 mg, 0.32 mmol) in tetrahydrofuran (3 mL) was added lithium aluminum hydride in tetrahydrofuran (2.5 M, 0.14 mL, 0.35 mmol), and the reaction mixture was stirred at 0°C for 1 hour. The mixture was quenched 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 = 3 / 1) to afford the desired product 21a (60 mg, 77%).

[0519] MS m / z(ESI):246[M+1]

[0520] Step 2

[0521] tert-Butyl(2-(2-chloro-4-nitrophenylethoxy)ethoxy)dimethylsilane(21b)

[0522] 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), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched 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 = 8 / 1) to afford the desired product 21b (80 mg, 91%).

[0523] Step 3

[0524] 4-(2-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)ethyl)-3-chloroaniline (21c)

[0525] 21c was synthesized by replacing 3b with 21b and referring to the second step of compound 3.

[0526] MS m / z(ESI):352[M+23]

[0527] Steps 4 to 5

[0528] N-(3-chloro-4-(2-(2-hydroxyethoxy)ethyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (21)

[0529] 21 was synthesized by replacing 9a with 21b and following the procedure from the first step to the second step in compound 9.

[0530] MS m / z(ESI):500[M+1]

[0531] 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),10.34(s,1H),7.79(d,J=1.9Hz,1H),7.69(d,J=7.8Hz,1H),7.55(s,1H) ,7.46(d,J=7.8Hz,1H),7.39(dd,J=8.3,2.0Hz,1H),7.31(d,J=8.4Hz,1H),5.11(dd,J=13.2,5.0Hz,1H),4.55 (t,J=5.4Hz,1H),4.45(d,J=17.3Hz,1H),4.32(d,J=17.3Hz,1H),3.79(s,2H),3.57(t,J=7.1Hz,2H),3.49–3. 45(m,2H),3.44–3.38(m,2H),2.96–2.84(m,3H),2.60(d,J=17.4Hz,1H),2.42–2.33(m,1H),2.05–1.96(m,1H).

[0532] Example 19

[0533] 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)

[0534] first step

[0535] tert-Butyl 2-(2-(2-chloro-4-nitrophenylethoxy)ethoxy)acetate (22a)

[0536] 21a was used to replace 2a, and 22a was synthesized by referring to the first step of compound 2.

[0537] MS m / z(ESI):382[M+23]

[0538] Step 2

[0539] 2-(2-(2-chloro-4-nitrophenylethoxy)ethoxy)1-ethanol (22b)

[0540] 22b was synthesized by replacing 5c ​​with 22a and referring to the first step of compound 21.

[0541] MS m / z(ESI):290[M+1]

[0542] Step 3

[0543] 2-(2-(4-amino-2-chlorophenethoxy)ethoxy)1-ethanol (22c)

[0544] To a solution of 22b (180 mg, 0.62 mmol) in acetic acid (5 mL) was added zinc powder (202 mg, 3.1 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture 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 obtain the desired product 22c (50 mg, 31%).

[0545] MS m / z(ESI):260[M+1]

[0546] Step 4

[0547] N-(3-chloro-4-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (22)

[0548] 22 was synthesized by using 22c instead of methylamine hydrochloride and intermediate A instead of 16e, following the procedure of step 5 in compound 16.

[0549] MS m / z(ESI):544[M+1]

[0550] 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),10.34(s,1H),7.79(d,J=2.0Hz,1H),7.69(d,J=7.8Hz,1H),7.55(s,1H ),7.46(d,J=7.9Hz,1H),7.38(dd,J=8.4,2.1Hz,1H),7.31(d,J=8.4Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4. 46(d,J=17.4Hz,1H),4.32(d,J=17.3Hz,1H),3.79(s,2H),3.57(t,J=7.1Hz,2H),3.51–3.45(m,6H),3.41–3. 38(m,2H),2.96–2.83(m,3H),2.60(d,J=16.8Hz,1H),2.39(ddd,J=26.5,13.3,4.4Hz,1H),2.05–1.96(m,1H).

[0551] Example 20

[0552] N-(3-chloro-4-(2-(2-hydroxyethoxy)ethyl)benzyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 23)

[0553] first step

[0554] 2-(4-Bromo-2-chlorophenethoxy)1-ethanol (23a)

[0555] 23a was synthesized by replacing 5c ​​with 4c and following the procedure of the first step in compound 21.

[0556] Step 2

[0557] tert-Butyl (3-chloro-4-(2-(2-hydroxyethoxy)ethyl)benzyl)carbamate (23b)

[0558] 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)Cl (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. The product was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 70 / 30) to obtain the desired product 23b (108 mg, 49%).

[0559] MS m / z(ESI):230[M+1-100]

[0560] Step 3

[0561] 2-(4-(Aminomethyl)-2-chlorophenethoxy)-1-ethanol (23c)

[0562] 23c was synthesized by replacing 9b with 23b and referring to the second step of compound 9.

[0563] MS m / z(ESI):230[M+1]

[0564] Step 4

[0565] N-(3-chloro-4-(2-(2-hydroxyethoxy)ethyl)benzyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (23)

[0566] 23 was synthesized by replacing 2g with 23c according to the seventh step of compound 2.

[0567] MS m / z(ESI):514[M+1]

[0568] 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.61(t,J=6.0Hz,1H),7.67(d,J=7.8Hz,1H),7.51(s,1H),7.42(d,J=8. 0Hz,1H),7.31(d,J=7.9Hz,1H),7.22(d,J=1.5Hz,1H),7.15–7.11(m,1H),5.11(dd,J=13.3,5.1Hz,1H),4.44( d,J=17.4Hz,1H),4.31(d,J=17.3Hz,1H),4.24(d,J=5.9Hz,2H),3.62(s,2H),3.58(t,J=7.1Hz,2H),3.49–3.4 5(m,2H),3.44–3.41(m,2H),2.98–2.84(m,3H),2.60(d,J=17.7Hz,1H),2.45–2.32(m,1H),2.03–1.96(m,1H).

[0569] Example 21

[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-methylacetamide (Compound 24)

[0571] first step

[0572] Tert-butyl (2-(2-chloro-4-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methoxy-1-oxoisoindolin-5-yl)acetamido)phenethoxy)ethyl)(methyl)carbamate (24a)

[0573] 24a was synthesized by replacing 2g with 5h and intermediate C with intermediate A according to the seventh step of compound 2.

[0574] MS m / z(ESI):543[M+1-100]

[0575] Step 2

[0576] 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)

[0577] Boron tribromide (1 mL) was added to a solution of 24a (70 mg, 0.11 mmol) in dichloromethane (5 mL), and the reaction mixture was stirred at room temperature for 2 hours, quenched with water, filtered, and the filter cake was dried to give the desired product 24b (30 mg, 52%).

[0578] MS m / z(ESI):529[M+1]

[0579] Step 3

[0580] 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 (24)

[0581] 24 was synthesized by using 24b instead of 2g and 2-hydroxyacetic acid instead of intermediate A, following the procedure of step 7 in compound 2.

[0582] MS m / z(ESI):587[M+1]

[0583] 1 H NMR(400MHz,DMSO-d6)δ10.98(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=6.4Hz,1H),5.10(dd,J=13.3,4.9Hz,1H),4.35(d,J=17.2H z,1H),4.24(d,J=17.2Hz,1H),4.05(d,J=16.2Hz,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=17.0Hz,1H),2.43–2.32(m,1H),2.06–1.97(m,1H).

[0584] Example 22

[0585] 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 (Compound 25)

[0586] first step

[0587] Tert-butyl (2-(2-chloro-4-(2-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)acetamido)phenethoxy)ethyl)(methyl)carbamate (25a)

[0588] 25a was synthesized by replacing 2g with 5h and intermediate B with intermediate A according to the seventh step of compound 2.

[0589] MS m / z(ESI):531[M+1-100]

[0590] Step 2

[0591] 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)

[0592] 25b was synthesized by replacing 9b with 25a according to the procedure of the second step of compound 9.

[0593] MS m / z(ESI):531[M+1]

[0594] Step 3

[0595] 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)

[0596] 25 was synthesized by using 25b instead of 2g and 2-hydroxyacetic acid instead of intermediate A, following the procedure of step 7 in compound 2.

[0597] MS m / z(ESI):589[M+1]

[0598] 1H NMR(400MHz,DMSO-d6)δ11.00(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=13.3,5.1Hz,1H),4.57(d,J=17.4Hz,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=5.5Hz,1H),3. 34–3.32(m,1H),2.97–2.77(m,6H),2.60(d,J=17.0Hz,1H),2.47–2.35(m,1H),2.06–1.96(m,1H).

[0599] Example 23

[0600] 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-N-(3-((1-(2-hydroxyacetyl)piperidin-4-yl)methyl)phenyl)acetamide (Compound 26)

[0601] first step

[0602] tert-Butyl 4-(3-nitrobenzylidene)piperidine-1-carboxylate (26c)

[0603] To a solution of diethyl (3-nitrobenzyl)phosphonate 26b (549 mg, 2.0 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (60%, 161 mg, 4.0 mmol), and the reaction mixture was stirred at 0°C for 10 minutes. 4-Oxopiperidine-1-carboxylic acid tert-butyl ester 26a (400 mg, 2.0 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. The mixture was quenched 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 = 19 / 1 v / v) to obtain the desired product 26c (400 mg, 63%).

[0604] MS m / z(ESI):263.1[M+H + -56]

[0605] Step 2

[0606] tert-Butyl 4-(3-aminobenzyl)piperidine-1-carboxylate (26d)

[0607] To a solution of 26c (400 mg, 1.3 mmol) in methanol (10 mL) was added palladium on carbon (10%, containing 55% water, 200 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the desired product 26d (350 mg, 96%).

[0608] MS m / z(ESI):191.2[M+H + -100]

[0609] Steps 3 to 5

[0610] 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-N-(3-((1-(2-hydroxyacetyl)piperidin-4-yl)methyl)phenyl)acetamide (26)

[0611] 26 was synthesized by replacing 9a with 26d and following the procedures of the first to third steps of compound 9.

[0612] MS m / z(ESI):533.3[M+H + ]

[0613] 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),10.16(s,1H),7.69(d,J=7.8Hz,1H),7.56(s,1H),7.52–7.37(m, 3H),7.20(t,J=7.8Hz,1H),6.85(d,J=7.3Hz,1H),5.11(dd,J=13.2,5.0Hz,1H),4.46(d,J=17.3Hz,1H) ,4.39–4.24(m,2H),4.15–3.94(m,2H),3.77(s,2H),3.65–3.52(m,2H),2.98–2.79(m,2H),2.65–2.54( m,2H),2.48–2.31(m,3H),2.06–1.93(m,1H),1.78–1.65(m,1H),1.64–1.51(m,2H),1.17–0.91(m,2H).

[0614] Example 24

[0615] N-(3-chloro-4-(3-(2-hydroxyethoxy)propyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 27)

[0616] first step

[0617] 2-((3-(2-chloro-4-nitrophenyl)prop-2-yn-1-yl)oxy)1-ethanol (27b)

[0618] To a solution of 2-chloro-1-iodo-4-nitrobenzene (1.5 g, 5.3 mmol), 2-(prop-2-yn-1-yloxy)ethan-1-ol 27a (795 mg, 7.9 mmol), Pd(PPh ) Cl (371 mg, 0.53 mmol) and triethylamine (1.6 g, 15.9 mmol) in tetrahydrofuran (20 mL) was added cuprous iodide (102 mg, 0.53 mmol), and the reaction mixture was stirred at room temperature for 6 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 v / v) to give the desired product 27b (800 mg, 59%).

[0619] MS m / z(ESI):256.1[M+H + ]

[0620] Step 2

[0621] 2-(3-(4-Amino-2-chlorophenyl)propoxy)1-ethanol (27c)

[0622] To a solution of 27b (800 mg, 3.1 mmol) in methanol (10 mL) was added palladium on carbon (10%, containing 55% water, 400 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 v / v) to obtain the desired product 27c (450 mg, 63%).

[0623] MS m / z(ESI):230.1[M+H + ]

[0624] Step 3

[0625] N-(3-chloro-4-(3-(2-hydroxyethoxy)propyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (27)

[0626] 27 was synthesized by replacing 2g with 27c according to the seventh step of compound 2.

[0627] MS m / z(ESI):514.2[M+H + ]

[0628] 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),10.32(s,1H),7.78(d,J=2.0Hz,1H),7.69(d,J=7.8Hz,1H),7.55(s,1H),7 .46(d,J=7.9Hz,1H),7.39(dd,J=8.3,2.0Hz,1H),7.26(d,J=8.4Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.55(t,J= 5.5Hz,1H),4.46(d,J=17.3Hz,1H),4.32(d,J=17.4Hz,1H),3.78(s,2H),3.51–3.47(m,2H),3.40–3.37(m,4H),2 .96–2.87(m,1H),2.69–2.65(m,2H),2.62–2.58(m,1H),2.45–2.32(m,1H),2.05–1.95(m,1H),1.79–1.72(m,2H).

[0629] Compounds 28 and 29 were prepared according to the same experimental procedure as for compound 27, except that different compounds were used in place of 2-chloro-1-iodo-4-nitrobenzene in the first step.

[0630] The NMR data of compounds 28 and 29 are as follows:

[0631] Example 25

[0632] N-(5-chloro-2-hydroxy-4-(3-(2-hydroxyethoxy)propyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 30)

[0633] Step 1 to Step 2

[0634] 2-Amino-4-chloro-5-(3-(2-hydroxyethoxy)propyl)phenol (30c)

[0635] 30c was synthesized by using 30a instead of 2-chloro-1-iodo-4-nitrobenzene and following the procedure from the first step to the second step in compound 27.

[0636] MS m / z(ESI):246.1[M+H + ]

[0637] Step 3

[0638] N-(5-chloro-2-hydroxy-4-(3-(2-hydroxyethoxy)propyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (30)

[0639] To a solution of 30c (65 mg, 0.26 mmol) and intermediate A (80 mg, 0.26 mmol) in DMF (10 mL) were added DIPEA (103 mg, 0.80 mmol) and PyBOP (166 mg, 0.32 mmol), and the mixture was stirred at room temperature for 30 minutes. Purification by reverse phase preparative HPLC afforded the desired product 30 (9 mg, 6%).

[0640] MS m / z(ESI):530.2[M+H + ]

[0641] 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),10.06(brs,1H),9.46(s,1H),7.91(s,1H),7.69(d,J=7.8Hz, 1H),7.56(s,1H),7.48(d,J=7.8Hz,1H),6.78(s,1H),5.11(dd,J=13.3,5.1Hz,1H),4.55(t,J=5.4Hz ,1H),4.46(d,J=17.3Hz,1H),4.32(d,J=17.3Hz,1H),3.90(s,2H),3.53–3.47(m,2H),3.46–3.36(m, 4H),2.96–2.85(m,1H),2.63–2.54(m,3H),2.44–2.31(m,1H),2.05–1.96(m,1H),1.78–1.69(m,2H).

[0642] Example 26

[0643] N-(3-chloro-4-(3-(2-(methylamino)ethoxy)propyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 31)

[0644] first step

[0645] Tert-butyl methyl (2-(prop-2-yn-1-yloxy)ethyl)carbamate (31b)

[0646] To a solution of tert-butyl (2-hydroxyethyl)(methyl)carbamate 31a (1.5 g, 8.6 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (60%, 1 g, 26 mmol), and the reaction mixture was stirred at 0°C for 20 minutes. 3-Bromopropyne (960 mg, 17.1 mmol) was added, and the reaction mixture was stirred at room temperature for 12 hours. Water was added to quench the mixture, 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 = 5 / 1 v / v) to obtain the desired product 31b (1.4 g, 77%).

[0647] MS m / z(ESI):158.1[M+H + -56]

[0648] Step 2

[0649] Tert-butyl (2-((3-(2-chloro-4-nitrophenyl)prop-2-yn-1-yl)oxy)ethyl)(methyl)carbamate (31c)

[0650] 31c was synthesized by replacing 27a with 31b and referring to the first step of compound 27.

[0651] MS m / z(ESI):313.1[M+H + -56]

[0652] Step 3

[0653] Tert-butyl (2-(3-(4-amino-2-chlorophenyl)propoxy)ethyl)(methyl)carbamate (31d)

[0654] To a solution of 31c (800 mg, 2.2 mmol) in methanol (10 mL) and dichloromethane (5 mL) was added palladium on carbon (10%, containing 55% water, 400 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 6 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford the desired product 31d (500 mg, 67%).

[0655] MS m / z(ESI):243.1[M+H + -100]

[0656] Step 4

[0657] Tert-butyl (2-(3-(2-chloro-4-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetylamino)phenyl)propoxy)ethyl)(methyl)carbamate (31e)

[0658] 31e was synthesized by replacing 2g with 31d according to the procedure of step 7 in compound 2.

[0659] MS m / z(ESI):527.2[M+H + -100]

[0660] Step 5

[0661] N-(3-chloro-4-(3-(2-(methylamino)ethoxy)propyl)phenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (31)

[0662] The reaction mixture 31e (220 mg, 0.35 mmol) and a solution of hydrogen chloride in 1,4-dioxane (4.0 M, 10 mL) were stirred at room temperature for 1 hour, concentrated under reduced pressure, and the residue was purified by reverse-phase preparative HPLC to obtain the desired product 31 (formate salt, 100 mg, 50%).

[0663] MS m / z(ESI):527.3[M+H + ]

[0664] 1 H NMR (400MHz, DMSO-d6) δ8.40(s,1H),7.76(s,1H),7.69(d,J=7.8Hz,1H),7.55(s,1H),7.46(d,J=7. 8Hz,1H),7.39(d,J=8.3Hz,1H),7.25(d,J=8.4Hz,1H),5.07(dd,J=13.2,5.0Hz,1H),4.45(d,J=17.4 Hz,1H),4.31(d,J=17.4Hz,1H),3.77(s,2H),3.40(t,J=6.3Hz,2H),2.96–2.82(m,3H),2.67(t,J=7 .6Hz,2H),2.62–2.58(m,1H),2.46(s,3H),2.43–2.32(m,1H),2.04–1.94(m,1H),1.82–1.70(m,2H).

[0665] Example 27

[0666] N-(4-(3-(2-aminoethoxy)propyl)-3-chlorophenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 32)

[0667] first step

[0668] Tert-butyl (2-((3-(2-chloro-4-nitrophenyl)prop-2-yn-1-yl)oxy)ethyl)carbamate (32b)

[0669] 32b was synthesized by replacing 27a with 32a and referring to the first step of compound 27.

[0670] MS m / z(ESI):255.1[M+H + -100]

[0671] Step 2

[0672] Tert-butyl (2-(3-(4-amino-2-chlorophenyl)propoxy)ethyl)carbamate (32c)

[0673] To a solution of 32b (491 mg, 1.4 mmol) in methanol (8 mL) were added palladium on carbon (10%, containing 55% water, 250 mg) and zinc chloride (38 mg, 0.28 mmol). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1 v / v) to give the desired product 32c (102 mg, 22%).

[0674] MS m / z(ESI):229.1[M+H + -100]

[0675] Steps 3 to 4

[0676] N-(4-(3-(2-aminoethoxy)propyl)-3-chlorophenyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (32)

[0677] 32 (formate salt) was synthesized by replacing 31d with 32c and referring to the procedures of steps 4 to 5 in compound 31.

[0678] MS m / z(ESI):513.3[M+H + ]

[0679] 1H NMR (400MHz, DMSO-d6) δ10.46(s,1H),8.39(s,1H),7.79(d,J=2.0Hz,1H),7.69(d,J=7.8Hz,1H),7.56(s,1H) ,7.46(d,J=7.9Hz,1H),7.41(dd,J=8.4,2.0Hz,1H),7.26(d,J=8.4Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.4 5(d,J=17.4Hz,1H),4.32(d,J=17.3Hz,1H),3.79(s,2H),3.46(t,J=5.5Hz,2H),3.40(t,J=6.4Hz,2H),2.97– 2.82(m,3H),2.73–2.66(m,2H),2.63–2.55(m,1H),2.44–2.35(m,1H),2.03–1.96(m,1H),1.82–1.74(m,2H).

[0680] Example 28 - Biological Experiment

[0681] Assay for GSPT1 degradation

[0682] 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). 50 For lower values, the starting concentration of the compound can be reduced.

[0683] 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). Cells were cultured in RPMI 1640 complete medium [which contains 10% FBS (GIBCO, catalog number 10099-141) and 100 units / mL penicillin-streptomycin mixture (Thermo Fisher, catalog number 15140122)]. Cells (400,000 cells / mL) were seeded in 90 μL of complete medium in a 96-well plate. After overnight culture, 10 μL of compound solution was added to each well and cultured for another 4 hours in a 37°C, 5% CO2 incubator. The cell culture plate was removed and equilibrated to room temperature, and then the plate was plated and plated. The HiBiT Lytic System kit (Promega, Cat. No. N3030) was operated according to the instructions, i.e., an equal volume of Nano-Glo reagent was added for complete lysis. After incubation at room temperature for 30 minutes, the luminescence signal was read using a microplate reader (EnVision, Perkin Elmer). A control containing 0.2% DMSO was used as a control for GSPT1 degradation. % degradation rate = luminescence signal 化合物 / cold light signal DMSO对照 ×100%, and XLfit software (ID Business Solutions Ltd., UK) was used to draw the induction curve of GSPT1 degradation by the compound and calculate its DC 50 The experimental results are shown in Table 1.

[0684] Determination of SK-BR-3 cell proliferation inhibition

[0685] The compound was dissolved in DMSO and diluted to 10 mM, and then serially diluted 5-fold with DMSO to 8 concentration points. Each concentration point was further diluted 50-fold with McCoy's 5A medium (Gibco, catalog number 12330031). 50 For lower values, the starting concentration of the compound can be reduced.

[0686] SK-BR-3 cells (Nanjing Kebai Biotechnology Co., Ltd., catalog number CBP60413) were cultured in the same complete cell culture medium as above. The cells (12500 cells / mL) were seeded in 36 μL of complete culture medium in a 384-well plate. After overnight culture, 4 μL of compound solution was added to each well. The cells were cultured in a 37°C, 5% CO2 incubator for 6 days. The cell culture plates were taken out and equilibrated to room temperature. The cells were lysed using the CTG kit (Promega, catalog number G7572) according to the manufacturer's instructions. 20 μL of CTG reagent was added for complete lysis. After standing at room temperature for 10 minutes, the luminescence signal was read using a microplate reader (EnVision, Perkin Elmer). The group treated with 0.2% DMSO was defined as 0% inhibition, and the group treated with the control compound CC-885 (for specific preparation, refer to the synthesis of compound 76 in Example 5 of WO2008027542A2) was defined as 100% inhibition. % Inhibition = (luminescence signal 化合物 -Cold light signal 100％抑制 ) / (cold light signal 0％ 抑制 -Cold light signal 100％抑制 )×100%, and XLfit software (ID Business Solutions Ltd., UK) was used to draw the inhibitory curve of the compound on SK-BR-3 cell proliferation and calculate its IC50 The experimental results are shown in Table 1.

[0687] Determination of NB-4 cell proliferation inhibition

[0688] The compound was dissolved in DMSO and diluted to 10 mM, and then serially diluted 5-fold with DMSO to 10 concentration points. Each concentration point was further diluted 50-fold with RPMI-1640 medium (Gibco, catalog number 72400-047). 50 For lower values, the starting concentration of the compound can be reduced.

[0689] NB-4 cells (Shanghai Jihe Biotechnology Co., Ltd., catalog number JH-H1370) were cultured in the same complete cell culture medium as above. The cells (20,000 cells / mL) were seeded in 90 μL of complete culture medium in a 96-well plate. After overnight culture, 10 μL of compound solution was added to each well. The cells were cultured in a 37°C, 5% CO2 incubator for 6 days. The cell culture plates were taken out and equilibrated to room temperature. The cells were lysed using the CTG kit (Promega, catalog number G7573) according to the manufacturer's instructions. 50 μL of CTG reagent was added for complete lysis. The cells were allowed to stand at room temperature for 10 minutes, and the luminescence signal was read using a microplate reader (EnVision, Perkin Elmer). The group containing 0.2% DMSO was defined as 0% inhibition, and the group treated with the control compound CC-885 (1 μM) was defined as 100% inhibition. % inhibition = (luminescence signal 化合物 -Cold light signal 100％抑制 ) / (cold light signal 0％抑制 -Cold light signal 100％抑制 )×100%, and XLfit software (ID Business Solutions Ltd., UK) was used to draw the inhibitory curve of the compound on NB-4 cell proliferation and calculate its IC 50 The experimental results are shown in Table 1.

[0690] The structure of CC-885 is as follows:

[0691] Table 1

Claims

1. A compound of 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; Each R 2 is independently H, halogen, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, 4- to 8-membered heterocyclic group or -OR′, where 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-(OC 2-6 alkylene) m1 -R 3′ -R 4 、-O(C 2-6 alkyleneO) m1 -R 3′ -R 4 、-C 1-6 alkylene-NR′R 6 or -NR′R 7 ; R 3′ is a 4- to 8-membered heterocyclic group; R 4 is -OH, -NR′R 5 or -C(O)C 1-6 alkylene-OH; R 5 , R 6 and R 7 Each is independently H or -C(O)C 1-6 Alkylene-OH, wherein one or two hydrogen atoms of the alkylene are optionally replaced by D, fluorine, C 1-6 Alkyl, fluorinated C 1-6 Alkyl or C 3-8 substituted by cycloalkyl; 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, provided that when R′ is H, R 6 and R 7 each cannot be H; when R′ is C 1-6 alkyl, R 7 cannot be H; n is 0 or 1; m is an integer from 1 to 6; m1 is an integer from 0 to 6; and p is an integer from 1 to 3.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, stable isotope derivative, and isomer thereof, wherein: A is a benzene ring; R 1 is H, a halogen or -OH; Each R 2 is independently 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-R 3′ -R 4 、-O-R 3′ -R 4 、-C 1-6 alkylene-NR′R 6 or -NR′R 7 ; R 3′ is a 4- to 8-membered heterocyclic group containing 1 to 2 nitrogen heteroatoms; R 4 is -OH, -NH2, -NH-C 1-6 alkyl, -NHC(O)C 1-6 alkylene-OH, -C(O)C 1-6 alkylene-OH or -N(C 1-6 alkyl)C(O)C 1-6 alkylene-OH; R 6 and R 7 each independently is H or -C(O)C 1-6 alkylene-OH; R′ is H or C 1-6 alkyl, provided that when R′ is H, R 6 and R 7 each cannot be H; when R′ is C 1-6 alkyl, R 7 cannot be H; n is 0 or 1; and m is an integer from 1 to 6; and p is an integer from 1 to 3.

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 or isomer thereof: Wherein: R 1 is H, halogen or -OH; Each R 2 is independently H, halogen, cyano, C 1-6 alkyl, C 3-8 cycloalkyl or -OR', where one or more hydrogens of the alkyl are optionally replaced 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-R 3′ -R 4 、-O-R 3′ -R 4 、-C 1-6 alkylene-NR′R 6 or -NR′R 7 ; R 3′ is a 4- to 8-membered heterocyclic group containing 1 to 2 nitrogen heteroatoms; R 4 is -OH, -NR′R 5 or -C(O)C 1-6 alkylene-OH; R 5 , R 6 and R 7 Each is independently H or -C(O)C 1-6 Alkylene-OH; R′ is H or C 1-6 alkyl, provided that when R′ is H, R 6 and R 7 each cannot be H; when R′ is C 1-6 alkyl, R 7 cannot be H; m is an integer from 1 to 6; and n is 0 or 1; p is an integer from 1 to 3.

4. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt, stable isotope derivative, and isomer thereof, wherein: R 1 is H, a halogen or -OH; Each R 2 is independently 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-R 3′ -R 4 、-O-R 3′ -R 4 、-C 1-6 alkylene-NR′R 6 or -NR′R 7 ; R 3′ is a 4- to 8-membered heterocyclic group containing 1 to 2 nitrogen heteroatoms; R 4 is -OH, -NH2, -NH-C 1-6 alkyl, -NHC(O)CH2OH, -C(O)CH2-OH or -N(CH3)C(O)CH2OH; R 6 and R 7 each independently is H or -C(O)CH2-OH; R′ is H or C 1-6 alkyl, provided that when R′ is H, R 6 and R 7 each cannot be H; when R′ is C 1-3 alkyl, R 7 cannot be H; m is 1 or 2; and p is an integer from 1 to 3.

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

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

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

9. Use of the compound according to any one of claims 1-5 or a pharmaceutically acceptable salt, stable isotope derivative, isomer, prodrug thereof, 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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