WEE1 degrading compounds and uses thereof

Abstract

Provided herein are compounds and compositions thereof that reduce WEE1 kinase protein levels. In some embodiments, compounds and compositions are provided for the treatment of WEE1-related diseases, such as cancer.

Description

Technical Field

[0001] This application claims priority to U.S. Provisional Application No. 63 / 357,449, filed on June 30, 2022, and U.S. Provisional Application No. 63 / 357,866, filed on July 1, 2022; each of these applications is incorporated herein by reference in its entirety for any purpose.

[0002] The present invention generally relates to compounds, compositions and methods of making the same and the use of the same for treating diseases and conditions associated with the WEE1 protein. Background Art

[0003] Targeted protein degradation is a therapeutic modality whereby small molecules induce novel protein-protein interactions and are able to destroy target proteins that drive disease. CRBN E3 ligase modulator (CELMoD) small molecules are a class of targeted protein therapeutics that bind to the CRL4-Cereblon E3 ubiquitin ligase complex, creating a new molecular "glue" interface on the Cereblon surface, recruiting and polyubiquitinating target proteins that are not normally ubiquitinated by Cereblon. The ubiquitin-tagged proteins are then transported to and subsequently degraded by the 26S proteasome. The choice of target proteins recruited by Cereblon is determined by the specific molecular structure of the CELMoD compound.

[0004] WEE1 is a tyrosine kinase that phosphorylates CDK1 and CDK2 cyclin-dependent kinases at their tyrosine-15 residues, thereby inhibiting kinase activity and arresting the cell cycle at the S and G2 / M cell cycle checkpoints. When cells are arrested at these checkpoints, cells repair stalled replication forks and DNA damage before entering mitosis; if DNA damage cannot be repaired or rises above an acceptable threshold, the cell undergoes planned apoptosis or mitotic catastrophe. Cancer cells often exhibit excessive replication stress, mutation induction, and genomic instability, prompting people to rely on cell cycle checkpoints to maintain DNA damage below the apoptotic threshold. Compared with normal cells, cancer cells often rely only on the S and G2 / M checkpoints because their G1 cell cycle checkpoints are disabled by various mechanisms, such as by limiting p53 and pRB activation, or by overactivating replication-promoting factors such as cyclin D and cyclin E. It is hypothesized that tumors that critically rely on WEE1-mediated S- and G2 / M checkpoints are abnormally sensitive to WEE1 loss, and therapeutic agents targeting WEE1 are expected to exhibit antitumor activity with a favorable therapeutic window.

[0005] Certain cancer therapeutics act by inducing replication stress and DNA damage, including, for example, carboplatin, cisplatin, gemcitabine, pemetrexed, topotecan, doxorubicin, decitabine, and methotrexate. By inducing DNA damage and replication stress, these agents enhance the dependence of dividing tumor cells on WEE1-mediated cell cycle checkpoints. Therefore, it is suggested that CELMoD compounds that degrade WEE1 be synergistically combined with DNA damaging agents.

[0006] Thus, in one aspect, provided herein are CELMoD compounds that induce Cereblon-mediated ubiquitination and degradation of WEE1 as single agents or in combination with sensitizing therapeutics to elicit broad anti-tumor activity. Summary of the invention

[0007] In certain embodiments, described herein are compounds and compositions thereof that degrade WEE1. In various embodiments, the compounds and compositions thereof can be used to treat diseases associated with WEE1, such as cancer.

[0008]

[0046] Embodiments of the present invention may be more fully understood with reference to the Detailed Description and Examples, which are intended to illustrate non-limiting embodiments.

[0009] In some embodiments, provided herein are compounds of formula (I) or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof, in A is a direct bond or an optionally substituted C 1-5 alkyl; B is selected from optionally substituted C 3-10 cycloalkyl, optionally substituted 3-14 membered heterocyclyl, optionally substituted C 6-14 aryl and optionally substituted 5-14 membered heteroaryl; W 1 and W 2 Each independently selected from H and CH 3 , or together to form an oxo group; W 3 and W 4 Each is H or together forms an oxo group; V is selected from H and CH 3 ; R' is a halogen atom; R" is selected from halogen atoms, optionally substituted C1-5 Alkyl and optionally substituted C 1-5 Alkoxy, or two R" may be combined with the carbon to which they are attached to form oxo; R'' is selected from a halogen atom, -CN, -OH, an optionally substituted amino group, an optionally substituted amide group, an optionally substituted C 1-5 Alkyl, optionally substituted C 1-5 Alkoxy, optionally substituted C 3-6 cycloalkyl-oxy, optionally substituted 5-10 membered heterocyclyl-oxy, optionally substituted 5-10 membered heteroaryl-oxy, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 5-10 membered aryl, and optionally substituted 5-10 membered heteroaryl; l is an integer from 0 to 3; m is an integer from 0 to 3; n is an integer from 0 to 7; and Where W 1 and W 2 or W 3 and W 4 At least one of them together forms an oxo group.

[0010] In some embodiments, provided herein is a method for reducing WEE1 kinase protein levels, the method comprising contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, isotopomer, or stereoisomer thereof. In some embodiments, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, isotopomer, or stereoisomer thereof in the preparation of a medicament for reducing WEE1 kinase protein levels.

[0011] In some embodiments, provided herein is a method for preventing or treating cancer in a subject, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof. In some embodiments, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof in the preparation of a medicament for preventing or treating cancer. DETAILED DESCRIPTION definition

[0012] As used herein, the terms "comprising" and "including" are used interchangeably. The terms "comprising" and "including" should be interpreted as specifying the presence of the stated features or components mentioned, but not excluding the presence or addition of one or more features or components or groups thereof. In addition, the terms "comprising" and "including" are intended to include examples covered by the term "consisting of". Therefore, the term "consisting of" can be used to replace the terms "comprising" and "including" to provide more specific embodiments of the present invention.

[0013] The term "consisting of" means that the object has at least 90%, 95%, 97%, 98% or 99% of the stated features or components consisting of them. In another embodiment, except for the features or components that are not essential to the technical effect to be achieved, the term "consisting of" excludes any other features or components from any subsequently listed categories.

[0014] As used herein, the term "or" should be interpreted as an inclusive "or", meaning any one or any combination. Thus, "A, B, or C" means any one of the following: "A; B; C; A and B; A and C; B and C; A, B, and C". Exceptions to this definition will only occur when a combination of elements, functions, steps, or actions are inherently mutually exclusive in some way.

[0015] In this specification, unless otherwise indicated, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value and, where appropriate, fractions thereof (such as tenths and hundredths of integers) within the recited range. In addition, unless otherwise indicated, any numerical range related to any physical characteristic, such as polymer subunits, size, or thickness, recited herein should be understood to include any integer within the recited range. As used herein, unless otherwise indicated, the terms "about" and "approximately" refer to ±20%, ±10%, ±5%, or ±1% of the indicated range, value, or structure.

[0016] "Alkyl" is a saturated, partially saturated or unsaturated straight or branched chain non-cyclic hydrocarbon having 1 to 10 carbon atoms (C 1 -C 10 alkyl), usually 1 to 8 carbons (C 1 -C 8 alkyl) or in some embodiments 1 to 6 (C 1 -C 6 alkyl), 1 to 4 (C 1 -C 4 alkyl), 1 to 3 (C 1 -C 3 alkyl) or 2 to 6 (C 2 -C6 In some embodiments, the alkyl group is a saturated alkyl group. Representative saturated alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched chain alkyl groups include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl, and the like. In some embodiments, the alkyl group is an unsaturated alkyl group, also known as an alkenyl or alkynyl group. "Alkenyl" is an alkyl group containing one or more carbon-carbon double bonds. "Alkynyl" is an alkyl group containing one or more carbon-carbon triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH (CH 3 ), -CH=C(CH 3 ) 2 、-C(CH 3 )=CH 2 、-C(CH 3 )=CH(CH 3 )、-C(CH 2 CH 3 )=CH 2 、-C≡CH、-C≡C(CH 3 )、-C≡C(CH 2 CH 3 ),-CH 2 C≡CH, -CH 2 C≡C(CH 3 ) and -CH 2 C≡C(CH 2 CH 3 ). The alkyl group may be substituted or unsubstituted. When an alkyl group described herein is referred to as "substituted", it may be substituted with any one or more of the substituents present in the exemplary compounds and embodiments disclosed herein, as well as halogen; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkoxy, arylalkoxy, heterocyclylalkyloxy, heteroarylalkoxy; oxo (=O); amine, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino, cycloalkylalkylamino, arylalkylamino, heterocyclyl Alkylamino, heteroarylalkylamino, imino, imido, amidino, guanidino, enamino, amide, sulfonylamino, urea, nitrourea, oxime, hydroxylamino, alkoxyamino, aralkyloxyamino, hydrazine, hydrazide, hydrazono, azido, nitro, sulfenyl (-SH), alkylthio, =S, sulfinyl, sulfonyl, aminosulfonyl, phosphonate, phosphinyl, acyl, formyl, carboxyl, ester, carbamate, amide, cyano, isocyanato, isothiocyanato, cyanate, thiocyano, or -B(OH) 2In certain embodiments, when an alkyl group described herein is referred to as being "substituted," it may be substituted with any one or more of the substituents present in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxy; alkoxy; alkoxyalkyl; amine; alkylamine; carboxyl; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; amide; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; carbamate; oxime; hydroxylamine; alkoxyamine; aralkyloxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH) 2 or -O(alkyl)aminocarbonyl.

[0017] A "cycloalkyl" group is a saturated or partially saturated cycloalkyl group (C 2+) of 3 to 10 carbon atoms having a single cyclic ring or multiple optionally substituted condensed or bridged rings. 3 -C 10 In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms (C 3 -C 8 In other embodiments, the number of ring carbon atoms is between 3 and 5 (C 3 -C 5 Cycloalkyl), 3 to 6 (C 3 -C 6 cycloalkyl) or 3 to 7 (C 3 -C 7 In some embodiments, the cycloalkyl is a saturated cycloalkyl. For example, such saturated cycloalkyl includes monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl and the like; or polycyclic or bridged ring structures such as 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl and the like. In other embodiments, the cycloalkyl is an unsaturated cycloalkyl. Examples of unsaturated cycloalkyls include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl. The cycloalkyl may be substituted or unsubstituted. Such substituted cycloalkyls include, for example, cyclohexanol and the like.

[0018] "Heterocyclyl" is a non-aromatic cycloalkyl radical in which one to four ring carbon atoms are independently replaced by heteroatoms selected from O, S and N. In some embodiments, the heterocyclyl radical includes 3 to 10 ring members, while other such radicals have 3 to 5, 3 to 6, or 3 to 8 ring members. The heterocyclyl radical may also be bonded to other radicals at any ring atom (i.e., at any carbon atom or heteroatom of the heterocycle). The heterocycloalkyl radical may be substituted or unsubstituted. The heterocyclyl radical encompasses saturated and partially saturated ring systems. In addition, regardless of the connection to the rest of the molecule, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring. The phrase also includes bridged polycyclic ring systems containing heteroatoms. Representative examples of heterocyclyl include, but are not limited to, aziridine, azetidinyl, azepanyl, pyrrolidinyl, imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dione), pyrazolidinyl, thiazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, piperidinyl, piperazinyl (e.g., piperazin-2-one), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl, 1,4-dioxaspiro[4.5]decyl, homopiperazinyl, quinuclidinyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclyls may be monosubstituted or multiply substituted, such as, but not limited to, pyridinyl or morpholinyl groups, which are 2-substituted, 3-substituted, 4-substituted, 5-substituted, or 6-substituted or disubstituted with a variety of substituents such as those listed below.

[0019] An "aryl" group is a 6 to 14 carbon atom (C 2 + 4) group having a single ring (eg, phenyl) or multiple condensed rings (eg, naphthyl or anthracenyl). 6 -C 14 In some embodiments, the aryl group contains 6 to 14 carbon atoms (C 6 -C 14 aryl), and in other embodiments contains 6 to 12 (C 6 -C 12 aryl) or even 6 to 10 carbon atoms (C 6 -C 10 aryl). Specific aryl groups include phenyl, biphenyl, naphthyl, and the like. Aryl groups may be substituted or unsubstituted. The phrase "aryl" also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).

[0020] "Heteroaryl" is an aromatic ring system having from one to four heteroatoms as ring atoms in the heteroaromatic ring system, wherein the remaining atoms are carbon atoms. In some embodiments, the heteroaryl group contains 3 to 6 ring atoms, and in other embodiments, contains 6 to 9 or even 6 to 10 atoms in the ring portion of the group. Suitable heteroatoms include oxygen, sulfur and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, benzothienyl, furanyl, benzofuranyl, indolyl (e.g., indol-2-one or isoindolin-1-one), azaindolyl (pyrrolopyridinyl or 1H-pyrrolo[2,3-b]pyridinyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), imidazolyl The heteroaryl group may be substituted or unsubstituted.

[0021] "Halogen" or "halo" is fluorine, chlorine, bromine or iodine.

[0022] An "alkoxy" group is an -O-(alkyl) group wherein alkyl is as defined above.

[0023] "Oxo" is a "=0" group bonded to carbon.

[0024] "Amino" is -NH 2 , wherein one or both of the hydrogen atoms may be substituted by an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group.

[0025] "Acylamide" is an amide group having the formula -NHC(O)-, wherein the hydrogen atom may be replaced by an alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group.

[0026] "Heteroaryl-oxy" is -O-(heteroaryl), wherein heteroaryl is as defined above. "Heterocyclyl-oxy" is -O-(heterocyclyl), wherein heterocyclyl is as defined above. "Cycloalkyl-oxy" is -O-(cycloalkyl), wherein cycloalkyl is as defined above.

[0027] When a group described herein other than alkyl, amino, and amido is referred to as "substituted," it may be substituted with any one or more suitable substituents. Illustrative examples of substituents are those present in the exemplary compounds and embodiments disclosed herein as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxy; alkoxy; alkoxyalkyl; amino; alkylamino; carboxyl; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; amido; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; carbamate; oxime; hydroxylamine; alkoxyamine; aralkyloxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxo (=O); B (OH) 2 , -O(alkyl)aminocarbonyl; cycloalkyl which may be a monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or heterocyclic which may be a monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, etc.); yl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolyl, isoquinolyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl or benzofuranyl); cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkoxy, arylalkoxy, heterocyclylalkoxy and heteroarylalkoxy.

[0028]

[00136] Embodiments of the present invention are intended to encompass pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers of the compounds provided herein, such as compounds of Formula (I).

[0029] As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base, including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts of the compound of formula (I) include, but are not limited to, metal salts prepared from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or organic salts prepared from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, p-aminobenzenesulfonic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric acid, hydrobromic acid, maleic acid, phosphoric acid, sulfuric acid, and methanesulfonic acid. Thus, examples of specific salts include hydrochlorides, formates, and methanesulfonates. Others are well known in the art, see, for example, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19th ed., Mack Publishing, Easton PA (1995).

[0030] As used herein and unless otherwise indicated, the term "stereoisomer" or "stereoisomerically pure" refers to one stereoisomer of a particular compound that is substantially free of other stereoisomers of the compound. For example, a stereoisomerically pure compound with one chiral center is substantially free of the relative mirror image isomer of the compound. A stereoisomerically pure compound with two chiral centers will be substantially free of other non-mirror image isomers of the compound. A typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. The compounds disclosed herein may have chiral centers and may exist as racemates, individual mirror image isomers or non-mirror image isomers, and mixtures thereof. All such isomeric forms are included within the embodiments disclosed herein, including mixtures thereof.

[0031] The embodiments disclosed herein encompass the use of stereoisomerically pure forms of the compounds disclosed herein as well as the use of mixtures of such forms. For example, mixtures containing equal or unequal amounts of mirror image isomers of a particular compound can be used in the methods and compositions disclosed herein. Such isomers can be resolved by asymmetric synthesis or using standard techniques such as chiral columns or chiral resolving agents. See, for example, Jacques, J. et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH, Tables of Resolving Agents and Optical Resolutions page 268 (EL Eliel, Univ. of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., SeparationOfEnantiomers:Synthetic Methods (Wiley-VCH Verlag GmbH&Co.KgaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation: Fundamentals and PracticalMethods (Springer Science&Business Media, 2007); Subramanian, G. Chiral Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0032] "Tautomers" refer to isomeric forms of a compound that are in equilibrium based on proton transfer. The concentration of the isomeric forms will depend on the environment in which the compound is present, and may vary depending on, for example, whether the compound is a solid or in an organic or aqueous solution. For example, in aqueous solution, pyrazole may exhibit the following isomeric forms, which are referred to as tautomers of each other:

[0033] As will be readily appreciated by those skilled in the art, various functional groups and other structures may exhibit tautomerism, and all tautomers of compounds of formula (I) are within the scope of the present invention.

[0034] It should also be noted that the compounds disclosed herein may contain unnatural proportions of atomic isotopes at one or more atoms. For example, the compounds may be radiolabeled with a radioactive isotope, such as tritium ( 3 H), iodine-125 ( 125 I), sulfur-35( 35 S) or carbon-14 ( 14 C), or may be isotopically enriched, such as with deuterium ( 2 H), carbon-13 ( 13 C) or nitrogen-15( 15 N) enriched. As used herein, an "isotopologue" is an isotopically enriched compound. The term "isotopically enriched" refers to an atom having an isotopic composition other than the natural isotopic composition of the atom. "Isotopically enriched" may also refer to at least one atom in a compound having an isotopic composition other than the natural isotopic composition of the atom. The term "isotopic composition" refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically enriched compounds are useful as therapeutic agents (e.g., cancer therapeutics), research reagents (e.g., binding assay reagents), and diagnostic agents (e.g., in vivo imaging agents). All isotopic variants of the compounds described herein, whether or not radioactive, are intended to be within the scope of the embodiments provided herein. In some embodiments, isotopologues of the compounds disclosed herein are provided, for example, such isotopologues are compounds enriched with deuterium, carbon 13, and / or nitrogen 15. As used herein, "deuterated" refers to a compound in which at least one hydrogen (H) has been deuterated (by D or 2 H indicates a deuterium-substituted compound, i.e., the compound is deuterium-enriched at at least one position.

[0035] It should be understood that, regardless of stereoisomerism or isotope composition, each compound disclosed herein can be provided in any pharmaceutically acceptable salt form discussed herein. Likewise, it should be understood that the isotope composition can be changed independently of the stereoisomerism composition of each compound mentioned herein. In addition, when limited to the elements present in the corresponding compound or its salt disclosed herein, the isotope composition can be changed independently of the selection of the pharmaceutically acceptable salt of the corresponding compound in other ways.

[0036] It should be noted that if there is an inconsistency between a depicted structure and the name of that structure, the depicted structure is given greater consideration.

[0037] As used herein, "treat" refers to the complete or partial relief of a disorder, disease or condition or one or more symptoms associated with a disorder, disease or condition, or slowing or arresting the further progression or worsening of those symptoms, or alleviating or eradicating the cause of the disorder, disease or condition itself. In one embodiment, the disorder is a neurodegenerative disease or a symptom thereof as described herein.

[0038] As used herein, "prevention" refers to delaying and / or preventing the complete or partial onset, recurrence, or spread of a disorder, disease, or condition; preventing a subject from developing a disorder, disease, or condition; or reducing the risk of a subject developing a disorder, disease, or condition. In one embodiment, the disorder is a neurodegenerative disease or a symptom thereof as described herein.

[0039] The term "effective amount" in connection with the compounds disclosed herein refers to an amount capable of treating or preventing a disorder, disease or condition disclosed herein, or a symptom thereof.

[0040] As used herein, the term "subject" or "patient" includes animals, including but not limited to animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits or guinea pigs, in one embodiment mammals, in another embodiment humans. In one embodiment, the subject is a human suffering from a WEE1-mediated disease or having symptoms thereof or being at risk thereof.

[0041] Although various features of the invention may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the invention may be described herein in the context of separate embodiments for clarity, the invention may also be implemented in a single embodiment. Compound

[0042] In one aspect, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof, in A is a direct bond or an optionally substituted C 1-5 alkyl; B is selected from optionally substituted C 3-10 cycloalkyl, optionally substituted 3-14 membered heterocyclyl, optionally substituted C 6-14 aryl and optionally substituted 5-14 membered heteroaryl; W 1 and W 2 Each independently selected from H and CH 3 , or together to form an oxo group; W3 and W 4 Each is H or together forms an oxo group; V is selected from H and CH 3 ; R' is a halogen atom; R" is selected from halogen atoms, optionally substituted C 1-5 Alkyl and optionally substituted C 1-5 Alkoxy, or two R" may be combined with the carbon to which they are attached to form oxo; R'' is selected from a halogen atom, -CN, -OH, an optionally substituted amino group, an optionally substituted amide group, an optionally substituted C 1-5 Alkyl, optionally substituted C 1-5 Alkoxy, optionally substituted C 3-6 cycloalkyl-oxy, optionally substituted 5-10 membered heterocyclyl-oxy, optionally substituted 5-10 membered heteroaryl-oxy, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 5-10 membered aryl, and optionally substituted 5-10 membered heteroaryl; l is an integer from 0 to 3; m is an integer from 0 to 3; n is an integer from 0 to 7; and Where W 1 and W 2 or W 3 and W 4 At least one of them together forms an oxo group.

[0043] In some embodiments, the compound of formula (I) is a compound of formula (Ia)

[0044] In some embodiments, W 3 and W 4 In some embodiments, A is a direct bond. In some embodiments, A is an optionally substituted C 1-3 In some embodiments, A is -CH 2 -.

[0045] In some embodiments, B is a monocyclic ring. In some embodiments, B is a bicyclic ring. In some embodiments, B is selected from optionally substituted C 6-14 In some embodiments, B is selected from optionally substituted C 3-10 cycloalkyl and optionally substituted 3-14 membered heterocyclyl.

[0046] In some embodiments, W1 and W 2 are all H. In some embodiments, W 1 and W 2 Together they form an oxo group. In some embodiments, W 1 H and W 2 CH 3 In some embodiments, V is H. In some embodiments, V is CH 3 .

[0047] In some embodiments, R' is selected from F and Cl. In some embodiments, R' is F. In some embodiments, R" is selected from F, Cl, optionally substituted C 1-3 Alkyl and optionally substituted C 1-3 In some embodiments, R" is selected from F, Cl, C 1-3 Alkyl and C 1-3 In some embodiments, R" is selected from F and -CH 3 .

[0048] In some embodiments, R'' is selected from a halogen atom, -CN, -OH, an optionally substituted amino group, an optionally substituted amide group, an optionally substituted C 1-5 Alkyl, optionally substituted C 1-5 Alkoxy, optionally substituted C 3-6 cycloalkyl-oxy, optionally substituted 5-10 membered heterocyclyl-oxy, optionally substituted 5-10 membered heteroaryl-oxy, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 5-10 membered aryl, and optionally substituted 5-10 membered heteroaryl. In some embodiments, R'' is selected from F, Cl, -CN, -OH, optionally substituted amino, optionally substituted C 1-3 Alkyl, optionally substituted C 1-3 Alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, and optionally substituted 5-10 membered heteroaryl.

[0049] In some embodiments, R'' is selected from -NH 2 、-NH(CH 3 )、-N(CH 3 ) 2 and -OCH 3 In some embodiments, R'' is C optionally substituted with 1 to 3 groups selected from 1-3 Alkyl: F atom, -O-(C 1-3 Alkyl), -OC4-6 In some embodiments, R'' is C optionally substituted with 1 to 2 groups selected from 3-6 Cycloalkyl: -OH, -C 1-3 Alkoxy and -CH 2 OCH 3 In some embodiments, R'' is a 3-10 membered heterocyclyl optionally substituted with 1 to 3 groups selected from the group consisting of F, OH, optionally substituted with 1 to 3 F atoms or -NH 2 Substituted C 1-3 alkyl, optionally substituted with 1-3 F atoms 1-3 Alkoxy, -C(O)CH 3 、-CH 2 OCH 3 、-NH 2 、-NH(CH 3 ) and -N(CH 3 ) 2 In some embodiments, R'' is a 5-10 membered heteroaryl group optionally substituted with 1 to 3 groups selected from the group consisting of F, Cl, CN, OH, optionally substituted with 1 to 3 F atoms or -NH 2 Substituted C 1-3 alkyl, optionally substituted with 1-3 F atoms 1-3 Alkoxy, -C(O)CH 3 、-CH 2 OCH 3 、-NH 2 、-NH(CH 3 )、-N(CH 3 ) 2 and C4-6 heterocycle.

[0050] In some embodiments, l is 0 or 1. In some embodiments, l is 0. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, n is 0 or 1.

[0051] In some embodiments, the compound is a compound according to formula (II) in A is a direct bond or an optionally substituted C 1-5 alkyl; R' is a halogen atom; R" is selected from halogen atoms, optionally substituted C 1-5 Alkyl and optionally substituted C 1-5 Alkoxy, or two R" may be combined with the carbon to which they are attached to form oxo; Z, Z' and Z" are each independently selected from N and CR 1 ; X, Y, X' and Y' are each independently selected from N and CR 2 ; Each R 1 are independently selected from H, a halogen atom, -CN, an optionally substituted C 1-5 Alkyl, optionally substituted C 1-5 alkoxy, optionally substituted 5-10 membered heteroaryl-oxy, optionally substituted C 3-6 cycloalkyl and optionally substituted 3-6 membered heterocyclyl; Each R 2 are independently selected from H, a halogen atom, -CN, -OH, an optionally substituted amino group, an optionally substituted amide group, an optionally substituted C 1-5 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, and optionally substituted 5-10 membered heteroaryl; l is an integer from 0 to 2; and m is an integer from 0 to 2.

[0052] In some embodiments, A is a direct bond. In some embodiments, A is an optionally substituted C 1-3 In some embodiments, A is -CH 2 -.

[0053] In some embodiments, R' is selected from F and Cl. In some embodiments, R" is selected from F, Cl, optionally substituted C 1-3 Alkyl and optionally substituted C 1-3 Alkoxy.

[0054] In some embodiments, Z, Z' and Z" are all CR 1 In some embodiments, Z is N and Z' and Z" are both CR 1 .

[0055] In some embodiments, X is N and Y, X' and Y' are CR 2 In some embodiments, X and X' are both N, and Y and Y' are both CR 2 In some embodiments, X, Y, X' and Y' are all CR 2 .

[0056] In some embodiments, each R 1 are independently selected from H, F, Cl, -CN, optionally substituted C 1-3 Alkyl, optionally substituted C 1-3 Alkoxy, optionally substituted C3-6 cycloalkyl and optionally substituted 3-6 membered heterocyclyl.

[0057] In some embodiments, each R 2 are independently selected from H, F, Cl, -CN, -OH, optionally substituted amino, optionally substituted amide, optionally substituted C 1-3 Alkyl, optionally substituted C 3-6 cycloalkyl and optionally substituted 4-8 membered heterocyclyl.

[0058] In some embodiments, R 1 or R 2 C 1-3 The alkyl group is selected from halogen, OH and C 1-3 In some embodiments, R 1 or R 2 C 3-6 Cycloalkyl is 1-3 selected from halogen, -OH, C 1-3 Alkyl, C 1-3 Alkoxy and -CH 2 OCH 3 In some embodiments, R 1 3-6 membered heterocyclic group or R 2 The 4-8 membered heterocyclic group is substituted by 1-3 groups selected from the following: halogen, -OH, C 1-3 Alkyl, C 1-3 Alkoxy, -NH 2 、-NH(CH 3 )、-N(CH 3 ) 2 and -C(O)CH 3 .

[0059] In some embodiments, l is 0 or 1. In some embodiments, l is 0. In some embodiments, m is 0 or 1. In some embodiments, m is 0.

[0060] In some embodiments, the compound is a compound according to formula (IIa) in A is a direct bond or an optionally substituted C 1-5 alkyl; R' is a halogen atom; R" is selected from halogen atoms, optionally substituted C 1-5 Alkyl and optionally substituted C 1-5 Alkoxy, or two R" may be combined with the carbon to which they are attached to form oxo; Z is selected from N and CR3 ; X, X' and Y' are each independently selected from N and CR 4 ; R 1 and R 3 are each independently selected from H, a halogen atom, -CN, an optionally substituted C 1-5 Alkyl, optionally substituted C 1-5 alkoxy, optionally substituted 5-10 membered heteroaryl-oxy, optionally substituted C 3-6 cycloalkyl and optionally substituted 3-6 membered heterocyclyl; R 2 and R 4 are each independently selected from H, a halogen atom, -CN, -OH, oxo, an optionally substituted amino group, an optionally substituted amide group, an optionally substituted C 1-5 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, and optionally substituted 5-10 membered heteroaryl; l is an integer from 0 to 1; and m is an integer from 0 to 1.

[0061] In some embodiments, A is a direct bond. In some embodiments, A is an optionally substituted C 1-3 In some embodiments, A is -CH 2 -.

[0062] In some embodiments, R' is selected from F and Cl. In some embodiments, R" is selected from F, Cl, optionally substituted C 1-3 Alkyl and optionally substituted C 1-3 Alkoxy.

[0063] In some embodiments, Z is N. In some embodiments, Z is CR 1 In some embodiments, X is N and X' and Y' are both CR 2 In some embodiments, X and X' are both N and Y' is CR 2 In some embodiments, X, X' and Y' are all CR 2 .

[0064] In some embodiments, R 1 and R 3 are each independently selected from H, F, Cl, -CN, optionally substituted C 1-3 Alkyl, optionally substituted C 1-3 Alkoxy, optionally substituted C 3-6In some embodiments, R 1 are independently selected from H and F. In some embodiments, R 3 For H.

[0065] In some embodiments, R 2 and R 4 are each independently selected from H, F, Cl, -CN, -OH, oxo, optionally substituted amino, optionally substituted amide, optionally substituted C 1-3 Alkyl, optionally substituted C 3-6 In some embodiments, R 2 independently selected from optionally substituted C 1-3 In some embodiments, R 4 For H.

[0066] In some embodiments,

[0067] In some embodiments, R 2 for

[0068] In some embodiments, l is 0. In some embodiments, m is 0.

[0069] In some embodiments, the compound is according to formula (III): in A is a direct bond or an optionally substituted C 1-5 alkyl; R' is a halogen atom; R" is selected from halogen atoms, optionally substituted C 1-5 Alkyl and optionally substituted C 1-5 Alkoxy, or two R" may be combined with the carbon to which they are attached to form oxo; Z is selected from N, CH and CR 3 ; Each R 3 are independently selected from -CN, optionally substituted C 1-5 Alkyl, optionally substituted C 3-6 alkoxy, optionally substituted 3-6 membered heterocyclyl, optionally substituted 5-10 membered aryl, and optionally substituted 5-10 membered heteroaryl; l is an integer from 0 to 2; m is an integer from 0 to 2; and p is an integer from 0 to 3.

[0070] In some embodiments, A is a direct bond. In some embodiments, A is an optionally substituted C 1-3 In some embodiments, A is -CH 2 -.

[0071] In some embodiments, R' is selected from F and Cl. In some embodiments, R" is selected from F, Cl, optionally substituted C 1-3 Alkyl and optionally substituted C 1-3 Alkoxy.

[0072] In some embodiments, Z is N. In some embodiments, Z is CH.

[0073] In some embodiments, each R 3 are independently selected from -CN, optionally substituted C 1-3 alkyl, optionally substituted 3-6 membered heterocyclyl, and optionally substituted 5-10 membered heteroaryl.

[0074] In some embodiments, l is 0 or 1. In some embodiments, l is 0. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, p is an integer from 0 to 2. In some embodiments, p is 0 or 1.

[0075] In some embodiments, the compound is according to formula (IIIa) or (IIIb): in A is a direct bond or an optionally substituted C 1-5 alkyl; R' is a halogen atom; R" is selected from halogen atoms, optionally substituted C 1-5 Alkyl and optionally substituted C 1-5 Alkoxy, or two R" may be combined with the carbon to which they are attached to form oxo; R 4 is an optionally substituted 3-6 membered heterocyclic group; l is 0 or 1; m is 0 or 1; and q is 0 or 2.

[0076] In some embodiments, A is a direct bond. In some embodiments, A is an optionally substituted C 1-3 In some embodiments, A is -CH 2 -.

[0077] In some embodiments, R' is selected from F and Cl. In some embodiments, R" is selected from F, Cl, optionally substituted C 1-3 Alkyl and optionally substituted C 1-3 In some embodiments, R 4 is an optionally substituted 6-membered heterocyclic group.

[0078] In some embodiments, l is 0. In some embodiments, m is 0. In some embodiments, q is 0 or 1.

[0079] In some embodiments, the compound is a compound of Table 1. In some embodiments, the compound is a compound of Table 2.

[0080] In the description herein, it should be understood that each description, variation, embodiment or aspect of one part can be combined with each description, variation, embodiment or aspect of other parts, just as each and every combination described is specifically and separately listed. For example, each description, variation, embodiment or aspect of the "B" group of formula (I) provided herein can be combined with A, W 1 , W 2 , V, R', R", R'", l, m and n, each description, variation, embodiment or combination of aspects, as if each and every combination were specifically and individually listed. It is also understood that all descriptions, variations, embodiments or aspects of formula (I) are equally applicable to other chemical formulas described in detail herein, as appropriate, and are described equally as if each description, variation, embodiment or aspect were listed separately and individually for all chemical formulas. It is also understood that all descriptions, variations, embodiments or aspects of formula (I) are equally applicable to any of the formulas described in detail herein, such as formulas (II), (IIa), (III), (IIIa) and (IIIb), as appropriate, and are described equally as if each and every description, variation, embodiment or aspect were listed separately and individually for all formulas.

[0081] In some embodiments, a compound selected from the compounds in Table 1 or 2 or a pharmaceutically acceptable salt thereof is provided. Although certain compounds described herein (including in Tables 1 and 2) may be present as specific stereoisomers and / or non-stereochemical forms, it should be understood that any or all stereochemical forms of the compounds of the present invention (including in Tables 1 and 2) are described herein, including any enantiomer or non-enantiomer form, and any tautomer or other form. Table 1. or a pharmaceutically acceptable salt thereof.

[0082] It is understood that in the present specification, combinations of substituents and / or variables of the depicted chemical formulas are permissible only if such actions result in stable compounds.

[0083] In addition, all compounds of formula (I) that exist in free alkali or free acid form can be converted into their pharmaceutically acceptable salts by methods known to those skilled in the art with appropriate inorganic or organic bases or inorganic or organic acids. The salts of compounds of formula (I) can be converted into their free alkali or free acid forms by standard techniques. Synthesis method

[0084] The compounds described herein can be prepared using conventional organic synthesis and commercially available starting materials or methods provided herein. By way of example and not limitation, compounds of formula (I) can be prepared as outlined in Schemes 1-3 and ii-i8 and the Examples described herein. It should be noted that one skilled in the art will know how to modify the procedures described in the illustrative schemes and Examples to obtain the desired product, including, for example, selecting starting materials (or racemic starting materials) with different stereochemistry to obtain the desired product with different stereochemistry.

[0085] In general, compounds of formula (I) can be obtained by reacting the aldehyde of interest with an amine in the pyrrolidinyl group of formula (I). In some embodiments, the reaction of the aldehyde is the last step in the reaction sequence. See, for example, the following Flow 1 and 2. In some embodiments, the reaction of the aldehyde with the amine in the pyrrolidinyl group is carried out in the middle of the reaction sequence. See, for example, the following Flow 3. The preparation of the aldehyde intermediate can be achieved by, for example, the synthetic pathways shown in Flow 11 to 18. Unless otherwise noted, all reactions in the flow are at room temperature. Process 1.

[0086] As outlined in Scheme 1, compound A can be synthesized by condensing starting material a and starting material b under basic conditions to produce intermediate c. The nitrile group of intermediate c can be reduced to an aldehyde, for example, with a Raney nickel catalyst, to form intermediate d, which can then be condensed with a dicarboximide intermediate e in the presence of a reducing agent such as sodium triacetoxyborohydride to form intermediate f. Pyrrolidine is deprotected under acidic conditions to give intermediate g, which can then be reductively alkylated with aldehyde h to produce compound A. As noted above, one skilled in the art will know how to modify these procedures to obtain desired products other than compound A, including, for example, selecting starting materials with different stereochemistry (or racemic starting materials) to obtain desired products with different stereochemistry than compound A. Process 2.

[0087] As outlined in Scheme 2, compound B can be synthesized by coupling glutarimide starting material e to starting material i to form intermediate j, which can then be protected to form intermediate k. Subsequent Pd-catalyzed substitution under basic conditions can provide intermediate l, which can form intermediate m via Mitsunobu reaction with intermediate b. Intermediate m can then be deprotected to form intermediate n and coupled with aldehyde o to produce compound B. As noted above, one skilled in the art will know how to modify these procedures to obtain desired products other than compound B, including, for example, selecting starting materials with different stereochemistry (or racemic starting materials) to obtain desired products with different stereochemistry than compound B. Process 3.

[0088] As outlined in Scheme 3, compound C can be synthesized by brominating starting material i to form intermediate o, which can then be coupled with amide p to form intermediate q. Intermediate q can be coupled with intermediate r to form intermediate s, which can undergo Pd-catalyzed hydrogenolysis to form intermediate t. Aldehyde h can be coupled with intermediate t to form intermediate u, which can then undergo a cyclization reaction to produce compound C. As noted above, one skilled in the art will know how to modify these procedures to obtain desired products other than compound C, including, for example, selecting starting materials with different stereochemistry (or racemic starting materials) to obtain desired products with different stereochemistry than compound C. In fact, compound C is a single stereoisomer of compound A in Scheme 1.

[0089] Aldehyde intermediates useful in the synthesis of compounds of formula (I) can be prepared as outlined in Schemes il-i8 and in the Examples described herein. It should be noted that one skilled in the art will know how to modify the procedures described in the illustrative schemes and examples to obtain the desired products. Process i1.

[0090] As outlined in Scheme il, aldehydes such as aldehyde iA can be synthesized by reducing starting material ia to form intermediate ib, which can be condensed with intermediate ic under basic conditions to form intermediate id containing a fused conjugated ring system. Pd-catalyzed Suzuki coupling of intermediate id with intermediate ie can form intermediate if, wherein the olefin of intermediate if can undergo oxidation to form aldehyde iA. Process i2.

[0091] As outlined in Scheme i2, aldehyde iB can be synthesized by coupling starting material ig with starting material ih under basic conditions to form intermediate ii, which can then undergo a Pd-catalyzed Suzuki coupling with intermediate ie to form intermediate if. Oxidation of the olefin of intermediate if can provide aldehyde iB. Process i3.

[0092] As outlined in Scheme i3, aldehyde iC can be synthesized by combining starting material ij with an amine such as 1-methylpiperazine to form intermediate ik, followed by Pd-catalyzed Suzuki coupling with intermediate ie to form intermediate il, which can then undergo oxidation to form aldehyde iC. Quinazolines equivalent to aldehyde iC can be prepared following Scheme i3, but starting with quinazolines equivalent to starting material ij. Process i4.

[0093] As outlined in Scheme i4, aldehyde iD can be synthesized by coupling starting material in and starting material io to form intermediate ip, which can then undergo intramolecular condensation to form intermediate iq. Oxidation of intermediate iq can form intermediate ir, which can then be coupled with olefin intermediate ie to form intermediate is. Oxidation of the olefin provides aldehyde iD. Process i5.

[0094] As outlined in Scheme i5, aldehyde iE can be synthesized by combining starting material it with an amine such as 1-methylpiperazine to form intermediate iu, followed by Pd-catalyzed Suzuki coupling with intermediate ie to form intermediate iv, which can then be oxidized to produce aldehyde iE. Process i6.

[0095] As outlined in Scheme i6, aldehyde iF can be synthesized by combining intermediate iw with an amine such as piperidin-4-ol to produce aldehyde iF. Process i7.

[0096] As outlined in Scheme i7, aldehyde iG can be synthesized by combining starting material ix with an amine such as 3-methoxyazetidine to produce intermediate iy. Intermediate iy can then be reduced using lithium borohydride, for example, to give intermediate iz, which can then be subjected to Dess-Martin oxidation to provide aldehyde iG. Process i8.

[0097] As outlined in Scheme i8, aldehyde iG can be synthesized by coupling starting material ia' with pyrrolidin-2-one to produce intermediate iH. How to use

[0098] Embodiments of the present invention provide a method of degrading WEE1, a method of reducing WEE1 protein content, and a method of preventing or treating a disease such as cancer in a subject in need thereof.

[0099] In one aspect, provided herein is a method for degrading WEE1 in a subject in need thereof, the method comprising contacting a cell with an effective amount of a compound of formula (I). The degradation of WEE1 can be assessed and confirmed by a variety of methods known in the art. Kits and commercially available assays, including cell-based assays, can be used to determine whether WEE1 has been degraded and the extent of its degradation. In some embodiments, the compound of formula (I) partially degrades WEE1. In some embodiments, the compound of formula (I) completely degrades WEE1.

[0100] In some embodiments, the compound of formula (I) degrades WEE1 by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the compounds of formula (I) degrade WEE1 by about 1-100%, 5-100%, 10-100%, 15-100%, 20-100%, 25-100%, 30-100%, 35-100%, 40-100%, 45-100%, 50-100%, 55-100%, 60-100%, 65-100%, 70-100%, 75-100%, 80-100%, 85-100%, 90-100%, 91-100%, 92-100%, 93-100%, 94-100%, 96-100%, 97-100%, 98-100%, 99-100%, 100-100%, 101-100%, 102-100%, 103-100%, 104-100%, 105-100%, 106-100%, 107-100%, 108-100%, 109-100%, 110-100%, 111-100%, 112-100%, 113-113%, 114-113%, 115-113%, 116-113%, 117-113%, 118-119%, 119-119%, 120-1 5-100%, 90-100%, 95-100%, 5-95%, 5-90%, 5-85%, 5-80%, 5-75%, 5-70%, 5-65%, 5-60%, 5-55%, 5-50%, 5-45%, 5-40%, 5-35%, 5-30%, 5-25%, 5-20%, 5-15%, 5-10%, 10-90%, 20-80%, 30-70% or 40-60%.

[0101] In some embodiments, provided herein is a method for reducing WEE1 kinase protein levels, the method comprising contacting a cell with an effective amount of a compound of formula (I). The reduction in WEE1 kinase protein levels can be assessed and confirmed by a variety of methods known in the art. Kits and commercially available assays, including cell-based assays, can be used to determine whether kinase protein levels have been reduced and the extent of the reduction.

[0102] In some embodiments, the compound of formula (I) reduces WEE1 kinase protein levels by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%. In some embodiments, the compounds of formula (I) reduce WEE1 kinase protein levels by about 1-100%, 5-100%, 10-100%, 15-100%, 20-100%, 25-100%, 30-100%, 35-100%, 40-100%, 45-100%, 50-100%, 55-100%, 60-100%, 65-100%, 70-100%, 75-100%, 80-100%, 85-100%, 90-100%, 91-100%, 92-100%, 93-100%, 94-100%, 96-100%, 97-100%, 98-100%, 99-100%, 100-100%, 101-100%, 102-100%, 103-100%, 104-100%, 105-100%, 106-100%, 107-100%, 108-100%, 109-100%, 110-100%, 111-100%, 112-100%, 113-113 0%, 85-100%, 90-100%, 95-100%, 5-95%, 5-90%, 5-85%, 5-80%, 5-75%, 5-70%, 5-65%, 5-60%, 5-55%, 5-50%, 5-45%, 5-40%, 5-35%, 5-30%, 5-25%, 5-20%, 5-15%, 5-10%, 10-90%, 20-80%, 30-70% or 40-60%.

[0103] In some embodiments, the compound of formula (I) has an EC of about 0.0003 μM to about 1 μM, or about 0.0003 μM to about 0.2 μM, or about 0.0003 μM to about 0.05 μM as measured in a WEE1 degradation assay. 50 In some embodiments, the compound of formula (I) has an EC of about 0.05 μM to about 0.2 μM. 50 In some embodiments, the compound of formula (I) has an EC of about 0.2 μM to about 1 μM. 50 In some embodiments, the compound of formula (I) has an EC50 of less than about 1 μM. In some embodiments, the compound of formula (I) has an EC50 value of less than 0.2 μM, less than 0.05 μM, less than 0.001 μM, or less than about 0.0003 μM.

[0104] In another aspect, provided herein is a method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I). In some embodiments, provided herein is a method for preventing cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I). In some embodiments, the cancer is selected from the group consisting of brain cancer, neck and brain cancer, esophageal cancer, thyroid cancer, small cell cancer, non-small cell cancer, breast cancer, lung cancer, stomach cancer, gallbladder / bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, uterine corpus cancer, uterine cervical cancer, renal pelvis / ureter cancer, bladder cancer, prostate cancer, penis cancer, testicular cancer, fetal cancer, Wilms' cancer, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's tumor, soft tissue sarcoma, acute leukemia, chronic lymphatic leukemia, chronic myelocytic leukemia, polycythemia vera, malignant lymphoma, multiple myeloma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma.

[0105] In some embodiments, the cancer is selected from gastric cancer, lung cancer, pancreatic cancer, ovarian cancer, breast cancer, skin cancer, colon cancer, neuroblastoma, osteosarcoma, uterine cancer, rectal cancer, and kidney cancer. In some embodiments, the cancer is selected from pancreatic ductal adenocarcinoma (PDAC), small cell lung cancer, non-small cell lung cancer (NSCLC), high-grade serous ovarian cancer, triple-negative breast cancer, uterine serous carcinoma, Ewing's sarcoma, melanoma, colon cancer, and clear cell renal cell carcinoma (ccRCC).

[0106] In some embodiments, administering a compound of formula (I) to a subject susceptible to cancer can prevent the subject from experiencing any symptoms of cancer (such as tumor growth or cancer metastasis). In some embodiments, administering a compound of formula (I) to a subject who has not yet shown symptoms of cancer can prevent the subject from experiencing any symptoms of cancer. In some embodiments, administering a compound of formula (I) to a subject in need can reduce the extent of the subject's cancer. In some embodiments, administering a compound of formula (I) to a subject in need can stabilize the cancer (prevent or delay the worsening of the cancer). In some embodiments, administering a compound of formula (I) to a subject in need can delay the occurrence or recurrence of cancer. In some embodiments, administering a compound of formula (I) to a subject in need can slow the progression of cancer. In some embodiments, administering a compound of formula (I) to a subject in need can provide partial relief of cancer. In some embodiments, administering a compound of formula (I) to a subject in need can provide overall relief of cancer. In some embodiments, administering a compound of formula (I) to a subject in need can reduce the dose of one or more other drugs required to treat cancer. In some embodiments, administering a compound of formula (I) to a subject in need can enhance the effect of another drug used to treat cancer. In some embodiments, administering a compound of formula (I) to a subject in need thereof can delay the progression of cancer. In some embodiments, administering a compound of formula (I) to a subject in need thereof can improve the quality of life of a subject with cancer. In some embodiments, administering a compound of formula (I) to a subject in need thereof can prolong the survival of a subject with cancer.

[0107] In one aspect, provided herein is a method of preventing a subject susceptible to cancer from developing cancer, the method comprising administering to the subject a compound of formula (I).

[0108] In some aspects, a method of reducing the extent of cancer in a subject is provided herein, the method comprising administering a compound of formula (I) to the subject. In some embodiments, a method for stabilizing cancer in a subject is provided herein, the method comprising administering a compound of formula (I) to the subject. In some embodiments, the method prevents the deterioration of cancer.

[0109] In another aspect, provided herein is a method for delaying the onset or recurrence of cancer in a subject, the method comprising administering to the subject a compound of Formula (I).

[0110] In some embodiments, a method of slowing down the progression of cancer in a subject is provided herein, the method comprising administering a compound of formula (I) to the subject. In some embodiments, the method provides partial relief of cancer. In some embodiments, the method provides complete relief of cancer.

[0111] In other aspects, provided herein are methods for reducing the dosage of one or more other drugs required for treating cancer in a subject, the method comprising administering a compound of formula (I) to the subject. In some embodiments, provided herein are methods for enhancing the effect of another drug for treating cancer in a subject, the method comprising administering a compound of formula (I) to the subject.

[0112] Also provided herein is a method for delaying the progression of cancer in a subject, the method comprising administering a compound of formula (I) to the subject. In some embodiments, the method improves the quality of life of a subject suffering from cancer. In some embodiments, the method prolongs the survival of a subject suffering from cancer.

[0113] In some embodiments, the compound of formula (I) can be used to manufacture a medicament for reducing WEE1 kinase protein levels. In some embodiments, the compound of formula (I) can be used to manufacture a medicament for preventing or treating a disease associated with WEE1. In some embodiments, the compound of formula (I) can be used to manufacture a medicament for preventing or treating cancer. In some embodiments, cancer is selected from gastric cancer, lung cancer, pancreatic cancer, ovarian cancer, breast cancer, skin cancer, colon cancer, neuroblastoma, osteosarcoma, uterine cancer, rectal cancer and renal cancer. In some embodiments, cancer is selected from pancreatic ductal adenocarcinoma (PDAC), small cell lung cancer, non-small cell lung cancer (NSCLC), high-grade serous ovarian cancer, triple-negative breast cancer, uterine serous carcinoma, Ewing's sarcoma, melanoma, colon cancer and clear cell renal cell carcinoma (ccRCC).

[0114] The methods and uses of the present invention may include compounds of formula (I) used alone or in combination with one or more additional therapies (eg, non-drug therapies or therapeutic agents).

[0115] The compound of formula (I) may be administered before, after, or simultaneously with one or more of such additional therapies. When combined, the dose of the compound of formula (I) and the dose of one or more additional therapies (e.g., non-drug treatments or therapeutic agents) may provide a therapeutic effect (e.g., a synergistic or additive therapeutic effect). The compound of formula (I) and the additional therapy (such as an anticancer agent) may be administered together (such as in a single pharmaceutical composition) or separately, and when administered separately, this may occur simultaneously or sequentially. Such sequential administration may be close or distant in time.

[0116] In some embodiments, the other therapy is the administration of a side effect limiter (e.g., an agent intended to reduce the occurrence or severity of a therapeutic side effect). For example, in some embodiments, the compound of formula (I) can be used in combination with a therapeutic agent for treating nausea. Examples of agents that can be used to treat nausea include, but are not limited to, dronabinol, granisetron, metoclopramide, ondansetron, prochlorperazine, and pharmaceutically acceptable salts thereof.

[0117] In some embodiments, one or more additional therapies include non-drug therapies (e.g., surgery or radiation therapy). In some embodiments, one or more additional therapies include therapeutic agents (e.g., compounds or biologics as antiproliferative agents). In some embodiments, one or more additional therapies include non-drug therapies and therapeutic agents. In other embodiments, one or more additional therapies include two therapeutic agents. In other embodiments, one or more other therapies include three therapeutic agents. In some embodiments, one or more additional therapies include four or more therapeutic agents. Pharmaceutical compositions and routes of administration

[0118] The compounds provided herein can be administered to a subject orally, topically or parenterally in conventional preparations such as capsules, microcapsules, tablets, granules, powders, dragees, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions.

[0119] The compounds disclosed herein can be administered to a subject orally, topically or parenterally in conventional preparation forms such as capsules, microcapsules, tablets, granules, powders, dragees, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions. Suitable formulations can be prepared by conventional methods using conventional organic or inorganic additives such as excipients (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose or starch), disintegrants (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or citric acid). The effective amount of the compound of formula (I) in the pharmaceutical composition may be in an amount that will achieve the desired effect; for example, for oral and parenteral administration, about 0.005 mg per kg of subject body weight to about 10 mg per kg of subject body weight in a unit dose.

[0120] The dosage of the compound of formula (I) to be administered to the subject varies widely and may be subject to the judgment of the health care practitioner. In general, the compounds disclosed herein can be administered one to four times a day at a dosage of about 0.001 mg per kilogram of subject body weight to about 10 mg per kilogram of subject body weight, but the above dosage can be appropriately changed depending on the age, weight and medical condition of the subject and the type of administration. In one embodiment, the dosage is about 0.001 mg / kg of subject body weight to about 5 mg / kg of subject body weight, about 0.01 mg / kg of subject body weight to about 5 mg / kg of subject body weight, about 0.05 mg / kg of subject body weight to about 1 mg / kg of subject body weight, about 0.1 mg / kg of subject body weight to about 0.75 mg / kg of subject body weight, or about 0.25 mg / kg of subject body weight to about 0.5 mg / kg of subject body weight. In one embodiment, a dose is administered once a day. In any given case, the dosage of the compound of formula (I) will depend on factors such as the solubility of the active ingredient, the formulation used, and the route of administration.

[0121] In some embodiments, the compound of formula (I) is administered to a subject at a dose of about 0.01 mg / day to about 750 mg / day, about 0.1 mg / day to about 375 mg / day, about 0.1 mg / day to about 150 mg / day, about 0.1 mg / day to about 75 mg / day, about 0.1 mg / day to about 50 mg / day, about 0.1 mg / day to about 25 mg / day, or about 0.1 mg / day to about 10 mg / day.

[0122] In another embodiment, provided herein is a unit dose formulation comprising about 0.1 mg to 500 mg, about 1 mg to 250 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 1 mg to about 25 mg, or about 1 mg to about 10 mg of a compound of Formula (I).

[0123] In a specific embodiment, provided herein is a unit dosage formulation comprising about 0.1 mg or 100 mg of a compound of Formula (I).

[0124] In another embodiment, provided herein is a unit dosage formulation comprising 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400 mg of a compound of Formula (I).

[0125] The compound of formula (I) can be administered once, twice, three times, four times or more per day. As a non-limiting example, a dose of 100 mg or less is administered once daily, and a dose of more than 100 mg is administered twice daily in an amount equal to half of the total daily dose.

[0126] The compound of formula (I) can be administered orally for reasons of convenience. In one embodiment, when administered orally, the compound of formula (I) is administered with a meal and water. In another embodiment, the compound of formula (I) is dispersed in water or fruit juice (e.g., apple juice or orange juice) or any other liquid and is administered orally in the form of a solution or suspension.

[0127] The compounds disclosed herein can also be administered intradermally, intramuscularly, intraperitoneally, transdermally, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, transmucosally, by inhalation or topically to the ear, nose, eye or skin. The mode of administration is determined by the judgment of the health care practitioner and may depend in part on the site of the medical condition.

[0128] In one embodiment, provided herein are capsules containing a compound of Formula (I) without additional carriers, excipients, or vehicles.

[0129] In another embodiment, a composition is provided herein, comprising an effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or vehicle, wherein the pharmaceutically acceptable carrier or vehicle may comprise an excipient, a diluent, or a mixture thereof. In one embodiment, the composition is a pharmaceutical composition.

[0130] The composition may be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, sugar-coated tablets, suppositories, spray-dried dispersions and suspensions and the like. The composition may be formulated to contain a daily dose or a suitable portion of a daily dose in a dosage unit form, which may be a single tablet or capsule or a liquid of a suitable volume. In one embodiment, the solution is prepared from a water-soluble salt such as a hydrochloride. In general, all compositions are prepared according to known methods in pharmaceutical chemistry. Capsules may be prepared by mixing the compound of formula (I) with a suitable carrier or diluent and filling the capsule with an appropriate amount of the mixture. Common carriers and diluents include, but are not limited to, inert powdered substances, such as many different types of starch; powdered cellulose, especially crystalline and microcrystalline cellulose; sugars, such as fructose, mannitol and sucrose; cereal flour and similar edible powders.

[0131] Tablets can be prepared by direct compression, wet granulation or dry granulation. Its formulation is usually combined with diluents, binders, lubricants and disintegrants and compounds. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, inorganic salts (such as sodium chloride) and powdered sugar. Powdered cellulose derivatives are also suitable. Typical tablet binders are substances such as starch, gelatin and sugar, such as lactose, fructose, glucose and the like. Natural and synthetic gums are also suitable, including gum arabic, alginates, methylcellulose, polyvinyl pyrrolidone and the like. Polyethylene glycol, ethyl cellulose and wax can also serve as binders.

[0132] Lubricants may be necessary for tablet formulations to prevent tablets and punches from sticking in the mold. Lubricants may be selected from slippery solids such as talc, magnesium stearate and calcium stearate, stearic acid and hydrogenated vegetable oils. Tablet disintegrants are materials that expand when wetted to break tablets and release compounds. They include starch, clay, cellulose, fucoidin and gum. More specifically, for example corn starch and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponges, cation exchange resins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose and sodium lauryl sulfate may be used. Tablets may be coated with sugar as a flavoring agent and sealant or coated with a film-forming protective agent to change the dissolution properties of tablets. Compositions may also be formulated into chewable tablets, for example, by using materials such as mannitol in formulation.

[0133] When it is desired to administer the compound of formula (I) in suppository form, typical bases may be used. Cocoa butter is a traditional suppository base which may be modified by the addition of waxes to slightly raise its melting point. Water-miscible suppository bases containing, inter alia, polyethylene glycols of various molecular weights are widely used.

[0134] The effect of the compound of formula (I) can be delayed or prolonged by appropriate formulation. For example, slowly soluble aggregates of the compound of formula (I) can be prepared and incorporated into tablets or capsules or as a slowly released implantable device. The technology also includes making pills with several different dissolution rates and filling capsules with a mixture of pills. The tablet or capsule can be coated with a film that resists dissolution for a predictable period of time. Even parenteral preparations can be made long-acting by dissolving or suspending the compound of formula (I) in an oily or emulsifying medium that allows it to be slowly dispersed in serum. Example

[0135] The following examples are presented by way of illustration and not limitation. One skilled in the art may modify the procedures set forth in the illustrative examples to obtain the desired products.

[0136] Salts of compounds described herein can be prepared by standard methods, such as including an acid (e.g., TFA, formic acid, or HCl) in the mobile phase during chromatographic purification, or stirring the product following chromatographic purification with a solution of an acid (e.g., aqueous HCl).

[0137] Unless otherwise noted, all reactions were performed at room temperature.

[0138] The following abbreviations may be relevant to this application. abbreviation Boc tert-Butyloxycarbonyl AIBN Azobisisobutyronitrile ACN Acetonitrile BSA Bis(trimethylsilyl)acetamide DCE 1,2-Dichloroethane DCM Dichloromethane DIEA N,N-Diisopropylethylamine DIPEA N,N-Diisopropylethylamine DME dimethyl ether DMF dimethylformamide DMSO Dimethyl sulfoxide DTBAD Di-tert-butyl azodicarboxylate Dtbbpy 4,4'-Di-tert-butyl-2,2'-bipyridine equiv equivalent ESI Electrospray ionization EtOH Ethanol FA Formic acid h Hour HATU O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HCl hydrochloric acid HOAc Acetic acid HPLC High performance liquid chromatography LAH Lithium Aluminum Hydride led Light Emitting Diode LqCy Lithium tert-butoxide MeCN Acetonitrile MeOH Methanol min minute MS Mass spectrometry NBS N-Bromosuccinimide NMO 4-Methylmorpholine 4-oxide NMP N-Methyl-2-pyrrolidone NMR Nuclear Magnetic Resonance PivOH Pivalic acid PMCB 4-Methoxybenzyl chloride Py Pyridine rt Room temperature RT Residence time sat. saturation t-BuOH Tert-Butanol t-BuOLi Lithium tert-butoxide TEA Triethylamine TFA Trifluoroacetic acid TxH Trifluoromethanesulfonic acid THF Tetrahydrofuran TLC Thin layer chromatography TMP 2,2,6,6-Tetramethylpiperidine Synthesis Example

[0139] It will be apparent to one skilled in the art that the compounds disclosed below and in Tables 1 and 2 may exist in various stereochemical forms. Where the stereochemistry of the ether bond between the pyrrolidine and isoindolinone and the stereochemistry between the piperidine-dione and isoindolinone are shown in the Examples and the compounds in Tables 1 and 2, the stereochemistry is absolute. Other stereocenters where stereochemistry is shown and represented as R or S (e.g., in the B and R'' groups in Formula (I)) may be relative stereochemistry. Example S1. 3-(5-(((S)-1-((2-methylquinazolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0140] N-(4-bromo-2-formylphenyl)acetamide. A solution of 2-amino-5-bromo-benzaldehyde (1.5 g, 7.50 mmol) in acetic anhydride (30 mL) was stirred at 50 ° C under nitrogen for 2 h. The precipitated solid was collected by filtration and washed with ethyl acetate (3×50 mL) to give the title compound (1.7 g, 7.02 mmol, 94% yield) as a light yellow solid. MS (ESI) m / z 242.1 [M+1] + .

[0141] 6-Bromo-2-methylquinazoline. To a solution of N-(4-bromo-2-formyl-phenyl)acetamide (1.7 g, 7.03 mmol) in ethanol (20 mL) was added ammonia (7 M in ethanol, 2 mL, 14 mmol), and the mixture was stirred at 140 ° C under nitrogen for 12 h. The mixture was concentrated and the crude product was recrystallized from 90% hexane / ethyl acetate to give the title compound (1.5 g, 6.72 mmol, 96% yield) as a yellow solid. MS (ESI) m / z 223.1 [M+1] + .

[0142] 2-Methyl-6-vinylquinazoline. To a solution of compound 6-bromo-2-methyl-quinazoline (1.0 g, 4.48 mmol), tributyl(vinyl)stannane (1.7 g, 5.38 mmol) in 1,4-dioxane (10 mL) was added bis(triphenylphosphine)palladium(II) chloride (629 mg, 0.90 mmol) and cesium fluoride (2.0 g, 13.17 mmol) and the mixture was stirred at 100 ° C under nitrogen for 3 h. Water was added to the resulting mixture and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 30% ethyl acetate / petroleum ether) to give the title compound (450 mg, 2.64 mmol, 59% yield) as a light yellow solid. MS (ESI) m / z 171.1 [M+1] + .

[0143] 2-Methylquinazoline-6-carboxaldehyde. To a solution of 2-methyl-6-vinyl-quinazoline (450 mg, 2.64 mmol), 4-methylmorpholine N-oxide (619 mg, 5.29 mmol) and citric acid (1.0 g, 5.29 mmol) in tert-butanol (5 mL) and water (5 mL) was added potassium osmate (97 mg, 0.26 mmol) and the mixture was stirred at room temperature for 5 h. Sodium periodate (1.7 g, 7.93 mmol) was added to the mixture and stirred for another 1 h. Water was added to the resulting mixture and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 50% ethyl acetate / petroleum ether) to give the title compound (220 mg, 1.28 mmol, 48% yield) as a light yellow solid. MS (ESI) m / z 173.1 [M+1] + .

[0144] 3-(5-(((S)-1-((2-methylquinazolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione; hydrochloride (120 mg, 0.33 mmol), 2-methylquinazoline-6-carbaldehyde (79 mg, 0.46 mmol) and triethylamine (50 mg, 0.49 mmol) in dichloromethane (10 mL) was added sodium triacetoxyborohydride (278 mg, 1.31 mmol), and the mixture was stirred at room temperature for 12 h. The resulting solution was concentrated and the residue was purified by silica gel chromatography (0-10% methanol / dichloromethane) and recrystallized from n-hexane / dichloromethane to give the title compound (66.5 mg, 0.14 mmol, 41% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ10.97(s,1H),9.49(s,1H),8.02(s,1H),7.95(d,J=8.8Hz,1H),7.88(d,J=8.7 Hz,1H),7.61(d,J=8.4Hz,1H),7.12(s,1H),7.01(d,J=8.5Hz,1H),5.07(m,2H),4 .37(d,J=17.2Hz,1H),4.25(d,J=17.2Hz,1H),3.85(s,2H),2.99-2.90(m,2H),2 .76(m,5H),2.59(m,2H),2.37(m,2H),1.98-1.80(m,3H); MS(ESI)m / z486.2[M+1] + . Example S2. 3-(5-(((3S,4S)-4-methyl-1-((2-methylquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0145] (3S,4S)-3-((2-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-4-methylpyrrolidine-1-carboxylic acid tert-butyl ester. 3-(5-bromo-1-oxoisoindolin-2-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (200 mg, 0.45 mmol), (3S,4S)-3-hydroxy-4-methylpyrrolidine-1-carboxylic acid tert-butyl ester (182 mg, 0.90 mmol), (4,4'-di-tert-butyl-2,2'-bipyridyl)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridyl-kN)-phenyl-kC]iridium(III) hexafluorophosphorus A vacuum purged solution of 1,2-dimethoxyethane (2 mL) was evacuated and purged with nitrogen three times, followed by irradiation with three 34W blue LEDs. The reactants were stirred at room temperature under nitrogen for 12 h. Water was added to the resulting mixture and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% methanol / dichloromethane) to give the title compound (70 mg, 0.12 mmol, 24% yield) as a light yellow oil. MS (ESI) m / z 586.4 [M+23] + .

[0146] 3-(5-(((3S,4S)-4-methylpyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2,2,2-trifluoroacetic acid. To a stirred solution of (3S,4S)-3-[2-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-1-oxo-isoindolin-5-yl]oxy-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (70 mg, 0.12 mmol) in TFA (1.5 mL) was added trifluoromethanesulfonic acid (0.1 mL). The solution was stirred at 50 °C under nitrogen for 12 h. The mixture was concentrated. The pH of the residue was adjusted to pH about 5 with sodium bicarbonate, filtered and the filtrate was purified by reverse phase flash chromatography (10-40% acetonitrile + 0.05% TFA / water over 25 min) to give the title compound (40 mg, 0.087 mmol, 73% yield) as a light yellow oil. MS (ESI) m / z 344.2 [M+1] + .

[0147] 3-(5-(((3S,4S)-4-methyl-1-((2-methylquinolin-6-yl)methyl)pyrrolidin-3-yl)-oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of 3-[5-[(3S,4S)-4-methylpyrrolidin-3-yl]oxy-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; 2,2,2-trifluoroacetic acid (40 mg, 0.087 mmol), 2-methylquinoline-6-carbaldehyde (25 mg, 0.15 mmol) and triethylamine (22 mg, 0.22 mmol) in dichloromethane (3 mL) was added sodium triacetoxyborohydride (93 mg, 0.44 mmol) at room temperature. The mixture was stirred at room temperature for 3 h. The resulting solution was concentrated and the residue was purified by silica gel chromatography (10% methanol / dichloromethane) and preparative HPLC under the following conditions: SunFire Prep C18 OBD column, 19×150 mm, 5 μm, 10 nm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5B to 25B in 7 min; 254 / 210 nm; RT 1 : 6.67. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (13 mg, 0.026 mmol, 30% yield) as a pale yellow solid. 1 H NMR (400 MHz, methanol-d 4)δ8.35(s,1H),8.22(s,1H),8.04-7.94(m,2H),7.83(d,J=8.7Hz,1H),7.69 (m,1H),7.54-7.46(m,1H),7.12-7.06(m,2H),5.17-5.06(m,2H),4.91-4.8 6(m,4H),3.81(m,1H),3.62(m,1H),3.48(m,1H),3.25(m,1H),2.92(m,1H), 2.81-2.75(m,5H),2.53-2.41(m,1H),2.19(m,1H),1.22(m,3H); MS(ESI)m / z 499.1[M+1] + . Example S3. 2-(2,6-dioxopiperidin-3-yl)-5-(((R)-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl)oxy)isoindoline-1,3-dione

[0148] (R)-dimethyl 4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)phthalate. To a solution of dimethyl 4-hydroxybenzene-1,2-dicarboxylate (840 mg, 4 mmol), tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (1 g, 5.34 mmol) and triphenylphosphine (2 g, 7.61 mmol) in THF (20 mL) was added diisopropyl azodicarboxylate (2 g, 9.89 mmol) at 0 °C. The mixture was stirred at room temperature under nitrogen for 2 h. The resulting mixture was concentrated, and the residue was stirred with diethyl ether. The solid was filtered off and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (0-10% hexane / ethyl acetate) to give the title compound (1 g, 2.63 mmol, 66% yield) as a light yellow oil. MS (ESI) m / z 380.2 [M+1] + .

[0149] (R)-4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)phthalic acid. To a stirred solution of dimethyl 4-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]oxybenzene-1,2-dicarboxylate (1 g, 2.63 mmol) in methanol (30 mL) and water (3 mL) was added sodium hydroxide (624 mg, 15.60 mmol) and the mixture was stirred at 50 °C under nitrogen for 12 h. The mixture was concentrated and the residue was added dropwise in hydrochloric acid (1 M aqueous solution) until pH ~3. The solid was collected and washed with acetone (3 mL) to give the title compound (870 mg, 2.47 mmol, 94% yield) as a light yellow solid. MS (ESI) m / z 352.1 [M+1] + .

[0150] (3R)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-pyrrolidine-1-carboxylic acid tert-butyl ester. A stirred solution of 4-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]oxyphthalic acid (300 mg, 0.85 mmol) and 3-aminopiperidine-2,6-dione; hydrochloride (281 mg, 1.71 mmol) in pyridine (2 mL) was stirred at 150 °C under nitrogen for 3 h. The reaction mixture was diluted with diethyl ether (30 mL) and the solid was collected to give the title compound (300 mg, 0.68 mmol, 80% yield) as a grey solid. MS (ESI) m / z 444.1 [M+1] + .

[0151] 2-(2,6-dioxopiperidin-3-yl)-5-(((R)-pyrrolidin-3-yl)oxy)isoindoline-1,3-dione; hydrochloride. A solution of (3R)-tert-butyl 3-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]oxypyrrolidine-1-carboxylate (300 mg, 0.68 mmol) in hydrochloric acid (4 M in dioxane, 1.70 mL, 6.81 mmol) was stirred at room temperature under nitrogen for 2 h. The solid was collected and washed with diethyl ether (3 mL) and acetone to give the title compound (200 mg, 0.52 mmol, 76% yield) as a light yellow solid. MS (ESI) m / z 344.1 [M+1] + .

[0152] 2-(2,6-dioxopiperidin-3-yl)-5-(((R)-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl)-oxy)isoindoline-1,3-dione. To a solution of compound 2-(2,6-dioxo-3-piperidinyl)-5-[(3R)-pyrrolidin-3-yl]oxy-isoindoline-1,3-dione; hydrochloride (120 mg, 0.32 mmol), quinoline-3-carboxaldehyde (74 mg, 0.47 mmol) and triethylamine (48 mg, 0.47 mmol) in dichloromethane (3 mL) was added sodium triacetoxyborohydride (268 mg, 1.26 mmol), and the mixture was stirred at room temperature under nitrogen for 2 h. The resulting mixture was concentrated. The residue was purified by silica gel chromatography (10% methanol / dichloromethane) and preparative HPLC under the following conditions: Sunfire prep C18 column, 30 * 150 mm, 5 μ m; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5B to 21B in 7 min; 254 / 210 nm; RT1: 7.00; The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (43 mg, 0.09 mmol, 28% yield) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4 )δ8.92(s,1H),8.37(d,J=2.7Hz,1H),8.05(d,J=8.5Hz,1H),7.97(d,J= 8.4Hz,1H),7.79(m,2H),7.65(m,1H),7.39-7.33(m,1H),7.28(m,J=8.5, 4.5,2.3Hz,1H),5.16-5.11(m,2H),4.06(m,2H),3.21-3.12(m,1H),3.0 6(m,2H),2.95-2.65(m,4H),2.51(m,1H),2.18-2.03(m,2H); MS(ESI)m / z 485.2[M+1] + . Example S4. 2-(2,6-dioxopiperidin-3-yl)-5-(((R)-1-(quinolin-6-ylmethyl)pyrrolidin-3-yl)oxy)isoindoline-1,3-dione

[0153] 2-(2,6-dioxopiperidin-3-yl)-5-(((R)-1-(quinolin-6-ylmethyl)pyrrolidin-3-yl)oxy)isoindoline-1,3-dione. To a solution of 2-(2,6-dioxo-3-piperidinyl)-5-[(3R)-pyrrolidin-3-yl]oxy-isoindoline-1,3-dione; hydrochloride (120 mg, 0.32 mmol), quinoline-6-carbaldehyde (74 mg, 0.47 mmol) and triethylamine (48 mg, 0.47 mmol) in dichloromethane (10 mL) was added sodium triacetoxyborohydride (268 mg, 1.26 mmol), and the mixture was stirred at room temperature under nitrogen for 2 h. The resulting mixture was concentrated. The residue was purified by silica gel chromatography (10% methanol / dichloromethane) and preparative HPLC under the following conditions: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5B to 21B in 7 min; 254 / 210 nm; RT1: 7.00. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (59 mg, 0.12 mmol, 38% yield) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4 )δ8.85(m,J=4.3,1.7Hz,1H),8.46(m,J=8.3,1.5Hz,1H),8.04(d,J=8.7Hz,1H),7.97( d,J=1.9Hz,1H),7.86(m,1H),7.78(d,J=8.3Hz,1H),7.55(m,1H),7.35(m,1H),7.27(m ,1H),5.19-5.15(m,1H),5.09(m,1H),4.17-4.04(m,2H),3.22(m,1H),3.19-3.08(m,2 H),2.93-2.79(m,2H),2.79-2.63(m,2H),2.50(m,1H),2.16-2.06(m,2H); MS(ESI)m / z 485.2[M+1] + . Example S5. 2-(2,6-dioxopiperidin-3-yl)-5-(((S)-1-(quinolin-5-ylmethyl)pyrrolidin-3-yl)oxy)isoindoline-1,3-dione

[0154] 2-(2,6-dioxopiperidin-3-yl)-5-(((S)-1-(quinolin-5-ylmethyl)pyrrolidin-3-yl)oxy)isoindoline-1,3-dione. To a solution of compound 2-(2,6-dioxo-3-piperidinyl)-5-[(3R)-pyrrolidin-3-yl]oxy-isoindoline-1,3-dione; hydrochloride (120 mg, 0.32 mmol), quinoline-5-carboxaldehyde (74 mg, 0.47 mmol) and triethylamine (47 mg, 0.47 mmol) in dichloromethane (10 mL) was added sodium triacetoxyborohydride (268 mg, 1.26 mmol), and the mixture was stirred at room temperature under nitrogen for 2 h. The resulting mixture was concentrated and purified by silica gel chromatography (10% methanol / dichloromethane) and preparative HPLC under the following conditions: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5B to 21B in 7 min; 254 / 210 nm; RT1: 7.00. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (35 mg, 0.072 mmol, 24% yield) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4 )δ8.90-8.81(m,2H),8.01(d,J=8.5Hz,1H),7.81-7.70(m,2H),7.68-7.62(m,2H),7.33(d,J=2.3Hz,1H),7.25(m,1H),5.16 -5.12(m,2H),4.29(s,2H),3.17(m,1H),3.06-2.95(m,2H),2.81-2.71(m,4H),2.44(m,1H),2.16-1.96(m,2H); MS(ESI)m / z 485.0[M+1] + . Example S6. 3-(5-(((S)-1-((2-methylquinolin-6-yl)methyl)pyrrolidin-3-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0155] 3-(5-(((S)-1-((2-methylquinolin-6-yl)methyl)pyrrolidin-3-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of 3-(1-oxo-5-(((S)-pyrrolidin-3-yl)amino)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (80 mg, 0.22 mmol), 2-methylquinoline-6-carbaldehyde (56 mg, 0.33 mmol) and triethylamine (33 mg, 0.33 mmol) in dichloromethane (10 mL) was added sodium triacetoxyborohydride (186 mg, 0.87 mmol) and the resulting mixture was stirred at room temperature under nitrogen for 12 h. The reaction mixture was concentrated and purified by preparative HPLC under the following conditions: column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5B to 21B in 7 min; 254 / 210 nm; RT 1 : 7.00. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (14 mg, 0.029 mmol, 9% yield) as a pale yellow solid. 1 H NMR (400 MHz, methanol-d 4 )δ8.35(s,H),8.26(d,J=8.5Hz,1H),8.04-7.95(m,2H),7.83(dd,J=8.7,2. 0Hz,1H),7.58-7.46(m,2H),6.76-6.67(m,2H),5.09(dd,J=13.3,5.1Hz,1H ),4.36-4.21(m,5H),3.45(m,1H),3.30(m,1H),3.15(m,1H),3.00(m,1H),2 .85(m,1H),2.75(m,1H),2.49(m,2H),2.15(m,1H),1.90(m,1H); MS(ESI)m / z 484.3[M+1] + . Example S7. 3-(1-oxo-5-(((R)-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl)methyl)isoindolin-2-yl)-piperidine-2,6-dione

[0156] (3S)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester. To a solution of 3-(5-bromo-1-oxoisoindolin-2-yl)-piperidine-2,6-dione (300 mg, 0.93 mmol) in acetonitrile (20 mL) were added (S)-tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate (737 mg, 2.79 mmol), quinuclidine (10 mg, 0.093 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (12 mg, 0.046 mmol), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridyl-kN)phenyl-kC]iridium(III) hexafluorophosphate (10 mg, 0.0093 mmol), nickel(II) chloride ethylene glycol dimethyl ether complex (10 mg, 0.046 mmol), and potassium carbonate (128 mg, 0.93 mmol). The mixture was stirred at room temperature under nitrogen with a 34W blue LED for 16 h. Water was added to the resulting mixture and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% methanol / dichloromethane) to give the title compound (285 mg, 0.66 mmol, 71% yield) as a yellow solid. MS (ESI) m / z 428.2 [M+1] + .

[0157] 3-(1-Oxo-5-(((S)-pyrrolidin-3-yl)methyl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride. To a solution of tert-butyl (3S)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)pyrrolidine-1-carboxylate (285 mg, 0.66 mmol) in 1,4-dioxane (4 mL) was added hydrogen chloride (1 M in dioxane, 20 mL, 20 mmol). The mixture was stirred at room temperature under nitrogen for 12 h. The solid was collected to give the title compound (180 mg, 0.55 mmol, 83% yield) as an off-white solid. MS (ESI) m / z 328.0 [M+1] + .

[0158] 3-(1-oxo-5-(((S)-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl)methyl)isoindolin-2-yl)piperidine-2,6-dione. To a solution of quinoline-3-carbaldehyde (90 mg, 0.58 mmol) in dichloromethane (10 mL) was added 3-(1-oxo-5-(((S)-pyrrolidin-3-yl)-methyl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (160 mg, 0.44 mmol), sodium triacetoxyborohydride (380 mg, 1.80 mmol) and triethylamine (70 mg, 0.70 mmol). The mixture was stirred at room temperature under nitrogen for 12 h. To the resulting mixture was added water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using the following gradient conditions: Column: Sunfire prepC18 column, 30×150 mm, 5 μm; Mobile phase A: water (0.05% formic acid), Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 5B to 18B in 7 min; 254 / 210 nm; RT1: 6.45. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (26.6 mg, 0.057 mmol, 10% yield) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4 )δ9.01(d,J=2.2Hz,1H),8.62(d,J=2.2Hz,1H),8.14(d,J=8.5Hz,1H),8.07(d,J =8.2Hz,1H),7.93(t,J=8.5,6.9,1.4Hz,1H),7.76(m,2H),7.49-7.43(m,2H),5.1 7(dd,J=13.3,5.1Hz,1H),4.69(s,2H),4.56-4.41(m,2H),3.59(m,2H),2.98-2. 86(m,4H),2.85-2.75(m,2H),2.51(m,1H),2.20(m,1H),2.00(m,1H); MS(ESI)m / z 469.1[M+1] + . Example S8. 3-(1-oxo-5-(((S)-1-(quinolin-5-ylmethyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione

[0159] 3-(1-oxo-5-(((S)-1-(quinolin-5-ylmethyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)-piperidine-2,6-dione. To a solution of quinoline-5-carbaldehyde (62 mg, 0.39 mmol) in dichloromethane (10 mL) was added 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione; hydrochloride (100 mg, 0.27 mmol), sodium triacetoxyborohydride (256 mg, 1.21 mmol) and triethylamine (45 mg, 0.45 mmol). The mixture was purged with nitrogen three times and stirred under nitrogen for 12 h. To the mixture was added water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using the following conditions: column: Sunfireprep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% hydrogen chloride), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 2B to 2B in 2 min; 254 / 210 nm; RT1: 7.07. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (47.7 mg, 0.10 mmol, 26%) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4 )δ9.82-9.65(m,1H),9.37(d,J=4.0Hz,1H),8.44(d,J=8.0Hz,1H),8.40-8.25(m,3H),7.75(m,1H),7.22-7.12(m,2H),5.41(m,1H),5 .27(m,2H),5.14(m,1H),4.56-4.39(m,2H),4.21-3.60(m,4H),2.99-2.72(m,2H),2.56-2.44(m,2H),2.39-2.13(m,2H); MS(ESI)m / z 471.2[M+1] + . Example S9. 3-(5-(((S)-1-((1,8- (4-pyridin-4-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione

[0160] 1,8- 4-Methyl-1,8- To a solution of pyridine (370 mg, 2.57 mmol) in 1,4-dioxane (16 mL) and water (2 mL) was added selenium dioxide (569 mg, 5.13 mmol). The mixture was stirred at 80 ° C under nitrogen for 1 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (0 to 50% ethyl acetate / petroleum ether) to give the title compound (296 mg, 1.86 mmol, 73% yield) as an orange oil. MS (ESI) m / z 159.0 [M + 1] + .

[0161] 3-(5-(((S)-1-((1,8- pyridin-4-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione. To a solution of pyridine-4-carboxaldehyde (45 mg, 0.28 mmol) in dichloromethane (10 mL) were added 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione; hydrochloride (80 mg, 0.22 mmol), sodium triacetoxyborohydride (185 mg, 0.87 mmol) and triethylamine (33 mg, 0.33 mmol). The mixture was stirred at room temperature under nitrogen for 12 h. The mixture was concentrated and the residue was purified by preparative HPLC using the following conditions: column: XSelect CSH Prep C18 OBD column, 5 μm, 19*150 mm; mobile phase A: water (0.05% TFA), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 2B to 2B in 2 min; 254 / 210 nm; RT1: 7.50. Fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound as an off-white solid (29.3 mg, 0.062 mmol, 21% yield). 1 H NMR (400 MHz, methanol-d 4)δ9.26-9.19(m,2H),9.02-8.95(m,1H),7.99(d,J=4.0Hz,1H),7.90-7.84(m,1H),7.7 4(dd,J=8.0Hz,J=4.0Hz,1H),7.18-7.06(m,2H),5.38(m,1H),5.23-5.08(m,3H),4.54 -4.36(m,2H),3.95(m,1H),3.91-3.79(m,2H),3.76-3.65(m,1H),2.98-2.85(m,1H),2 .84-2.74(m,1H),2.73-2.63(m,1H),2.57-2.37(m,2H),2.23-2.12(m,1H); MS(ESI)m / z 472.2[M+1] + . Example S10. 3-(1-oxo-6-(((S)-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione

[0162] 3-(1-oxo-6-(((S)-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione. To a solution of quinoline-3-carbaldehyde (65 mg, 0.41 mmol) in dichloromethane (10 mL) were added 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione; hydrochloride (100 mg, 0.27 mmol), sodium triacetoxyborohydride (256 mg, 1.21 mmol) and triethylamine (45 mg, 0.45 mmol). The mixture was stirred at room temperature under nitrogen for 12 h. To the resulting mixture was added water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using the following gradient conditions: Column: XBridgePrep C18 OBD column, 19×150 mm 5 μm; Mobile phase A: water (0.1% formic acid), Mobile phase B: acetonitrile; Flow rate: 25 mL / min; Gradient: 2B to 16B in 8 min; 254, 210 nm; RT1: 7.63. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (41.7 mg, 0.088 mmol, 21%) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4)δ8.93(d,J=4.0Hz,1H),8.06(d,J=8.0Hz,1H),7.97(d,J=8.0Hz,1H),7.84- 7.76(m,1H),7.71(d,J=8.0Hz,1H),7.69-7.61(m,1H),7.11-7.01(m,2H),5.1 7-5.05(m,2H),4.50-4.36(m,2H),4.07(s,2H),3.22-3.12(m,1H),3.11-3.00 (m,2H),2.98-2.74(m,3H),2.55-2.41(m,2H),2.21-2.04(m,2H); MS(ESI)m / z 471.2[M+1] + . Example S11. 3-(1-oxo-5-(((S)-1-(quinolin-4-ylmethyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione

[0163] 3-(1-oxo-5-(((S)-1-(quinolin-4-ylmethyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione. To a solution of quinoline-4-carbaldehyde (84 mg, 0.53 mmol) in dichloromethane (10 mL) was added 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione; hydrochloride (150 mg, 0.41 mmol), sodium triacetoxyborohydride (261 mg, 1.23 mmol) and triethylamine (62 mg, 0.62 mmol). The mixture was stirred under nitrogen for 12 h. The resulting mixture was concentrated. The residue was purified by preparative HPLC using the following gradient conditions: column: Sunfireprep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 2B to 2B in 2 min; 254 / 210 nm; RT1: 8.92. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (58 mg, 0.12 mmol, 23% yield) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4)δ8.81(d,J=4.0Hz,1H),8.40-8.31(m,1H),8.06(d,J=8.0Hz,1H),7.84-7.76( m,1H),7.74-7.58(m,3H),7.08-6.98(m,2H),5.16-5.09(m,1H),5.02(m,1H),4. 44-4.39(m,2H),4.23(d,J=8.0Hz,2H),3.16-3.07(m,1H),2.99-2.84(m,3H),2. 83-2.68(m,2H),2.49-2.37(m,2H),2.16(m,1H),2.06-1.96(m,1H); MS(ESI)m / z 471.2[M+1] + . Example S12. 3-(1-oxo-6-(((R)-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione

[0164] (3R)-tert-butyl 3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)pyrrolidine-1-carboxylate. To a solution of 3-(5-bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (300 mg, 0.93 mmol) in acetonitrile (20 mL) were added (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (736 mg, 3.93 mmol), quinuclidine (10 mg, 0.09 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (12 mg, 0.045 mmol), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-kN)phenyl-kC]iridium(III) hexafluorophosphate (10 mg, 0.01 mmol), nickel(II) chloride dimethoxyethane adduct (10 mg, 0.0455 mmol), and potassium carbonate (128 mg, 0.93 mmol). The reactant was evacuated and purged with nitrogen three times, then irradiated with three 80W blue LEDs at room temperature under nitrogen for 16 h. Water was added to the resulting mixture and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (20 to 70% ethyl acetate / petroleum ether) to give the title compound (250 mg, 0.58 mmol, 62% yield) as a yellow solid. MS (ESI) m / z 430.2 [M+1] + .

[0165] 3-(1-Oxo-5-(((R)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione hydrochloride. To a solution of tert-butyl (3R)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)pyrrolidine-1-carboxylate (250 mg, 0.58 mmol) in 1,4-dioxane (4 mL) was added HCl (1 M in dioxane, 20 mL, 20 mmol). The mixture was stirred at room temperature under nitrogen for 12 h. The solid was filtered and recrystallized from diethyl ether to give the title compound (75 mg, 0.20 mmol, 34% yield) as an off-white solid. MS (ESI) m / z 330.0 [M+1] + .

[0166] 3-(1-oxo-6-(((R)-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione. To a solution of compound quinoline-3-carbaldehyde (41 mg, 0.27 mmol) in dichloromethane (10 mL) was added 3-[1-oxo-5-[(3R)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione hydrochloride (75 mg, 0.20 mmol), sodium triacetoxyborohydride (130 mg, 0.62 mmol) and triethylamine (31 mg, 0.31 mmol). The mixture was stirred at room temperature under nitrogen for 12 h. The resulting mixture was concentrated. The residue was purified by preparative HPLC using the following gradient conditions: column: XSelect CSH Prep C18 OBD column, 5 μm, 19*150 mm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 2B to 25B in 7 min; 254 / 210 nm; RT1: 5.60. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (50.2 mg, 0.11 mmol, 55% yield) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4)δ8.95(d,J=4.0Hz,1H),8.41(s,1H),8.07(d,J=8.0Hz,1H),7.99(d,J=12.0Hz,1 H),7.86-7.78(m,1H),7.75-7.63(m,2H),7.12-7.03(m,2H),5.17-5.08(m,2H),4 .51-4.36(m,2H),4.02(s,2H),3.28(m,1H),3.24-3.14(m,2H),3.01-2.85(m,2H) ,2.80-2.75(m,1H),2.58-2.41(m,2H),2.19-2.10(m,2H); MS(ESI)m / z471.2[M+1] + . Example S13. 3-(1-oxo-5-(((R)-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl)methyl)isoindolin-2-yl)-piperidine-2,6-dione

[0167] (3R)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester. To a solution of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (323 mg, 1.00 mmol) in acetonitrile (20 mL) were added (R)-tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate (792 mg, 3.00 mmol), quinuclidine (11 mg, 0.10 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (13 mg, 0.05 mmol), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridyl-kN)phenyl-kC]iridium(III) hexafluorophosphate (11 mg, 0.01 mmol), nickel(II) chloride ethylene glycol dimethyl ether complex (11 mg, 0.05 mmol), and potassium carbonate (138 mg, 1.00 mmol). The mixture was stirred at room temperature under nitrogen with a 34W blue LED for 16 h. Water was added to the resulting mixture and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% methanol / dichloromethane) to give the title compound (264 mg, 0.62 mmol, 62% yield) as a yellow solid. MS (ESI) m / z 428.2 [M+1] + .

[0168] 3-(1-Oxo-5-(((R)-pyrrolidin-3-yl)methyl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride. To a solution of compound (3R)-tert-butyl 3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)pyrrolidine-1-carboxylate (264 mg, 0.62 mmol) in 1,4-dioxane (4 mL) was added hydrogen chloride (1 M in dioxane, 20 mL, 20 mmol). The mixture was stirred at room temperature under nitrogen for 12 h. The solid was collected to give the title compound (174 mg, 0.48 mmol, 77% yield) as an off-white solid. MS (ESI) m / z 328.0 [M+1] + .

[0169] 3-(1-oxo-5-(((R)-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl)methyl)isoindolin-2-yl)piperidine-2,6-dione. To a solution of quinoline-3-carbaldehyde (45 mg, 0.29 mmol) in dichloromethane (10 mL) was added 3-(1-oxo-5-(((R)-pyrrolidin-3-yl)methyl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (80 mg, 0.22 mmol), sodium triacetoxyborohydride (190 mg, 0.90 mmol) and triethylamine (33 mg, 0.33 mmol). The mixture was stirred at room temperature under nitrogen for 12 h. The resulting mixture was concentrated and the residue was purified by preparative HPLC using the following gradient conditions: column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5B to 18B in 7 min; 254 / 210 nm; RT1: 6.45. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (30.2 mg, 0.064 mmol, 29% yield) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4)δ8.95(d,J=4.0Hz,1H),8.70(d,J=4.0Hz,1H),8.08(d,J=8.0Hz,1H),8.00(dd,J=8.0Hz, J=4.0Hz,1H),7.85(t,J=8.0Hz,1H),7.76-7.65(m,2H),7.45(s,1H),7.40(d,J=8.0Hz,1H) ,5.15(dd,J=12.0Hz,J=4.0Hz,1H),4.54-4.31(m,4H),3.32-3.14(m,3H),2.99-2.85(m,4H) ),2.84-2.69(m,2H),2.57-2.41(m,1H),2.22-2.03(m,2H),1.86-1.72(m,1H); MS(ESI)m / z 469.2[M+1] + . Example S14. 2-(2,6-dioxopiperidin-3-yl)-5-(((S)-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl)oxy)isoindoline-1,3-dione

[0170] (S)-dimethyl 4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)phthalate. To a solution of dimethyl 4-hydroxybenzene-1,2-dicarboxylate (1000 mg, 4.76 mmol), tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (1.19 g, 6.35 mmol) and triphenylphosphine (2.38 g, 9.06 mmol) in THF (20 mL) was added diisopropyl azodicarboxylate (2.38 g, 11.77 mmol) at room temperature under nitrogen, and the mixture was stirred for 2 h. The resulting mixture was concentrated, and the residue was stirred with diethyl ether. The solid was filtered off and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (0-10% hexane / ethyl acetate) to give the title compound (1.5 g, 3.95 mmol, 83% yield) as a light yellow oil. MS (ESI) m / z 380.2 [M+1] + .

[0171] (S)-4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)phthalic acid. To a stirred solution of dimethyl 4-[(3S)-1-tert-butoxycarbonylpyrrolidin-3-yl]oxybenzene-1,2-dicarboxylate (1 g, 2.63 mmol) in methanol (30 mL) and water (3 mL) was added sodium hydroxide (600 mg, 15.00 mmol), and the mixture was stirred at 50 °C under nitrogen for 12 h. The mixture was concentrated and the residue was added dropwise to hydrochloric acid (1 M aqueous solution) until pH about 3. The solid was collected and washed with acetone (3 mL) to give the title compound (720 mg, 2.04 mmol, 78% yield) as a light yellow solid. MS (ESI) m / z 352.1 [M+1] + .

[0172] (3S)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-pyrrolidine-1-carboxylic acid tert-butyl ester. A stirred solution of 4-[(3S)-1-tert-butoxycarbonylpyrrolidin-3-yl]oxyphthalic acid (300 mg, 0.85 mmol) and 3-aminopiperidine-2,6-dione; hydrochloride (281 mg, 1.71 mmol) in pyridine (3 mL) was stirred at 150 °C under nitrogen for 3 h. The reaction mixture was diluted with diethyl ether (30 mL) and the solid was collected to give the title compound (350 mg, 0.68 mmol, 79% yield) as a grey solid. MS (ESI) m / z 444.1 [M+1] + .

[0173] 2-(2,6-dioxopiperidin-3-yl)-5-(((S)-pyrrolidin-3-yl)oxy)isoindoline-1,3-dione hydrochloride. A solution of (3S)-tert-butyl 3-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]oxypyrrolidine-1-carboxylate (300 mg, 0.68 mmol) in hydrochloric acid (4 M in 1,4-dioxane, 3 mL, 12 mmol) was stirred at room temperature under nitrogen for 2 h. The solid was collected and washed with diethyl ether (3 mL) and acetone to give the title compound (250 mg, 0.65 mmol, 96% yield) as a light yellow solid. MS (ESI) m / z 344.1 [M+1] + .

[0174] 2-(2,6-dioxopiperidin-3-yl)-5-(((S)-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl)-oxy)isoindoline-1,3-dione. To a solution of compound 2-(2,6-dioxopiperidin-3-yl)-5-(((S)-pyrrolidin-3-yl)oxy)isoindoline-1,3-dione hydrochloride (120 mg, 0.32 mmol), quinoline-3-carboxaldehyde (74 mg, 0.47 mmol) and triethylamine (48 mg, 0.47 mmol) in dichloromethane (3 mL) was added sodium triacetoxyborohydride (268 mg, 1.26 mmol), and the mixture was stirred at room temperature under nitrogen for 2 h. The resulting mixture was concentrated. The residue was purified by silica gel chromatography (10% methanol / dichloromethane) and preparative HPLC under the following conditions: Sunfire prep C18 column, 30 * 150 mm, 5 μ m; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5B to 21B in 7 min; 254 / 210 nm; RT1: 7.00; The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (43 mg, 0.09 mmol, 28% yield) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4 )δ8.92(s,1H),8.37(d,J=2.7Hz,1H),8.05(d,J=8.5Hz,1H),7.97(d,J= 8.4Hz,1H),7.79(m,2H),7.65(m,1H),7.39-7.33(m,1H),7.28(m,J=8.5, 4.5,2.3Hz,1H),5.16-5.11(m,2H),4.06(m,2H),3.21-3.12(m,1H),3.0 6(m,2H),2.95-2.65(m,4H),2.51(m,1H),2.18-2.03(m,2H); MS(ESI)m / z 485.2[M+1] + . Example S15. 3-(5-(((S)-1-((5-fluoroquinolin-3-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0175] 5-Fluoroquinoline-3-carboxaldehyde. To a solution of 3-bromo-5-fluoro-quinoline (200 mg, 0.88 mmol) in DMSO (3 mL) was added 2-isocyano-2-methyl-propane (88 mg, 1.06 mmol), palladium (II) acetate (10 mg, 0.04 mmol), 1,2-bis(diphenylphosphino)ethane (23 mg, 0.057 mmol) and sodium formate (120 mg, 1.77 mmol). The mixture was stirred at 120 ° C under nitrogen for 3 h. Water was added to the mixture and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 40% ethyl acetate / petroleum ether) to give the title compound (145 mg, 0.82 mmol, 93% yield) as a brown solid. MS (ESI) m / z 176.0 [M+1] + .

[0176] 3-(5-(((S)-1-((5-fluoroquinolin-3-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione; hydrochloride (209 mg, 0.57 mmol) in dichloromethane (10 mL) were added 5-fluoroquinoline-3-carbaldehyde (129 mg, 0.74 mmol), sodium triacetoxyborohydride (363 mg, 1.71 mmol) and triethylamine (86 mg, 0.85 mmol). The mixture was stirred at room temperature under nitrogen for 12 h. To the mixture was added water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using the following gradient conditions: column: XSelect CSH Prep C18 OBD column, 5 μm, 19*150 mm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 5B to 20B in 7 min; 254 / 210 nm; RT1: 6.37. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (17.3 mg, 0.035 mmol, 6% yield) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4)δ9.00(d,J=4.0Hz,1H),8.59(s,1H),7.91(d,J=8.0Hz,1H),7.83-7.69(m,2H),7.38-7.34(m,1H),7.12-7.02(m,2H),5.17-5 .08(m,2H),4.44(m,2H),4.14(m,2H),3.26-3.06(m,3H),2.98-2.73(m,3H),2.56-2.40(m,2H),2.22-2.04(m,2H); MS(ESI)m / z 489.2[M+1] + . Example S16. 3-(5-(((S)-1-((1-methylisoquinolin-3-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0177] (Z)-1-phenylethan-1-one oxime. To a solution of 1-phenylethanone (500 mg, 4.16 mmol) in ethanol (20 mL) was added hydroxylamine hydrochloride (431 mg, 6.24 mmol) and triethylamine (1.74 mL, 12.48 mmol). The mixture was stirred at 85 ° C under nitrogen for 3 h. Water was added to the resulting mixture and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 30% ethyl acetate / petroleum ether) to give the title compound (430 mg, 3.15 mmol, 76% yield) as a light yellow solid. MS (ESI) m / z 136.1 [M + 1] + .

[0178] Methylisoquinoline-3-carbaldehyde. To a solution of 1-phenylethanone oxime (250 mg, 1.85 mmol) in acetonitrile (20 mL) was added prop-2-enal (275 mg, 4.910 mmol), pivalic acid (370 mg, 0.53 mmol), bis[(pentamethylcyclopentadienyl)dichloro-rhodium] (10 mg, 0.10 mmol) and silver (I) carbonate (1000 mg, 5.26 mmol). The mixture was stirred for 12 h under a nitrogen atmosphere. To the resulting mixture was added water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 20% ethyl acetate / petroleum ether) to give the title compound (155 mg, 92% yield) as an off-white solid. MS (ESI) m / z 172.1 [M+1] + .

[0179] 3-(5-(((S)-1-((1-methylisoquinolin-3-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of 1-methylisoquinoline-3-carbaldehyde (70 mg, 0.41 mmol) in dichloromethane (10 mL) was added 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione; hydrochloride (100 mg, 0.27 mmol), sodium triacetoxyborohydride (240 mg, 1.13 mmol) and triethylamine (50 mg, 0.49 mmol). The mixture was stirred under nitrogen for 12 h. The resulting mixture was concentrated. The residue was purified by preparative HPLC using the following gradient conditions: Column: Column: Sunfire prep C18 column, 30*150, 5 μm; Mobile phase A: water (0.1% formic acid), Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 6B to 30B in 7 min; 254 / 210 nm; RT1: 6.38. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (51.9 mg, 0.10 mmol, 26% yield) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4 )δ8.31(d,J=8.0Hz,1H),7.79(d,J=8.0Hz,1H),7.90-7.73(m,4H),7.21-7.09 (m,2H),5.37(m,1H),5.14(dd,J=16.0Hz,J=8.0Hz,1H),4.79-4.66(m,2H),4. 54-4.39(m,2H),3.93-3.76(m,3H),3.76-3.65(m,1H),3.00(s,3H),2.98-2.7 5(m,2H),2.70-2.57(m,1H),2.56-2.42(m,2H),2.21-2.14(m,1H); MS(ESI)m / z 485.2[M+1] + . Example S17. 3-(5-(((S)-1-((7-fluoroisoquinolin-3-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0180] 2-(3,3-diethoxyprop-1-yn-1-yl)-5-fluorobenzaldehyde. To a solution of 2-bromo-5-fluoro-benzaldehyde (1.0 g, 4.93 mmol) in THF (20 mL) was added 3,3-diethoxyprop-1-yn (0.8 g, 6.24 mmol), palladium (II) acetate (0.2 g, 0.89 mmol), triethylamine (1.5 g, 14.78 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (0.90 g, 1.89 mmol). The mixture was stirred at 60 ° C under nitrogen for 12 h. To the resulting mixture was added water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10 to 30% ethyl acetate / petroleum ether) to give the title compound (250 mg, 0.99 mmol, 20% yield) as a yellow solid. MS (ESI) m / z 251.1 [M+1] + .

[0181] 3-(Diethoxymethyl)-7-fluoroisoquinoline. A solution of 2-(3,3-diethoxyprop-1-yn-1-yl)-5-fluorobenzaldehyde (250 mg, 0.99 mmol) in ammonia (7M in methanol, 15 mL) was heated at 100 °C under nitrogen in a microwave reactor under microwave irradiation for 20 min. The solution was concentrated to give the crude title compound, which was used directly in the next step without further purification. MS (ESI) m / z 250.1 [M+1] + .

[0182] 7-Fluoroisoquinoline-3-carbaldehyde. To a solution of 3-(diethoxymethyl)-7-fluoroisoquinoline (335 mg, 1.34 mmol) in water (1 mL) was added hydrochloric acid (6 M aqueous solution, 10 mL). The mixture was stirred under nitrogen for 12 h. The mixture was concentrated and the residue was basified to pH about 7 with saturated sodium bicarbonate and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 25% ethyl acetate / petroleum ether) to give the title compound (70 mg, 0.40 mmol, 30% yield) as a yellow solid. MS (ESI) m / z 176.0 [M+1] + .

[0183] 3-(5-(((S)-1-((7-fluoroisoquinolin-3-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxo-isoindolin-2-yl)piperidine-2,6-dione. To a solution of 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione; hydrochloride (100 mg, 0.27 mmol) in dichloromethane (10 mL) were added 7-fluoroisoquinoline-3-carbaldehyde (62 mg, 0.35 mmol), sodium triacetoxyborohydride (200 mg, 0.81 mmol) and triethylamine (83 mg, 0.82 mmol). The mixture was purged with nitrogen three times and stirred under nitrogen for 12 h. To the resulting mixture was added water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using the following gradient conditions: column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 6B to 30B in 7 min; 254 / 210 nm; RT1: 6.38. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (29.3 mg, 0.060 mmol, 21% yield) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4 )δ9.27(s,1H),8.03(dd,J=8.0Hz,J=4.0Hz,1H),7.94(s,1H),7.82(dd,J=8.0Hz,J=4.0Hz,1H ),7.72(d,J=8.0Hz,1H),7.69-7.61(m,1H),7.11(s,1H),7.09-7.03(m,1H),5.21-5.08(m,2H ),4.53-4.41(m,2H),4.40-4.26(m,2H),3.47-3.38(m,1H),3.38-3.27(m,2H),3.18-3.08(m, 1H),2.98-2.85(m,1H),2.83-2.75(m,1H),2.58-2.41(m,2H),2.25-2.10(m,2H).;MS(ESI)m / z 489.2[M+1] + . Example S18. 3-(6-(((S)-1-((2-methylquinolin-3-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0184] 2-Methylquinoline-3-carboxaldehyde. To a solution of 2-chloroquinoline-3-carboxaldehyde (750 mg, 3.91 mmol) in 1,4-dioxane (15 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxaborane (borinane) (1012 mg, 8.06 mmol), potassium carbonate (1612 mg, 11.74 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (340 mg, 0.39 mmol). The mixture was stirred at 100 ° C under nitrogen for 12 h. Water was added to the resulting mixture and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 90% ethyl acetate / petroleum ether) to give the title compound (350 mg, 2.03 mmol, 52% yield) as a brown solid. MS (ESI) m / z 172.1 [M+1] + .

[0185] 3-(5-(((S)-1-((5-fluoroquinolin-3-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of 3-[1-oxo-6-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione; hydrochloride (100 mg, 0.27 mmol) in dichloromethane (10 mL) was added 2-methylquinoline-3-carbaldehyde (70 mg, 0.41 mmol), sodium triacetoxyborohydride (250 mg, 1.18 mmol) and triethylamine (55 mg, 0.55 mmol). The mixture was stirred under nitrogen for 12 h. The mixture was concentrated and the residue was purified by preparative HPLC using the following gradient conditions: column: XSelect CSH Prep C18 OBD column, 5 μm, 19*150 mm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 5B to 15B in 7 min; 254 / 210 nm; RT1: 6.28. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (27.1 mg, 0.056 mmol, 20% yield) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4)δ8.27(s,1H),7.97(d,J=8.0Hz,1H),7.91(d,J=8.0Hz,1H),7.74(t,J=8.0Hz,1 H),7.57(m,1H),7.48(m,1H),7.31-7.17(m,2H),5.14(dd,J=12.0Hz,J=4.0Hz,1H ),5.05(s,1H),4.50-4.34(m,2H),4.03(s,2H),3.21(m,1H),3.11-2.99(m,2H), 2.97-2.74(m,6H),2.56-2.39(m,2H),2.21-2.03(m,2H); MS(ESI)m / z485.2[M+1] + . Example S19. 3-(1-oxo-5-(((S)-1-(quinazolin-2-ylmethyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione

[0186] 3-(1-Oxo-5-(((S)-1-(quinazolin-2-ylmethyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione. To a solution of 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione; hydrochloride (100 mg, 0.27 mmol) in DMF (3 mL) was added 2-(chloromethyl)quinazoline (60 mg, 0.34 mmol) and triethylamine (140 mg, 1.38 mmol). The mixture was stirred at room temperature under nitrogen for 12 h. The resulting mixture was concentrated and the residue was purified by preparative HPLC using the following gradient conditions: column: XSelect CSH Prep C18 OBD column, 5 μm, 19*150 mm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 5B to 17B in 7 min; 254 / 210 nm; RT1: 5.85. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (59.8 mg, 0.13 mmol, 48%) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4)δ9.57(s,1H),8.15(d,J=8.0Hz,1H),8.11-8.00(m,2H),7.83-7.70(m,2H),7.16-7.06(m,2H),5.26-5.09(m,2H),4.56-4.38(m,4H), 3.54(m,1H),3.50-3.38(m,2H),3.26(m,1H),2.99-2.85(m,1H),2.85-2.74(m,1H),2.61-2.42(m,2H),2.27-2.14(m,2H); MS(ESI)m / z 472.2[M+1] + . Example S20. 3-(5-(((S)-1-((2-chloroquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0187] 3-(5-(((S)-1-((2-chloroquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione; hydrochloride (100 mg, 0.27 mmol) and triethylamine (0.07 mL, 0.50 mmol) in dichloromethane (10 mL) were added 2-chloroquinoline-6-carbaldehyde (65 mg, 0.34 mmol) and sodium triacetoxyborohydride (235 mg, 1.11 mmol). The mixture was stirred at room temperature under nitrogen for 12 h. The resulting mixture was concentrated and the residue was purified by preparative HPLC using the following gradient conditions: column: XSelect CSH Prep C18 OBD column, 5 μm, 19*150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 2B to 8B in 7 min; 254 / 210 nm; RT: 7.20 min. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (59.2 mg, 0.12 mmol, 43% yield) as a light yellow solid. 1 H NMR (400 MHz, methanol-d 4)δ8.33(d,J=8.0Hz,2H),8.04-7.93(m,2H),7.90(d,J=8.0Hz,1H),7.70(d,J=8.0Hz ,1H),7.54(d,J=8.0Hz,1H),7.11-7.01(m,2H),5.18-5.07(m,2H),4.50-4.35(m,2H ),4.28-4.17(m,2H),3.40-3.32(m,1H),3.30-3.18(m,2H),3.09-2.99(m,1H),2.93 -2.84(m,1H),2.83-2.73(m,1H),2.58-2.39(m,2H),2.21-2.11(m,2H); MS(ESI)m / z 505.2[M+1] + . Example S21. 3-(5-(((2S,3S)-2-methyl-1-((2-methylquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0188] (2S,3S)-3-((2-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester. 3-(5-bromo-1-oxoisoindolin-2-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (200 mg, 0.45 mmol), (2S,3S)-3-hydroxy-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (272 mg, 1.35 mmol), (4,4'-di-tert-butyl-2,2'-bipyridyl)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridyl-kN)phenyl-kC]iridium (III) hexafluorophosphate (5 mg, 0.005 mmol), quinuclidine (12 mg, 0.11 mmol), potassium carbonate (62 mg, 0.45 mmol) in anhydrous acetonitrile (4 mL) were added nickel (II) chloride dimethoxyethane adduct (5 mg, 0.023 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (6 mg, 0.022 mmol) in anhydrous acetonitrile (2 mL). The reactants were evacuated and purged with nitrogen three times, then irradiated with three 34W blue LEDs. The reactants were stirred at room temperature under nitrogen for 12 h. The resulting reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 70% ethyl acetate / petroleum ether) to give the title compound (65 mg, 0.12 mmol, 25% yield) as a light yellow solid. MS (ESI) m / z 564.3 [M+1]+ .

[0189] 3-(5-(((2S,3S)-2-methylpyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2,2,2-trifluoroacetic acid. To a solution of tert-butyl (2S,3S)-3-((2-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-2-methylpyrrolidine-1-carboxylate (70 mg, 0.12 mmol) in TFA (3 mL) was added trifluoromethanesulfonic acid (0.2 mL, 2.27 mmol). The mixture was stirred at 60 °C under nitrogen for 12 h. The resulting solution was concentrated under reduced pressure. The residue was diluted with water and adjusted to pH 6-7 with saturated sodium bicarbonate. The crude product was purified by reverse phase flash chromatography (10-30% acetonitrile + 0.05% TFA in water over 20 min) to give the title compound (40 mg, 0.087 mmol, 73% yield) as a light yellow oil. MS (ESI) m / z 344.1 [M+1] + .

[0190] 3-(5-(((2S,3S)-2-methyl-1-((2-methylquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of 3-(5-(((2S,3S)-2-methylpyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2,2,2-trifluoroacetic acid (40 mg, 0.087 mmol), 2-methylquinoline-6-carbaldehyde (20 mg, 0.12 mmol) and triethylamine (0.03 mL, 0.23 mmol) in dichloromethane (4 mL) was added sodium triacetoxyborohydride (99 mg, 0.47 mmol). The flask was evacuated and purged with nitrogen five times. The mixture was stirred at room temperature under nitrogen for 2 h. The resulting solution was concentrated under reduced pressure at 25° C. The crude material was purified by silica gel column chromatography (0-10% methanol / dichloromethane) and further purified by reverse phase preparative HPLC under the following conditions: Column: Sun Fire Prep C18 OBD column, 19×150 mm 5 μm 10 nm; Mobile phase A: water (0.1% formic acid), Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 5B to 18B in 7 min; 254 / 210 nm; RT 1 : 6.42. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (11.4 mg, 0.022 mmol, 25% yield) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4)δ8.35-8.27(m,2H),8.10-8.01(m,2H),7.89(dd,J=8.7,2.0Hz,1H),7.76(d,J=8.5Hz,1H),7.52(d,J =8.5Hz,1H),7.20-7.15(m,2H),5.14-5.10(m,2H),4.64(d,J=13.0Hz,1H),4.54-4.39(m,2H),4.12(d, J=13.0Hz,1H),3.52(m,1H),3.34(m,1H),3.10-3.01(m,1H),2.92-2.87(m,1H),2.84-2.73(m,1H),2. 77(s,3H),2.62-2.41(m,2H),2.21-2.13(m,1H),2.11-2.01(m,1H),1.51(d,J=6.6Hz,3H).MS(ESI)m / z 499.1[M+1] + . Example S22. 3-(5-(((2S,3S)-2-methyl-1-((2-methylquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0191] (2R,3R)-3-(benzoyloxy)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester. To a stirred solution of (2R,3S)-3-hydroxy-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 2.48 mmol), benzoic acid (303 mg, 2.48 mmol) and triphenylphosphine (980 mg, 3.73 mmol) in toluene (10 mL) was added di-tert-butyl azodicarboxylate (857 mg, 3.73 mmol). The reaction mixture was then stirred at 80 °C under nitrogen for 3 h. The resulting solution was concentrated under reduced pressure. The crude material was purified by reverse phase flash chromatography (0-80% acetonitrile + 0.05% TFA in water over 20 min) to give the title compound (200 mg, 0.65 mmol, 26% yield) as a light yellow oil. MS (ESI) m / z 250.0 [M-55] + .

[0192] Tert-butyl (2R,3R)-3-hydroxy-2-methylpyrrolidine-1-carboxylate. To a stirred solution of tert-butyl (2R,3R)-3-(benzoyloxy)-2-methylpyrrolidine-1-carboxylate (200 mg, 0.65 mmol) in methanol (6 mL) and water (3 mL) was added lithium hydroxide monohydrate (55 mg, 1.31 mmol) at room temperature and then stirred at 50 °C under nitrogen for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (130 mg, 0.64 mmol, 98% yield), which was used directly in the next step without further purification. 1 HNMR (400 MHz, CHLOROFORM-d) δ 4.34-4.29 (m, 1H), 3.86 (t, J = 6.6 Hz, 1H), 3.48-3.31 (m, 2H), 2.08-2.01 (m, 1H), 1.87-1.82 (m, 1H), 1.75-1.60 (m, 1H), 1.46 (s, 9H), 1.19 (d, J = 6.5 Hz, 3H).

[0193] 3-(5-Hydroxy-1-oxoisoindolin-2-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione. To a solution of 3-(5-bromo-1-oxoisoindolin-2-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (120 mg, 0.27 mmol) in DMF (3 mL) was added mesylate(2-(di-tert-butylphosphino)-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (6.8 mg, 0.0081 mmol), (E)-benzaldehyde oxime (39 mg, 0.32 mmol) and cesium carbonate (176 mg, 0.54 mmol) at room temperature. The reaction mixture was then stirred at 80° C. under nitrogen for 12 h. The resulting mixture was filtered and purified by reverse phase flash chromatography (0-80% acetonitrile + 0.05% TFA in water over 20 min) to give the title compound (75 mg, 0.19 mmol, 70% yield) as a light yellow solid. MS (ESI) m / z 403.1 [M+1] + .

[0194] (2R,3S)-tert-butyl 3-((2-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-2-methylpyrrolidine-1-carboxylate. To a stirred solution of 3-(5-hydroxy-1-oxoisoindolin-2-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (200 mg, 0.53 mmol), (2R,3R)-tert-butyl 3-hydroxy-2-methylpyrrolidine-1-carboxylate (158 mg, 0.79 mmol) and triphenylphosphine (207 mg, 0.79 mmol) in toluene (10 mL) was added di-tert-butyl azodicarboxylate (181 mg, 0.79 mmol). The reaction mixture was then stirred at 80 °C under nitrogen for 3 h. The resulting reaction mixture was concentrated in vacuo. The crude material was purified by reverse phase flash chromatography (0-80% acetonitrile + 0.05% TFA in water over 20 min) to give the title compound (130 mg, 0.23 mmol, 44% yield) as a light yellow solid. MS (ESI) m / z 586.3 [M+23] + .

[0195] 3-(5-(((2R,3S)-2-methylpyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of tert-butyl (2R,3S)-3-((2-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-2-methylpyrrolidine-1-carboxylate (120 mg, 0.21 mmol) in TFA (3 mL) was added trifluoromethanesulfonic acid (0.3 mL). The mixture was stirred at 60 °C under nitrogen for 12 h. The resulting solution was concentrated under reduced pressure. The residue was diluted with water and adjusted to pH 6-7 with saturated sodium bicarbonate. The crude product was purified by reverse phase flash chromatography (10-30% acetonitrile + 0.05% TFA in water over 20 min) to give the title compound (70 mg, 0.20 mmol, 95% yield) as a light yellow oil. MS (ESI) m / z 344.1 [M+1] + .

[0196] 3-(5-(((2R,3S)-2-methyl-1-((2-methylquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of 3-(5-(((2R,3S)-2-methylpyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (70 mg, 0.20 mmol), 2-methylquinoline-6-carbaldehyde (42 mg, 0.24 mmol) and triethylamine (0.06 mL, 0.41 mmol) in dichloromethane (4 mL) was added sodium triacetoxyborohydride (172 mg, 0.82 mmol). The flask was evacuated and purged with nitrogen five times. The mixture was stirred at room temperature under nitrogen for 2 h. The resulting solution was concentrated under reduced pressure at room temperature. The crude material was purified by silica gel column chromatography (0-10% methanol / dichloromethane) and further purified by reverse phase preparative HPLC under the following conditions: column: X select CSH OBD column 30*150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 2B to 20B in 7 min; 210 / 254 nm; RT 1 : 5.2. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (38.6 mg, 0.077 mmol, 37% yield) as a white solid. 1 H NMR (400 MHz, methanol-d 4 )δ8.82(dd,J=8.6,3.2Hz,1H),8.40(t,J=2.6Hz,1H),8.27-8.17(m,2H),7.91(dd,J=8.6,2. 9Hz,1H),7.74(dd,J=14.7,8.5Hz,1H),7.17-7.09(m,2H),5.21-5.10(m,1H),5.04(m,1H),4 .98(m,1H),4.73(d,J=13.2Hz,1H),4.56-4.41(m,2H),4.08(m,1H),3.78-3.63(m,2H),2.99 -2.81(m,5H),2.50-2.39(m,3H),2.21-2.19(m,1H),1.59(dd,J=7.1,1.7Hz,3H);MS(ESI)m / z 499.1[M+1] + . Example S23. 3-(5-(((S)-1-((2,3-dihydrofuro[2,3-c]pyridin-5-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0197] (2,3-Dihydrofuro[2,3-c]pyridin-5-yl)methanol. To a solution of furo[2,3-c]pyridine-5-carbaldehyde (100 mg, 0.68 mmol) in methanol (6 mL) was added palladium 10% on carbon (100 mg, wetted with about 55% water) and the mixture was stirred at room temperature under hydrogen (about 2 bar) for 12 h. The resulting mixture was filtered and concentrated to give the title compound (70 mg, 0.46 mmol, 68% yield) as an off-white solid. MS (ESI) m / z 152.0 [M+1] + .

[0198] 2,3-Dihydrofurano[2,3-c]pyridine-5-carbaldehyde. To a stirred solution of 2,3-dihydrofurano[2,3-c]pyridin-5-ylmethanol (65 mg, 0.43 mmol) in dichloromethane (4 mL) was added manganese dioxide (299 mg, 3.44 mmol) at room temperature. The reaction mixture was then stirred at 60 ° C under nitrogen for 3 h. The resulting reaction mixture was diluted with dichloromethane, filtered and concentrated to give the title compound (60 mg, 0.40 mmol, 93% yield) as a light yellow solid. MS (ESI) m / z 150.0 [M+1] + .

[0199] 3-(5-(((S)-1-((2,3-dihydrofuro[2,3-c]pyridin-5-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a stirred solution of 2,3-dihydrofuro[2,3-c]pyridine-5-carbaldehyde (45 mg, 0.30 mmol) and 3-(1-oxo-5-(((S)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione (100 mg, 0.30 mmol) in dichloromethane (6 mL) at 0°C were added triethylamine (0.08 mL, 0.60 mmol) and sodium triacetoxyborohydride (257 mg, 1.21 mmol). The mixture was stirred at room temperature under nitrogen for 2 h. The resulting solution was concentrated at 25°C. The residue was purified by silica gel column chromatography (0-10% methanol / dichloromethane) and further purified by reverse phase preparative HPLC under the following conditions: column: Sun Fire Prep C18 OBD column, 19×150 mm 5 μm 10 nm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5B to 30B in 7 min; 254 / 210 nm; RT1: 4.65. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (12.1 mg, 0.026 mmol, 9% yield) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4 )δ8.35(s,1H),8.06(s,1H),7.75(d,J=8.4Hz,1H),7.42(s,1H),7.15-7.10(m,2H) ,5.23(s,1H),5.14(dd,J=13.3,5.2Hz,1H),4.67(t,J=8.9Hz,2H),4.54-4.39(m,2H ),4.33-4.20(m,2H),3.53-3.38(m,3H),3.33-3.22(m,3H),2.97-2.88(m,1H),2.83 -2.76(m,1H),2.60-2.41(m,2H),2.28-2.23(m,1H),2.21-2.15(m,1H).MS(ESI)m / z 463.1[M+1] + . Example S24. 3-(1-oxo-5-(((S)-1-((2-(prop-1-yn-1-yl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione

[0200] 2-(Prop-1-yn-1-yl)quinoline-6-carboxaldehyde. To a stirred solution of 2-chloroquinoline-6-carboxaldehyde (150 mg, 0.78 mmol), prop-1-yn (63 mg, 1.57 mmol) in acetonitrile (6 mL) at room temperature, dichlorobis(triphenylphosphine)palladium(II) dichloromethane adduct (64 mg, 0.08 mmol), triethylamine (0.42 mL, 3.06 mmol), copper(I) iodide (30 mg, 0.16 mmol) were added. The reaction mixture was then stirred at 60 ° C under nitrogen for 2 h. The resulting mixture was filtered and the filtrate was concentrated. The crude product was purified by reverse phase flash chromatography (10-40% acetonitrile + 0.05% aqueous ammonium bicarbonate solution, over 20 min) to give the title compound (55 mg, 0.28 mmol, 36% yield) as a yellow solid. MS (ESI) m / z 196.1 [M+1] + .

[0201] 3-(1-Oxo-5-(((S)-1-((2-(prop-1-yn-1-yl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione. To a stirred solution of 2-(prop-1-yn-1-yl)quinoline-6-carbaldehyde (50 mg, 0.26 mmol), 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione; 2,2-trifluoroacetic acid (115 mg, 0.26 mmol), triethylamine (0.07 mL, 0.52 mmol) in dichloromethane (5 mL) pre-stirred for 15 min was added sodium triacetoxyborohydride (220 mg, 1.0 mmol) and the solution was stirred at room temperature under nitrogen for 4 h. The resulting solution was purified by silica gel chromatography (0 to 10% methanol / dichloromethane). Pure fractions were evaporated and further purified by preparative HPLC under the following conditions: column: Sun fire Prep C18 OBD column, 19*250 mm, 10 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 2% B to 18% B in 10 min, 18% B to 18% B in 11 min, 18% B; wavelength: 254 / 210 nm; RT1 (min): 10.38; number of runs: 0. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (28.8 mg, 0.056 mmol, 22% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6)δ10.97(s,1H),8.32(m,1H),8.14(s,1H),7.90(d,J=8.6Hz,2H),7.76(m,1H),7.61 (d,J=8.5Hz,1H),7.52(d,J=8.4Hz,1H),7.11(t,J=1.8Hz,1H),7.01(m,1H),5.04(m, 2H),4.37(d,J=17.2Hz,1H),4.24(m,1H),3.85(s,2H),3.07-2.70(m,4H),2.59(d,J =17.3Hz,2H),2.40-2.32(m,2H),2.14(s,3H),1.97(m,1H),1.87(m,1H); MS(ESI)m / z 509.1[M+1] + . Example S25. 3-(5-(methyl((S)-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0202] (3S)-tert-butyl 3-((2-(1-(3,4-dimethoxybenzyl)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)(methyl)amino)pyrrolidine-1-carboxylate. To a solution of 3-(5-bromo-1-oxoisoindolin-2-yl)-1-(3,4-dimethoxybenzyl)piperidine-2,6-dione (450 mg, 0.95 mmol), (S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (228 mg, 1.14 mmol) and cesium carbonate (929 mg, 2.85 mmol) in 1,4-dioxane (10.0 mL) was added mesylate(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)-(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (79 mg, 0.094 mmol). The flask was evacuated and purged with nitrogen five times. The mixture was stirred at 100 °C under nitrogen for 3 h. The mixture was diluted with ethyl acetate and filtered. The resulting solution was concentrated and purified by silica gel chromatography (0 to 90% ethyl acetate / petroleum ether) to give the title compound (250 mg, 0.42 mmol, 44% yield) as a light yellow oil. MS (ESI) m / z 537.0 [M+1-56] + .

[0203] 3-(5-(Methyl((S)-pyrrolidin-3-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2,2,2-trifluoroacetic acid. To a solution of tert-butyl (3S)-3-((2-(1-(3,4-dimethoxybenzyl)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)(methyl)amino)pyrrolidine-1-carboxylate (250 mg, 0.42 mmol) in TFA (2.5 mL) was added trifluoromethanesulfonic acid (0.5 mL) dropwise at 0°C. The mixture was stirred at 50°C under nitrogen for 12 h. The resulting solution was concentrated and saturated ammonium bicarbonate was added to the residue to pH 5-6 and purified by reverse phase flash chromatography (10-40% acetonitrile + 0.05% TFA in water over 25 min) to give the title compound as an oil (75 mg, 0.16 mmol, 38% yield). MS (ESI) m / z 343.0 [M+1] + .

[0204] 3-(5-(methyl((S)-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of 3-(5-(methyl((S)-pyrrolidin-3-yl)-amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2,2,2-trifluoroacetic acid (75 mg, 0.17 mmol), quinoline-3-carbaldehyde (52 mg, 0.33 mmol) and triethylamine (27 mg, 0.26 mmol) in dichloromethane (10 mL) was added sodium triacetoxyborohydride (186 mg, 0.88 mmol). The flask was evacuated and purged with nitrogen five times. The mixture was stirred at room temperature under nitrogen for 2 h. The resulting mixture was concentrated and the residue was purified by preparative HPLC using the following conditions: column: Xselect CSH OBD column 30*150mm 5μm; mobile phase A: water (0.05% TFA), mobile phase B: acetonitrile; flow rate: 60mL / min; gradient: 5B to 5B in 2min; 254 / 210nm; RT1: 8.48min. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (25.5mg, 0.053mmol, 31% yield) as a yellow solid. 1 H NMR (400 MHz, methanol-d 4)δ9.09(d,J=2.2Hz,1H),8.72(d,J=2.2Hz,1H),8.16(d,J=8.5Hz,1H),8.11(d,J=8.2Hz,1H),7.96(m ,1H),7.79(m,1H),7.65(d,J=9.3Hz,1H),7.04(m,2H),5.11(m,1H),4.99(m,1H),4.80(d,J=13.2Hz, 1H),4.75(d,J=13.3Hz,1H),4.49-4.34(m,2H),3.86-3.76(m,1H),3.71-3.52(m,3H),3.01(s,3H),2 .91(m,1H),2.84-2.74(m,1H),2.55-2.41(m,2H),2.34(m,1H),2.16(m,1H); MS(ESI)m / z484.1[M+1] + . Example S26. 3-(5-(((S)-1-(isoquinolin-3-ylmethyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0205] 3-(5-(((S)-1-(isoquinolin-3-ylmethyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of 3-(1-oxo-5-(((S)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (100 mg, 0.27 mmol), isoquinoline-3-carbaldehyde (65 mg, 0.41 mmol) and triethylamine (33 mg, 0.33 mmol) in dichloromethane (10.0 mL) was added sodium triacetoxyborohydride (232 mg, 1.09 mmol). The solution was stirred at room temperature under nitrogen for 2 h. The resulting mixture was concentrated and the residue was purified by silica gel chromatography (0 to 5% methanol / dichloromethane) and further purified by preparative HPLC under the following conditions: column: XSelect CSH Prep C18 OBD column, 5 μm, 19*150 mm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 5B to 20B in 7 min; 254 / 210 nm; RT: 6.67 min. The pure fractions were concentrated to give the title compound (26.0 mg, 0.05 mmol, 35% yield) as an off-white solid. 1 H NMR (300 MHz, methanol-d 4)δ9.29(s,1H),8.13(d,J=8.2Hz,1H),8.00-7.89(m,2H),7.88-7.77(m,1H),7.83-7.67(m,2H),7.15-7.03(m,2H),5.19-5.13(m,1H), 4.45(m,2H),4.35(m,2H),3.43(m,1H),3.32(m,2H),3.17(m,1H),3.01-2.70(m,2H),2.62-2.39(m,2H),2.24-2.05(m,2H); MS(ESI)m / z 471.1[M+1] + . Example S27. 3-(5-(((S)-1-((2,3-dimethylpyridin-4-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0206] 2,3-Dimethylisonicotinaldehyde. To a solution of 4-bromo-2,3-dimethylpyridine (200 mg, 1.07 mmol), 2-isocyano-2-methyl-propane (107 mg, 1.29 mmol), 1,2-bis(diphenylphosphino)ethane (86 mg, 0.21 mmol) and sodium formate (146 mg, 2.15 mmol) in DMSO (5.0 mL), palladium (II) acetate (24 mg, 0.11 mmol) was added. The mixture was stirred at 120 ° C under nitrogen for 3 h. The resulting solution was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30% to 100% ethyl acetate / petroleum ether) to give the title compound (80 mg, 0.59 mmol, 55% yield) as a yellow oil. MS (ESI) m / z 136.0 [M+1] + .

[0207] 6-Bromo-5-fluoro-2-(tetrahydro-2H-pyran-4-yl)quinoline. To a solution of 2,3-dimethylisonicotinaldehyde (44 mg, 0.33 mmol), 3-(1-oxo-5-(((S)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (100 mg, 0.27 mmol) and triethylamine (33 mg, 0.33 mmol) in dichloromethane (10.0 mL) was added sodium triacetoxyborohydride (232 mg, 1.09 mmol). The mixture was stirred at room temperature under nitrogen for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 2B to 2B in 2 min; 254 / 210 nm; RT1: 7.53. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (18.5 mg, 0.041 mmol, 15% yield) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4 )δ8.29-8.20(m,2H),7.73(d,J=8.4Hz,1H),7.44(d,J=5.5Hz,1H),7.10(d,J=2.2Hz,1H),7 .06(dd,J=8.5,2.2Hz,1H),5.13(dd,J=13.3,5.2Hz,1H),5.08(m,1H),4.53-4.38(m,2H),3. 92-3.87(m,2H),3.13(m,1H),3.01-2.85(m,2H),2.85-2.72(m,2H),2.68(m,1H),2.58(s,3 H),2.49(m,2H),2.38(s,3H),2.22-2.13(m,1H),2.10-2.02(m,1H); MS(ESI)m / z449.1[M+1] + . Example S28. 3-(5-(((S)-1-((3,4-dihydro-2H-pyrano[2,3-c]pyridin-5-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0208] (E) -3- (3,5- dibromopyridin-4-yl) ethyl acrylate. To a solution of 3,5- dibromoisonicotinaldehyde (1.0 g, 3.78 mmol) in toluene (5.0 mL) was added ethyl 2- (triphenyl-λ^5-phosphanylidene) acetate (1.5 g, 4.15 mmol). The flask was evacuated and flushed with nitrogen three times. The mixture was stirred at 80 ° C under nitrogen for 12 h. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 25% ethyl acetate / petroleum ether) to give the title compound (1.2 g, 3.58 mmol, 95% yield) as a light yellow solid. MS (ESI) m / z 334.0 [M + 1] + .

[0209] 3-(3,5-dibromopyridin-4-yl)propan-1-ol. Sodium borohydride (135 mg, 3.58 mmol) was added to a solution of (E)-3-(3,5-dibromopyridin-4-yl)ethyl acrylate (600 mg, 1.79 mmol) in methanol (10.0 mL). The mixture was stirred at room temperature for 1.5 h. Lithium borohydride (35 mg, 1.59 mmol) was then added to the mixture, and stirred at 50 ° C under nitrogen for 12 h. After cooling to room temperature, glacial acetic acid was added and the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with aqueous hydrogen chloride solution (1 M), saturated sodium bicarbonate and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0 to 25% ethyl acetate / petroleum ether) to give the title compound (400 mg, 1.35 mmol, 76% yield) as an off-white solid. MS (ESI) m / z 294.0 [M+1] + .

[0210] 5-bromo-3,4-dihydro-2H-pyrano[2,3-c]pyridine. Sodium methoxide (30% in methanol, 366 mg, 2.03 mmol) was added to a solution of 3-(3,5-dibromopyridin-4-yl)propan-1-ol (400 mg, 1.36 mmol), pyridine-2-amine (13 mg, 0.14 mmol) and copper (I) chloride (13 mg, 0.14 mmol). A sealed tube was filled with nitrogen. The mixture was heated with microwave irradiation at 135 ° C in a microwave reactor for 6 h. A saturated sodium bicarbonate solution was then added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 25% ethyl acetate / petroleum ether) to give the title compound (280 mg, 1.30 mmol, 96% yield) as a yellow oil. MS (ESI) m / z 214.0 [M+1] + .

[0211] 5-vinyl-3,4-dihydro-2H-pyrano[2,3-c]pyridine. To a solution of 5-bromo-3,4-dihydro-2H-pyrano[2,3-c]pyridine (280 mg, 1.31 mmol), tributyl(vinyl)stannane (498 mg, 1.57 mmol) and cesium fluoride (298 mg, 1.96 mmol) in 1,4-dioxane (5.0 mL) was added dichlorobis(triphenylphosphine)palladium(II) dichloromethane adduct (184 mg, 0.26 mmol). The flask was evacuated and purged with nitrogen five times. The mixture was stirred at 80 ° C under nitrogen for 3 h. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20% to 100% ethyl acetate / petroleum ether) to give the title compound (120 mg, 0.75 mmol, 57% yield) as a colorless oil. MS (ESI) m / z 162.0 [M+1] + .

[0212] 3,4-dihydro-2H-pyrano[2,3-c]pyridine-5-carboxaldehyde. To a solution of 5-vinyl-3,4-dihydro-2H-pyrano[2,3-c]pyridine (120 mg, 0.74 mmol), potassium osmate (27 mg, 0.07 mmol), 4-methylmorpholine N-oxide (174 mg, 1.49 mmol) in tert-butanol (3.0 mL) and water (3.0 mL) was added citric acid (285 mg, 1.49 mmol). The mixture was stirred at room temperature under nitrogen for 6 h, then sodium periodate (478 mg, 2.23 mmol) was added and the mixture was stirred at room temperature for another 3 h. The resulting solution was diluted with water and then extracted with ethyl acetate. The organic layers were combined, washed with brine, dried and concentrated to give the title compound (80 mg, 0.49 mmol, 66% yield) as a brown oil. MS (ESI) m / z 164.0 [M+1] + .

[0213] 3-(5-(((S)-1-((3,4-dihydro-2H-pyrano[2,3-c]pyridin-5-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of 3,4-dihydro-2H-pyrano[2,3-c]pyridine-5-carbaldehyde (80 mg, 0.49 mmol), 3-(1-oxo-5-(((S)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (100 mg, 0.27 mmol) and triethylamine (33 mg, 0.33 mmol) in dichloromethane was added sodium triacetoxyborohydride (232 mg, 1.09 mmol). The flask was evacuated and purged with nitrogen five times. The mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XSelect CSH Prep C18 OBD column, 5 μm, 19*150 mm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 2B to 14B in 7 min; 254 / 210 nm; RT1: 6.30. The pure fractions were concentrated to give the title compound (13.7 mg, 0.03 mmol, 10%) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4 )δ8.02(d,J=12.0Hz,2H),7.73(d,J=8.5Hz,1H),7.13-7.03(m,2H),5.13(m,2H),4.53-4.38(m,2H),4.28-4.21(m,2H),3.9 1(s,2H),3.29-3.11(m,1H),3.08(m,2H),2.99-2.76(m,5H),2.49(m,2H),2.26-2.10(m,1H),2.13-2.04(m,3H); MS(ESI)m / z 477.1[M+1] + . Example S29. 3-(5-(((S)-1-((8-fluoroisoquinolin-3-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0214] 2-(3,3-diethoxyprop-1-yn-1-yl)-6-fluorobenzaldehyde. To a solution of 2-bromo-6-fluorobenzaldehyde (1.0 g, 4.93 mmol) and 3,3-diethoxyprop-1-yn (631 mg, 4.93 mmol) in triethylamine (30 mL) was added dichlorobis(triphenylphosphine)-palladium(II) dichloromethane adduct (346 mg, 0.49 mmol) and cuprous iodide (47 mg, 0.25 mmol). The flask was evacuated and flushed with nitrogen three times. The mixture was stirred at 60 ° C under nitrogen for 12 h. The mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 25% ethyl acetate / petroleum ether) to give the title compound (500 mg, 1.99 mmol, 41% yield) as a brown oil. MS (ESI) m / z 251.0 [M+1] + .

[0215] 3-(Diethoxymethyl)-8-fluoroisoquinoline. 2-(3,3-Diethoxyprop-1-yn-1-yl)-6-fluorobenzaldehyde (500 mg, 1.99 mmol) was added to ammonia (7M in MeOH, 10 mL) and the reaction was heated in a microwave reactor at 100 °C under nitrogen with microwave irradiation for 20 min. The resulting solution was concentrated to give the crude title compound. MS (ESI) m / z 250.0 [M+1] + .

[0216] 8-Fluoroisoquinoline-3-carbaldehyde. To a solution of 3-(diethoxymethyl)-8-fluoroisoquinoline (1.0 g crude material, about 4.01 mmol) in THF (10.0 mL) was added HCl (6 M, 10.0 mL). The flask was evacuated and flushed with nitrogen three times. The mixture was stirred at 40 ° C under nitrogen for 12 h. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (30% to 100% ethyl acetate / petroleum ether) to give the title compound (75 mg, 0.42 mmol, 11% yield) as an off-white solid. MS (ESI) m / z 176.0 [M + 1] + .

[0217] 3-(5-(((S)-1-((8-fluoroisoquinolin-3-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of 8-fluoroisoquinoline-3-carbaldehyde (80 mg, 0.46 mmol), 3-(1-oxo-5-(((S)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (100 mg, 0.27 mmol) and triethylamine (33 mg, 0.33 mmol) in dichloromethane (10.0 mL) was added sodium triacetoxyborohydride (232 mg, 1.09 mmol). The flask was evacuated and purged with nitrogen five times. The mixture was stirred at room temperature under nitrogen for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XSelect CSH Prep C18 OBD column, 5 μm, 19*150 mm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 8B to 20B in 7 min; 254 / 210 nm; RT1: 5.92. The pure fractions were concentrated to give the title compound (20.7 mg, 0.04 mmol, 15% yield) as a colorless solid. 1 H NMR (400 MHz, methanol-d 4 )δ9.51(s,1H),8.34(s,1H),7.97(s,1H),7.86-7.77(m,2H),7.74(d,J=8.4Hz,1H ),7.46-7.37(m,1H),7.16-7.06(m,2H),5.21(m,1H),5.14(dd,J=13.3,5.2Hz,1H) ,4.46(d,J=6.8Hz,2H),4.41(m,2H),3.48(m,1H),3.41-3.32(m,2H),3.21-3.15(m ,1H),2.92(m,1H),2.79(m,1H),2.59-2.45(m,2H),2.29-2.11(m,2H); MS(ESI)m / z 489.2[M+1] + . Example S30. 3-(1-oxo-5-(((S)-1-(quinoxalin-2-ylmethyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione

[0218] 3-(1-oxo-5-(((S)-1-(quinoxalin-2-ylmethyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione. To a solution of 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxyisoindolin-2-yl]piperidine-2,6-dione; hydrochloride (120 mg, 0.33 mmol), quinoxaline-2-carbaldehyde (78 mg, 0.49 mmol) and triethylamine (49 mg, 0.49 mmol) in dichloromethane (5 mL) was added sodium triacetoxyborohydride (278 mg, 1.31 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was concentrated and the residue was purified by silica gel chromatography (10% methanol / dichloromethane) and preparative HPLC under the following conditions: XSelect CSH Prep C18 OBD column, 5 μm, 19*150 mm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 5B to 23B in 7 min; 254 / 210 nm; RT1: 5.33. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (45.4 mg, 0.096 mmol, 29% yield) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4 )δ9.01(d,J=1.8Hz,1H),8.16-8.06(m,2H),7.92-7.82(m,2H),7.72(d,J=8.5Hz,1H),7.14-7.03(m,2H),5.14(m,2H),4 .42(m,4H),3.39(m,1H),3.20(m,2H),3.03-2.85(m,2H),2.83-2.74(m,1H),2.57-2.42(m,2H),2.17(m,2H); MS(ESI)m / z 472.2[M+1] + . Example S31. 3-(5-(methyl((R)-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0219] Tert-butyl (3R)-3-((2-(1-(3,4-dimethoxybenzyl)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)(methyl)amino)pyrrolidine-1-carboxylate. To a stirred solution of 3-(5-bromo-1-oxoisoindolin-2-yl)-1-(2,4-dimethoxybenzyl)piperidine-2,6-dione (500 mg, 1.06 mmol), (R)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (254 mg, 1.27 mmol) and cesium carbonate (1.0 g, 3.07 mmol) in DMF (5.0 mL) was added mesylate(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (90 mg, 0.11 mmol) and the mixture was stirred at 120° C. under nitrogen for 12 h. The resulting mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% methanol / dichloromethane) to give the title compound (238 mg, 0.40 mmol, 45% yield) as a light yellow solid. MS (ESI) m / z 537.0 [M+1-56] + .

[0220] 3-(5-(Methyl((R)-pyrrolidin-3-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2,2,2-trifluoroacetic acid. To a solution of tert-butyl (3R)-3-((2-(1-(3,4-dimethoxybenzyl)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)(methyl)amino)pyrrolidine-1-carboxylate (200 mg, 0.34 mmol) in TFA (5.0 mL) was added trifluoromethanesulfonic acid (0.2 mL) at room temperature and the resulting mixture was stirred at 50 °C under nitrogen for 4 h. The resulting solution was concentrated and saturated ammonium bicarbonate was added to the residue to pH 5-6, filtered and the filtrate was purified by reverse phase flash chromatography (10-40% acetonitrile + 0.05% TFA in water over 25 min) to give the title compound (90 mg, 0.20 mmol, 59% yield) as a light yellow oil. MS (ESI) m / z 343.0 [M+1] + .

[0221] 3-(5-(methyl((R)-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of compound 3-(5-(methyl((R)-pyrrolidin-3-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2,2,2-trifluoroacetic acid (95 mg, 0.25 mmol), quinoline-3-carbaldehyde (59 mg, 0.37 mmol) and triethylamine (38 mg, 0.38 mmol) in dichloromethane (5.0 mL) was added sodium triacetoxyborohydride (213 mg, 1.00 mmol), and the mixture was stirred at room temperature under nitrogen for 2 h. The mixture was concentrated and the crude product was purified by preparative HPLC under the following conditions: column: XSelect CSH Prep C18 OBD column, 5 μm, 19*150 mm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 5B to 20B in 7 min; 254 / 210 nm; RT1: 6.22. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (9.5 mg, 0.020 mmol, 8% yield) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ10.94(s,1H),8.92(d,J=2.1Hz,1H),8.28(s,1H),8.06-7.95(m,2H),7.75(m,1H),7. 62(m,1H),7.47(d,J=8.4Hz,1H),6.94-6.86(m,2H),5.03(dd,J=13.3,5.1Hz,1H),4.63( m,1H),4.29(d,J=16.7Hz,1H),4.17(d,J=16.7Hz,1H),3.89(m,2H),2.95(s,3H),2.92-2 .83(m,2H),2.74-2.58(m,3H),2.38-2.20(m,3H),1.94(m,1H),1.77(m,1H); MS(ESI)m / z 484.3[M+1] + . Example S32. 3-(5-(((S)-1-((3-methylquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0222] 3-Methylquinoline-6-carbaldehyde. 1,2-bis(diphenylphosphino)ethane (52 mg, 0.13 mmol) was added to a solution of 6-bromo-3-methyl-quinoline (450 mg, 2.03 mmol), 2-isocyano-2-methyl-propane (202 mg, 4.10 mmol), palladium acetate (23 mg, 0.10 mmol) and potassium formate (341 mg, 4.05 mmol) in DMSO (2 mL), and the resulting mixture was stirred at 120 ° C under nitrogen for 3 h. The mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10% hexane / ethyl acetate) to give the title compound (183 mg, 1.06 mmol, 53% yield) as a yellow solid. MS (ESI) m / z 172.1 [M+1] + .

[0223] 3-(5-(((S)-1-((3-methylquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione; hydrochloride (128 mg, 0.35 mmol), 3-methylquinoline-6-carbaldehyde (90 mg, 0.53 mmol) and triethylamine (53 mg, 0.53 mmol) in dichloromethane (5 mL) was added sodium triacetoxyborohydride (297 mg, 1.40 mmol), and the resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated and purified by silica gel chromatography (10% methanol / dichloromethane) and preparative HPLC under the following conditions: XSelect CSH Prep C18 OBD column, 5μm, 19*150mm; Mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; Flow rate: 25mL / min; Gradient: 5B to 35B in 7min; 254 / 210nm; RT1: 3.77; The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (11.8mg, 0.02mmol, 7% yield) as an off-white solid. 1H NMR (400MHz, DMSO-d6) δ10.97 (s, 1H), 8.75 (d, J = 2.2Hz, 1H), 8.10 (m, 1H), 7.96 (d ,J=8.6Hz,1H),7.84(m,1H),7.69(d,J=8.7Hz,1H),7.62(d,J=8.4Hz,1H),7.13(m, 1H),7.02(m,1H),5.06(m,2H),4.38(d,J=17.2Hz,1H),4.25(m,1H),3.92(m,2H),2 .90(m,4H),2.59(m,2H),2.48(s,3H),2.38(m,2H),1.98-1.80(m,2H); MS(ESI)m / z 485.1[M+1] + . Example S33. 3-(5-(((S)-1-((5,6-difluoroquinolin-3-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0224] 1,2-Difluoro-3-nitro-4-vinylbenzene. To a solution of 1-bromo-3,4-difluoro-2-nitro-benzene (1.0 g, 4.20 mmol), tributyl(vinyl)stannane (1.6 g, 5.04 mmol) and potassium carbonate (1.7 g, 12.61 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was added [1'1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (615 mg, 0.84 mmol), and the mixture was stirred at 100 °C under nitrogen for 12 h. Water was added to the resulting mixture and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 20% ethyl acetate / petroleum ether) to give the title compound (410 mg, 2.20 mmol, 53% yield) as a yellow solid. MS (ESI) m / z 186.1 [M+1] + .

[0225] 3,4-difluoro-2-nitrobenzaldehyde. To a solution of compound 1,2-difluoro-3-nitro-4-vinyl-benzene (410 mg, 2.22 mmol), potassium osmate (163 mg, 0.44 mmol), 4-methylmorpholine N-oxide (519 mg, 4.43 mmol) in tert-butanol (5 mL) and water (5 mL) was added citric acid (851 mg, 4.43 mmol) under air atmosphere. The resulting mixture was stirred at room temperature for 5 h. Sodium periodate (1.4 g, 6.64 mmol) was then added under air atmosphere. The resulting mixture was stirred for 1 h at room temperature. Water was added to the resulting mixture and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 20% ethyl acetate / petroleum ether) to give the title compound (330 mg, 1.76 mmol, 78% yield) as a yellow oil. MS (ESI) m / z 188.1 [M+1] + .

[0226] 5,6-difluoroquinoline-3-formic acid methyl ester. To a solution of compound 4,5-difluoro-6-nitro-cyclohexa-2,4-diene-1-carboxaldehyde (300mg, 1.59mmol), 3,3-dimethoxypropionic acid methyl ester (588mg, 3.97mmol) in ethanol (5mL) under a nitrogen atmosphere, tin chloride (1.4g, 6.35mmol) was added. The resulting mixture was stirred at 90 ° C for 3h. Water was added to the resulting mixture and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 10% ethyl acetate / petroleum ether) to give the title compound (190mg, 0.85mmol, 54% yield) as a yellow solid. MS (ESI) m / z 224.2 [M+1] + .

[0227] 5,6-difluoroquinoline-3-carboxaldehyde. To a solution of 5,6-difluoroquinoline-3-carboxylic acid methyl ester in THF (10mL) was added lithium aluminum hydride (2.5M in THF, 0.36mL, 0.89mmol) at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1h. The mixture was quenched with water, and the pH value was adjusted to =5 with 15% sodium hydroxide. The solid was filtered out and washed with ethyl acetate. The filtrate was concentrated and purified by preparative TLC (5% methanol / dichloromethane) to give the title compound (118mg, 0.66mmol, 71% yield) as a light yellow solid. Then manganese dioxide (530mg, 6.15mmol) was added to chloroform (3mL) containing (5,6-difluoro-3-quinolyl) methanol (118mg, 0.614mmol, 1 equivalent) under an air atmosphere. The resulting mixture was stirred at room temperature for 12h. The solid was filtered off and the filtrate was concentrated to give the title compound (90 mg, 0.51 mmol, 76% yield) as a pale yellow solid. MS (ESI) m / z 178.2 [M+1] + .

[0228] 3-(5-(((S)-1-((5,6-difluoroquinolin-3-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of compound 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione; hydrochloride (113 mg, 0.31 mmol), 5,6-difluoroquinoline-3-carbaldehyde (90 mg, 0.46 mmol) and triethylamine (47 mg, 0.46 mmol) in dichloromethane (5 mL) was added sodium triacetoxyborohydride (262 mg, 1.24 mmol) under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was stirred at room temperature for 3 h. The resulting solution was concentrated and purified by preparative TLC (10% methanol / dichloromethane) and preparative HPLC under the following conditions: XSelect CSH Prep C18 OBD column, 5μm, 19*150mm; Mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; Flow rate: 25mL / min; Gradient: 5B to 25B in 7min; 254 / 210nm; RT1: 6.12; The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (32.5mg, 0.06mmol, 20% yield) as an off-white solid. 1 HNMR (400 MHz, DMSO-d 6)δ10.98(s,1H),8.96(d,J=2.1Hz,1H),8.41(d,J=2.1Hz,1H),7.95(m,J=9.5,4.7Hz,1H),7.87(m,J=10.6 ,8.8Hz,1H),7.61(d,J=8.4Hz,1H),7.12(d,J=2.0Hz,1H),7.02(m,J=8.4,2.2Hz,1H),5.12-4.99(m,2H),4 .38(d,J=17.2Hz,1H),4.25(d,J=16.8Hz,1H),3.92(s,2H),2.99(s,1H),2.91(m,J=18.2,13.5,5.4Hz,1H) ,2.82(s,1H),2.75(m,J=8.2Hz,1H),2.64-2.55(m,2H),2.45-2.33(m,2H),1.91-1.83(m,2H);MS(ESI)m / z 507.2[M+1] + . Example S34. 3-(5-(((S)-1-((5,6-dimethylpyridin-3-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0229] 5,6-Dimethylnicotinaldehyde. To a solution of 5-bromo-2,3-dimethyl-pyridine (200 mg, 1.08 mmol), 2-isocyano-2-methyl-propane (107 mg, 1.29 mmol) and sodium formate (146 mg, 2.15 mmol) in DMSO (3 mL) was added palladium acetate (12 mg, 0.05 mmol), 1,2-bis(diphenylphosphino)ethane (104 mg, 0.26 mmol), and the mixture was stirred at 120 ° C under nitrogen for 3 h. The mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% petroleum ether / ethyl acetate) to give the title compound (86 mg, 0.63 mmol, 59% yield) as a yellow oil. MS (ESI) m / z 136.1 [M+1] + .

[0230] 3-(5-(((S)-1-((5,6-dimethylpyridin-3-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione; hydrochloride (100 mg, 0.27 mmol), 5,6-dimethylpyridine-3-carbaldehyde (55 mg, 0.40 mmol) and triethylamine (41 mg, 0.41 mmol) in dichloromethane (5 mL) was added sodium triacetoxyborohydride (232 mg, 1.09 mmol), and the mixture was stirred at room temperature under nitrogen for 12 h. The resulting mixture was concentrated. The residue was purified by silica gel chromatography (10% methanol / dichloromethane) and preparative HPLC under the following conditions: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 2B to 2B in 2 min; 254 / 210 nm; RT1: 7.75. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (37.7 mg, 0.075 mmol, 28% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ10.98(s,1H),8.17(m,J=9.7,1.9Hz,2H),7.61(d,J=8.4Hz,1H),7.45(d,J=2 .1Hz,1H),7.11(s,1H),7.00(m,1H),5.08(m,1H),5.00(m,1H),4.39(d,J=17.2 Hz,1H),4.25(m,J=17.4,2.9Hz,1H),3.58(s,2H),2.98-2.87(m,2H),2.80-2.6 0(m,3H),2.50-2.30(m,6H),2.24(s,3H),1.98(m,1H),1.82(m,1H); MS(ESI)m / z 449.2[M+1] + . Example S35. 3-(1-oxo-5-(((S)-1-((5-(trifluoromethyl)pyridin-3-yl)methyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione

[0231] 5-(Trifluoromethyl)nicotinaldehyde. To a solution of (5-(trifluoromethyl)-pyridin-3-yl)methanol (100 mg, 0.57 mmol) in dichloromethane (5 mL) was added manganese dioxide (492 mg, 5.65 mmol), and the resulting mixture was stirred at room temperature under nitrogen for 12 h. The mixture was diluted with dichloromethane, filtered and the filtrate was concentrated to give the title compound (95 mg, 0.54 mmol, 96% yield) as a yellow oil. MS (ESI) m / z 176.1 [M+1] + .

[0232] 3-(1-Oxo-5-(((S)-1-((5-(trifluoromethyl)pyridin-3-yl)methyl)pyrrolidin-3-yl)-oxy)isoindolin-2-yl)piperidine-2,6-dione. To a solution of 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione; hydrochloride (100 mg, 0.27 mmol), 5-(trifluoromethyl)pyridine-3-carbaldehyde (57 mg, 0.33 mmol) and triethylamine (41 mg, 0.41 mmol) in dichloromethane (5 mL) was added sodium triacetoxyborohydride (232 mg, 1.09 mmol) and the mixture was stirred at room temperature under nitrogen for 2 h. The resulting mixture was concentrated. The residue was purified by silica gel chromatography column (10% methanol / dichloromethane) and preparative HPLC under the following conditions: XSelect CSH Prep C18 OBD column, 5 μm, 19*150 mm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 2B to 2B in 1 min; 254 / 210 nm; RT1: 7.95. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (35.8 mg, 0.07 mmol, 26% yield) as an off-white solid. 1H NMR (400MHz, DMSO-d6) δ10.98(s,1H),8.91-8.83(m,2H),8.18-8.10(m,1H),7.62(d,J= 8.4Hz,1H),7.12(d,J=2.2Hz,1H),7.01(m,1H),5.12-5.01(m,1H),5.01(d,J=6.9Hz,1H) ,4.39(d,J=17.2Hz,1H),4.26(d,J=17.1Hz,1H),3.85-3.73(m,2H),3.00-2.92(m,2H), 2.85-2.75(m,2H),2.69-2.57(m,2H),2.46-2.31(m,2H),1.98-1.87(m,2H); MS(ESI)m / z 489.1[M+1] + . Example S36. 3-(1-oxo-6-(((S)-1-(quinolin-6-ylmethyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione

[0233] 3-(1-oxo-6-(((S)-1-(quinolin-6-ylmethyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)-piperidine-2,6-dione. To a solution of 3-(1-oxo-6-(((S)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (150 mg, 0.41 mmol) in dichloromethane (10.0 mL) was added quinoline-6-carbaldehyde (84 mg, 0.53 mmol), triethylamine (0.17 mL, 1.23 mmol) and sodium triacetoxyborohydride (348 mg, 1.64 mmol). The mixture was stirred at room temperature for 2 h. The crude product was purified by preparative HPLC under the following gradient conditions: column: Sunfire prep C18 column, 5 μm; 30*150 mm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5B to 13B in 7 min; 254 / 210 nm; RT: 6.32 min. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (74.1 mg, 0.16 mmol, 39% yield) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4)δ8.90(d,J=4.3Hz,1H),8.41(d,J=8.3Hz,1H),8.13-8.04(m,2H),7.91(d,J=8 .6Hz,1H),7.60(dd,J=8.3,4.3Hz,1H),7.50(d,J=8.3Hz,1H),7.30(d,J=2.3Hz ,1H),7.22(d,J=8.4Hz,1H),5.15(m,2H),4.51-4.28(m,4H),3.44(m,1H),3.35 (m,2H),3.16(m,1H),2.92-2.74(m,2H),2.51(m,2H),2.10(m,2H);MS(ESI)m / z 471.1[M+1] + . Example S37. 3-(6-(((S)-1-(isoquinolin-3-ylmethyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)-piperidine-2,6-dione

[0234] 3-(6-(((S)-1-(isoquinolin-3-ylmethyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of isoquinoline-3-carbaldehyde (65 mg, 0.41 mmol), 3-(1-oxo-6-(((S)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (100 mg, 0.27 mmol) and triethylamine (33 mg, 0.330 mmol) in dichloromethane (10 mL) was added sodium triacetoxyborohydride (232 mg, 1.09 mmol). The mixture was stirred at room temperature under nitrogen for 2 h. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 7B to 20B in 7 min; 254 / 210 nm; RT1: 6.60. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (29.3 mg, 0.06 mmol, 22% yield) as a pale yellow solid. 1 HNMR (400 MHz, methanol-d 4)δ9.32(s,1H),8.14(d,J=8.2Hz,1H),8.00-7.92(m,2H),7.84(t,J=7.6Hz,1H),7.74(t,J= 7.5Hz,1H),7.52(d,J=8.3Hz,1H),7.33(d,J=2.3Hz,1H),7.25(d,J=8.3Hz,1H),5.21(m,1H) ,5.15(dd,J=13.3,5.1Hz,1H),4.50(m,2H),4.44(d,J=8.4Hz,2H),3.68-3.53(m,3H),3.39 -3.31(m,1H),2.92(m,1H),2.80(m,1H),2.50(m,2H),2.29(m,1H),2.18(m,1H); MS(ESI)m / z 471.1[M+1] + . Example S38. 3-(6-(((S)-1-(isoquinolin-6-ylmethyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0235] 3-(6-(((S)-1-(isoquinolin-6-ylmethyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of isoquinoline-6-carbaldehyde (65 mg, 0.41 mmol), 3-(1-oxo-6-(((S)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (100 mg, 0.27 mmol) and triethylamine (33 mg, 0.33 mmol) in dichloromethane (10.0 mL) was added sodium triacetoxyborohydride (232 mg, 1.09 mmol). The mixture was stirred at room temperature under nitrogen for 2 h. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XSelect CSH Prep C18 OBD column, 5 μm, 19*150 mm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 2B to 12B in 7 min; 254 / 210 nm; RT1: 5.78. The pure fractions were concentrated to give the title compound (21.8 mg, 0.046 mmol, 17% yield) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4)δ9.28(s,1H),8.49(d,J=5.8Hz,1H),8.18(d,J=8.5Hz,1H),8.04(s,1H),7.86(d,J=5.9Hz, 1H),7.82(dd,J=8.5,1.6Hz,1H),7.51(d,J=8.4Hz,1H),7.30(m,1H),7.22(m,1H),5.19-5.10 (m,2H),4.47(d,J=16.8Hz,1H),4.40(d,J=16.9Hz,1H),4.31(m,2H),3.39(m,1H),3.31(m,2 H),3.11(m,1H),2.92(m,1H),2.85-2.75(m,1H),2.61-2.42(m,2H),2.20(m,2H); MS(ESI)m / z 471.2[M+1] + . Example S39. 3-(5-(((S)-1-((4-chloro-2-methylquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0236] 4-chloro-2-methylquinoline-6-carboxaldehyde. To a solution of 6-bromo-4-chloro-2-methylquinoline (200 mg, 0.78 mmol), tert-butyl isocyanide (97 mg, 1.17 mmol), 1,2-bis(diphenylphosphino)ethane (124 mg, 0.31 mmol) and sodium formate (106 mg, 1.56 mmol) in DMSO (2.5 mL) in a sealed tube, palladium (II) acetate (35 mg, 0.16 mmol) was added. The sealed tube was filled with nitrogen. The mixture was stirred at 120 ° C under nitrogen for 3 h. The resulting solution was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 25% ethyl acetate / petroleum ether) to give the title compound (80 mg, 0.39 mmol, 50% yield) as an off-white solid. MS (ESI) m / z 206.0 [M+1] + .

[0237] 3-(5-(((S)-1-((4-chloro-2-methylquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of 4-chloro-2-methylquinoline-6-carbaldehyde (84 mg, 0.41 mmol), 3-(1-oxo-5-(((S)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (100 mg, 0.27 mmol) and triethylamine (33 mg, 0.33 mmol) in dichloromethane (10.0 mL) was added sodium triacetoxyborohydride (232 mg, 1.09 mmol). The flask was evacuated and purged with nitrogen five times. The mixture was stirred at room temperature under nitrogen for 2 h. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 5% methanol / dichloromethane) and preparative HPLC under the following conditions: column: Xselect CSH OBD column 30*150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 3B to 25B in 9 min; 210 / 254 nm; RT1: 8.13. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (27.7 mg, 0.05 mmol, 19% yield) as an off-white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ10.96(s,1H),8.05(s,1H),7.96(d,J=8.6Hz,1H),7.80(dd,J=8.7,1.9Hz,1H),7.67(s,1H),7 .61(d,J=8.3Hz,1H),7.11(d,J=2.0Hz,1H),7.01(dd,J=8.5,2.2Hz,1H),5.12-4.98(m,2H),4.3 8(d,J=17.1Hz,1H),4.25(dd,J=17.2,3.3Hz,1H),3.91-3.82(m,2H),2.93(m,2H),2.83-2.71(m ,2H),2.65(s,3H),2.62(m,1H),2.56(m,1H),2.38(m,2H),1.98(m,1H),1.87(m,1H); MS(ESI)m / z 519.0[M+1] + . Example S40. 3-Methyl-3-(5-(((S)-1-((2-methylquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0238] 3-Methyl-3-(5-(((S)-1-((2-methylquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of 3-methyl-3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione; hydrochloride (70 mg, 0.18 mmol), 2-methylquinoline-6-carbaldehyde (41 mg, 0.24 mmol) and triethylamine (0.05 mL, 0.37 mmol) in dichloromethane (10 mL) was added sodium triacetoxyborohydride (117 mg, 0.55 mmol) at room temperature. The mixture was stirred under nitrogen for 12 h. To the mixture was added water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using the following gradient conditions: Column: Sunfire prep C18 OBD column, 19×150 mm, 5 μm 10 nm; Mobile phase A: water (0.1% formic acid), Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 8B to 20B in 10 min; 210 / 254 nm; RT1: 8.45. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (25.7 mg, 0.051 mmol, 28% yield) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4 )δ8.35(s,1H),8.26(d,J=8.0Hz,1H),8.03-7.85(m,2H),7.74(d,J=8.0Hz,1H),7.53(d,J=8.0Hz ,1H),735(d,J=8.0Hz,1H),7.01(s,1H),6.94(d,J=8.0Hz,1H),5.18(m,1H),4.60-4.48(m,2H),4. 31-4.22(m,2H),3.29(m,1H),3.21-3.13(m,2H),3.01(m,1H),2.80-2.62(m,5H),2.61-2.11(m,1 H),2.50-2.36(m,1H),2.15-2.03(m,1H),1.97-1.83(m,1H),1.67(s,3H); MS(ESI)m / z499.1[M+1] + . Example S41. 3-(((3S)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)pyrrolidin-1-yl)methyl)quinoline-2-carbonitrile

[0239] 2-Iodoquinoline-3-carboxaldehyde. To a solution of 2-chloroquinoline-3-carboxaldehyde (800mg, 4.18mmol) and sodium iodide (4.4g, 29.23mmol) in acetonitrile (20.0mL), hydrochloric acid (12M, 0.1mL) was added. The flask was purged with nitrogen and evacuated five times. The mixture was stirred at 90 °C under nitrogen for 3h. The resulting mixture was concentrated. The residue was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 50% ethyl acetate / petroleum ether) to give the title compound 2-iodoquinoline-3-carboxaldehyde (400mg, 1.41mmol, 34% yield) as an orange solid. MS (ESI) m / z 284.0 [M+1] + .

[0240] 3-Formylquinoline-2-carbonitrile. To a solution of 2-iodoquinoline-3-carboxaldehyde (400mg, 1.41mmol) in acetonitrile (5.0mL), copper (I) cyanide (152mg, 1.70mmol) was added. The flask was purged with nitrogen and evacuated five times. The mixture was stirred at 90 °C under nitrogen for 5h. The resulting mixture was filtered and the filter cake was washed with acetonitrile. The filtrate was concentrated and the residue was purified by silica gel chromatography (0 to 10% ethyl acetate / petroleum ether) to give the title compound (200mg, 1.09mmol, 78% yield) as a brown solid. MS (ESI) m / z 183.0 [M+1] + .

[0241] 3-(((3S)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)pyrrolidinyl)methyl)quinoline-2-carbonitrile. To a solution of 3-formylquinoline-2-carbonitrile (90 mg, 0.49 mmol), 3-(1-oxo-5-(((S)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (150 mg, 0.41 mmol) and triethylamine (50 mg, 0.49 mmol) in dichloromethane (15.0 mL) was added sodium triacetoxyborohydride (261 mg, 1.23 mmol). The flask was evacuated and purged with nitrogen five times. The mixture was stirred at room temperature under nitrogen for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 5% methanol / dichloromethane) and preparative HPLC under the following conditions: column: SunFire Prep C18 OBD column, 19×150 mm 5 μm 10 nm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5B to 23B in 10 min; 210 / 254 nm; RT1: 9.73. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (6.6 mg, 0.01 mmol, 3% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ10.97(s,1H),8.62(s,1H),8.14(d,J=8.4Hz,2H),7.91(m,1H),7.85-7.77(m,1H),7.61(d,J= 8.4Hz,1H),7.13(d,J=2.2Hz,1H),7.02(dd,J=8.4,2.2Hz,1H),5.06(m,2H),4.38(d,J=17.2Hz,1 H),4.25(d,J=17.2Hz,1H),4.04(d,J=13.9Hz,1H),3.98(d,J=13.8Hz,1H),3.11(m,1H),2.97-2 .81(m,2H),2.78(m,1H),2.68-2.54(m,2H),2.37(m,2H),1.97(m,1H),1.89(m,1H).;MS(ESI)m / z 496.1[M+1] + . Example S42. 3-(5-(((3S,5R)-5-methyl-1-((2-methylquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0242] (2R,4S)-4-((2-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester. 3-(5-bromo-1-oxoisoindolin-2-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (200 mg, 0.45 mmol), (2R,4S)-4-hydroxy-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (272 mg, 1.35 mmol), (4,4'-di-tert-butyl-2,2'-bipyridyl)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridyl-kN)phenyl-kC]iridium (III) hexafluorophosphate (5 mg, 0.005 mmol), quinuclidine (13 mg, 0.12 mmol), potassium carbonate (62 mg, 0.45 mmol) in anhydrous acetonitrile (4 mL) were added nickel (II) chloride dimethoxyethane adduct (5 mg, 0.023 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (6 mg, 0.022 mmol) in anhydrous acetonitrile (2 mL). The reactants were evacuated and purged with nitrogen three times, then irradiated with three 34W blue LEDs. The reactants were stirred at room temperature under nitrogen for 12 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 70% ethyl acetate / petroleum ether) to give the title compound (140 mg, 0.25 mmol, 55% yield) as a light yellow solid. MS (ESI) m / z 564.5 [M+1] + .

[0243] 3-(5-(((3S,5R)-5-methylpyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a stirred solution of tert-butyl (2R,4S)-4-((2-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-2-methylpyrrolidine-1-carboxylate (140 mg, 0.25 mmol) in TFA (3 mL) was added trifluoromethanesulfonic acid (0.1 mL). The mixture was stirred at 60 °C under nitrogen for 12 h. The resulting solution was concentrated under reduced pressure. The residue was diluted with water, then adjusted to pH 6-7 with saturated sodium bicarbonate and filtered. The crude product was purified by reverse phase flash chromatography (10-30% acetonitrile + 0.05% TFA in water over 20 min) to give the title compound (40 mg, 0.12 mmol, 40% yield) as a light yellow oil. MS (ESI) m / z 344.1 [M+1] + .

[0244] 3-(5-(((3S,5R)-5-methyl-1-((2-methylquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of 3-(5-(((3S,5R)-5-methylpyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2,2,2-trifluoroacetic acid (140 mg, 0.30 mmol), 2-methylquinoline-6-carbaldehyde (60 mg, 0.35 mmol) and triethylamine (0.08 mL, 0.60 mmol) in dichloromethane (3 mL) was added sodium triacetoxyborohydride (197 mg, 0.93 mmol). The flask was evacuated and flushed with nitrogen three times. The reaction mixture was stirred at room temperature under nitrogen for 2 hours. The resulting solution was concentrated under reduced pressure at room temperature. The crude material was purified by silica gel column chromatography (0-10% methanol / dichloromethane) and reverse phase preparative HPLC under the following conditions: column: X select CSH OBD column 30*150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 3B to 18B in 7 min; 210 / 254 nm; RT1: 7.85. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (36.1 mg, 0.072 mmol, 24% yield) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4 )δ8.96(d,J=8.7Hz,1H),8.48(s,1H),8.26(d,J=3.7Hz,2H),7.98(d,J=9.2Hz,1H),7.73(d,J= 8.4Hz,1H),7.13-7.07(m,2H),5.30(m,1H),5.14-5.12(m,1H),4.97(m,1H),4.61(m,1H),4.52 -4.36(m,2H),3.94(m,1H),3.81-3.76(m,1H),3.70(m,1H),3.11-2.94(m,4H),2.91-2.79(m,1 H),2.76-2.67(m,1H),2.49-2.45(m,1H),2.21-2.03(m,2H),1.60(d,J=6.6Hz,3H).MS(ESI)m / z 499.2[M+1] + . Example S43. 3-(5-(((3S,5S)-5-methyl-1-((2-methylquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0245] (2S,4S)-4-((2-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester. 3-(5-bromo-1-oxoisoindolin-2-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (100 mg, 0.23 mmol), (2S,4S)-4-hydroxy-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (136 mg, 0.68 mmol), (4,4'-di-tert-butyl-2,2'-bipyridyl)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridyl-kN)phenyl-kC] Iridium (III) hexafluorophosphate (3 mg, 0.003 mmol), quinuclidine (6 mg, 0.06 mmol), potassium carbonate (31 mg, 0.23 mmol) in anhydrous acetonitrile (2 mL) were added nickel (II) chloride dimethoxyethane adduct (3 mg, 0.014 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (3 mg, 0.01 mmol) in anhydrous acetonitrile (2 mL). The reactants were evacuated and purged with nitrogen three times, then irradiated with three 34W blue LEDs. The reactants were stirred at room temperature under nitrogen for 12 h. The resulting reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 70% ethyl acetate / petroleum ether) to give the title compound (70 mg, 0.12 mmol, 55% yield) as a light yellow solid. MS (ESI) m / z 564.5 [M+1] + .

[0246] 3-(5-(((3S,5S)-5-methylpyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of tert-butyl (2S,4S)-4-((2-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-2-methylpyrrolidine-1-carboxylate (70 mg, 0.12 mmol) in TFA (3 mL, 0.12 mmol) was added trifluoromethanesulfonic acid (0.05 mL, 0.62 mmol). The mixture was stirred at 60 °C under nitrogen for 12 h. The resulting solution was concentrated under reduced pressure. The residue was diluted with water, adjusted to pH 6-7 with saturated sodium bicarbonate and filtered. The crude product was purified by reverse phase flash chromatography (10-30% acetonitrile + 0.05% TFA in water over 20 min) to give the title compound (40 mg, 0.12 mmol, 97% yield) as a light yellow oil. MS (ESI) m / z 344.1 [M+1] + .

[0247] 3-(5-(((3S,5S)-5-methyl-1-((2-methylquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of 3-(5-(((3S,5S)-5-methylpyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (40 mg, 0.12 mmol), 2-methylquinoline-6-carbaldehyde (30 mg, 0.17 mmol) and triethylamine (0.02 mL, 0.14 mmol) in dichloromethane (3 mL) was added sodium triacetoxyborohydride (99 mg, 0.47 mmol). The flask was evacuated and flushed with nitrogen three times. The reaction mixture was stirred at room temperature under nitrogen for 2 hours. The resulting solution was concentrated under reduced pressure at 25°C. The crude material was purified by silica gel column chromatography (0-10% methanol / dichloromethane) and further purified by reverse phase preparative HPLC under the following conditions: column: X select CSH OBD column 30*150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 3B to 23B in 7 min; 210 / 254 nm; RT1: 7.47. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (22.4 mg, 0.045 mmol, 38% yield) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4 )δ8.78(t,1H),8.35(d,1H),8.25-8.15(m,2H),7.92-7.88(m,1H),7.70-7.59(m,1H),7.09(m,1H) ,7.01-6.92(m,1H),5.27-5.12(m,2H),4.88(m,1H),4.68(m,1H),4.53-4.37(m,2H),4.15(m,1H), 4.06-3.96(m,1H),3.70(t,J=12.4Hz,2H),3.00(s,3H),2.99-2.92(m,1H),2.86-2.82(m,1H),2.6 6-2.62(m,1H),2.51-2.40(m,1H),2.27-2.20(m,1H),2.20-2.17(m,1H),1.61(t,3H); MS(ESI)m / z 499.2[M+1] + . Example S44. 3-(5-(((S)-1-((2-(difluoromethyl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0248] 6-bromo-2-(difluoromethyl)quinolone. To a stirred solution of 6-bromoquinoline-2-carboxaldehyde (400 mg, 1.69 mmol) in dichloromethane (15 mL) was added a solution of bis(2-methoxyethyl)aminosulfur trifluoride (749 mg, 3.39 mmol) in dichloromethane and ethanol (0.02 mL) at 0 ° C. The mixture was stirred at room temperature for 12 h. The resulting mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 50% ethyl acetate / petroleum ether) to give the title compound (300 mg, 1.16 mmol, 68% yield) as a light yellow solid. MS (ESI) m / z 258.0 [M+1] + .

[0249] 2-(Difluoromethyl)quinoline-6-carboxaldehyde. To a solution of 6-bromo-2-(difluoromethyl)quinoline (290 mg, 1.12 mmol), tert-butyl isocyanide (93 m, 1.12 mmol), 1,2-bis(diphenylphosphino)ethane (90 mg, 0.22 mmol) and sodium formate (153 mg, 2.25 mmol) in DMSO (6 mL) was added palladium (II) acetate (25 mg, 0.11 mmol). The mixture was stirred at 120 ° C under nitrogen for 3 h. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (0 to 50% ethyl acetate / petroleum ether) to give the title compound (70 mg, 0.33 mmol, 30% yield) as a light yellow solid. MS (ESI) m / z 208.1 [M+1] + .

[0250] 3-(5-(((S)-1-((2-(difluoromethyl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of 3-(1-oxo-5-(((S)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione (95 mg, 0.29 mmol), 2-(difluoromethyl)quinoline-6-carbaldehyde (60 mg, 0.29 mmol) and triethylamine (0.08 mL, 0.58 mmol) in dichloromethane (4 mL) was added sodium triacetoxyborohydride (245 mg, 1.16 mmol). The flask was evacuated and purged with nitrogen five times. The mixture was stirred at room temperature under nitrogen for 2 h. The resulting solution was concentrated under reduced pressure at 25 °C. The crude material was purified by silica gel column chromatography (0-10% methanol / dichloromethane) and further purified by preparative HPLC under the following conditions: Column: Sun Fire Prep C18 OBD column, 19×150 mm 5 μm 10 nm; Mobile phase A: water (0.1% formic acid), Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 5B to 18B in 10 min; 254 / 210 nm; RT 1 : 10.33. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (36.8 mg, 0.07 mmol, 24% yield) as a white solid. 1 H NMR (400 MHz, methanol-d 4 )δ8.52(dd,J=8.5,1.9Hz,1H),8.13(d,J=8.7Hz,1H),8.02(s,1H),7.93(dd,J=8.7,1. 9Hz,1H),7.80(d,J=8.5Hz,1H),7.71(d,J=8.4Hz,1H),7.11-6.98(m,2H),6.87-6.72( m,1H),5.14-5.07(m,2H)),4.51-4.36(m,2H),4.12-4.00(m,2H),3.16-3.13(m,1H),3 .11-2.99(m,2H),2.91-2.73(m,3H),2.55-2.39(m,2H),2.21-2.03(m,2H); MS(ESI)m / z 521.1[M+1] + . Example S45. 3-(5-(((S)-1-((2-cyclopropylquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0251] 6-bromo-2-cyclopropylquinoline. To a stirred solution of (2-amino-5-bromophenyl)methanol (700mg, 3.46mmol) in toluene (10mL), 1-cyclopropylethanone (583mg, 6.93mmol) and lithium tert-butoxide (554mg, 6.93mmol) were added. The reaction mixture was stirred at 110°C for 2 days. The resulting mixture was then diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 50% ethyl acetate / petroleum ether) to give the title compound (300mg, 1.21mmol, 35% yield) as a yellow oil. MS (ESI) m / z 248.0 [M+1] + .

[0252] 2-Cyclopropylquinoline-6-carboxaldehyde. To a stirred solution of 6-bromo-2-cyclopropylquinoline (290 mg, 1.17 mmol) in DMSO (5 mL) was added sodium formate (0.16 g, 2.34 mmol), 1,2-bis(diphenylphosphino)ethane (47 mg, 0.12 mmol), palladium acetate (53 mg, 0.23 mmol) and tert-butyl isocyanide (1.5 mL, 1.32 mmol). The resulting mixture was stirred at 120 ° C under nitrogen for 3 h. Water was added to the reaction solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse phase flash chromatography to give the title compound (130 mg, 0.65 mmol, 56% yield) as a yellow solid. MS (ESI) m / z 198.2 [M+1] + .

[0253] 3-(5-(((S)-1-((2-cyclopropylquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a stirred solution of 3-(1-oxo-5-(((S)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione (100 mg, 0.30 mmol) in dichloromethane (3 mL) was added 2-cyclopropylquinoline-6-carbaldehyde (72 mg, 0.37 mmol), sodium triacetoxyborohydride (258 mg, 1.22 mmol) and triethylamine (0.05 mL, 0.37 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1.5 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved with DMF and purified by preparative HPLC under the following conditions: SunFire Prep C18 OBD column, 19×150 mm, 5 μm 10 nm; Mobile phase A: water (0.1% formic acid), Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 3B to 20B in 7 min; 254 / 210 nm; RT1: 5.96; RT2. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (37.2 mg, 0.073 mmol, 24% yield) as a white solid. 1 H NMR (300 MHz, methanol-d 4 )δ88.18(d,J=8.6Hz,1H),7.96(d,J=8.7Hz,1H),7.90(d,J=1.7Hz,1H),7.83-7 .68(m,2H),7.30(d,J=8.6Hz,1H),7.13-7.02(m,2H),5.13(m,2H),4.44(m,2H) ,4.22(d,J=2.3Hz,2H),3.42(m,1H),3.25(m,2H),3.07(m,1H),2.92-2.73(m,2 H),2.53-2.40(m,2H),2.31(m,1H),2.20-2.10(m,2H),1.16(m,4H); MS(ESI)m / z 511.0[M+1] + . Example S46. 3-(5-(((S)-1-((2-cyclopropylquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0254] (3R, 4S) -3- (bromomethyl) -4- hydroxypyrrolidine -1- carboxylic acid tert-butyl ester. To a solution of (3S, 4S) -3-hydroxy-4- (hydroxymethyl) pyrrolidine -1- carboxylic acid tert-butyl ester (300 mg, 1.38 mmol), 2,6-lutidine (600 mg, 5.60 mmol) in acetone (15 mL) was added methanesulfonyl chloride (0.12 mL, 1.53 mmol) dropwise at 0 ° C, and the resulting solution was stirred at room temperature under nitrogen for 3 h. The reaction mixture was then filtered. Sodium bromide (600 mg, 5.83 mmol) was added to the filtrate and the mixture was stirred at 75 ° C under nitrogen for 3 h. Water was added to the resulting mixture and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 50% ethyl acetate / petroleum ether) to give the title compound (350 mg, 1.25 mmol, 90% yield) as a colorless oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ 4.31 (m, 1H), 3.70 (m, 2H), 3.42 (m, 2H), 3.27 (m, 2H), 2.52 (m, 1H), 1.48 (s, 9H).

[0255] (3S, 4R) -3-hydroxy-4-methylpyrrolidine-1-carboxylic acid tert-butyl ester. To a solution of (3R, 4S) -3- (bromomethyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (600 mg, 2.14 mmol) in DMSO (8 mL) was added sodium borohydride (600 mg, 15.86 mmol) in several portions at 0 ° C, and the resulting solution was stirred at 80 ° C under nitrogen for 2 h. Water was added to the resulting mixture and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 50% ethyl acetate / petroleum ether) to give the title compound as a colorless oil (350 mg, 1.74 mmol, 81% yield). 1 H NMR (400 MHz, CHLOROFORM-d) δ 3.86 (m, 1H), 3.66-3.49 (m, 2H), 3.25-3.11 (m, 1H), 2.96 (m, 1H), 2.09 (m, 1H), 1.42 (s, 9H), 1.03-0.91 (d, 3H).

[0256] (3S,4R)-3-((2-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-4-methylpyrrolidine-1-carboxylic acid tert-butyl ester. 3-(5-Bromo-1-oxoisoindolin-2-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (350 mg, 0.79 mmol), (3S,4R)-3-hydroxy-4-methylpyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 2.48 mmol), potassium carbonate (110 mg, 0.80 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (11 mg, 0.04 mmol), A mixture of quinuclidine (24 mg, 0.22 mmol) and (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridyl-kN)phenyl-kC]iridium(III) hexafluorophosphate (10 mg, 0.01 mmol) in acetonitrile (0.50 mL) / N,N-dimethylacetamide (1.5 mL) was stirred at room temperature under nitrogen for 12 h under 90 W blue LED irradiation. Water was added to the resulting mixture and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 50% ethyl acetate / petroleum ether) to give the title compound (150 mg, 0.27 mmol, 34% yield) as a light yellow semisolid. MS (ESI) m / z 586.1 [M+23] + .

[0257] 3-(5-(((3S,4R)-4-methylpyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2,2,2-trifluoroacetic acid. To a solution of tert-butyl (3S,4R)-3-((2-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-4-methylpyrrolidine-1-carboxylate (200 mg, 0.35 mmol) in TFA (5 mL) was added trifluoromethanesulfonic acid (0.2 mL) at 0°C and the solution was stirred at 60°C under nitrogen for 2 h. The solution was concentrated and sodium bicarbonate was added to the residue to pH about 5 and filtered. The filtrate was purified by reverse phase flash chromatography (0-40% acetonitrile + 0.05% TFA in water over 25 min) to give the title compound (120 mg, 0.26 mmol, 74% yield) as an off-white semisolid. MS (ESI) m / z 344.0 [M+1] + .

[0258] 3-(5-(((3S,4R)-4-methyl-1-((2-methylquinolin-6-yl)methyl)pyrrolidin-3-yl)-oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of 3-(5-(((3S,4R)-4-methylpyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2,2,2-trifluoroacetic acid (120 mg, 0.26 mmol) and 2-methylquinoline-6-carbaldehyde (50 mg, 0.29 mmol) in dichloromethane (5 mL) was added triethylamine (0.08 mL, 0.59 mmol) and sodium triacetoxyborohydride (110 mg, 0.52 mmol) at 0°C. The resulting mixture was stirred at room temperature for 2 h. Most of the solution was removed and the residue was purified by silica gel column chromatography (0-10% methanol / dichloromethane) and further purified by preparative HPLC under the following conditions: SunFire Prep C18 OBD column, 19×150 mm 5 μm 10 nm; Mobile phase A: water (0.1% formic acid), Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 2B to 20B in 7 min; 254 / 220 nm; RT1: 6.53; RT2. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (23.4 mg, 0.047 mmol, 19% yield) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4 )δ8.25(m,1H),8.02-7.92(m,2H),7.83(dd,J=8.7,2.0Hz,1H),7.72(dd,J=8.4,1.9Hz,1H ),7.48(d,J=8.5Hz,1H),7.11-7.01(m,2H),5.13(dd,J=13.4,5.1Hz,1H),4.75(m,1H),4. 61-4.35(m,2H),4.20(m,2H),3.42(m,2H),3.33-3.21(m,1H),2.98-2.85(m,1H),2.84-2. 74(m,4H),2.71-2.56(m,2H),2.48(m,1H),2.16(m,1H),1.26(d,J=6.7Hz,3H); MS(ESI)m / z 499.1[M+1] + . Example S47. 3-(1-oxo-5-(((S)-1-((1,2,3,4-tetrahydroquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione

[0259] 1-(2,4-dimethoxybenzyl)-1,2,3,4-tetrahydroquinoline. To a solution of 1,2,3,4-tetrahydroquinoline (1 g, 7.51 mmol) and 2,4-dimethoxybenzaldehyde (1.5 g, 9.01 mmol) in methanol (15 mL) was added acetic acid (0.1 mL) at room temperature. After stirring at 0 ° C for 0.5 hours, sodium cyanoborohydride (1.44 g, 22.92 mmol) was added to the reactant in several portions at 0 ° C under nitrogen. The reaction mixture was stirred at room temperature for 12 h. The resulting mixture was quenched with water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by silica gel column chromatography (0 to 50% ethyl acetate / petroleum ether) to give the title compound (1.2 g, 4.22 mmol, 56% yield) as a light yellow oil. MS (ESI) m / z 284.1 [M + 1] + .

[0260] 1-(2,4-dimethoxybenzyl)-1,2,3,4-tetrahydroquinoline-6-carbaldehyde. Phosphorus oxychloride (1.08 g, 7.05 mmol) was added dropwise to anhydrous DMF (773 mg, 10.59 mmol) at 0 ° C, and the mixture was then stirred at this temperature for 30 min. A solution of 1-(2,4-dimethoxybenzyl)-1,2,3,4-tetrahydroquinoline (1 g, 3.53 mmol) in DMF (2 mL) was added dropwise to the reaction mixture. The resulting mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography (0 to 50% ethyl acetate / petroleum ether) to give the title compound (450 mg, 1.44 mmol, 40% yield) as a light yellow oil. MS (ESI) m / z 312.1 [M+1] + .

[0261] 3-(5-(((S)-1-((1-(2,4-dimethoxybenzyl)-1,2,3,4-tetrahydroquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a stirred solution of 3-(1-oxo-5-(((S)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione (150 mg, 0.46 mmol), 1-(2,4-dimethoxybenzyl)-1,2,3,4-tetrahydroquinoline-6-carbaldehyde (142 mg, 0.45 mmol) and triethylamine (92 mg, 0.91 mmol) in dichloromethane (8 mL) was added sodium triacetoxyborohydride (386 mg, 1.82 mmol) at 0°C. The reaction mixture was then stirred at room temperature under nitrogen for 3 h. The resulting mixture was concentrated and purified by silica gel column chromatography (0 to 100% ethyl acetate / petroleum ether) to give the title compound (200 mg, 0.32 mmol, 71% yield) as a light yellow oil. MS (ESI) m / z 625.3 [M+1] + .

[0262] 3-(1-oxo-5-(((S)-1-((1,2,3,4-tetrahydroquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione. To a stirred solution of 3-(5-(((S)-1-((1-(2,4-dimethoxybenzyl)-1,2,3,4-tetrahydroquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (180 mg, 0.29 mmol) in dichloromethane (4 mL) was added TFA (1 mL) at 0°C. The mixture was stirred at room temperature under nitrogen for 1 h. The resulting solution was concentrated under reduced pressure at room temperature. The crude material was purified by silica gel column chromatography (0-10% methanol / dichloromethane) and further purified by preparative HPLC under the following conditions: Column: Sun Fire Prep C18 OBD column, 19×150 mm 5 μm 10 nm; Mobile phase A: water (0.1% formic acid), Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 2B to 18B in 7 min; 254 / 210 nm; RT 1 : 5.26. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (33.6 mg, 0.070 mmol, 23% yield) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4)δ8.50(s,1H),7.74(d,J=8.4Hz,1H),7.13(d,J=2.2Hz,1H),7.07(dd,J=8.4,2.2Hz,1H),7.00-6. 92(m,2H),6.52-6.45(m,1H),5.22(s,1H),5.12(dd,J=13.3,5.2Hz,1H),4.48-4.44(m,2H),4.16- 4.04(m,2H),3.50-3.42(m,3H),3.30-3.21(m,3H),2.95-2.85(m,1H),2.83-2.76(m,1H),2.73-2. 68(m,2H),2.59-2.39(m,2H),2.31-2.20(m,1H),2.19-2.12(m,1H),1.93-1.82(m,2H); MS(ESI)m / z 473.3[M-1] - . Example S48. 3-(5-(((S)-1-((5,8-dihydro-6H-pyrano[3,4-b]pyridin-3-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0263] (5,8-dihydro-6H-pyrano[3,4-b]pyridin-3-yl)methanol. To a stirred solution of 6,8-dihydro-5H-pyrano[3,4-b]pyridine-3-carboxylic acid (150 mg, 0.84 mmol) in THF (8 mL) was added lithium aluminum hydride (2.5 N in THF, 0.5 mL, 1.25 mmol) at 0 ° C under nitrogen. The reaction mixture was then stirred at this temperature for 1 h. The mixture was quenched with water, filtered, concentrated and the crude product was purified by reverse phase flash chromatography (10-70% acetonitrile + 0.05% aqueous ammonium bicarbonate solution over 20 min) to give the title compound (50 mg, 0.30 mmol, 36% yield) as a light yellow oil. MS (ESI) m / z 166.1 [M+1] + .

[0264] 5,8-dihydro-6H-pyrano[3,4-b]pyridine-3-carbaldehyde. To a stirred solution of (5,8-dihydro-6H-pyrano[3,4-b]pyridin-3-yl)methanol (50 mg, 0.30 mmol) in dichloromethane (5 mL) was added manganese dioxide (395 mg, 4.54 mmol) at room temperature and stirred at 60 ° C under nitrogen for 12 h. The reaction mixture was filtered and the filtrate was concentrated to give the title compound (40 mg, 0.24 mmol, 81% yield). MS (ESI) m / z 164.1 [M+1] + .

[0265] 3-(5-(((S)-1-((5,8-dihydro-6H-pyrano[3,4-b]pyridin-3-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a stirred solution of 3-(1-oxo-5-(((S)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione (60 mg, 0.18 mmol) and 5,8-dihydro-6H-pyrano[3,4-b]pyridine-3-carbaldehyde (30 mg, 0.18 mmol) in dichloromethane (6 mL) was added triethylamine (0.05 mL, 0.37 mmol) and sodium triacetoxyborohydride (154 mg, 0.73 mmol) at 0°C, and the mixture was stirred at room temperature under nitrogen for 2 h. The resulting solution was concentrated under reduced pressure at 25° C. The crude material was purified by silica gel column chromatography (0-10% methanol / dichloromethane) and further purified by preparative HPLC under the following conditions: column: X select CSH OBD column 30*150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 3B to 17B in 10 min; 254 / 210 nm; RT 1 : 7.98. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (20 mg, 0.042 mmol, 23% yield) as a pale yellow semisolid. 1 H NMR (400 MHz, methanol-d 4)δ8.53(s,1H),7.83-7.77(m,2H),7.18(s,1H),7.13(d,J=8.3Hz,1H),5.36( s,1H),5.15(dd,J=13.3,5.2Hz,1H),4.79(s,2H),4.56(s,2H),4.51-4.40(m, 2H),4.01(t,J=5.6Hz,2H),3.75(m,3H),3.58(m,1H),3.00-2.86(m,3H),2.80 -2.75(m,1H),2.65(m,1H),2.49-2.31(m,2H),2.20-2.16(m,1H).MS(ESI)m / z 477.1[M+1] + . Example S49. 6-(((3S)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)pyrrolidin-1-yl)methyl)quinazoline-2-carbonitrile

[0266] 6-Methylquinazoline-2-carbonitrile. Zinc cyanide (126 mg, 1.07 mmol) and tris(dibenzylideneacetone)dipalladium (65 mg, 0.070 mmol) were added to a stirred solution of 2-chloro-6-methyl-quinazoline (160 mg, 0.90 mmol) in NMP (5 mL). The above mixture was stirred at 90 ° C under nitrogen for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 35% ethyl acetate / petroleum ether) to give the title compound (120 mg, 0.71 mmol, 79% yield) as a yellow solid. MS (ESI) m / z 170.2 [M+1] + .

[0267] 6-(Bromomethyl)quinazoline-2-carbonitrile. To a solution of 6-methylquinazoline-2-carbonitrile (100 mg, 0.59 mmol) in carbon tetrachloride (3 mL) was added NBS (125 mg, 0.70 mmol) and benzoyl peroxide (15 mg, 0.06 mmol). The above mixture was stirred at 80 ° C under nitrogen for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 35% ethyl acetate / petroleum ether) to give the title compound (60 mg, 0.24 mmol, 41% yield) as a yellow solid. MS (ESI) m / z 248.1 [M+1] + .

[0268] 6-(((3S)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)pyrrolidin-1-yl)methyl)quinazoline-2-carbonitrile. To a solution of 6-(bromomethyl)quinazoline-2-carbonitrile (60 mg, 0.24 mmol) and 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione (80 mg, 0.24 mmol) in acetonitrile (3 mL) was added potassium carbonate (100 mg, 0.72 mmol). The flask was evacuated and purged with nitrogen five times. The mixture was stirred at room temperature under nitrogen for 5 h. The resulting mixture was filtered and the filtrate was concentrated. The residue was purified by reverse phase flash chromatography (10-100% acetonitrile + 0.05% TFA in water over 25 min) and preparative HPLC (column: SunFire Prep C18 OBD column, 19×150 mm 5 μm 10 nm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5B to 30B in 7 min; 254 / 210 nm; RT 1 : 4.97. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (16 mg, 0.032 mmol, 13% yield) as a white solid. 1 HNMR (300 MHz, methanol-d 4 )δ9.60(d,J=0.9Hz,1H),8.22(d,J=9.9Hz,2H),8.12(d,J=8.6Hz,1H),7.70(d,J=8.4Hz,1H),7.09-7.00(m,2H),5.11-5.07( m,2H),4.42(d,J=3.9Hz,2H),4.04(s,2H),3.09-2.74(m,6H),2.49-2.45(m,2H),2.20-2.02(m,2H).MS(ESI)m / z497.2[M+1] + . Example S50. 3-(1-oxo-5-(((S)-1-((2-(trifluoromethyl)quinazolin-6-yl)methyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione

[0269] 6-methyl-2-(trifluoromethyl)-4H-benzo[d][1,3]oxazine-4-one. To a solution of 2-amino-5-methylbenzoic acid (2 g, 13.23 mmol) in dichloromethane (30 mL) was slowly added trifluoroacetic anhydride (3.5 mL) with stirring. The reaction mixture was stirred at room temperature under nitrogen for 12 h. The resulting mixture was evaporated under reduced pressure. The residue was poured into ice and filtered to give the title compound (500 mg, 2.18 mmol, 16% yield) as a light yellow solid.

[0270] 6-Methyl-2-(trifluoromethyl)quinazolin-4(1H)-one. A solution of 6-methyl-2-(trifluoromethyl)-4H-benzo[d][1,3]oxazin-4-one (500 mg, 2.18 mmol) in DMF (10 mL) was first stirred at 0 ° C. and then warmed to room temperature in ammonia (about 2 bar) and maintained overnight. The crude product was purified by reverse phase flash chromatography (10-40% acetonitrile + 0.05% aqueous ammonium bicarbonate solution, over 25 min) to give the title compound (350 mg, 1.53 mmol, 70% yield) as a light yellow solid. MS (ESI) m / z 229.0 [M+1] + .

[0271] 4-Chloro-6-methyl-2-(trifluoromethyl)quinazoline. A solution of 6-methyl-2-(trifluoromethyl)quinazoline-4(1H)-one (330 mg, 1.31 mmol) in phosphorus oxychloride (10 mL) was stirred at 100 ° C under nitrogen for 3 h. The reaction mixture was cooled and evaporated under reduced pressure. The residue was diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (0 to 50% ethyl acetate / petroleum ether) to give the title compound (220 mg, 0.89 mmol, 68% yield) as an off-white solid. MS (ESI) m / z 246.9 [M+1] + .

[0272] 6-Methyl-2-(trifluoromethyl)quinazoline. To a solution of 4-chloro-6-methyl-2-(trifluoromethyl)quinazoline (200 mg, 0.81 mmol) in ethyl acetate (10 mL) was added cesium carbonate (790 mg, 2.43 mmol) and 10% palladium / carbon (100 mg, wetted with about 50% water) under nitrogen. The reaction mixture was then stirred at room temperature under hydrogen (about 2 bar) for 1 h. The resulting mixture was diluted with ethyl acetate, filtered and concentrated to give the title compound (160 mg, 0.75 mmol, 93% yield). MS (ESI) m / z 213.1 [M+1] + .

[0273] 6-(Bromomethyl)-2-(trifluoromethyl)quinazoline. To a stirred solution of 6-methyl-2-(trifluoromethyl)quinazoline (150 mg, 0.70 mmol) in carbon tetrachloride (10 mL) was added NBS (151 mg, 0.85 mmol) and benzoyl peroxide (17 mg, 0.07 mmol) at room temperature. The reaction mixture was then stirred at 60 ° C under nitrogen for 12 h. The resulting mixture was concentrated and the residue was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0 to 50% ethyl acetate / petroleum ether) to give the title compound (150 mg, 0.52 mmol, 74% yield) as a white solid. MS (ESI) m / z 290.9 [M+1] + .

[0274] 3-(1-oxo-5-(((S)-1-((2-(trifluoromethyl)quinazolin-6-yl)methyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione. To a stirred solution of 6-(bromomethyl)-2-(trifluoromethyl)quinazoline (62 mg, 0.21 mmol) in acetonitrile (3 mL) was added potassium carbonate (88 mg, 0.64 mmol) and 3-(1-oxo-5-(((S)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione (70 mg, 0.21 mmol) at room temperature. The reaction mixture was then stirred at room temperature for 1 h. The resulting reaction mixture was filtered and concentrated under reduced pressure at room temperature. The crude product was purified by silica gel chromatography (0-10% methanol / dichloromethane) and further purified by preparative HPLC under the following conditions: Column: SunFire Prep C18 OBD column, 19×150 mm 5 μm 10 nm; Mobile phase A: water (0.1% formic acid), Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 5B to 35B in 7 min; 254 / 210 nm; RT 1 : 6.32. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (34.3 mg, 0.06 mmol, 29% yield) as a white solid. 1 HNMR (400 MHz, methanol-d 4)δ9.68(s,1H),8.24-8.18(m,3H),7.71(dd,J=8.6,1.8Hz,1H),7.11-7.01(m,2H),5.12-5.08(m,2H),4.51-4.36(m,2H), 4.07(s,2H),3.18-3.09(m,1H),3.08-2.91(m,3H),2.84-2.72(m,2H),2.55-2.43(m,2H),2.22-2.02(m,2H).MS(ESI)m / z 540.1[M+1] + . Example S51. 3-(5-(((S)-1-((3-(methoxymethyl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0275] (6-bromoquinolin-3-yl)methanol. To a stirred solution of methyl 6-bromoquinoline-3-carboxylate (500 mg, 1.88 mmol) in THF (20 mL) was added lithium aluminum hydride (2.5 M in THF, 0.75 mL, 1.88 mmol) at 0 ° C under nitrogen. The reaction mixture was then stirred at 0 ° C under nitrogen for 0.5 h. The resulting mixture was quenched with water, anhydrous sodium sulfate was added, filtered and concentrated to give the title compound (380 mg, 1.60 mmol, 88% yield) as an orange solid. MS (ESI) m / z 238.0 [M+1] + .

[0276] 6-bromo-3-(methoxymethyl)quinoline. Sodium hydride (60% dispersion in mineral oil, 65 mg, 1.63 mmol) was added to a stirred solution of (6-bromoquinoline-3-yl)methanol (380 mg, 1.60 mmol) in THF (15 mL) at 0 ° C, and the resulting mixture was stirred at room temperature for 30 min, and then iodomethane (339 mg, 2.39 mmol) was added. The reaction mixture was stirred at room temperature for 12 h. The resulting mixture was quenched with water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 40% ethyl acetate / petroleum ether) to give the title compound (260 mg, 1.03 mmol, 64% yield) as a yellow solid. MS (ESI) m / z 252.0 [M+1] + .

[0277] 3-(Methoxymethyl)quinoline-6-carboxaldehyde. To a solution of 6-bromo-3-(methoxymethyl)quinoline (240 mg, 0.95 mmol), sodium formate (129 mg, 1.90 mmol), palladium (II) acetate (21 mg, 0.0094 mmol) and 1,2-bis(diphenylphosphino)ethane (76 mg, 0.19 mmol) in DMSO (10 mL), tert-butyl isocyanide (118 mg, 1.43 mmol) was added. The mixture was stirred at 120 ° C under nitrogen for 4 h. The resulting solution was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography (0 to 50% ethyl acetate / petroleum ether) to give the title compound (80 mg, 0.39 mmol, 41% yield) as a yellow solid. MS (ESI) m / z 202.2 [M+1] + .

[0278] 3-(5-(((S)-1-((3-(methoxymethyl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a stirred solution of 3-(methoxymethyl)quinoline-6-carbaldehyde (70 mg, 0.35 mmol), 3-(1-oxo-5-(((S)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione (115 mg, 0.35 mmol) and triethylamine (0.10 mL, 0.69 mmol) in dichloromethane (3 mL) was added sodium triacetoxyborohydride (295 mg, 1.39 mmol). The mixture was stirred at room temperature under nitrogen for 2 h. The resulting reaction mixture was filtered and concentrated under reduced pressure at 25 °C. The crude product was purified by silica gel chromatography (0-10% methanol / dichloromethane) and further purified by preparative HPLC under the following conditions: Column: Sun Fire Prep C18 OBD column, 19×150 mm 5 μm 10 nm; Mobile phase A: water (0.1% formic acid), Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 5B to 30B in 7 min; 254 / 210 nm; RT 1 : 4.52. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (35.1 mg, 0.068 mmol, 19% yield) as an off-white solid. 1 H NMR (400 MHz, methanol-d 4)δ8.87(d,J=2.1Hz,1H),8.31(m,2H),8.08(d,J=8.7Hz,1H),8.01(s,1H),7.87(dd,J=8. 8,2.0Hz,1H),7.72(d,J=8.4Hz,1H),7.13-7.03(m,2H),5.18-5.08(m,2H),4.71(s,2H),4 .51-4.36(m,2H),4.24(m,2H),3.50(s,3H),3.40-3.34(m,1H),3.24(m,2H),3.05(m,1H) ,2.91-2.84(m,1H),2.83-2.74(m,1H),2.59-2.41(m,2H),2.17-2.11(m,2H); MS(ESI)m / z 515.2[M+1] + . Example S52. 3-(((3S)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)pyrrolidin-1-yl)methyl)-N-methylisoquinoline-7-carboxamide

[0279] (7-Bromoisoquinolin-3-yl)methanol. To a stirred solution of methyl 7-bromoisoquinoline-3-carboxylate (500 mg, 1.88 mmol) in THF (4 mL) and ethanol (0.40 mL) was added sodium borohydride (142 mg, 3.76 mmol) at room temperature. The reaction mixture was then stirred under nitrogen for 12 h at room temperature. The resulting mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (350 mg, 1.47 mmol, 78% yield) as a light yellow oil, which was used directly in the next step without further purification. MS (ESI) m / z 238.1 [M+1] + .

[0280] 7-Bromo-3-(((tert-butyldiphenylsilyl)oxy)methyl)isoquinoline. To a stirred solution of (7-bromo-3-isoquinolyl)methanol (350 mg, 1.47 mmol) in THF (15 mL) was added sodium hydride (60% dispersion in mineral oil, 70 mg, 1.75 mmol) and tert-butylchlorodiphenylsilane (808 mg, 2.94 mmol) sequentially at 0 °C under nitrogen. The reaction mixture was then stirred at room temperature for 12 h. To the resulting mixture was added water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 10% ethyl acetate / petroleum ether) to give the title compound (450 mg, 0.94 mmol, 64% yield) as a light yellow oil. MS (ESI) m / z 476.1 [M+1] + .

[0281] Methyl 3-(((tert-butyldiphenylsilyl)oxy)methyl)isoquinoline-7-carboxylate. To a solution of (7-bromo-3-isoquinolinyl)methoxy-tert-butyl-diphenyl-silane (450 mg, 0.94 mmol) in methanol (15 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (77 mg, 0.09 mmol) and triethylamine (0.39 mL, 2.83 mmol). The reaction mixture was then stirred at 120 °C under 50 bar carbon monoxide for 12 h. The resulting mixture was filtered and concentrated. The crude product was purified by silica gel column chromatography (0 to 20% ethyl acetate / petroleum ether) to give the title compound (380 mg, 0.83 mmol, 88% yield) as a light yellow oil. MS (ESI) m / z 456.1 [M+1] + .

[0282] 3-(((tert-Butyldiphenylsilyl)oxy)methyl)-N-methylisoquinoline-7-carboxamide. A solution of methyl 3-(((tert-Butyldiphenylsilyl)oxy)methyl)isoquinoline-7-carboxylate (380 mg, 0.83 mmol) in 30% methylamine / ethanol (4 mL) was stirred at 50 °C under nitrogen for 12 h. The resulting mixture was concentrated and the crude product was purified by silica gel column chromatography (0 to 35% ethyl acetate / petroleum ether) to give the title compound (360 mg, 0.79 mmol, 94% yield) as a light yellow oil. MS (ESI) m / z 455.3 [M+1] + .

[0283] 3-(Hydroxymethyl)-N-methylisoquinoline-7-carboxamide. To a stirred solution of 3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-methylisoquinoline-7-carboxamide (320 mg, 0.70 mmol) in THF (7 mL) was added triethylamine trihydrofluoride (2.3 g, 14.26 mmol) at room temperature and stirred at this temperature for 5 h. The reaction mixture was concentrated to give the title compound (150 mg, 0.69 mmol, 98% yield) as a light yellow oil, which was used directly in the next step without further purification. MS (ESI) m / z 217.2 [M+1] + .

[0284] 3-Formyl-N-methylisoquinoline-7-carboxamide. To a stirred solution of 3-(hydroxymethyl)-N-methylisoquinoline-7-carboxamide (140 mg, 0.65 mmol) in dichloromethane (4 mL) was added manganese dioxide (563 mg, 6.47 mmol) at room temperature and stirred at 60 ° C under nitrogen for 3 h. The reaction mixture was filtered and concentrated. The crude product was purified by silica gel column chromatography (0 to 40% ethyl acetate / petroleum ether) to give the title compound as a white solid (35 mg, 0.16 mmol, 25% yield). MS (ESI) m / z 215.2 [M + 1] + .

[0285] 3-(((3S)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)pyrrolidin-1-yl)methyl)-N-methylisoquinoline-7-carboxamide. To a stirred solution of 3-formyl-N-methylisoquinoline-7-carboxamide (30 mg, 0.14 mmol), 3-(1-oxo-5-(((S)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione (46 mg, 0.14 mmol) and triethylamine (0.04 mL, 0.28 mmol) in dichloromethane (3 mL) was added sodium triacetoxyborohydride (119 mg, 0.56 mmol). The mixture was stirred at room temperature under nitrogen for 2 h. The resulting mixture was filtered and concentrated at room temperature. The crude product was purified by silica gel chromatography (0-10% methanol / dichloromethane) and further purified by preparative HPLC under the following conditions: Column: Column: Sun Fire Prep C18 column, 30*150, 5 μm; Mobile phase A: water (0.1% formic acid), Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 2B to 25B in 8 min; 254 / 220 nm; RT 1 : 7. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (14.6 mg, 0.028 mmol, 20% yield) as a white solid.1 H NMR (400 MHz, methanol-d 4 )δ9.25(s,1H),8.46(d,J=1.7Hz,1H),8.08-8.06(m,1H),7.92-7.84(m,2H ),7.61(dd,J=8.4,1.9Hz,1H),6.99-6.94(m,2H),5.07-4.98(m,2H),4.37 -4.24(m,4H),3.46(m,1H),3.42-3.35(m,2H),3.22-3.14(m,1H),2.89(s, 3H),2.79-2.65(m,2H),2.41-2.33(m,2H),2.11-2.03(m,2H); MS(ESI)m / z 528.2[M+1] + . Example S53. 3-(6-Fluoro-5-(((S)-1-(isoquinolin-3-ylmethyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0286] 4-bromo-2-(bromomethyl)-5-fluorobenzoic acid methyl ester. To a stirred solution of 4-bromo-5-fluoro-2-methylbenzoic acid methyl ester (1.8g, 7.29mmol) in carbon tetrachloride (25mL) was added NBS (930mg, 8.74mmol) and 2,2'-azobis(2-methylpropionitrile) (179mg, 1.09mmol) at room temperature. The reaction mixture was then stirred at 80 °C under nitrogen for 12h. The resulting reaction mixture was concentrated. Water was added to the residue and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 40% ethyl acetate / petroleum ether) to give the title compound (2.4g, 7.36mmol, 101% yield) containing the starting material as a light yellow oil.

[0287] Methyl 2-(((2,6-bis(benzyloxy)pyridin-3-yl)amino)methyl)-4-bromo-5-fluorobenzoate. To a stirred solution of methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate (2.4 g, 7.36 mmol) and 2,6-bis(benzyloxy)pyridin-3-amine (2.48 g, 8.1 mmol) in DMF (50 mL) was added N,N-diisopropylethylamine (1.13 mL, 14.73 mmol) at room temperature. The reaction mixture was then stirred at 80 °C under nitrogen for 3 h. To the resulting mixture was added water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 40% ethyl acetate / petroleum ether) to give the title compound (2.6 g, 4.71 mmol, 64% yield) as an orange oil. MS (ESI) m / z 551.1 [M+1] + .

[0288] 2-(2,6-bis(benzyloxy)pyridin-3-yl)-5-bromo-6-fluoroisoindolin-1-one. A solution of methyl 2-(((2,6-bis(benzyloxy)pyridin-3-yl)amino)methyl)-4-bromo-5-fluorobenzoate (2.59 g, 4.7 mmol) in acetic acid (3 mL) was stirred at 100 ° C under nitrogen for 0.5 h. Water was added to the resulting mixture and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 40% ethyl acetate / petroleum ether) to give the title compound (1.4 g, 2.69 mmol, 57% yield) as a light yellow solid. MS (ESI) m / z 518.9 [M+1] + .

[0289] 2-(2,6-bis(benzyloxy)pyridin-3-yl)-6-fluoro-5-hydroxyisoindolin-1-one. To a solution of 2-(2,6-bis(benzyloxy)pyridin-3-yl)-5-bromo-6-fluoroisoindolin-1-one (1.38 g, 2.66 mmol) in anhydrous DMF (20 mL) was added mesylate(2-(di-tert-butylphosphino)-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (67 mg, 0.08 mmol), (E)-benzaldehyde oxime (385 mg, 3.19 mmol) and cesium carbonate (1.73 g, 5.31 mmol) at room temperature. The reaction mixture was then stirred at 80° C. under nitrogen for 3 h. To the resulting mixture was added water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 50% ethyl acetate / petroleum ether) to give the title compound (1.02 g, 2.23 mmol, 84% yield) as a light orange solid. MS (ESI) m / z 457.1 [M+1] + .

[0290] (S)-tert-butyl 3-((2-(2,6-bis(benzyloxy)pyridin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)oxy)pyrrolidine-1-carboxylate. To a stirred solution of 2-(2,6-bis(benzyloxy)pyridin-3-yl)-6-fluoro-5-hydroxyisoindolin-1-one (1 g, 2.19 mmol), (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (410 mg, 2.19 mmol) and triphenylphosphine (862 mg, 3.29 mmol) in toluene (20 mL) was added di-tert-butyl azodicarboxylate (756 mg, 3.29 mmol). The reaction mixture was then stirred at 80 °C under nitrogen for 2 h. The resulting mixture was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0 to 50% ethyl acetate / petroleum ether) to give the title compound (1.25 g, 1.99 mmol, 91% yield) as an off-white solid. MS (ESI) m / z 626.3 [M+1] + .

[0291] To a solution of (S)-tert-butyl 3-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)oxy)pyrrolidine-1-carboxylate (1.24 g, 1.98 mmol) in ethanol (100 mL) was added Pd(OH) under nitrogen. 2 / C (1.2 g, 11.28 mmol). The reaction mixture was then stirred at room temperature under hydrogen (about 2 bar) for 2 h. The resulting mixture was filtered and the filtrate was concentrated to give the title compound (500 mg, 1.11 mmol, 56% yield) as a light yellow solid. MS (ESI) m / z 446.2 [M-1] - .

[0292] 3-(6-Fluoro-1-oxo-5-(((S)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione. To a stirred solution of tert-butyl (3S)-3-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)oxy)pyrrolidine-1-carboxylate (470 mg, 1.05 mmol) in dichloromethane (3 mL) was added TFA (1 mL, 1.05 mmol) at room temperature and stirred at this temperature for 1 h. The mixture was concentrated to give the title compound (300 mg, 0.86 mmol, 82% yield), which was used directly in the next step without further purification. MS (ESI) m / z 348.2 [M+1] + .

[0293] 3-(6-Fluoro-5-(((S)-1-(isoquinolin-3-ylmethyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a stirred solution of 3-(6-fluoro-1-oxo-5-(((S)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione (150 mg, 0.43 mmol), isoquinoline-3-carbaldehyde (68 mg, 0.43 mmol) and triethylamine (0.15 mL, 0.87 mmol) in dichloromethane (5 mL) was added sodium triacetoxyborohydride (366 mg, 1.73 mmol). The mixture was stirred at room temperature under nitrogen for 2 h. The resulting mixture was concentrated under reduced pressure at 25 °C. The crude material was purified by silica gel column chromatography (0-10% methanol / dichloromethane) and further purified by preparative HPLC under the following conditions: column: Sun Fireprep C18 column, 30*150, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5B to 20B in 10 min; RT 1 : 9.67. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (76.6 mg, 0.15 mmol, 36% yield) as a white solid. 1 H NMR (400 MHz, methanol-d 4)δ9.30(s,1H),8.38(s,1H),8.13(d,J=8.2Hz,1H),7.99-7.91(m,2H),7.83-7.81(m,1H),7.7 3-7.71(m,1H),7.50(dd,J=9.8,3.1Hz,1H),7.30(d,J=7.0Hz,1H),5.25(m,1H),5.15-5.10(m, 1H),4.51-4.35(m,4H),3.68-3.57(m,1H),3.51-3.47(m,2H),3.31-3.25(m,1H),2.90-2.84(m ,1H),2.83-2.74(m,1H),2.62-2.39(m,2H),2.34-2.26(m,1H),2.17-2.11(m,1H).MS(ESI)m / z 489.1[M+1] + . Example S54. 3-(5-(((S)-1-((2-ethynylquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0294] (2-Chloroquinoline-6-yl)methanol. Lithium aluminum hydride (2.5M in THF, 1.6mL, 4mmol) was added dropwise to a stirred solution of methyl 2-chloroquinoline-6-carboxylate (410mg, 1.85mmol) in THF (10mL) at 0°C under nitrogen. The reaction mixture was then warmed and stirred at room temperature for 2h. The resulting mixture was quenched with sodium hydroxide (2M aqueous solution, 5mL, 10mmol) at 0°C, then stirred at this temperature for 30min and filtered. The filter cake was washed with 20mL THF and 10mL methanol. The combined filtrate was concentrated to give the title compound (350mg, 1.80mmol, 97% yield) as a yellow solid. MS (ESI) m / z 194.0 [M+1] + .

[0295] 2-Chloroquinoline-6-carboxaldehyde. To a stirred solution of (2-chloro-6-quinolyl)methanol (380 mg, 1.96 mmol) in dichloromethane (2 mL) was added manganese (IV) oxide (341 mg, 3.90 mmol) at room temperature. The reaction mixture was then stirred at room temperature under nitrogen for 12 h. The mixture was filtered and the filtrate was concentrated to give the title compound (300 mg, 1.56 mmol, 79% yield) as a yellow solid. MS (ESI) m / z 192.1 [M+1] + .

[0296] 2-((Trimethylsilyl)ethynyl)quinoline-6-carboxaldehyde. To a stirred solution of 2-chloroquinoline-6-carboxaldehyde (150mg, 0.78mmol), ethynyl(trimethyl)silane (153mg, 1.6mmol) in acetonitrile (6mL) at room temperature, dichlorobis(triphenylphosphine)palladium(II) (64mg, 0.092mmol), triethylamine (0.54mL, 3.9mmol), copper(I)iodide (30mg, 0.16mmol) were added. The reaction mixture was then stirred at 60°C under nitrogen for 2h. The resulting mixture was filtered and the filtrate was concentrated. The crude product was purified by reverse phase flash chromatography (10-40% acetonitrile + 0.05% aqueous ammonium bicarbonate solution, over 20min) to give the title compound (85mg, 0.33mmol, 42% yield) as a yellow solid. MS(ESI)m / z 254.1[M+1] + .

[0297] 3-[1-Oxo-5-[(3S)-1-[[2-(2-trimethylsilylethynyl)-6-quinolyl]methyl]pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione. To a stirred solution of 2-(2-trimethylsilylethynyl)quinoline-6-carbaldehyde (45.6 mg, 0.18 mmol), 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione (118 mg, 0.36 mmol), triethylamine (0.05 mL, 0.37 mmol) in dichloromethane (5 mL) pre-stirred for 15 min at 0°C was added sodium triacetoxyborohydride (154 mg, 0.73 mmol) and the solution was stirred at room temperature under nitrogen for 12 h. The resulting solution was directly purified by reverse phase flash chromatography (10-40% acetonitrile + 0.05% TFA in water over 25 min) to give the title compound (70 mg, 0.12 mmol, 68% yield) as a yellow oil. MS (ESI) m / z 567.2 [M+1] + .

[0298] 3-(5-(((S)-1-((2-ethynylquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a stirred solution of 3-[1-oxo-5-[(3S)-1-[[2-(2-trimethylsilylethynyl)-6-quinolinyl]methyl]pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione (80 mg, 0.14 mmol) in THF (5 mL) at 0°C was added tetrabutylammonium fluoride (46 mg, 0.18 mmol). The reaction mixture was then stirred at room temperature under nitrogen for 2 h. The resulting solution was purified by silica gel chromatography (0 to 5% methanol / dichloromethane). Pure fractions were evaporated and further purified by reverse phase semi-preparative HPLC (10-30% acetonitrile + 0.05% TFA in water over 30 min) to give the title compound (3.7 mg, 0.007 mmol, 5% yield) as a light orange solid. 1 H NMR (400 MHz, DMSO-d 6 )δ8.38(d,J=8.5Hz,1H),8.00-7.86(m,2H),7.79(m,1H),7.61(t,J=8.2Hz,2H), 7.11(s,1H),7.01(m,1H),5.13-4.95(m,2H),4.46(s,1H),4.37(d,J=17.2Hz,1H) ,4.24(d,J=17.1Hz,1H),3.90-3.76(m,2H),3.02-2.84(m,2H),2.84-2.68(m,2H) ,2.65-2.52(m,2H),2.35(m,2H),1.98(s,1H),1.85(d,J=7.6Hz,1H);MS(ESI)m / z 495.2[M+1] + . Example S55. 3-(1-oxo-5-(((S)-1-((2-(prop-1-yn-1-yl)quinazolin-6-yl)methyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione

[0299] 2-(Prop-1-yn-1-yl)quinazoline-6-carboxaldehyde. To a mixture of 2-chloroquinazoline-6-carboxaldehyde (90 mg, 0.47 mmol), prop-1-yn (187 mg, 4.67 mmol), copper (I) iodide (18 mg, 0.095 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (34 mg, 0.05 mmol) in THF (1 mL) was added triethylamine (0.41 mL, 2.34 mmol), and the mixture was heated in a microwave reactor at 130 ° C for 1 h under microwave irradiation. Water was added to the resulting mixture and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 30% ethyl acetate / petroleum ether) to give the title compound (20 mg, 0.10 mmol, 22% yield) as a light yellow oil. MS (ESI) m / z 197.1 [M+1] + .

[0300] 3-(1-oxo-5-(((S)-1-((2-(prop-1-yn-1-yl)quinazolin-6-yl)methyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione. To a solution of 2-(prop-1-yn-1-yl)quinazoline-6-carbaldehyde (20 mg, 0.10 mmol), 3-(1-oxo-5-(((S)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione (70 mg, 0.21 mmol) and triethylamine (40 mg, 0.40 mmol) in dichloromethane (4 mL) was added sodium triacetoxyborohydride (95 mg, 0.45 mmol). The mixture was stirred at room temperature under nitrogen for 3 h. The resulting mixture was concentrated. The residue was purified by preparative HPLC under the following conditions: column: Xselect CSH OBD column 30*150 mm 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 6B to 26B in 7 min; RT 1 : 5.75. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (10.5 mg, 0.02 mmol, 20% yield) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d 6)δ9.59(s,1H),8.30(s,1H),8.19-8.11(m,1H),8.04(d,J=8.7Hz,1H),7 .68(d,J=8.3Hz,1H),7.18(s,1H),7.08(d,J=8.4Hz,1H),5.28(m,1H),5. 10-4.99(m,1H),4.68(m,2H),4.43-4.24(m,2H),3.50(m,4H),2.87(m,1H ),2.64(m,2H),2.37(m,2H),2.15(s,3H),2.06-1.94(m,1H); MS(ESI)m / z 510.3[M+1] + . Example S56. 3-(5-(((S)-1-((2-(4-methyltetrahydro-2H-pyran-4-yl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0301] 6-bromo-2-(4-methyltetrahydro-2H-pyran-4-yl)quinoline. To a stirred solution of 1-(4-methyltetrahydro-2H-pyran-4-yl)ethan-1-one (1126 mg, 7.92 mmol) and (2-amino-5-bromophenyl)methanol (800 mg, 3.96 mmol) in toluene (25 mL) was added lithium tert-butoxide (640 mg, 7.92 mmol) at room temperature. The mixture was then stirred at 110 ° C under nitrogen for 12 h. The resulting mixture was filtered and concentrated. The crude product was purified by reverse phase flash chromatography (40-80% acetonitrile + 0.05% aqueous ammonium bicarbonate solution over 20 min) to give the title compound (490 mg, 1.60 mmol, 40% yield) as a yellow solid. MS (ESI) m / z 306.1 [M+1] + .

[0302] 2-(4-methyltetrahydro-2H-pyran-4-yl)-6-vinylquinoline. To a solution of 6-bromo-2-(4-methyltetrahydro-2H-pyran-4-yl)quinoline (470 mg, 1.53 mmol) in 1,4-dioxane (12.5 mL) and water (2.5 mL) were added potassium trifluoro(vinyl)borate (308 mg, 2.30 mmol), 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (125 mg, 0.15 mmol) and sodium carbonate (488 mg, 4.60 mmol) at room temperature. The reaction mixture was then stirred at 80 °C under nitrogen for 2 h. The resulting mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated and purified by silica gel column chromatography (0 to 40% ethyl acetate / petroleum ether) to give the title compound (290 mg, 1.14 mmol, 74% yield) as a yellow oil. MS (ESI) m / z 254.2 [M+1] + .

[0303] 2-(4-methyltetrahydro-2H-pyran-4-yl)quinoline-6-carbaldehyde. To a stirred solution of 2-(4-methyltetrahydro-2H-pyran-4-yl)-6-vinylquinoline (280 mg, 1.11 mmol), 4-methylmorpholine N-oxide (259 mg, 2.21 mmol) and citric acid (464 mg, 2.21 mmol) in tert-butanol (4 mL) and water (4 mL) was added potassium osmate (41 mg, 0.11 mmol) under nitrogen. The reaction mixture was stirred at room temperature under nitrogen for 3 h. Sodium periodate (591 mg, 2.76 mmol) was then added to the reaction mixture and stirred for 1 h. The resulting reaction mixture was adjusted to pH ~7 with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the title compound (200 mg, 0.78 mmol, 70% yield) as a light yellow oil. MS (ESI) m / z 256.1 [M+1] + .

[0304] 3-(5-(((S)-1-((2-(4-methyltetrahydro-2H-pyran-4-yl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a stirred solution of 2-(4-methyltetrahydro-2H-pyran-4-yl)quinoline-6-carbaldehyde (100 mg, 0.39 mmol), 3-(1-oxo-5-(((S)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione (129 mg, 0.39 mmol) and triethylamine (0.11 mL, 0.78 mmol) in dichloromethane (4 mL) was added sodium triacetoxyborohydride (332 mg, 1.57 mmol). The mixture was stirred at room temperature under nitrogen for 2 h. The resulting mixture was concentrated under reduced pressure at room temperature. The crude material was purified by silica gel column chromatography (0-10% methanol / dichloromethane) and further purified by preparative HPLC under the following conditions: column: Sun Fire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5B to 20B in 11 min; 254 / 220 nm; RT 1 : 10.38. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (38.6 mg, 0.068 mmol, 17% yield) as a white solid. 1 H NMR (400 MHz, methanol-d 4 )δ8.28-8.21(m,1H),8.02(d,J=8.7Hz,1H),7.89(s,1H),7.82-7.75(m,1H),7.71(d,J=8.4Hz,1H),7 .63(d,J=8.7Hz,1H),7.12-7.01(m,2H),5.16-5.07(m,2H),4.51-4.36(m,2H),4.16-4.04(m,2H),3. 84-3.81(m,2H),3.66-3.59(m,2H),3.25-3.18(m,1H),3.13(m,2H),2.97-2.88(m,2H),2.83-2.73(m ,1H),2.53-2.41(m,4H),2.21-2.08(m,2H),1.92-1.81(m,2H),1.38(s,3H); MS(ESI)m / z569.2[M+1] + . Example S57. (3-(5-(((S)-1-((2-(((1S,4R)-4-methoxycyclohexyl)oxy)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0305] 6-bromoquinolin-2-ol. To a stirred solution of 6-bromo-2-chloro-quinoline (1 g, 4.12 mmol) in 4-methoxycyclohexanol (6 mL) was added potassium 2-methylpropan-2-olate (2.3 g, 20.5 mmol). The above mixture was stirred under nitrogen at 120 ° C for 12 h. The reaction mixture was concentrated. The residue was purified by reverse phase flash chromatography (10-100% acetonitrile + 0.05% aqueous ammonium bicarbonate solution, over 25 min) to give the title compound (600 mg, 2.68 mmol, 65% yield) as an off-white solid. MS (ESI) m / z 223.8 [M + 1] + .

[0306] 6-bromo-2-((4-methoxycyclohexyl)oxy)quinoline. A solution of 6-bromoquinolin-2-ol (600 mg, 2.68 mmol), 4-methoxycyclohexanol (348 mg, 2.68 mmol), triphenylphosphine (1053 mg, 4.02 mmol) and diisopropyl azodicarboxylate (813 mg, 4.02 mmol) in toluene (10 mL) was stirred at 100 ° C under nitrogen for 12 h. The solution was then concentrated. Water was added to the residue and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 40% ethyl acetate / petroleum ether) to give the title compound (400 mg, 1.19 mmol, 44% yield) as a light yellow oil. MS (ESI) m / z 336.1 [M+1] + .

[0307] 2-(((1S,4S)-4-methoxycyclohexyl)oxy)-6-vinylquinoline. To a stirred solution of 6-bromo-2-((4-methoxycyclohexyl)oxy)quinoline (300 mg, 0.89 mmol) and potassium trifluoro(vinyl)borate (143 mg, 1.07 mmol) in 1,4-dioxane (6 mL) and water (0.5 ml) was added tetrakis(triphenylphosphine)palladium (75 mg, 0.064 mmol) and cesium carbonate (580 mg, 1.78 mmol). The above mixture was stirred at 80 °C under nitrogen for 3 h. To the resulting mixture was added water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 25% ethyl acetate / petroleum ether). The residue was then further purified by analytical SFC under the following conditions: column: CHIRALPAK AD-H SFC, 5*25 cm, 5 μm; mobile phase A: carbon dioxide, mobile phase B: ethanol: hexane = 1:1 (2 M ammonia / methanol); flow rate: 150 mL / min; gradient: 30% B; 220 nm; RT 1 : 3.3; RT2: 3.89; injection volume: 3 ml; number of runs: 10, the title compound (40 mg, 0.14 mmol, 16% yield) was obtained as a light yellow oil. MS (ESI) m / z 284.2 [M+1] + .

[0308] 2-(((1S,4S)-4-methoxycyclohexyl)oxy)quinoline-6-carbaldehyde. To a stirred solution of 2-((4-methoxycyclohexyl)oxy)-6-vinylquinoline (40 mg, 0.14 mmol) in tert-butyl alcohol (4 mL) and water (4 mL) was added 4-methyl-morpholine 4-oxide (33 mg, 0.28 mmol), potassium osmate (6 mg, 0.016 mmol) and citric acid (54 mg, 0.28 mmol). The above mixture was stirred at room temperature under nitrogen for 3 h. Then sodium periodate (90 mg, 0.42 mmol) was added to the mixture and stirred for another 1 hour. A saturated solution of sodium bicarbonate was added to the mixture to a pH of about 7 and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 25% ethyl acetate / petroleum ether) to give the title compound (30 mg, 0.10 mmol, 71% yield) as a light yellow oil. MS (ESI) m / z 286.1 [M+1] + .

[0309] (3-(5-(((S)-1-((2-(((1S,4R)-4-methoxycyclohexyl)oxy)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. 2-(((1S,4S)-4-methoxycyclohexyl)oxy)quinoline-6-carbaldehyde (30 mg, 0.10 mmol), 3-(1-oxo-5-(((S)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione were added. To a solution of 2-(4-yl)piperidin-2,6-dione (53 mg, 0.16 mmol) and triethylamine (35 mg, 0.35 mmol) in dichloromethane (4 mL) was added sodium triacetoxyborohydride (90 mg, 0.42 mmol). The mixture was stirred under nitrogen at room temperature for 48 h. The resulting mixture was concentrated. The residue was purified by silica gel chromatography (0 to 10% methanol / dichloromethane) and preparative HPLC under the following conditions: column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 2% B to 5% B within 2 min, 5% B to 25% B within 10 min, 25% B; wavelength: 254 / 220 nm; RT 1 (min): 10.38. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (12.2 mg, 0.02 mmol, 20% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ10.96(s,1H),8.18-8.16(m,1H),7.79-7.67(m,2H),7.64-7.55(m,2H),7.15-6.88(m,3H),5.21-5 .18(m,1H),5.10-4.96(m,2H),4.37(d,J=17.2Hz,1H),4.24-4.20(m,1H),3.81-3.70(m,2H),3.30(m, 4H),2.99-2.85(m,2H),2.75(m,1H),2.71-2.67(m,1H),2.63-2.55(m,2H),2.42-2.29(m,2H),2.15- 2.05(m,2H),2.04-1.91(m,3H),1.90-1.77(m,1H),1.61-1.47(m,2H),1.40-1.37(m,2H); MS(ESI)m / z 599.3[M+1] + . Example S58. 3-(5-(((S)-1-((2-(((1R,4S)-4-methoxycyclohexyl)oxy)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0310] 2-(((1R,4R)-4-methoxycyclohexyl)oxy)-6-vinylquinoline. The crude compound (200 mg) was purified by analytical SFC under the following conditions: column: CHIRALPAK AD-H SFC, 5*25 cm, 5 μm; mobile phase A: carbon dioxide, mobile phase B: ethanol: hexane = 1:1 (2M ammonia / methanol); flow rate: 150 mL / min; gradient: 30% B; 220 nm; RT 1 :3.3;RT 2 : 3.89; injection volume: 3 ml; number of runs: 10. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (55 mg, 0.19 mmol, 27% yield) as a pale yellow oil. MS (ESI) m / z 284.2 [M+1] + .

[0311] 2-(((1R,4R)-4-methoxycyclohexyl)oxy)quinoline-6-carbaldehyde. To a stirred solution of 2-(((1R,4R)-4-methoxycyclohexyl)oxy)-6-vinylquinoline (55 mg, 0.19 mmol) in tert-butyl alcohol (4 mL) and water (4 mL) was added potassium osmate (8 mg, 0.02 mmol), 4-methyl-morpholine 4-oxide (45 mg, 0.39 mmol) and citric acid (83 mg, 0.39 mmol). The above mixture was stirred at room temperature under nitrogen for 3 h. Then sodium periodate (124 mg, 0.58 mmol) was added to the mixture and stirred for another 1 h. A saturated solution of sodium bicarbonate was added to the mixture to a pH of about 7 and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 25% ethyl acetate / petroleum ether) to give the title compound (50 mg, 0.17 mmol, 89% yield) as a light yellow oil. MS (ESI) m / z 286.1 [M+1] + .

[0312] 3-(5-(((S)-1-((2-(((1R,4S)-4-methoxycyclohexyl)oxy)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of 2-(((1R,4R)-4-methoxycyclohexyl)oxy)quinoline-6-carbaldehyde (50 mg, 0.17 mmol), 3-(1-oxo-5-(((S)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione (60 mg, 0.18 mmol) and triethylamine (40 mg, 0.4 mmol) in dichloromethane (4 mL) was added triacetoxyborohydride (140 mg, 0.66 mmol). The mixture was stirred at room temperature under nitrogen for 48 h. The resulting mixture was concentrated. The residue was purified by silica gel chromatography (0 to 10% methanol / dichloromethane) and preparative HPLC under the following conditions: column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 2% B to 10% B in 2 min, 10% B to 30% B in 10 min, 30% B; wavelength: 254 / 220 nm; RT 1 (min): 9.67. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (24.2 mg, 0.04 mmol, 23% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ10.96(s,1H),8.22-8.15(m,1H),7.77(s,1H),7.72-7.58(m,3H),7.10(t,J=2.2Hz, 1H),7.03-6.92(m,2H),5.28(m,1H),5.06-5.01(m,2H),4.37(d,J=17.2Hz,1H),4.24- 4.20(m,1H),3.82-3.70(m,2H),3.30(m,1H),3.25(s,3H),2.98-2.85(m,2H),2.80-2. 66(m,2H),2.61(m,2H),2.36(m,2H),1.97-1.95(m,1H),1.91-1.64(m,9H); MS(ESI)m / z 599.3[M+1] + . Example S59. 3-(5-(((S)-1-((2-(3,3-dimethylmorpholino)quinazolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0313] 4-(6-bromoquinazoline-2-yl)-3,3-dimethylmorpholine. To a stirred solution of 6-bromo-2-chloroquinazoline (300 mg, 1.23 mmol) in NMP (12 mL) was added 3,3-dimethylmorpholine (420 mg, 3.65 mmol) and N,N-diisopropylethylamine (0.42 mL, 2.48 mmol). The above mixture was stirred at 80 ° C under nitrogen for 12 h. The reaction mixture was filtered and the filtrate was purified by reverse phase flash chromatography (10-100% acetonitrile + 0.05% ammonium bicarbonate / water, over 25 min) to give the title compound as a light yellow oil (120 mg, 0.37 mmol, 30% yield). MS (ESI) m / z 321.9 [M + 1] + .

[0314] 3,3-Dimethyl-4-(6-vinylquinazoline-2-yl)morpholine. To a stirred solution of 4-(6-bromoquinazoline-2-yl)-3,3-dimethyl-morpholine (120 mg, 0.37 mmol) and potassium trifluoro(vinyl)borate (60 mg, 0.45 mmol) in 1,4-dioxane (5 mL) was added tetrakis(triphenylphosphine)palladium (32 mg, 0.03 mmol) and cesium carbonate (242 mg, 0.74 mmol). The above mixture was stirred at 80 °C under nitrogen for 3 h. Water was then added to the mixture and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 40% ethyl acetate / petroleum ether) to give the title compound (80 mg, 0.30 mmol, 81% yield) as a light yellow oil. MS (ESI) m / z 270.1 [M+1] + .

[0315] 2-(3,3-dimethylmorpholino)quinazoline-6-carboxaldehyde. To a stirred solution of 3,3-dimethyl-4-(6-vinylquinazoline-2-yl)morpholine (80 mg, 0.30 mmol) in tert-butanol (4 mL) and water (4 mL) was added potassium osmate (11 mg, 0.03 mmol), 4-methylmorpholine N-oxide (70 mg, 0.59 mmol) and citric acid (127 mg, 0.59 mmol). The above mixture was stirred at room temperature under nitrogen for 3 h. Sodium periodate (190 mg, 0.89 mmol) was then added to the mixture and stirred for another 1 h. A saturated solution of sodium bicarbonate was added to the mixture to a pH of about 7 and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 40% ethyl acetate / petroleum ether) to give the title compound (40 mg, 0.15 mmol, 50% yield) as a light yellow oil. MS (ESI) m / z 272.2 [M+1] + .

[0316] 3-(5-(((S)-1-((2-(3,3-dimethylmorpholino)quinazolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of 2-(3,3-dimethylmorpholino)quinazoline-6-carbaldehyde (40 mg, 0.15 mmol), 3-(1-oxo-5-(((S)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione (80 mg, 0.24 mmol) and triethylamine (50 mg, 0.50 mmol) in dichloromethane (4 mL) was added sodium triacetoxyborohydride (130 mg, 0.61 mmol). The mixture was stirred at room temperature under nitrogen for 12 h. The resulting mixture was concentrated. The residue was purified by silica gel chromatography (0 to 10% methanol / dichloromethane) and preparative HPLC under the following conditions: column: Sunfireprep C18 column, 30*150, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5B to 35B in 7 min; 254 / 220 nm; RT 1 : 6.32. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (25.4 mg, 0.043 mmol, 29% yield) as an off-white solid. 1 H NMR (300 MHz, methanol-d 4)δ9.12(t,J=0.8Hz,1H),7.85-7.78(m,2H),7.72(d,J=8.4Hz,1H),7.63(d,J=9 .2Hz,1H),7.12-7.03(m,2H),5.12-5.09(m,2H),4.44(d,J=3.5Hz,2H),4.09-3 .90(m,6H),3.53(s,2H),3.24-3.22(m,1H),3.14(m,2H),2.97-2.85(m,2H),2. 83-2.74(m,1H),2.48-2.44(m,2H),2.13-2.10(m,2H),1.61(s,6H); MS(ESI)m / z 585.4[M+1] + . Example S60. 3-(5-(((S)-1-((2-(3,3-dimethylmorpholino)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0317] Methyl 2-(3,3-dimethylmorpholino)quinoline-6-carboxylate. To a stirred solution of methyl 2-chloroquinoline-6-carboxylate (100 mg, 0.45 mmol) in toluene (5 mL) was added 3,3-dimethylmorpholine (80 mg, 0.69 mmol), bis(di-tert-butyl)-4-dimethylaminophenylphosphine (11 mg, 0.04 mmol), methanesulfonate {[4-(N,N-dimethylamino)phenyl]di-tert-butylphosphino}(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (43 mg, 0.067 mmol) and cesium carbonate (440 mg, 1.35 mmol) at room temperature. The reaction mixture was then stirred at 100 °C under nitrogen for 12 h. The resulting mixture was filtered and the filtrate was concentrated. The crude product was purified by silica gel chromatography (0 to 50% ethyl acetate / petroleum ether) to give the title compound (99 mg, 0.33 mmol, 73% yield) as a yellow oil. MS (ESI) m / z 301.0 [M+1] + .

[0318] (2-(3,3-dimethylmorpholino)quinolin-6-yl)methanol. To a stirred solution of methyl 2-(3,3-dimethylmorpholin-4-yl)quinoline-6-carboxylate (90 mg, 0.30 mmol) in THF (5 mL) was added lithium aluminum hydride (2.5 M in THF, 0.24 mL, 0.47 mmol) dropwise at 0 ° C under nitrogen. The reaction mixture was then warmed and stirred at room temperature for 2 h. The resulting mixture was quenched with sodium hydroxide (2 M aqueous solution, 1 mL, 2 mmol) at 0 ° C, then stirred at this temperature for 30 min and filtered. The filter cake was washed with 10 mL of THF and 5 mL of methanol. The combined filtrate was concentrated to give the title compound (80 mg, 0.29 mmol, 97% yield) as a yellow solid. MS (ESI) m / z 273.2 [M+1] + .

[0319] 2-(3,3-dimethylmorpholino)quinoline-6-carboxaldehyde. To a stirred solution of [2-(3,3-dimethylmorpholin-4-yl)-6-quinolinyl]methanol (80 mg, 0.29 mmol) in dichloromethane (5 mL) was added Dess-Martin periodinane (160 mg, 0.38 mmol) at 0 ° C. The reaction mixture was then stirred at room temperature under nitrogen for 2 h. The resulting solution was purified by silica gel chromatography (0 to 40% ethyl acetate / petroleum ether). Pure fractions were evaporated to give the title compound (55 mg, 0.20 mmol, 69% yield) as a yellow oil. MS (ESI) m / z 271.1 [M+1] + .

[0320] 3-(5-(((S)-1-((2-(3,3-dimethylmorpholino)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a stirred solution of 2-(3,3-dimethylmorpholin-4-yl)quinoline-6-carbaldehyde (50 mg, 0.18 mmol), 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione; 2,2,2-trifluoroacetic acid (70 mg, 0.16 mmol), triethylamine (0.05 mL, 0.33 mmol) in dichloromethane (5 mL) pre-stirred for 15 min was added sodium triacetoxyborohydride (154 mg, 0.73 mmol) at 0°C and the solution was stirred at room temperature under nitrogen for 4 h. The resulting solution was purified by silica gel chromatography (0 to 15% methanol / dichloromethane). Pure fractions were evaporated and further purified by preparative HPLC under the following conditions: column: Sunfire prep C18 column, 30*150, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5B to 35B in 7 min, 254 / 220 nm; rt 1 : 4.82. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (70 mg, 0.12 mmol, 67% yield) as a yellow oil. 1 H NMR (300 MHz, DMSO-d 6 )δ10.96(s,1H),8.03(dd,J=9.1,1.1Hz,1H),7.70-7.51(m,4H),7.26(d,J=9.1Hz,1H), 7.11(t,J=1.9Hz,1H),7.01(m,1H),5.12-4.94(m,2H),4.38(d,J=17.2Hz,1H),4.25(m, 1H),3.86-3.67(m,4H),3.50(t,J=5.0Hz,2H),3.40(s,2H),2.91(m,2H),2.69(m,1H),2 .50(m,1H),2.35-2.27(m,2H),2.04-1.92(m,1H),1.84(m,1H),1.48(s,6H).MS(ESI)m / z 584.3[M+1] + . Example S61. 3-(5-(((S)-1-((2-((S)-3,3-dimethyltetrahydro-2H-pyran-4-yl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0321] N-methoxy-N,3,3-trimethyltetrahydro-2H-pyran-4-carboxamide. To a stirred solution of 3,3-dimethyltetrahydropyran-4-carboxylic acid (1.0 g, 6.32 mmol) in dichloromethane (20 mL) was added N-methoxymethylamine; hydrochloride (1.1 g, 11.3 mmol) and CDI (1.1 g, 6.78 mmol) at room temperature. The mixture was then stirred under nitrogen for 12 h at room temperature. Water was added to the resulting mixture and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse phase flash chromatography (20-70% acetonitrile + 0.05% aqueous ammonium bicarbonate solution, over 25 min) to give the title compound (350 mg, 1.73 mmol, 27% yield) as a yellow solid. MS (ESI) m / z 202.2 [M+1] + .

[0322] 1-(3,3-Dimethyltetrahydro-2H-pyran-4-yl)ethan-1-one. To a stirred solution of N-methoxy-N,3,3-trimethyl-tetrahydropyran-4-carboxamide (600 mg, 2.96 mmol) in THF (20 mL) was added methylmagnesium bromide (1.5 M in diethyl ether, 2 mL, 3 mmol) dropwise at 0 ° C, and the mixture was stirred at room temperature under nitrogen for 2 h. Saturated ammonium chloride was added to the reaction mixture and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (400 mg, 2.55 mmol, 86% yield) as a yellow oil. MS (ESI) m / z 157.1 [M+1] + .

[0323] 6-bromo-2-(3,3-dimethyltetrahydro-2H-pyran-4-yl)quinoline. To a stirred solution of 1-(3,3-dimethyltetrahydropyran-4-yl)ethanone (400 mg, 2.55 mmol) in toluene (10 mL) was added (2-amino-5-bromo-phenyl)methanol (773 mg, 3.83 mmol), lithium tert-butoxide (616 mg, 7.7 mmol) at room temperature. The reaction mixture was then stirred at 100 ° C under nitrogen for 12 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by reverse phase flash chromatography (30-80% acetonitrile + 0.05% aqueous ammonium bicarbonate solution, over 20 min) to give the title compound (200 mg, 0.62 mmol, 24% yield) as a yellow oil. MS (ESI) m / z 320.1 [M+1] + .

[0324] 2-(3,3-dimethyltetrahydro-2H-pyran-4-yl)-6-vinylquinoline. To a solution of 6-bromo-2-(3,3-dimethyltetrahydropyran-4-yl)quinoline (353 mg, 1.10 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added potassium trifluoro(vinyl)borate (300 mg, 2.24 mmol), dichlorobis(triphenylphosphine)palladium(II) dichloromethane adduct (182 mg, 0.24 mmol) and sodium carbonate (116.9 mg, 1.13 mmol) at room temperature. The reaction mixture was then stirred at 80 °C under nitrogen for 4 h. The resulting mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 30% ethyl acetate / petroleum ether) to give the title compound (160 mg, 0.60 mmol, 54% yield) as a light yellow oil. MS (ESI) m / z 268.1 [M+1] + .

[0325] (S)-2-(3,3-Dimethyltetrahydro-2H-pyran-4-yl)-6-vinylquinoline. 2-(3,3-Dimethyltetrahydro-2H-pyran-4-yl)-6-vinylquinoline (160 mg, 0.60 mmol) was purified by preparative SFC under the following conditions: column: CHIRALPAK IH, 2*25 cm, 5 μm; mobile phase A: hexane (0.5% 2M ammonia-methanol)--HPLC, mobile phase B: ethanol--HPLC; flow rate: 20 mL / min; gradient: 3% B to 3% B in 7.5 min; wavelength: 220 / 254 nm; room temperature 1 (min): 4.76; room temperature 2 (min): 5.80; Sample solvent: ethanol--HPLC; Injection volume: 0.5 mL; Number of runs: 13. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (31 mg, 0.12 mmol, 20% yield). MS (ESI) m / z 268.1 [M+1] + .

[0326] (S)-2-(3,3-dimethyltetrahydro-2H-pyran-4-yl)quinoline-6-carbaldehyde. To a stirred solution of 2-[(4S)-3,3-dimethyltetrahydropyran-4-yl]-6-vinyl-quinoline (31 mg, 0.12 mmol), 4-methylmorpholine N-oxide (26.3 mg, 0.22 mmol) and citric acid (43 mg, 0.22 mmol) in water (2 mL) and tert-butanol (2 mL) was added potassium osmate (4 mg, 0.010 mmol). The reaction mixture was stirred at room temperature under nitrogen for 3 h. Sodium periodate (75 mg, 0.35 mmol) was then added to the above mixture. The resulting mixture was stirred at room temperature under nitrogen for 1 h. Saturated sodium bicarbonate was added to the mixture to pH about 7 and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 50% ethyl acetate / petroleum ether) to give the title compound (30 mg, 0.11 mmol, 92% yield) as a yellow oil. MS (ESI) m / z 270.2 [M+1] + .

[0327] 3-(5-(((S)-1-((2-((S)-3,3-dimethyltetrahydro-2H-pyran-4-yl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a stirred solution of 2-[(4S)-3,3-dimethyltetrahydropyran-4-yl]quinoline-6-carbaldehyde (25 mg, 0.092 mmol), 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione; 2,2,2-trifluoroacetic acid (56 mg 0.13 mmol), triethylamine (0.03 mL, 0.22 mmol) in dichloromethane (5 mL) pre-stirred for 15 min at 0° C. was added sodium triacetoxyborohydride (94 mg, 0.44 mmol) and the solution was stirred at room temperature under nitrogen for 4 h. The resulting solution was purified by silica gel chromatography (0 to 5% methanol / dichloromethane). The pure fractions were evaporated and further purified by preparative HPLC under the following conditions: column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 2% B to 27% B in 7 min, 27% B; wavelength: 254 / 220 nm; room temperature 1 (min): 6.98. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (45.3 mg, 0.078 mmol, 85% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6 )δ8.44(d,J=8.6Hz,1H),8.21-8.07(m,2H),7.93(m,1H),7.64(m,2H),7.18(s,1H),7.08(d,J=8 .4Hz,1H),5.28(s,1H),5.04(m,1H),4.65(s,2H),4.40(m,1H),4.27(d,J=17.4Hz,1H),4.05(m, 1H),3.60-3.40(m,7H),3.25(m,1H),3.08(m,1H),2.95-2.82(m,1H),2.66-2.57(m,1H),2.39(m ,2H),2.16(m,1H),2.03-1.95(m,1H),1.57-1.49(m,1H),0.90(s,3H),0.74(s,3H); MS(ESI)m / z 583.2[M+1] + . Example S62. 3-(5-(((S)-1-((2-methoxyquinazolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0328] 6-bromo-2-methoxyquinazoline. To a stirred solution of 6-bromo-2-chloroquinazoline (500 mg, 2.05 mmol) in methanol (6 mL) was added sodium methoxide (30% in methanol, 2 mL). The above mixture was stirred at 70 ° C under nitrogen for 12 h. Water was added to the resulting mixture and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (400 mg, 1.67 mmol, 81% yield) as a light yellow solid. MS (ESI) m / z 238.9 [M + 1] + .

[0329] 2-Methoxy-6-vinylquinazoline. To a stirred solution of 6-bromo-2-methoxyquinazoline (400 mg, 1.67 mmol) and potassium trifluoro(vinyl)borate (269 mg, 2.01 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added tetrakis(triphenylphosphine)palladium (141 mg, 0.12 mmol) and cesium carbonate (1087 mg, 3.35 mmol). The above mixture was stirred at 80 ° C under nitrogen for 3 h. Water was added to the resulting mixture and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 40% ethyl acetate / petroleum ether) to give the title compound (180 mg, 0.96 mmol, 57% yield) as a light yellow oil. MS (ESI) m / z 187.0 [M+1] + .

[0330] 2-Methoxyquinazoline-6-carboxaldehyde. To a stirred solution of 2-methoxy-6-vinyl-quinazoline (100 mg, 0.54 mmol) in tert-butanol (4 mL) and water (4 mL) was added potassium osmate (20 mg, 0.05 mmol), 4-methylmorpholine N-oxide (126 mg, 1.07 mmol) and citric acid (230 mg, 1.20 mmol). The above mixture was stirred at room temperature under nitrogen for 3 h. Sodium periodate (345 mg, 1.61 mmol) was then added to the mixture and stirred for another 1 h. The reaction mixture was concentrated and the residue was purified by reverse phase flash chromatography (10-100% acetonitrile + 0.05% aqueous ammonium bicarbonate solution, over 25 min) to give the title compound (50 mg, 0.26 mmol, 48% yield) as an off-white solid. MS (ESI) m / z 189.2 [M+1] + .

[0331] 3-(5-(((S)-1-((2-methoxyquinazolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of 2-methoxyquinazoline-6-carbaldehyde (50 mg, 0.26 mmol), 3-(1-oxo-5-(((S)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione (183 mg, 0.56 mmol) and triethylamine (104 mg, 1.03 mmol) in dichloromethane (4 mL) was added triacetoxyborohydride (248 mg, 1.17 mmol). The mixture was stirred at room temperature under nitrogen for 12 h. The resulting mixture was concentrated. The residue was purified by silica gel chromatography (0 to 10% methanol / dichloromethane) and preparative HPLC under the following conditions: column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5B to 35B in 7 min; RT 1 : 6.32. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (30.5 mg, 0.061 mmol, 22% yield) as a white solid. 1 H NMR (400 MHz, methanol-d 4 )δ9.33(d,J=0.7Hz,1H),8.06-7.97(m,2H),7.84(d,J=8.6Hz,1H),7.71(d ,J=8.4Hz,1H),7.10-7.03(m,2H),5.16-5.08(m,2H),4.49-4.38(m,2H),4. 11(m,5H),3.23-3.20(m,1H),3.18-3.08(m,2H),2.90-2.88(m,2H),2.79- 2.75(m,1H),2.56-2.41(m,2H),2.21-2.07(m,2H); MS(ESI)m / z502.2[M+1] + . Example S63. 3-(5-(((S)-1-((2-((R)-3,3-dimethyltetrahydro-2H-pyran-4-yl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0332] (R)-2-(3,3-dimethyltetrahydro-2H-pyran-4-yl)-6-vinylquinoline. 2-(3,3-dimethyltetrahydro-2H-pyran-4-yl)-6-vinylquinoline (160 mg, 0.60 mmol) was purified by preparative SFC under the following conditions: column: CHIRALPAK IH, 2*25 cm, 5 μm; mobile phase A: hexane (0.5% 2M ammonia-methanol)--HPLC, mobile phase B: ethanol--HPLC; flow rate: 20 mL / min; gradient: 3% B to 3% B in 7.5 min; wavelength: 220 / 254 nm; room temperature 1 (min): 4.76; room temperature 2 (min): 5.80; Sample solvent: ethanol--HPLC; Injection volume: 0.5 mL; Number of runs: 13. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (30 mg, 0.11 mmol, 19% yield). MS (ESI) m / z 268.1 [M+1] + .

[0333] (R)-2-(3,3-dimethyltetrahydro-2H-pyran-4-yl)quinoline-6-carbaldehyde. To a stirred solution of (R)-2-(3,3-dimethyltetrahydro-2H-pyran-4-yl)-6-vinylquinoline (30 mg, 0.11 mmol), 4-methylmorpholine N-oxide (26.3 mg, 0.22 mmol) and citric acid (43 mg, 0.22 mmol) in water (2 mL) and tert-butanol (2 mL) was added potassium osmate (4 mg, 0.01 mmol). The reaction mixture was stirred at room temperature under nitrogen for 3 h. Sodium periodate (75 mg, 0.35 mmol) was then added to the above mixture. The resulting mixture was stirred at room temperature under nitrogen for 1 h. Saturated sodium bicarbonate was added to the mixture to pH about 7 and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 50% ethyl acetate / petroleum ether) to give the title compound (28 mg, 0.10 mmol, 93% yield) as a yellow oil. MS (ESI) m / z 270.2 [M+1] + .

[0334] 3-(5-(((S)-1-((2-((R)-3,3-dimethyltetrahydro-2H-pyran-4-yl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a stirred solution of (R)-2-(3,3-dimethyltetrahydro-2H-pyran-4-yl)quinoline-6-carbaldehyde (25 mg, 0.090 mmol), 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione; 2,2,2-trifluoroacetic acid (56 mg, 0.13 mmol), triethylamine (20 mg, 0.2 mmol) in dichloromethane (5 mL) pre-stirred for 15 min was added sodium triacetoxyborohydride (94 mg, 0.44 mmol) at 0° C. and the solution was stirred at room temperature under nitrogen for 4 h. The resulting solution was purified by silica gel chromatography (0 to 5% methanol / dichloromethane). The pure fractions were evaporated and further purified by preparative HPLC under the following conditions: column: sun fireprep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 2% B to 27% B in 7 min, wavelength: 254 / 220 nm; room temperature 1 (min): 6.98. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (34.9 mg, 0.060 mmol, 67% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ8.42(d,J=8.5Hz,1H),8.188.07(m,2H),7.92(m,1H),7.67(d,J=8.4Hz,1H),7.59(d,J=8.6Hz,1H),7. 19(s,1H),7.08(d,J=8.2Hz,1H),5.28(s,1H),5.04(m,1H),4.65(s,2H),4.40(m,1H),4.28(d,J=17.4Hz, 1H),4.08-4.01(m,1H),3.60-3.40(m,7H),3.25(d,J=11.1Hz,1H),3.07(m,1H),2.88(m,1H),2.61(m,1H ),2.40(m,2H),2.16(m,1H),2.04-1.94(m,1H),1.55-1.50(m,1H),0.90(s,3H),0.74(s,3H); MS(ESI)m / z 583.3[M+1] + . Example S64. 3-(5-(((S)-1-((2-((1R,3R)-3-methoxycyclopentyl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0335] (2-((1R,3R)-3-methoxycyclopentyl)quinolin-6-yl)methanol. The product (460 mg, 1.89 mmol) of (2-(3-methoxycyclopentyl)quinolin-6-yl)methanol was separated by preparative chiral-HPLC (column: CHIRALPAK IH, 2*25 cm, 5 μm; mobile phase A: Hex (0.5% 2M ammonia-methanol)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 20% B to 20% B in 14 min; wavelength: 220 / 254 nm; RT1 (min): 5.921; RT2 (min): 10.26; sample solvent: EtOH--HPLC; injection volume: 0.5 mL; number of runs: 5) to give the title compound (3rd peak, 60 mg, 0.23 mmol, 13% yield). MS (ESI) m / z 258.2 [M+1] + .

[0336] 2-((1R,3R)-3-methoxycyclopentyl)quinoline-6-carbaldehyde. To a stirred solution of (2-((1R,3R)-3-methoxycyclopentyl)quinolin-6-yl)methanol (60 mg, 0.23 mmol) in dichloromethane (3 mL) was added manganese dioxide (203 mg, 2.33 mmol) at room temperature. The reaction mixture was then stirred at 50 °C under nitrogen for 12 h. The resulting mixture was filtered and concentrated under reduced pressure to give the title compound (60 mg, 0.23 mmol, 100% yield) as a light yellow oil. MS (ESI) m / z 256.1 [M+1] + .

[0337] 3-(5-(((S)-1-((2-((1R,3S)-3-methoxycyclopentyl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a stirred solution of 2-((1R,3R)-3-methoxycyclopentyl)quinoline-6-carbaldehyde (60 mg, 0.23 mmol), 3-(1-oxo-5-(((S)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione; 2,2,2-trifluoroacetic acid (100 mg, 0.23 mmol) and triethylamine (47 mg, 0.47 mmol) in dichloromethane (4 mL) was added sodium triacetoxyborohydride (192 mg, 0.91 mmol). The mixture was stirred at room temperature under nitrogen for 2 h. The resulting solution was concentrated. The residue was further purified by silica gel column chromatography (0-10% methanol / dichloromethane) and by preparative HPLC under the following conditions: column: Sun fire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B to 30% B in 7 min, 30% B; wavelength: 254 / 220 nm; RT 1 (min): 5.5. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (32.6 mg, 0.057 mmol, 25% yield) as a white solid. 1 H NMR (400 MHz, methanol-d 4 )δ8.34-8.22(m,1H),8.03(d,J=8.7Hz,1H),7.93(s,1H),7.82(dd,J=8.6,1.9Hz,1H),7.72(dd,J=8.4,1.2 Hz,1H),7.52(d,J=8.5Hz,1H),7.13-7.02(m,2H),5.13(dd,J=13.6,5.4Hz,2H),4.52-4.37(m,2H),4.21-4. 15(m,2H),4.02(m,1H),3.63-3.45(m,1H),3.36(s,3H),3.31-3.30(m,1H),3.22(m,2H),3.12-3.01(m,1H), 2.99-2.88(m,1H),2.83-2.72(m,1H),2.58-2.41(m,3H),2.26-2.13(m,3H),2.06-1.88(m,4H); MS(ESI)m / z 569.2[M+1] + . Example S65. 3-(5-(((S)-1-((2-((1S,3S)-3-methoxycyclopentyl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0338] (2-((1S,3S)-3-methoxycyclopentyl)quinolin-6-yl)methanol. The product (460 mg, 1.79 mmol) of (2-(3-methoxycyclopentyl)quinolin-6-yl)methanol was separated by preparative chiral-HPLC (column: CHIRALPAK IH, 2*25 cm, 5 μm; mobile phase A: Hex (0.5% 2M ammonia-methanol)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: 20% B to 20% B in 14 min; wavelength: 220 / 254 nm; RT1 (min): 5.921; RT2 (min): 10.26; sample solvent: EtOH-HPLC; injection volume: 0.5 mL; number of runs: 5) to obtain the title compound (460 mg, 1.79 mmol) (peak 4, 40 mg, 0.15 mmol, 8% yield). MS (ESI) m / z 258.2 [M+1] + .

[0339] 2-((1S,3S)-3-methoxycyclopentyl)quinoline-6-carbaldehyde. To a stirred solution of (2-((1S,3S)-3-methoxycyclopentyl)quinolin-6-yl)methanol (40 mg, 0.15 mmol) in dichloromethane (3 mL) was added manganese dioxide (135 mg, 1.55 mmol) at room temperature. The reaction mixture was then stirred at 50 °C under nitrogen for 12 h. The resulting mixture was diluted with dichloromethane, filtered and concentrated under reduced pressure to give the title compound (40 mg, 0.15 mmol, 100% yield) as a light yellow oil. MS (ESI) m / z 256.1 [M+1] + .

[0340] 3-(5-(((S)-1-((2-((1R,3S)-3-methoxycyclopentyl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a stirred solution of 2-((1S,3S)-3-methoxycyclopentyl)quinoline-6-carbaldehyde (40 mg, 0.15 mmol), 3-(1-oxo-5-(((S)-pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione; 2,2,2-trifluoroacetic acid (70 mg, 0.16 mmol) and triethylamine (32 mg, 0.32 mmol) in dichloromethane (4 mL) was added sodium triacetoxyborohydride (134 mg, 0.63 mmol). The mixture was stirred at room temperature under nitrogen for 2 h. The resulting solution was concentrated. The residue was further purified by silica gel column chromatography (0-10% methanol / dichloromethane) and by preparative HPLC under the following conditions: column: Sun fire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B to 30% B in 7 min, 30% B; wavelength: 254 / 220 nm; RT 1 (min): 5.5. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (29.1 mg, 0.05 mmol, 32% yield) as a white solid. 1 H NMR (400 MHz, methanol-d 4 )δ8.34-8.22(m,1H),8.03(d,J=8.7Hz,1H),7.93(s,1H),7.82(dd,J=8.6,1.9Hz,1H),7.72(dd,J=8.4,1 .2Hz,1H),7.62(d,J=8.5Hz,1H),7.13-7.02(m,2H),5.21-5.13(m,2H),4.52-4.39(m,2H),4.23-4.17(m, 2H),4.04(m,1H),3.51-3.42(m,1H),3.36(s,3H),3.31-3.30(m,1H),3.22(m,2H),3.12-3.01(m,1H),2. 99-2.88(m,1H),2.83-2.75(m,1H),2.58-2.41(m,3H),2.26-2.13(m,3H),2.06-1.82(m,4H); MS(ESI)m / z 569.2[M+1] + . Example S66. 3-(5-(((S)-1-((2-((1s,4R)-4-hydroxycyclohexyl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0341] (1s,4s)-4-(6-(Hydroxymethyl)quinolin-2-yl)cyclohexan-1-ol. 4-(6-(Hydroxymethyl)quinolin-2-yl)cyclohexan-1-ol (1 g, 3.70 mmol) was purified by preparative chiral SFC under the following conditions: column: daicel dcpak p4vp, 4.6*50 mm, 3 μm; mobile phase B: methanol; flow rate: 2 mL / min; gradient: isocratic 10% B; wavelength: 220 nm. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (500 mg, 1.94 mmol, 52% yield) as a white solid. MS (ESI) m / z 258.2 [M+1] + .

[0342] 2-((1s,4s)-4-hydroxycyclohexyl)quinoline-6-carbaldehyde. To a stirred solution of (130 mg, 0.51 mmol) in dichloromethane (10 mL) was added manganese dioxide (421 mg, 4.84 mmol), and the mixture was stirred at 50 ° C under nitrogen for 5 h. The resulting mixture was filtered and the filtrate was concentrated to give the title compound (100 mg, 0.39 mmol, 76% yield) as a white solid. MS (ESI) m / z 256.0 [M+1] + .

[0343] 3-(5-(((S)-1-((2-((1s,4R)-4-hydroxycyclohexyl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a stirred mixture of 2-((1s,4s)-4-hydroxycyclohexyl)quinoline-6-carbaldehyde (50 mg, 0.20 mmol), 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione; hydrochloride (70 mg, 0.2 mmol) and triethylamine (0.06 mL, 0.4 mmol) in dichloromethane (5 mL) was added sodium triacetoxyborohydride (160 mg, 0.75 mmol) in several portions and the mixture was stirred at room temperature under nitrogen for 2 h. The resulting mixture was concentrated. The residue was purified by silica gel chromatography (0-10% methanol / dichloromethane) and further purified by preparative HPLC under the following conditions: column: sunfire prep C18 column, 30 * 150 mm, 5 μ m; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B to 20% B in 7 min, 20% B; wavelength: 254 / 210 nm; RT1 (min): 4.92; fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound as a white solid (32 mg, 0.056 mmol, 28% yield). 1 H NMR (400 MHz, methanol-d 4 )δ8.26(m,1H),8.01-8.03(d,J=8.6Hz,1H),7.89(s,1H),7.80(m,1H),7.71(d,J=8.4 Hz,1H),7.50(d,J=8.6Hz,1H),7.11-7.02(m,2H),5.14-5.12(m,2H),4.51-4.36(m,2 H),4.09-3.97(m,2H),3.69-3.67(m,1H),3.16-3.00(m,3H),2.98-2.74(m,4H),2.47 (m,2H),2.13(m,3H),2.04(m,3H),1.88-1.74(m,2H),1.51-1.47(m,2H).;MS(ESI)m / z 569.4[M+1] + . Example S67. 3-(5-(((S)-1-((2-((1r,4S)-4-hydroxycyclohexyl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0344] Methyl 2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)quinoline-6-carboxylate. To a stirred mixture of methyl 2-chloroquinoline-6-carboxylate (2 g, 9.03 mmol), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (1.5 g, 5.64 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (800 mg, 1.09 mmol) in 1,4-dioxane (200 mL) and water (20 mL) was added sodium carbonate (2 g, 18.87 mmol) and the resulting mixture was stirred at 90 °C under nitrogen for 3 h. The mixture was concentrated and the residue was purified by reverse phase flash chromatography (10-70% acetonitrile + 0.05% aqueous ammonium bicarbonate over 20 min) to give the title compound (1.8 g, 5.52 mmol, 61% yield) as a yellow solid. MS (ESI) m / z 326.2 [M+1] + .

[0345] 2-(1,4-dioxaspiro[4.5]dec-8-yl)quinoline-6-carboxylic acid methyl ester. To a stirred solution of 2-(1,4-dioxaspiro[4.5]dec-7-ene-8-yl)quinoline-6-carboxylic acid methyl ester (1.8 g, 5.53 mmol) in methanol (30 mL) was added palladium 10% / carbon (360 mg, wetted with about 55% water) at room temperature, and the resulting mixture was stirred for 2 h under hydrogen (about 2 bar) at room temperature. The resulting mixture was filtered and the filtrate was concentrated to give the title compound (1.7 g, 5.19 mmol, 94% yield) as a white solid. MS (ESI) m / z 328.0 [M+1] + .

[0346] 2-(4-oxocyclohexyl)quinoline-6-carboxylic acid methyl ester. To a stirred solution of 2-(1,4-dioxaspiro[4.5]dec-8-yl)quinoline-6-carboxylic acid methyl ester (1.7 g, 5.19 mmol) in dichloromethane (12 mL) was added TFA (12 mL, 156.7 mmol) at 0 ° C. The solution was stirred under nitrogen for 3 h at room temperature. The mixture was concentrated. Saturated sodium bicarbonate was added to the residue to a pH of about 7 and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to give the title compound (1.1 g, 3.87 mmol, 75% yield) as a yellow solid. MS (ESI) m / z 284.2 [M+1] + .

[0347] 4-(6-(Hydroxymethyl)quinolin-2-yl)cyclohexan-1-ol. To a stirred solution of methyl 2-(4-oxocyclohexyl)quinoline-6-carboxylate (1.1 g, 3.87 mmol) in THF (15 mL) was added lithium aluminum hydride (1 N in THF, 4 mL, 4 mmol) at 0 °C, and the resulting solution was stirred at this temperature under nitrogen for 0.5 h. The mixture was diluted with THF, sodium sulfate decahydrate was added, filtered and concentrated to give the title compound (550 mg, 2.13 mmol, 55% yield) as a yellow solid. MS (ESI) m / z 258.2 [M+1] + .

[0348] (1R,4r)-4-(6-(Hydroxymethyl)quinolin-2-yl)cyclohexan-1-ol. 4-(6-(Hydroxymethyl)quinolin-2-yl)cyclohexan-1-ol (1 g, 3.87 mmol) was purified by preparative chiral SFC under the following conditions: column: daicel dcpak p4vp, 4.6*50 mm, 3 μm; mobile phase B: methanol; flow rate: 2 mL / min; gradient: isocratic 10% B; wavelength: 220 nm. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (500 mg, 1.94 mmol, 50% yield) as a white solid. MS (ESI) m / z 258.2 [M+1] + .

[0349] 2-((1R,4r)-4-hydroxycyclohexyl)quinoline-6-carbaldehyde. To a stirred solution of (1r,4r)-4-(6-(hydroxymethyl)quinolin-2-yl)cyclohexan-1-ol (130 mg, 0.51 mmol) in dichloromethane (10 mL) was added manganese dioxide (439 mg, 5.1 mmol), and the mixture was stirred at 50 °C under nitrogen for 5 h. The mixture was filtered and the filtrate was concentrated to give the title compound (100 mg, 0.39 mmol, 76% yield) as a white solid. MS (ESI) m / z 256.0 [M+1] + .

[0350] 3-(5-(((S)-1-((2-((1r,4S)-4-hydroxycyclohexyl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a stirred mixture of 2-((1r,4r)-4-hydroxycyclohexyl)quinoline-6-carbaldehyde (50 mg, 0.20 mmol), 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione; hydrochloride (70 mg, 0.2 mmol) and triethylamine (0.06 mL, 0.4 mmol) in dichloromethane (5 mL) was added sodium triacetoxyborohydride (160 mg, 0.75 mmol) in several portions and stirred at room temperature under nitrogen for 2 h. The resulting mixture was concentrated. The residue was purified by silica gel chromatography (0-10% methanol / dichloromethane) and further purified by preparative HPLC under the following conditions: column: Sunfire prep C18 column, 30 * 150 mm, 5 μ m; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 2% B to 17% B in 9 min, 17% B; wavelength: 254 / 210 nm; RT1 (min): 8.72] to give the title compound as a white solid (35 mg, 0.061 mmol, 31% yield). 1 HNMR (400 MHz, methanol-d 4 )δ8.26(m,1H),8.01-8.03(d,J=8.6Hz,1H),7.89(s,1H),7.80-7.82(m,1H),7.71( d,J=8.4Hz,1H),7.50(d,J=8.6Hz,1H),7.11-7.02(m,2H),5.12-5.14(m,2H),4.51- 4.36(m,2H),4.15-4.05(m,2H),3.29-3.20(m,1H),3.08-3.00(m,3H),2.98-2.74( m,4H),2.55(m,3H),2.10(m,4H),2.00-1.90(m,2H),1.80-1.70(m,4H); MS(ESI)m / z 569.1[M+1] + . Example S68. 3-(5-(((S)-1-((7-(2-methoxypropan-2-yl)isoquinolin-3-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0351] 3-Chloro-7-(2-methoxypropan-2-yl)isoquinoline. To a solution of 2-(3-chloroisoquinolin-7-yl)propan-2-ol (210 mg, 0.95 mmol) in THF (5 mL) was added sodium hydride (60% dispersion in mineral oil, 45 mg, 1.12 mmol) at 0 °C, and the suspension was stirred for 30 min. Iodomethane (267 mg, 1.88 mmol) was then added and the mixture was stirred at 0 °C for 1 h. The resulting mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse phase flash chromatography (10-70% acetonitrile + 0.05% ammonium bicarbonate / water, over 20 min) to give the title compound as a white solid (200 mg, 0.85 mmol, 89% yield). MS (ESI) m / z 236.2 [M + 1] + .

[0352] 7-(2-methoxypropan-2-yl)-3-vinylisoquinoline. To a solution of 3-chloro-7-(2-methoxypropan-2-yl)isoquinoline (200 mg, 0.85 mmol), potassium vinyl trifluoroborate (300 mg, 2.22 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) were added tetrakis(triphenylphosphine)palladium (71 mg, 0.06 mmol) and cesium carbonate (827 mg, 2.55 mmol). The mixture was stirred at 100 °C under nitrogen for 5 h. The resulting mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse phase flash chromatography (10-70% acetonitrile + 0.05% ammonium bicarbonate / water, over 20 min) to give the title compound as a white solid (110 mg, 0.48 mmol, 57% yield). MS (ESI) m / z 228.0 [M+1] + .

[0353] 7-(2-methoxypropan-2-yl)isoquinoline-3-carbaldehyde. To a solution of 7-(2-methoxypropan-2-yl)-3-vinylisoquinoline (110 mg, 0.48 mmol), potassium osmate (40 mg, 0.11 mmol) and 4-methylmorpholine N-oxide (110 mg, 0.94 mmol) in 1-butanol (5 mL) and water (5 mL) was added citric acid (380 mg, 1.04 mmol) and the resulting mixture was stirred at room temperature under nitrogen for 4 h. Then sodium periodate (310 mg, 1.45 mmol) was added to the above mixture in several portions at 0 °C and the resulting mixture was stirred at room temperature for 1 h. Saturated sodium bicarbonate solution was added to the mixture to pH about 7 and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude title compound (35 mg, 0.15 mmol, 31% yield) as a yellow solid. MS (ESI) m / z 230.2 [M+1] + .

[0354] 3-(5-(((S)-1-((7-(2-methoxypropan-2-yl)isoquinolin-3-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a stirred mixture of 7-(2-methoxypropan-2-yl)isoquinoline-3-carbaldehyde (35 mg, 0.15 mmol), 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione (60 mg, 0.18 mmol) and triethylamine (0.05 mL, 0.35 mmol) in dichloromethane (5 mL) was added sodium triacetoxyborohydride (140 mg, 0.66 mmol) in several portions, and the mixture was stirred at room temperature under nitrogen for 3 h. The mixture was concentrated and the residue was first purified by silica gel chromatography (0-10% methanol / dichloromethane) and further purified by silica gel column: xselectcsh obd column 30*150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 10% B to 28% B in 10 min, 28% B; wavelength: 254 / 220 nm; RT1 (min): 8.45. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (15.6 mg, 0.03 mmol, 18% yield) as a white solid. 1 H NMR (400 MHz, methanol-d 4)δ9.37(s,1H),8.16(s,1H),7.99(s,2H),7.94(s,1H),7.76(d,J=8.4Hz,1H),7.20(m,1H ),7.14(d,J=8.2Hz,1H),5.37(m,1H),5.14-5.12(m,1H),4.84-4.72(m,2H),4.56-4.40(m ,2H),3.83-3.76(m,3H),3.75-3.68(m,1H),3.14(m,3H),2.92-2.90(m,1H),2.79(m,1H) ,2.70-2.60(m,1H),2.60-2.50(m,2H),2.20-2.14(m,1H),1.71-1.63(m,6H); MS(ESI)m / z 543.2[M+1] + . Example S69. 3-(5-(((S)-1-((7-(2-hydroxypropan-2-yl)isoquinolin-3-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0355] 1-(3-Chloroisoquinolin-7-yl)ethan-1-one. A solution of 7-bromo-3-chloroisoquinoline (1.5 g, 6.19 mmol), tributyl(1-ethoxyvinyl)stannane (4.4 g, 12.18 mmol) and tetrakis(triphenylphosphine)palladium (523 mg, 0.45 mmol) in toluene (8 mL) was stirred at 100 °C under nitrogen for 6 h. Hydrochloric acid (2N aqueous solution, 8 mL) was then added to the above mixture and the mixture was stirred at room temperature for 3 h. The resulting mixture was filtered and the filtrate was concentrated. The residue was purified by reverse phase flash chromatography (10-70% acetonitrile + 0.05% aqueous ammonium bicarbonate solution over 20 min) to give the title compound (350 mg, 1.70 mmol, 28% yield) as a yellow solid. MS (ESI) m / z 206.1 [M+1] + .

[0356] 2-(3-Chloroisoquinolin-7-yl)propan-2-ol. To a solution of 1-(3-chloroisoquinolin-7-yl)ethan-1-one (1.24 g, 6.03 mmol) in THF (20 mL) was added methylmagnesium bromide (1 N in THF, 18 mL, 18 mmol) dropwise at 0 °C. The mixture was stirred under nitrogen for 3 h at room temperature. To the resulting mixture was added water and extracted with ethyl acetate. The extract was washed with sodium carbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (600 mg, 2.71 mmol, 45% yield) as a yellow oil. MS (ESI) m / z 222.1 [M+1] + .

[0357] 2-(3-vinylisoquinolin-7-yl)propan-2-ol. To a solution of 2-(3-chloroisoquinolin-7-yl)propan-2-ol (600 mg, 2.71 mmol), potassium vinyl trifluoroborate (1.1 g, 8.15 mmol) in 1,4-dioxane (5 mL) and water (5 mL) were added tetrakis(triphenylphosphine)palladium (270 mg, 0.23 mmol) and cesium carbonate (2.64 g, 8.12 mmol). The mixture was stirred at 100 °C under nitrogen for 5 h. To the resulting mixture was added water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 30% ethyl acetate / petroleum ether) to give the title compound (310 mg, 1.45 mmol, 54% yield) as a white solid. MS (ESI) m / z 214.0 [M+1] + .

[0358] 7-(2-Hydroxypropan-2-yl)isoquinoline-3-carbaldehyde. To a solution of 2-(3-vinylisoquinolin-7-yl)propan-2-ol (310 mg, 1.45 mmol), potassium osmate (40 mg, 0.11 mmol) and 4-methylmorpholine N-oxide (330 mg, 2.82 mmol) in 1-butanol (5 mL) and water (5 mL) was added citric acid (550 mg, 2.86 mmol) at room temperature and the resulting mixture was stirred at room temperature under nitrogen for 4 h. Then sodium periodate (930 mg, 4.31 mmol) was added to the above mixture in several portions at 0° C. and the resulting mixture was stirred at room temperature under nitrogen for 3 h. To the resulting mixture was added water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% ethyl acetate / petroleum ether) to give the title compound (50 mg, 0.23 mmol, 16% yield) as a yellow solid. MS (ESI) m / z 216.2 [M+1] + .

[0359] 3-(5-(((S)-1-((7-(2-hydroxypropan-2-yl)isoquinolin-3-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a stirred mixture of 7-(2-hydroxypropan-2-yl)isoquinoline-3-carbaldehyde (50 mg, 0.23 mmol), 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione; 2,2,2-trifluoroacetic acid (108 mg, 0.24 mmol) and triethylamine (0.06 mL, 0.47 mmol) in dichloromethane (5 mL) was added sodium triacetoxyborohydride (200 mg, 0.94 mmol) in several portions and the mixture was stirred at room temperature under nitrogen for 2 h. The mixture was concentrated and the residue was first purified by silica gel chromatography (0-10% methanol / dichloromethane) and further purified by preparative HPLC under the following conditions: Sunfire prep C18 column, 30*150 mm, 5 μm; Mobile phase A: water (0.1% formic acid), Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 5% B to 30% B in 7 min, 30% B; Wavelength: 254 / 220 nm; RT1 (min): 5.08; The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (15.6 mg, 0.03 mmol, 0.13% yield) as a white solid. 1 H NMR (300 MHz, methanol-d 4 )δ9.28(s,1H),8.21(d,J=1.8Hz,1H),8.00-7.98(m,1H),7.96-7.86(m,2H) ,7.73(d,J=8.4Hz,1H),7.16-7.04(m,2H),5.22(m,1H),5.13-5.11(m,1H),4 .54-4.33(m,4H),3.58-3.35(m,3H),3.26(m,1H),2.92-2.87(m,1H),2.84- 2.72(m,1H),2.63-2.38(m,2H),2.30-2.12(m,2H),1.66(s,6H); MS(ESI)m / z 529.1[M+1] + . Example S70. 3-(5-(((S)-1-((2-(1-hydroxycyclobutyl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0360] 1-(6-methylquinoline-2-yl)cyclobutane-1-ol. A solution of 2-bromo-6-methyl-quinoline (450mg, 2.03mmol) in THF (10mL) was cooled to -78 °C under nitrogen, followed by dropwise addition of butyllithium (3M in THF, 3.0mL, 9.00mmol) over 10min. The reaction mixture was stirred at this temperature for 30min and then a solution of cyclobutanone (800mg, 11.26mmol) in THF (0.5mL) was added over 5min. The reaction mixture was stirred at -78 °C under nitrogen for 1h. The mixture was quenched with water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 20% ethyl acetate / petroleum ether) to give the title compound (320mg, 1.50mmol, 74% yield) as a light yellow oil. MS (ESI) m / z 214.2 [M+1] + .

[0361] 1-(6-(Bromomethyl)quinolin-2-yl)cyclobutan-1-ol. To a solution of 1-(6-methyl-2-quinolinyl)cyclobutanol (100 mg, 0.47 mmol) in carbon tetrachloride (5 mL) was added NBS (75 mg, 0.42 mmol) and 2,2'-dimethyl-2,2'-azobispropionitrile (23 mg, 0.14 mmol) under nitrogen. The resulting mixture was stirred at 70 °C under nitrogen for 2 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (0 to 50% ethyl acetate / petroleum ether) to give the title compound (80 mg, 0.27 mmol, 57% yield) as a yellow oil. MS (ESI) m / z 292.1 [M+1] + .

[0362] 3-(5-(((S)-1-((2-(1-hydroxycyclobutyl)quinolin-6-yl)methyl)pyrrolidin-3-yl)-oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione; hydrochloride (80 mg, 0.22 mmol) and 1-[6-(bromomethyl)-2-quinolinyl]cyclobutanol (70 mg, 0.24 mmol) in acetonitrile (5 mL) was added potassium carbonate (91 mg, 0.66 mmol) at room temperature. The mixture was stirred at room temperature for 12 h. The resulting mixture was concentrated and the residue was purified by silica gel chromatography (0-10% methanol / dichloromethane) and preparative HPLC under the following conditions: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B to 14% B in 10 min, 14% B; wavelength: 254 / 220 nm; RT 1 (min): 9.67. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (16.7 mg, 0.031 mmol, 14% yield) as a pale yellow solid. 1 H NMR (400 MHz, methanol-d 4 )δ8.32(d,J=8.6Hz,1H),8.14(d,J=8.5Hz,1H),8.01(s,1H),7.84(m,2H),7.71(m,J=8.4,2. 9Hz,1H),7.11(s,1H),7.06(m,1H),5.23(d,J=6.1Hz,1H),5.12(m,1H),4.51-4.36(m,4H),3. 56(d,J=12.6Hz,1H),3.45(m,2H),3.29(d,J=7.5Hz,1H),2.90(m,1H),2.79(m,3H),2.56(m,1 H),2.45(m,3H),2.30-2.22(m,1H),2.15(m,1H),2.05(m,1H),2.01-1.87(m,1H); MS(ESI)m / z 541.2[M+1] + . Example S71. 3-(5-(((S)-1-((2-(1-methoxycyclobutyl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0363] 2-(1-methoxycyclobutyl)-6-methylquinoline. To a solution of 1-(6-methylquinolin-2-yl)cyclobutan-1-ol (100 mg, 0.47 mmol) in THF (10 mL) was added sodium hydride (60% dispersion in mineral oil, 34 mg, 0.85 mmol) at 0 ° C under nitrogen and the suspension was stirred for 30 min. Then iodomethane (70 mg, 0.52 mmol) was added to the above mixture at 0 ° C and the mixture was stirred at room temperature under nitrogen for 1 h. Water was added to the resulting mixture and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 50% ethyl acetate / petroleum ether) to give the title compound (100 mg, 0.44 mmol, 94% yield) as a light yellow oil. MS (ESI) m / z 228.1 [M+1] + .

[0364] 6-(Bromomethyl)-2-(1-methoxycyclobutyl)quinolone. To a solution of 2-(1-methoxycyclobutyl)-6-methyl-quinoline (90 mg, 0.40 mmol) in carbon tetrachloride (5 mL) was added NBS (63 mg, 0.36 mmol) and 2,2'-dimethyl-2,2'-azobispropionitrile (20 mg, 0.12 mmol). The mixture was stirred at 70 ° C under nitrogen for 2 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (0 to 50% ethyl acetate / petroleum ether) to give the title compound (80 mg, 0.26 mmol, 66% yield) as a yellow oil. MS (ESI) m / z 306.0 [M+1] + .

[0365] 3-(5-(((S)-1-((2-(1-methoxycyclobutyl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione; hydrochloride (80 mg, 0.22 mmol), 6-(bromomethyl)-2-(1-methoxycyclobutyl)quinoline (73 mg, 0.24 mmol) in acetonitrile (5 mL) was added potassium carbonate (91 mg, 0.66 mmol) at room temperature. The mixture was stirred under nitrogen for 12 h at room temperature. The resulting mixture was concentrated and the residue was purified by silica gel chromatography (0 to 50% ethyl acetate / petroleum ether) and preparative HPLC under the following conditions: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 10% B to 30% B in 10 min, 30% B; wavelength: 254 / 220 nm; RT 1 (min): 9.67. The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (44.6 mg, 0.08 mmol, 36% yield) as an off-white solid. 1 H NMR (300 MHz, methanol-d 4 )δ8.31(d,J=8.6Hz,1H),8.12(d,J=8.7Hz,1H),7.94(s,1H),7.88-7.79(m,1H),7.72(d,J=8.4Hz,1H), 7.66(d,J=8.6Hz,1H),7.13-7.01(m,2H),5.12(m,J=13.3,5.2Hz,2H),4.44(d,J=3.7Hz,2H),4.16(d,J =2.7Hz,2H),3.27(s,1H),3.16(d,J=8.8Hz,2H),3.03(s,3H),3.03-2.87(m,2H),2.90-2.67(m,3H),2. 53(m,J=14.2,7.0Hz,1H),2.50-2.34(m,3H),2.16(m,2H),1.96(m,1H),1.87-1.72(m,1H); MS(ESI)m / z 555.3[M+1] + . Example S72. 3-(5-(((S)-1-((2-(3-(methylamino)oxetan-3-yl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0366] 6-(Methoxycarbonyl)quinoline 1-oxide. To a stirred solution of quinoline-6-carboxylic acid methyl ester (5.0 g, 26.7 mmol) in dichloromethane (50 mL) was added meta-chloroperbenzoic acid (12.5 g, 72.4 mmol) at room temperature. The reaction mixture was then stirred at room temperature under nitrogen for 12 h. A saturated solution of sodium bicarbonate was added to the reaction mixture to a pH of about 7 and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (4.0 g, 19.7 mmol, 74% yield...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof, in A is a direct bond or an optionally substituted C 1-5 alkyl; B is selected from optionally substituted C 3-10 cycloalkyl, optionally substituted 3-14 membered heterocyclyl, optionally substituted C 6-14 aryl and optionally substituted 5-14 membered heteroaryl; W 1 and W 2 Each is independently selected from H and CH3, or together form oxo; W 3 and W 4 Each is H or together forms an oxo group; V is selected from H and CH3; R' is a halogen atom; R" is selected from halogen atoms, optionally substituted C 1-5 Alkyl and optionally substituted C 1-5 Alkoxy, or two R" may be combined with the carbon to which they are attached to form oxo; R"' is selected from a halogen atom, -CN, -OH, an optionally substituted amino group, an optionally substituted amide group, an optionally substituted C 1-5 Alkyl, optionally substituted C 1-5 Alkoxy, optionally substituted C 3-6 cycloalkyl-oxy, optionally substituted 5-10 membered heterocyclyl-oxy, optionally substituted 5-10 membered heteroaryl-oxy, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 5-10 membered aryl, and optionally substituted 5-10 membered heteroaryl; l is an integer from 0 to 3; m is an integer from 0 to 3; n is an integer from 0 to 7; and Where W 1 and W 2 or W 3 and W 4 At least one of them together forms an oxo group.

2. The compound according to claim 1, wherein the compound is a compound of formula (Ia) 3. The compound according to claim 1 or 2, wherein W 3 and W 4 Together they form an oxo group.

4. A compound according to any one of the preceding claims, wherein A is a direct bond.

5. A compound according to any one of claims 1 to 3, wherein A is an optionally substituted C 1-3 alkyl. The compound according to claim 5 , wherein A is —CH 2 —.

7. The compound according to any one of claims 1 to 6, wherein B is a monocyclic ring.

8. The compound according to any one of claims 1 to 6, wherein B is a bicyclic ring.

9. The compound according to any one of claims 1 to 8, wherein B is selected from optionally substituted C 6-14 aryl and optionally substituted 5-14 membered heteroaryl.

10. The compound according to any one of claims 1 to 8, wherein B is selected from optionally substituted C 3-10 cycloalkyl and optionally substituted 3-14 membered heterocyclyl.

11. A compound according to any one of claims 1 to 10, wherein W 1 and W 2 Both are H.

12. A compound according to any one of claims 1 to 10, wherein W 1 and W 2 Together they form an oxo group.

13. The compound according to any one of claims 1 to 12, wherein V is H.

14. The compound according to any one of claims 1 to 13, wherein R' is selected from F and Cl.

15. A compound according to any one of claims 1 to 14, wherein R" is selected from F, Cl, optionally substituted C 1-3 Alkyl and optionally substituted C 1-3 Alkoxy.

16. A compound according to any one of claims 1 to 15, wherein R"' is selected from F, Cl, -CN, -OH, optionally substituted amino, optionally substituted C 1-3 Alkyl, optionally substituted C 1-3 Alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, and optionally substituted 5-10 membered heteroaryl.

17. The compound according to any one of claims 1 to 16, wherein l is 0 or 1.

18. A compound according to any one of claims 1 to 17, wherein l is 0.

19. The compound according to any one of claims 1 to 18, wherein m is 0 or 1.

20. The compound according to any one of claims 1 to 19, wherein m is 0.

21. The compound according to any one of claims 1 to 20, wherein n is 0 or 1.

22. The compound according to any one of claims 1 to 3, wherein the compound is a compound of formula (II): in A is a direct bond or an optionally substituted C 1-5 alkyl; R' is a halogen atom; R" is selected from halogen atoms, optionally substituted C 1-5 Alkyl and optionally substituted C 1-5 Alkoxy, or two R" may be combined with the carbon to which they are attached to form oxo; Z, Z' and Z" are each independently selected from N and CR 1 ; X, Y, X' and Y' are each independently selected from N and CR 2 ; Each R 1 are independently selected from H, a halogen atom, -CN, an optionally substituted C 1-5 Alkyl, optionally substituted C 1-5 alkoxy, optionally substituted 5-10 membered heteroaryl-oxy, optionally substituted C 3-6 cycloalkyl and optionally substituted 3-6 membered heterocyclyl; Each R 2 are independently selected from H, a halogen atom, -CN, -OH, oxo, an optionally substituted amino group, an optionally substituted amide group, an optionally substituted C 1-5 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, and optionally substituted 5-10 membered heteroaryl; l is an integer from 0 to 2; and m is an integer from 0 to 2.

23. The compound according to claim 22, wherein A is a direct bond.

24. The compound according to claim 22, wherein A is an optionally substituted C 1-3 alkyl.

25. The compound according to claim 24, wherein A is -CH2-.

26. The compound according to any one of claims 22 to 25, wherein R' is selected from F and Cl.

27. according to the compound described in any one of claims 22 to 26, wherein R "is selected from F, Cl, optionally substituted C 1-3 Alkyl and optionally substituted C 1-3 Alkoxy.

28. The compound according to any one of claims 22 to 27, wherein Z, Z' and Z" are CR 1 .

29. A compound according to any one of claims 22 to 27, wherein Z is N and Z' and Z" are both CR 1 .

30. A compound according to any one of claims 22 to 29, wherein X is N and Y, X' and Y' are CR 2 .

31. A compound according to any one of claims 22 to 29, wherein X and X' are both N and Y and Y' are both CR 2 .

32. A compound according to any one of claims 22 to 30, wherein X, Y, X' and Y' are CR 2 .

33. A compound according to any one of claims 22 to 32, wherein each R 1 are independently selected from H, F, Cl, -CN, optionally substituted C 1-3 Alkyl, optionally substituted C 1-3 Alkoxy, optionally substituted C 3-6 cycloalkyl and optionally substituted 3-6 membered heterocyclyl.

34. according to the compound described in any one of claims 22 to 32, wherein each R 2 independently selected from H, F, Cl, -CN, -OH, oxo, optionally substituted amino, optionally substituted amide, optionally substituted C 1-3 Alkyl, optionally substituted C 3-6 cycloalkyl and optionally substituted 4-8 membered heterocyclyl.

35. A compound according to any one of claims 22 to 34, wherein l is 0 or 1.

36. A compound according to any one of claims 22 to 35, wherein l is 0.

37. A compound according to any one of claims 22 to 36, wherein m is 0 or 1.

38. A compound according to any one of claims 22 to 37, wherein m is 0.

39. The compound according to claim 22, wherein the compound is a compound of formula (IIa): in A is a direct bond or an optionally substituted C 1-5 alkyl; R' is a halogen atom; R" is selected from halogen atoms, optionally substituted C 1-5 Alkyl and optionally substituted C 1-5 Alkoxy, or two R" may be combined with the carbon to which they are attached to form oxo; Z is selected from N and CR 3 ; X, X' and Y' are each independently selected from N and CR 4 ; R 1 and R 3 are each independently selected from H, a halogen atom, -CN, an optionally substituted C 1-5 Alkyl, optionally substituted C 1-5 alkoxy, optionally substituted 5-10 membered heteroaryl-oxy, optionally substituted C 3-6 cycloalkyl and optionally substituted 3-6 membered heterocyclyl; R 2 and R 4 are each independently selected from H, a halogen atom, -CN, -OH, oxo, an optionally substituted amino group, an optionally substituted amide group, an optionally substituted C 1-5 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, and optionally substituted 5-10 membered heteroaryl; l is an integer from 0 to 1; and m is an integer from 0 to 1.

40. The compound according to claim 39, wherein A is a direct bond.

41. A compound according to claim 39, wherein A is optionally substituted C 1-3 alkyl.

42. A compound according to claim 41, wherein A is -CH2-.

43. A compound according to any one of claims 39 to 42, wherein R' is selected from F and Cl.

44. according to the compound described in any one of claims 39 to 43, wherein R "is selected from F, Cl, optionally substituted C 1-3 Alkyl and optionally substituted C 1-3 Alkoxy.

45. A compound according to any one of claims 39 to 44, wherein Z is N.

46. ​​A compound according to any one of claims 39 to 44, wherein Z is CR 1 .

47. A compound according to any one of claims 39 to 46, wherein X is N and X' and Y' are both CR 2 .

48. A compound according to any one of claims 39 to 46, wherein X and X' are both N and Y' is CR 2 .

49. A compound according to any one of claims 39 to 46, wherein X, X' and Y' are CR 2 .

50. A compound according to any one of claims 39 to 49, wherein R 1 and R 3 are each independently selected from H, F, Cl, -CN, optionally substituted C 1-3 Alkyl, optionally substituted C 1-3 Alkoxy, optionally substituted C 3-6 cycloalkyl and optionally substituted 3-6 membered heterocyclyl.

51. A compound according to any one of claims 39 to 50, wherein R 1 Independently selected from H and F.

52. according to the compound described in any one of claims 39 to 51, wherein R 3 For H.

53. according to the compound described in any one of claims 39 to 52, wherein R 2 and R 4 are each independently selected from H, F, Cl, -CN, -OH, oxo, optionally substituted amino, optionally substituted amide, optionally substituted C 1-3 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, and optionally substituted 5-10 membered heteroaryl.

54. according to the compound described in any one of claims 39 to 53, wherein R 2 are independently selected from optionally substituted C 1-3 alkyl and optionally substituted 3-10 membered heterocyclyl.

55. according to the compound described in any one of claims 39 to 54, wherein R 4 For H.

56. A compound according to any one of claims 39 to 55, wherein: for 57. A compound according to any one of claims 39 to 56, wherein: R 2 for 58. A compound according to any one of claims 39 to 57, wherein l is 0.

59. A compound according to any one of claims 39 to 58, wherein m is 0.

60. A compound according to any one of claims 1 to 3, wherein the compound is a compound of formula (III): in A is a direct bond or an optionally substituted C 1-5 alkyl; R' is a halogen atom; R" is selected from halogen atoms, optionally substituted C 1-5 Alkyl and optionally substituted C 1-5 Alkoxy, or two R" may be combined with the carbon to which they are attached to form oxo; Z is selected from N, CH and CR 3 ; Each R 3 are independently selected from -CN, optionally substituted C 1-5 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted 5-10 membered aryl, and optionally substituted 5-10 membered heteroaryl; l is an integer from 0 to 2; m is an integer from 0 to 2; and p is an integer from 0 to 3.

61. The compound according to claim 60, wherein A is a direct bond.

62. A compound according to claim 60, wherein A is an optionally substituted C 1-3 alkyl.

63. A compound according to claim 62, wherein A is -CH2-.

64. A compound according to any one of claims 60 to 63, wherein R' is selected from F and Cl.

65. according to the compound described in any one of claim 60 to 64, wherein R "is selected from F, Cl, optionally substituted C 1-3 Alkyl and optionally substituted C 1-3 Alkoxy.

66. A compound according to any one of claims 60 to 65, wherein Z is N.

67. A compound according to any one of claims 60 to 65, wherein Z is CH.

68. according to the compound described in any one of claims 60 to 67, wherein each R 3 are independently selected from -CN, optionally substituted C 1-3 alkyl, optionally substituted 3-6 membered heterocyclyl, and optionally substituted 5-10 membered heteroaryl.

69. A compound according to any one of claims 60 to 68, wherein l is 0 or 1.

70. A compound according to any one of claims 60 to 69, wherein l is 0.

71. A compound according to any one of claims 60 to 70, wherein m is 0 or 1.

72. A compound according to any one of claims 60 to 71, wherein m is 0.

73. A compound according to any one of claims 60 to 72, wherein p is an integer from 0 to 2.

74. A compound according to any one of claims 60 to 73, wherein p is 0 or 1.

75. A compound according to claim 60, wherein the compound is a compound of formula (IIIa) or (IIIb): in A is a direct bond or an optionally substituted C 1-5 alkyl; R' is a halogen atom; R" is selected from halogen atoms, optionally substituted C 1-5 Alkyl and optionally substituted C 1-5 Alkoxy, or two R" may be combined with the carbon to which they are attached to form oxo; R 4 is an optionally substituted 3-6 membered heterocyclic group; l is 0 or 1; m is 0 or 1; and q is 0 or 2.

76. A compound according to claim 75, wherein A is a direct bond.

77. A compound according to claim 75, wherein A is optionally substituted C 1-3 alkyl.

78. A compound according to claim 77, wherein A is -CH2-.

79. A compound according to any one of claims 75 to 78, wherein R' is selected from F and Cl.

80. according to the compound described in any one of claims 75 to 79, wherein R "is selected from F, Cl, optionally substituted C 1-3 Alkyl and optionally substituted C 1-3 Alkoxy.

81. according to the compound described in any one of claims 75 to 80, wherein R 4 is an optionally substituted 6-membered heterocyclic group.

82. A compound according to any one of claims 75 to 81, wherein l is 0.

83. A compound according to any one of claims 75 to 82, wherein m is 0.

84. A compound according to any one of claims 75 to 83, wherein q is 0 or 1.

85. A compound selected from: 3-(1-oxo-5-(((S)-1-((2-(tetrahydro-2H-pyran-4-yl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((2-morpholinoquinazolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((2-morpholinoquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-((2-(tetrahydro-2H-pyran-4-yl)quinazolin-6-yl)methyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-((7-(tetrahydro-2H-pyran-4-yl)isoquinolin-3-yl)methyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((2-(2-hydroxypropan-2-yl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-((2-((R)-tetrahydrofuran-3-yl)quinazolin-6-yl)methyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-((2-((R)-tetrahydrofuran-3-yl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-((2-(2-oxopyrrolidin-1-yl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione; (S)-3-(5-(((S)-1-((8-fluoro-2-(tetrahydro-2H-pyran-4-yl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (S)-3-(1-oxo-5-(((S)-1-((2-(tetrahydro-2H-pyran-4-yl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione; (S)-3-(5-(((S)-1-((2-morpholinoquinazolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (S)-3-(5-(((S)-1-((2-morpholinoquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (S)-3-(1-oxo-5-(((S)-1-((2-(tetrahydro-2H-pyran-4-yl)quinazolin-6-yl)methyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione; (S)-3-(1-oxo-5-(((S)-1-((7-(tetrahydro-2H-pyran-4-yl)isoquinolin-3-yl)methyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione; and (S)-3-(5-(((S)-1-((2-(2-hydroxypropan-2-yl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof.

86. A compound selected from the group consisting of the compounds listed in Table 2, or pharmaceutically acceptable salts, tautomers, isotopomers or stereoisomers thereof.

87. A method of reducing WEE1 kinase protein levels, the method comprising contacting a cell with an effective amount of a compound according to any one of claims 1 to 86, or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

88. The method of claim 87, wherein the cell is in a subject.

89. A method for preventing or treating cancer in a subject, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 86 or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof.

90. The method of claim 89, wherein the cancer is selected from gastric cancer, lung cancer, pancreatic cancer, ovarian cancer, breast cancer, skin cancer, colon cancer, neuroblastoma, osteosarcoma, uterine cancer, rectal cancer, and kidney cancer.

91. The method of claim 90, wherein the cancer is selected from pancreatic ductal adenocarcinoma (PDAC), small cell lung cancer, non-small cell lung cancer (NSCLC), high-grade serous ovarian cancer, triple-negative breast cancer, uterine serous carcinoma, Ewing's sarcoma, melanoma, colon cancer, and clear cell renal cell carcinoma (ccRCC).

92. Use of a compound according to any one of claims 1 to 86 or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof in the preparation of a medicament for reducing WEE1 kinase protein levels.

93. Use of a compound according to any one of claims 1 to 86 or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof in the preparation of a medicament for preventing or treating cancer.

94. The use according to claim 93, wherein the cancer is selected from gastric cancer, lung cancer, pancreatic cancer, ovarian cancer, breast cancer, skin cancer, colon cancer, neuroblastoma, osteosarcoma, uterine cancer, rectal cancer and kidney cancer.

95. The use according to claim 94, wherein the cancer is selected from pancreatic ductal adenocarcinoma (PDAC), small cell lung cancer, non-small cell lung cancer (NSCLC), high-grade serous ovarian cancer, triple-negative breast cancer, uterine serous carcinoma, Ewing's sarcoma, melanoma, colon cancer and clear cell renal cell carcinoma (ccRCC).

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