WEE1-degradable compounds and their use

Abstract

Compounds and compositions that reduce the WEE1 kinase protein level are provided herein. In certain embodiments, the compounds and compositions are provided for the treatment of WEE1-related diseases such as cancer.

Description

Technical Field

[0001] Field This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 63 / 357,449, filed Jun. 30, 2022, and U.S. Provisional Application No. 63 / 357,866, filed Jul. 1, 2022, each of which is hereby incorporated by reference in its entirety for all purposes.

[0002] The present invention generally relates to compounds, compositions, and methods for their manufacture and use of compounds and compositions for the treatment of diseases and conditions involving the WEE1 protein.

Background Art

[0003] Background Targeted proteolysis is a therapeutic modality in which small molecules induce novel protein-protein interactions and enable the destruction of target proteins that cause disease. CRBN E3 ligase modulator (CELMoD) small molecules are a class of targeted protein therapeutics that recruit the CRL4-Cereblon ubiquitin ligase complex, gather target proteins that are not normally ubiquitinated by Cereblon, and create a novel molecular "adhesive" contact on the surface of Cereblon that polyubiquitinates them. The ubiquitin-tagged proteins are then transported to the 26S proteasome and subsequently degraded. The selection of target proteins gathered 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 residue, thereby inhibiting kinase activity and arresting the cell cycle at the intra-S and G2 / M cell cycle checkpoints. Although arrested at these checkpoints, cells repair stalled replication forks and DNA damage before entering mitosis; if the DNA damage cannot be repaired or rises above an acceptable threshold, the cells are subject to programmed apoptosis or mitotic cell death. Cancer cells often exhibit excessive replication stress, mutagenesis, and genomic instability, and are promoted to rely on cell cycle checkpoints to maintain DNA damage below the apoptosis threshold. Compared to normal cells, cancer cells often rely only on the intra-S and G2 / M checkpoints because the G1 cell cycle checkpoint does not function due to various mechanisms such as restriction of p53 and pRB activation or overactive replication promoters such as cyclin D and cyclin. Tumors that are highly dependent on the WEE1-mediated intra-S and G2 / M checkpoints have been hypothesized to be particularly sensitive to WEE1 loss, and therapies targeting WEE1 are expected to exhibit antitumor activity with a favorable therapeutic window.

[0005] Certain cancer therapies, for example, include carboplatin, cisplatin, gemcitabine, pemetrexed, topotecan, doxorubicin, decitabine, and methotrexate, and function by inducing replication stress and DNA damage. By inducing DNA damage and replication stress, these agents enhance the dependence of dividing tumor cells on the WEE1-mediated cell cycle checkpoint. Accordingly, it has been proposed to combinatorially administer CELMoD compounds that degrade WEE1 with DNA-damaging agents. SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0006] Accordingly, in one aspect, provided herein are CELMoD compounds that induce cereblon-mediated ubiquitination and WEE1 degradation and exhibit broad antitumor activity as a single agent or in combination with radiosensitization therapy.

Means for Solving the Problems

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

[0008] This embodiment can be more fully understood with reference to the detailed description and examples that illustrate non-limiting embodiments.

[0009] In one embodiment, formula (I)

Chemical Formula

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

[0011] In one embodiment, there is provided a method of preventing or treating cancer in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof. In one embodiment, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof in the manufacture of a medicament for the prevention or treatment of cancer.

BEST MODE FOR CARRYING OUT THE INVENTION

[0012] DETAILED DESCRIPTION DEFINITIONS As used herein, the terms "comprising" and "including" may be used interchangeably. The terms "comprising" and "including" are to be construed as specifying the presence of the stated features or components as referred to, but not excluding the presence or addition of one or more features or components or groups thereof. Further, the terms "comprising" and "including" are to be construed as including examples subsumed by the term "consisting of". As a result, the term "consisting of" can be used in place of the terms "comprising" and "including" to provide more specific embodiments of the present invention.

[0013] The term "consisting of" means that the subject has at least 90%, 95%, 97%, 98% or 99% of the features or components described as constituting it. In other embodiments, the term "consisting of" excludes any other features or components from any range subsequently described, except for those that are not essential to the technical advantages to be achieved.

[0014] As used herein, the term "or" is to be construed as an inclusive "or" meaning any one or any combination. Thus, "A, B or C" means any of the following: "A; B; C; A and B; A and C; B and C; A, B and C". This definition is excepted only when the combination of elements, functions, steps or acts are mutually exclusive in nature.

[0015] In this description, every concentration range, percentage range, ratio range or integer range should be construed to include every integer value within the recited range, and, when appropriate, fractions thereof (such as 1 / 10 and 1 / 100 of an integer), unless otherwise specified. Also, every numerical range recited herein that is associated with any physical property such as polymer subunit, size or thickness should be construed to include every integer within the recited range, unless otherwise specified. As used herein, the terms "about" and "approximately" mean ±20%, ±10%, ±5% or ±1% of the recited range, value or structure, unless otherwise specified.

[0016] An "alkyl" group has 1 to 10 carbon atoms (C1-C 10(alkyl), typically having 1 to 8 carbon atoms (C1-C8 alkyl) or in certain embodiments, 1 to 6 (C1-C6 alkyl), 1 to 4 (C1-C4 alkyl), 1 to 3 (C1-C3 alkyl) or 2 to 6 (C2-C6 alkyl) carbon atoms, and is a saturated, partially saturated or unsaturated straight-chain or branched acyclic hydrocarbon. In certain 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 alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl and the like. In certain embodiments, the alkyl group is an unsaturated alkyl group also referred to as an alkenyl or alkynyl group. An "alkenyl" group is an alkyl group containing one or more carbon-carbon double bonds. An "alkynyl" group is an alkyl group containing one or more carbon-carbon triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, those containing unsaturated alkyl groups. The alkyl group can be substituted or unsubstituted.If the alkyl group described herein is described as "substituted", then it may be substituted with any one or more substituents such as those found in the exemplary compounds and embodiments disclosed herein and halogen; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, arylalkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; oxo(=O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino, cycloalkylalkylamino, arylalkylamino, heterocyclylalkylamino, heteroarylalkylamino; imino; imide; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxylamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazide; hydrazono; azide; nitro; thio(-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amide; cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; or -B(OH)2. In certain embodiments, the alkyl group described herein is "substituted" and may be substituted with any one or more substituents such as those found in the exemplary compounds and embodiments disclosed herein and halogen (chloro, iodo, bromo or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidino; guanidino; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2 or -O(alkyl)aminocarbonyl.

[0017] The "cycloalkyl" group is a saturated or partially saturated cyclic alkyl group having 3 to 10 carbon atoms (C3-C 10 cycloalkyl) in a monocyclic ring or a polycondensed or bridged ring, which may be optionally substituted. In certain embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms (C3-C8 cycloalkyl), while in other embodiments, the number of ring carbon atoms ranges from 3 to 5 (C3-C5 cycloalkyl), 3 to 6 (C3-C6 cycloalkyl) or 3 to 7 (C3-C7 cycloalkyl). In certain embodiments, the cycloalkyl group is a saturated cycloalkyl group. Such saturated cycloalkyl groups include, by way of example only, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, etc. or poly- 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, etc. In other embodiments, the cycloalkyl group is an unsaturated cycloalkyl group. Examples of unsaturated cycloalkyl groups include, in particular, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl. The cycloalkyl group can be substituted or unsubstituted. Such substituted cycloalkyl groups include, by way of example only, cyclohexanol, etc.

[0018] "Heterocyclyl" is a non-aromatic cycloalkyl in which 1 to 4 of the ring carbon atoms are independently replaced by heteroatoms selected from O, S, and N. In certain embodiments, the heterocyclyl group contains 3 to 10 ring members, while other such groups contain 3 to 5, 3 to 6, or 3 to 8 ring members. Heterocyclyl can also be attached to other groups at any ring atom (i.e., any carbon or heteroatom of the heterocyclic ring). The heterocycloalkyl group can be substituted or unsubstituted. Heterocyclyl groups include saturated and partially saturated ring systems. Further, the term heterocyclyl is intended to include any non-aromatic ring containing at least one heteroatom, and the ring can be fused to an aryl or heteroaryl ring, regardless of its attachment to the remainder of the molecule. The term also includes bridged polycyclic ring systems containing heteroatoms. Representative examples of a heterocyclyl group include, but are not limited to, aziridinyl, azetidinyl, azepanyl, pyrrolidinyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidinyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl, 1,4-dioxaspiro[4.5]decan-1-yl, homopiperazinyl, quinuclidinyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclyl groups can be mono-substituted or substituted with more than one substituent, e.g., a pyridyl or morpholinyl group substituted with various substituents at the 2-, 3-, 4-, 5-, or 6-position or disubstituted as listed below, but not limited thereto.

[0019] An "aryl" group is an aromatic carbocyclic group of 6 to 14 carbon atoms (C6-C 14 aryl) having a monocyclic (e.g., phenyl) or polycondensed ring (e.g., naphthyl or anthryl). In certain embodiments, the aryl group has 6 to 14 carbons (C6-C 14 aryl) in the ring portion of the group and otherwise 6 to 12 (C6-C 12Aryl) or 6 to 10 carbon atoms (C6-C 10 Have an aryl). Specific aryls include phenyl, biphenyl, naphthyl, and the like. The aryl group may be substituted or unsubstituted. The term "aryl group" also includes groups containing fused rings such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.).

[0020] A "heteroaryl" group is an aromatic ring system having 1 to 4 heteroatoms as ring atoms in a heteroaromatic ring system, while the remaining atoms are carbon atoms. In certain embodiments, the heteroaryl group has 3 to 6 ring atoms and otherwise 6 to 9 or 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 pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl (e.g., indolyl-2-onyl or isoindoline-1-onyl), azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), imidazopyridyl (e.g., azabenzimidazolyl or 1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-onyl), tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups, etc., but are not limited thereto. The heteroaryl group may be substituted or unsubstituted.

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

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

[0023] An "oxo" group is a "=O" group bonded to carbon.

[0024] An "amino" group is -NH2 (wherein one or both of the hydrogen atoms may be substituted with alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl).

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

[0026] A "heteroaryl-oxy" group is -O-(heteroaryl) (wherein heteroaryl is as defined above). A "heterocyclyl-oxy" group is -O-(heterocyclyl) (wherein heterocyclyl is as defined above). A "cycloalkyl-oxy" group is -O-(cycloalkyl) (wherein cycloalkyl is as defined above).

[0027] Except for alkyl, amino, and amide groups, if a group described herein is described as being "substituted", it may be substituted with any suitable one or more substituents. Illustrative examples of substituents are those found in the exemplary compounds and embodiments disclosed herein and include halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxo (=O); B(OH)2, -O(alkyl)aminocarbonyl; cycloalkyl which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or heterocyclyl which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, arylalkyloxy, heterocyclylalkyloxy, and heteroarylalkyloxy.

[0028] Embodiments of the present invention are intended to include pharmaceutically acceptable salts, tautomers, isotopologs, and stereoisomers of the compounds provided herein, such as compounds of formula (I).

[0029] As used herein, the term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts of the compounds 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 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, phthalic 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, sulfanilic 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 hydrochloride, formate and mesylate. Others are well known in the art, for example, see Remington's Pharmaceutical Sciences, 18 th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19 th eds., Mack Publishing, Easton PA (1995).

[0030] As used herein and unless otherwise indicated, the term "stereoisomer" or "stereoisomerically pure" means a particular stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center is substantially free of the opposite enantiomer of that compound. A stereoisomerically pure compound having two chiral centers is substantially free of other diastereomers of that compound. Typical stereoisomerically pure compounds include greater than about 80% by weight of one isomer of the compound and less than about 20% by weight of the other stereoisomer of that compound, greater than about 90% by weight of one isomer of the compound and less than about 10% by weight of the other stereoisomer of that compound, greater than about 95% by weight of one isomer of the compound and less than about 5% by weight of the other stereoisomer of that compound or greater than about 97% by weight of one isomer of the compound and less than about 3% by weight of the other stereoisomer of that compound. The compounds disclosed herein may have chiral centers and may exist as racemates, individual enantiomers or diastereomers and mixtures thereof. All such isomeric forms, including mixtures thereof, are included within the scope of the embodiments disclosed herein.

[0031] The use of the compounds disclosed herein in stereoisomerically pure form and the use of mixtures of these forms are encompassed by the embodiments disclosed herein. For example, mixtures containing equal or unequal amounts of enantiomers of a particular compound can be used in the methods and compositions disclosed herein. These isomers can be asymmetrically synthesized or resolved 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, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw Hill, NY, 1962); Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation Of Enantiomers : Synthetic Methods (Wiley-VCH Verlag GmbH & Co. KgaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation: Fundamentals and Practical Methods (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 depends on the environment in which the compound is found and can depend, for example, on whether the compound is a solid or in an organic or aqueous solution. For example, in an aqueous solution, pyrazole can exhibit the following isomeric forms, which are tautomers of each other.

Chemical formula

[0033] As will be readily understood by those skilled in the art, a wide variety of functional groups and other structures exhibit tautomerism, and all tautomers of the 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, at one or more atoms, an unnatural proportion of atomic isotopes. For example, the compound 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 deuterium ( 2 H), carbon-13 ( 13 C) or nitrogen-15 ( 15It may be isotope-enriched with N). Here, the “isotopolog” used is an isotope-enriched compound. The term “isotope enrichment” refers to an atom having an isotope composition other than the natural isotope composition of the atom. “Isotope enrichment” may also refer to a compound containing at least one atom having an isotope composition other than the natural isotope composition of the atom. The term “isotope composition” refers to the amount of each isotope present for a certain atom. Radiolabels and isotope-enriched compounds are useful as therapeutic agents, for example, cancer therapeutic agents, research reagents, for example, binding assay reagents, and diagnostic agents, for example, in vivo contrast agents. All isotope variations of the compounds described herein, whether radioactive or otherwise, are intended to be included within the scope of the embodiments provided herein. In certain embodiments, isotopologs of the compounds disclosed herein are provided, for example, the isotopologs are deuterium, carbon-13 and / or nitrogen-15 enriched compounds. Here, the “deuteration” used refers to a compound in which at least one hydrogen (H) is replaced with deuterium (D or 2 shown as H), that is, the compound is enriched with deuterium at at least one position.

[0035] Regardless of stereoisomerism or isotope composition, it should be understood that each of the compounds disclosed herein can be provided in any form of the pharmaceutically acceptable salts described herein. Similarly, the isotope composition can vary independently of the stereoisomer composition of each compound described herein. Furthermore, the isotope composition is limited to the elements present in each compound or its salt disclosed herein, but can vary otherwise independently of the selection of the pharmaceutically acceptable salt of each compound.

[0036] It should be noted that if there is a contradiction between the described structure and the name of the structure, the described structure shall prevail.

[0037] As used herein, "treatment" means the reduction, in whole or in part, of one or more of a disorder, disease or condition or symptoms associated with a disorder, disease or condition, or the deceleration, arrest or reduction of further progression or worsening of these symptoms, or the reduction or eradication of the disorder, disease or condition itself. In certain embodiments, the disorder is a neurodegenerative disease or a symptom thereof described herein.

[0038] As used herein, "prevention" means delaying and / or preventing, in whole or in part, the onset, recurrence or spread of a disorder, disease or condition; excluding the acquisition of the disorder, disease or condition by a subject; or reducing the risk that a subject will acquire the disorder, disease or condition. In certain embodiments, the disorder is a neurodegenerative disease or a symptom thereof described herein.

[0039] The term "effective amount" as related to a compound disclosed herein means an amount capable of treating or preventing a disorder, disease or condition or a symptom thereof disclosed herein.

[0040] As used herein, the term "subject" or "patient" includes, but is not limited to, animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits or guinea pigs, and in certain embodiments, mammals, and in other embodiments, humans. In certain embodiments, the subject is a human having or at risk of having a WEE1-mediated disease or a symptom thereof.

[0041] Although the various features of the invention may be described in the context of one embodiment, these features may also be provided separately or in any suitable combination. Conversely, although the invention may be described in the context of separate embodiments for clarity, the invention may also be practiced in one embodiment.

[0042] Compound In certain embodiments, formula (I)

Chemical formula

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

Chemical formula

[0044] In certain embodiments, W 3 and W 4 combine to form an oxo group. In certain embodiments, A is a direct bond. In certain embodiments, A is an optionally substituted C 1-3 alkyl. In certain embodiments, A is -CH2-.

[0045] In certain embodiments, B is monocyclic. In certain embodiments, B is bicyclic. In certain embodiments, B is selected from optionally substituted C 6-14 aryl and optionally substituted 5- to 14-membered heteroaryl. In certain embodiments, B is selected from optionally substituted C 3-10 cycloalkyl and optionally substituted 3- to 14-membered heterocyclyl.

[0046] In certain embodiments, W 1 and W 2 are both H. In certain embodiments, W 1 and W 2 combine to form an oxo group. In certain embodiments, W 1 is H and W 2 is CH3. In certain embodiments, V is H. In certain embodiments, V is CH3.

[0047] In certain embodiments, R’ is selected from F and Cl. In certain embodiments, R’ is F. In certain embodiments, R’’ is F, Cl, optionally substituted C 1-3 alkyl and optionally substituted C 1-3 alkoxy. In certain embodiments, R’’ is F, Cl, C 1-3 alkyl and C 1-3 alkoxy. In certain embodiments, R’’ is selected from F and -CH3.

[0048] In certain embodiments, R’’’ is a halogen atom, -CN, -OH, optionally substituted amino, optionally substituted amide, optionally substituted C 1-5 alkyl, optionally substituted C 1-5 alkoxy, optionally substituted C 3-6 cycloalkyl-oxy, optionally substituted 5- to 10-membered heterocyclyl-oxy, optionally substituted 5- to 10-membered heteroaryl-oxy, optionally substituted C 3-6 cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted 5- to 10-membered aryl and optionally substituted 5- to 10-membered heteroaryl. In certain embodiments, R’’’ is 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- to 10-membered heterocyclyl and optionally substituted 5- to 10-membered heteroaryl.

[0049] In certain embodiments, R’’’ is selected from -NH2, -NH(CH3), -N(CH3)2 and -OCH3. In certain embodiments, R’’’ is, optionally, an F atom, -O-(C 1-3 alkyl), -O-C 4-6C substituted with 1 to 3 groups selected from heterocyclyl and OH 1-3 is alkyl. In certain embodiments, R''' is optionally -OH, -C 1-3 substituted with 1 to 2 groups selected from alkoxy and -CH2OCH3 C 3-6 is cycloalkyl. In certain embodiments, R''' is optionally F, OH, C optionally substituted with 1 to 3 F atoms or -NH2 1-3 alkyl, C optionally substituted with 1 to 3 F atoms 1-3 is a 3- to 10-membered heterocyclyl substituted with 1 to 3 groups selected from alkoxy, -C(O)CH3, -CH2OCH3, -NH2, -NH(CH3), and -N(CH3)2. In certain embodiments, R''' is optionally F, Cl, CN, OH, C optionally substituted with 1 to 3 F atoms or -NH2 1-3 alkyl, C optionally substituted with 1 to 3 F atoms or -NH2 1-3 is a 5- to 10-membered heteroaryl substituted with 1 to 3 groups selected from alkoxy, -C(O)CH3, -CH2OCH3, -NH2, -NH(CH3), -N(CH3)2, and C 4-6 heterocycle.

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

[0051] In certain embodiments, the compound has the formula (II)

Chemical formula

[0052] In certain embodiments, A is a direct bond. In certain embodiments, A is optionally substituted C 1-3 alkyl. In certain embodiments, A is -CH2-.

[0053] In certain embodiments, R' is selected from F and Cl. In certain embodiments, R'' is selected from F, Cl, optionally substituted C 1-3 alkyl and optionally substituted C 1-3 alkoxy.

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

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

[0056] In certain embodiments, each R 1 is 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- to 6-membered heterocyclyl.

[0057] In certain embodiments, each R 2 is 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- to 8-membered heterocyclyl.

[0058] In certain embodiments, the C 1 alkyl of R 2 or R 1-3 is substituted with 1 to 3 groups selected from halogen, OH, and C 1-3 alkoxy. In certain embodiments, the C 1 cycloalkyl of R 2 or R 3-6 is substituted with halogen, -OH, C 1-3 alkyl, C 1-3It is substituted with 1 to 3 groups selected from alkoxy and -CH2OCH3. In certain embodiments, R 1 is a 3- to 6-membered heterocyclyl or R 2 is a 4- to 8-membered heterocyclyl which is substituted with 1 to 3 groups selected from halogen, -OH, C 1-3 alkyl, C 1-3 alkoxy, -NH2, -NH(CH3), -N(CH3)2 and -C(O)CH3.

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

[0060] In certain embodiments, the compound is of formula (IIa)

Chemical formula

[0061] In certain embodiments, A is a direct bond. In certain embodiments, A is C 1-3 alkyl optionally substituted. In certain embodiments, A is -CH2-.

[0062] In certain embodiments, R' is selected from F and Cl. In certain embodiments, R'' is selected from F, Cl, C 1-3 alkyl optionally substituted, and C 1-3 alkoxy optionally substituted.

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

[0064] In certain embodiments, R 1 and R 3 are each independently selected from H, F, Cl, -CN, C 1-3 alkyl optionally substituted, C 1-3 alkoxy optionally substituted, C 3-6It is selected from cycloalkyl and optionally substituted 3- to 6-membered heterocyclyl. In certain embodiments, R 1 is independently selected from H and F. In certain embodiments, R 3 is H.

[0065] In certain 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 cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl and optionally substituted 5- to 10-membered heteroaryl. In certain embodiments, R 2 is independently selected from optionally substituted C 1-3 alkyl and optionally substituted 3- to 10-membered heterocyclyl. In certain embodiments, R 4 is H.

[0066] In certain embodiments,

Chemical formula

Chemical formula

[0067] In certain embodiments, R 2 is

Chemical formula

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

[0069] In certain embodiments, the compound is of formula (III):

Chemical formula

[0070] In certain embodiments, A is a direct bond. In certain embodiments, A is C optionally substituted with 1-3 alkyl. In certain embodiments, A is -CH2-.

[0071] In certain embodiments, R' is selected from F and Cl. In certain embodiments, R'' is selected from F, Cl, C optionally substituted with 1-3 alkyl and C optionally substituted with 1-3 alkoxy.

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

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

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

[0075] In certain embodiments, the compound is of formula (IIIa) or (IIIb):

Chemical formula

Chemical formula

[0076] In certain embodiments, A is a direct bond. In certain embodiments, A is optionally substituted C 1-3 alkyl. In certain embodiments, A is -CH2-.

[0077] In certain embodiments, R’ is selected from F and Cl. In certain embodiments, R’’ is F, Cl, optionally substituted C 1-3 alkyl and optionally substituted C 1-3 alkoxy. In certain embodiments, R 4 is an optionally substituted 6-membered heterocyclyl.

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

[0079] In certain embodiments, the compound is a compound from Table 1. In certain embodiments, the compound is a compound from Table 2.

[0080] It is understood that in the descriptions herein, all descriptions, variations, embodiments or aspects of a part can be combined with all descriptions, variations, embodiments or aspects of another part to the same extent as if each and every combination were specifically and individually listed. For example, all descriptions, variations, embodiments or aspects provided herein with respect to the “B” group of formula (I) are combined with A, W 1 、W 2All descriptions, variations, embodiments or aspects of V, R’, R’’, R’’’, l, m and n, and descriptions of each and all combinations can be combined to the same extent as if specifically and individually listed. All descriptions, variations, embodiments or aspects of formula (I), when applicable, are equally applicable to other formulas detailed herein, and it is also understood that each and all descriptions, variations, embodiments or aspects are equally described as if separately and individually listed for the entire formula. For example, all descriptions, variations, embodiments or aspects of formula (I), when applicable, are equally applicable to other formulas detailed herein, such as formula (II), (IIa), (III), (IIIa) and (IIIb), and each and all descriptions, variations, embodiments or aspects are equally described as if separately and individually listed for the entire formula.

[0081] In certain embodiments, compounds selected from the compounds in Table 1 or 2 or pharmaceutically acceptable salts thereof are provided. Although certain compounds described herein, including Tables 1 and 2, may be provided in specific stereoisomeric and / or non-stereochemical forms, it is understood that any or all stereochemical forms, including any enantiomeric or diastereomeric forms and any tautomeric or other forms of the compounds of the invention, including Tables 1 and 2, are described herein. [Table 1] [Table 2] [Table 3] [Table 4] or a pharmaceutically acceptable salt thereof.

[0082] In this description, it is understood that combinations of substituents and / or variable groups of the described formulas are only permitted when such contributions result in stable compounds.

[0083] Furthermore, all compounds of formula (I) that exist in free base or acid form can be converted into pharmaceutically acceptable salts by treatment with appropriate inorganic or organic bases or acids in a manner known to those skilled in the art. The salts of the compounds of formula (I) can be converted into the free base or acid form by standard techniques.

[0084] Synthetic Methods The compounds described herein can be prepared using conventional organic synthesis and commercially available starting materials or by the methods provided herein. By way of example and not limitation, the compounds of formula (I) can be prepared as outlined in Schemes 1 - 3 and i1 - i8 and in the Examples shown below. It should be noted that those skilled in the art know how to modify the methods shown in the illustrative schemes and examples, for example, to include starting materials (or racemic starting materials) with different stereochemistry in order to reach the desired product with different stereochemistry.

[0085] Generally, the compounds of formula (I) can be obtained by reaction of the aldehyde with an amine in the pyrrolidine group of formula (I). In certain embodiments, the reaction of the aldehyde is the final step in a series of reactions. See, for example, Schemes 1 and 2 below. In certain embodiments, the reaction of the aldehyde with an amine in the pyrrolidine group is carried out in the middle of a series of reactions. See, for example, Scheme 3 below. The preparation of the aldehyde intermediate can be achieved, for example, by the synthetic routes shown in Schemes i1 - i8. All reactions in the schemes below are at room temperature unless otherwise specified.

[0086]

Chemical Structure

[0087]

Chemical formula

[0088]

Chemical formula

[0089] The aldehyde intermediates that can be used in the synthesis of the compounds of formula (I) can be prepared as outlined in Schemes i1 - i8 and the examples shown below. It should be noted that one of ordinary skill in the art knows how to modify the methods shown in the illustrative schemes and examples to reach a desired product.

[0090]

Chemical formula

[0091]

Chemical formula

[0092]

Chemical formula

[0093]

Chemical formula

[0094]

Chemical formula

[0095]

Chemical formula

[0096]

Chemical formula

[0097]

Chemical formula

[0098] Method of Use Embodiments of the present invention provide a method for degrading WEE1, a method for reducing the WEE1 protein level, and a method for preventing or treating diseases such as cancer in a subject in need of treatment.

[0099] In one aspect, provided herein is a method for degrading WEE1 in a subject in need of treatment, the method comprising contacting a cell with an effective amount of a compound of formula (I). Degradation of WEE1 can be assayed and demonstrated by a variety of methods known in the art. Commercially available assays, including kits and cell-based assays, can be utilized to determine whether and to what extent WEE1 has been degraded. In certain embodiments, the compound of formula (I) partially degrades WEE1. In certain embodiments, the compound of formula (I) completely degrades WEE1.

[0100] In certain 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 certain embodiments, the compound of formula (I) degrades 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%, 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 certain embodiments, provided herein is a method of reducing WEE1 kinase protein level, the method comprising contacting a cell with an effective amount of a compound of formula (I). Reduction of WEE1 kinase protein level can be assayed and demonstrated by a variety of methods known in the art. Commercially available assays, including kits and cell-based assays, can be utilized to determine whether and to what extent the kinase protein level is reduced.

[0102] In certain embodiments, the compound of formula (I) reduces the WEE1 kinase protein level 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 certain embodiments, the compound of formula (I) reduces the WEE1 kinase protein level 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%, 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 certain embodiments, the compound of formula (I) has an EC 50 value of from about 0.0003 μM to about 1 μM or from about 0.0003 μM to about 0.2 μM or from about 0.0003 μM to about 0.05 μM as measured in a WEE1 degradation assay. In certain embodiments, the compound of formula (I) has an EC 50 of from about 0.05 μM to about 0.2 μM. In certain embodiments, the compound of formula (I) has an EC 50 of from about 0.2 μM to about 1 μM. In certain embodiments, the compound of formula (I) has an EC 50 of less than about 1 μM. In certain embodiments, the compound of formula (I) has an EC 50 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 of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I). In certain embodiments, provided herein is a method of preventing cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I). In certain embodiments, the cancer is selected from brain cancer, cervicobrain cancer, esophageal cancer, thyroid cancer, small cell cancer, non-small cell cancer, breast cancer, lung cancer, gastric cancer, gallbladder / bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, endometrial cancer, cervical cancer, renal pelvis / ureter cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonal carcinoma, Wilms' tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's tumor, soft tissue sarcoma, acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, polycythemia vera, malignant lymphoma, multiple myeloma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma.

[0105] In certain embodiments, the cancer is selected from gastric, lung, pancreatic, ovarian, breast, skin, colon, neuroblastoma, osteosarcoma, uterine, rectal, and renal cancers. In certain 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, and clear cell renal cell carcinoma (ccRCC).

[0106] In certain embodiments, administration of a compound of formula (I) to a subject predisposed to cancer prevents the subject from developing any symptoms of cancer (e.g., tumor growth or metastasis). In certain embodiments, administration of a compound of formula (I) to a subject who does not yet exhibit symptoms of cancer prevents the subject from developing any symptoms of cancer. In certain embodiments, administration of a compound of formula (I) to a subject in need of treatment reduces the degree of cancer in the subject. In certain embodiments, administration of a compound of formula (I) to a subject in need of treatment stabilizes the cancer (prevents or delays progression of the cancer). In certain embodiments, administration of a compound of formula (I) to a subject in need of treatment delays the onset or recurrence of cancer. In certain embodiments, administration of a compound of formula (I) to a subject in need of treatment slows the progression of cancer. In certain embodiments, administration of a compound of formula (I) to a subject in need of treatment provides a partial remission of the cancer. In certain embodiments, administration of a compound of formula (I) to a subject in need of treatment provides a complete remission of the cancer. In certain embodiments, administration of a compound of formula (I) to a subject in need of treatment decreases the dosage of one or more other medicaments required for the treatment of cancer. In certain embodiments, administration of a compound of formula (I) to a subject in need of treatment enhances the effect of other medicaments used in the treatment of cancer. In certain embodiments, administration of a compound of formula (I) to a subject in need of treatment delays the progression of cancer. In certain embodiments, administration of a compound of formula (I) to a subject in need of treatment improves the quality of life of a subject having cancer. In certain embodiments, administration of a compound of formula (I) to a subject in need of treatment extends the lifespan of a subject having cancer.

[0107] Provided herein is a method of preventing the onset of cancer in a subject predisposed to cancer, the method comprising administering to the subject a compound of formula (I).

[0108] In one aspect, provided herein is a method of reducing the degree of cancer in a subject, the method comprising administering to the subject a compound of formula (I). In certain embodiments, provided herein is a method of stabilizing cancer in a subject, the method comprising administering to the subject a compound of formula (I). In certain embodiments, the method prevents cancer from worsening.

[0109] In other aspects, provided herein is a method of delaying the occurrence or recurrence of cancer in a subject, the method comprising administering to the subject a compound of formula (I).

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

[0111] In a further aspect, provided herein is a method of reducing the dosage of one or more other medicaments required for treating cancer in a subject, the method comprising administering to the subject a compound of formula (I). In certain embodiments, provided herein is a method of enhancing the effect of other medicaments used for treating cancer in a subject, the method comprising administering to the subject a compound of formula (I).

[0112] Also provided herein is a method of delaying the progression of cancer in a subject, the method comprising administering to the subject a compound of formula (I). In certain embodiments, the method improves the quality of life of a subject having cancer. In certain embodiments, the method extends the lifespan of a subject having cancer.

[0113] In certain embodiments, the compounds of formula (I) are useful for the manufacture of a medicament for reducing the level of WEE1 kinase protein. In certain embodiments, the compounds of formula (I) are useful for the manufacture of a medicament for the prevention or treatment of a disease associated with WEE1. In certain embodiments, the compounds of formula (I) are useful for the manufacture of a medicament for the prevention or treatment of cancer. In certain embodiments, the cancer is selected from stomach, lung, pancreas, ovary, breast, skin, colon, neuroblastoma, osteosarcoma, uterus, rectal, and kidney cancers. In certain 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 sarcoma, melanoma, colon, and clear cell renal cell carcinoma (ccRCC).

[0114] The methods and uses of the present invention involve the use of a compound of formula (I), alone or in combination with one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents).

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

[0116] In certain embodiments, the additional therapy is the administration of a side effect limiting agent (e.g., an agent intended to reduce the occurrence or severity of treatment side effects). For example, in certain 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 for the treatment of nausea include, but are not limited to, dronabinol, granisetron, metoclopramide, ondansetron, prochlorperazine, and pharmaceutically acceptable salts thereof.

[0117] In certain embodiments, one or more additional treatments include non-drug treatments (e.g., surgery or radiation therapy). In certain embodiments, one or more additional treatments include therapeutic agents (e.g., compounds or biological agents that are anti-proliferative agents). In certain embodiments, one or more additional treatments include non-drug treatments and therapeutic agents. In other embodiments, one or more additional treatments include two therapeutic agents. In still other embodiments, one or more additional treatments include three therapeutic agents. In certain embodiments, one or more additional treatments include four or more therapeutic agents.

[0118] Pharmaceutical Compositions and Routes of Administration The compounds provided herein can be administered to a subject orally, topically, or parenterally in formulations in conventional forms such as capsules, microcapsules, tablets, granules, powders, troches, 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 forms of preparations such as capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions. Suitable preparations can be prepared by conventional methods using conventional organic or inorganic additives such as additives (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 hydroxypropyl cellulose, sodium bicarbonate, calcium phosphate or calcium citrate), lubricants (e.g., magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate), flavoring agents (e.g., citric acid, menthol, glycine or orange powder), preservatives (e.g., sodium benzoate, sodium bisulfite, methylparaben or propylparaben), stabilizers (e.g., citric acid, sodium citrate or acetic acid), suspending agents (e.g., methylcellulose, polyvinylpyrrolidone or aluminum stearate), dispersing agents (e.g., hydroxypropylmethylcellulose), diluents (e.g., water) and wax bases (e.g., cocoa butter, white petrolatum or polyethylene glycol). The effective amount of the compound of formula (I) in the pharmaceutical composition can be at a level that exhibits the desired effect; for example, it can be from about 0.005 mg / kg of subject body weight to about 10 mg / kg of subject body weight per unit dose for both oral and parenteral administrations.

[0120] The dosage of the compound of formula (I) to be administered to a subject can vary rather widely and can be left to the judgment of the medical caregiver. Generally, the compounds disclosed herein can be administered 1 to 4 times a day at a dosage of about 0.001 mg / kg of subject body weight to about 10 mg / kg of subject body weight, although the above dosage can be appropriately varied depending on the age, weight and medical condition of the subject and the type of administration. In certain embodiments, 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 certain embodiments, one dosage is administered once a day. In any case, the amount of the compound of formula (I) to be administered depends on factors such as the solubility of the active ingredient, the formulation used and the route of administration.

[0121] In certain embodiments, the compound of formula (I) is administered to the subject at a dosage 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 other embodiments, unit dosage formulations are provided herein that contain 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 the compound of formula (I).

[0123] In certain embodiments, unit dosage formulations are provided herein that contain about 0.1 mg or 100 mg of the compound of formula (I).

[0124] In other embodiments, unit dosage formulations are provided herein that contain a compound of formula (I) in an amount of 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.

[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 as a once-daily dose, and a dose exceeding 100 mg is administered twice daily in an amount equal to half of the total daily dose.

[0126] For reasons of convenience, the compound of formula (I) can be administered orally. In certain embodiments, when administered orally, the compound of formula (I) is administered with food and water. In other embodiments, the compound of formula (I) is dispersed in water or juice (e.g., apple juice or orange juice) or any other liquid and administered orally as a solution or suspension.

[0127] The compounds disclosed herein can also be administered intradermally, intramuscularly, intraperitoneally, transdermally, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracranially, intravaginally, percutaneously, rectally, mucosally, by inhalation or topically to the ear, nose, eye or skin. The method of administration is at the discretion of the medical practitioner and may depend in part on the site of the medical condition.

[0128] In certain embodiments, capsules are provided herein that contain a compound of formula (I) without additional carriers, additives or vehicles.

[0129] In other embodiments, compositions are provided herein that contain an effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or vehicle, where the pharmaceutically acceptable carrier or vehicle can include additives, diluents or mixtures thereof. In certain embodiments, the composition is a pharmaceutical composition.

[0130] The composition can be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories, spray-dried dispersions and suspensions, etc. The composition can be formulated into a dosage unit which can be a single tablet or capsule or a convenient volume of liquid and contains a daily dose or a convenient fraction of the daily dose. In certain embodiments, the solution is formed from a water-soluble salt such as a hydrochloride. Generally, all the compositions are manufactured by methods known in pharmaceutical chemistry. Capsules can be manufactured by mixing a compound of formula (I) with a suitable carrier or diluent and filling a suitable amount of the mixture into the capsules. Common carriers and diluents include, but are not limited to, various types of starches, pulverized cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, and inert pulverized substances such as wheat flour and similar edible powders.

[0131] Tablets can be manufactured by direct compression, wet granulation or dry granulation. The formulation usually contains a diluent, a binder, a lubricant and a disintegrant as well as the present compound. Typical diluents include, for example, various types of starches, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, inorganic salts such as sodium chloride and pulverized sugars. Pulverized cellulose derivatives are also useful. Typical tablet binders are substances such as starches, gelatin and sugars such as lactose, fructose, glucose. Natural and synthetic gums including acacia, alginate, methylcellulose, polyvinylpyrrolidine, etc. are also convenient. Polyethylene glycol, ethylcellulose and wax can also serve as binders.

[0132] Lubricants are necessary in tablet formulations to prevent tablets and punches from adhering to the die. Lubricants can be selected from slippery solids such as talc, magnesium and calcium stearates, stearic acid and hydrogenated vegetable oils. Tablet disintegrants are substances that expand when wet, break up the tablet and release the compound. They include starches, clays, celluloses, algins and gums. More specifically, for example, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resin, alginic acid, guar gum, citrus pulp and carboxymethylcellulose and sodium lauryl sulfate can be used. Tablets can be coated with sugar as a flavor and sealant or with a film-forming protective agent to modify the solubility properties of the tablet. The composition can be formulated as chewable tablets, for example, by using substances such as mannitol in the formulation.

[0133] When it is desired to administer the compound of formula (I) as a suppository, typical bases can be used. Cocoa butter is a traditional suppository base and can be modified by the addition of wax to slightly raise the melting point. In particular, the use of water-miscible suppository bases containing polyethylene glycols of various molecular weights is widespread.

[0134] The effect of the compound of formula (I) can be delayed or extended by appropriate formulation. For example, slowly dissolving pellets of the compound of formula (I) can be produced and incorporated into tablets or capsules or manufactured as sustained-release implantable devices. This technique also includes producing several different dissolution rate pellets and filling capsules with mixtures of these pellets. Tablets or capsules can be coated with a film that withstands dissolution for a predicted period. Even parenteral formulations can be made sustained by dissolving or suspending the compound of formula (I) in an oily or emulsified medium that allows it to disperse slowly in serum.

Examples

[0135] The following examples are presented for illustrative purposes and not by way of limitation. Those skilled in the art can modify the procedures shown in the illustrative examples to reach the desired products.

[0136] The salts of the compounds described herein can be prepared by standard methods such as adding an acid (e.g., TFA, formic acid or HCl) to the mobile phase during chromatographic purification or by stirring the product with an acid solution (e.g., aqueous HCl solution) after chromatographic purification.

[0137] Unless otherwise specified, all reactions are at room temperature.

[0138] The following abbreviations may be relevant to this application.

Table 5

[0139] Synthetic Examples As will be apparent to those skilled in the art, the compounds disclosed below and in Tables 1 and 2 can exist in various stereochemical forms. When the stereochemistry is shown for the ether bond between pyrrolidine and isoindolinone in the examples and the compounds of Tables 1 and 2 and when the stereochemistry is shown between piperidine-dione and isoindolinone, the stereochemistry is absolute. For other stereocenters where the stereochemistry is shown and designated as R or S, e.g., the B and R''' groups of formula (I), the stereochemistry can be relative stereochemistry.

[0140] Example S1. 3-(5-(((S)-1-((2-methylquinazolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chemical Formula

[0141] 6-Bromo-2-methylquinazoline. Ammonia (7M ethanol solution, 2 mL, 14 mmol) was added to a solution of N-(4-bromo-2-formyl-phenyl)acetamide (1.7 g, 7.03 mmol) in ethanol (20 mL), and the mixture was stirred at 140 °C for 12 hours under nitrogen. The mixture was concentrated, and the crude product was recrystallized from a 90% hexane in ethyl acetate solution 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. Bis(triphenylphosphine)palladium(II) chloride (629 mg, 0.90 mmol) and cesium fluoride (2.0 g, 13.17 mmol) were added to a solution of compound 6-bromo-2-methyl-quinazoline (1.0 g, 4.48 mmol) and tributyl(vinyl)stannane (1.7 g, 5.38 mmol) in 1,4-dioxane (10 mL), and the mixture was stirred at 100 °C for 3 hours under nitrogen. Water was added to the resulting mixture, and the mixture was 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 in petroleum ether solution) to give the title compound (450 mg, 2.64 mmol, 59% yield) as a bright yellow solid. MS (ESI) m / z 171.1 [M+1] + .

[0143] 2-Methylquinazoline-6-carbaldehyde. 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 an additional 1 h. Water was added to the resulting mixture, and the mixture was 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 (petroleum ether solution of 0 - 50% ethyl acetate) to give the title compound (220 mg, 1.28 mmol, 48% yield) as a pale 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-oxoiso-indolin-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 (dichloromethane solution of 0 - 10% methanol) and recrystallized from n-hexane / dichloromethane to give the title compound (66.5 mg, 0.14 mmol, 41% yield) as an off-white solid. 11H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.49 (s, 1H), 8.02 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 7.01 (d, J = 8.5 Hz, 1H), 5.07 (m, 2H), 4.37 (d, J = 17.2 Hz, 1H), 4.25 (d, J = 17.2 Hz, 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 / z 486.2 [M+1] + .

[0145] 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

Chem.

[0146] 3-(5-(((3S,4S)-4-Methylpyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2,2,2-trifluoroacetic acid. Trifluoromethanesulfonic acid (0.1 mL) was added to a stirred solution of tert-butyl (3S,4S)-3-[2-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-1-oxoisoindolin-5-yl]oxy-4-methyl-pyrrolidine-1-carboxylate (70 mg, 0.12 mmol) in TFA (1.5 mL). The solution was stirred at 50 °C for 12 h under nitrogen. The mixture was concentrated. The pH of the residue was adjusted to about pH 5 with sodium bicarbonate, filtered, and the filtrate was purified by reverse flash (10–40% acetonitrile + 0.05% aqueous TFA, over 25 min) to give the title compound (40 mg, 0.087 mmol, 73% yield) as a pale 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. 3-[5-[(3S,4S)-4-Methylpyrrolidin-3-yl]oxy-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; A solution of 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 hours. The resulting solution was concentrated and the residue was purified by silica gel chromatography (dichloromethane solution of 10% methanol) and preparative HPLC under the following conditions: SunFire Prep C18 OBD column, 19×150 mm 5μm 10nm; Mobile phase A: water (0.1% formic acid), Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 5B~25B for 7 minutes; 254 / 210 nm; RT1: 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-d4) δ 8.35 (s, 1H), 8.22 (s, 1H), 8.04 - 7.94 (m, 2H), 7.83 (d, J = 8.7 Hz, 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 - 4.86 (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] + .

[0148] Example S3. 2-(2,6-Dioxopiperidin-3-yl)-5-(((R)-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl)oxy)isoindoline-1,3-dione [Chemical formula] Dimethyl (R)-4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)phthalate. Diisopropyl azodicarboxylate (2 g, 9.89 mmol) was added 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) at 0 °C. The mixture was stirred at room temperature for 2 hours under nitrogen. 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 (ethyl acetate solution of 0 - 10% hexane) to give the title compound (1 g, 2.63 mmol, 66% yield) as a pale yellow oil. MS (ESI) m / z 380.2 [M+1] + .

[0149] (R)-4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)phthalic acid. Sodium hydroxide (624 mg, 15.60 mmol) was added 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), and the mixture was stirred at 50 °C for 12 hours under nitrogen. The mixture was concentrated, and hydrochloric acid (1 M aqueous solution) was added dropwise to the residue to pH about 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 pale yellow solid. MS (ESI) m / z 352.1 [M+1] + .

[0150] tert-Butyl (3R)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-pyrrolidine-1-carboxylate. 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 for 3 h under nitrogen. The reaction mixture was diluted with ether (30 mL), and the solid was collected to give the title compound (300 mg, 0.68 mmol, 80% yield) as a gray 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. Hydrochloric acid (4 M dioxane solution, 1.70 mL, 6.81 mmol) was added to tert-butyl (3R)-3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxypyrrolidine-1-carboxylate (300 mg, 0.68 mmol), and the mixture was stirred at room temperature for 2 h under nitrogen. The solid was collected and washed with ether (3 mL) and acetone to give the title compound (200 mg, 0.52 mmol, 76% yield) as a bright 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. Compound 2-(2,6-dioxo-3-piperidyl)-5-[(3R)-pyrrolidin-3-yl]oxy-isoindoline-1,3-dione; hydrochloride (120 mg, 0.32 mmol), quinoline-3-carbaldehyde (74 mg, 0.47 mmol) and triethylamine (48 mg, 0.47 mmol) in dichloromethane (3 mL) solution, sodium triacetoxyborohydride (268 mg, 1.26 mmol) was added, and the mixture was stirred at room temperature for 2 hours under nitrogen. The resulting mixture was concentrated. The residue was purified by silica gel chromatography (dichloromethane solution of 10% methanol) 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~21B for 7 minutes; 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-d4) δ 8.92 (s, 1H), 8.37 (d, J = 2.7 Hz, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.79 (m, 2H), 7.65 (m, 1H), 7.39-7.33 (m, 1H), 7.28 (m, J = 8.5, 4.5, 2.3 Hz, 1H), 5.16-5.11 (m, 2H), 4.06 (m, 2H), 3.21-3.12 (m, 1H), 3.06 (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] + .

[0153] Example S4. 2-(2,6-Dioxopiperidin-3-yl)-5-(((R)-1-(quinolin-6-ylmethyl)pyrrolidin-3-yl)oxy)isoindoline-1,3-dione

Chemical formula

[0154] Example S5. 2-(2,6-Dioxopiperidin-3-yl)-5-(((S)-1-(quinolin-5-ylmethyl)pyrrolidin-3-yl)oxy)isoindoline-1,3-dione [Chemical Structure] 2-(2,6-Dioxopiperidin-3-yl)-5-(((S)-1-(quinolin-5-ylmethyl)pyrrolidin-3-yl)oxy)isoindoline-1,3-dione. 2-(2,6-Dioxo-3-piperidyl)-5-[(3R)-pyrrolidin-3-yl]oxy-isoindoline-1,3-dione; hydrochloride (120 mg, 0.32 mmol), quinoline-5-carbaldehyde (74 mg, 0.47 mmol) and triethylamine (47 mg, 0.47 mmol) in dichloromethane (10 mL) were added sodium triacetoxyborohydride (268 mg, 1.26 mmol), and the mixture was stirred at room temperature for 2 h under nitrogen. The resulting mixture was concentrated and purified by silica gel chromatography (dichloromethane solution of 10% methanol) 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~21B for 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-d4) δ 8.90-8.81 (m, 2H), 8.01 (d, J = 8.5 Hz, 1H), 7.81-7.70 (m, 2H), 7.68-7.62 (m, 2H), 7.33 (d, J = 2.3 Hz, 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] + .

[0155] Example S6. 3-(5-(((S)-1-((2-Methylquinolin-6-yl)methyl)pyrrolidin-3-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [Chemical formula] 3-(5-(((S)-1-((2-Methylquinolin-6-yl)methyl)pyrrolidin-3-yl)amino)-1-oxoiso-indolin-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 for 12 h under nitrogen. The reaction mixture was concentrated and 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: 5B~21B for 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 (14 mg, 0.029 mmol, 9% yield) as a pale yellow solid. 1 H NMR (400 MHz, methanol-d4) δ 8.35 (s, H), 8.26 (d, J = 8.5 Hz, 1H), 8.04-7.95 (m, 2H), 7.83 (dd, J = 8.7, 2.0 Hz, 1H), 7.58-7.46 (m, 2H), 6.76-6.67 (m, 2H), 5.09 (dd, J = 13.3, 5.1 Hz, 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] + .

[0156] Example S7. 3-(1-Oxo-5-(((R)-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl)methyl)isoindolin-2-yl)-piperidine-2,6-dione

Chemical formula

[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 dioxane solution, 20 mL, 20 mmol). The mixture was stirred at room temperature for 12 h under nitrogen. 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) were 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 for 12 h under nitrogen. Water was added to the resulting mixture, and the mixture was 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 (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5B~18B for 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. 11H NMR (400 MHz, methanol-d4) δ 9.01 (d, J = 2.2 Hz, 1H), 8.62 (d, J = 2.2 Hz, 1H), 8.14 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.93 (t, J = 8.5, 6.9, 1.4 Hz, 1H), 7.76 (m, 2H), 7.49 - 7.43 (m, 2H), 5.17 (dd, J = 13.3, 5.1 Hz, 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] + .

[0159] Example S8. 3-(1-Oxo-5-(((S)-1-(quinolin-5-ylmethyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione [Chemical formula] 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) 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 flushed with nitrogen three times and stirred under nitrogen for 12 h. Water was added to the mixture and the mixture was 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 under the following conditions: column: Sunfire prep 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~2B for 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-d4) δ 9.82-9.65 (m, 1H), 9.37 (d, J = 4.0 Hz, 1H), 8.44 (d, J = 8.0 Hz, 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] + .

[0160] Example S9. 3-(5-(((S)-1-((1,8-Naphthyridin-4-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [Chemical formula] 1,8-Naphthyridine-4-carbaldehyde. Selenium dioxide (569 mg, 5.13 mmol) was added to a solution of 4-methyl-1,8-naphthyridine (370 mg, 2.57 mmol) in 1,4-dioxane (16 mL) and water (2 mL). The mixture was stirred at 80 °C for 1 hour under nitrogen. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (petroleum ether solution of 0 - 50% ethyl acetate) to obtain 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-Naphthyridin-4-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of 1,8-naphthyridine-4-carbaldehyde (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 for 12 hours under nitrogen. The mixture was concentrated and 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% TFA), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 2B - 2B for 2 minutes; 254 / 210 nm; RT1: 7.50. The fractions containing the desired product were collected and evaporated under reduced pressure to obtain the title compound (29.3 mg, 0.062 mmol, 21% yield) as an off-white solid. 11H NMR (400 MHz, methanol-d4) δ 9.26 - 9.19 (m, 2H), 9.02 - 8.95 (m, 1H), 7.99 (d, J = 4.0 Hz, 1H), 7.90 - 7.84 (m, 1H), 7.74 (dd, J = 8.0 Hz, J = 4.0 Hz, 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] + .

[0162] Example S10. 3-(1-Oxo-6-(((S)-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione [Chemical formula] 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) 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 stirred at room temperature for 12 h under nitrogen. Water was added to the resulting mixture, and the mixture was 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: XBridge Prep 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~16B for 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-d4) δ 8.93 (d, J = 4.0 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.84-7.76 (m, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.69-7.61 (m, 1H), 7.11-7.01 (m, 2H), 5.17-5.05 (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] + .

[0163] Example S11. 3-(1-Oxo-5-(((S)-1-(quinolin-4-ylmethyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione

Chemical Structure

[0164] Example S12. 3-(1-Oxo-6-(((R)-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione

Chem.

[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 dioxane solution, 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) were 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~25B for 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. 11H NMR (400 MHz, methanol-d4) δ 8.95 (d, J = 4.0 Hz, 1H), 8.41 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 12.0 Hz, 1H), 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 / z 471.2 [M+1] + .

[0167] Example S13. 3-(1-Oxo-5-(((R)-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl)methyl)isoindolin-2-yl)-piperidine-2,6-dione

Chemical formula

[0168] 3-(1-Oxo-5-(((R)-pyrrolidin-3-yl)methyl)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)methyl)pyrrolidine-1-carboxylate (264 mg, 0.62 mmol) in 1,4-dioxane (4 mL) was added hydrogen chloride (1 M dioxane solution, 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) were 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~18B for 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. 11H NMR (400 MHz, methanol-d4) δ 8.95 (d, J = 4.0 Hz, 1H), 8.70 (d, J = 4.0 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 8.00 (dd, J = 8.0 Hz, J = 4.0 Hz, 1H), 7.85 (t, J = 8.0 Hz, 1H), 7.76 - 7.65 (m, 2H), 7.45 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 5.15 (dd, J = 12.0 Hz, J = 4.0 Hz, 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] + .

[0170] Example S14. 2-(2,6-Dioxopiperidin-3-yl)-5-(((S)-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl)oxy)isoindoline-1,3-dione

Chemical formula

[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 hydrochloric acid (1 M aqueous solution) was added dropwise to the residue to pH ~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 pale yellow solid. MS (ESI) m / z 352.1 [M+1] + .

[0172] tert-Butyl (3S)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-pyrrolidine-1-carboxylate. 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 for 3 h under nitrogen. The reaction mixture was diluted with 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 tert-butyl (3S)-3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxoisoindolin-5-yl]oxypyrrolidine-1-carboxylate (300 mg, 0.68 mmol) in hydrochloric acid (4 M 1,4-dioxane solution, 3 mL, 12 mmol) was stirred at room temperature for 2 h under nitrogen. 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 bright 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. A solution of the 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-carbaldehyde (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 for 2 h under nitrogen. The resulting mixture was concentrated. The residue was purified by silica gel chromatography (dichloromethane solution of 10% methanol) 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~21B for 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-d4) δ 8.92 (s, 1H), 8.37 (d, J = 2.7 Hz, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.79 (m, 2H), 7.65 (m, 1H), 7.39-7.33 (m, 1H), 7.28 (m, J = 8.5, 4.5, 2.3 Hz, 1H), 5.16-5.11 (m, 2H), 4.06 (m, 2H), 3.21-3.12 (m, 1H), 3.06 (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] + .

[0175] Example S15. 3-(5-(((S)-1-((5-Fluoroquinolin-3-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [Chemical formula] 5-Fluoroquinoline-3-carbaldehyde. To a solution of 3-bromo-5-fluoroquinoline (200 mg, 0.88 mmol) in DMSO (3 mL) were 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 for 3 hours under nitrogen. Water was added to the mixture, and the mixture was 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 (petroleum ether solution of 0 - 40% ethyl acetate) to obtain 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. 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) was 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 for 12 h under nitrogen. Water was added to the mixture and it was 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~20B for 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-d4) δ 9.00 (d, J = 4.0 Hz, 1H), 8.59 (s, 1H), 7.91 (d, J = 8.0 Hz, 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] + .

[0177] Example S16. 3-(5-(((S)-1-((1-Methylisoquinolin-3-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [Chemical formula] (Z)-1-Phenylethan-1-one oxime. Hydroxylamine hydrochloride (431 mg, 6.24 mmol) and triethylamine (1.74 mL, 12.48 mmol) were added to a solution of 1-phenylethanone (500 mg, 4.16 mmol) in ethanol (20 mL). The mixture was stirred at 85 °C for 3 hours under nitrogen. Water was added to the resulting mixture, and the mixture was 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 in petroleum ether solution) to obtain the title compound (430 mg, 3.15 mmol, 76% yield) as a pale 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), prop-2-enal (275 mg, 4.910 mmol), pivalic acid (370 mg, 0.53 mmol), bis[(pentamethylcyclopentadienyl)dichlororhodium] (10 mg, 0.10 mmol), and silver(I) carbonate (1000 mg, 5.26 mmol) were added. The mixture was stirred for 12 hours under a nitrogen atmosphere. Water was added to the resulting mixture, and the mixture was 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 - 20% ethyl acetate in petroleum ether solution) to obtain 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-oxoiso-indolin-2-yl)piperidine-2,6-dione. To a solution of 1-methylisoquinoline-3-carbaldehyde (70 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 (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: 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~30B for 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-d4) δ 8.31 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.90-7.73 (m, 4H), 7.21-7.09 (m, 2H), 5.37 (m, 1H), 5.14 (dd, J = 16.0 Hz, J = 8.0 Hz, 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), 2.98-2.75 (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] + .

[0180] Example S17. 3-(5-(((S)-1-((7-Fluoroisoquinolin-3-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [Chemical formula] 2-(3,3-Diethoxyprop-1-yn-1-yl)-5-fluorobenzaldehyde. To a solution of 2-bromo-5-fluorobenzaldehyde (1.0 g, 4.93 mmol) in THF (20 mL) were added 3,3-diethoxyprop-1-yne (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′-tri-i-propyl-1,1′-biphenyl (0.90 g, 1.89 mmol). The mixture was stirred at 60 °C for 12 h under nitrogen. Water was added to the resulting mixture, and the mixture was 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 - 30% ethyl acetate in 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. Ammonia (7M methanol solution, 15 mL) of 2-(3,3-diethoxyprop-1-yn-1-yl)-5-fluorobenzaldehyde (250 mg, 0.99 mmol) was heated by microwave irradiation at 100 °C for 20 min under nitrogen in a microwave reactor. 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 (petroleum ether solution of 0 - 25% ethyl acetate) 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-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) 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 flushed with nitrogen three times and stirred under nitrogen for 12 h. Water was added to the resulting mixture, and the mixture was 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 - 30B over 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. 11H NMR (400 MHz, methanol-d4) δ 9.27 (s, 1H), 8.03 (dd, J = 8.0 Hz, J = 4.0 Hz, 1H), 7.94 (s, 1H), 7.82 (dd, J = 8.0 Hz, J = 4.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 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] + .

[0184] Example S18. 3-(6-(((S)-1-((2-methylquinolin-3-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chemical formula

[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) were 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 for 12 h under nitrogen. 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 - 15B for 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. 11H NMR (400 MHz, methanol-d4) δ 8.27 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.57 (m, 1H), 7.48 (m, 1H), 7.31 - 7.17 (m, 2H), 5.14 (dd, J = 12.0 Hz, J = 4.0 Hz, 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 / z 485.2 [M+1] + .

[0186] Example S19. 3-(1-Oxo-5-(((S)-1-(quinazolin-2-ylmethyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione

Chemical formula

[0187] Example S20. 3-(5-(((S)-1-((2-chloroquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chem.

[0188] 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

Chemical formula

[0189] 3-(5-(((2S,3S)-2-Methylpyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2,2,2-trifluoroacetic acid. Trifluoromethanesulfonic acid (0.2 mL, 2.27 mmol) was added 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). The mixture was stirred at 60 °C for 12 h under nitrogen. 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 (10-30% acetonitrile + 0.05% aqueous TFA, over 20 min) to give the title compound (40 mg, 0.087 mmol, 73% yield) as a pale 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. 3-(5-(((2S,3S)-2-Methylpyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; A solution of 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 5 times and flushed with nitrogen. The mixture was stirred under nitrogen at room temperature for 2 hours. The resulting solution was concentrated under reduced pressure at 25 °C. The crude product was purified by silica gel column chromatography (dichloromethane solution of 0 - 10% methanol), and further purified by preparative reverse-phase 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 - 18B for 7 minutes; 254 / 210 nm; RT1: 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. 11H NMR (400 MHz, methanol-d4) δ 8.35 - 8.27 (m, 2H), 8.10 - 8.01 (m, 2H), 7.89 (dd, J = 8.7, 2.0 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.20 - 7.15 (m, 2H), 5.14 - 5.10 (m, 2H), 4.64 (d, J = 13.0 Hz, 1H), 4.54 - 4.39 (m, 2H), 4.12 (d, J = 13.0 Hz, 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 = 6.6 Hz, 3H). MS (ESI) m / z 499.1 [M+1] + .

[0191] 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 [Chemical formula] tert-Butyl (2R,3R)-3-(benzoyloxy)-2-methylpyrrolidine-1-carboxylate. To a stirred solution of tert-butyl (2R,3S)-3-hydroxy-2-methylpyrrolidine-1-carboxylate (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 for 3 h under nitrogen. The resulting solution was concentrated under reduced pressure. The crude product was purified by reverse phase flash (0 - 80% acetonitrile + 0.05% aqueous TFA, over 20 min) to afford the title compound (200 mg, 0.65 mmol, 26% yield) as a pale 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 the mixture was then stirred at 50 °C for 1 h under nitrogen. 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 H NMR (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) were added methanesulfonate (2-(di-t-butylphosphino)-3-methoxy-6-methyl-2’,4’,6’-tri-i-propyl-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 for 12 h under nitrogen. The resulting mixture was filtered and purified by reverse phase flash (0 - 80% acetonitrile + 0.05% aqueous TFA, over 20 min) to give the title compound (75 mg, 0.19 mmol, 70% yield) as a pale yellow solid. MS (ESI) m / z 403.1 [M+1] + .

[0194] tert-Butyl (2R,3S)-3-((2-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-2-methylpyrrolidine-1-carboxylate. To a solution of 3-(5-hydroxy-1-oxoisoindolin-2-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (200 mg, 0.53 mmol), tert-butyl (2R,3R)-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 for 3 h under nitrogen. The resulting reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse-phase flash (0 - 80% acetonitrile + 0.05% aqueous TFA, over 20 min) to give the title compound (130 mg, 0.23 mmol, 44% yield) as a pale 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 for 12 h under nitrogen. 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 (10 - 30% acetonitrile + 0.05% aqueous TFA, over 20 min) to give the title compound (70 mg, 0.20 mmol, 95% yield) as a pale 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 5 times and flushed with nitrogen. The mixture was stirred under nitrogen at room temperature for 2 hours. The resulting solution was concentrated under reduced pressure at room temperature. The crude product was purified by silica gel column chromatography (dichloromethane solution of 0 - 10% methanol) 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: 2B - 20B for 7 minutes; 210 / 254 nm; RT1: 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. 11H NMR (400 MHz, methanol-d4) δ 8.82 (dd, J = 8.6, 3.2 Hz, 1H), 8.40 (t, J = 2.6 Hz, 1H), 8.27 - 8.17 (m, 2H), 7.91 (dd, J = 8.6, 2.9 Hz, 1H), 7.74 (dd, J = 14.7, 8.5 Hz, 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 = 13.2 Hz, 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, 1.7 Hz, 3H); MS (ESI) m / z 499.1 [M+1] + .

[0197] 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 [Chemical formula] (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% / carbon (100 mg, moistened with about 55% water), and the mixture was stirred for 12 h at room temperature under hydrogen (about 2 bar). 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-Dihydrofuro[2,3-c]pyridine-5-carbaldehyde. Manganese dioxide (299 mg, 3.44 mmol) was added to a stirred solution of 2,3-dihydrofuro[2,3-c]pyridin-5-ylmethanol (65 mg, 0.43 mmol) in dichloromethane (4 mL) at room temperature. The reaction mixture was then stirred at 60 °C for 3 h under nitrogen. 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 pale 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. Triethylamine (0.08 mL, 0.60 mmol) and sodium triacetoxyborohydride (257 mg, 1.21 mmol) were added 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. The mixture was stirred at room temperature for 2 h under nitrogen. The resulting solution was concentrated at 25 °C. The residue was purified by silica gel column chromatography (0–10% methanol in dichloromethane) and further purified by preparative reverse-phase 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–30B over 7 min; 254 / 210 nm; RT1: 4.65. 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. 11H NMR (400 MHz, methanol-d4) δ 8.35 (s, 1H), 8.06 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.42 (s, 1H), 7.15 - 7.10 (m, 2H), 5.23 (s, 1H), 5.14 (dd, J = 13.3, 5.2 Hz, 1H), 4.67 (t, J = 8.9 Hz, 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] + .

[0200] 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

Chemical Structure

[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. 2-(Prop-1-yn-1-yl)quinoline-6-carbaldehyde (50 mg, 0.26 mmol) and 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione, which had been stirred for 15 minutes beforehand, were added to a solution of 2,2,2-trifluoroacetic acid (115 mg, 0.26 mmol) and triethylamine (0.07 mL, 0.52 mmol) in dichloromethane (5 mL). Sodium triacetoxyborohydride (220 mg, 1.0 mmol) was added thereto at 0 °C, and the solution was stirred at room temperature for 4 hours under nitrogen. The resulting solution was purified by silica gel chromatography (dichloromethane solution of 0 - 10% methanol). The 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 over 10 minutes, 18% B to 18% B over 11 minutes, 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 obtain the title compound (28.8 mg, 0.056 mmol, 22% yield) as a white solid. 11H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.32 (m, 1H), 8.14 (s, 1H), 7.90 (d, J = 8.6 Hz, 2H), 7.76 (m, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.11 (t, J = 1.8 Hz, 1H), 7.01 (m, 1H), 5.04 (m, 2H), 4.37 (d, J = 17.2 Hz, 1H), 4.24 (m, 1H), 3.85 (s, 2H), 3.07 - 2.70 (m, 4H), 2.59 (d, J = 17.3 Hz, 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] + .

[0202] Example S25. 3-(5-(Methyl((S)-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [Chemical formula] tert-Butyl (3S)-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), tert-butyl (S)-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 methanesulfonato(2-dicyclohexylphosphino-2’,6’-di-i-propoxy-1,1’-biphenyl)-(2’-amino-1,1’-biphenyl-2-yl)palladium(II) (79 mg, 0.094 mmol). The flask was evacuated 5 times and flushed with nitrogen. The mixture was stirred at 100 °C for 3 h under nitrogen. The mixture was diluted with ethyl acetate and filtered. The obtained solution was concentrated and purified by silica gel chromatography (petroleum ether solution of 0 - 90% ethyl acetate) to give the title compound (250 mg, 0.42 mmol, 44% yield) as a pale 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 for 12 h under nitrogen. The resulting solution was concentrated, and saturated ammonium bicarbonate was added to the residue to adjust the pH to 5 - 6. The residue was purified by reverse-phase flash (10 - 40% acetonitrile + 0.05% aqueous TFA, over 25 min) to afford the title compound (75 mg, 0.16 mmol, 38% yield) as an oil. 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 5 times and flushed with nitrogen. The mixture was stirred at room temperature for 2 h under nitrogen. The resulting mixture was concentrated, and 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: 5B - 5B for 2 min; 254 / 210 nm; RT1: 8.48 min. The fractions containing the desired product were collected and evaporated under reduced pressure to afford the title compound (25.5 mg, 0.053 mmol, 31% yield) as a yellow solid.1 1H NMR (400 MHz, methanol-d4) δ 9.09 (d, J = 2.2 Hz, 1H), 8.72 (d, J = 2.2 Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 7.96 (m, 1H), 7.79 (m, 1H), 7.65 (d, J = 9.3 Hz, 1H), 7.04 (m, 2H), 5.11 (m, 1H), 4.99 (m, 1H), 4.80 (d, J = 13.2 Hz, 1H), 4.75 (d, J = 13.3 Hz, 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 / z 484.1 [M+1] + .

[0205] Example S26. 3-(5-(((S)-1-(isoquinolin-3-ylmethyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chem.

[0206] Example S27. 3-(5-(((S)-1-((2,3-dimethylpyridin-4-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [Chemical formula] 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) was added palladium(II) acetate (24 mg, 0.11 mmol). The mixture was stirred at 120 °C for 3 hours under nitrogen. 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 (petroleum ether solution of 30% - 100% ethyl acetate) 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 for 2 h under nitrogen. 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~2B for 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-d4) δ 8.29-8.20 (m, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 5.5 Hz, 1H), 7.10 (d, J = 2.2 Hz, 1H), 7.06 (dd, J = 8.5, 2.2 Hz, 1H), 5.13 (dd, J = 13.3, 5.2 Hz, 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, 3H), 2.49 (m, 2H), 2.38 (s, 3H), 2.22-2.13 (m, 1H), 2.10-2.02 (m, 1H);; MS (ESI) m / z 449.1 [M+1] + .

[0208] 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 [Chemical formula] Ethyl (E)-3-(3,5-dibromopyridin-4-yl)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 three times and flushed with nitrogen. The mixture was stirred at 80 °C for 12 hours under nitrogen. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether solution of 0 - 25% ethyl acetate) to obtain the title compound (1.2 g, 3.58 mmol, 95% yield) as a pale yellow solid. MS (ESI) m / z 334.0 [M+1] + .

[0209] 3-(3,5-Dibromopyridin-4-yl)propan-1-ol. To a solution of ethyl (E)-3-(3,5-dibromopyridin-4-yl)acrylate (600 mg, 1.79 mmol) in methanol (10.0 mL) was added sodium borohydride (135 mg, 3.58 mmol). The mixture was stirred at room temperature for 1.5 hours. Then, lithium borohydride (35 mg, 1.59 mmol) was added to the mixture, and the mixture was stirred at 50 °C for 12 hours under nitrogen. 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 hydrochloric acid (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 (petroleum ether solution of 0 - 25% ethyl acetate) to obtain 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% methanol solution, 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), pyridin-2-amine (13 mg, 0.14 mmol) and copper(I) chloride (13 mg, 0.14 mmol). The sealed tube was filled with nitrogen. The mixture was heated by microwave irradiation in a microwave reactor at 135 °C for 6 hours. Then, saturated sodium bicarbonate solution was 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 - 25% ethyl acetate in 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. Dichlorobis(triphenylphosphine)palladium(II) dichloromethane adduct (184 mg, 0.26 mmol) was added 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). The flask was evacuated 5 times and flushed with nitrogen. The mixture was stirred under nitrogen at 80 °C for 3 hours. 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 (20% - 100% ethyl acetate in 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-carbaldehyde. 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), and 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 for 6 h under nitrogen, then sodium periodate (478 mg, 2.23 mmol) was added and the mixture was stirred at room temperature for an additional 3 h. The resulting solution was diluted with water and then extracted with ethyl acetate. The combined organic layers were 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 dichloromethane 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), sodium triacetoxyborohydride (232 mg, 1.09 mmol) was added. The flask was evacuated 5 times and flushed with nitrogen. The mixture was stirred for 2 hours at room temperature under a nitrogen atmosphere. 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~14B for 7 minutes; 254 / 210 nm; RT1: 6.30. The pure fraction was concentrated to give the title compound (13.7 mg, 0.03 mmol, 10%) as an off-white solid. 1 H NMR (400 MHz, methanol-d4) δ 8.02 (d, J = 12.0 Hz, 2H), 7.73 (d, J = 8.5 Hz, 1H), 7.13-7.03 (m, 2H), 5.13 (m, 2H), 4.53-4.38 (m, 2H), 4.28-4.21 (m, 2H), 3.91 (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] + .

[0214] Example S29. 3-(5-(((S)-1-((8-Fluoroisoquinolin-3-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chemical formula

[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 MeOH solution, 10 mL), and the reaction was heated by microwave irradiation at 100 °C for 20 min under nitrogen in a microwave reactor. 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, about 4.01 mmol) in THF (10.0 mL) was added HCl (6 M, 10.0 mL). The flask was evacuated three times and flushed with nitrogen. The mixture was stirred at 40 °C for 12 h under nitrogen. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether solution of 30% - 100% ethyl acetate) 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 five times and flushed with nitrogen. The mixture was stirred at room temperature for 2 h under nitrogen. 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 - 20B for 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. 11H NMR (400 MHz, methanol-d4) δ 9.51 (s, 1H), 8.34 (s, 1H), 7.97 (s, 1H), 7.86 - 7.77 (m, 2H), 7.74 (d, J = 8.4 Hz, 1H), 7.46 - 7.37 (m, 1H), 7.16 - 7.06 (m, 2H), 5.21 (m, 1H), 5.14 (dd, J = 13.3, 5.2 Hz, 1H), 4.46 (d, J = 6.8 Hz, 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] + .

[0218] Example S30. 3-(1-Oxo-5-(((S)-1-(quinoxalin-2-ylmethyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione

Chemical Structure

[0219] Example S31. 3-(5-(Methyl((R)-1-(quinolin-3-ylmethyl)pyrrolidin-3-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chem.

[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 hours. The resulting solution was concentrated, saturated ammonium bicarbonate was added to the residue to pH 5 - 6, filtered, and the filtrate was purified by reverse-phase flash (10 - 40% acetonitrile + 0.05% aqueous TFA, over 25 minutes) to give the title compound (90 mg, 0.20 mmol, 59% yield) as a pale 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 hours. 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 - 20B over 7 minutes; 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 pale yellow solid.1 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.92 (d, J = 2.1 Hz, 1H), 8.28 (s, 1H), 8.06 - 7.95 (m, 2H), 7.75 (m, 1H), 7.62 (m, 1H), 7.47 (d, J = 8.4 Hz, 1H), 6.94 - 6.86 (m, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.63 (m, 1H), 4.29 (d, J = 16.7 Hz, 1H), 4.17 (d, J = 16.7 Hz, 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] + .

[0222] Example S32. 3-(5-(((S)-1-((3-Methylquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chemical formula

[0223] 3-(5-(((S)-1-((3-Methylquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. 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) solution, sodium triacetoxyborohydride (297 mg, 1.40 mmol) was added and the resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated and purified by silica gel chromatography (dichloromethane solution of 10% methanol) and preparative HPLC under the following conditions: 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: 5B~35B for 7 min; 254 / 210 nm; RT1: 3.77; the fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (11.8 mg, 0.02 mmol, 7% yield) as an off-white solid. 11H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.75 (d, J = 2.2 Hz, 1H), 8.10 (m, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.84 (m, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.13 (m, 1H), 7.02 (m, 1H), 5.06 (m, 2H), 4.38 (d, J = 17.2 Hz, 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] + .

[0224] Example S33. 3-(5-(((S)-1-((5,6-Difluoroquinolin-3-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chemical formula

[0225] 3,4-Difluoro-2-nitrobenzaldehyde. To a solution of 1,2-difluoro-3-nitro-4-vinyl-benzene (410 mg, 2.22 mmol), potassium osmate (163 mg, 0.44 mmol), and 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 an air atmosphere. The resulting mixture was stirred at room temperature for 5 h. Then, sodium periodate (1.4 g, 6.64 mmol) was added to the mixture under an air atmosphere. The resulting mixture was stirred at room temperature for 1 h. Water was added to the resulting mixture, and the mixture was 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 (petroleum ether solution of 0 - 20% ethyl acetate) 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] Methyl 5,6-difluoroquinoline-3-carboxylate. To a solution of 4,5-difluoro-6-nitro-cyclohexa-2,4-diene-1-carbaldehyde (300 mg, 1.59 mmol) and methyl 3,3-dimethoxypropanoate (588 mg, 3.97 mmol) in ethanol (5 mL) was added tin(II) chloride (1.4 g, 6.35 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 3 h. Water was added to the resulting mixture, and the mixture was 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 (petroleum ether solution of 0 - 10% ethyl acetate) to give the title compound (190 mg, 0.85 mmol, 54% yield) as a yellow solid. MS (ESI) m / z 224.2 [M+1] + .

[0227] 5,6-Difluoroquinoline-3-carbaldehyde. To a solution of methyl 5,6-difluoroquinoline-3-carboxylate (118 mg, 0.66 mmol, 71% yield) in THF (10 mL) was added lithium aluminum hydride (2.5 M solution in THF, 0.36 mL, 0.89 mmol) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. The mixture was quenched with water and adjusted to pH = 5 with 15% sodium hydroxide. The solid was filtered off and washed with ethyl acetate. The filtrate was concentrated and purified by prep TLC (5% methanol in dichloromethane) to give the title compound (118 mg, 0.66 mmol, 71% yield) as a pale yellow solid. Subsequently, manganese dioxide (530 mg, 6.15 mmol) was added to a solution of (5,6-difluoro-3-quinolyl)methanol (118 mg, 0.614 mmol, 1 equiv) in chloroform (3 mL) under an air atmosphere. The resulting mixture was stirred at room temperature for 12 h. 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. 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) solution, sodium triacetoxyborohydride (262 mg, 1.24 mmol) was added under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was stirred at room temperature for 3 hours. The resulting solution was concentrated and the residue was purified by preparative TLC (10% methanol in dichloromethane solution) 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~25B for 7 minutes; 254 / 210 nm; RT1: 6.12; fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (32.5 mg, 0.06 mmol, 20% yield) as an off-white solid. 11H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.96 (d, J = 2.1 Hz, 1H), 8.41 (d, J = 2.1 Hz, 1H), 7.95 (m, J = 9.5, 4.7 Hz, 1H), 7.87 (m, J = 10.6, 8.8 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 2.0 Hz, 1H), 7.02 (m, J = 8.4, 2.2 Hz, 1H), 5.12 - 4.99 (m, 2H), 4.38 (d, J = 17.2 Hz, 1H), 4.25 (d, J = 16.8 Hz, 1H), 3.92 (s, 2H), 2.99 (s, 1H), 2.91 (m, J = 18.2, 13.5, 5.4 Hz, 1H), 2.82 (s, 1H), 2.75 (m, J = 8.2 Hz, 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] + .

[0229] Example S34. 3-(5-(((S)-1-((5,6-dimethylpyridin-3-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [Chemical formula] 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) were added palladium acetate (12 mg, 0.05 mmol), 1,2-bis(diphenylphosphino)ethane (104 mg, 0.26 mmol), and the mixture was stirred under nitrogen at 120 °C 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 (ethyl acetate solution of 0 - 50% petroleum ether) 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. 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) were added sodium triacetoxyborohydride (232 mg, 1.09 mmol), and the mixture was stirred under nitrogen at room temperature for 12 h. The resulting mixture was concentrated. The residue was purified by silica gel chromatography (dichloromethane solution of 10% methanol) 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~2B for 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. 11H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.17 (m, J = 9.7, 1.9 Hz, 2H), 7.61 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 2.1 Hz, 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, 2.9 Hz, 1H), 3.58 (s, 2H), 2.98 - 2.87 (m, 2H), 2.80 - 2.60 (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] + .

[0231] 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 [Chemical Structure] 5-(Trifluoromethyl)nicotinaldehyde. Manganese dioxide (492 mg, 5.65 mmol) was added to a solution of (5-(trifluoromethyl)pyridin-3-yl)methanol (100 mg, 0.57 mmol) in dichloromethane (5 mL), and the resulting mixture was stirred at room temperature for 12 h under nitrogen. 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. 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) solution, sodium triacetoxyborohydride (232 mg, 1.09 mmol) was added, and the mixture was stirred for 2 hours at room temperature under nitrogen. The resulting mixture was concentrated. The residue was purified by silica gel chromatography column (dichloromethane solution of 10% methanol) 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~2B for 1 minute; 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. 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.91 - 8.83 (m, 2H), 8.18 - 8.10 (m, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 2.2 Hz, 1H), 7.01 (m, 1H), 5.12 - 5.01 (m, 1H), 5.01 (d, J = 6.9 Hz, 1H), 4.39 (d, J = 17.2 Hz, 1H), 4.26 (d, J = 17.1 Hz, 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]+.

[0233] Example S36. 3-(1-Oxo-6-(((S)-1-(quinolin-6-ylmethyl)pyrrolidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione [Chemical formula] 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) were 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 hours. 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 for 7 minutes; 254 / 210 nm; RT: 6.32 minutes. 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. 11H NMR (400 MHz, methanol-d4) δ 8.90 (d, J = 4.3 Hz, 1H), 8.41 (d, J = 8.3 Hz, 1H), 8.13 - 8.04 (m, 2H), 7.91 (d, J = 8.6 Hz, 1H), 7.60 (dd, J = 8.3, 4.3 Hz, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 2.3 Hz, 1H), 7.22 (d, J = 8.4 Hz, 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] + .

[0234] Example S37. 3-(6-(((S)-1-(isoquinolin-3-ylmethyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)-piperidine-2,6-dione [Chemical formula] 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 for 2 h under nitrogen. 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~20B for 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 H NMR (400 MHz, methanol-d4) δ 9.32 (s, 1H), 8.14 (d, J = 8.2 Hz, 1H), 8.00 - 7.92 (m, 2H), 7.84 (t, J = 7.6 Hz, 1H), 7.74 (t, J = 7.5 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 2.3 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H), 5.21 (m, 1H), 5.15 (dd, J = 13.3, 5.1 Hz, 1H), 4.50 (m, 2H), 4.44 (d, J = 8.4 Hz, 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] + .

[0235] Example S38. 3-(6-(((S)-1-(isoquinolin-6-ylmethyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [Chemical formula] 3-(6-(((S)-1-(isoquinolin-6-ylmethyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. Sodium triacetoxyborohydride (232 mg, 1.09 mmol) was added 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). The mixture was stirred at room temperature for 2 hours under nitrogen. 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~12B for 7 minutes; 254 / 210 nm; RT1: 5.78. The pure fraction was concentrated to give the title compound (21.8 mg, 0.046 mmol, 17% yield) as an off-white solid. 11H NMR (400 MHz, methanol-d4) δ 9.28 (s, 1H), 8.49 (d, J = 5.8 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 8.04 (s, 1H), 7.86 (d, J = 5.9 Hz, 1H), 7.82 (dd, J = 8.5, 1.6 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.30 (m, 1H), 7.22 (m, 1H), 5.19 - 5.10 (m, 2H), 4.47 (d, J = 16.8 Hz, 1H), 4.40 (d, J = 16.9 Hz, 1H), 4.31 (m, 2H), 3.39 (m, 1H), 3.31 (m, 2H), 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] + .

[0236] 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 [Chemical Structure] 4-Chloro-2-methylquinoline-6-carbaldehyde. 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 was added palladium(II) acetate (35 mg, 0.16 mmol). The sealed tube was filled with nitrogen. The mixture was stirred at 120 °C for 3 h under nitrogen. 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 (petroleum ether solution of 0-25% ethyl acetate) 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 five times and flushed with nitrogen. 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 - 5% methanol in 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 - 25B over 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. 11H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.05 (s, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.80 (dd, J = 8.7, 1.9 Hz, 1H), 7.67 (s, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.11 (d, J = 2.0 Hz, 1H), 7.01 (dd, J = 8.5, 2.2 Hz, 1H), 5.12 - 4.98 (m, 2H), 4.38 (d, J = 17.1 Hz, 1H), 4.25 (dd, J = 17.2, 3.3 Hz, 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] + .

[0238] 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 [Chemical formula] 3-Methyl-3-(5-(((S)-1-((2-methylquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. 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) were added sodium triacetoxyborohydride (117 mg, 0.55 mmol) at room temperature. The mixture was stirred under nitrogen for 12 h. Water was added to the mixture and the mixture was 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 5μm 10nm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 8B~20B for 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. 11H NMR (400 MHz, methanol-d4) δ 8.35 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.03 - 7.85 (m, 2H), 7.74 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.01 (s, 1H), 6.94 (d, J = 8.0 Hz, 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, 1H), 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 / z 499.1 [M+1] + .

[0239] Example S41. 3-(((3S)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)pyrrolidin-1-yl)methyl)quinoline-2-carbonitrile [Chemical formula] 2-Iodoquinoline-3-carbaldehyde. Hydrochloric acid (12 M, 0.1 mL) was added to a solution of 2-chloroquinoline-3-carbaldehyde (800 mg, 4.18 mmol) and sodium iodide (4.4 g, 29.23 mmol) in acetonitrile (20.0 mL). The flask was evacuated 5 times and flushed with nitrogen. The mixture was stirred at 90 °C for 3 hours under nitrogen. 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 (petroleum ether solution of 0 - 50% ethyl acetate) to obtain the title compound 2-iodoquinoline-3-carbaldehyde (400 mg, 1.41 mmol, 34% yield) as an orange solid. MS (ESI) m / z 284.0 [M+1] + .

[0240] 3-Formylquinoline-2-carbonitrile. Cuprous cyanide (152 mg, 1.70 mmol) was added to a solution of 2-iodoquinoline-3-carbaldehyde (400 mg, 1.41 mmol) in acetonitrile (5.0 mL). The flask was evacuated 5 times and flushed with nitrogen. The mixture was stirred at 90 °C for 5 hours under nitrogen. 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 (petroleum ether solution of 0 - 10% ethyl acetate) to obtain the title compound (200 mg, 1.09 mmol, 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 five times and flushed with nitrogen. 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 - 5% methanol in 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 - 23B over 10 min; 210 / 254 nm; RT1: 9.73. 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. 11H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.62 (s, 1H), 8.14 (d, J = 8.4 Hz, 2H), 7.91 (m, 1H), 7.85 - 7.77 (m, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 2.2 Hz, 1H), 7.02 (dd, J = 8.4, 2.2 Hz, 1H), 5.06 (m, 2H), 4.38 (d, J = 17.2 Hz, 1H), 4.25 (d, J = 17.2 Hz, 1H), 4.04 (d, J = 13.9 Hz, 1H), 3.98 (d, J = 13.8 Hz, 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] + .

[0242] 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

Chem.

[0243] 3-(5-(((3S,5R)-5-methylpyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. Trifluoromethanesulfonic acid (0.1 mL) was added to a 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). The mixture was stirred at 60 °C for 12 h under nitrogen. 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 (10 - 30% acetonitrile + 0.05% aqueous TFA, over 20 min) to give the title compound (40 mg, 0.12 mmol, 40% yield) as a pale 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. 3-(5-(((3S,5R)-5-Methylpyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; To a solution of 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 three times and flushed with nitrogen. The reaction mixture was stirred at room temperature for 2 h under nitrogen. The resulting solution was concentrated under reduced pressure at room temperature. The crude product was purified by silica gel column chromatography (0 - 10% methanol in dichloromethane) and preparative reverse-phase 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 - 18B over 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. 11H NMR (400 MHz, methanol-d4) δ 8.96 (d, J = 8.7 Hz, 1H), 8.48 (s, 1H), 8.26 (d, J = 3.7 Hz, 2H), 7.98 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 8.4 Hz, 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, 1H), 2.76 - 2.67 (m, 1H), 2.49 - 2.45 (m, 1H), 2.21 - 2.03 (m, 2H), 1.60 (d, J = 6.6 Hz, 3H). MS (ESI) m / z 499.2 [M+1] + .

[0245] 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 [Chemical formula] tert-Butyl (2S,4S)-4-((2-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-2-methylpyrrolidine-1-carboxylate. A solution of 3-(5-bromo-1-oxoisoindolin-2-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (100 mg, 0.23 mmol), tert-butyl (2S,4S)-4-hydroxy-2-methylpyrrolidine-1-carboxylate (136 mg, 0.68 mmol), (4,4'-di-t-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-kN)phenyl-kC]iridium(III) hexafluorophosphate (3 mg, 0.003 mmol), quinuclidine (6 mg, 0.06 mmol), and potassium carbonate (31 mg, 0.23 mmol) in dry acetonitrile (2 mL) was added to a solution of 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 dry acetonitrile (2 mL). The reaction was evacuated three times and flushed with nitrogen, and then irradiated with a 34 W blue LED. The reaction mixture was stirred at room temperature for 12 h under nitrogen. The resulting reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 - 70% ethyl acetate in petroleum ether) to give the title compound (70 mg, 0.12 mmol, 55% yield) as a pale 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. Trifluoromethanesulfonic acid (0.05 mL, 0.62 mmol) was added 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). The mixture was stirred at 60 °C for 12 h under nitrogen. 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 (10 - 30% acetonitrile + 0.05% aqueous TFA, over 20 min) to give the title compound (40 mg, 0.12 mmol, 97% yield) as a pale 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 three times and flushed with nitrogen. The reaction mixture was stirred under nitrogen at room temperature for 2 h. The resulting solution was concentrated under reduced pressure at 25 °C. The crude product was purified by silica gel column chromatography (0–10% methanol in dichloromethane solution) and further purified by preparative reverse-phase 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–23B over 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. 11H NMR (400 MHz, methanol-d4) δ 8.78 (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 = 12.4 Hz, 2H), 3.00 (s, 3H), 2.99 - 2.92 (m, 1H), 2.86 - 2.82 (m, 1H), 2.66 - 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] + .

[0248] Example S44. 3-(5-(((S)-1-((2-(Difluoromethyl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chemical formula

[0249] 2-(Difluoromethyl)quinoline-6-carbaldehyde. To a solution of 6-bromo-2-(difluoromethyl)quinoline (290 mg, 1.12 mmol), tert-butyl isocyanide (93 μL, 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 for 3 h under nitrogen. The resulting solution was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0 - 50% ethyl acetate in petroleum ether) to give the title compound (70 mg, 0.33 mmol, 30% yield) as a pale 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 five times and flushed with nitrogen. The mixture was stirred under nitrogen at room temperature for 2 hours. The resulting solution was concentrated under reduced pressure at 25 °C. The crude product was purified by silica gel column chromatography (0 - 10% methanol in dichloromethane solution) and further purified by preparative HPLC under the following conditions: column: Sun Fire Prep C18 OBD column, 19×150 mm 5μm 10nm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5B - 18B for 10 minutes; 254 / 210 nm; RT1: 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. 11H NMR (400 MHz, methanol-d4) δ 8.52 (dd, J = 8.5, 1.9 Hz, 1H), 8.13 (d, J = 8.7 Hz, 1H), 8.02 (s, 1H), 7.93 (dd, J = 8.7, 1.9 Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 8.4 Hz, 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] + .

[0251] Example S45. 3-(5-(((S)-1-((2-Cyclopropylquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [Chemical formula] 6-Bromo-2-cyclopropylquinoline. To a stirred solution of (2-amino-5-bromophenyl)methanol (700 mg, 3.46 mmol) in toluene (10 mL) were added 1-cyclopropylethanone (583 mg, 6.93 mmol) and lithium tert-butoxide (554 mg, 6.93 mmol). 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 - 50% ethyl acetate in petroleum ether) to give the title compound (300 mg, 1.21 mmol, 35% yield) as a yellow oil. MS (ESI) m / z 248.0 [M+1] + .

[0252] 2-Cyclopropylquinoline-6-carbaldehyde. To a stirred solution of 6-bromo-2-cyclopropylquinoline (290 mg, 1.17 mmol) in DMSO (5 mL) were added sodium formate (0.16 g, 2.34 mmol), 1,2-bis(diphenylphosphino)ethane (47 mg, 0.12 mmol), palladium(II) acetate (53 mg, 0.23 mmol) and tert-butyl isocyanide (1.5 mL, 1.32 mmol). The resulting mixture was stirred at 120 °C for 3 h under nitrogen. Water was added to the reaction solution and the mixture was 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 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) were 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 for 1.5 h under nitrogen. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in 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~20B for 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. 11H NMR (300 MHz, methanol-d4) δ 88.18 (d, J = 8.6 Hz, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.90 (d, J = 1.7 Hz, 1H), 7.83-7.68 (m, 2H), 7.30 (d, J = 8.6 Hz, 1H), 7.13-7.02 (m, 2H), 5.13 (m, 2H), 4.44 (m, 2H), 4.22 (d, J = 2.3 Hz, 2H), 3.42 (m,1H), 3.25 (m, 2H), 3.07 (m, 1H), 2.92-2.73 (m, 2H), 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] + .

[0254] Example S46. 3-(5-(((S)-1-((2-Cyclopropylquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [Chemical formula] tert-Butyl (3R,4S)-3-(bromomethyl)-4-hydroxypyrrolidine-1-carboxylate. To a solution of tert-butyl (3S,4S)-3-hydroxy-4-(hydroxymethyl)pyrrolidine-1-carboxylate (300 mg, 1.38 mmol) and 2,6-dimethylpyridine (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 for 3 hours under nitrogen. Then, the reaction mixture was filtered. Sodium bromide (600 mg, 5.83 mmol) was added to the filtrate, and the mixture was stirred at 75 °C for 3 hours under nitrogen. Water was added to the resulting mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0 - 50% ethyl acetate in petroleum ether solution) to obtain 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] tert-Butyl (3S,4R)-3-hydroxy-4-methylpyrrolidine-1-carboxylate. To a solution of tert-butyl (3R,4S)-3-(bromomethyl)-4-hydroxypyrrolidine-1-carboxylate (600 mg, 2.14 mmol) in DMSO (8 mL) was added sodium borohydride (600 mg, 15.86 mmol) portionwise at 0 °C, and the resulting solution was stirred at 80 °C for 2 hours under nitrogen. Water was added to the resulting mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0 - 50% ethyl acetate in petroleum ether solution) to obtain the title compound (350 mg, 1.74 mmol, 81% yield) as a colorless oil. 11H 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] tert-Butyl (3S,4R)-3-((2-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-4-methylpyrrolidine-1-carboxylate. A mixture of 3-(5-bromo-1-oxoisoindolin-2-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (350 mg, 0.79 mmol), tert-butyl (3S,4R)-3-hydroxy-4-methylpyrrolidine-1-carboxylate (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), quinuclidine (24 mg, 0.22 mmol) and (4,4'-di-t-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-kN)phenyl-kC]iridium(III) hexafluorophosphate (10 mg, 0.01 mmol) in acetonitrile (0.50 mL) / N,N-dimethylacetamide (1.5 mL) was stirred under nitrogen at room temperature for 12 h with 90 W blue LED irradiation. Water was added to the resulting mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0 - 50% ethyl acetate in petroleum ether) to give the title compound (150 mg, 0.27 mmol, 34% yield) as a pale yellow semi-solid. 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. Trifluoromethanesulfonic acid (0.2 mL) was added 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) at 0 °C, and the solution was stirred at 60 °C for 2 hours under nitrogen. The solution was concentrated, sodium bicarbonate was added to the residue to a pH of about 5, and the mixture was filtered. The filtrate was purified by reverse-phase flash (0 - 40% acetonitrile + 0.05% aqueous TFA, over 25 minutes) to give the title compound (120 mg, 0.26 mmol, 74% yield) as an off-white semi-solid. 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. 3-(5-(((3S,4R)-4-Methylpyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; To a solution of 2,2,2-trifluoroacetic acid (120 mg, 0.26 mmol) and 2-methylquinoline-6-carbaldehyde (50 mg, 0.29 mmol) in dichloromethane (5 mL) were 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 in 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 - 20B for 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. 11H NMR (400 MHz, methanol-d4) δ 8.25 (m, 1H), 8.02 - 7.92 (m, 2H), 7.83 (dd, J = 8.7, 2.0 Hz, 1H), 7.72 (dd, J = 8.4, 1.9 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.11 - 7.01 (m, 2H), 5.13 (dd, J = 13.4, 5.1 Hz, 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 = 6.7 Hz, 3H); MS (ESI) m / z 499.1 [M+1] + .

[0259] 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

Chemical Structure

[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 then the mixture was 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, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether solution of 0 - 50% ethyl acetate) to obtain the title compound (450 mg, 1.44 mmol, 40% yield) as a pale 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. Sodium triacetoxyborohydride (386 mg, 1.82 mmol) was added 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) at 0 °C. The reaction mixture was then stirred at room temperature for 3 h under nitrogen. The resulting mixture was concentrated and purified by silica gel column chromatography (petroleum ether solution of 0 - 100% ethyl acetate) to give the title compound (200 mg, 0.32 mmol, 71% yield) as a pale 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. TFA (1 mL) was added 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) 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 product was purified by silica gel column chromatography (dichloromethane solution of 0 - 10% methanol) 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 - 18B for 7 min; 254 / 210 nm; RT1: 5.26. 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. 11H NMR (400 MHz, methanol-d4) δ 8.50 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 2.2 Hz, 1H), 7.07 (dd, J = 8.4, 2.2 Hz, 1H), 7.00 - 6.92 (m, 2H), 6.52 - 6.45 (m, 1H), 5.22 (s, 1H), 5.12 (dd, J = 13.3, 5.2 Hz, 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] - .

[0263] 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

Chemical Structure

[0264] 5,8-Dihydro-6H-pyrano[3,4-b]pyridine-3-carbaldehyde. Manganese dioxide (395 mg, 4.54 mmol) was added 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) at room temperature, and the mixture was stirred at 60 °C for 12 h under nitrogen. 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. Triethylamine (0.05 mL, 0.37 mmol) and sodium triacetoxyborohydride (154 mg, 0.73 mmol) were added 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) at 0 °C, and the mixture was stirred at room temperature for 2 h under nitrogen. The resulting solution was concentrated under reduced pressure at 25 °C. The crude product was purified by silica gel column chromatography (dichloromethane solution with 0 - 10% methanol) 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 - 17B over 10 min; 254 / 210 nm; RT1: 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 semi-solid. 11H NMR (400 MHz, methanol-d4) δ 8.53 (s, 1H), 7.83 - 7.77 (m, 2H), 7.18 (s, 1H), 7.13 (d, J = 8.3 Hz, 1H), 5.36 (s, 1H), 5.15 (dd, J = 13.3, 5.2 Hz, 1H), 4.79 (s, 2H), 4.56 (s, 2H), 4.51 - 4.40 (m, 2H), 4.01 (t, J = 5.6 Hz, 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] + .

[0266] Example S49. 6 - (((3S)-3 - ((2-(2,6 - dioxopiperidin - 3 - yl)-1 - oxoisoindolin - 5 - yl)oxy)pyrrolidin - 1 - yl)methyl)quinazoline - 2 - carbonitrile [Chemical formula] 6 - methylquinazoline - 2 - carbonitrile. To a stirred solution of 2 - chloro - 6 - methyl - quinazoline (160 mg, 0.90 mmol) in NMP (5 mL) were added zinc cyanide (126 mg, 1.07 mmol) and tris(dibenzylideneacetone)dipalladium (65 mg, 0.070 mmol). The above mixture was stirred at 90 °C for 12 h under nitrogen. 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 - 35% ethyl acetate in 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) were added NBS (125 mg, 0.70 mmol) and benzoyl peroxide (15 mg, 0.06 mmol). The above mixture was stirred at 80 °C for 12 h under nitrogen. 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 (petroleum ether solution of 0 - 35% ethyl acetate) 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 5 times and flushed with nitrogen. The mixture was stirred at room temperature for 5 h under nitrogen. The resulting mixture was filtered and the filtrate was concentrated. The residue was purified by reverse phase flash (10 - 100% acetonitrile + 0.05% aqueous TFA, over 25 min) and preparative HPLC (column: SunFire Prep C18 OBD column, 19×150 mm 5μm 10nm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5B - 30B over 7 min; 254 / 210 nm; RT1: 4.97). The fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound t (16 mg, 0.032 mmol, 13% yield) as a white solid. 11H NMR (300 MHz, methanol-d4) δ 9.60 (d, J = 0.9 Hz, 1H), 8.22 (d, J = 9.9 Hz, 2H), 8.12 (d, J = 8.6 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.09 - 7.00 (m, 2H), 5.11 - 5.07 (m, 2H), 4.42 (d, J = 3.9 Hz, 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 / z 497.2 [M+1] + .

[0269] 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

Chem.

[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 overnight to room temperature under ammonia (ca. 2 bar). The crude product was purified by reverse-phase flash (10 - 40% acetonitrile + 0.05% aqueous ammonium bicarbonate solution, over 25 minutes) to give the title compound (350 mg, 1.53 mmol, 70% yield) as a bright 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)quinazolin-4(1H)-one (330 mg, 1.31 mmol) in phosphorus oxychloride (10 mL) was stirred at 100 °C for 3 hours under nitrogen. The reaction mixture was cooled and evaporated under reduced pressure. The residue was diluted with ethyl acetate and 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 - 50% ethyl acetate in 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) were added cesium carbonate (790 mg, 2.43 mmol) and 10% palladium / carbon (100 mg, moistened with ca. 50% water) under nitrogen. The reaction mixture was then stirred for 1 hour at room temperature under hydrogen (ca. 2 bar). 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) were 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 for 12 h under nitrogen. 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 crude product was purified by silica gel chromatography (0 - 50% ethyl acetate in 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) were 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 in 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 - 35B for 7 min, 254 / 210 nm; RT1: 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. 11H NMR (400 MHz, methanol-d4) δ 9.68 (s, 1H), 8.24 - 8.18 (m, 3H), 7.71 (dd, J = 8.6, 1.8 Hz, 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] + .

[0275] Example S51. 3-(5-(((S)-1-((3-(Methoxymethyl)quinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chem.

[0276] 6-Bromo-3-(methoxymethyl)quinoline. To a stirred solution of (6-bromoquinolin-3-yl)methanol (380 mg, 1.60 mmol) in THF (15 mL) was added sodium hydride (60% dispersion in mineral oil, 65 mg, 1.63 mmol) at 0 °C, and the resulting mixture was stirred at room temperature for 30 minutes, then iodomethane (339 mg, 2.39 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. 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 - 40% ethyl acetate in petroleum ether solution) 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-carbaldehyde. 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) was added tert-butyl isocyanide (118 mg, 1.43 mmol). The mixture was stirred at 120 °C for 4 hours under nitrogen. 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 product was purified by silica gel chromatography (0 - 50% ethyl acetate in petroleum ether solution) 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 for 2 h under nitrogen. 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 in 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 - 30B for 7 min, 254 / 210 nm; RT1: 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. 11H NMR (400 MHz, methanol-d4) δ 8.87 (d, J = 2.1 Hz, 1H), 8.31 (m, 2H), 8.08 (d, J = 8.7 Hz, 1H), 8.01 (s, 1H), 7.87 (dd, J = 8.8, 2.0 Hz, 1H), 7.72 (d, J = 8.4 Hz, 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] + .

[0279] Example S52. 3-(((3S)-3-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)pyrrolidin-1-yl)methyl)-N-methylisoquinoline-7-carboxamide

Chemical formula

[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) were successively added sodium hydride (60% dispersion in mineral oil, 70 mg, 1.75 mmol) and tert-butylchlorodiphenylsilane (808 mg, 2.94 mmol) at 0 °C under nitrogen. The reaction mixture was then stirred at room temperature for 12 h. Water was added to the resulting mixture, and the mixture was 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% ethyl acetate in petroleum ether) to give the title compound (450 mg, 0.94 mmol, 64% yield) as a pale 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-isoquinolyl)methoxy-tert-butyl-diphenyl-silane (450 mg, 0.94 mmol) in methanol (15 mL) were added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (77 mg, 0.09 mmol) and triethylamine (0.39 mL, 2.83 mmol). The reaction mixture was then stirred at 120 °C for 12 h under 50 bar of carbon monoxide. The resulting mixture was filtered and concentrated. The crude product was purified by silica gel column chromatography (0 - 20% ethyl acetate in petroleum ether) to give the title compound (380 mg, 0.83 mmol, 88% yield) as a pale 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 (4 mL) in ethanol was stirred at 50 °C for 12 h under nitrogen. The resulting mixture was concentrated, and the crude product was purified by silica gel column chromatography (0 - 35% ethyl acetate in petroleum ether) to give the title compound (360 mg, 0.79 mmol, 94% yield) as a pale 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 the mixture was 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 pale 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 the mixture was stirred at 60 °C for 3 h under nitrogen. The reaction mixture was filtered and concentrated. The crude product was purified by silica gel column chromatography (0 - 40% ethyl acetate in petroleum ether) to give the title compound (35 mg, 0.16 mmol, 25% yield) as a white solid. 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 for 2 h under nitrogen. The resulting mixture was filtered and concentrated at room temperature. The crude product was purified by silica gel chromatography (0 - 10% methanol in dichloromethane) and further purified by preparative HPLC under the following conditions: 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 - 25B over 8 min; 254 / 220 nm; RT1: 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-d4) δ 9.25 (s, 1H), 8.46 (d, J = 1.7 Hz, 1H), 8.08 - 8.06 (m, 1H), 7.92 - 7.84 (m, 2H), 7.61 (dd, J = 8.4, 1.9 Hz, 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] + .

[0286] Example S53. 3-(6-Fluoro-5-(((S)-1-(isoquinolin-3-ylmethyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [Chemical formula] Methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate. To a stirred solution of methyl 4-bromo-5-fluoro-2-methylbenzoate (1.8 g, 7.29 mmol) in carbon tetrachloride (25 mL) were added NBS (930 mg, 8.74 mmol) and 2,2'-azobis(2-methylpropionitrile) (179 mg, 1.09 mmol) at room temperature. The reaction mixture was then stirred at 80 °C for 12 h under nitrogen. The resulting reaction mixture was concentrated. Water was added to the residue, and the mixture was 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 (petroleum ether solution of 0 - 40% ethyl acetate) to give the title compound (2.4 g, 7.36 mmol, 101% yield) containing the starting material as a pale 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 for 3 h under nitrogen. Water was added to the resulting mixture, and the mixture was 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 (petroleum ether solution of 0 - 40% ethyl acetate) 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 for 0.5 h under nitrogen. Water was added to the resulting mixture, and the mixture was 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 - 40% ethyl acetate in petroleum ether) to give the title compound (1.4 g, 2.69 mmol, 57% yield) as a pale 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 dry DMF (20 mL) were added methanesulfonato(2-(di-t-butylphosphino)-3-methoxy-6-methyl-2’,4’,6’-tri-i-propyl-1,1’-biphenyl)(2’-amino-1,1’-biphenyl-2-yl)palladium(II) (67 mg, 0.08 mmol), (E)-benzaldoxime (385 mg, 3.19 mmol), and cesium carbonate (1.73 g, 5.31 mmol) at room temperature. Then, the reaction mixture was stirred at 80 °C for 3 h under nitrogen. Water was added to the resulting mixture, and the mixture was 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 in petroleum ether) to give the title compound (1.02 g, 2.23 mmol, 84% yield) as an orange solid. MS (ESI) m / z 457.1 [M+1] + .

[0290] tert-butyl (S)-3-((2-(2,6-bis(benzyloxy)pyridin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)oxy)pyrrolidine-1-carboxylate. To a solution of 2-(2,6-bis(benzyloxy)pyridin-3-yl)-6-fluoro-5-hydroxyisoindolin-1-one (1 g, 2.19 mmol), tert-butyl (R)-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 for 2 h under nitrogen. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether solution of 0 - 50% ethyl acetate) 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] tert-butyl (3S)-3-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)oxy)pyrrolidine-1-carboxylate. To a solution of tert-butyl (S)-3-((2-(2,6-bis(benzyloxy)pyridin-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)2 / C (1.2 g, 11.28 mmol) under nitrogen. The reaction mixture was then stirred at room temperature for 2 h under hydrogen (ca. 2 bar). 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. TFA (1 mL, 1.05 mmol) was added 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) at room temperature, and the mixture was 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. Sodium triacetoxyborohydride (366 mg, 1.73 mmol) was added 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). The mixture was stirred at room temperature for 2 h under nitrogen. The resulting mixture was concentrated under reduced pressure at 25 °C. The crude product was purified by silica gel column chromatography (dichloromethane solution of 0 - 10% methanol), and further purified by preparative HPLC under the following conditions: 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: 5B - 20B for 10 min; RT1: 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. 11H NMR (400 MHz, methanol-d4) δ 9.30 (s, 1H), 8.38 (s, 1H), 8.13 (d, J = 8.2 Hz, 1H), 7.99 - 7.91 (m, 2H), 7.83 - 7.81 (m, 1H), 7.73 - 7.71 (m, 1H), 7.50 (dd, J = 9.8, 3.1 Hz, 1H), 7.30 (d, J = 7.0 Hz, 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] + .

[0294] Example S54. 3-(5-(((S)-1-((2-Ethynylquinolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chemical Structure

[0295] 2-Chloroquinoline-6-carbaldehyde. Manganese(IV) oxide (341 mg, 3.90 mmol) was added to a stirred solution of (2-chloro-6-quinolyl)methanol (380 mg, 1.96 mmol) in dichloromethane (2 mL) 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-carbaldehyde. Dichlorobis(triphenylphosphine)palladium(II) (64 mg, 0.092 mmol), triethylamine (0.54 mL, 3.9 mmol), and copper(I) iodide (30 mg, 0.16 mmol) were added to a stirred solution of 2-chloroquinoline-6-carbaldehyde (150 mg, 0.78 mmol) and ethynyl(trimethyl)silane (153 mg, 1.6 mmol) in acetonitrile (6 mL) at room temperature. 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 (10 - 40% acetonitrile + 0.05% aqueous ammonium bicarbonate over 20 min) to give the title compound (85 mg, 0.33 mmol, 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), and triethylamine (0.05 mL, 0.37 mmol) in dichloromethane (5 mL) that had been stirred for 15 minutes in advance, sodium triacetoxyborohydride (154 mg, 0.73 mmol) was added at 0 °C, and the solution was stirred at room temperature for 12 hours under nitrogen. The resulting solution was purified directly by reverse-phase flash (10 - 40% acetonitrile + 0.05% aqueous TFA, over 25 minutes) to obtain 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-quinolyl]methyl]pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione (80 mg, 0.14 mmol) in THF (5 mL), tetrabutylammonium fluoride (46 mg, 0.18 mmol) was added at 0 °C. Then, the reaction mixture was stirred at room temperature for 2 hours under nitrogen. The resulting solution was purified by silica gel chromatography (0 - 5% methanol in dichloromethane solution). The pure fractions were evaporated and further purified by reverse-phase semi-preparative HPLC (10 - 30% acetonitrile + 0.05% aqueous TFA, over 30 minutes) to obtain the title compound (3.7 mg, 0.007 mmol, 5% yield) as a bright orange solid. 11H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 8.5 Hz, 1H), 8.00 - 7.86 (m, 2H), 7.79 (m, 1H), 7.61 (t, J = 8.2 Hz, 2H), 7.11 (s, 1H), 7.01 (m, 1H), 5.13 - 4.95 (m, 2H), 4.46 (s, 1H), 4.37 (d, J = 17.2 Hz, 1H), 4.24 (d, J = 17.1 Hz, 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 = 7.6 Hz, 1H); MS (ESI) m / z 495.2 [M+1] + .

[0299] 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 [Chemical Structure] 2-(Prop-1-yn-1-yl)quinazoline-6-carbaldehyde. A solution of a mixture of 2-chloroquinazoline-6-carbaldehyde (90 mg, 0.47 mmol), prop-1-yne (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 with triethylamine (0.41 mL, 2.34 mmol), and the mixture was heated by microwave irradiation at 130 °C for 1 hour in a microwave reactor. Water was added to the resulting mixture, and the mixture was 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 (petroleum ether solution of 0 - 30% ethyl acetate) to obtain 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 for 3 h under nitrogen. 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~26B for 7 min; RT1: 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-d6) δ 9.59 (s, 1H), 8.30 (s, 1H), 8.19 - 8.11 (m, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.18 (s, 1H), 7.08 (d, J = 8.4 Hz, 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] + .

[0301] 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 [Chemical formula] 6-Bromo-2-(4-methyltetrahydro-2H-pyran-4-yl)quinoline. Lithium tert-butoxide (640 mg, 7.92 mmol) was added to a solution of stirred 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) at room temperature. The mixture was then stirred at 110 °C for 12 h under nitrogen. The resulting mixture was filtered and concentrated. The crude product was purified by reverse-phase flash (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-palladium(II) dichloride 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 for 2 h under nitrogen. 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 (petroleum ether solution of 0 - 40% ethyl acetate) 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 for 3 h under nitrogen. Then sodium periodate (591 mg, 2.76 mmol) was added to the reaction mixture and stirred for 1 h. The resulting reaction mixture was adjusted to pH about 7 with saturated aqueous sodium bicarbonate 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 bright 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 for 2 h under nitrogen. The resulting mixture was concentrated under reduced pressure at room temperature. The crude product was purified by silica gel column chromatography (0 - 10% methanol in dichloromethane solution) 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 - 20B for 11 min, 254 / 220 nm; RT1: 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. 11H NMR (400 MHz, methanol-d4) δ 8.28 - 8.21 (m, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.89 (s, 1H), 7.82 - 7.75 (m, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.7 Hz, 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 / z 569.2 [M+1] + .

[0305] 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 [Chemical formula] 6-Bromoquinolin-2-ol. To a stirred solution of 6-bromo-2-chloroquinoline (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 at 120 °C for 12 h under nitrogen. The reaction mixture was concentrated. The residue was purified by reverse-phase flash (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 for 12 h under nitrogen. The solution was then concentrated. Water was added to the residue and the mixture was 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 - 40% ethyl acetate in petroleum ether) to give the title compound (400 mg, 1.19 mmol, 44% yield) as a pale 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) were 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 for 3 h under nitrogen. Water was added to the resulting mixture, and the mixture was 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 (petroleum ether solution of 0 - 25% ethyl acetate). Then, the residue was further purified by Anal-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 (methanol solution of 2M ammonia); flow rate: 150 mL / min; gradient: 30% B; 220 nm; RT1: 3.3; RT2: 3.89; injection volume: 3 mL; number of runs: 10) to obtain the title compound (40 mg, 0.14 mmol, 16% yield) as a pale 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-butanol (4 mL) and water (4 mL) were 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 for 3 hours under nitrogen. Then, sodium periodate (90 mg, 0.42 mmol) was added to the mixture and stirred for an additional 1 hour. A 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. The residue was purified by silica gel chromatography (petroleum ether solution of 0-25% ethyl acetate) to give the title compound (30 mg, 0.10 mmol, 71% yield) as a pale 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. To a solution of 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 (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 at room temperature for 48 h under nitrogen. The resulting mixture was concentrated. The residue was purified by silica gel chromatography (0 - 10% methanol in 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 - 5% B over 2 min, 5% B - 25% B over 10 min, 25% B; wavelength: 254 / 220 nm; RT1 (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. 11H NMR (400 MHz, DMSO-d6) δ 10.96 (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 = 17.2 Hz, 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]+.

[0310] 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

Chem.

[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-butanol (4 mL) and water (4 mL) were 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 for 3 hours under nitrogen. Then, sodium periodate (124 mg, 0.58 mmol) was added to the mixture and stirred for an additional 1 hour. A saturated sodium bicarbonate solution was added to the mixture until pH was about 7, and the mixture was 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 (petroleum ether solution of 0 - 25% ethyl acetate) to obtain the title compound (50 mg, 0.17 mmol, 89% yield) as a pale 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 - 10% methanol in 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 - 10% B over 2 min, 10% B - 30% B over 10 min, 30% B; wavelength: 254 / 220 nm; RT1 (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. 11H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.22 - 8.15 (m, 1H), 7.77 (s, 1H), 7.72 - 7.58 (m, 3H), 7.10 (t, J = 2.2 Hz, 1H), 7.03 - 6.92 (m, 2H), 5.28 (m, 1H), 5.06 - 5.01 (m, 2H), 4.37 (d, J = 17.2 Hz, 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] + .

[0313] 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

Chemical formula

[0314] 3,3-Dimethyl-4-(6-vinylquinazolin-2-yl)morpholine. To a stirred solution of 4-(6-bromoquinazolin-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) were 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 for 3 h under nitrogen. Then, water was added to the mixture, and the mixture was 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 (petroleum ether solution of 0 - 40% ethyl acetate) to give the title compound (80 mg, 0.30 mmol, 81% yield) as a pale yellow oil. MS (ESI) m / z 270.1 [M+1] + .

[0315] 2-(3,3-Dimethylmorpholino)quinazoline-6-carbaldehyde. To a stirred solution of 3,3-dimethyl-4-(6-vinylquinazolin-2-yl)morpholine (80 mg, 0.30 mmol) in tert-butanol (4 mL) and water (4 mL) were 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 for 3 h under nitrogen. Then, sodium periodate (190 mg, 0.89 mmol) was added to the mixture, and the mixture was stirred for an additional 1 h. A saturated sodium bicarbonate solution was added to the mixture until pH was about 7, and the mixture was 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 (petroleum ether solution of 0 - 40% ethyl acetate) to give the title compound (40 mg, 0.15 mmol, 50% yield) as a pale 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 for 12 h under nitrogen. The resulting mixture was concentrated. The residue was purified by silica gel chromatography (0 - 10% methanol in dichloromethane) and 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 - 35B for 7 min, 254 / 220 nm; RT1: 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-d4) δ 9.12 (t, J = 0.8 Hz, 1H), 7.85 - 7.78 (m, 2H), 7.72 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 9.2 Hz, 1H), 7.12 - 7.03 (m, 2H), 5.12 - 5.09 (m, 2H), 4.44 (d, J = 3.5 Hz, 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] + .

[0317] 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 [Chemical formula] 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) were added 3,3-dimethylmorpholine (80 mg, 0.69 mmol), bis(di-tert-butyl)-4-dimethylaminophenylphosphine (11 mg, 0.04 mmol), methanesulfonato{[4-(N,N-dimethylamino)phenyl]di-t-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 under nitrogen at 100 °C for 12 h. The resulting mixture was filtered and the filtrate was concentrated. The crude product was purified by silica gel chromatography (0 - 50% ethyl acetate in 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 THF solution, 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-carbaldehyde. To a stirred solution of [2-(3,3-dimethylmorpholin-4-yl)-6-quinolyl]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 for 2 h under nitrogen. The resulting solution was purified by silica gel chromatography (petroleum ether solution of 0 - 40% ethyl acetate). The 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. 2-(3,3-Dimethylmorpholin-4-yl)quinoline-6-carbaldehyde (50 mg, 0.18 mmol) and 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione, which had been stirred for 15 minutes in advance, were added to a solution of 2,2,2-trifluoroacetic acid (70 mg, 0.16 mmol) and triethylamine (0.05 mL, 0.33 mmol) in dichloromethane (5 mL). Sodium triacetoxyborohydride (154 mg, 0.73 mmol) was added thereto at 0 °C, and the solution was stirred at room temperature for 4 hours under nitrogen. The resulting solution was purified by silica gel chromatography (dichloromethane solution containing 0 to 15% methanol). The 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 for 7 minutes, 254 / 220 nm; rt1: 4.82. The fractions containing the desired product were collected and evaporated under reduced pressure to obtain the title compound (70 mg, 0.12 mmol, 67% yield) as a yellow oil. 11H NMR (300 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.03 (dd, J = 9.1, 1.1 Hz, 1H), 7.70 - 7.51 (m, 4H), 7.26 (d, J = 9.1 Hz, 1H), 7.11 (t, J = 1.9 Hz, 1H), 7.01 (m, 1H), 5.12 - 4.94 (m, 2H), 4.38 (d, J = 17.2 Hz, 1H), 4.25 (m, 1H), 3.86 - 3.67 (m, 4H), 3.50 (t, J = 5.0 Hz, 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] + .

[0321] 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

Chem.

[0322] 1-(3,3-Dimethyltetrahydro-2H-pyran-4-yl)ethan-1-one. To a stirred solution of N-methoxy-N,3,3-trimethyl-tetrahydro-4-pyran carboxamide (600 mg, 2.96 mmol) in THF (20 mL) was added methylmagnesium bromide (1.5 M solution in diethyl ether, 2 mL, 3 mmol) dropwise at 0 °C, and the mixture was stirred under nitrogen at room temperature for 2 h. Saturated ammonium chloride was added to the reaction mixture, and the mixture was 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) were added (2-amino-5-bromo-phenyl)methanol (773 mg, 3.83 mmol) and lithium tert-butoxide (616 mg, 7.7 mmol) at room temperature. The reaction mixture was then stirred at 100 °C for 12 h under nitrogen. The mixture was filtered and the filtrate was concentrated. The residue was purified by reverse phase flash (30 - 80% acetonitrile + 0.05% aqueous ammonium bicarbonate, 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) were 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 for 4 h under nitrogen. 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 - 30% ethyl acetate in petroleum ether) to give the title compound (160 mg, 0.60 mmol, 54% yield) as a bright 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 for 7.5 min; wavelength: 220 / 254 nm; RT1 (min): 4.76; RT2 (min): 5.80; sample solvent: ethanol--HPLC; injection volume: 0.5 mL; number of runs: 13. The fraction containing the desired product was 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 for 3 h under nitrogen. Then, sodium periodate (75 mg, 0.35 mmol) was added to the above mixture. The resulting mixture was stirred at room temperature for 1 h under nitrogen. Saturated sodium bicarbonate was added to the mixture to pH about 7 and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% ethyl acetate in petroleum ether solution) 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. 2-[(4S)-3,3-Dimethyltetrahydropyran-4-yl]quinoline-6-carbaldehyde (25 mg, 0.092 mmol), which had been stirred for 15 minutes in advance, 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) solution, sodium triacetoxyborohydride (94 mg, 0.44 mmol) was added at 0 °C, and the solution was stirred at room temperature for 4 hours under nitrogen. The resulting solution was purified by silica gel chromatography (0 - 5% methanol in dichloromethane solution). 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 - 27% B over 7 minutes, then 27% B; Wavelength: 254 / 220 nm; RT1 (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. 11H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 8.6 Hz, 1H), 8.21-8.07 (m, 2H), 7.93 (m, 1H), 7.64 (m, 2H), 7.18 (s, 1H), 7.08 (d, J = 8.4 Hz, 1H), 5.28 (s, 1H), 5.04 (m, 1H), 4.65 (s, 2H), 4.40 (m, 1H), 4.27 (d, J = 17.4 Hz, 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] + .

[0328] Example S62. 3-(5-(((S)-1-((2-Methoxyquinazolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [Chemical Structure Diagram] 6-Bromo-2-methoxyquinazoline. Sodium methoxide (30% methanol solution, 2 mL) was added to a stirred solution of 6-bromo-2-chloroquinazoline (500 mg, 2.05 mmol) in methanol (6 mL). The above mixture was stirred at 70 °C for 12 h under nitrogen. Water was added to the resulting mixture, and the mixture was 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) were 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 for 3 h under nitrogen. Water was added to the resulting mixture, and the mixture was 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 - 40% ethyl acetate in petroleum ether solution) to give the title compound (180 mg, 0.96 mmol, 57% yield) as a pale yellow oil. MS (ESI) m / z 187.0 [M+1] + .

[0330] 2-Methoxyquinazoline-6-carbaldehyde. To a stirred solution of 2-methoxy-6-vinyl-quinazoline (100 mg, 0.54 mmol) in tert-butanol (4 mL) and water (4 mL) were 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 for 3 h under nitrogen. Then, sodium periodate (345 mg, 1.61 mmol) was added to the mixture, and the mixture was stirred for an additional 1 h. The reaction mixture was concentrated, and the residue was purified by reverse-phase flash (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 stirred solution of 2-methoxyquinazolin-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 - 10% methanol in 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 - 35B over 7 min; RT1: 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-d4) δ 9.33 (d, J = 0.7 Hz, 1H), 8.06 - 7.97 (m, 2H), 7.84 (d, J = 8.6 Hz, 1H), 7.71 (d, J = 8.4 Hz, 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 / z 502.2 [M+1] + .

[0332] 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 [Chemical formula] (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 for 7.5 minutes; wavelength: 220 / 254 nm; RT1 (min): 4.76; RT2 (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 for 3 h under nitrogen. Then, sodium periodate (75 mg, 0.35 mmol) was added to the above mixture. The resulting mixture was stirred at room temperature for 1 h under nitrogen. Saturated sodium bicarbonate was added to the mixture until pH was about 7, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% ethyl acetate in 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. (R)-2-(3,3-Dimethyltetrahydro-2H-pyran-4-yl)quinoline-6-carbaldehyde (25 mg, 0.090 mmol) and 3-[1-oxo-5-[(3S)-pyrrolidin-3-yl]oxy-isoindolin-2-yl]piperidine-2,6-dione, which had been stirred for 15 minutes beforehand, were added to a solution of 2,2,2-trifluoroacetic acid (56 mg, 0.13 mmol) and triethylamine (20 mg, 0.2 mmol) in dichloromethane (5 mL). Sodium triacetoxyborohydride (94 mg, 0.44 mmol) was added thereto at 0 °C, and the solution was stirred at room temperature for 4 hours under nitrogen. The resulting solution was purified by silica gel chromatography (dichloromethane solution containing 0 - 5% methanol). The pure fractions were evaporated 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% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 2% B - 27% B over 7 minutes, wavelength: 254 / 220 nm; RT1 (min): 6.98. The fractions containing the desired product were collected and evaporated under reduced pressure to obtain the title compound (34.9 mg, 0.060 mmol, 67% yield) as a white solid. 11H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 8.5 Hz, 1H), 8.18 8.07 (m, 2H), 7.92 (m, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.19 (s, 1H), 7.08 (d, J = 8.2 Hz, 1H), 5.28 (s, 1H), 5.04 (m, 1H), 4.65 (s, 2H), 4.40 (m, 1H), 4.28 (d, J = 17.4 Hz, 1H), 4.08 - 4.01 (m, 1H), 3.60 - 3.40 (m, 7H), 3.25 (d, J = 11.1 Hz, 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]+.

[0335] 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

Chemical Structure

[0336] 2-((1R,3R)-3-Methoxycyclopentyl)quinoline-6-carbaldehyde. Manganese dioxide (203 mg, 2.33 mmol) was added to a stirred solution of (2-((1R,3R)-3-methoxycyclopentyl)quinolin-6-yl)methanol (60 mg, 0.23 mmol) in dichloromethane (3 mL) at room temperature. The reaction mixture was then stirred at 50 °C for 12 hours under nitrogen. The resulting mixture was filtered and concentrated under reduced pressure to obtain the title compound (60 mg, 0.23 mmol, 100% yield) as a pale 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. Sodium triacetoxyborohydride (192 mg, 0.91 mmol) was added 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). The mixture was stirred at room temperature for 2 hours under nitrogen. The resulting solution was concentrated. The residue was purified by silica gel column chromatography (0 - 10% methanol in dichloromethane) and further 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 - 30% B over 7 minutes, then 30% B; Wavelength: 254 / 220 nm; RT1 (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. 11H NMR (400 MHz, methanol-d4) δ 8.34 - 8.22 (m, 1H), 8.03 (d, J = 8.7 Hz, 1H), 7.93 (s, 1H), 7.82 (dd, J = 8.6, 1.9 Hz, 1H), 7.72 (dd, J = 8.4, 1.2 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.13 - 7.02 (m, 2H), 5.13 (dd, J = 13.6, 5.4 Hz, 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] + .

[0338] 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 [Chemical Structure] (2-((1S,3S)-3-Methoxycyclopentyl)quinolin-6-yl)methanol. The product of (2-(3-methoxycyclopentyl)quinolin-6-yl)methanol (460 mg, 1.79 mmol) 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 over 14 minutes; 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 (4th peak, 40 mg, 0.15 mmol, 8% yield). MS (ESI) m / z 258.2 [M+1] + .

[0339] 2-((1S,3S)-3-Methoxycyclopentyl)quinoline-6-carbaldehyde. Manganese dioxide (135 mg, 1.55 mmol) was added to a stirred solution of (2-((1S,3S)-3-methoxycyclopentyl)quinolin-6-yl)methanol (40 mg, 0.15 mmol) in dichloromethane (3 mL) at room temperature. The reaction mixture was then stirred at 50 °C for 12 hours under nitrogen. 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 pale 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. Sodium triacetoxyborohydride (134 mg, 0.63 mmol) was added 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). The mixture was stirred at room temperature for 2 h under nitrogen. The resulting solution was concentrated. The residue was purified by silica gel column chromatography (0 - 10% methanol in dichloromethane) and further 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 - 30% B over 7 min, then 30% B; wavelength: 254 / 220 nm; RT1 (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. 11H NMR (400 MHz, methanol-d4) δ 8.34 - 8.22 (m, 1H), 8.03 (d, J = 8.7 Hz, 1H), 7.93 (s, 1H), 7.82 (dd, J = 8.6, 1.9 Hz, 1H), 7.72 (dd, J = 8.4, 1.2 Hz, 1H), 7.62 (d, J = 8.5 Hz, 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] + .

[0341] 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 [Chemical formula] (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. Manganese dioxide (421 mg, 4.84 mmol) was added to a stirred solution of (130 mg, 0.51 mmol) in dichloromethane (10 mL), and the mixture was stirred at 50 °C for 5 h under nitrogen. 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. Sodium triacetoxyborohydride (160 mg, 0.75 mmol) was added portionwise to a stirred solution 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), and the mixture was stirred at room temperature for 2 h under nitrogen. The resulting mixture was concentrated. The residue was purified by silica gel chromatography (0 - 10% methanol in dichloromethane) 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% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B - 20% B over 7 min to 20% B; wavelength: 254 / 210 nm; RT1 (min): 4.92; the fractions containing the desired product were collected and evaporated under reduced pressure to give the title compound (32 mg, 0.056 mmol, 28% yield) as a white solid. 11H NMR (400 MHz, methanol-d4) δ 8.26 (m, 1H), 8.01 - 8.03 (d, J = 8.6 Hz, 1H), 7.89 (s, 1H), 7.80 (m, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.6 Hz, 1H), 7.11 - 7.02 (m, 2H), 5.14 - 5.12 (m, 2H), 4.51 - 4.36 (m, 2H), 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] + .

[0344] 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

Chemical formula

[0345] Methyl 2-(1,4-dioxaspiro[4.5]decane-8-yl)quinoline-6-carboxylate. To a stirred solution of methyl 2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)quinoline-6-carboxylate (1.8 g, 5.53 mmol) in methanol (30 mL) was added palladium 10% / carbon (360 mg, moistened with ca. 55% water) at room temperature, and the resulting mixture was stirred at room temperature for 2 h under hydrogen (ca. 2 bar). 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] Methyl 2-(4-oxocyclohexyl)quinoline-6-carboxylate. To a stirred solution of methyl 2-(1,4-dioxaspiro[4.5]decane-8-yl)quinoline-6-carboxylate (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 at room temperature for 3 hours under nitrogen. The mixture was concentrated. Saturated sodium bicarbonate was added to the residue to a pH of about 7, and the mixture was 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 (petroleum ether solution of 0 - 30% ethyl acetate) 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 (1N THF solution, 4 mL, 4 mmol) at 0 °C, and the resulting solution was stirred at this temperature for 0.5 hour under nitrogen. 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 for 5 h under nitrogen. 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. A solution of sodium triacetoxyborohydride (160 mg, 0.75 mmol) was added portionwise to a stirred solution 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). The mixture was stirred under nitrogen at room temperature for 2 h. The resulting mixture was concentrated. The residue was purified by silica gel chromatography (0 - 10% methanol in dichloromethane) and further by 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 - 17% B over 9 min to 17% B; wavelength: 254 / 210 nm; RT1 (min): 8.72] to give the title compound (35 mg, 0.061 mmol, 31% yield) as a white solid. 1 H NMR (400 MHz, methanol-d4) δ 8.26 (m, 1H), 8.01 - 8.03 (d, J = 8.6 Hz, 1H), 7.89 (s, 1H), 7.80 - 7.82 (m, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.6 Hz, 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] + .

[0351] 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 [Chemical formula] 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 minutes. Then, iodomethane (267 mg, 1.88 mmol) was added, and the mixture was stirred at 0 °C for 1 hour. 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 (10 - 70% acetonitrile + 0.05% aqueous ammonium bicarbonate solution, over 20 minutes) to give the title compound (200 mg, 0.85 mmol, 89% yield) as a white solid. 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) and potassium vinyltrifluoroborate (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 for 5 h under nitrogen. 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 (10 - 70% acetonitrile + 0.05% aqueous ammonium bicarbonate solution, over 20 min) to give the title compound (110 mg, 0.48 mmol, 57% yield) as a white solid. 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 for 4 h under nitrogen. Then, sodium periodate (310 mg, 1.45 mmol) was added portionwise to the above mixture at 0 °C in several portions, and the resulting mixture was stirred at room temperature for 1 h. Saturated sodium bicarbonate solution was added to the mixture until pH was about 7, and the mixture was 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. Sodium triacetoxyborohydride (140 mg, 0.66 mmol) was added portionwise to a solution of stirred 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), and the mixture was stirred under nitrogen at room temperature for 3 h. The mixture was concentrated and the residue was first purified by silica gel chromatography (0 - 10% methanol in dichloromethane) and further purified by silica gel 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: 10% B - 28% B over 10 min to 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. 11H NMR (400 MHz, methanol-d4) δ 9.37 (s, 1H), 8.16 (s, 1H), 7.99 (s, 2H), 7.94 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.20 (m, 1H), 7.14 (d, J = 8.2 Hz, 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] + .

[0355] 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

Chemical Structure

[0356] 2-(3-Chloroisoquinolin-7-yl)propan-2-ol. To a stirred 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 THF solution, 18 mL, 18 mmol) dropwise at 0 °C. The mixture was stirred at room temperature under nitrogen for 3 h. Water was added to the resulting mixture, and the mixture was extracted with ethyl acetate. The extract was washed with sodium carbonate and 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 stirred solution of 2-(3-chloroisoquinolin-7-yl)propan-2-ol (600 mg, 2.71 mmol) and potassium vinyltrifluoroborate (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. Water was added to the resulting mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The re...

Claims

1. Formula (I) 【Chemical 1】 〔wherein, A is C which is directly bonded or optionally substituted １－５ and is alkyl; B is C which is optionally substituted ３－１０ cycloalkyl, optionally substituted 3- to 14-membered heterocyclyl, optionally substituted C ６－１４ selected from aryl and optionally substituted 5- to 14-membered heteroaryl; W １ and W ２ are each independently selected from H and CH ３ or together form an oxo group; W ３ and W ４ each is H or together they form an oxo group; V is selected from H and CH ３ and is selected from; R’ is a halogen atom; R’’ is a halogen atom, C １－５ alkyl which may be optionally substituted and C １－５ alkoxy which may be optionally substituted, or two R’’s together with the carbon to which they are attached can form an oxo group; R''' is a halogen atom, -CN, -OH, amino optionally substituted, amide optionally substituted, C １－５ alkyl optionally substituted, C １－５ alkoxy optionally substituted, C ３－６ cycloalkyloxy optionally substituted, 5- to 10-membered heterocyclyloxy optionally substituted, 5- to 10-membered heteroaryloxy optionally substituted, C ３－６ cycloalkyl optionally substituted, 3- to 10-membered heterocyclyl optionally substituted, 5- to 10-membered aryl optionally substituted and 5- to 10-membered heteroaryl optionally substituted, selected from; 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 W １ and W ２ or W ３ and W ４ At least one of them combines to form an oxo group. the compound or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

2. The compound according to claim 1, wherein the compound is of formula (Ia) 【Chemical 2】

3.

4. W ３ and W ４ The compound according to claim 1 or 2, wherein W and W are integrated to form an oxo group. The compound according to any one of claims 1 to 3, wherein A is a direct bond.

5.

6. C in which A is optionally replaced １－３ The compound according to any one of claims 1 to 3, which is alkyl.

7. A is -CH ２ The compound of claim 5, wherein A is - The compound according to any one of claims 1 to 6, wherein B is monocyclic.

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

9.

10. C in which B is optionally replaced ６－１４ A compound according to any one of claims 1 to 8, selected from aryl and optionally substituted 5- to 14-membered heteroaryl.

11. C in which B is optionally replaced ３－１０ A compound according to any one of claims 1 to 8, selected from cycloalkyl and optionally substituted 3- to 14-membered heterocyclyl.

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

13. W １ and W ２ A compound according to any one of claims 1 to 10, wherein W and W are integrated to form an oxo group. 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.

16. R’’ is F, Cl, C alkyl optionally substituted, and C alkoxy optionally substituted １－３ alkyl selected from, and any compound of claims 1 to 14 １－３ optionally substituted alkoxy

17. R''' is selected from F, Cl, -CN, -OH, amino optionally substituted, C １－３ alkyl optionally substituted, C １－３ alkoxy optionally substituted, C ３－６ cycloalkyl, 3- to 10-membered heterocyclyl optionally substituted, and 5- to 10-membered heteroaryl optionally substituted, a compound according to any one of claims 1 to 15. The compound according to any one of claims 1 to 16, wherein l is 0 or 1.

18. The 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 is of formula (II): 〔wherein, 【Chemical Formula 3】 R’ is a halogen atom; C directly bonded or optionally substituted by A １－５ is alkyl; l is an integer from 0 to 2; and R'' is a halogen atom, optionally substituted C １－５ alkyl and optionally substituted C １－５ alkoxy, or two R''s together can form an oxo group with the carbon to which they are attached; Z, Z', and Z'' are each independently N and CR １ selected from; X, Y, X' and Y' are each independently selected from N and CR ２ ; and Each R １ is independently selected from H, a halogen atom, -CN, C １－５ alkyl optionally substituted, C １－５ alkoxy, 5- to 10-membered heteroaryloxy optionally substituted, C ３－６ cycloalkyl and 3- to 6-membered heterocyclyl optionally substituted; Each R ２ is independently selected from H, a halogen atom, -CN, -OH, oxo, amino optionally substituted, amide optionally substituted, C １－５ alkyl optionally substituted, C ３－６ cycloalkyl optionally substituted, 3- to 10-membered heterocyclyl optionally substituted, and 5- to 10-membered heteroaryl optionally substituted; m is an integer from 0 to 2.〕 The compound according to any one of claims 1 to 3.

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

24.

25. C in which A is optionally replaced １－３ The compound of claim 22, wherein is alkyl.

26. A is -CH ２ The compound of claim 24, wherein A is - The compound according to any one of claims 22 to 25, wherein R’ is selected from F and Cl.

27.

28. R’’ is F, Cl, C alkyl optionally substituted, and C alkoxy optionally substituted １－３ alkyl optionally substituted, and C １－３ The compound according to any one of claims 22 to 26, selected from alkoxy

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

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

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

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

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

34. Each R １ is independently selected from H, F, Cl, -CN, C １－３ alkyl optionally substituted, C １－３ alkoxy optionally substituted, C ３－６ cycloalkyl and 3- to 6-membered heterocyclyl optionally substituted, a compound according to any one of claims 22 to 32.

35. Each R ２ independently represents H, F, Cl, -CN, -OH, oxo, amino optionally substituted, amide optionally substituted, C １－３ alkyl optionally substituted, C ３－６ cycloalkyl and a 4- to 8-membered heterocyclyl optionally substituted, a compound according to any one of claims 22 to 32. The compound according to any one of claims 22 to 34, wherein l is 0 or 1.

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

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

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

39. The compound is of formula (IIa): 〔wherein, 【Chemical Formula 4】 R’ is a halogen atom; C which is directly bonded or optionally substituted by A １－５ is alkyl; l is an integer from 0 to 1; and R'' is a halogen atom, optionally substituted C １－５ alkyl and optionally substituted C １－５ alkoxy, or two R''s together with the carbon to which they are attached can form an oxo group; Z is N and CR ３ selected from; X, X' and Y' are each independently N and CR ４ selected from; R １ and R ３ are each independently selected from H, a halogen atom, -CN, optionally substituted C １－５ alkyl, optionally substituted C １－５ alkoxy, optionally substituted 5- to 10-membered heteroaryl-oxy, optionally substituted C ３－６ cycloalkyl and optionally substituted 3- to 6-membered heterocyclyl; R ２ and R ４ are each independently selected from H, a halogen atom, -CN, -OH, oxo, amino optionally substituted, amide optionally substituted, C １－５ alkyl optionally substituted, C ３－６ cycloalkyl optionally substituted, 3- to 10-membered heterocyclyl optionally substituted, and 5- to 10-membered heteroaryl optionally substituted; m is an integer from 0 to 1.〕 The compound according to claim 22.

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

41.

42. C in which A is optionally replaced １－３ The compound of claim 39, wherein it is alkyl. ​ A is -CH ２ The compound of claim 41, wherein A is -

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

44. R’’ is F, Cl, C alkyl optionally substituted, and C alkoxy optionally substituted １－３ alkyl optionally substituted, and C １－３ The compound according to any one of claims 39 to 43, which is selected from alkoxy

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

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

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

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

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

50. R １ and R ３ each independently is 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- to 6-membered heterocyclyl, a compound according to any one of claims 39 to 49.

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

52. R ３ A compound according to any one of claims 39 to 51, wherein R is H.

53. R ２ and R ４ each independently is H, F, Cl, -CN, -OH, oxo, amino optionally substituted, amide optionally substituted, C １－３ alkyl optionally substituted, C ３－６ cycloalkyl optionally substituted, 3- to 10-membered heterocyclyl optionally substituted, and 5- to 10-membered heteroaryl optionally substituted, a compound according to any one of claims 39 to 52.

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

55. R ４ A compound according to any one of claims 39 to 54, wherein R is H.

56. 【Fig. 5】 is 【Chemical Formula 6】 A compound according to any one of claims 39 to 55.

57. R ２ is 【Chemical Formula 7】 A compound according to any one of claims 39 to 56.

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. The compound is of formula (III): 【Chemical 8】 〔wherein, C to which A is directly bonded or optionally substituted １－５ is alkyl; R' is a halogen atom; R'' is a halogen atom, optionally substituted C １－５ alkyl and optionally substituted C １－５ alkoxy, or two R''s together with the carbon to which they are attached can form an oxo group; Z is N, CH, and CR ３ selected from; Each R ３ is independently -CN, C optionally substituted １－５ alkyl, C optionally substituted ３～６ member cycloalkyl, 3-6 member heterocyclyl optionally substituted, 5-10 member aryl optionally substituted and 5-10 member heteroaryl optionally substituted, selected from; 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.〕 A compound according to any one of claims 1 to 3.

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

62. C in which A is optionally replaced １－３ The compound of claim 60, which is alkyl.

63. A is -CH ２ The compound of claim 62, wherein it is

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

65. R’’ is F, Cl, C alkyl optionally substituted, and C alkoxy optionally substituted １－３ selected from the group consisting of: alkyl optionally substituted, and C alkoxy optionally substituted １－３ A compound according to any one of claims 60 to 64, wherein R’’ is selected from F, Cl, optionally substituted C alkyl, and optionally substituted C 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. Each R ３ is independently -CN, C optionally substituted, １－３ alkyl, optionally substituted 3- to 6-membered heterocyclyl and optionally substituted 5- to 10-membered heteroaryl, a compound according to any one of claims 60 to 67.

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. The compound is of formula (IIIa) or (IIIb): 【Chemical Formula 9】 【Chemical 10】 〔wherein, C which is directly bonded or optionally substituted by A １－５ is alkyl; R' is a halogen atom; R″ is a halogen atom, C-alkyl optionally substituted, and C-alkoxy optionally substituted, or two R″'s together with the carbon to which they are attached can form an oxo group; １－５ selected from, or two R″'s together with the carbon to which they are attached can form an oxo group; １－５ selected from, or two R″'s together with the carbon to which they are attached can form an oxo group; R ４ is a 3- to 6-membered heterocyclyl optionally substituted as desired; l is 0 or 1; m is 0 or 1; and q is 0 or 2.〕 A compound according to claim 60.

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

77. C in which A is optionally replaced １－３ The compound of claim 75, wherein it is alkyl.

78. A is -CH ２ The compound of claim 77, wherein A is -

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

80. R’’ is F, Cl, C alkyl optionally substituted, and C alkoxy optionally substituted １－３ alkyl, and any compound of claims 75 to 79 selected from C alkoxy optionally substituted １－３ ​

81. R ４ A compound according to any one of claims 75 to 80, wherein R is a 6-membered heterocyclyl optionally substituted as desired.

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 the following: - 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-morpholinokynazolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; - 3-(5-(((S)-1-((2-morpholinquinolin-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)kynazolin-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)kynazolin-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-morpholinokynazolin-6-yl)methyl)pyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; - (S)-3-(5-(((S)-1-((2-morpholinokynolin-6-yl)methyl)oxypyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; - (S)-3-(1-oxo-5-(((S)-1-((2-(tetrahydro-2H-pyran-4-yl)kynazolin-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)oxypyrrolidin-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, isotopologue or stereoisomer thereof.

86. A compound selected from the compounds in Table 2 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

87. A method for reducing the WEE1 kinase protein level, 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, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 86 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

90. The method of claim 89, wherein the cancer is selected from the group consisting of stomach, lung, pancreas, ovary, breast, skin, colon, neuroblastoma, osteosarcoma, uterus, rectum, and kidney.

91. The method of claim 90, wherein the cancer is selected from the group consisting of 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 sarcoma, melanoma, colon, and clear cell renal cell carcinoma (ccRCC).

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

93. Use of a compound of any one of claims 1 to 86 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof in the manufacture of a medicament for the prevention or treatment of cancer.

94. The use of claim 93, wherein the cancer is selected from the group consisting of stomach, lung, pancreas, ovary, breast, skin, colon, neuroblastoma, osteosarcoma, uterus, rectum, and kidney.

95. The use of claim 94, wherein the cancer is selected from the group consisting of 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 sarcoma, melanoma, colon, and clear cell renal cell carcinoma (ccRCC).

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