Indole compounds that degrade IKZF2 and uses thereof

Abstract

The present invention relates to an indole compound derivative that degrades IKZF2 and its uses. Specifically, the compound of Chemical Formula 1 provides an agent having a novel mechanism of action against the IKZF2 protein, and is useful for treating diseases and disorders associated with the IKZF2 protein, and is particularly useful for preventing or treating cancer.

Description

[Technical Field]

[0001] The present invention relates to an indole compound derivative that degrades IKZF2 and uses thereof, and more particularly to an indole derivative compound that degrades IKZF2 and exhibits the effect of preventing or treating cancer. [Background technology]

[0002] Regulatory T cells (Treg) are a type of CD4+ T cell that suppress excessive immune responses, maintaining immune self-tolerance and immune system homeostasis. However, Treg cells exposed to cancer also suppress anti-cancer immune responses by suppressing the activity of tumor-specific effector T (Teff) cells and increasing the expression of immunosuppressive receptors such as PD-1 (Padmanee Sharma et al., 2017 & Hiroyoshi Nishikawa et al., 2014). IKZF2 (Helio), a zinc finger transcription factor belonging to the Ikaros family, is primarily expressed in Tregs and lymphocytes and regulates lymphocyte development (Kaitlin A et al., 2021 & Qi Cai et al., 2009 & Angela M et al., 2010). In a syngeneic murine model, loss of IKZF2 induces Treg cell destabilization and promotes the secretion of pro-inflammatory cytokines, enhancing anti-cancer immune responses (Hye-Jung Kim et al., 2015 & Giuliana P Mognol et al., 2017). Furthermore, chronic T cell hyperactivation and hypersecretion of pro-inflammatory cytokines in Treg and Teff cells have been reported in humans with IKZF2 mutations (Iivo Hetemaki et al., 2021 & Tala Shahin et al., 2022). Furthermore, a recent study reported that drugs that degrade IKZF2 induce the destabilization of Treg cells, converting them into Teff cells and promoting the secretion of inflammatory cytokines such as IFNγ, and inhibit the growth of solid tumors when administered to an immune-humanized murine model (Eric S Wang et al., 2021 & Jonathan Solomon et al., 2022). Therefore, degradation of IKZF2 in T cells, including Tregs, induces anti-cancer immune responses, and because it acts through a different mechanism than existing PD-1 / PD-L1 inhibitors, synergistic effects can be expected when used in combination.

[0003] Patent Document 1: International Publication No. WO2019-038717 and Patent Document 2: International Publication No. WO2021-260528 provide methods for producing and uses of compounds of formula I' for treating IKAROS family zinc finger 2 (IKZF2)-dependent diseases or disorders, or when reducing IKZF2 or IKZF4 protein levels can ameliorate the disease or disorder.

[0004] [ka]

[0005] Patent Document 1: In [Chemical Formula I'] of International Patent Publication WO2019-038717, X1 is CH, and R2 is (C1-C6) alkyl, —C(O)(C1-C6) alkyl, —C(O)(CH2) 0-3 (C6-C 10 ) aryl, -C(O)O(CH2) 0-3 (C6-C 10 ) aryl, (C6-C 10 )aryl, a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, (C3-C8)cycloalkyl, or a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one or more R5; aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are limited to being optionally substituted with one or more R5, except that R2 is -C(O)(C6-C 10 ) Heteroaryl -C(O) indole substituted compounds are not directly disclosed.

[0006] The present inventors have found that, compared to the compounds developed in the existing prior art, R2 in Chemical Formula 1 of the present invention is -C(O)(C6-C 10 ) It has been confirmed that compounds in which the heteroaryl -C(O) indole is substituted exhibit excellent physiological activity against cancer cells, leading to the completion of the present invention. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Patent Publication No. WO2019-038717 [Patent Document 2] International Patent Publication No. WO2021-260528 [Non-patent literature]

[0008] [Non-Patent Document 1] Padmanee Sharma et al,2017 & Hiroyoshi Nishikawa et al,2014 [Non-patent document 2] Kaitlin A et al,2021 & Qi Cai et al,2009 & Angela M et al,2010 [Non-patent document 3] Hye-Jung Kim et al,2015 & Giuliana P Mognol et al,2017 [Non-patent document 4] Iivo Hetemaki et al,2021 & Tala Shahin et al,2022 [Non-patent document 5] Eric S Wang et al,2021 & Jonathan Solomon et al,2022 Summary of the Invention [Problem to be solved by the invention]

[0009] The present inventors developed indole derivative compounds that degrade IKZF2 and exhibit cancer preventive or therapeutic effects, evaluated their activity, and completed the present invention.

[0010] Therefore, an object of the present invention is to provide a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof: [Means for solving the problem]

[0011] The present invention relates to a compound represented by the following Chemical Formula 1, a stereoisomer thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[0012] [ka]

[0013] During the ceremony,

[0014] X is independently C, CH, N, or NR3:

[0015] Y is —CH— or —C(O)—;

[0016] R1 is hydrogen or C 1-5 substituted with alkyl;

[0017] TIFF2026508123000004.tif20166

[0018] TIFF2026508123000005.tif26166

[0019] R4 is independently substituted with hydrogen, halogen, or hydroxy;

[0020] TIFF2026508123000006.tif39166

[0021] R5 is substituted with hydrogen, deuterium, halogen, or hydroxy;

[0022] R6 is substituted with hydrogen or deuterium;

[0023] TIFF2026508123000007.tif20166

[0024] m is an integer from 1 to 3;

[0025] n is independently an integer of 0 or 1;

[0026] The present invention relates to a compound, a stereoisomer thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein the above Chemical Formula 1 is represented by the following Chemical Formula 2:

[0027] [ka]

[0028] During the ceremony,

[0029] X is independently C, CH, N, or NR3;

[0030] Y is —CH— or —C(O)—;

[0031] R1 is hydrogen or C 1-5 substituted with alkyl;

[0032] TIFF2026508123000009.tif26166

[0033] TIFF2026508123000010.tif32166

[0034] R4 is independently substituted with hydrogen, halogen, or hydroxy;

[0035] R5 is substituted with hydrogen, deuterium, halogen, or hydroxy;

[0036] R6 is substituted with hydrogen or deuterium;

[0037] TIFF2026508123000011.tif20166

[0038] m is an integer from 1 to 3;

[0039] n is independently an integer of 0 or 1;

[0040] The present invention relates to a compound, a stereoisomer thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein the above Chemical Formula 1 is represented by the following Chemical Formula 3:

[0041] [ka]

[0042] During the ceremony,

[0043] X is independently C, CH, N, or NR3;

[0044] Y is —CH— or —C(O)—;

[0045] R1 is hydrogen or C 1-5 substituted with alkyl;

[0046] TIFF2026508123000013.tif26166

[0047] TIFF2026508123000014.tif32166

[0048] R4 is independently substituted with hydrogen, halogen, or hydroxy;

[0049] R5 is substituted with hydrogen, deuterium, halogen, or hydroxy;

[0050] R6 is substituted with hydrogen or deuterium;

[0051] TIFF2026508123000015.tif13166

[0052] m is an integer from 1 to 3;

[0053] n is independently an integer of 0 or 1;

[0054] The present invention relates to a compound, a stereoisomer thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein the above Chemical Formula 1 is represented by the following Chemical Formula 4:

[0055] [ka]

[0056] During the ceremony,

[0057] X is independently C, CH, N, or NR3;

[0058] Y is —CH— or —C(O)—;

[0059] R1 is hydrogen or C 1-5 substituted with alkyl;

[0060] TIFF2026508123000017.tif26166

[0061] TIFF2026508123000018.tif32166

[0062] R4 is independently substituted with hydrogen, halogen, or hydroxy;

[0063] R6 is substituted with hydrogen or deuterium;

[0064] TIFF2026508123000019.tif20166

[0065] m is an integer from 1 to 3;

[0066] n is independently an integer of 0 or 1;

[0067] The present invention relates to a compound, a stereoisomer thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein the above Chemical Formula 1 is represented by the following Chemical Formula 5:

[0068] [ka]

[0069] During the ceremony,

[0070] X is independently C, CH, N, or NR3;

[0071] Y is —CH— or —C(O)—;

[0072] R1 is hydrogen or C 1-5 substituted with alkyl;

[0073] TIFF2026508123000021.tif26166

[0074] TIFF2026508123000022.tif32166

[0075] R4 is independently substituted with hydrogen, halogen, or hydroxy;

[0076] R6 is substituted with hydrogen or deuterium;

[0077] TIFF2026508123000023.tif13166

[0078] m is an integer from 1 to 3;

[0079] n is independently an integer of 0 or 1;

[0080] The present invention relates to a compound, a stereoisomer thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein the above Chemical Formula 1 is represented by the following Chemical Formula 6:

[0081] [ka]

[0082] During the ceremony,

[0083] X is independently CH, N, or NR3;

[0084] Y is —CH— or —C(O)—;

[0085] R1 is hydrogen or C 1-5 substituted with alkyl;

[0086] TIFF2026508123000025.tif26166

[0087] TIFF2026508123000026.tif32166

[0088] R4 is independently substituted with hydrogen, halogen, or hydroxy;

[0089] TIFF2026508123000027.tif45166

[0090] R5 is substituted with hydrogen, deuterium, halogen, or hydroxy;

[0091] R6 is substituted with hydrogen or deuterium;

[0092] TIFF2026508123000028.tif20166

[0093] m is an integer from 1 to 3;

[0094] n is independently an integer of 0 or 1;

[0095] The present invention relates to a compound, a stereoisomer thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein the above Chemical Formula 1 is represented by the following Chemical Formula 6:

[0096] [ka]

[0097] During the ceremony,

[0098] X is independently CH, N, or NR3;

[0099] Y is —CH— or —C(O)—;

[0100] R1 is hydrogen or C 1-5 substituted with alkyl;

[0101] TIFF2026508123000030.tif26166

[0102] TIFF2026508123000031.tif32166

[0103] R4 is independently substituted with hydrogen, halogen, or hydroxy;

[0104] TIFF2026508123000032.tif45166

[0105] R5 is substituted with hydrogen, deuterium, halogen, or hydroxy;

[0106] R6 is substituted with hydrogen or deuterium;

[0107] TIFF2026508123000033.tif20166

[0108] m is an integer from 1 to 3;

[0109] n is independently an integer of 0 or 1;

[0110] More specific examples of the compound of the present invention represented by the above formula 1 include:

[0111] 3-(5-(1-(6-chloro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 1);

[0112] 3-(5-(1-(6,7-dichloro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 2);

[0113] 3-(5-(1-(5-chloro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 3);

[0114] 3-(5-(1-(4-chloro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 4);

[0115] 3-(5-(1-(6-methoxy-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 5);

[0116] 3-(5-(1-(4,6-dichloro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 6);

[0117] 3-(5-(1-(6-fluoro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 7);

[0118] 3-(5-(1-(7-chloro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 8);

[0119] 3-(5-(1-(1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 9);

[0120] 3-(5-(1-(5-methoxy-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 10);

[0121] 3-(5-(1-(4-methoxy-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 11);

[0122] 3-(5-(1-(7-methoxy-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 12);

[0123] 3-(5-(1-(5-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 13);

[0124] 3-(5-(1-(4-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 14);

[0125] 3-(5-(1-(6-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 15);

[0126] 3-(5-(1-(7-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 16);

[0127] 3-(5-(1-(5-fluoro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 17);

[0128] 3-(5-(1-(6-hydroxy-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 18);

[0129] 3-(5-(1-(7-fluoro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 19);

[0130] 3-(5-(1-(4-fluoro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 20);

[0131] 3-(5-(1-(3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 21);

[0132] 3-(5-(1-(3-chloro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 22);

[0133] 3-(5-(3-(1-(1H-indole-3-carbonyl)piperidin-4-yl)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 23);

[0134] 3-(5-((1-(1H-indole-2-carbonyl)piperidin-4-ylidene)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 24);

[0135] 3-(5-((1-(1H-indole-3-carbonyl)piperidin-4-ylidene)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 25);

[0136] 3-(5-((1-(6-chloro-1H-indole-2-carbonyl)piperidin-4-ylidene)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 26);

[0137] 3-(5-((1-(3-methyl-1H-indole-2-carbonyl)piperidin-4-ylidene)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 27);

[0138] 3-(5-(1-(1,3-dimethyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 28);

[0139] 3-(5-(1-(3-ethyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 29);

[0140] 3-(5-(1-(3-methoxy-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 30);

[0141] 3-(5-(1-(3-methyl-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 31);

[0142] 3-(5-(1-(6-amino-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 32);

[0143] 3-(5-(1-(5-bromo-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 33);

[0144] 3-(5-(1-(3-(morpholinomethyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 34);

[0145] 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-1H-indole-3-carbaldehyde (compound 35);

[0146] 3-(5-(1-(3-bromo-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 36);

[0147] 3-(5-(1-(3-fluoro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 37);

[0148] 3-(5-(1-(5-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 38);

[0149] 3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 39);

[0150] 3-(5-(1-(5,6-dimethoxy-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 40);

[0151] 3-(1-oxo-5-(1-(6-(trifluoromethyl)-1H-indole-2-carbonyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (compound 41);

[0152] 3-(5-(1-(6-methoxy-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 42);

[0153] 3-(5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 43);

[0154] 3-(5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-ylidene)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 44);

[0155] 3-(5-(1-(6-chloro-1H-pyrrolo[3,2-b]pyridine-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 45);

[0156] 3-(5-(1-(6-chloro-1H-pyrrolo[3,2-c]pyridine-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 46);

[0157] 3-(5-(1-(6-hydroxy-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 47);

[0158] 3-(5-(1-(3-methyl-6-(trifluoromethyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 48);

[0159] 3-(5-(1-(6-bromo-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 49);

[0160] 3-(5-(1-(6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 50);

[0161] 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-1H-indole-3-carbonitrile (compound 51);

[0162] 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-3-methyl-1H-indole-6-carbonitrile (compound 52);

[0163] 3-(5-(1-(3-methyl-6-(trifluoromethoxy)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 53);

[0164] 3-(5-(1-(6-fluoro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 54);

[0165] 3-(5-(1-(3-methyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 55);

[0166] 3-(5-(1-(6-(tert-butyl)-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 56);

[0167] 3-(5-(8-(6-chloro-1H-indole-2-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 57);

[0168] 3-(5-(8-(6-chloro-3-methyl-1H-indole-2-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 58);

[0169] 3-(5-(1-(6-chloro-1H-indole-2-carbonyl)-2-methylpiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 59);

[0170] 3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)-2-methylpiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 60);

[0171] 3-(5-(1-(6-amino-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 61);

[0172] 3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)-[1,4'-bipiperidin]-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 62);

[0173] 3-(5-(1-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)azetidin-3-yl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 63);

[0174] 3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 64);

[0175] 3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)-2,5-dihydro-1H-pyrrol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 65);

[0176] 3-(5-(1-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 66);

[0177] 3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)pyrrolidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 67);

[0178] 3-(5-((1-(3-methyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 68);

[0179] 3-(5-(1-(3,6-dimethyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 69);

[0180] 3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 70);

[0181] 3-(5-(1-(6-chloro-5-methoxy-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 71);

[0182] 3-(5-(1-(5,6-dichloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 72);

[0183] N-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-3-methyl-1H-indol-6-yl)acetamide (compound 73);

[0184] N-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-3-methyl-1H-indol-6-yl)methanesulfonamide (compound 74);

[0185] 1-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-3-methyl-1H-indol-6-yl)-3-ethylurea (compound 75);

[0186] 3-(5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)azetidin-3-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 76);

[0187] 3-(5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)-3-hydroxyazetidin-3-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 77);

[0188] 3-(5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)pyrrolidin-3-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 78);

[0189] 3-(5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)-3-hydroxypyrrolidin-3-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 79);

[0190] 3-(5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)-4-hydroxypiperidin-4-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 80);

[0191] 6-chloro-2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-1H-indole-3-carbaldehyde (compound 81);

[0192] 3-(5-(1-(6-chloro-3-(morpholinomethyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 82);

[0193] 3-(5-(1-(5-bromo-6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 83);

[0194] 3-(5-(1-(5-chloro-3-methyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 84);

[0195] 3-(5-(1-(3,5-dimethyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 85);

[0196] 3-(5-(1-(5-hydroxy-3-methyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 86);

[0197] 3-(5-(1-(6-chloro-3-((dimethylamino)methyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 87);

[0198] 3-(5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)ethynyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 88);

[0199] 3-(5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)ethynyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 89);

[0200] 3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 90);

[0201] 3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 91);

[0202] 5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (compound 92);

[0203] 3-(6-fluoro-5-(1-(3-methyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 93);

[0204] 3-(4-fluoro-5-(1-(3-methyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 94);

[0205] 2-(2,6-dioxopiperidin-3-yl)-5-(1-(3-methyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)isoindoline-1,3-dione (compound 95);

[0206] 5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)ethynyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (compound 96);

[0207] 3-(5-(1-(5-methoxy-3-methyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 97);

[0208] 3-(5-(1-(6-chloro-7-fluoro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 98);

[0209] 3-(5-(1-(6-chloro-7-fluoro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 99);

[0210] 3-(5-(1-(6-chloro-3,7-dimethyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 100);

[0211] 3-(5-(1-(6-chloro-5-hydroxy-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 101);

[0212] 3-(5-(1-(6-chloro-5-fluoro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 102);

[0213] 3-(5-(1-(6-chloro-3,5-dimethyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 103);

[0214] 3-(5-(1-(3-methyl-6-morpholino-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 104);

[0215] 3-(5-(1-(6-chloro-3-(hydroxymethyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 105);

[0216] 3-(5-(1-(3-methyl-6-(piperazin-1-ylmethyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (compound 106);

[0217] 3-(5-(1-(4,6-dichloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 107);

[0218] 3-(5-(1-(6-chloro-5-methoxy-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 108);

[0219] 3-(5-(1-(6-chloro-3-methyl-5-(piperazin-1-ylmethyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione dihydrochloride (compound 109);

[0220] 3-(5-(1-(6-methoxy-3-(morpholinomethyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 110);

[0221] 3-(5-(1-(6-methoxy-3-(morpholinomethyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 111);

[0222] 3-(5-(1-(6-chloro-5-fluoro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 112);

[0223] 3-(5-(1-(6-chloro-5-fluoro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 113);

[0224] 3-(5-(1-(6-chloro-3-((4-methylpiperazin-1-yl)methyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 114);

[0225] 3-(5-(1-(6-chloro-5-hydroxy-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 115);

[0226] 3-(4-fluoro-5-(1-(3-methyl-6-morpholino-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 116);

[0227] 3-(5-(1-(6-chloro-7-fluoro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 117);

[0228] 2-(4-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-3-methyl-1H-indole-6-carbonitrile (compound 118);

[0229] 6-chloro-2-(4-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-3-methyl-1H-indole-5-carbonitrile (compound 119);

[0230] 2-(4-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-5-fluoro-3-methyl-1H-indole-6-carbonitrile (compound 120);

[0231] 5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (compound 121);

[0232] 2-(4-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-7-fluoro-3-methyl-1H-indole-6-carbonitrile (compound 122);

[0233] (3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl pivalate (compound 123);

[0234] 3-(4-fluoro-5-(1-(7-fluoro-3-methyl-6-morpholino-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 124);

[0235] 3-(4-fluoro-5-(1-(5-fluoro-3-methyl-6-morpholino-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 125);

[0236] 3-(4-fluoro-5-(1-(7-fluoro-3-methyl-6-(4-methylpiperazin-1-yl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 126); and

[0237] 3-(4-fluoro-5-(1-(5-fluoro-3-methyl-6-(4-methylpiperazin-1-yl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 127); its stereoisomer, solvate, prodrug, or pharmaceutically acceptable salt thereof.

[0238] The present invention relates to a pharmaceutical composition for treating, preventing, suppressing, or eliminating IKZF2-dependent diseases or disorders, comprising a compound represented by the above chemical formula 1, its stereoisomer, its solvate, its prodrug, or its pharmaceutically acceptable salt as an active ingredient.

[0239] The present invention also relates to a pharmaceutical composition for preventing or treating IKZF2-dependent diseases, such as solid cancers and blood cancers, which comprises, as an active ingredient, a compound represented by the above chemical formula 1, its stereoisomer, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof.

[0240] The solid cancer may be selected from the group consisting of non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), prostate cancer, breast carcinoma, lymphoma, leukemia, melanoma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid cancer, nasopharyngeal carcinoma, tongue cancer, pancreatic cancer, esophageal cancer, bile duct carcinoma, gastric cancer, soft tissue sarcoma, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, tubular carcinoma, and Ewing's sarcoma, but is not particularly limited thereto.

[0241] The blood cancer may be selected from the group consisting of acute myeloid leukemia (AML), chronic myeloid leukemia (CML), Abelson oncogene-associated CML (Bcr-ABL translocation), myelodysplastic syndrome (MDS), acute B-lymphoblastic leukemia (B-ALL), acute T-lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myeloproliferative neoplasm (MPN), Richter's syndrome, hairy cell leukemia (HCL), blastic plasmacytic dendritic cell neoplasm (BPDCN), non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL), Hodgkin's lymphoma, systemic mastocytosis, and Burkitt's lymphoma, but is not particularly limited thereto.

[0242] The compound represented by Chemical Formula 1 of the present invention, its stereoisomer, solvate, prodrug, or pharmaceutically acceptable salt thereof can enhance the therapeutic effect of cancer when used in combination with an anticancer agent. The anticancer agent that can be used in the combination therapy may be selected from taxane anticancer agents, antitumor alkylating agents, antitumor antimetabolites, antitumor antibiotics, plant-derived antitumor agents, antitumor platinum complexes, antitumor camptothecin derivatives, antitumor kinase inhibitors, antitumor antibodies, hormonal antitumor agents, antitumor viral agents, and angiogenesis inhibitors.

[0243] The taxane anticancer drug is paclitaxel, docetaxel, cabazitaxel, larotaxel, BMS-184476, BMS-188797, BMS275183, mirataxel, ortaxel, TL-310, docosahexaenoic acid-paclitaxel (DHA-paclitaxel), nab-paclitaxel, EndoTAG+paclitaxel, XRP9881, polymer-mycel-paclitaxel, or RPR-109881A, and the antitumor alkylating agent is nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, or the like. The antitumor metabolite is methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, camofur, cytarabine, cytarabine octphosphate, enocitabine, S-1, gemcitabine, fludarabine, or pemetrexed disodium, and the antitumor antibiotic is actinomycin D, doxorubicin, daunorubicin, neocainestatin, bleomycin, peprolol the plant-derived antitumor agent is vincristine, vinblastine, vindesine, etoposide, sobuzoxane, docetaxel, paclitaxel, or vinorelbine; the antitumor platinum complex is cisplatin, carboplatin, nedaplatin, or oxaliplatin; the antitumor camptothecin derivative is irinotecan, topotecan, or camptothecin; the antitumor quina the enzyme inhibitor is gefitinib, imatinib, or erlotinib; the antitumor antibody is cetuximab, bevacizumab, rituximab, bevacizumab, alemtuzumab, or trastuzumab; the hormonal antitumor agent is goserelin, leuprolide, or tamoxifen; the antitumor virus agent is Imlygic; the angiogenesis inhibitor is Avastin, bevacizumab, ramucirumab, aflibercept, cetuximab, panitumumab,The compound may be, but is not limited to, regorafenib, sunitinib, sorafenib, pazopanib, vandetanib, axitinib, cediranib, vatalanib, motesanib, rucatinib, intedanib, semaxanib, afatinib, lenvatinib, cabozantinib, or a combination thereof.

[0244] Anticancer drugs that can be used in combination therapy include paclitaxel, docetaxel, cabazitaxel, larotaxel, BMS-184476, BMS-188797, BMS275183, mirataxel, ortaxel, TL-310, docosahexaenoic acid-paclitaxel (DHA-paclitaxel), nab-paclitaxel, EndoTAG+paclitaxel, XRP9881, polymer-mycel paclitaxel, RPR-109881A, nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulan, and mitobronchial. Nititol, carboquone, thiotepa, ranimustine, nimustine, temozolomide, carmustine, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, camofur, cytarabine, cytarabine ocphosphate, enocitabine, S-1, gemcitabine, fludarabine, pemetrexed disodium, actinomycin D, doxorubicin, daunorubicin, neocasinostatin, bleomycin, peplomycin, mitomycin C, aclarubicin, pirarubicin , epirubicin, zinostatin stimalamer, idarubicin, sirolimus, valrubicin, vincristine, vinblastine, vindesine, etoposide, sobuzoxane, docetaxel, paclitaxel, vinorelbine, cisplatin, carboplatin, nedaplatin or oxaliplatin, irinotecan, topotecan, camptothecin, gefitinib, imatinib, erlotinib, cetuximab, bevacizumab, rituximab, bevacizumab, alemtuzumab or trastuzumab, goserelin, Leuprolide The present invention relates to a pharmaceutical composition comprising one or more compounds selected from the group consisting of leuprolide, tamoxifen, Imlygic, Avastin, bevacizumab, ramucirumab, aflibercept, cetuximab, panitumumab, regorafenib, sunitinib, sorafenib, pazopanib, vandetanib, axitinib, cediranib, vatalanib, motesanib, rucatinib, intedanib, semaxanib, afatinib, lenvatinib, and cabozantinib.

[0245] In addition, the compound represented by Chemical Formula 1 of the present invention, its stereoisomer, solvate, prodrug, or pharmaceutically acceptable salt thereof can be used as an immunomodulatory cell therapy agent or immunomodulatory preparation to enhance the cancer therapeutic effect when used in combination therapy with one or more cellular or immunomodulatory agents selected from a PD-1 inhibitor, a PD-L1 inhibitor, a LAG-3 inhibitor, a CTLA-4 antagonist, an A2A antagonist, a GITR agonist, a TIM-3 inhibitor, a STING agonist, and a TLR7 agonist.

[0246] The PD-1 inhibitors include nivolumab (BMS), pembrolizumab (Merck), BCD-100 (Biocad), cemiplimab (Regeneron Pharmaceuticals Inc.), sintilimab (IBI-308 from Eli Lilly / Innovent Biologics, Inc.), spartalizumab (PDR-001 from Novartis AG), camrelizumab (SHR-1210 from Incyte Corporation / Jiangsu Hengrui), tislelizumab (BeiGene Limited), AGEN-2034 (Agenus Inc.), and ted), MEDI-0680 (AMP-514; Amplimmune / MedImmune LLC), toripalimab (JS-001 from Shanghai Junshi Bioscience Company Limited), dostarimab (TSR-042 from Tesaro Inc.), ABBV-181 (AbbVie Inc.), AK-104 (Akeso BioPharma Inc.), AK-105 (Akeso BioPharma Inc.), BAT-1306 (Biothera Solutions Limited), BI754091 (Boehringer Ingelheim CBT-501, genolimuzumab (CBT Pharmaceuticals Inc. / Zeno), GLS-010 (Harbinger of Langlois / Uxi / Arcus), LZM-009 (Livzon Pharmaceutical Group Inc.), MGA-012 (Insight Corporation / MacroGenics), MGD-013 (MacroGenics Inc.), PF-06801591 (Pfizer Inc.), Sym-021 (Symphogen A / S), CS-1003 (C Stone Pharmaceuticals Company Limited), HLX-10 (Henrix Biotech / Shanghai Henrix Biotech Company Limited), AK-103 (Akeso Biopharmaceuticals Inc.), AM-0001 (Alumo Biosciences Inc.), TILT-123 (Tilt Biotherapeutics Limited), BH-2922 (Beijing Hanmi Pharmaceutical), BH-2941 (Beijing Hanmi Pharmaceutical), BH-2950 (Beijing Hanmi Pharmaceutical),CX-188 (Cytomex Therapeutics, Inc.), ENUM244C8 (Enumeral Biomedical Holdings), ENUM-388D4 (Enumeral Biomedical Holdings), HAB-21 (Suzhou Steinway Biotech, Inc.), HEISCOIII-003 (Sichuan Heisco Pharmaceuticals), IKT-202 (Iselcarex Therapeutics), JS-003 (Shanghai Junshi Bioscience), JTX-4014 (Johns Therapeutics, Inc.), MCLA-134 (Mers NV), MGD-019 (Macrogenics, Inc.), MT-17000 (Molecular Template Twin, Inc.), PEGMP-7 (D5 Pharma Incorporated), PRS-332 (Pieris Pharmaceuticals Inc.), RXI-762 (RXi Pharmaceuticals Corporation), STI-1110 (Res Laboratoire Toilet Servier / Sorrento), VXM-10 (Vexim AG), XmAb-20717 (Gencoin Corporation), XmAb-23104 (Gencoin Corporation), AK-112 (Akeso Biopharmaceuticals Inc.), HLX-20 (Henrix Biotech / Shanghai Henrix Biotech Company Limited), SSI-361 (Libgen Biopharmaceuticals Limited), AT-16201 (AIMM Therapeutics BV), and SNA-01 (Fountain Biopharmaceuticals Inc.).

[0247] The PD-L1 inhibitors include atezolizumab (Genentech Inc.), avelumab (Merck KGaA / Pfizer), davalumab (AstraZeneca Pharmaceuticals LP / MedImmune), BGB-A333 (BeiGene Limited), CX-072 (Cytomex Therapeutics Inc.), GNS-1480 (Limited Corporation / Xenosco), AMP-224 (MedImmune LLC), and CA-170 (OriginDiscovery). Lee Technologies Limited), CK-301 (Checkpoint Therapeutics / TG Therapeutics), CS-1001 (C-Stone Pharmaceuticals Company Limited), FAZ-053 (Novartis AG), emvapolimab (ASC22 or KN-035; Suzhou Alfalfamab / 3DMed), LY-3300054 (Eli Lilly and Company), M-7824 (Merck KGaA), HTI-1088 (HTI-131, SHR-1316;Atridia and Jiangsu Hengrui Pharmaceutical), MSB-2311 (Mabspace Biosciences (Suzhou) Company Limited), STI-A1014 (Leeds Pharmaceuticals / Sorrento), AK106 (Akeso Biopharmaceuticals, Inc.), AVA-004 (Abacta Life Sciences, Ltd.), BBI-801 (Boston Biomedical, Inc.), CA-327 (Orijen / Curis), CBA-0710 (Sorrento Therapeutics, Inc.), CBT-502 (CBT Pharmaceuticals / Ciatai Tianqing Pharmaceuticals), FPT-155 (Five Prime Therapeutics, Inc.) Incorporated), FS-118 (F-Star Biotechnology Limited), IKT-201 (Iselcarex Therapeutics), IKT-703 (Iselcarex Therapeutics), IO-103 (IO Biotech APS), JS-003 (Shanghai Junshi Bioscience), KD-033 (Kadomon Corporation / Jonwa Pharmaceuticals), KY-1003 (Kymab Limited), MCLA-145 (Mers NV / Insight), MT-5050 (Molecular Template Twin Corporation), and SNA-02 (Fountain BioPharma Corporation);

[0248] The CTLA-4 antagonist is selected from the group consisting of ipilimumab (BMS), tremelimumab (Astrazeneca), and MEDI5752 (a bispecific antibody that simultaneously targets PD-1 and CTLA-4).

[0249] The compounds represented by Formula 1 of the present invention, their stereoisomers, solvates, prodrugs, or pharmaceutically acceptable salts thereof may be administered simultaneously (as a single formulation or separate formulations), sequentially, separately, or over a period of time with other drug therapies or treatment modalities. Generally, combination therapy contemplates the administration of two or more drugs during a single cycle or course of treatment. Therapeutic agents may be, for example, chemical compounds, peptides, antibodies, antibody fragments, or nucleic acids, which are therapeutically active or enhance therapeutic activity when administered to a patient in combination with the compounds of Formula 1 of the present invention.

[0250] The compounds of Formula I of the present invention, their stereoisomers, solvates, prodrugs, or pharmaceutically acceptable salts thereof are used in combination with one or more other anti-HER2 antibodies, such as trastuzumab, pertuzumab, margetuximab, or the aforementioned HT-19, or other anti-HER2 conjugates, such as ado-trastuzumab emtansine (also known as Kadcyla® or T-DM1). In other embodiments, the compounds of Formula I of the present invention, their stereoisomers, solvates, prodrugs, or pharmaceutically acceptable salts thereof are used in combination with one or more tyrosine kinase inhibitors, including, but not limited to, EGFR inhibitors, Her3 inhibitors, IGFR inhibitors, and Met inhibitors, to treat diseases, such as cancer. For example, tyrosine kinase inhibitors include erlotinib hydrochloride (Tarceva®); linifanib (N-[4-(3-amino 1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea (also known as ABT869); sunitinib malate (Sutent®); bosutinib (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-( These include, but are not limited to, 4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile (also known as SKI-606); dasatinib (Sprycel®); pazopanib (Votrient®); sorafenib (Nexavar®); Zactima (ZD6474); and imatinib or imatinib mesylate (Gilvec® and Gleevec®).Epidermal growth factor receptor (EGFR) inhibitors include erlotinib hydrochloride (Tarceva®), gefitinib (Iressa®); N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3'S'')-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide, Tovok®); vandetanib (Caprelsa®); lapatinib (Tykerb®); (3R,4R)-4-amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-3-ol (BMS690514); canertinib hydrochloride (CI-1033); 6-[4-[(4-ethyl-1-piperazinyl)methyl]phenyl]- N-[(1R)-1-Phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (AEE788, CAS 497839-62-0); mubritinib (TAK165); pelitinib (EKB569); afatinib (Gilotrif®); neratinib (HKI272); N-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino] N-(3,4-dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα)-octahydro-2-methylcyclopentane[c]pyrrol-5-yl]methoxy]-4-quinazolinamine (XL647, CAS 781613-23-8); and 4-[4-[[(1R)-1-phenylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol (PKI166, CAS 187724-61-4).EGFR antibodies include, but are not limited to, cetuximab (Erbitux®); panitumumab (Vectibix®); matuzumab (EMD-72000); nimotuzumab (hR3); zalutumumab; TheraCIM h-R3; MDX0447 (CAS 339151-96-1); and ch806 (mAb-806, CAS 946414-09-1).

[0251] For purposes of the present invention, the following terms have the following meanings unless otherwise specified: Any term not defined has its art-understood meaning.

[0252] As used herein, "halo" or "halogen" refers to fluoro (F), chlorine (Cl), bromine (Br), and iodo (I).

[0253] As used herein, the term "alkyl" refers to a single-bonded straight or branched chain hydrocarbon group, including, but not limited to, methyl, ethyl, propyl, and the like.

[0254] As used herein, the term "alkoxy" refers to a single bonded straight or branched chain saturated hydrocarbon attached oxygen radical, including but not limited to methoxy, ethoxy, propoxy, and the like.

[0255] As used herein, the term "haloalkyl" refers to a substituted alkyl group as defined above, wherein one or more hydrogen atoms on the alkyl group have been replaced with a halo group, including, but not limited to, trifluoromethyl, difluoromethyl, trifluoroethyl, and the like.

[0256] As used herein, the term "haloalkoxy" refers to an alkyl-O- group in which one or more hydrogen atoms on the alkyl group have been replaced with a halo group, including, but not limited to, trifluoromethoxy.

[0257] As used herein, the term "aryl" refers to aromatic ring compounds, including, but not limited to, phenyl, naphthalene, anthracene, and the like.

[0258] The compound of Chemical Formula 1 of the present invention may include, in addition to pharmaceutically acceptable salts, all salts that can be prepared by conventional methods, solvates thereof, stereoisomers thereof, and prodrugs thereof.

[0259] "Pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising the dosage form and / or the mammal being treated therewith.

[0260] "Hydrate" means a solvate where the solvent molecule is water.

[0261] "Prodrug" means a compound that is convertible in vivo by metabolic means (e.g., hydrolysis) to a disclosed compound. Generally, such prodrugs contain metabolically cleavable groups and are rapidly transformed in vivo to yield the parent compound, e.g., by hydrolysis in blood, and generally include ester and amide analogs of the parent compound. Prodrugs are formulated for improved chemical stability, improved patient acceptability and compliance, improved bioavailability, extended duration of action, improved organ selectivity, improved formulation (e.g., increased aqueous solubility), and / or reduced side effects (e.g., toxicity). Generally, the prodrug itself has little or no biological activity and is stable under normal conditions.

[0262] "Solvate" refers to a complex of variable stoichiometry formed by a solute (e.g., a compound of Formula I' or Formula I) and a solvent (e.g., water, ethanol, or acetic acid). This physical association may involve varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. Generally, such solvents selected for the purposes of this disclosure will not interfere with the biological activity of the solute. Solvate includes all solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, methanolates, and the like.

[0263] "Stereoisomers" means mixtures of enantiomers, partial stereoisomers, and cis / trans isomers produced from the procedures described above, which may be separated into their single components by chiral salt techniques, normal-phase, reverse-phase, or chiral column chromatography, depending on the attributes of the separation.

[0264] Any resulting racemic compounds or intermediates of the present disclosure can be resolved into their optical antipodes by known methods, for example, by separation of their partial stereoisomeric salts obtained with optically active acids or bases and liberating the optically active acid or base compounds. Thus, basic moieties can be utilized to resolve compounds of the present disclosure into their optical antipodes, for example, by fractional crystallization of salts formed from optically active acids, such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or campo-10-sulfonic acid, among others. Furthermore, racemic compounds or racemic intermediates of the present disclosure may be resolved by chiral chromatography, for example, high-performance liquid chromatography (HPLC) using a chiral adsorbent. Any mixture of stereoisomers produced may be separated on the basis of the physicochemical differences of the constituent components, for example, by chromatography and / or fractional crystallization, into pure or substantially pure geometric or optical isomers, partial stereoisomers, and racemates, and all such compounds and stereoisomers are included within the scope of the present invention.

[0265] In the present invention, the term "pharmaceutically acceptable salt" refers to a salt or complex of Formula 1 that has the desired biological activity. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), as well as salts formed with acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, and polygalacturonic acid. The compounds may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate, and diphenylacetate), among others.

[0266] The acid addition salt according to the present invention can be prepared by a conventional method. For example, the acid addition salt can be prepared by dissolving the derivative of Chemical Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc., adding an organic or inorganic acid, filtering and drying the resulting precipitate, or by distilling the solvent and excess acid under reduced pressure, drying the resulting precipitate, and crystallizing it in an organic solvent.

[0267] Pharmaceutically acceptable metal salts can also be prepared using bases. Alkali metal or alkaline earth metal salts can be obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating the filtrate to dryness. In this case, it is pharmaceutically appropriate to prepare sodium, potassium, or calcium salts as metal salts. The corresponding salts can also be obtained by reacting an alkali metal or alkaline earth metal salt with an appropriate silver salt (e.g., silver nitrate).

[0268] The pharmaceutical composition of the present invention may be formulated into an appropriate form in combination with a commonly used pharmaceutically acceptable carrier. "Pharmaceutically acceptable" refers to a composition that is physiologically acceptable and does not normally cause allergic or similar reactions, such as gastrointestinal disorders or dizziness, when administered to humans. Furthermore, the composition can be formulated into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, topical preparations, suppositories, and sterile injections by conventional methods.

[0269] Carriers, excipients, and diluents that can be contained in the composition may include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl parahydroxybenzoate, propyl parahydroxybenzoate, talc, magnesium stearate, and mineral oil. When formulated, commonly used diluents or excipients such as fillers, stabilizers, binders, disintegrants, and surfactants are used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid formulations are prepared by mixing the compound of the present invention with at least one excipient, such as starch, microcrystalline cellulose, sucrose, lactose, low-substituted hydroxypropyl cellulose, hypromellose, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Oral liquid formulations include suspensions, liquid preparations, emulsions, syrups, etc., and may contain various excipients, such as wetting agents, sweeteners, flavorings, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, and suppositories. Examples of non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Examples of suppository bases include witepsol, macrogol, Tween 61, cocoa butter, lauric butter, glycerol, and gelatin. To prepare a parenteral preparation, the compound of Formula 1 or a pharmaceutically acceptable salt thereof is sterilized and / or mixed with auxiliary agents such as preservatives, stabilizers, hydrating agents or emulsifiers, salts for adjusting osmotic pressure and / or buffers, and other therapeutically useful substances in water to prepare a solution or suspension, which can be packaged in a unit dosage form such as ampoules or vials.

[0270] The pharmaceutical composition includes the compound of Formula 1 and an excipient. The compound may be added in an amount of preferably 0.001% to 50% by weight, more preferably 0.001% to 40% by weight, and most preferably 0.001% to 30% by weight, based on the total weight of the entire composition.

[0271] Pharmaceutical compositions containing the compound of Formula 1 disclosed in the present invention as an active ingredient may be administered to mammals, such as rodents, livestock, and humans, via various routes. All administration routes are possible, but they may be administered orally, rectally, or by intravenous, intramuscular, subcutaneous, intrauterine, intradural, or intracerebrovascular injection. The dosage may vary depending on the age, sex, and weight of the patient, the specific disease or condition being treated, the severity of the disease or condition, the administration time, the administration route, the absorption, distribution, and excretion rate of the drug, the type of other drugs used, and the prescriber's discretion. Determining the dosage based on these factors is within the skill of the art. Generally, dosages range from 0.01 mg / kg / day to about 2000 mg / kg / day. A more preferred dosage is 1 mg / kg / day to 500 mg / kg / day. The drug may be administered once daily or in multiple divided doses. The dosages listed above are not intended to limit the scope of the present invention in any way. [Effects of the Invention]

[0272] The compound of Chemical Formula 1 according to the present invention provides an agent having a novel mechanism of action against IKZF2 protein, and is useful for treating diseases and disorders associated with IKZF2 protein, and is particularly useful for preventing or treating cancer. [Brief explanation of the drawings]

[0273] [Figure 1] 1 shows the results of a Western blot experiment using Helios protein degradation assay for Compound 39 of the present invention (FIG. 1-B) and Comparative Substance 1 (DKY709) (FIG. 1-A). DETAILED DESCRIPTION OF THE INVENTION

[0274] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described in detail below with reference to preferred embodiments thereof. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the concept of the present invention to those skilled in the art.

[0275] <Production Example 1. Synthesis of an indole derivative compound that degrades IKZF2 and confirmation of its physicochemical properties>

[0276] The compound of the present invention represented by Chemical Formula 1 can be prepared by the following reaction schemes 1 to 15.

[0277] [ka]

[0278] 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione ( 3 ) synthesis

[0279] 1 (5.0 g, 16.2 mmol) in DMF (15 mL) 2 After adding 1.2g (3.1g, 24.4mmol) and potassium carbonate (6.7g, 48.7mmol), the mixture was stirred at 110°C for 3 hours. After cooling the reaction mixture, water was added. The solid precipitate was washed with water, filtered, and dried. 3 (4.5 g, 86%) was obtained.

[0280] 1H NMR (300 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.90 (s, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.48 (d, J = 17.6 Hz, 1H), 4.34 (d, J = 17.7 Hz, 1H), 2.97-2.85 (m, 1H), 2.63-2.57 (m, 1H), 2.44-2.29 (m, 1H), 2.07-1.95 (m, 1H)

[0281] tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate ( 5 ) synthesis

[0282] 3 (4.0 g, 12.4 mmol), 4 (5.0 g, 16.1 mmol), potassium carbonate (4.3 g, 30.9 mmol), and Pd(dppf)Cl2·DCM (1.0 g, 1.2 mmol) were dissolved in DMF (15 mL) and stirred at 110 °C for 12 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was filtered through Celite. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated mixture was purified by column chromatography. 5 (1.6g, 30%)

[0283] 1H NMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.66 (s, 1H), 7.60 (d, J = 8.2 Hz, 1H), 6.31 (s, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 4.04 (s, 2H), 3.57 (t, J = 5.6 Hz, 2H), 3.00-2.84 (m, 1H), 2.66-2.55 (m, 1H), 2.47-2.26 (m, 2H), 2.07-1.96 (m, 1H), 1.44 (s, 9H), 1.30-1.17 (m, 1H)

[0284] tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carboxylate ( 6 ) synthesis

[0285] 5 (1.6 g, 3.8 mmol) and 10% Pd / C (0.4 g) were dissolved in DMF (15 mL) and stirred under hydrogen pressure for 12 hours. After the reaction was completed, the reaction mixture was filtered through Celite. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated. 6 (1.4g, 87%)

[0286] 1H NMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.51 (s, 1H), 7.41 (d, J = 7.9 Hz, 1H), 5.11 (dd, J = 13.3, 5.0 Hz, 1H), 4.43 (d, J = 17.2 Hz, 1H), 4.29 (d, J = 17.2 Hz, 1H), 4.10 (s, 2H), 2.97-2.74 (m, 4H), 2.63 (d, J = 13.2 Hz, 1H), 2.44-2.38 (m, 1H), 2.03-1.96 (m, 1H), 1.79 (d, J = 12.8 Hz, 2H), 1.56 (t, J = 12.3 Hz, 2H), 1.43 (d, J = 2.6 Hz, 9H)

[0287] 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride ( 7 ) synthesis

[0288] 6 (2.5 g, 5.8 mmol) was dissolved in DCM (20 mL), and 4N HCl in 1,4-dioxane (15 mL) was added, followed by stirring at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. 7 (1.2g, 88%)

[0289] 1H NMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.81 (s, 2H), 7.71 (d, J = 7.8 Hz, 1H), 7.47 (s, 1H), 7.39 (d, J = 7.9 Hz, 1H), 5.12 (dd, J = 13.2, 5.0 Hz, 1H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 3.43-3.37 (m, 2H), 3.08-2.96 (m, 3H), 2.66-2.55 (m, 1H), 2.44-2.35 (m, 1H), 2.03-1.81 (m, 5H)

[0290] [ka]

[0291] 1-(tert-butyl) 4-(1,3-dioxoisoindolin-2-yl)piperidine-1,4-dicarboxylate ( 1-2-9 ) synthesis

[0292] 1-2-8 (4.22 g, 18.39 mmol), 2-hydroxyisoindoline-1,3-dione (3 g, 18.39 mmol), EDCI (3.88 g, 20.23 mmol), and DMAP (0.225 g, 1.839 mmol) were added to DCM (15 mL) and stirred at room temperature for 12 hours. After the reaction was completed, the reaction mixture was diluted with water and extracted with EA. The organic layer was washed with NaHCO3, collected, concentrated under reduced pressure, and purified by column chromatography. 1-2-9 obtained.

[0293] 1 H NMR (400 MHz, DMSO-d6) δ 8.01-7.93 (m, 4H), 3.91-3.84 (m, 2H), 3.19-3.10 (m, 1H), 3.06-2.93 (m, 2H), 2.03-1.95 (m, 2H), 1.64-1.53 ​​(m, 2H), 1.41 (s, 9H)

[0294] tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carboxylate ( 6 ) synthesis

[0295] [ka]

[0296] 1-2-9 (52.1 mg, 0.139 mmol), 3-(5-bromo-1-oxoindolin-2-yl)piperidine-2,6-dione (30 mg, 0.093 mmol), NiBr2(dtbbpy) (22.47 mg, 0.046 mmol), Hantzsch ester (47.0 mg, 0.186 mmol), and NaHCO3 (31.2 mg, 0.371 mmol) were added to DMA (1 mL), followed by nitrogen purging for 15 minutes and stirring at room temperature for 12 hours under purple LEDs (160-390 nm). After completion of the reaction, the reaction mixture was diluted with water and extracted with EA. The organic layer was washed with brine, collected, concentrated under reduced pressure, and purified by column chromatography. 6 obtained.

[0297] 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.50 (s, 1H), 7.40 (d, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.43 (d, J = 17.2 Hz, 1H), 4.29 (d, J = 17.2 Hz, 1H), 4.14-4.04 (m, 2H), 2.96-2.79 (m, 4H), 2.64-2.57 (m, 1H), 2.45-2.34 (m, 1H), 2.03-1.96 (m, 1H), 1.83-1.76 (m, 2H), 1.60-1.48 (m, 2H), 1.43 (s, 9H)

[0298] [ka]

[0299] Synthesis of 3-(5-(1-(6-chloro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 1)

[0300] 7 (20 mg, 0.055 mmol), 6-chloro-1H-indole-2-carboxylic acid (10.8 mg, 0.055 mmol), EDCI-HCl (11.6 mg, 0.06 mmol), HOBt (8.2 mg, 0.06 mmol), and DIPEA (29 μL, 0.165 mmol) were dissolved in DMF (1 mL) and stirred at room temperature for 12 hours. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated mixture was subjected to column chromatography to obtain compound 1 (14 mg, 52%).

[0301] 1H NMR (300 MHz, DMSO-d6) δ 13.62 (s, 1H), 10.98 (s, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.54 (s, 1H), 7.44 (dd, J = 7.9, 1.4 Hz, 1H), 7.25 (dd, J = 8.7, 1.8 Hz, 1H), 5.10 (dd, J = 13.2, 5.1 Hz, 1H), 4.90 (d, J = 13.1 Hz, 1H), 4.78 (d, J = 12.8 Hz, 1H), 4.42 (d, J = 17.3 Hz, 1H), 4.28 (d, J = 17.3 Hz, 1H), 3.09-2.83 (m, 4H), 2.65-2.53 (m, 1H), 2.39 (dd, J = 13.2, 4.6 Hz, 1H), 2.05-1.83 (m, 3H), 1.77-1.65 (m, 2H)

[0302] [ka]

[0303] tert-Butyl 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate ( 9 ) synthesis

[0304] 3 (200 mg, 0.62 mmol), 8 (201 mg, 0.68 mmol), potassium carbonate (214 mg, 1.55 mmol), and Pd(dppf)Cl2·DCM (51 mg, 0.06 mmol) were dissolved in DMF (2 mL) and stirred at 110 °C for 12 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was filtered through Celite. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated mixture was purified by column chromatography. 9(45 mg, 18%) was obtained.

[0305] 1 H NMR (500MHz, CDCl3) δ 8.14(s, 1H), 7.86(t, J = 7.5, 7.5Hz, 1H), 7.53(s, 1H), 7.43(s, 1H), 6.29(s , 1H), 5.31-5.14(m, 1H), 4.51(d, J = 16.7Hz, 3H), 4.34(s, 3H), 2.95-2.81(m, 1H), 2.44-2.17(m, 3H), 1.50(s, 9H)

[0306] tert-Butyl 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidine-1-carboxylate ( 10 ) synthesis

[0307] 9 (20 mg, 0.05 mmol) and 10% Pd / C (10 mg) were dissolved in DMF (1 mL) and stirred under hydrogen pressure for 12 hours. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated mixture was purified by column chromatography. 10 (17 mg, 85%) was obtained.

[0308] 1H NMR(500MHz, CDCl3) δ 8.07(s, 1H), 7.87(d, J = 7.7Hz, 1H), 7.40(d, J = 8.1Hz, 1H), 7.36(s, 1H), 5.26(d, J = 12.7Hz, 1H), 4.51(d, J = 15.7Hz, 1H), 4.36(d, J = 15.7Hz, 1H), 3.90-3.83(m, 1H), 3.70-3.62(m, 1H), 3.53-3.44(m, 2H), 3.39(d, J = 9.9Hz, 1H), 2.91-2.83(m, 1H), 2.41-2.30(m, 2H), 2.29-2.22(m, 1H), 2.09-2.01(m, 2H), 1.51(s, 9H)

[0309] 3-(1-oxo-5-(pyrrolidin-3-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride ( 11 ) synthesis

[0310] 10 (20 mg, 5.8 mmol) was dissolved in DCM (1 mL), and a 4N HCl solution in 1,4-dioxane (0.1 mL) was added, followed by stirring at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. 11 (14 mg, 100%) was obtained.

[0311] 1 H NMR(300MHz, DMSO-d6) δ 11.02 (s, 1H), 9.53(s, 2H), 7.79-7.66(m, 3H), 6.63(s, 1H), 5.12(dd, J = 13.4 , 5.1Hz, 1H), 4.49(d, J = 17.4Hz, 1H), 4.44-4.32(m, 3H), 4.19(s, 2H), 2.97-2.85(m, 1H), 2.68-2.55(m, 1H), 2.46-2.37(m, 1H), 2.08-1.97(m, 1H)

[0312] [ka]

[0313] 3-(5-(2,5-dihydro-1H-pyrrol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride ( 12 ) synthesis

[0314] 9 (20 mg, 0.06 mmol) was dissolved in DCM (1 mL), and a 1,4-dioxane solution (0.1 mL) of 4N HCl was added, followed by stirring at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. 12 (16 mg, 95%) was obtained.

[0315] 1 H NMR (300 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.53 (s, 2H), 7.79-7.66 (m, 3H), 6.63 (s, 1H), 5.12 (dd, J = 13.4, 5.1 Hz, 1H), 4.49 (d, J = 17.4 Hz, 1H), 4.44 - 4.32 (m, 3H), 4.19 (s, 2H), 2.97-2.85 (m, 1H), 2.68-2.55 (m, 1H), 2.46-2.37 (m, 1H), 2.08-1.97 (m, 1H)

[0316] Synthesis of 3-(1-oxo-5-(1,2,3,6-tetrahydropyridin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (5-2)

[0317] [ka]

[0318] 5 (20 mg) was dissolved in DCM (1 mL), and a 1,4-dioxane solution (0.1 mL) of 4N HCl was added, followed by stirring at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. 5-2 (15 mg) was obtained.

[0319] [ka]

[0320] tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate ( 14 ) synthesis

[0321] 3 (100 mg, 0.31 mmol), 13 (130 mg, 0.40 mmol), potassium carbonate (107 mg, 0.77 mmol), and Pd(dppf)Cl2·DCM (25 mg, 0.03 mmol) were dissolved in DMF (2 mL) and stirred at 110 °C for 12 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was filtered through Celite. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated mixture was purified by column chromatography. 14 (46 mg, 34%)

[0322] 1 H NMR(300MHz, DMSO-d6) δ 11.00 (s, 1H), 7.70(d, J = 8.1Hz, 1H), 7.66(s, 1H), 7.59(d, J = 8.1Hz, 1H), 6.27(s, 1H), 5.12(dd, J = 13.2, 5.1Hz, 1H), 4.55(s, 1H), 4.46(d, J = 17.3Hz, 1H), 4.32(d, J = 17.3Hz, 1H), 4.11(d, J = 13.1Hz, 1H), 3.07-2.86(m, 2H), 2.64-2.56(m, 1H), 2.48-2.31(m, 2H), 2.08-1.93(m, 1H), 1.44(s, 9H), 1.23(d, J = 6.6Hz, 3H)

[0323] tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2-methylpiperidine-1-carboxylate ( 15 ) synthesis

[0324] 14 (40 mg, 0.09 mmol) and 10% Pd / C (13 mg) were dissolved in DMF (1 mL) and stirred under hydrogen pressure for 12 hours. After the reaction was completed, the reaction mixture was filtered through Celite. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated. 15 (35 mg, 86%) was obtained.

[0325] 1 H NMR(300MHz, DMSO-d6) δ 10.99 (s, 1H), 7.65(dd, J = 8.0, 1.7Hz, 1H), 7.51(s, 1H), 7.42(d, J = 7.8Hz, 1H), 5.11(dd, J = 13.1, 5.0Hz, 1H), 4.43(d, J = 17.2Hz, 1H), 4.29(d, J = 17.3Hz, 1H), 3.94-3.79(m, 1H), 3.64(s, 1H), 2.89-2.82(m, 1H), 2.65-2.55(m, 1H), 2.41(d, J = 13.2Hz, 1H), 2.20(dd, J = 5.9, 1.8Hz, 1H) , 2.10-1.94(m, 2H), 1.86-1.68(m, 2H), 1.56(s, 1H), 1.43(s, 9H), 1.25-1.20(m, 1H), 1.16(d, J = 6.4Hz, 3H)

[0326] 3-(5-(2-methylpiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride ( 16 ) synthesis

[0327] 15(30 mg, 0.07 mmol) was dissolved in DCM (1 mL), and a 1,4-dioxane solution (0.1 mL) of 4N HCl was added, followed by stirring at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. 16 (26 mg, 100%) was obtained.

[0328] 1 H NMR(300MHz, DMSO-d6) δ 11.00(s, 1H), 8.92(s, 1H), 8.62(s, 1H), 7.71(d, J = 7.9Hz, 1H), 7.49(d, J = 12.5Hz, 1H), 7.41(t, J = 9.2Hz, 1H), 5.11(dd, J = 13.2, 5.0Hz, 1H), 4.46(d, J = 17.3Hz, 1H), 4.32(d, J = 17.3Hz, 1H), 3.68(s, 1H), 3.30-3.13(m, 2H), 3.10-2.96(m, 2H), 2.95-2.85(m, 1H), 2.69-2.56(m, 1H), 2.43-2.34(m, 1H), 2.05- 1.92(m, 3H), 1.88-1.79(m, 1H), 1.33(dd, J = 32.6, 6.6Hz, 3H)

[0329] [ka]

[0330] tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-hydroxypiperidine-1-carboxylate ( 17 ) synthesis

[0331] 5(50 mg, 0.12 mmol), phenylsilane (25 mg, 0.24 mmol), and Mn(dpm)3 (36 mg, 0.06 mmol) were dissolved in a mixture of DCM (1 mL), i-PrOH (1 mL), and DMF (0.2 mL), and the mixture was stirred under an oxygen atmosphere for 16 hours. After the reaction was completed, the reaction mixture was filtered through Celite. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated mixture was purified by column chromatography. 17 (30 mg, 58%) was obtained.

[0332] 1 H NMR(300MHz, DMSO-d6) δ 10.99(s, 1H), 7.72(s, 1H), 7.70-7.62 (m, 2H), 5.31(s, 1H), 5.11(dd, J = 13.3, 5.1Hz, 1H), 4.44(d, J = 17.4Hz, 1H), 4.30(d, J = 17.3Hz, 1H), 3.95-3.75(m, 2H), 3.61-3.47(m, 1H), 3.27 -3.08(m, 2H), 3.01-2.82(m, 2H), 2.65-2.59(m, 1H), 2.43-2.36(m, 1H), 2.13-1.79(m, 4H), 1.61(d, J = 13.2Hz, 2H), 1.43(s, 9H)

[0333] 3-(5-(4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride ( 18 ) synthesis

[0334] 17 (30 mg, 0.07 mmol, 1 eq) was dissolved in DCM (1 mL), and 4N HCl dissolved in 1,4-dioxane (0.1 mL) was added, followed by stirring at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. 18 (26 mg, 100%) was obtained.

[0335] 1H NMR(300MHz, DMSO-d6) δ 11.00 (s, 1H), 8.93(d, J = 28.5Hz, 2H), 7.74(d, J = 7.9Hz, 1H), 7.69(s, 1H), 7.60(d, J = 8.0Hz, 1H), 7.43(s, 1H), 5.12(dd, J = 13.3, 4.8Hz, 1H), 4.47(d, J = 17.3Hz, 1H), 4.33(d, J = 17.2Hz, 1H), 3.71-3.57(m, 3H), 3.10-2.84(m, 3H), 2.65-2.56(m, 2H), 2.34-2.19(m, 3H), 2.08-1.93(m, 2H)

[0336] [ka]

[0337] tert-Butyl 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate ( 20 ) synthesis

[0338] 3 (50 mg, 0.16 mmol), 19 (67 mg, 0.20 mmol), potassium carbonate (54 mg, 0.39 mmol), and Pd(dppf)Cl2·DCM (13 mg, 0.02 mmol) were dissolved in DMF (2 mL) and stirred at 110 °C for 12 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was filtered through Celite. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated mixture was purified by column chromatography. 20 (13 mg, 19%) was obtained.

[0339] 1H NMR (400 MHz, DMSO-d6) δ 10.98 (d, J = 8.5 Hz, 1H), 7.72-7.54 (m, 2H), 7.25 (s, 1H), 6.69 (d, J = 5.3 Hz, 1H), 5.11 (dd, J = 13.3, 5.0 Hz, 1H), 4.49-4.22 (m, 4H), 3.08-2.83 (m, 2H), 2.65-2.55 (m, 1H), 2.47-2.28 (m, 2H), 2.22 - 2.06 (m, 1H), 2.04-1.80 (m, 3H), 1.80-1.61 (m, 1H), 1.38 (s, 6H), 1.08 (s, 3H)

[0340] tert-Butyl 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate ( 21 ) synthesis

[0341] 20 (10 mg, 0.02 mmol) and 10% Pd / C (5 mg) were dissolved in DMF (1 mL) and stirred under hydrogen pressure for 12 hours. After the reaction was completed, the reaction mixture was filtered through Celite. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated. 21 (8 mg, 80%) was obtained.

[0342] 1H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.66 (dd, J = 7.9, 4.6 Hz, 1H), 7.55 (s, 1H), 7.49-7.42 (m, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.43 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.1 Hz, 1H), 4.26-4.11 (m, 2H), 2.97-2.87 (m, 1H), 2.68-2.56 (m, 2H), 2.45-2.32 (m, 2H), 2.02-1.81 (m, 4H), 1.79-1.56 (m, 3H), 1.46 (d, J = 4.3 Hz, 6H), 1.28-1.26 (m, 1H), 1.24 (s, 3H)

[0343] tert-Butyl 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate ( 22 ) synthesis

[0344] 21 (8 mg, 0.18 mmol) was dissolved in DCM (1 mL), and 4N HCl / 1,4-dioxane solution (0.1 mL) was added, followed by stirring at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. 22 (8 mg, 100%) was obtained.

[0345] 1H NMR (500 MHz, DMSO-d6) δ 11.01 (s, 1H), 9.10-8.93 (m, 1H), 8.91-8.73 (m, 1H), 7.76-7.67 (m, 2H), 7.64-7.46 (m, 1H), 5.12 (dd, J = 13.4, 5.4 Hz, 1H), 4.45 (d, J = 17.1 Hz, 1H), 4.36-4.30 (m, 1H), 4.11-4.00 (m, 2H), 3.55-3.45 (m, 1H), 3.31-3.22 (m, 1H), 3.00-2.85 (m, 1H), 2.70-2.58 (m, 1H), 2.48-2.34 (m, 2H), 2.28-2.16 (m, 1H), 2.16-1.98 (m, 4H), 1.93-1.82 (m, 2H)

[0346] [ka]

[0347] tert-Butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methylene)piperidine-1-carboxylate ( 24 ) synthesis

[0348] 3 (200 mg, 0.62 mmol), 23 (260 mg, 0.81 mmol), potassium carbonate (257 mg, 1.86 mmol), and Pd(dppf)Cl2·DCM (51 mg, 0.06 mmol) were dissolved in DMF (3 mL) and stirred at 110 °C for 12 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was filtered through Celite. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated mixture was purified by column chromatography. 24 (71 mg, 26%)

[0349] 1H NMR(500MHz, CDCl3) δ 8.48 (s, 1H), 7.82(d, J = 7.8Hz, 1H), 7.29(d, J = 7.8Hz, 1H), 7.26(s, 1H), 6.42 (s, 1H), 5.23(dd, J = 13.3, 5.1Hz, 1H), 4.47(d, J = 15.9Hz, 1H), 4.32(d, J = 15.9Hz, 1H), 3.52(t, J = 5.8Hz, 2H), 3.41(t, J = 5.8Hz, 2H), 2.93-2.80(m, 2H), 2.45(t, J = 5.9Hz, 2H), 2.38-2.30(m, 3H), 2.22- 2.16(m, 1H), 1.47(s, 9H)

[0350] 3-(1-oxo-5-(piperidin-4-ylidenemethyl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride ( 25 ) synthesis

[0351] 24 (65 mg, 0.15 mmol, 1 eq) was dissolved in DCM (1 mL), and then a 4N HCl solution in 1,4-dioxane (0.4 mL) was added, followed by stirring at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. 25 (55 mg, 100%) was obtained.

[0352] 1 H NMR(300MHz, DMSO-d6) δ 10.99 (s, 1H), 9.00(s, 2H), 7.71(t, J = 6.8Hz, 1H), 7.48(d, J = 5.4Hz, 1H), 7.38(t, J = 6.6Hz, 1H), 6.58(s, 1H), 5.11(dd, J = 13.1, 6.4Hz, 1H), 4.46(dd, J = 17.3, 5.4Hz, 1H), 4.32(dd, J = 17.6, 5.4Hz, 1H), 3.57(d, J = 5.5Hz, 3H), 3.13(d, J = 26.6Hz, 4H), 2.90(d, J = 15.2Hz, 1H), 2.66- 2.57(m, 4H)

[0353] [ka]

[0354] tert-Butyl 4-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)prop-2-yn-1-yl)piperidine-1-carboxylate ( 27 ) synthesis

[0355] 3 (600mg, 1.86mmol), 26 (456 mg, 2.04 mmol), Pd(dppf)Cl2 (136 mg, 0.19 mmol), CuI (35 mg, 0.19 mmol), and DIPEA (0.65 mL) were dissolved in DMSO (10 mL) and stirred at 100 °C for 12 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was filtered through Celite. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated mixture was purified by column chromatography. 27 (375 mg, 43%)

[0356] 1 H NMR(500MHz, CDCl3) δ 8.27 (s, 1H), 7.82(d, J = 7.9Hz, 1H), 7.52(d, J = 7.9Hz, 1H), 7.50(s, 1H), 5.24 (dd, J = 13.3, 5.1Hz, 1H), 4.49(d, J = 16.0Hz, 1H), 4.33(d, J = 16.0Hz, 1H), 4.16(d, J = 13.3Hz, 2H), 2.98-2.80(m, 2H), 2.78-2.70(m, 2H), 2.42(d, J = 6.6Hz, 2H), 2.40-2.33(m, 1H), 2.26-2.21(m, 1H), 1.84(d, J = 12.4Hz, 2H), 1.78-1.72(m, 1H), 1.48(s, 9H), 1.35-1.26(m, 2H)

[0357] 3-(1-oxo-5-(3-(piperidin-4-yl)prop-1-yn-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride ( 28 ) synthesis

[0358] 27 (370 mg, 0.80 mmol, 1 eq) was dissolved in DCM (3 mL), and a 4N HCl solution in 1,4-dioxane (2.0 mL) was added, followed by stirring at room temperature for 3 hours. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure. 28 (300 mg, 94%) was obtained.

[0359] 1 H NMR(300MHz, DMSO-d6) δ 11.01(s, 1H), 8.92(s, 1H), 8.60(s, 1H), 7.71(d, J = 7.8Hz, 1H), 7.67(s, 1H), 7.54(d, J = 7.9Hz, 1H), 5.12(dd, J = 13.3, 5.1Hz, 1H), 4.45(d, J = 17.5Hz, 1H), 4.32(d, J = 17.5Hz, 1H), 3.76-3.63(m, 1H), 3.57(s, 1H), 3.27(s, 2H), 2.98-2.86(m, 3H), 2.60(d, J = 18.1Hz, 2H), 2.45-2.37 (m, 1H), 2.06-1.80(m, 4H), 1.60-1.51(m, 2H)

[0360] [ka]

[0361] tert-Butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)ethynyl)piperidine-1-carboxylate( 30 ) synthesis

[0362] 3 (2.5g, 7.74mmol), 29(1.8 g, 8.51 mmol), Pd(dppf)Cl2 (566 mg, 0.77 mmol), CuI (147 mg, 0.77 mmol), and DIPEA (2.7 mL) were dissolved in DMSO (30 mL) and stirred at 100 °C for 12 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was filtered through Celite. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated mixture was purified by column chromatography. 30 (2.0 g, 58%)

[0363] 1 H NMR(300MHz, DMSO-d6) δ 11.01 (s, 1H), 7.72-7.63(m, 2H), 7.53(d, J = 8.1Hz, 1H), 5.10(dd, J = 13.3, 5.1 Hz, 1H), 4.45(d, J = 17.6Hz, 1H), 4.32(d, J = 17.5Hz, 1H), 3.70-3.60(m, 2H), 3.15(t, J = 10.9Hz, 2H), 2.96-2.84(m, 2H), 2.60(d, J = 16.7Hz, 1H), 2.43-2.27(m, 1H), 2.08-1.95(m, 1H), 1.84(4.6Hz, 2H), 1.58-1.47 (m, 2H), 1.40(s, 9H)

[0364] 3-(1-oxo-5-(piperidin-4-ylethynyl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride ( 31 ) synthesis

[0365] 30 (2 g, 4.4 mmol, 1 eq) was dissolved in DCM (10 mL), and 4N HCl / 1,4-dioxane solution (11 mL) was added, followed by stirring at room temperature for 3 hours. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure. 31 (1.7g, 99%)

[0366] 1H NMR(500MHz, DMSO-d6) δ 11.01(s, 1H), 8.78(d, J = 26.0Hz, 2H), 7.71(d, J = 7.9Hz, 1H), 7.67(s, 1H), 7.55(dd, J = 7.8, 1.4Hz, 1H), 5.10(dd, J = 13.3, 5.1Hz, 1H), 4.43(s, 1H), 4.32(d, J = 17.5Hz, 1H), 3.26- 3.18(m, 2H), 3.07-2.98(m, 3H), 2.94-2.86(m, 1H), 2.64-2.56(m, 1H), 2.44-2.34(m, 1H), 2.09-1.97(m, 3H), 1.87-1.78(m, 2H)

[0367] [ka]

[0368] tert-Butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)azetidine-1-carboxylate ( 32 ) synthesis

[0369] 7 (50 mg, 0.14 mmol), tert-butyl 3-oxoazetidine-1-carboxylate (26 mg, 0.15 mmol), NaBH(OAc)3 (41 mg, 0.19 mmol), and DIPEA (71 μL) were dissolved in DMF (1 mL) and stirred at room temperature for 12 hours. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated mixture was purified by column chromatography. 32 (33 mg, 50%) was obtained.

[0370] 1H NMR(300MHz, DMSO-d6) δ 11.20 (s, 1H), 11.00(s, 1H), 7.72(d, J = 7.9Hz, 1H), 7.48(s, 1H), 7.41(d, J = 7.6Hz, 1H), 5.12(dd, J = 13.2, 5.0Hz, 1H), 4.46(d, J = 17.3Hz, 1H), 4.32(d, J = 17.4Hz, 1H), 4.21(s, 1H), 4.14-4.00(m, 3H), 3.58-3.49(m, 2H), 3.10-2.82(m, 5H), 2.63-2.55(m, 2H), 2.10-1.95(m, 5H), 1.40(s, 9H)

[0371] 3-(5-(1-(azetidin-3-yl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione dihydrochloride ( 33 ) synthesis

[0372] compound 32 (33 mg, 0.07 mmol, 1 eq) was dissolved in DCM (1 mL), and a 1,4-dioxane solution (170 μL) of 4N HCl was added, followed by stirring at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. 33 (31 mg, 100%) was obtained.

[0373] 1 H NMR(300MHz, DMSO-d6) δ 12.43 (s, 1H), 11.00(s, 1H), 9.66(s, 1H), 9.19(s, 1H), 7.72(d, J = 7.8Hz, 1H), 7.48(s, 1H), 7.41(d, J = 7.9Hz, 1H), 5.12(dd, J = 13.2, 5.1Hz, 1H), 4.62-4.42(m, 3H), 4.32(d, J = 17.4Hz, 1H), 4.12(s, 2H), 3.78-3.65(m, 1H), 3.10-2.83(m, 4H), 2.65-2.60(m, 1H), 2.43-2.25(m, 1H), 2.20-1.93(m, 5H)

[0374] [ka]

[0375] tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-[1,4'-bipiperidine]-1'-carboxylate ( 33 ) synthesis

[0376] 7 (50 mg, 0.14 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (30 mg, 0.15 mmol), NaBH(OAc)3 (41 mg, 0.19 mmol), and DIPEA (71 μL) were dissolved in DMF (1 mL) and stirred at room temperature for 12 hours. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated mixture was purified by column chromatography. 33 (20 mg, 29%) was obtained.

[0377] 1 H NMR(300MHz, DMSO-d6) δ 11.00 (s, 1H), 10.30(s, 1H), 7.72(d, J = 7.9Hz, 1H), 7.47(s, 1H), 7.40(d, J = 7.9Hz, 1H), 5.12(dd, J = 13.2, 5.1Hz, 1H), 4.46(d, J = 17.4Hz, 1H), 4.32(d, J = 17.4Hz, 1H), 4.09(d, J = 13.1Hz, 2H), 3.56(d, J = 11.9Hz, 2H), 3.17-3.07(m, 2H), 3.02-2.90(m, 2H), 2.81-2.70(m, 2H), 2.65-2.56 (m, 1H), 2.15-1.96(m, 8H), 1.66-1.51(m, 3H), 1.41(s, 9H)

[0378] 3-(5-([1,4'-bipiperidin]-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione dihydrochloride ( 34 ) synthesis

[0379] 33 (20 mg, 0.04 mmol) was dissolved in DCM (1 mL), and a 1,4-dioxane solution (0.1 mL) of 4N HCl was added, followed by stirring at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. 34 (14 mg, 74%)

[0380] 1 H NMR(300MHz, DMSO-d6) δ 11.26 (s, 1H), 11.00(s, 1H), 9.14(s, 1H), 8.99(d, J = 11.8Hz, 1H), 7.72(d, J = 7.8Hz, 1H), 7.47(s, 1H), 7.41(d, J = 7.9Hz, 1H), 5.12(dd, J = 13.2, 5.1Hz, 1H), 4.47(d, J = 17.4Hz, 1H), 4.32(d, J = 17.4Hz, 1H), 3.55-3.47(m, 3H), 3.21-2.82(m, 7H), 2.64-2.57(m, 1H), 2.43-2.17(m, 6H), 2.09 -1.93(m, 5H)

[0381] [ka]

[0382] 3-(1-oxo-5-((trimethylsilyl)ethynyl)isoindolin-2-yl)piperidine-2,6-dione ( 35 ) synthesis

[0383] 3(680 mg, 2.1 mmol), ethynyltrimethylsilane (1 g, 10.5 mmol), Pd(PPh3)2·Cl2 (148 mg, 0.21 mmol), CuI (40 mg, 0.21 mmol), and DIPEA (1.1 mL, 6.31 mmol) were dissolved in DMF (10 mL) and stirred at 65°C for 12 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was filtered through Celite. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated mixture was purified by column chromatography. 35 (400 mg, 56%) was obtained.

[0384] 1 H NMR(500MHz, DMSO-d6) δ 11.02 (s, 1H), 7.75-7.70 (m, 2H), 7.58(d, J = 8.0Hz, 1H), 5.12(dd, J = 13.3, 5.1 Hz, 1H), 4.46(d, J = 17.5Hz, 1H), 4.34(d, J = 17.5Hz, 1H), 2.96-2.87(m, 1H), 2.65-2.56(m, 1H), 2.46-2.35 (m, 1H), 2.05-1.98(m, 1H), 0.26(s, 9H)

[0385] tert-Butyl 4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate ( 37 ) synthesis

[0386] 35 (20 mg, 0.06 mmol), 36(15 mg, 0.068 mmol), sodium ascorbate (2.3 mg, 0.01 mmol), and CuSO4 (1.9 mg, 0.01 mmol) were dissolved in a mixture of THF (1 mL) and H2O (1 mL) and stirred at room temperature for 10 hours. After the reaction was completed, the reaction mixture was filtered through Celite. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated mixture was purified by column chromatography. 37 (8 mg, 28%) was obtained.

[0387] 1 H NMR(500MHz, CDCl3) δ 8.09(s, 1H), 8.02(s, 1H), 7.94(s, 1H), 7.88(s, 1H), 7.84(d, J = 8.0Hz, 1H), 5.24(dd, J = 13.4, 5.0Hz, 1H), 4.74-4.65(m, 1H), 4.55(d, J = 16.0Hz, 1H), 4.40(d, J = 15.9Hz, 1H), 4.31 (s, 2H), 3.03-2.79(m, 4H), 2.44-2.34(m, 1H), 2.30-2.21(m, 3H), 2.07-1.95(m, 2H), 1.49(s, 9H)

[0388] 3-(1-oxo-5-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride ( 38 ) synthesis

[0389] 37 (8 mg, 0.02 mmol, 1 eq) was dissolved in DCM (1 mL), and a 1,4-dioxane solution of 4N HCl (0.04 mL) was added, followed by stirring at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. 38 (7 mg, 100%) was obtained.

[0390] LC / MS (ESI) m / z 395 [M+H] +

[0391] [ka]

[0392] 3-(5-(1-(3-methyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione( 40 ) synthesis

[0393] 7 (50 mg, 0.14 mmol), 39 (33 mg, 0.15 mmol), EDCI-HCl (29 mg, 0.15 mmol), HOBt (20 mg, 0.15 mmol), and DIPEA (72 μL) were dissolved in DMF (1 mL) and stirred at room temperature for 12 hours. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrate was purified by column chromatography. 40 (35 mg, 48%)

[0394] 1 H NMR(300MHz, DMSO-d6) δ 12.10 (s, 1H), 11.01(s, 1H), 8.28(d, J = 2.1Hz, 1H), 7.93(dd, J = 8.9, 2.1Hz, 1H), 7.77(d, J = 8.8Hz, 1H), 7.69(d, J = 7.8Hz, 1H), 7.52(s, 1H), 7.44(dd, J = 8.0, 1.2Hz, 1H), 5.11(dd, J = 13.2, 5.1Hz, 1H), 4.55(s, 1H), 4.45(d, J = 17.3Hz, 1H), 4.31(d, J = 17.3Hz, 1H), 3.85(s, 1H), 3.13-2.82(m, 4H), 2.65-2.56(m, 1H), 2.44-2.36(m, 1H), 2.34(s, 3H), 2.02-1.82(m, 3H), 1.75-1.57(m, 2H))

[0395] 3-(5-(1-(6-amino-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione( 41 ) synthesis

[0396] 40 (5 mg, 0.01 mmol, 1 eq) and 10% Pd / C (5 mg) were dissolved in DMF (1 mL) and stirred under hydrogen pressure for 12 hours. After the reaction was completed, the reaction mixture was filtered through Celite. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated. 41 (13 mg, 92%)

[0397] 1 H NMR(500MHz, DMSO-d6) δ 11.00(s, 1H), 10.56(s, 1H), 7.68(d, J = 7.8Hz, 1H), 7.52(s, 1H), 7.43(d, J = 7.9Hz, 1H), 7.19(d, J = 8.3Hz, 1H), 6.49(s, 1H), 6.42(d, J = 8.5Hz, 1H), 5.11(dd, J = 13.4, 5.1Hz, 1H), 4.91(s, 2H), 4.44(d, J = 17.2Hz, 1H), 4.36-4.21(m, 3H), 3.11-2.90(m, 4H), 2.67-2.60(m, 1H), 2.42 -2.36(m, 1H), 2.22(s, 3H), 2.04-1.94(m, 1H), 1.92-1.83(m, 2H), 1.74-1.60(m, 2H)

[0398] [ka]

[0399] tert-Butyl-4(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)piperidine-1-carboxylate ( 43 ) synthesis

[0400] 42 (52.1 mg, 0.139 mmol), 3-(5-bromo-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (30 mg, 0.088 mmol), NiBr2(dtbbpy) (22.47 mg, 0.046 mmol), Hantzsch ester (47.0 mg, 0.186 mmol), and NaHCO3 (31.2 mg, 0.371 mmol) were added to DMA (1 mL), purged with nitrogen for 15 minutes, and then stirred at room temperature for 12 hours under purple LEDs (160-390 nm). After the reaction was complete, the reaction mixture was diluted with water and extracted with EA. The organic layer was washed with brine. The organic layer was collected, concentrated under reduced pressure, and purified by column chromatography. 43 obtained.

[0401] 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.57-7.50 (m, 2H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.55 (d, J = 17.4 Hz, 1H), 4.38 (d, J = 17.3 Hz, 1H), 4.15-4.04 (m, 2H), 3.16-3.07 (m, 1H), 2.98-2.80 (m, 3H), 2.64-2.57 (m, 1H), 2.47-2.39 (m, 1H), 2.04-1.96 (m, 1H), 1.80-1.72 (m, 2H), 1.67-1.55 (m, 2H), 1.43 (s, 9H)

[0402] Example 1: Synthesis of indole derivative compounds that degrade IKZF2 and confirmation of their physicochemical properties

[0403] The preparation process and physicochemical properties of compounds 1 to 127 of the present invention are as follows:

[0404] Compound 1. Preparation of 3-(5-(1-(6-chloro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0405] [ka]

[0406] Compound 1. 3-(5-(1-(6-chloro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0407] Intermediates 7 (20 mg, 0.055 mmol), 6-chloro-1H-indole-2-carboxylic acid (10.8 mg, 0.055 mmol), EDCI-HCl (11.6 mg, 0.06 mmol), HOBt (8.2 mg, 0.06 mmol), and DIPEA (29 μL, 0.165 mmol) were dissolved in DMF (1 mL) and stirred at room temperature for 12 hours. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated mixture was subjected to column chromatography to obtain compound 1 (14 mg, 52%).

[0408] 1H NMR (300 MHz, DMSO-d6) δ 13.62 (s, 1H), 10.98 (s, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.54 (s, 1H), 7.44 (dd, J = 7.9, 1.4 Hz, 1H), 7.25 (dd, J = 8.7, 1.8 Hz, 1H), 5.10 (dd, J = 13.2, 5.1 Hz, 1H), 4.90 (d, J = 13.1 Hz, 1H), 4.78 (d, J = 12.8 Hz, 1H), 4.42 (d, J = 17.3 Hz, 1H), 4.28 (d, J = 17.3 Hz, 1H), 3.09-2.83 (m, 4H), 2.65-2.53 (m, 1H), 2.39 (dd, J = 13.2, 4.6 Hz, 1H), 2.05-1.83 (m, 3H), 1.77-1.65 (m, 2H)

[0409] Compound 2. 3-(5-(1-(6,7-dichloro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0410] [ka]

[0411] Intermediates 7 Compound 2 was synthesized in the same manner as compound 1, except that 6,7-dichloro-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0412] 1H NMR (500 MHz, DMSO-d6) δ 12.07 (s, 1H), 11.00 (s, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.54 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 6.87 (s, 1H), 5.12 (dd, J = 13.9, 4.9 Hz, 1H), 4.45 (d, J = 17.2 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H), 3.26 (s, 1H), 3.10-2.90 (m, 3H), 2.61 (d, J = 17.2 Hz, 2H), 2.55 (s, 1H), 2.01 (d, J = 8.8 Hz, 2H), 1.90 (s, 2H), 1.74 (s, 2H)

[0413] Compound 3. 3-(5-(1-(5-chloro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0414] [ka]

[0415] Intermediates 7 Compound 3 was synthesized in the same manner as compound 1, except that 5-chloro-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0416] 1H NMR (500 MHz, DMSO-d6) δ 11.82 (s, 1H), 11.00 (s, 1H), 7.70-7.66 (m, 2H), 7.56 (s, 1H), 7.45 (t, J = 9.2 Hz, 2H), 7.20 (dd, J = 8.7, 2.2 Hz, 1H), 6.82 (s, 1H), 5.12 (d, J = 12.0 Hz, 1H), 4.60 (s, 2H), 4.44 (d, J = 17.2 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H), 3.05 (s, 2H), 2.92 (s, 1H), 2.61 (d, J = 16.5 Hz, 2H), 2.38 (d, J = 12.7 Hz, 1H), 2.00 (s, 1H), 1.93 (d, J = 12.8 Hz, 2H), 1.74 (s, 2H)

[0417] Compound 4. 3-(5-(1-(4-chloro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0418] [ka]

[0419] Intermediates 7 Compound 4 was synthesized in the same manner as compound 1, except that 4-chloro-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0420] 1H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 11.00 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.15 (d, J = 7.4 Hz, 1H), 6.81 (s, 1H), 5.12 (dd, J = 13.4, 4.9 Hz, 1H), 4.60 (s, 2H), 4.44 (d, J = 17.2 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H),3.10-2.89 (m, 3H), 2.61 (d, J = 17.4 Hz, 2H), 2.44-2.37 (m, 1H), 2.00 (s, 1H), 1.93 (d, J = 11.8 Hz, 2H), 1.76 (s, 2H)

[0421] Compound 5. 3-(5-(1-(6-methoxy-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0422] [ka]

[0423] Intermediates 7 Compound 5 was synthesized in the same manner as compound 1, except that 6-methoxy-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0424] 1H NMR (500 MHz, DMSO-d6) δ 11.40 (s, 1H), 11.00 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.55 (s, 1H), 7.48 (dd, J = 14.7, 8.5 Hz, 2H), 6.90 (d, J = 2.7 Hz, 1H), 6.78 (d, J = 2.4 Hz, 1H), 6.71 (dd, J = 8.9, 2.3 Hz, 1H), 5.12 (dd, J = 13.4, 4.9 Hz, 1H), 4.64 (d, J = 13.0 Hz, 2H), 4.44 (d, J = 17.2 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H), 3.78 (s, 3H), 3.21-3.00 (m, 3H), 2.97-2.88 (m, 1H), 2.65-2.59 (m, 1H), 2.45-2.36 (m, 1H), 2.00 (s, 1H), 1.92 (d, J = 12.8 Hz, 2H), 1.72 (d, J = 13.0 Hz, 2H)

[0425] Compound 6. 3-(5-(1-(4,6-dichloro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0426] [ka]

[0427] Intermediates 7 Compound 6 was synthesized in the same manner as compound 1, except that 4,6-dichloro-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0428] 1H NMR (500 MHz, DMSO-d6) δ 12.15 (s, 1H), 11.00 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.56 (s, 1H), 7.47 (d, J = 10.6 Hz, 2H), 7.26 (d, J = 2.2 Hz, 1H), 6.84 (d, J = 2.9 Hz, 1H), 5.12 (dd, J = 13.3, 5.0 Hz, 1H), 4.58 (s, 2H), 4.44 (d, J = 17.2 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H), 3.09-3.00 (m, 1H), 2.92 (t, J = 15.3 Hz, 1H), 2.62-2.59 (m, 1H), 2.44-2.37 (m, 1H), 1.99 (d, J = 10.4 Hz, 1H), 1.93 (d, J = 12.6 Hz, 2H), 1.75 (s, 2H)

[0429] Compound 7. 3-(5-(1-(6-fluoro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0430] [ka]

[0431] Intermediates 7 Compound 7 was synthesized in the same manner as compound 1, except that 6-fluoro-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0432] 1H NMR (500 MHz, DMSO-d6) δ 11.67 (s, 1H), 10.99 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.63 (dd, J = 8.7, 5z.8 Hz, 1H), 7.54 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 10.1 Hz, 1H), 6.95-6.89 (m, 1H), 6.86 (s, 1H), 5.11 (dd, J = 13.3, 4.9 Hz, 1H), 4.61 (d, J = 12.9 Hz, 2H), 4.43 (d, J = 17.1 Hz, 1H), 4.30 (d, J = 17.2 Hz, 1H), 3.12-2.87 (m, 3H), 2.59 (d, J = 17.1 Hz, 1H), 2.44-2.36 (m, 1H), 2.01-1.96 (m, 1H), 1.91 (d, J = 12.8Hz, 2H), 1.79-1.66 (m, 2H)

[0433] Compound 8. 3-(5-(1-(7-chloro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0434] [ka]

[0435] Intermediates 7 Compound 8 was synthesized in the same manner as compound 1, except that 7-chloro-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0436] 1H NMR (500 MHz, DMSO-d6) δ 11.85 (s, 1H), 11.01 (s, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 7.07 (t, J = 7.7 Hz, 1H), 6.85 (s, 1H), 5.12 (dd, J = 13.4, 4.9 Hz, 1H), 4.66 (s, 1H), 4.45 (d, J = 17.1 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H), 4.25 (s, 1H), 3.09-2.89 (m, 3H), 2.61 (k, J = 17.1 Hz, 1H), 2.45-2.36 (m, 1H), 2.06-1.95 (m, 1H), 1.90 (s, 2H), 1.74 (s, 2H)

[0437] Compound 9. 3-(5-(1-(1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0438] [ka]

[0439] Intermediates 7 Compound 9 was synthesized in the same manner as compound 1, except that 1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0440] 1H NMR (300 MHz, DMSO-d6) δ 11.59 (m, 1H), 11.00 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.45 (t, J = 8.1 Hz, 2H), 7.19 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.83 (d, J = 2.1 Hz, 1H), 4.63 (d, J = 12.7 Hz, 1H), 4.44 (d, J = 17.2 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 3.28-2.85 (m, 4H), 2.64-2.56 (m, 1H), 2.44-2.32 (m, 1H), 2.04-1.88 (m, 3H), 1.80-1.65 (m, 2H)

[0441] Compound 10. 3-(5-(1-(5-methoxy-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0442] [ka]

[0443] Intermediates 7 Compound 10 was synthesized in the same manner as compound 1, except that 5-methoxy-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0444] 1H NMR (300 MHz, DMSO-d6) δ 11.44 (s, 1H), 11.00 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 8.9 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.84 (dd, J = 8.9, 2.5 Hz, 1H), 6.74 (d, J = 2.1 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.62 (d, J = 13.0 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 3.76 (s, 3H), 3.23-2.85 (m, 4H), 2.64-2.56 (m, 1H), 2.45-2.26 (m, 1H), 2.04-1.87 (m, 3H), 1.80-1.65 (m, 2H)

[0445] Compound 11. 3-(5-(1-(4-methoxy-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0446] [ka]

[0447] Intermediates 7 Compound 11 was synthesized in the same manner as compound 1, except that 4-methoxy-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0448] 1H NMR (300 MHz, DMSO-d6) δ 11.60 (d, J = 2.3 Hz, 1H), 10.99 (s, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.56 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.78 (d, J = 2.2 Hz, 1H), 6.53 (d, J = 7.5 Hz, 1H), 5.11 (dd, J = 13.3, 5.0 Hz, 1H), 4.63 (d, J = 12.9 Hz, 2H), 4.44 (d, J = 17.2 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 3.88 (s, 3H), 3.24-2.91 (m, 4H), 2.62 (s, 1H), 2.57 (s, 1H), 2.05-1.90 (m, 3H), 1.73 (d, J = 12.8 Hz, 2H)

[0449] Compound 12. 3-(5-(1-(7-methoxy-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0450] [ka]

[0451] Intermediates 7 Compound 12 was synthesized in the same manner as compound 1, except that 7-methoxy-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0452] 1H NMR (300 MHz, DMSO-d6) δ 11.48 (s, 1H), 10.99 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.54 (s, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 6.97 (t, J = 7.8 Hz, 1H), 6.76-6.69 (m, 2H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 3.92 (s, 3H), 3.18-2.82 (m, 4H), 2.63 (s, 1H), 2.57 (s, 1H), 2.08-1.65 (m, 5H)

[0453] Compound 13. 3-(5-(1-(5-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0454] [ka]

[0455] Intermediates 7 Compound 13 was synthesized in the same manner as compound 1, except that 5-methyl-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0456] 1H NMR (300 MHz, DMSO-d6) δ 11.44 (s, 1H), 10.99 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.55 (s, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.38 (s, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.02 (dd, J = 8.4, 1.6 Hz, 1H), 6.72 (d, J = 2.1 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.62 (d, J = 13.0 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.2 Hz, 1H), 3.23-2.98 (m, 3H), 2.93-2.84 (m, 1H), 2.63 (s, 1H), 2.57 (s, 1H), 2.37 (s, 3H), 2.04-1.88 (m, 3H), 1.80-1.65 (m, 2H)

[0457] Compound 14. 3-(5-(1-(4-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0458] [ka]

[0459] Intermediates 7 Compound 14 was synthesized in the same manner as compound 1, except that 4-methyl-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0460] 1H NMR (300 MHz, DMSO-d6) δ 11.54 (s, 1H), 10.98 (s, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 7.07 (dd, J = 8.2, 7.0 Hz, 1H), 6.84 (s, 1H), 6.83 (d, J = 2.5 Hz, 1H), 5.11 (dd, J = 13.3, 5.0 Hz, 1H), 4.64 (d, J = 12.9 Hz, 2H), 4.44 (d, J = 17.2 Hz, 1H), 4.30 (d, J = 17.2 Hz, 1H), 3.21-2.96 (m, 3H), 2.94-2.84 (m, 1H), 2.65-2.55 (m, 1H), 2.49 (s, 3H), 2.44-2.35 (m, 1H), 2.03-1.89 (m, 3H), 1.80-1.60 (m, 2H)

[0461] Compound 15. 3-(5-(1-(6-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0462] [ka]

[0463] Intermediates 7 Compound 15 was synthesized in the same manner as compound 1, except that 6-methyl-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0464] 1H NMR (300 MHz, DMSO-d6) δ 11.42 (s, 1H), 10.99 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.47 (t, J = 8.8 Hz, 2H), 7.22 (s, 1H), 6.89 (dd, J = 8.2, 1.5 Hz, 1H), 6.77 (d, J = 2.1 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.63 (d, J = 12.9 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.2 Hz, 1H), 3.20-3.00 (m, 3H), 2.94-2.84 (m, 1H), 2.63 (s, 1H), 2.57 (s, 1H), 2.40 (s, 3H), 2.06-1.86 (m, 3H), 1.78-1.63 (m, 2H)

[0465] Compound 16. 3-(5-(1-(7-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0466] [ka]

[0467] Intermediates 7 Compound 16 was synthesized in the same manner as compound 1, except that 7-methyl-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0468] 1H NMR (300 MHz, DMSO-d6) δ 11.44 (s, 1H), 10.99 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.55 (s, 1H), 7.48-7.40 (m, 2H), 6.96 (d, J = 6.1 Hz, 2H), 6.78 (d, J = 2.0 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.59 (d, J = 12.5 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 3.20-2.96 (m, 3H), 2.92-2.86 (m, 1H), 2.60 (d, J = 16.9 Hz, 1H), 2.43-2.37 (m, 1H), 2.04-1.88 (m, 3H), 1.81-1.63 (m, 2H)

[0469] Compound 17. 3-(5-(1-(5-fluoro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0470] [ka]

[0471] Intermediates 7 Compound 17 was synthesized in the same manner as compound 1, except that 5-fluoro-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0472] 1H NMR (300 MHz, DMSO-d6) δ 11.67 (s, 1H), 10.96 (s, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.54 (s, 1H), 7.47-7.33 (m, 3H), 7.07-7.00 (m, 1H), 6.80 (d, J = 2.1 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.59 (d, J = 13.0 Hz, 2H), 4.43 (d, J = 17.2 Hz, 1H), 4.29 (d, J = 17.3 Hz, 1H), 3.20-2.83 (m, 4H), 2.59 (d, J = 18.0 Hz, 1H), 2.42-4.36 (mz, 1H), 2.03-1.88 (m, 3H), 1.78-1.70 (m, 2H)

[0473] Compound 18. 3-(5-(1-(6-hydroxy-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0474] [ka]

[0475] Intermediates 7 Compound 18 was synthesized in the same manner as compound 1, except that 6-hydroxy-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0476] 1H NMR (300 MHz, DMSO-d6) δ 11.14 (s, 1H), 10.97 (s, 1H), 9.15 (s, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.54 (s, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 8.6 Hz, 1H), 6.79 (d, J = 2.1 Hz, 1H), 6.72 (d, J = 2.1 Hz, 1H), 6.58 (dd, J = 8.6, 2.1 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.64 (d, J = 13.0 Hz, 2H), 4.44 (d, J = 17.2 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 3.19-2.84 (m, 4H), 2.60 (d, J = 17.3 Hz, 1H), 2.45-2.26 (m, 1H), 2.02-1.90 (m, 3H), 1.78-1.65 (m, 2H)

[0477] Compound 19. 3-(5-(1-(7-fluoro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0478] [ka]

[0479] Intermediates 7 Compound 19 was synthesized in the same manner as compound 1, except that 7-fluoro-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0480] 1H NMR (300 MHz, DMSO-d6) δ 12.04 (s, 1H), 10.97 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.45 (dd, J = 8.6, 5.8 Hz, 2H), 7.07-6.98 (m, 2H), 6.86 (d, J = 3.1 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.45 (d, J = 17.2 Hz, 3H), 4.31 (d, J = 17.2 Hz, 1H), 3.22-2.83 (m, 4H), 2.64-2.56 (m, 1H), 2.43-2.35 (m, 1H), 2.07-1.84 (m, 4H), 1.80-1.65 (m 2H)

[0481] Compound 20. 3-(5-(1-(4-fluoro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0482] [ka]

[0483] Intermediates 7 Compound 20 was synthesized in the same manner as compound 1, except that 4-fluoro-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0484] 1H NMR (300 MHz, DMSO-d6) δ 11.92 (s, 1H), 10.96 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.56 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.121-7.13(m, 1H), 6.89-6.80 (m, 2H), 5.09 (d, J = 5.1 Hz, 1H), 4.60 (d, J = 13.1 Hz, 2H), 4.44 (d, J = 17.2 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 3.24-2.86 (m, 4H), 2.63-2.57 (m, 1H), 2.44-2.38 (m, 1H), 2.09-1.89 (m, 3H), 1.85-1.70 (m, 2H)

[0485] Compound 21. 3-(5-(1-(3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0486] [ka]

[0487] Intermediates 7 Compound 21 was synthesized in the same manner as compound 1, except that 3-methyl-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0488] 1H NMR (300 MHz, DMSO-d6) δ 11.20 (s, 1H), 10.97 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.58-7.50 (m, 2H), 7.43 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.21-7.12 (m, 1H), 7.04 (t, J = 7.4 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.45 (d, J = 17.2 Hz, 1H), 4.31 (d, J = 17.2Hz, 3H), 3.17-2.84 (m, 4H), 2.65-2.55 (m 1H), 2.45-2.35 (m, 1H), 2.31 (s, 3H), 2.04-1.84 (m, 3H), 1.77-1.59 (m, 2H)

[0489] Compound 22. 3-(5-(1-(3-chloro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0490] [ka]

[0491] Intermediates 7 Compound 22 was synthesized in the same manner as compound 1, except that 3-chloro-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0492] 1H NMR (300 MHz, DMSO-d6) δ 11.91 (s, 1H), 10.97 (s, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.58-7.50 (m, 2H), 7.44 (t, J = 6.8 Hz, 1H), 7.31-7.24 (m, 1H), 7.18 (t, J = 7.5 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.60 (s, 1H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H), 3.89 (s, 1H), 3.24-2.81 (m, 3H), 2.61 (d, J = 17.6 Hz, 2H), 2.09-1.84 (m, 3H), 1.77-1.68 (m, 2H)

[0493] Compound 23. 3-(5-(3-(1-(1H-indole-3-carbonyl)piperidin-4-yl)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0494] [ka]

[0495] Intermediates 28 Compound 23 was synthesized using the same method as that for compound 1 using 1H-indole-2-carboxylic acid.

[0496] 1H NMR (300 MHz, DMSO-d6) δ 11.55 (s, 1H), 11.00 (s, 1H), 7.70-7.64 (m, 4H), 7.52 (d, J = 7.9 Hz, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.19-7.05 (m, 2H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.45 (d, J = 17.5 Hz, 1H), 4.32 (d, J = 12.6 Hz, 3H), 3.17 (d, J = 5.3 Hz, 1H), 3.03-2.83 (m, 3H), 2.60 (d, J = 18.0 Hz, 2H), 2.42 -2.25 (m, 1H), 2.03-1.72 (m, 4H), 1.39-1.19 (m, 2H)

[0497] Compound 24. 3-(5-((1-(1H-indole-2-carbonyl)piperidin-4-ylidene)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0498] [ka]

[0499] Intermediates 25 Compound 24 was synthesized using the same method as that for compound 1 using 1H-indole-2-carboxylic acid.

[0500] 1H NMR (300 MHz, DMSO-d6 )δ 11.61 (s, 1H), 11.00 (s, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.50 (s, 1H), 7.42 (t, J = 8.6 Hz, 2H),7.19 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.84 (d, J = 2.1 Hz, 1H), 6.57 (s, 1H), 5.12 (dd, J = 13.3, 5.0 Hz, 1H), 4.47 (d, J = 17.3 Hz, 1H), 4.33 (d, J = 17.3 Hz, 1H), 3.87 (s, 2H), 3.78 (s, 2H), 2.99-2.83 (m, 1H), 2.65-2.60 (m, 4H), 2.53-2.41 (m, 1H), 2.05-1.94 (m, 1H)

[0501] Compound 25. 3-(5-((1-(1H-indole-3-carbonyl)piperidin-4-ylidene)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0502] [ka]

[0503] Intermediates 25 Compound 25 was synthesized using the same method as that for compound 1 using 1H-indole-2-carboxylic acid.

[0504] 1H NMR (300 MHz, DMSO-d6) δ 11.60 (s, 1H), 11.00 (s, 1H), 7.72 (t, J = 3.4 Hz, 2H), 7.69 (d, J = 3.8 Hz, 1H), 7.48 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.20-7.13 (m, 1H), 7.13-7.07 (m, 1H), 6.54 (s, 1H), 5.12 (dd, J = 13.2, 5.0 Hz, 1H), 4.45 (d, J = 17.4 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 3.75 (t, J = 5.8 Hz, 2H), 3.65 (d, J = 6.3 Hz, 2H), 2.99-2.85 (m, 1H), 2.65-2.53 (m, 4H), 2.47-2.40 (m, 2H), 2.03-1.95 (m, 1H)

[0505] Compound 26. 3-(5-((1-(6-chloro-1H-indole-2-carbonyl)piperidin-4-ylidene)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0506] [ka]

[0507] Intermediates 25 Compound 26 was synthesized using the same method as that for compound 1 using 6-chloro-1H-indole-2-carboxylic acid.

[0508] 1H NMR (300 MHz, DMSO-d6) δ 11.77 (s, 1H), 11.00 (s, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.50 (s, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.42-7.36 (m, 1H), 7.08 (dd, J = 8.5, 1.9 Hz, 1H), 6.89 (d, J = 2.5 Hz, 1H), 6.57 (s, 1H), 5.13 (dd, J = 13.2, 5.0 Hz, 1H), 4.46 (d, J = 17.4 Hz, 1H), 4.33 (d, J = 17.3 Hz, 1H), 3.86 (s, 2H), 3.77 (s, 2H), 3.03-2.81 (m, 1H), 2.62 (s, 4H), 2.43-2.33 (m, 1H), 2.03-1.99 (m, 1H)

[0509] Compound 27. 3-(5-((1-(3-methyl-1H-indole-2-carbonyl)piperidin-4-ylidene)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0510] [ka]

[0511] Intermediates 25 Compound 27 was synthesized using the same method as that for compound 1 using 3-methyl-1H-indole-2-carboxylic acid.

[0512] 1H NMR (300 MHz, DMSO-d6) δ 11.25 (s, 1H), 11.00 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.48 (s, 1H), 7.36(t, J = 9.0 Hz 2H),7.17 (t, J = 7.0 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.55 (s, 1H), 5.11 (dd, J = 13.2, 5.0 Hz, 1H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 3.68 (s, 2H), 3.58 (s, 2H), 2.98-2.86z (m, 1H), 2.66-2.52 (m, 3H), 2.43 (s, 2H), 2.29 (s, 3H), 2.10-1.93 (m, 1H)

[0513] Compound 28. 3-(5-(1-(1,3-dimethyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0514] [ka]

[0515] Compound 28 was synthesized in the same manner as compound 1, except that 1,3-dimethyl-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0516] 1H NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.67 (dd, J = 7.8, 4.0 Hz, 1H), 7.59-7.52 (m, 2H), 7.49-7.41 (m, 2H), 7.23 (t, J = 7.6 Hz, 1H), 7.13-6.98 (m, 1H), 5.11 (dd, J = 13.1, 5.1 Hz, 1H), 4.76 (d, J = 13.0 Hz, 1H), 4.44 (dd, J = 17.4, 4.1 Hz, 1H), 4.30 (dd, J = 17.3, 3.7 Hz, 1H), 3.81 (d, J = 13.3 Hz, 1H), 3.73 (s, 2H), 3.65 (s, 1H), 3.10-2.80 (m, 2H), 2.60 (d, J = 19.4 Hz, 2H), 2.31 (s, 1H), 2.23 (s, 2H), 2.05-1.90 (s, 2H), 1.80-1.45 (m, 2H)

[0517] Compound 29. 3-(5-(1-(3-ethyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0518] [ka]

[0519] Compound 29 was synthesized in the same manner as compound 1, except that 3-ethyl-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0520] 1H NMR (300 MHz, DMSO-d6) δ 11.21 (s, 1H), 11.00 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.51 (s, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.18-7.11 (m, 1H), 7.06-7.00 (m, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 3.15-2.84 (m, 4H), 2.79-2.72 (m, 2H), 2.60 (d, J = 17.0 Hz, 1H), 2.43-2.37 (m, 1H), 2.05-1.92 (m, 1H), 1.88 (d, J = 12.6 Hz, 2H), 1.72-1.60 (m, 2H), 1.23 (t, J = 7.5 Hz, 3H)

[0521] Compound 30. 3-(5-(1-(3-methoxy-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0522] [ka]

[0523] Compound 30 was synthesized in the same manner as compound 1, except that 3-methoxy-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0524] 1H NMR (500 MHz, DMSO-d6) δ δ 11.07 (s, 1H), 10.99 (s, 1H), 7.67 (t, J = 7.6 Hz, 2H), 7.53 (s, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.20-7.15 (m, 1H), 7.07-6.98 (m, 1H), 5.11 (dd, J = 13.2, 5.0 Hz, 1H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 3.97 (s, 3H), 3.25-2.85 (m, 4H), 2.58 (s, 1H), 2.44-2.28 (m, 1H), 2.05-1.91 (m, 3H), 1.77-1.59 (m, 2H)

[0525] Compound 31. 3-(5-(1-(3-methyl-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0526] [ka]

[0527] Compound 31 was synthesized in the same manner as compound 1, except that 3-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0528] 1H NMR (300 MHz, DMSO-d6) δ 11.75 (s, 1H), 10.99 (s, 1H), 8.27 (dd, J = 4.7, 1.6 Hz, 1H), 7.99 (dd, J = 8.0, 1.6 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.10 (dd, J = 7.9, 4.6 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4,70 (s,1 H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H), 3.90 (s,1 H), 3.18-2.84 (m, 4H), 2.60 (d, J = 16.8 Hz, 1H), 2.46-2.37 (m, 1H), 2.29 (s, 3H), 2.05-1.95 (m, 1H), 1.86 (s, 2H), 1.76-1.63 (m, 2H)

[0529] Compound 32. 3-(5-(1-(6-amino-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0530] [ka]

[0531] Compound 32 was synthesized in the same manner as compound 1, except that 6-amino-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0532] 1H NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.92 (s, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.54 (s, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 6.64 (s, 1H), 6.55 (s, 1H), 6.44 (dd, J = 8.5, 2.0 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.99 (s, 1H), 4.64 (d, J = 12.8 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 3.81 (s, 1H), 3.20-2.82 (m, 3H), 2.65-2.54 (m, 2H), 2.38 (d, J = 4.2 Hz, 1H), 2.06-1.84 (m, 3H), 1.76-1.67 (m, 2H)

[0533] Compound 33. 3-(5-(1-(5-bromo-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0534] [ka]

[0535] Compound 33 was synthesized in the same manner as compound 1, except that 5-bromo-3-methyl-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0536] 1H NMR (300 MHz, DMSO-d6) δ 11.46 (s, 1H), 10.99 (s, 1H), 7.75 (d, J = 1.8 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.6 Hz, 1H), 7.27 (dd, J = 8.6, 1.8 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 3.26-2.81 (m, 4H), 2.60 (d, J = 19.4 Hz, 1H), 2.47-2.37 (m, 1H), 2.01-1.97 (m, 3H), 1.73-1.64 (m, 2H)

[0537] Compound 34. 3-(5-(1-(3-(morpholinomethyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0538] [ka]

[0539] Compound 34 was synthesized in the same manner as compound 1, except that 3-(morpholinomethyl)-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0540] 1H NMR (300 MHz, DMSO) δ 11.41 (s, 1H), 10.99 (s, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.50 (s, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.04 (t, J = 7.4 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H), 3.66 (s, 2H), 3.53 (t, J = 4.6 Hz, 4H), 3.19-2.83 (m, 4H), 2.63-2.57 (m, 1H), 2.42 (d, J = 4.5 Hz, 1H), 2.36 (s, 4H), 2.03-1.81 (m, 3H), 1.78-1.59 (m, 2H)

[0541] Compound 35. 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-1H-indole-3-carbaldehyde

[0542] [ka]

[0543] Compound 35 was synthesized in the same manner as compound 1, except that 3-formyl-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0544] 1H NMR (300 MHz, DMSO-d6) δ 12.68 (s, 1H), 11.00 (s, 1H), 10.03 (s, 1H), 8.15 (dd, J = 6.9, 1.7 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 6.2 Hz, 2H), 7.45 (d, J = 7.6 Hz, 1H), 7.36-7.25 (m, 2H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.72 (s, 1H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 3.63 (s, 1H), 3.30 (s, 1H), 3.12-2.82 (m, 4H), 2.60 (d, J = 16.8 Hz, 1H), 2.44-2.27 (m, 1H), 2.07-1.87 (m, 2H), 1.80-1.60 (m, 3H)

[0545] Compound 36. 3-(5-(1-(3-bromo-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0546] [ka]

[0547] Compound 36 was synthesized in the same manner as compound 1, except that 3-bromo-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0548] 1H NMR (300 MHz, DMSO) δ 12.03 (s, 1H), 11.00 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.52-7.40 (m, 4H), 7.27 (td, J = 7.6, 1.3 Hz, 1H), 7.18 (td, J = 7.4, 1.1 Hz, 1H), 5.11 (dd, J = 13.2, 5.0 Hz, 1H), 4.66 (s, 1H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 3.78 (s, 1H), 3.21-2.83 (m, 4H), 2.66-2.56 (m, 1H), 2.44-2.26 (m, 1H), 2.04-1.82 (m, 3H), 1.80-1.60 (m, 2H)

[0549] Compound 37. 3-(5-(1-(3-fluoro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0550] [ka]

[0551] Compound 37 was synthesized in the same manner as compound 1, except that 3-fluoro-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0552] 1H NMR (500 MHz, DMSO-d6) δ 11.46 (s, 1H), 11.00 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.54 (s, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.5 Hz, 1H), 5.12 (d, J = 13.5 Hz, 1H), 4.61 (s, 1H), 4.45 (d, J = 17.1 Hz, 1H), 4.31 (d, J = 17.1 Hz, 1H), 4.17 (s, 1H), 3.13-2.84 (m, 3H), 2.70-2.55 (m, 2H), 2.46-2.33 (m, 1H), 2.06-1.85 (m, 3H), 1.75-1.65 (m, 2H)

[0553] Compound 38. 3-(5-(1-(5-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0554] [ka]

[0555] Compound 38 was synthesized in the same manner as compound 1, except that 5-chloro-3-methyl-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0556] 1H NMR (500 MHz, DMSO-d6) δ 11.46 (s, 1H), 11.00 (s, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 7.52 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.7 Hz, 1H), 7.17 (dd, J = 8.9, 2.1 Hz, 1H), 5.12 (dd, J = 13.3, 5.0 Hz, 1H), 4.44 (d, J = 17.2 Hz, 1H), 4.31 (d, J = 17.1 Hz, 1H), 3.24-2.86 (m, 4H), 2.66-2.57 (m, 1H), 2.48-2.34 (m, 1H), 2.28 (s, 3H), 2.04-1.80 (m, 3H), 1.75-1.65 (m, 2H)

[0557] Compound 39. 3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0558] [ka]

[0559] Compound 39 was synthesized in the same manner as compound 1, except that 6-chloro-3-methyl-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0560] 1H NMR (500 MHz, DMSO-d6) δ 11.43 (s, 1H), 11.00 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.52 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.38 (s, 1H), 7.06 (d, J = 8.6 Hz, 1H), 5.12 (d, J = 13.5 Hz, 1H), 4.44 (d, J = 17.2 Hz, 1H), 4.31 (d, J = 17.1 Hz, 1H), 3.19-2.88 (m, 4H), 2.66-2.56 (m, 1H), 2.45-2.34 (m, 1H), 2.30 (s, 3H), 2.05-1.80 (m, 3H), 1.75-1.60. (m, 2H)

[0561] Compound 40. 3-(5-(1-(5,6-dimethoxy-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0562] [ka]

[0563] Compound 40 was synthesized in the same manner as compound 1, except that 5,6-dimethoxy-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0564] 1H NMR (500 MHz, DMSO-d6) δ 11.29 (s, 1H), 11.00 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.55 (s, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.08 (s, 1H), 6.91 (s, 1H), 6.72 (d, J = 2.2 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.65 (d, J = 12.9 Hz, 2H), 4.44 (d, J = 17.2 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 3.23-2.98 (m, 3H), 2.95-2.85 (m, 1H), 2.67-2.57 (m, 1H), 2.47-2.34 (m, 1H), 2.05-1.86 (m, 3H), 1.72 (q, J = 12.3Hz, 2H)

[0565] Compound 41. 3-(1-oxo-5-(1-(6-(trifluoromethyl)-1H-indole-2-carbonyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0566] [ka]

[0567] Compound 41 was synthesized in the same manner as compound 1, except that 6-(trifluoromethyl)-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0568] 1H NMR (500 MHz, DMSO-d6) δ 12.08 (s, 1H), 10.99 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.75 (s, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.34 (dd, J = 8.4, 1.7 Hz, 1H), 6.97 (d, J = 2.1 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.59 (s, 2H), 4.43 (d, J = 17.2 Hz, 1H), 4.30 (d, J = 17.2 Hz, 1H), 3.28-2.99 (m, 3H), 2.95-2.84 (m, 1H), 2.66-2.56 (m, 1H), 2.44-2.34 (m, 1H), 2.03-1.88 (m, 3H), 1.75 (s, 2H)

[0569] Compound 42. 3-(5-(1-(6-methoxy-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0570] [ka]

[0571] Compound 42 was synthesized in the same manner as compound 1, except that 6-methoxy-3-methyl-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0572] 1H NMR (300 MHz, DMSO-d6) δ 11.02 (s, 1H), 10.99 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.44 (d, J = 2.j4 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 6.82 (d, J = 2.2 Hz, 1H), 6.69 (dd, J = 8.7, 2.3 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.3 Hz, 3H), 3.77 (s, 3H), 3.19-2.83 (m, 4H), 2.66-2.55 (m, 1H), 2.45-2.35 (m, 1H), 2.27 (s, 3H), 2.06-1.84 (m, 3H), 1.76-1.56 (m, 2H)

[0573] Compound 43. 3-(5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0574] [ka]

[0575] Intermediates 31 Compound 43 was synthesized using the same method as that for compound 1 using 6-chloro-3-methyl-1H-indole-2-carboxylic acid.

[0576] 1H NMR (300 MHz, DMSO-d6) δ 11.39 (s, 1H), 11.01 (s, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.68 (s, 1H), 7.56 (t, J = 8.3 Hz, 2H), 7.36 (d, J = 1.9 Hz, 1H), 7.06 (dd, J = 8.5, 1.9 Hz, 1H), 5.12 (dd, J = 13.2, 5.1 Hz, 1H), 4.45 (d, J = 17.6 Hz, 1H), 4.32 (d, J = 17.6 Hz, 1H), 3.86 (s, 2H), 3.50-3.41 (m, 2H), 3.11-3.00 (m, 1H), 2.98-2.84 (m, 1H), 2.64-2.56 (m, 1H), 2.45 - 2.35 (m, 1H), 2.27 (s, 3H), 2.07-1.91 (m, 3H), 1.75-1.61 (m, 2H)

[0577] Compound 44. 3-(5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-ylidene)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0578] [ka]

[0579] Intermediates 25 Compound 44 was synthesized in the same manner as compound 1 using 6-chloro-3-methyl-1H-indole-2-carboxylic acid.

[0580] 1H NMR (300 MHz, DMSO-d6) δ 11.43 (s, 1H), 10.99 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.48 (s, 1H), 7.40-7.34 (m, 2H), 7.06 (dd, J = 8.5, 1.9 Hz, 1H), 6.55 (s, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.45 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 3.62 (d, J = 27.6 Hz, 4H), 3.00-2.82 (m, 1H), 2.63 (s, 1H), 2.47-2.40 (m, 2H), 2.28 (s, 3H), 2.08-1.94 (m, 1H)

[0581] Compound 45. 3-(5-(1-(6-chloro-1H-pyrrolo[3,2-b]pyridine-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0582] [ka]

[0583] Compound 45 was synthesized in the same manner as compound 1, except that 6-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0584] 1H NMR (500 MHz, DMSO) δ 12.30 (s, 1H), 11.01 (s, 1H), 8.40 (d, J = 2.2 Hz, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.56 (s, 1H), 7.47 (d, J = 7.9 Hz, 1H), 6.98 (s, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.70-4.55 (m, 2H), 4.44 (d, J = 17.2 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H), 3.15-2.88 (m, 4H), 2.63-2.58 (m, 1H), 2.46-2.36 (m, 1H), 2.03-1.90 (m, 3H), 1.86-1.68 (m, 2H)

[0585] Compound 46. 3-(5-(1-(6-chloro-1H-pyrrolo[3,2-c]pyridine-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0586] [ka]

[0587] Compound 46 was synthesized in the same manner as compound 1, except that 6-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0588] 1H NMR (300 MHz, DMSO-d6) δ 12.30 (s, 1H), 11.01 (s, 1H), 8.73 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.41 (s, 1H), 7.02 (s, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.56 (s, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 3.2202.86 (m, 4H), 2.66-2.56 (m, 1H), 2.45-2.27 (m, 1H), 2.04-j1.86 (m, 3H), 1.84-1.58 (m, 2H)

[0589] Compound 47. 3-(5-(1-(6-hydroxy-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0590] [ka]

[0591] Compound 47 was synthesized in the same manner as compound 1, except that 6-hydroxy-3-methyl-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0592] 1H NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.78 (s, 1H), 9.11 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.51 (s, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 6.69 (d, J = 2.0 Hz, 1H), 6.56 (dd, J = 8.5, 2.1 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.44 (d, J = 17.2 Hz, 1H), 4.37-4.21 (m, 3H), 3.12-2.91 (m, 3H), 2.67-2.55 (m, 1H), 2.44-2.30 (m, 1H), 2.25 (s, 3H), 2.03-1.97 (m, 1H), 1.92-1.84 (m, 2H), 1.75-1.60 (m, 2H)

[0593] Compound 48. 3-(5-(1-(3-methyl-6-(trifluoromethyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0594] [ka]

[0595] Compound 48 was synthesized in the same manner as compound 1, except that 3-methyl-6-(trifluoromethyl)-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0596] 1H NMR (300 MHz, DMSO-d6) δ 11.76 (s, 1H), 11.00 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.71-7.65 (m, 2H), 7.52 (s, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.33 (dd, J = 8.4, 1.6 Hz, 1H), 5.11 (dd, J = 13.3, 5.0 Hz, 1H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 3.24-2.84 (m, 4H), 2.66-2.56 (m, 1H), 2.40 (dd, J = 13.1, 4.5 Hz, 1H), 2.33 (s, 1H). 2.09-1.80 (m, 3H), 1.77-1.56 (m, 2H)

[0597] Compound 49. 3-(5-(1-(6-bromo-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0598] [ka]

[0599] Compound 49 was synthesized in the same manner as compound 1, except that 6-bromo-3-methyl-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0600] 1H NMR (300 MHz, DMSO-d6) δ 11.42 (s, 1H), 10.99 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.55-7.50 (m, 2H), 7.43 (d, J = 7.9 Hz, 1H), 7.17 (dd, J = 8.4, 1.9 Hz, 1H), 5.11 (dd, J = 13.2, 5.0 Hz, 1H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 3.22-2.83 (m, 4H), 2.64-2.56 (m, 1H), 2.46-2.30 (m, 1H), 2.29 (s, 3H), 2.04-1.80 (m, 3H), 1.75-1.58 (m, 2H)

[0601] Compound 50. 3-(5-(1-(6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0602] [ka]

[0603] Compound 50 was synthesized in the same manner as compound 1, except that 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0604] 1H NMR (300 MHz, DMSO-d6) δ 12.40 (s, 1H), 11.02 (s, 1H), 8.09 (d, J = 8.3 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 6.84 (s, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.66-4.39 (m, 3H), 4.30 (d, J = 17.3 Hz, 1H), 3.23-2.83 (m, 4H), 2.66-2.56 (m, 1H), 2.44-2.24 (m, 1H), 2.07-1.85 (m, 3H), 1.83-1.63 (m, 2H)

[0605] Compound 51. 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-1H-indole-3-carbonitrile

[0606] [ka]

[0607] Compound 51 was synthesized in the same manner as compound 1, except that 3-cyano-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0608] 1H NMR (300 MHz, DMSO-d6) δ 12.80 (s, 1H), 10.99 (s, 1H), 7.69 (dd, J = 7.8, 3.9 Hz, 2H), 7.56 (d, J = 1.3 Hz, 1H), 7.51 (s, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.40-7.24 (m, 2H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H),4.70 (s,1 H) 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 4.05 (s, 1H), 3.23-2.83 (m, 4H), 2.67-2.55 (m, 1H), 2.45-2.33 (m, 1H), 2.04-1.90 (m, 3H), 1.82-1.60 (m, 2H)

[0609] Compound 52. 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-3-methyl-1H-indole-6-carbonitrile

[0610] [ka]

[0611] Compound 52 was synthesized in the same manner as compound 1, except that 6-cyano-3-methyl-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0612] 1H NMR (500 MHz, DMSO-d6) δ 11.91 (s, 1H), 11.00 (s, 1H), 7.84 (s, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.52 (s, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.39 (dd, J = 8.3, 1.4 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.66 (s, 1H), 4.44 (d, J = 17.2 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H), 3.77 (s, 1H), 3.25-2.82 (m, 4H), 2.64-2.58 (m, 1H), 2.45-2.35 (m, 1H), 2.04-1.82 (m, 3H), 1.76-1.60 (m, 2H)

[0613] Compound 53. 3-(5-(1-(3-methyl-6-(trifluoromethoxy)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0614] [ka]

[0615] Compound 53 was synthesized in the same manner as compound 1, except that 3-methyl-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0616] 1H NMR (300 MHz, DMSO-d6) δ11.54 (s, 1H), 10.99 (s, 1H), 7.67 (dd, J = 8.3, 6.7 Hz, 2H), 7.52 (s, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.30 (s, 1H), 7.03 (ddd, J = 8.7, 2.2, 1.1 Hz, 1H), 5.11 (dd, J = 13.3, 5.0 Hz, 1H), 4.44 (d, J = 17.3 Hz, 1H), 4.35-3.88 (m, 3H), 3.23-2.84 (m, 4H), 2.66-2.56 (m, 1H), 2.45-2.37 (m, 1H), 2.31 (s, 3H), 2.05-1.83 (m, 3H), 1.77-1.60 (m, 2H)

[0617] Compound 54. 3-(5-(1-(6-fluoro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0618] [ka]

[0619] Compound 54 was synthesized in the same manner as compound 1, except that 6-fluoro-3-methyl-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0620] 1H NMR (500 MHz, DMSO-d6) δ 11.34 (s, 1H), 11.00 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.60-7.54 (m, 1H), 7.52 (s, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.14-7.06 (m, 1H), 6.94-6.88 (m, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.44 (d, J = 17.2 Hz, 1H), 4.31 (d, J = 17.1 Hz, 1H), 3.21-2.86 (m, 4H), 2.66-2.56 (m, 1H), 2.46-2.34 (m, 2H), 2.30 (s, 2H), 2.03-1.97 (m, 1H), 1.93-1.85 (m, 2H), 1.72-1.62 (m, 2H).

[0621] Compound 55. 3-(5-(1-(3-methyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0622] [ka]

[0623] Compound 55 was synthesized in the same manner as compound 1, except that 3-methyl-6-nitro-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0624] 1H NMR (300 MHz, DMSO-d6 δ 12.10 (s, 1H), 11.01 (s, 1H), 8.28 (d, J = 2.1 Hz, 1H), 7.93 (dd, J = 8.9, 2.1 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.44 (dd, J = 8.0, 1.2 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.55 (s, 1H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 3.85 (s, 1H), 3.13-2.82 (m, 4H), 2.65-2.56 (m, 1H), 2.44-2.36 (m, 1H), 2.02-1.82 (m, 3H), 1.75-1.57 (m, 2H)

[0625] Compound 56. 3-(5-(1-(6-(tert-butyl)-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0626] [ka]

[0627] Compound 56 was synthesized in the same manner as compound 1, except that 6-(tert-butyl)-3-methyl-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0628] 1H NMR (300 MHz, DMSO-d6) δ 11.05 (s, 1H), 10.99 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 1.6 Hz, 1H), 7.14 (dd, J = 8.5, 1.7 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.50 - 4.21 (m, 3H), 3.21 - 2.83 (m, 4H), 2.66 - 2.54 (m, 1H), 2.43 - 2.36 (m, 1H), 2.28 (s, 3H), 2.04 - 1.82 (m, 3H), 1.76 - 1.57 (m, 2H), 1.33 (s, 9H)

[0629] Compound 57. 3-(5-(8-(6-chloro-1H-indole-2-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0630] [ka]

[0631] Intermediates 22 Compound 57 was synthesized using the same method as that for compound 1 using 6-chloro-1H-indole-2-carboxylic acid.

[0632] 1H NMR (300 MHz, DMSO-d6) δ 11.77 (s, 1H), 10.99 (s, 1H), 7.69-7.59 (m, 2H), 7.56-7.42 (m, 3H), 7.08 (dt, J = 8.5, 2.4 Hz, 1H), 7.03 (d, J = 4.7 Hz, 1H), 5.10 (dd, J = 13.2, 4.8 Hz, 1H), 4.93-4.78 (m, 2H), 4.42 (dd, J = 17.4, 4.6 Hz, 1H), 4.28 (dd, J = 17.2, 4.6 Hz, 1H), 3.02-2.75 (m, 2H), 2.64-2.56 (m, 1H), 2.43-2.32 (m, 1H), 2.06-1.76 (m, 9H)

[0633] Compound 58. 3-(5-(8-(6-chloro-3-methyl-1H-indole-2-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0634] [ka]

[0635] Intermediates 22 Compound 58 was synthesized using the same method as that for compound 1 using 6-chloro-3-methyl-1H-indole-2-carboxylic acid.

[0636] 1H NMR (300 MHz, DMSO-d6) δ 11.51 (d, J = 3.6 Hz, 1H), 10.99 (s, 1H), 7.67 (dd, J = 7.9, 2.9 Hz, 1H), 7.62-7.56 (m, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 2.0 Hz, 1H), 7.06 (dt, J = 8.5, 2.3 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.73-4.51 (m, 1H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 4.25-4.10 (m, 1 H), 3.00-2.84 (m, 2H), 2.64-2.57 (m, 1H), 2.44-2.36 (m, 1H), 2.33 (d, J = 8.0 Hz, 3H), 2.08-1.69 (m, 9H)

[0637] Compound 59. 3-(5-(1-(6-chloro-1H-indole-2-carbonyl)-2-methylpiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0638] [ka]

[0639] Intermediates 16 Compound 59 was synthesized using the same method as that for compound 1 using 6-chloro-1H-indole-2-carboxylic acid.

[0640] 1H NMR (300 MHz, DMSO-d6) δ 11.76 (s, 1H), 10.99 (s, 1H), 7.72-7.61 (m, 2H), 7.56 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.07 (dd, J = 8.5, 1.9 Hz, 1H), 6.91-6.83 (m, 1H), 5.11 (dd, J = 13.2, 5.0 Hz, 1H), 4.44 (d, J = 17.0 Hz, 1H), 4.30 (d, J = 17.2 Hz, 1H), 4.25-4.14 (m, 1H), 3.01-2.84 (m, 2H), 2.65-2.56 (m, 1H), 2.41-2.35 (m, 1H), 2.05-1.84 (m, 4H), 1.81-1.69 (m, 1H), 1.50-1.37 (m, 1H), 1.31 (d, J = 6.3 Hz, 3H)

[0641] Compound 60. 3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)-2-methylpiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0642] [ka]

[0643] Intermediates 16 Compound 60 was synthesized in the same manner as compound 1 using 6-chloro-3-methyl-1H-indole-2-carboxylic acid.

[0644] 1H NMR (300 MHz, DMSO-d6) δ 11.42 (s, 1H), 10.99 (s, 1H), 7.68 (dd, J = 7.9, 1.8 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.54 (s, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.37 (d, J = 1.9 Hz, 1H), 7.06 (dd, J = 8.5, 1.9 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.44 (d, J = 17.2 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 4.24-4.17 (m, 1H), 3.65-3.57 (m, 1H), 3.02-2.86 (m, 2H), 2.65-2.59 (m, 1H), 2.44-2.36 (m, 1H), 2.28 (d, J = 1.8 Hz, 3H), 2.07-1.85 (m, 4H), 1.73-1.62 (m, 1H), 1.40-1.33 (m, 1H), 1.26 (d, J = 6.5 Hz, 3H)

[0645] Compound 61. 3-(5-(1-(6-amino-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0646] [ka]

[0647] Intermediates 7 Compound 61 was synthesized in the same manner as compound 1, except that 6-amino-3-methyl-1H-indole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0648] 1H NMR (500 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.56 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 6.49 (s, 1H), 6.42 (d, J = 8.5 Hz, 1H), 5.11 (dd, J = 13.4, 5.1 Hz, 1H), 4.91 (s, 2H), 4.44 (d, J = 17.2 Hz, 1H), 4.36-4.21 (m, 3H), 3.11-2.90 (m, 4H), 2.67-2.60 (m,, 1H), 2.42-2.36 (m, 1H), 2.22 (s, 3H), 2.04-1.94 (m, 1H), 1.92-1.83 (m, 2H), 1.74-1.60 (m, 2H)

[0649] Compound 62. 3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)-[1,4'-bipiperidin]-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0650] [ka]

[0651] Intermediates 34 Compound 62 was synthesized using the same method as that for compound 1 using 6-chloro-3-methyl-1H-indole-2-carboxylic acid.

[0652] 1H NMR (300 MHz, DMSO-d6) δ 11.39 (s, 1H), 10.99 (s, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.49 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.06 (dd, J = 8.5, 1.9 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.42 (d, J = 17.3 Hz, 1H), 4.28 (d, J = 17.3 Hz, 1H), 3.07-2.82 (m, 5H), 2.66-2.55 (m, 3H), 2.45-2.28 (m, 3H), 2.25 (s, 3H), 2.06-1.93 (m, 2H), 1.87-1.75 (m, 4H), 1.74-1.58 (m, 2H), 1.54-1.37 (m, 3H)

[0653] Compound 63. 3-(5-(1-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)azetidin-3-yl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0654] [ka]

[0655] Intermediates 33 Compound 63 was synthesized using the same method as that for compound 1 using 6-chloro-3-methyl-1H-indole-2-carboxylic acid.

[0656] 1H NMR (300 MHz, DMSO-d6) δ 11.23 (s, 1H), 10.99 (s, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.50 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 1.9 Hz, 1H), 7.07 (dd, J = 8.5, 1.9 Hz, 1H), 5.09 (d, J = 5.0 Hz, 1H), 4.43 (d, J = 17.3 Hz, 1H), 4.33-3.89 (m, 5H), 3.27-3.16 (m, 1H), 3.03-2.85 (m, 3H), 2.75-2.58 (m, 3H), 2.39 (s, 3H), 2.04-1.89 (m, 3H), 1.87-1.64 (m, 4H)

[0657] Compound 64. 3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0658] [ka]

[0659] Intermediates 18 Compound 64 was synthesized using the same method as that for compound 1 using 6-chloro-3-methyl-1H-indole-2-carboxylic acid.

[0660] 1H NMR (300 MHz, DMSO-d6) δ 11.40 (s, 1H), 11.00 (s, 1H), 7.76-7.65 (m, 3H), 7.58 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 1.9 Hz, 1H), 7.06 (dd, J = 1.9, 8.5 Hz, 1H), 5.48 (s, 1H), 5.12 (dd, J = 5.1, 13.2 Hz, 1H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hzz, 1H), 3.56-3.42 (m,1H), 3.01-2.82 (m, 1H), 2.66-2.58 (m, 1H), 2.43-2.37 (m, 2H), 2.29 (s, 3H), 2.14-1.91 (m, 4H), 1.77-1.61 (m, 2H)

[0661] Compound 65. 3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)-2,5-dihydro-1H-pyrrol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0662] [ka]

[0663] Intermediates 12 Compound 65 was synthesized using the same method as that for compound 1 using 6-chloro-3-methyl-1H-indole-2-carboxylic acid.

[0664] 1H NMR (300 MHz, DMSO-d6) δ 11.35 (s, 1H), 10.99 (s, 1H), 7.69 (s, 1H), 7.63-7.43 (m, 3H), 7.37 (s, 1H), 7.05 (d, J = 8.6 Hz, 1H), 5.11 (d, J = 10.5 Hz, 1H), 4.41 (s, 1H), 4.38-4.24 (m, 1H), 3.69-3.57 (m, 5H), 2.99-2.84 (m, 1H), 2.65-2.60 (m, 1H), 2.45-2.36 (m, 2H), 2.33 (s, 3H), 2.14-1.96 (m, 2H)

[0665] Compound 66. 3-(5-(1-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0666] [ka]

[0667] Intermediates 38 Compound 66 was synthesized using the same method as that for compound 1 using 6-chloro-3-methyl-1H-indole-2-carboxylic acid.

[0668] 1H NMR (300 MHz, DMSO-d6) δ 11.43 (s, 1H), 11.02 (s, 1H), 8.87 (d, J = 3.4 Hz, 1H), 8.11 (s, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.38 (s, 1H), 7.07 (d, J = 8.6 Hz, 1H), 5.13 (d, J = 13.1 Hz, 1H), 4.94 (s, 1H), 4.54 (d, J = 17.4 Hz, 1H), 4.43 (s, 1H), 4.23 (s, 2H), 3.07-2.80 (m, 2H), 2.65-2.58 (m, 1H), 2.31 (s, 3H), 2.28-2.20 (m, 2H), 2.12-1.90 (m, 4H)

[0669] Compound 67. 3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)pyrrolidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0670] [ka]

[0671] Intermediates 11 Compound 67 was synthesized using the same method as that for compound 1 using 6-chloro-3-methyl-1H-indole-2-carboxylic acid.

[0672] 1H NMR (500 MHz, DMSO-d6) δ 11.36 (s, 1H), 11.01 (s, 1H), 7.78-7.37 (m, 5H), 7.06 (s, 1H), 5.12 (s, 1H), 4.44 (s, 1H), 4.32 (s, 1H), 4.04-3.86 (m, 3H), 2.97-2.86 (m, 1H), 2.67-2.59 (m, 3H), 2.44-2.36 (m, 2H), 2.33 (s, 3H), 2.22-1.95 (m, 2H)

[0673] Compound 68. 3-(5-((1-(3-methyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0674] [ka]

[0675] Intermediates 31 Compound 68 was synthesized using the same method as that for compound 1 using 3-methyl-6-nitro-1H-indole-2-carboxylic acid.

[0676] 1H NMR (300 MHz, DMSO-d6) δ 12.06 (s, 1H), 11.02 (s, 1H), 8.27 (d, J = 2.1 Hz, 1H), 7.93 (dd, J = 8.9, 2.1 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.68 (s, 1H), 7.55 (dd, J = 7.8, 1.4 Hz, 1H), 5.12 (dd, J = 13.2, 5.0 Hz, 1H), 4.46 (d, J = 17.7 Hz, 1H), 4.32 (d, J = 17.6 Hz, 1H), 3.13-2.86 (m, 4H), 2.65-2.56 (m, 1H), 2.46-2.35 (m, 2H), 2.31 (s, 3H), 2.06-1.88 (s, 4H), 1.74-1.60 (d, J = 10.5 Hz, 2H)

[0677] Compound 69. 3-(5-(1-(3,6-dimethyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0678] [ka]

[0679] Intermediates 7 Compound 69 was synthesized using the same method as that for compound 1 using 3,6-dimethyl-1H-indole-2-carboxylic acid.

[0680] 1H NMR (300 MHz, DMSO-d6) δ 11.05 (s, 1H), 10.99 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.13 (s, 1H), 6.87 (d, J = 8.2 Hz, 1H), 5.11 (dd, J = 13.1, 5.0 Hz, 1H), 4.45 (d, J = 17.3 Hz, 1H), 4.34-4.15 (m, 3H), 3.14-2.86 (m, 4H), 2.67-2.61 (m, 1H), 2.39 (s, 3H), 2.28 (s, 3H), 1.95 (d, J = 21.5 Hz, 3H), 1.76-1.60 (m, 2H)

[0681] Compound 70. 3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0682] [ka]

[0683] Intermediates 5 Compound 70 was synthesized in the same manner as in the synthesis of Compound 1 using the compound from which the tert-Boc group was removed and 6-chloro-3-methyl-1H-indole-2-carboxylic acid.

[0684] 1H NMR (300 MHz, DMSO-d6) δ 11.43 (s, 1H), 10.99 (s, 1H), 7.73-7.66 (m, 2H), 7.65-7.57 (m, 2H), 7.37 (d, J = 1.9 Hz, 1H), 7.07 (dd, J = 8.5, 1.9 Hz, 1H), 6.37 (s, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.46 (d, J = 17.3 Hz, 1H), 4.37-4.27 (m, 3H), 3.82-3.77 (m, 2H), 2.98-2.84 (m, 2H), 2.67-2.62 (m, 3H), 2.30 (s, 3H), 2.05-1.97 (m, 1H)

[0685] Compound 71. 3-(5-(1-(6-chloro-5-methoxy-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0686] [ka]

[0687] Intermediates 1 Compound 71 was synthesized using the same method as that for compound 1 using 6-chloro-5-methoxy-3-methyl-1H-indole-2-carboxylic acid.

[0688] 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 11.00 (s, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.52 (s, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.39 (s, 1H), 7.20 (s, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.44 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H), 3.87 (s, 3H), 3.19-2.87 (m, 4H), 2.68-2.56 (m, 1H), 2.46-2.32 (m, 1H), 2.29 (s, 3H), 2.02-1.85 (m, 3H), 1.74-1.61 (m, 2H)

[0689] Compound 72. 3-(5-(1-(5,6-dichloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0690] [ka]

[0691] Intermediates 1 Compound 72 was synthesized using the same method as that for compound 1 using 5,6-dichloro-3-methyl-1H-indole-2-carboxylic acid.

[0692] 1H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 11.00 (s, 1H), 7.85 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.57 (s, 1H), 7.52 (s, 1H), 7.43 (d, J = 7.9 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.70-4.50 (m, 1H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 4.16-3.66 (m, 1H), 3.16-2.84 (m, 4H), 2.64-2.57 (m, 1H), 2.44-2.33 (m, 1H), 2.03-1.95 (m, 1H), 1.93-1.81 (m, 2H), 1.77-1.59 (m, 2H)

[0693] Compound 73. N-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-3-methyl-1H-indol-6-yl)acetamide

[0694] [ka]

[0695] Compound 61 (15 mg, 0.03 mmol), acetic acid (1.89 μL, 0.033 mmol), EDCI-HCl (6.33 mg, 0.033 mmol), HOBt (4.46 mg, 0.033 mmol), and DIPEA (16 μL, 0.033 mmol) were dissolved in DMF (1 mL) and stirred at room temperature for 12 hours. Upon completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrate was purified by column chromatography to obtain the desired compound 73 (2 mg, 15%).

[0696] 1H NMR (300 MHz, DMSO-d6) δ 11.10 (s, 1H), 11.01 (s, 1H), 9.90 (s, 1H), 7.95 (d, J = 1.0 Hz, 1H), 7.95-7.92 (m, 1H), 7.70-7.63 (m, 2H), 7.52 (s, 1H), 7.51-7.47 (m, 1H), 7.45 (d, J = 1.7 Hz, 1H), 7.42 (d, J = 2.6 Hz, 1H), 7.40-7.34 (m, 1H), 7.06 (dd, J = 8.6, 1.8 Hz, 1H), 5.12 (dd, J = 13.2, 5.1 Hz, 1H), 4.44 (d, J = 17.3 Hz, 1H), 4.35-4.18 (m, 3H), 3.15-2.84 (m, 4H), 2.65-2.56 (m, 1H), 2.44-2.35 (m, 1H), 2.27 (s, 3H), 2.05 (s, 3H), 2.02-1.96 (m, 1H), 1.93-1.83 (m, 2H), 1.75-1.58 (m, 2H)

[0697] Compound 74. N-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-3-methyl-1H-indol-6-yl)methanesulfonamide

[0698] [ka]

[0699] Compound 61 (15 mg, 0.03 mmol) and methanesulfonyl chloride (2.56 μL, 0.033 mmol) were dissolved in dioxane (1 mL) and stirred at 90° C. for 12 hours. Upon completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrate was purified by column chromatography to give the desired compound 74 (3 mg, 15%).

[0700] 1H NMR (300 MHz, DMSO-d6) δ 11.20 (s, 1H), 11.00 (s, 1H), 9.55 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 9.6 Hz, 2H), 7.43 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 1.8 Hz, 1H), 6.95 (dd, J = 8.5, 1.9 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.45 (d, J = 17.3 Hz, 1H), 4.36-4.17 (m, 3H), 3.18-2.95 (m, 4H), 2.90 (s, 3H), 2.65-2.60 (m, 1H), 2.43-2.36 (m, 1H), 2.28 (s, 3H), 2.04-1.84 (m, 3H), 1.74-1.62 (m, 2H)

[0701] Compound 75. 1-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-3-methyl-1H-indol-6-yl)-3-ethylurea

[0702] [ka]

[0703] Compound 61 (15 mg, 0.03 mmol) and isocyanatoethane (2.1 mg, 0.03 mmol) were dissolved in THF (1 mL) and stirred at room temperature for 12 hours. Upon completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrate was purified by column chromatography to give the desired compound 75 (3 mg, 15%).

[0704] 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.96 (s, 1H), 8.41 (s, 1H), 7.71 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.06 (s, 1H), 5.11 (dd, J = 13.4, 5.1 Hz, 1H), 4.44 (d, J = 17.2 Hz, 1H), 4.36-4.18 (m, 3H), 3.11 (t, J = 6.8, 6.8 Hz, 2H), 3.02-2.84 (m, 4H), 2.64-2.56 (m, 1H), 2.42-2.38 (m, 1H), 2.26 (s, 3H), 2.06-1.95 (m, 2H), 1.94-1.80 (m, 3H), 1.06 (t, J = 6.9, 6.9 Hz, 3H)

[0705] Compound 76. 3-(5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)azetidin-3-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0706] [ka]

[0707] Compound 76 was synthesized in the same manner as compound 1 using 6-chloro-3-methyl-1H-indole-2-carboxylic acid and 3-(5-(azetidin-3-ylethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride.

[0708] 1H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 11.02 (s, 1H), 7.75-7.69 (m, 2H), 7.60 (dd, J = 12.1, 8.2 Hz, 2H), 7.38 (s, 1H), 7.07 (dd, J = 8.5, 1.8 Hz, 1H), 5.11 (d, J = 5.1 Hz, 1H), 4.58-4.43 (m, 3H), 4.33 (d, J = 17.5 Hz, 1H), 4.14 (s, 1H), 3.94-3.84 (m, 1H), 2.98-2.85 (m, 1H), 2.64-2.55 (m, 1H), 2.40 (s, 3H), 2.38-2.33 (m, 1H), 2.04-1.97 (m, 1H)

[0709] Compound 77. 3-(5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)-3-hydroxyazetidin-3-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0710] [ka]

[0711] Compound 77 was synthesized in the same manner as compound 1 using 6-chloro-3-methyl-1H-indole-2-carboxylic acid and 3-(5-((3-hydroxyazetidin-3-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride.

[0712] 1H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 11.02 (s, 1H), 7.75 (d, J = 6.8 Hz, 2H), 7.66-7.56 (m, 2H), 7.38 (s, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.88 (s, 1H), 5.12 (dd, J = 13.5, 5.0 Hz, 1H), 4.67-4.41 (m, 3H), 4.39-4.19 (m, 3H), 2.98-2.84 (m, 1H), 2.68-2.57 (m, 1H), 2.41 (s, 3H), 2.39-2.34 (m, 1H), 2.07-1.90 (m, 2H)

[0713] Compound 78. 3-(5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)pyrrolidin-3-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0714] [ka]

[0715] Compound 78 was synthesized in the same manner as compound 1 using 6-chloro-3-methyl-1H-indole-2-carboxylic acid and 3-(1-oxo-5-(pyrrolidin-3-ylethynyl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride.

[0716] 1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 11.02 (s, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.65 (s, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.53 (s, 1H), 7.37 (d, J = 1.8 Hz, 1H), 7.06 (dd, J = 8.5, 1.9 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.45 (d, J = 17.5 Hz, 1H), 4.33 (d, J = 17.5 Hz, 1H), 3.93-3.79 (m, 1H), 3.77-3.66 (m, 1H), 3.65-3.56 (m, 2H), 3.42 (s, 1H), 2.99-2.83 (m, 1H), 2.64-2.58 (m, 1H), 2.45-2.36 (m, 2H), 2.33 (s, 3H), 2.14-1.90 (m, 3H)

[0717] Compound 79. 3-(5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)-3-hydroxypyrrolidin-3-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0718] [ka]

[0719] Compound 79 was synthesized in the same manner as compound 1 using 6-chloro-3-methyl-1H-indole-2-carboxylic acid and 3-(5-((3-hydroxypyrrolidin-3-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride.

[0720] 1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 11.02 (s, 1H), 7.76 - 7.65 (m, 2H), 7.62 - 7.52 (m, 2H), 7.37 (s, 1H), 7.07 (d, J = 8.5 Hz, 1H), 6.18 (d, J = 51.9 Hz, 1H), 5.13 (d, J = 13.3 Hz, 1H), 4.46 (d, J = 17.1 Hz, 1H), 4.34 (d, J = 17.6 Hz, 1H), 3.91 - 3.54 (m, 5H), 2.97 - 2.86 (m, 1H), 2.62 (s, 1H), 2.45 - 2.35 (m, 2H), 2.33 (s, 3H), 2.04 - 1.96 (m, 1H)

[0721] Compound 80. 3-(5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)-4-hydroxypiperidin-4-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0722] [ka]

[0723] Compound 80 was synthesized in the same manner as compound 1 using 6-chloro-3-methyl-1H-indole-2-carboxylic acid and 3-(5-((4-hydroxypiperidin-4-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride.

[0724] 1H NMR (400 MHz, DMSO-d6) δ 11.39 (s, 1H), 11.02 (s, 1H), 7.79-7.68 (m, 2H), 7.64-7.56 (m, 2H), 7.36 (s, 1H), 7.06 (d, J = 8.5 Hz, 1H), 5.97 (s, 1H), 5.13 (dd, J = 13.4, 5.1 Hz, 1H), 4.47 (d, J = 17.5 Hz, 1H), 4.35 (d, J = 17.4 Hz, 1H), 3.85-3.75 (m, 2H), 3.65-3.47 (m, 2H), 2.98-2.84 (m, 1H), 2.65-2.57 (m, 1H), 2.41 (d, J = 11.7 Hz, 1H), 2.04-1.91 (m, 3H), 1.85-1.73 (m, 2H)

[0725] Compound 81. 6-chloro-2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-1H-indole-3-carbaldehyde

[0726] [ka]

[0727] Intermediates 7 Compound 81 was synthesized using the same method as that for compound 1 using 6-chloro-3-formyl-1H-indole-2-carboxylic acid.

[0728] 1H NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 11.00 (s, 1H), 10.02 (s, 1H), 8.13 (d, J = 8.5 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 1.8 Hz, 1H), 7.52 (s, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.32 (dd, J = 8.5, 1.9 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.78-4.64 (m, 1H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H), 3.71-3.56 (m, 1H), 3.32-3.27 (m, 1H), 3.10-2.85 (m, 3H), 2.63-2.58 (m, 1H), 2.45-2.32 (m, 1H), 2.05-1.89 (m, 2H), 1.83-1.65 (m, 3H)

[0729] Compound 82. 3-(5-(1-(6-chloro-3-(morpholinomethyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0730] [ka]

[0731] Intermediates 7 Compound 82 was synthesized in the same manner as compound 1 using 6-chloro-3-(morpholinomethyl)-1H-indole-2-carboxylic acid.

[0732] 1H NMR (400 MHz, DMSO-d6) δ 11.60 (s, 1H), 11.00 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.49 (s, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.39 (s, 1H), 7.06 (d, J = 8.5 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.44 (d, J = 17.2 Hz, 1H), 4.30 (d, J = 17.2 Hz, 1H), 3.63 (s, 2H), 3.52 (s, 4H), 3.05-2.86 (m, 4H), 2.63-2.58 (m, 1H), 2.45-2.39 (m, 1H), 2.34 (s, 4H), 2.01-1.91 (m, 2H), 1.89-1.83 (m, 1H), 1.70-1.60 (m, 2H)

[0733] Compound 83. 3-(5-(1-(5-bromo-6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0734] [ka]

[0735] Intermediates 7 Compound 83 was synthesized in the same manner as compound 1 using 5-bromo-6-chloro-3-methyl-1H-indole-2-carboxylic acid.

[0736] 1H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 10.99 (s, 1H), 7.98 (s, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.57 (s, 1H), 7.51 (s, 1H), 7.42 (d, J = 7.9 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.43 (d, J = 17.2 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 3.17 - 2.85 (m, 4H), 2.63-2.57 (m, 1H), 2.42-2.32 (m, 1H), 2.27 (s, 3H), 2.01-1.82 (m, 3H), 1.71-1.59 (m, 2H)

[0737] Compound 84. 3-(5-(1-(5-chloro-3-methyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0738] [ka]

[0739] Intermediates 7 Compound 84 was synthesized using the same method as that for compound 1 using 5-chloro-3-methyl-6-nitro-1H-indole-2-carboxylic acid.

[0740] 1H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 11.00 (s, 1H), 8.12 (s, 1H), 7.95 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 5.11 (dd, J = 13.4, 5.1 Hz, 1H), 4.64 (s, 1H), 4.44 (d, J = 17.2 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H), 3.73 (s, 1H), 3.13-2.82 (m, 4H), 2.66-2.58 (m, 1H), 2.47-2.38 (m, 1H), 2.31 (s, 3H), 2.03-1.84 (m, 3H), 1.76-1.60 (m, 2H)

[0741] Compound 85. 3-(5-(1-(3,5-dimethyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0742] [ka]

[0743] Intermediates 7 Compound 85 was synthesized using the same method as that for compound 1 using 3,5-dimethyl-6-nitro-1H-indole-2-carboxylic acid.

[0744] 1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 11.00 (s, 1H), 8.10 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.62 (s, 1H), 7.52 (s, 1H), 7.43 (d, J = 7.9 Hz, 1H), 5.11 (dd, J = 13.4, 5.1 Hz, 1H), 4.60 (s, 1H), 4.44 (d, J = 17.2 Hz, 1H), 4.31 (d, J = 17,2 Hz, 1H), 3.79 (s, 1H), 3.13-2.83 (m, 4H), 2.62 (s, 3H), 2.60-2.56 (m, 1H), 2.43-2.36 (m, 1H), 2.31 (s, 3H), 2.03-1.84 (m, 3H), 1.74-1.60 (m, 2H)

[0745] Compound 86. 3-(5-(1-(5-hydroxy-3-methyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0746] [ka]

[0747] Intermediates 7 Compound 86 was synthesized using the same method as that for compound 1 using 5-hydroxy-3-methyl-6-nitro-1H-indole-2-carboxylic acid.

[0748] 1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 11.00 (s, 1H), 10.07 (s, 1H), 8.00 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.16 (s, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.63 (s, 1H), 4.44 (d, J = 17.2 Hz, 1H), 4.33 (s, 1H), 3.76 (s, 1H), 3.12-2.86 (m, 4H), 2.62-2.57 (m, 1H), 2.45-2.34 (m, 1H), 2.23 (s, 3H), 2.03-1.84 (m, 3H), 1.76-1.60 (m, 2H)

[0749] Compound 87. 3-(5-(1-(6-chloro-3-((dimethylamino)methyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0750] [ka]

[0751] Intermediates 7 Compound 87 was synthesized using the same method as that for compound 1 using 6-chloro-3-((dimethylamino)methyl)-1H-indole-2-carboxylic acid.

[0752] 1H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 10.98 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.49 (s, 1H), 7.46-7.39 (m, 2H), 7.08 (d, J = 8.6 Hz, 1H), 5.10 (d, J = 13.5 Hz, 1H), 4.44 (d, J = 17.1 Hz, 1H), 4.30 (d, J = 17.2 Hz, 1H), 3.87-3.58 (m, 2H), 3.17-2.89 (m, 4H), 2.66-2.56 (m, 1H), 2.40-2.35 (m, 1H), 2.26 (s, 6H), 2.01-1.82 (m, 3H), 1.74-1.65 (m, 2H)

[0753] Compound 88. 3-(5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)ethynyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0754] [ka]

[0755] Compound 88 was synthesized in the same manner as compound 1 using 3-(6-fluoro-1-oxo-5-(piperidin-4-ylethynyl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride and 6-chloro-3-methyl-1H-indole-2-carboxylic acid.

[0756] 1H NMR (400 MHz, DMSO-d6) δ 11.39 (s, 1H), 11.02 (s, 1H), 7.78 (d, J = 6.0 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.06 (dd, J = 8.4, 2.0 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.44 (d, J = 17.4 Hz, 1H), 4.32 (d, J = 17.4 Hz, 1H), 3.84 (s, 2H), 3.46-3.38 (m, 2H), 3.15-3.08 (m, 1H), 2.97-2.85 (m, 1H), 2.63-2.58 (m, 1H), 2.45-2.33 (m, 1H), 2.27 (s, 3H), 2.06-1.92 (m, 3H), 1.74-1.62 (m, 2H)

[0757] Compound 89. 3-(5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)ethynyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0758] [ka]

[0759] Compound 89 was synthesized in the same manner as compound 1 using (3-(8-fluoro-1-oxo-5-(piperidin-4-ylethynyl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride and 6-chloro-3-methyl-1H-indole-2-carboxylic acid.

[0760] 1H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 11.03 (s, 1H), 7.65 (d, J = 6.7 Hz, 1H), 7.59 (s, 1H), 7.56 (s, 1H), 7.37 (d, J = 2.1 Hz, 1H), 7.06 (dd, J = 8.5, 2.0 Hz, 1H), 5.13 (dd, J = 13.3, 5.0 Hz, 1H), 4.59 (d, J = 17.5 Hz, 1H), 4.42 (d, J = 17.5 Hz, 1H), 3.84 (s, 2H), 3.47-3.38 (m, 2H), 3.16-3.07 (m, 1H), 2.98-2.86 (m, 1H), 2.66-2.57 (m, 1H), 2.47-2.37 (m, 1H), 2.27 (s, 3H), 2.07-1.89 (m, 3H), 1.74-1.62 (m, 2H)

[0761] Compound 90. 3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0762] [ka]

[0763] (1) Intermediate 3-(6-fluoro-1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride ( E ) synthesis

[0764] [ka]

[0765] (1-1) tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (C )manufacturing

[0766] compound A (500mg, 1.5mmol), compound B (589 mg, 1.91 mmol), potassium carbonate (506 mg, 3.7 mmol), and Pd(dppf)Cl2·DCM (120 mg, 0.15 mmol) were dissolved in DMF (10 mL) and stirred at 110 °C for 12 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was filtered through Celite. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated mixture was purified by column chromatography to identify the compound C (692 mg, 48%)

[0767] 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.61 (d, 0H), 7.52 (d, J = 7.7 Hz, 2H), 7.07-6.95 (m, 1H), 5.12 (dd, 1H), 4.97-4.81 (m, 1H), 4.44 (d, 1H), 4.30 (d, J = 5.4 Hz, 1H), 4.05-4.01 (m, 1H), 3.90-3.84 (m, 1H), 3.59-3.47 (m, 2H), 2.97-2.85 (m, 1H), 2.65-2.56 (m, 1H), 2.44-2.32 (m, 1H), 2.18-2.08 (m, 1H), 2.05-1.95 (m, 1H), 1.79-1.68 (m, 1H), 1.46 (s, 5H), 1.44 (s, 4H)

[0768] (1-2) tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidine-1-carboxylate ( D ) production

[0769] compound C(620 mg, 1.40 mmol) and 10% Pd / C (186 mg) were dissolved in DMF (10 mL) and stirred under hydrogen pressure for 12 hours. After the reaction was completed, the reaction mixture was filtered through Celite. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated to give the target compound. D (528 mg, 85%)

[0770] 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.63 (d, J = 5.9 Hz, 1H), 7.49 (d, J = 2.3 Hz, 1H), 5.12 (dd, J = 13.3, 2.4 Hz, 1H), 4.42 (d, J = 17.3 Hz, 1H), 4.29 (d, J = 17.2 Hz, 1H), 4.22-3.94 (m, 2H), 3.15-3.04 (m, 1H), 2.98-2.75 (m, 3H), 2.64-2.55 (m, 1H), 2.47-2.33 (m, 1H), 2.06-1.95 (m, 1H), 1.81-1.71 (m, 2H), 1.65-1.51 (m, 2H), 1.43 (s, 9H)

[0771] (1-3) 3-(6-fluoro-1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride ( E ) production

[0772] compound D (250 mg, 0.56 mmol) was dissolved in DCM (5 mL), and a 1,4-dioxane solution (1.4 mL) of 4N HCl was added, followed by stirring at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain the target compound. E (134 mg, 63%)

[0773] 1H NMR (300 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.94 (s, 2H), 7.57-7.51 (m, 2H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.46 (d, J = 17.3 Hz, 1H), 4.33 (d, J = 17.3 Hz, 1H), 3.32-3.19 (m, 1H), 3.15-2.85 (m, 3H), 2.65-2.55 (m, 1H), 2.47-2.31 (m, 1H), 2.06-1.87 (m, 5H)

[0774] (2) The intermediate E Compound 90 was synthesized in the same manner as compound 1 using 6-chloro-3-methyl-1H-indole-2-carboxylic acid.

[0775] 1 H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 11.01 (s, 1H), 7.63 (d, J = 6.2 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.51 (d, J = 9.1 Hz, 1H), 7.37 (d, J = 2.1 Hz, 1H), 7.06 (dd, J = 8.6, 2.0 Hz, 1H), 5.12 (dd, J = 13.6, 5.1 Hz, 1H), 4.41 (s, 1H), 4.31 (d, J = 17.2 Hz, 1H), 3.31-3.07 (m, 3H), 2.99-2.85 (m, 1H), 2.65-2.56 (m, 1H), 2.46-2.36 (m, 1H), 2.30 (s, 3H), 2.04-1.96 (m, 1H), 1.92-1.81 (m, 2H), 1.76-1.62 (m, 2H)

[0776] Compound 91. 3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0777] [ka]

[0778] (1) Synthesis of intermediate 3-(4-fluoro-1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (K)

[0779] [ka]

[0780] (1-1) Bromo-4-fluoro-3-hydroxyisobenzofuran-1(3H)( G ) production

[0781] Add 2M n-BuLi / n-hexane (45.7 ml, 91 mmol) to a round-bottom flask and then cool to -70°C. Dissolve 2,2,6,6-tetramethylpiperidine (19.43 ml, 114 mmol) in tetrahydrofuran (50 ml) and add it in small portions. Stir the reaction mixture at -70°C for 20 minutes and then at 4°C for 30 minutes. 4-Bromo-3-fluorobenzoic acid ( F ) (5 g, 22.83 mmol) is dissolved in tetrahydrofuran (12.5 mL) and added portionwise to the reaction mixture at -70°C. The reaction mixture is stirred at 4°C for 1.5 hours. Dimethylformamide (3.54 ml, 45.7 mmol) is dissolved in tetrahydrofuran (7.5 mL) and added portionwise to the reaction mixture at -70°C. The reaction mixture is stirred at 4°C for 2 hours. After the reaction is complete, 300 mL of 1N HCl is added to the reaction mixture and then washed with dichloromethane.

[0782] 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.03 (dd, J = 8.0, 5.9 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 6.85 (s, 1H)

[0783] (1-2) 3-(5-bromo-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione ( H ) production

[0784] compound G (5.64 g, 22.83 mmol), 3-aminopiperidine-2,6-dione (5.64 g, 34.2 mmol), and NaBH(OAc)3 (9.68 g, 45.7 mmol) were dissolved in dimethylformamide (50 ml) and stirred at room temperature for 12 hours. Upon completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrate was purified by column chromatography to obtain the target compound. H (2.7g, 35%)

[0785] 1 H NMR (300 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.89 (dd, J = 8.0, 6.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.63 (d, J = 17.7 Hz, 1H), 4.46 (d, J = 17.6 Hz, 1H), 3.00-2.85 (m, 1H), 2.65-2.55 (m, 1H), 2.47-2.36 (m, 1H), 2.10-1.96 (m, 1H)

[0786] (1-3) tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate ( I )

[0787] compound H (3.0g, 8.8mmol), compound B(3.5 g, 11.4 mmol), potassium carbonate (3.0 g, 22.0 mmol), and Pd(dppf)Cl2·DCM (0.7 g, 0.88 mmol) were dissolved in dimethylformamide (30 mL) and stirred at 110 °C for 12 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was filtered through Celite. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated mixture was purified by column chromatography to obtain the target compound. I (1.7g, 44%)

[0788] (1-4) tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)piperidine-1-carboxylate ( J ) production

[0789] compound I (2.0 g, 4.5 mmol) and 10% Pd / C (0.8 g) were dissolved in dimethylformamide (15 mL) and stirred under hydrogen pressure for 12 hours. After the reaction was completed, the reaction mixture was filtered through Celite. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated to give compound (II). J (2.0 g, 100%)

[0790] 1 H NMR (500 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.58-7.51 (m, 2H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.56 (d, J = 17.3 Hz, 1H), 4.38 (d, J = 17.3 Hz, 1H), 4.17-4.02 (m, 2H), 3.14-3.07 (m, 1H), 2.96-2.84 (m, 3H), 2.63-2.58 (m, 1H), 2.45-2.41 (m, 1H), 2.03-1.97 (m, 1H), 1.80-1.71 (m, 2H), 1.66-1.55 (m, 2H), 1.43 (s, 9H)

[0791] (1-5) 3-(4-fluoro-1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride ( K ) production

[0792] compound J (2.0 g, 4.49 mmol) was dissolved in dichloromethane (20 mL), and a 1,4-dioxane solution (15 mL) of 4N HCl was added, followed by stirring at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain compound K (1.7g, 88%)

[0793] 1 H NMR (300 MHz, DMSO-d6) δ 11.01 (s, 1H), 9.20-9.00 (m, 2H), 7.62 (d, J = 7.7 Hz, 1H), 7.51-7.42 (m, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.57 (d, J = 17.4 Hz, 1H), 4.39 (d, J = 17.4 Hz, 1H), 3.14-2.77 (m, 5H), 2.66-2.57 (m, 1H), 2.45-2.36 (m, 1H), 2.10-1.86 (m, 6H)

[0794] (2) The intermediate K Compound 91 was synthesized using the same method as that for compound 1 using 6-chloro-3-methyl-1H-indole-2-carboxylic acid.

[0795] 1H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 11.02 (s, 1H), 7.61-7.51 (m, 3H), 7.37 (s, 1H), 7.06 (d, J = 8.5 Hz, 1H), 5.12 (dd, J = 13.2, 5.0 Hz, 1H), 4.56 (d, J = 17.4 Hz, 1H), 4.38 (d, J = 17.3 Hz, 1H), 3.31-3.07 (m, 3H), 2.99-2.85 (m, 1H), 2.64-2.57 (m, 1H), 2.48-2.37 (m, 1H), 2.29 (s, 3H), 2.06-1.95 (m, 1H), 1.93-1.80 (m, 2H), 1.79-1.67 (m, 2H)

[0796] Compound 92. 5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0797] [ka]

[0798] Compound 92 was synthesized in the same manner as compound 1 using 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yl)isoindoline-1,3-dione hydrochloride and 6-chloro-3-methyl-1H-indole-2-carboxylic acid.

[0799] 1H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 11.14 (s, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.86 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.38 (s, 1H), 7.06 (d, J = 8.5 Hz, 1H), 5.15 (dd, J = 12.8, 5.3 Hz, 1H), 4.60-4.08 (m, 2H), 3.19-3.04 (m, 3H), 2.93-2.84 (m, 1H), 2.64-2.57 (m, 2H), 2.29 (s, 3H), 2.08-2.01 (m, 1H), 1.95-1.84 (m, 2H), 1.78-1.65 (m, 3H)

[0800] Compound 93. 3-(6-fluoro-5-(1-(3-methyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0801] [ka]

[0802] Intermediates E Compound 93 was synthesized using the same method as that for compound 1 using 3-methyl-6-nitro-1H-indole-2-carboxylic acid.

[0803] 1H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 11.01 (s, 1H), 8.28 (d, J = 2.1 Hz, 1H), 7.93 (dd, J = 8.9, 1.9 Hz, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.64 (d, J = 6.2 Hz, 1H), 7.51 (d, J = 9.1 Hz, 1H), 5.12 (dd, J = 13.4, 5.1 Hz, 1H), 4.65 (s, 1H), 4.44 (d, J = 17.2 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H), 3.81 (s, 1H), 3.30-3.02 (m, 3H), 2.98-2.86 (m, 1H), 2.64-2.57 (m, 1H), 2.42-2.37 (m, 1H), 2.34 (s, 3H), 2.04-1.98 (m, 1H), 1.95-1.79 (m, 2H), 1.78-1.62 (m, 2H)

[0804] Compound 94. 3-(4-fluoro-5-(1-(3-methyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0805] [ka]

[0806] Intermediates K Compound 94 was synthesized using the same method as that for compound 1 using 3-methyl-6-nitro-1H-indole-2-carboxylic acid.

[0807] 1H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 11.02 (s, 1H), 8.28 (d, J = 1.9 Hz, 1H), 7.97-7.90 (m, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.63-7.51 (m, 2H), 5.12 (dd, J = 13.3, 5.0 Hz, 1H), 4.80-4.60 (m, 1H), 4.56 (d, J = 17.3 Hz, 1H), 4.39 (d, J = 17.3 Hz, 1H), 3.79 (s, 1H), 3.33-3.01 (m, 3H), 2.98-2.88 (m, 1H), 2.64-2.57 (m, 1H), 2.46-2.36 (m, 1H), 2.34 (s, 3H), 2.04-1.96 (m, 1H), 1.93-1.68 (m, 4H)

[0808] Compound 95. 2-(2,6-dioxopiperidin-3-yl)-5-(1-(3-methyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)isoindoline-1,3-dione

[0809] [ka]

[0810] Compound 95 was synthesized in the same manner as compound 1 using (2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yl)isoindoline-1,3-dione hydrochloride and 3-methyl-6-nitro-1H-indole-2-carboxylic acid.

[0811] 1H NMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 11.19 (s, 1H), 8.29 (d, J = 2.1 Hz, 1H), 7.95-7.85 (m, 3H), 7.83-7.74 (m, 2H), 5.15 (dd, J = 12.9, 5.4 Hz, 1H), 3.19-3.07 (m, 2H), 2.96-2.84 (m, 2H), 2.64-2.58 (m, 2H), 2.34 (s, 3H), 2.09-2.02 (m, 1H), 1.97-1.85 (m, 2H), 1.80-1.69 (m, 2H)

[0812] Compound 96. 5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)ethynyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0813] [ka]

[0814] Compound 96 was synthesized in the same manner as compound 1 using 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-ylethynyl)isoindoline-1,3-dione hydrochloride and 6-chloro-3-methyl-1H-indole-2-carboxylic acid.

[0815] 1H NMR (400 MHz, DMSO-d6) δ 11.39 (s, 1H), 11.15 (s, 1H), 7.92 (d, J = 8.6 Hz, 3H), 7.58 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 1.9 Hz, 1H), 7.06 (d, J = 8.9 Hz, 1H), 5.17 (dd, J = 12.8, 5.4 Hz, 1H), 3.86 (s, 2H), 3.48-3.38 (m, 2H), 3.10 (s, 1H), 2.95-2.82 (m, 1H), 2.65-2.57 (m, 1H), 2.56-2.53 (m, 1H), 2.27 (s, 3H), 2.12-2.03 (m, 1H), 1.99-1.89 (m, 2H), 1.74-1.63 (m, 2H)

[0816] Compound 97. 3-(5-(1-(5-methoxy-3-methyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0817] [ka]

[0818] Intermediates 7 Compound 97 was synthesized using the same method as that for compound 1 using 5-methoxy-3-methyl-6-nitro-1H-indole-2-carboxylic acid.

[0819] 1H NMR (500 MHz, DMSO-d6) δ 11.72 (s, 1H), 11.00 (s, 1H), 7.92 (s, 1H), 7.68 (d, J = 7.4 Hz, 1H), 7.51 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.35 (s, 1H), 5.10 (dd, J = 13.7, 4.8 Hz, 1H), 4.76-4.52 (m, 1H), 4.43 (d, J = 17.0 Hz, 1H), 4.30 (d, J = 17.2 Hz, 1H), 3.92 (s, 3H), 3.90-3.61 (m, 1H), 3.26-2.86 (m, 4H), 2.64-2.56 (m, 1H), 2.45-2.33 (m, 1H), 2.30 (s, 3H), 2.02-1.80 (m, 3H), 1.74-1.59 (m, 2H)

[0820] Compound 98. 3-(5-(1-(6-chloro-7-fluoro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (KMG-2516)

[0821] [ka]

[0822] Intermediates 7 Compound 98 was synthesized using the same method as that for compound 1 using 6,7-dichloro-3-methyl-1H-indole-2-carboxylic acid.

[0823] 1H NMR (300 MHz, DMSO-d6) δ 11.76 (s, 1H), 10.97 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.51 (s, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.81-4.53 (m, 1H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 3.74 (s, 1H), 3.13-2.78 (m, 4H), 2.67-2.54 (m, 1H), 2.44-2.39 (m, 1H), 2.27 (s, 3H), 1.94-1.59 (m, 5H)

[0824] Compound 99. 3-(5-(1-(6-chloro-7-fluoro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0825] [ka]

[0826] Intermediates 7 Compound 99 was synthesized using the same method as that for compound 1 using 6-chloro-7-fluoro-3-methyl-1H-indole-2-carboxylic acid.

[0827] 1H NMR (300 MHz, DMSO-d6) δ 11.97 (s, 1H), 10.99 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.46-7.39 (m, 2H), 7.17-7.09 (m, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.814.48-3.98 (m, 1H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 4.25-3.98 (m, 1H), 3.09-2.83 (m, 4H), 2.65-2.57 (m, 1H), 2.44-2.34 (m, 1H), 2.28 (s, 3H), 1.91-1.55 (m, 5H)

[0828] Compound 100. 3-(5-(1-(6-chloro-3,7-dimethyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0829] [ka]

[0830] Intermediates 7 Compound 100 was synthesized in the same manner as compound 1 using 6-chloro-3,7-dimethyl-1H-indole-2-carboxylic acid.

[0831] 1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 10.99 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 5.02-4.47 (m, 1H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 4.09-3.51 (m, 1H), 3.11-2.84 (m, 4H), 2.65-2.58 (m, 1H), 2.52 (s, 3H), 2.42-2.36 (m, 1H), 2.27 (s, 3H), 2.03-1.95 (m, 2H), 1.93-1.81 (m, 2H), 1.74-1.59 (m, 3H)

[0832] Compound 101. 3-(5-(1-(6-chloro-5-hydroxy-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0833] [ka]

[0834] Intermediates 7 Compound 101 was synthesized using the same method as that for compound 1 using 6-chloro-5-hydroxy-3-methyl-1H-indole-2-carboxylic acid.

[0835] 1H NMR (500 MHz, DMSO-d6) δ 11.03 (s, 1H), 11.00 (s, 1H), 9.49 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.52 (s, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.30 (s, 1H), 7.03 (s, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.86-4.34 (m, 2H), 4.34-3.84 (m, 2H), 3.13-2.85 (m, 4H), 2.63-2.57 (m, 1H), 2.42-2.39 (m, 1H), 2.22 (s, 3H), 2.03-1.97 (m, 1H), 1.92-1.83 (m, 2H), 1.72-1.61 (m, 2H)

[0836] Compound 102. 3-(5-(1-(6-chloro-5-fluoro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0837] [ka]

[0838] Intermediates 7 Compound 102 was synthesized in the same manner as compound 1 using 6-chloro-5-fluoro-3-methyl-1H-indole-2-carboxylic acid.

[0839] 1H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 11.00 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 9.9 Hz, 1H), 7.52 (s, 1H), 7.49 (d, J = 6.2 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 5.11 (dd, J = 13.4, 5.0 Hz, 1H), 4.44 (d, J = 17.2 Hz, 1H), 4.30 (d, J = 17.2 Hz, 1H), 3.23-2.85 (m, 4H), 2.63-2.56 (m, 1H), 2.42-2.36 (m, 1H), 2.27 (s, 3H), 2.04-1.95 (m, 1H), 1.94-1.83 (m, 2H), 1.74-1.60 (m, 2H)

[0840] Compound 103. 3-(5-(1-(6-chloro-3,5-dimethyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0841] [ka]

[0842] Intermediates 7 Compound 103 was synthesized using the same method as that for compound 1 using 6-chloro-3,5-dimethyl-1H-indole-2-carboxylic acid.

[0843] 1H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 11.00 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.51 (s, 2H), 7.43 (d, J = 7.9 Hz, 1H), 7.38 (s, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.44 (d, J = 17.1 Hz, 1H), 4.30 (d, J = 17.2 Hz, 1H), 3.20-2.85 (m, 4H), 2.65-2.56 (m, 1H), 2.40 (s, 3H), 2.27 (s, 3H), 2.02-1.96 (m, 1H), 1.91-1.81 (m, 2H), 1.72-1.61 (m, 2H)

[0844] Compound 104. 3-(5-(1-(3-methyl-6-morpholino-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0845] [ka]

[0846] Intermediates 7 Compound 104 was synthesized in the same manner as compound 1 using 3-methyl-6-morpholino-1H-indole-2-carboxylic acid.

[0847] 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 10.89 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.42 (t, J = 8.6, 8.6 Hz, 2H), 6.85 (d, J = 8.8 Hz, 1H), 6.76 (s, 1H), 5.11 (dd, J = 13.4, 5.1 Hz, 1H), 4.44 (d, J = 17.2 Hz, 1H), 4.35-4.19 (m, 3H), 3.77 (t, J = 4.7, 4.7 Hz, 4H), 3.07 (t, J = 4.7, 4.7 Hz, 5H), 3.04-2.87 (m, 3H), 2.64-2.58 (m, 1H), 2.42-2.35 (m, 1H), 2.27 (s, 3H), 2.04-1.96 (m, 1H), 1.91-1.83 (m, 2H), 1.74-1.62 (m, 2H)

[0848] Compound 105. 3-(5-(1-(6-chloro-3-(hydroxymethyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0849] [ka]

[0850] Intermediates 7 Compound 105 was synthesized in the same manner as compound 1 using 6-chloro-3-(hydroxymethyl)-1H-indole-2-carboxylic acid.

[0851] 1H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 11.00 (s, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.39 (s, 1H), 7.08 (d, J = 8.5 Hz, 1H), 5.11 (dd, J = 13.5, 5.0 Hz, 1H), 4.98 (t, J = 5.3, 5.3 Hz, 1H), 4.66 (d, J = 5.1 Hz, 2H), 4.44 (d, J = 17.2 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H), 3.09-2.86 (m, 4H), 2.63-2.57 (m, 2H), 2.44-2.33 (m, 2H), 2.04-1.96 (m, 1H), 1.93-1.81 (m, 2H), 1.77-1.59 (m, 2H)

[0852] Compound 106. 3-(5-(1-(3-methyl-6-(piperazin-1-ylmethyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione dihydrochloride

[0853] [ka]

[0854] Intermediates 7 Compound 106 was synthesized using the same method as that for compound 1.

[0855] 1H NMR (300 MHz, DMSO-d6) δ 11.78- 11.35 (m,2H), 11.00 (s, 1H), 9.50-9.24 (m, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.62 (s, 2H), 7.52 (s, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.25 (s, 1H), 5.12 (dd, J = 13.1, 5.1 Hz, 1H), 4.55-4.39 (m, 3H), 4.31 (d, J = 17.4 Hz, 1H), 3.55 (s, 2H), 3.24-2.85 (m, 9H), 2.77-2.57 (m, 4H), 2.44-2.35 (m, 1H), 2.31 (s, 3H), 2.04-1.87 (m, 3H), 1.76-1.58 (m, 2H)

[0856] Compound 107. 3-(5-(1-(4,6-dichloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0857] [ka]

[0858] Intermediates 7 Compound 107 was synthesized using the same method as that for compound 1 using 4,6-dichloro-1H-indole-2-carboxylic acid.

[0859] 1H NMR (300 MHz, DMSO-d6) δ 11.81 (s, 1H), 11.00 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 1.7 Hz, 1H), 7.13 (d, J = 1.7 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.44 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H), 3.21 -2.82 (m, 4H), 2.64-2.54 (m, 1H), 2.44-2.36 (m, 1H), 2.05-1.85 (m, 3H), 1.74-1.51 (m, 2H)

[0860] Compound 108. 3-(5-(1-(6-chloro-5-methoxy-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0861] [ka]

[0862] Intermediates K Compound 108 was synthesized in the same manner as compound 1 using 6-chloro-5-methoxy-1H-indole-2-carboxylic acid.

[0863] 1H NMR (300 MHz, DMSO-d6) δ 11.23 (s, 1H), 11.02 (s, 1H), 7.62-7.50 (m, 2H), 7.39 (s, 1H), 7.21 (s, 1H), 5.12 (dd, J = 13.2, 5.0 Hz, 1H), 4.57 (d, J = 17.4 Hz, 1H), 4.45-4.07 (m, 3H), 3.87 (s, 3H), 3.23-2.84 (m, 4H), 2.64-2.58 (m, 1H), 2.46-2.39 (m, 1H), 2.29 (s, 3H), 2.06-1.94 (m, 1H), 1.94-1.63 (m, 4H)

[0864] Compound 109. 3-(5-(1-(6-chloro-3-methyl-5-(piperazin-1-ylmethyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione dihydrochloride

[0865] [ka]

[0866] Intermediates 7 Compound 109 was synthesized using the same method as that for compound 1.

[0867] 1H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 11.70 (s, 1H), 11.00 (s, 1H), 9.89 (s, 2H), 8.15 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 5.5 Hz, 2H), 7.44 (d, J = 8.2 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.55-4.40 (m, 3H), 4.31 (d, J = 17.4 Hz, 1H), 3.51 (s, 2H), 3.19-2.84 (m, 9H), 2.62-2.59 (m, 1H), 2.39 (s, 1H), 2.31 (s, 3H), 2.27-2.22 (m, 1H), 2.05-1.84 (m, 5H), 1.72-1.62 (m, 2H)

[0868] Compound 110. 3-(5-(1-(6-methoxy-3-(morpholinomethyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0869] [ka]

[0870] Intermediates 7 Compound 110 was synthesized using the same method as that for compound 1.

[0871] 1H NMR (300 MHz, DMSO-d6) δ 11.22 (s, 1H), 11.00 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.50 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 2.3 Hz, 1H), 6.70 (dd, J = 8.7, 2.3 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 3H), 3.77 (s, 3H), 3.63 (s, 2H), 3.53 (s, 4H), 3.1-2.83 (m, 4H), 2.66-2.58 (m, 1H), 2.46-2.39 (m, 1H), 2.35 (s, 4H), 2.05-1.94 (m, 1H), 1.94-1.83 (m, 2H), 1.76-1.59 (m, 2H)

[0872] Compound 111. 3-(5-(1-(6-methoxy-3-(morpholinomethyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0873] [ka]

[0874] Intermediates 7 Compound 111 was synthesized using the same method as that for compound 1 using 6-chloro-3-methyl-5-morpholino-1H-indole-2-carboxylic acid.

[0875] 1H NMR (300 MHz, DMSO-d6) δ 11.26 (s, 1H), 11.00 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.41 (s, 1H), 7.33 (s, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.45 (d, J = 17.3 Hz, 1H), 4.35-4.05 (m, 3H), 3.82-3.69 (m, 4H), 3.19-2.99 (m, 3H), 2.96 (t, J = 4.6, 4.6 Hz, 4H), 2.92-2.85 (m, 1H), 2.65-2.56 (m, 1H), 2.44-2.36 (m, 1H), 2.29 (s, 3H), 2.06-1.83 (m, 3H), 1.75-1.57 (m, 2H)

[0876] Compound 112. 3-(5-(1-(6-chloro-5-fluoro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0877] [ka]

[0878] Intermediates E Compound 112 was synthesized using the same method as that for compound 1 using 6-chloro-5-fluoro-3-methyl-1H-indole-2-carboxylic acid.

[0879] 1H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 11.01 (s, 1H), 7.63 (d, J = 6.2 Hz, 1H), 7.58 (d, J = 10.0 Hz, 1H), 7.50 (dd, J = 9.4, 7.7 Hz, 2H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.43 (d, J = 17.2 Hz, 1H), 4.33 (s, 1H), 3.31-3.10 (m, 3H), 2.97-2.86 (m, 1H), 2.64-2.58 (m, 1H), 2.46-2.34 (m, 1H), 2.27 (s, 3H), 2.05-1.96 (m, 1H), 1.93-1.81 (m, 2H), 1.78-1.63 (m, 2H)

[0880] Compound 113. 3-(5-(1-(6-chloro-5-fluoro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0881] [ka]

[0882] Intermediates K Compound 113 was synthesized using the same method as that for compound 1 using 6-chloro-5-fluoro-3-methyl-1H-indole-2-carboxylic acid.

[0883] 1H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 11.01 (s, 1H), 7.64-7.51 (m, 3H), 7.49 (d, J = 6.3 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.56 (d, J = 17.3 Hz, 1H), 4.38 (d, J = 17.3 Hz, 1H), 3.31-3.04 (m, 3H), 2.97-2.87 (m, 1H), 2.64-2.58 (m, 1H), 2.47-2.37 (m, 1H), 2.27 (s, 3H), 2.03-1.94 (m, 1H), 1.91-1.81 (m, 2H), 1.78-1.66 (m, 2H)

[0884] Compound 114. 3-(5-(1-(6-chloro-3-((4-methylpiperazin-1-yl)methyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0885] [ka]

[0886] Intermediates 7 Compound 114 was synthesized using the same method as that for compound 1.

[0887] 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 10.99 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.50 (s, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 1.9 Hz, 1H), 7.08 (dd, J = 8.5, 1.9 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.44 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H), 3.75 (s, 2H), 3.03-2.84 (m, 7H), 2.68-2.65 (m, 1H), 2.63 (s, 3H), 2.61-2.52 (m, 4H), 2.43-2.33 (m, 2H), 2.03-1.85 (m, 3H), 1.71-1.63 (m, 2H)

[0888] Compound 115. 3-(5-(1-(6-chloro-5-hydroxy-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0889] [ka]

[0890] Intermediates K Compound 115 was synthesized using the same method as that for compound 1 using 6-chloro-5-hydroxy-3-methyl-1H-indole-2-carboxylic acid.

[0891] 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 11.01 (s, 1H), 9.47 (s, 1H), 7.60-7.50 (m, 2H), 7.30 (s, 1H), 7.02 (s, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.56 (d, J = 17.3 Hz, 1H), 4.45-4.08 (m, 3H), 3.25-3.03 (m, 3H), 2.97-2.87 (m, 1H), 2.63-2.59 (m, 1H), 2.46-2.38 (m, 1H), 2.21 (s, 3H), 2.07-1.92 (m, 2H), 1.91-1.79 (m, 2H), 1.76-1.71 (m, 1H)

[0892] Compound 116. 3-(4-fluoro-5-(1-(3-methyl-6-morpholino-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0893] [ka]

[0894] Intermediates K Compound 116 was synthesized using the same method as that for compound 1 using 3-methyl-6-morpholino-1H-indole-2-carboxylic acid.

[0895] 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 10.91 (s, 1H), 7.60-7.53 (m, 2H), 7.41 (d, J = 8.7 Hz, 1H), 6.85 (dd, J = 8.8, 2.2 Hz, 1H), 6.75 (d, J = 2.2 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.56 (d, J = 17.4 Hz, 1H), 4.39 (d, J = 17.3 Hz, 1H), 4.26 (s, 2H), 3.77 (t, J = 4.7, 4.7Hz, 4H), 3.29-3.23 (m, 1H), 3.20-3.11 (m, 2H), 3.07 (t, J = 4.8, 4.8 Hz, 4H), 2.98-2.87 (m, 1H), 2.66-2.58 (m, 1H), 2.47-2.41 (m, 1H), 2.27 (s, 3H), 2.06-1.97 (m, 1H), 1.89-1.82 (m, 2H), 1.78-1.70 (m, 2H)

[0896] Compound 117. 3-(5-(1-(6-chloro-7-fluoro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0897] [ka]

[0898] Intermediates K Compound 117 was synthesized using the same method as that for compound 1 using 6-chloro-7-fluoro-3-methyl-1H-indole-2-carboxylic acid.

[0899] 1H NMR (400 MHz, DMSO-d6) δ 11.97 (s, 1H), 11.01 (s, 1H), 7.61-7.52 (m, 2H), 7.41 (d, J = 8.5 Hz, 1H), 7.13 (dd, J = 8.5, 6.4 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.56 (d, J = 17.3 Hz, 1H), 4.39 (d, J = 17.3 Hz, 1H), 3.3-3.20 (m, 3H), 2.97-2.87 (m, 1H), 2.64-2.58 (m, 1H), 2.48-2.35 (m, 1H), 2.28 (s, 3H), 2.07-1.95 (m, 1H), 1.92-1.63 (m, 4H)

[0900] Compound 118. 2-(4-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-3-methyl-1H-indole-6-carbonitrile

[0901] [ka]

[0902] Intermediates K Compound 118 was synthesized using the same method as that for compound 1 using 6-cyano-3-methyl-1H-indole-2-carboxylic acid.

[0903] 1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 11.01 (s, 1H), 7.83 (s, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.57-7.52 (m, 1H), 7.39 (d, J = 8.3 Hz, 1H), 5.12 (dd, J = 13.4, 5.1 Hz, 1H), 4.56 (d, J = 17.3 Hz, 1H), 4.39 (d, J = 17.3 Hz, 1H), 3.27-2.87 (m, 4H), 2.65-2.58 (m, 1H), 2.46-2.38 (m, 2H), 2.32 (s, 3H), 2.05-1.97 (m, 1H), 1.94-1.82 (m, 2H), 1.79-1.70 (m, 2H)

[0904] Compound 119. 6-chloro-2-(4-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-3-methyl-1H-indole-5-carbonitrile

[0905] [ka]

[0906] Intermediates K Compound 119 was synthesized using the same method as that for compound 1 using 6-chloro-5-cyano-3-methyl-1H-indole-2-carboxylic acid.

[0907] 1H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 11.01 (s, 1H), 8.32 (s, 1H), 7.63 (s, 1H), 7.60-7.51 (m, 3H), 5.12 (dd, J = 13.2, 5.1 Hz, 2H), 4.97-4.60 (m, 1H), 4.56 (d, J = 17.3 Hz, 1H), 4.39 (d, J = 17.3 Hz, 1H), 3.91-3.73 (m, 1H), 3.31-3.17 (m, 4H), 2.95-2.88 (m, 1H), 2.63-2.58 (m, 1H), 2.47-2.38 (m, 1H), 2.32 (s, 3H), 2.04-1.98 (m, 2H), 1.90-1.83 (m, 2H), 1.77-1.70 (m, 2H)

[0908] Compound 120. 2-(4-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-5-fluoro-3-methyl-1H-indole-6-carbonitrile

[0909] [ka]

[0910] Intermediates K Compound 120 was synthesized in the same manner as compound 1 using 6-cyano-5-fluoro-3-methyl-1H-indole-2-carboxylic acid.

[0911] 1H NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 11.03 (s, 1H), 7.84 (s, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.62-7.52 (m, 2H), 7.41-7.36 (m, 1H), 5.12 (dd, J = 13.2, 5.1 Hz, 1H), 4.57 (d, J = 17.4 Hz, 1H), 4.38 (d, J = 17.4 Hz, 1H), 3.31-3.06 (m, 3H), 3.00-2.84 (m, 1H), 2.66-2.56 (m, 1H), 2.47-2.39 (m, 1H), 2.32 (s, 3H), 2.05-1.67 (m, 5H)

[0912] Compound 121. 5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione

[0913] [ka]

[0914] Intermediates K Compound 121 was synthesized using the same method as that for compound 1 using 6-chloro-3-methyl-1H-indole-2-carboxylic acid.

[0915] 1H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 11.15 (s, 1H), 7.92-7.87 (m, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.39-7.35 (m, 1H), 7.08-7.04 (m, 1H), 5.15 (dd, J = 12.8, 5.4 Hz, 1H), 4.85-3.62 (m, 2H), 3.31-3.05 (m, 3H), 2.95-2.84 (m, 1H), 2.66-2.56 (m, 1H), 2.29 (s, 3H), 2.29-2.21 (m, 1H), 2.10-2.01 (m, 1H), 1.92-1.82 (m, 2H), 1.77-1.67 (m, 2H)

[0916] Compound 122. 2-(4-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-7-fluoro-3-methyl-1H-indole-6-carbonitrile

[0917] [ka]

[0918] Intermediates K Compound 122 was synthesized using the same method as that for compound 1 using 6-cyano-7-fluoro-3-methyl-1H-indole-2-carboxylic acid.

[0919] 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 11.01 (s, 1H), 7.61-7.53 (m, 3H), 7.39-7.34 (m, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.83-4.60 (m, 1H), 4.56 (d, J = 17.3 Hz, 1H), 4.38 (d, J = 17.3 Hz, 1H), 3.81- 3.55 (m, 1H), 3.12-2.97 (m, 1H), 2.95-2.87 (m, 1H), 2.64-2.56 (m, 1H), 2.47-2.39 (m, 1H), 2.30 (s, 3H), 2.03-1.96 (m, 1H), 1.96-1.68 (m, 5H)

[0920] Compound 123. (3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl pivalate

[0921] [ka]

[0922] Compound 121 (20 mg, 0.037 mmol), chloromethyl pivalate (6.98 μL, 0.048 mmol), and K2CO3 (7.72 mg, 0.056 mmol) were added to dimethylformamide (1 mL) and stirred at 50 °C for 5 hours. Upon completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The extracted organic layer was washed with brine and then purified with anhydrous magnesium sulfate to remove residues. After filtration, the mixture was concentrated under reduced pressure and purified by column chromatography to yield compound 123.

[0923] 1H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 7.62-7.53 (m, 3H), 7.39-7.36 (m, 1H), 7.08-7.04 (m, 1H), 5.68-5.57 (m, 2H), 5.31 (dd, J = 13.2, 5.0 Hz, 1H), 4.93-4.68 (m, 1H), 4.60 (d, J = 17.1 Hz, 1H), 4.35 (d, J = 17.2 Hz, 1H), 4.21-3.75 (m, 1H), 3.25-3.06 (m, 3H), 2.88-2.79 (m, 1H), 2.69-2.54 (m, 1H), 2.46-2.41 (m, 1H), 2.29 (s, 3H), 2.01-1.94 (m, 1H), 1.91-1.81 (m, 2H), 1.77-1.70 (m, 2H), 1.11 (s, 9H)

[0924] Compound 124. 3-(4-fluoro-5-(1-(7-fluoro-3-methyl-6-morpholino-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0925] [ka]

[0926] Intermediates K Compound 124 was synthesized using the same method as that for compound 1 using 7-fluoro-3-methyl-6-morpholino-1H-indole-2-carboxylic acid.

[0927] LC / MS 606.2 [M+H] +

[0928] Compound 125. 3-(4-fluoro-5-(1-(5-fluoro-3-methyl-6-morpholino-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0929] [ka]

[0930] Intermediates K Compound 125 was synthesized using 5-fluoro-3-methyl-6-morpholino-1H-indole-2-carboxylic acid in the same manner as in the synthesis of compound 1.

[0931] LC / MS 606.4 [M+H] +

[0932] Compound 126. 3-(4-fluoro-5-(1-(7-fluoro-3-methyl-6-(4-methylpiperazin-1-yl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0933] [ka]

[0934] Intermediates K Compound 126 was synthesized in the same manner as compound 1 using 7-fluoro-3-methyl-6-(4-methylpiperazin-1-yl)-1H-indole-2-carboxylic acid.

[0935] LC / MS 609.3 [M+H] +

[0936] Compound 127. 3-(4-fluoro-5-(1-(5-fluoro-3-methyl-6-(4-methylpiperazin-1-yl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0937] [ka]

[0938] Intermediates K Compound 127 was synthesized in the same manner as compound 1 using 5-fluoro-3-methyl-6-(4-methylpiperazin-1-yl)-1H-indole-2-carboxylic acid.

[0939] LC / MS 609.1 [M+H] +

[0940] <Production of comparative substances>

[0941] Comparative substance 2. 3-(5-(1-(6-chloro-1H-indole-3-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0942] [ka]

[0943] Comparative substance 2 was synthesized in the same manner as compound 1, except that 6-chloro-1H-indole-3-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0944] 1H NMR (300 MHz, DMSO-d6) δ 13.62 (s, 1H), 10.98 (s, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.54 (s, 1H), 7.44 (dd, J = 7.9, 1.4 Hz, 1H), 7.25 (dd, J = 8.7, 1.8 Hz, 1H), 5.10 (dd, J = 13.2, 5.1 Hz, 1H), 4.90 (d, J = 13.1 Hz, 1H), 4.78 (d, J = 12.8 Hz, 1H), 4.42 (d, J = 17.3 Hz, 1H), 4.28 (d, J = 17.3 Hz, 1H), 3.09-2.83 (m, 4H), 2.65-2.53 (m, 1H), 2.39 (dd, J = 13.2, 4.6 Hz, 1H), 2.05-1.83 (m, 3H), 1.77-1.65 (m, 2H)

[0945] Comparative substance 3. 3-(5-(1-(6-chloro-1H-benzo[d]imidazole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0946] [ka]

[0947] Comparative substance 3 was synthesized in the same manner as compound 1, except that 6-chloro-1H-benzo[d]imidazole-2-carboxylic acid was used instead of 6-chloro-1H-indole-2-carboxylic acid.

[0948] 1H NMR (300 MHz, DMSO-d6) δ 13.31 (s, 1H), 10.99 (s, 1H), 7.67 (d, J = 7.8 Hz, 3H), 7.55 (s, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.32 (dd, J = 8.8, 1.9 Hz, 1H), 5.66 (d, J = 13.1 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.74 (d, J = 12.8 Hz, 1H), 4.43 (d, J = 17.2 Hz, 1H), 4.29 (d, J = 17.3 Hz, 1H), 3.18-2.84 (m, 4H), 2.59 (d, J = 17.9 Hz, 1H), 2.44-2.34 (m, 1H), 1.97 (s, 3H), 1.81-1.68 (m, 2H)

[0949] Comparative substance 4: N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-6-methoxy-2-naphthamide

[0950] [ka]

[0951] It was synthesized based on the information reported in the literature (Sun-Mi Park et al. 2023).

[0952] 1H NMR (300 MHz, DMSO-d6) δ 11.01 (s, 1H), 10.68 (s, 1H), 8.56 (s, 1H), 8.20 (s, 1H), 8.05-7.96 (m, 3H), 7.89 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 2.5 Hz, 1H), 7.29 (dd, J = 9.0, 2.5 Hz, 1H), 5.13 (d, J = 13.3 Hz, 1H), 4.50 (d, J = 17.2 Hz, 1H), 4.35 (d, J = 17.3 Hz, 1H), 3.93 (s, 3H), 2.97-2.85 (m, 1H), 2.75-2.62 (m, 1H), 2.30-2.25 (m, 1H), 2.11-1.95 (m, 1H)

[0953] <Experimental Example 1. Evaluation of IKZF2 degradation activity>

[0954] Experimental Example 1: Helios protein degrader screening using Nano-Glo HiBiT cell line

[0955] To observe intracellular Helios degradation, we applied the Nano-glo HiBiT detection system (Promega). A HiBiT tagging gene sequence was injected (knocked-in) into the N-terminus of the Helios gene in the T lymphocyte cell line Jurkat using the CRISPR system. Cells expressing HiBiT-fused Helios were verified using the Nano-glo HiBiT detection system (Promega) according to the prescribed protocol. After dissociating into single cells and culturing them in complete medium, single cell lines were established.

[0956] For compound screening, including comparative substances 1 to 4, the cells were dispensed into a 96-well plate in complete medium at 50,000 cells per well, and then treated with compounds (10 μM) for 6 hours in a 37°C carbon dioxide incubator. After 6 hours, each well was treated with the Nano-glo HiBiT detection reagent in the same volume as the cells dispensed into the 96 wells, and incubated at room temperature for 10 minutes. After incubation, HiBiT luminescence (luciferase) values ​​were measured using a microplate reader (Perkin Elmer). Measurements were repeated for each compound in three wells, and the results are shown in Table 1.

[0957] Experimental Example 2: DCs using WB-IKZF2 cell line 50 (nM) and D max (%) Screening

[0958] Cells in complete medium were treated with serial dilutions of candidate lytic agents and then incubated for 6 hours in a 37°C CO2 incubator. After 6 hours, cells were harvested and lysed in RIPA buffer (150 mM NaCl, 1% Triton X-100, 1% Na deoxycholate, 0.1% SDS, 50 mM Tris-HCl pH 7.5, and 2 mM EDTA) containing protease inhibitors (Roche). After vortexing every 10 minutes, the cells were incubated on ice for 30 minutes, and then centrifuged at 13,000 rpm for 10 minutes at 4°C to separate proteins. The separated proteins were quantified by the Bradford assay (Bio-Rad, 5000006). Proteins were separated on an 8% SDS-polyacrylamide gel. After electrophoresis, the proteins were transferred to a nitrocellulose membrane (Amersham, 10600002) and incubated with the respective primary antibodies for 18 hours at 4°C. The primary antibodies used were as follows: Helios rabbit monoclonal antibody (Cell Signaling, 42427, 1:3000), beta-actin mouse monoclonal antibody (Santa Cruz, sc-47778, 1:5000). Beta-actin was used as a loading control. The following day, the membrane was washed with 1X TBST for 30 minutes and incubated with the corresponding horseradish peroxidase (HRP)-containing secondary antibody for 1 hour at room temperature. The secondary antibodies used were as follows: anti-mouse IgG, HRP-linked antibody (Sigma, A9044, 1:5000), anti-rabbit IgG, HRP-linked antibody (Cell Signaling, 7074, 1:5000). After washing with 1X TBST for 30 minutes, protein expression was visualized using Pierce ECL Western solution (Thermofisher, 32106), and images were acquired using a chemiluminescence image analysis system (GE Healthcare, AI680), and the images were quantified using the ImageJ program.

[0959] [Table 1] TIFF2026508123000185.tif248166TIFF2026508123000186.tif248166TIFF2026508123000187.tif248166TIFF2026508123000188.tif210166

[0960] As shown in Table 1, it was confirmed that the compounds of the present invention in which piperidine is linked via an indole carbonyl structure exhibit superior IKZF2 degradation effects compared to the comparative compound 1 in which piperidine is linked via a benzyl structure.

[0961] In the present invention, when the compound is linked to piperidine via an indole carbonyl structure, the compound in which the carbonyl is substituted at the second position of the indole exhibited superior IKZF degradation effect compared to Comparative Substance 2, which is a compound in which the carbonyl is substituted at the third position of the indole, while Comparative Substance 3, which is substituted with a benzimidazole structure instead of the indole structure, was found to have no IKZF2 degradation effect.

[0962] The compounds of the present invention, which have a substituted indole structure with a substituent at the 6th position of the indole (Compound 1), showed superior IKZF2 degradation effect compared to compounds with substituents at the 4th, 5th, and 7th positions of the indole (Compounds 3 and 4).

[0963] Among the compounds of the present invention, those having a substituent at position 3 of the indole structure (compounds 21, 34-36) showed superior IKZF2 degradation effects compared to unsubstituted compounds, and those having simultaneous substitutions at positions 3 and 6 of the indole structure (compounds 39, 42, 47-49, 52-56, 60-64, 84-87, 90-95, 97-121) showed even superior IKZF2 degradation effects.

[0964] Furthermore, compounds of the present invention in which piperidine was replaced with azabicyclo[3,2,1]octane or azetidine (compounds 58 and 63) also showed excellent IKZF2 degradation effects.

[0965] The compounds of the present invention, when having an amine group such as methylmorpholine (compound 82) at the 3-position in the indole structure, exhibited a selective degradation effect on IKZF2 compared to IKZF1, IKZF3, and IKZF4.

[0966] <Experimental Example 3. Measurement of Helios protein degradation using Western blot technique>

[0967] To confirm the degradation of Helios protein by the degrading agent, Western blot analysis was performed. Jurkat cells (5x10) in complete medium were cultured. 6 ) and serially diluted with the compounds, and treated for 6 hours in a 37°C carbon dioxide incubator.

[0968] After harvesting, the cells were lysed in RIPA buffer (LPS solution, CRB002) containing protease inhibitor (Roche). After vortexing every 10 minutes and leaving the cells on ice for 30 minutes, the cells were centrifuged at 13,000 rpm for 10 minutes at 4°C to separate the cell lysate. The separated cell lysate was quantified by the Bradford assay (Bio-Rad, 5000006).

[0969] After separating 30 μg of cell lysate using 8% SDS-polyacrylamide gel electrophoresis, proteins were transferred to a nitrocellulose (NC) membrane (Amersham, 10600002) and incubated with the respective primary antibodies for 18 hours at 4°C. The primary antibodies used were as follows: Helios rabbit monoclonal antibody (Cell signaling, 42427, 1:3000), beta-actin mouse monoclonal antibody (Santa Cruz, sc-47778, 1:5000). Beta-actin was used as a loading control.

[0970] The NC membrane was washed with 1X TBST for 30 minutes and then incubated with the corresponding horseradish peroxidase (HRP)-containing secondary antibody at room temperature for 1 hour: anti-mouse IgG, HRP-linked (Sigma, A9044, 1:5000) and anti-rabbit IgG, HRP-linked (Cell Signaling, 7074, 1:5000).

[0971] After washing with 1X TBST for 30 minutes, protein expression was visualized using Pierce ECL Western solution (Thermofisher, 32106), and images were acquired using a chemiluminescence image analysis system (GE Healthcare, AI680). The images were quantified using the Image J program. The results of the Helios proteolysis assay for compound 39 of the present invention and the comparative compound DKY709 are shown in Figure 1.

[0972] As shown in FIG. 1, it was confirmed that the effect of compound 39 of the present invention on decomposing Helios protein by Western blot analysis was 1000 times or more superior to that of comparative substance 1 (DKY709).

[0973] <Formulation Example 1. Manufacture of powder>

[0974] 392 g of the compound of the present invention and 1 g of lactose were mixed and filled into an airtight pack to prepare a powder.

[0975] <Formulation Example 2. Tablet manufacturing>

[0976] 100 mg of the compound of the present invention 39, 100 mg of microcrystalline cellulose, 60 mg of lactose hydrate, 20 mg of low-substituted hydroxypropyl cellulose, and 2 mg of magnesium stearate were mixed and compressed into tablets by a conventional tablet manufacturing method.

[0977] <Formulation Example 3. Production of Capsules>

[0978] 100 mg of the compound of the present invention (39), 100 mg of microcrystalline cellulose, 60 mg of lactose hydrate, 20 mg of low-substituted hydroxypropyl cellulose, and 2 mg of magnesium stearate were mixed, and then the mixture was mixed according to a conventional capsule manufacturing method and filled into gelatin capsules to prepare capsules.

[0979] <Formulation Example 4. Manufacture of pills>

[0980] 3990 mg of the compound of the present invention, 5 mg of glutinous rice starch, 5 mg of purified water, and small amounts of dextrin, maltodextrin, corn starch, and microcrystalline cellulose (MCC) as additives to inhibit hygroscopicity were mixed, and then 100 mg pills were prepared by a conventional method.

[0981] <Formulation Example 5. Manufacture of injections>

[0982] 3910 mg of the compound of the present invention, an appropriate amount of sterile distilled water for injection, and an appropriate amount of a pH adjuster were mixed, and then prepared into an ampoule (2 ml) with the above-mentioned ingredient content according to a conventional method for preparing an injection.

Claims

1. The following chemical formula 1: 【Chemistry 1】 (In the formula, X is independently C, CH, N, or NR ３ and: Y is -CH ２ - or -C(O)-; R １ is hydrogen or C １－５ substituted with alkyl; 【change】 【change】 R ４ are independently substituted with hydrogen, halogen, or hydroxy; 【change】 R ５ is substituted with hydrogen, deuterium, halogen, or hydroxy; R ６ is substituted with hydrogen or deuterium; 【change】 m is an integer from 1 to 3; n is independently an integer of 0 or 1; It is displayed as A compound, a stereoisomer thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, characterized in that:

2. The formula 1 can be represented by the following formula 2: 【Chemistry 2】 (In the formula, X is independently C, CH, N, or NR ３ and Y is -CH ２ - or -C(O)-; R １ is hydrogen or C １－５ substituted with alkyl; 【change】 【change】 R ４ are independently substituted with hydrogen, halogen, or hydroxy; R ５ is substituted with hydrogen, deuterium, halogen, or hydroxy; R ６ is substituted with hydrogen or deuterium; 【change】 m is an integer from 1 to 3; n is independently an integer of 0 or 1; It is displayed as 2. The compound of claim 1, its stereoisomer, its solvate, its prodrug, or its pharmaceutically acceptable salt.

3. The formula 1 can be represented by the following formula 3: 【Transformation 3】 (In the formula, X is independently C, CH, N, or NR ３ and Y is -CH ２ - or -C(O)-; R １ is hydrogen or C １－５ substituted with alkyl; 【change】 【change】 R ４ are independently substituted with hydrogen, halogen, or hydroxy; R ５ is substituted with hydrogen, deuterium, halogen, or hydroxy; R ６ is substituted with hydrogen or deuterium; 【change】 m is an integer from 1 to 3; n is independently an integer of 0 or 1; It is displayed as 2. The compound of claim 1, its stereoisomer, its solvate, its prodrug, or its pharmaceutically acceptable salt.

4. The formula 1 can be represented by the following formula 4: 【Chemistry 4】 (In the formula, X is independently C, CH, N, or NR ３ and Y is -CH ２ - or -C(O)-; R １ is hydrogen or C １－５ substituted with alkyl; 【change】 【change】 R ４ are independently substituted with hydrogen, halogen, or hydroxy; R ６ is substituted with hydrogen or deuterium; 【change】 m is an integer from 1 to 3; n is independently an integer of 0 or 1; It is displayed as 2. The compound of claim 1, its stereoisomer, its solvate, its prodrug, or its pharmaceutically acceptable salt.

5. The formula 1 can be represented by the following formula 5: 【Transformation 5】 (In the formula, X is independently C, CH, N, or NR ３ and Y is -CH ２ - or -C(O)-; R １ is hydrogen or C １－５ substituted with alkyl; 【change】 【change】 R ４ are independently substituted with hydrogen, halogen, or hydroxy; R ６ is substituted with hydrogen or deuterium; 【change】 m is an integer from 1 to 3; n is independently an integer of 0 or 1; It is displayed as 2. The compound of claim 1, its stereoisomer, its solvate, its prodrug, or its pharmaceutically acceptable salt.

6. The formula 1 can be represented by the following formula 6: 【Transformation 6】 (In the formula, X is independently CH, N, or NR ３ and Y is -CH ２ - or -C(O)-; R １ is hydrogen or C １－５ substituted with alkyl; 【change】 【change】 R ４ are independently substituted with hydrogen, halogen, or hydroxy; 【change】 R ５ is substituted with hydrogen, deuterium, halogen, or hydroxy; R ６ is substituted with hydrogen or deuterium; 【change】 m is an integer from 1 to 3; n is independently an integer of 0 or 1; It is displayed as 2. The compound of claim 1, its stereoisomer, its solvate, its prodrug, or its pharmaceutically acceptable salt.

7. Represented by the formula 6 【Transformation 7】 (In the formula, X is independently CH, N, or NR ３ and Y is -CH ２ - or -C(O)-; R １ is hydrogen or C １－５ substituted with alkyl; 【change】 【change】 R ４ are independently substituted with hydrogen, halogen, or hydroxy; 【change】 R ５ is substituted with hydrogen, deuterium, halogen, or hydroxy; R ６ is substituted with hydrogen or deuterium; 【change】 m is an integer from 1 to 3; n is independently an integer of 0 or 1; 7. The compound of claim 6, its stereoisomer, its solvate, its prodrug, or its pharmaceutically acceptable salt.

8. The compound of Formula 1 is 3-(5-(1-(6-chloro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 1); 3-(5-(1-(6,7-dichloro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 2); 3-(5-(1-(5-chloro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 3); 3-(5-(1-(4-chloro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 4); 3-(5-(1-(6-methoxy-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 5); 3-(5-(1-(4,6-dichloro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 6); 3-(5-(1-(6-fluoro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 7); 3-(5-(1-(7-chloro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 8); 3-(5-(1-(1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 9); 3-(5-(1-(5-methoxy-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 10); 3-(5-(1-(4-methoxy-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 11); 3-(5-(1-(7-methoxy-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 12); 3-(5-(1-(5-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 13); 3-(5-(1-(4-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 14); 3-(5-(1-(6-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 15); 3-(5-(1-(7-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 16); 3-(5-(1-(5-fluoro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 17); 3-(5-(1-(6-hydroxy-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 18); 3-(5-(1-(7-fluoro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 19); 3-(5-(1-(4-fluoro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 20); 3-(5-(1-(3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 21); 3-(5-(1-(3-chloro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 22); 3-(5-(3-(1-(1H-indole-3-carbonyl)piperidin-4-yl)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 23); 3-(5-((1-(1H-indole-2-carbonyl)piperidin-4-ylidene)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 24); 3-(5-((1-(1H-indole-3-carbonyl)piperidin-4-ylidene)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 25); 3-(5-((1-(6-chloro-1H-indole-2-carbonyl)piperidin-4-ylidene)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 26); 3-(5-((1-(3-methyl-1H-indole-2-carbonyl)piperidin-4-ylidene)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 27); 3-(5-(1-(1,3-dimethyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 28); 3-(5-(1-(3-ethyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 29); 3-(5-(1-(3-methoxy-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 30); 3-(5-(1-(3-methyl-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 31); 3-(5-(1-(6-amino-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 32); 3-(5-(1-(5-bromo-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 33); 3-(5-(1-(3-(morpholinomethyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 34); 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-1H-indole-3-carbaldehyde (compound 35); 3-(5-(1-(3-bromo-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 36); 3-(5-(1-(3-fluoro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 37); 3-(5-(1-(5-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 38); 3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 39); 3-(5-(1-(5,6-dimethoxy-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 40); 3-(1-oxo-5-(1-(6-(trifluoromethyl)-1H-indole-2-carbonyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (compound 41); 3-(5-(1-(6-methoxy-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 42); 3-(5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 43); 3-(5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-ylidene)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 44); 3-(5-(1-(6-chloro-1H-pyrrolo[3,2-b]pyridine-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 45); 3-(5-(1-(6-chloro-1H-pyrrolo[3,2-c]pyridine-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 46); 3-(5-(1-(6-hydroxy-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 47); 3-(5-(1-(3-methyl-6-(trifluoromethyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 48); 3-(5-(1-(6-bromo-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 49); 3-(5-(1-(6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 50); 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-1H-indole-3-carbonitrile (compound 51); 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-3-methyl-1H-indole-6-carbonitrile (compound 52); 3-(5-(1-(3-methyl-6-(trifluoromethoxy)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 53); 3-(5-(1-(6-fluoro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 54); 3-(5-(1-(3-methyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 55); 3-(5-(1-(6-(tert-butyl)-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 56); 3-(5-(8-(6-chloro-1H-indole-2-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 57); 3-(5-(8-(6-chloro-3-methyl-1H-indole-2-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 58); 3-(5-(1-(6-chloro-1H-indole-2-carbonyl)-2-methylpiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 59); 3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)-2-methylpiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 60); 3-(5-(1-(6-amino-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 61); 3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)-[1,4′-bipiperidin]-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 62); 3-(5-(1-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)azetidin-3-yl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 63); 3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)-4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 64); 3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)-2,5-dihydro-1H-pyrrol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 65); 3-(5-(1-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 66); 3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)pyrrolidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 67); 3-(5-((1-(3-methyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 68); 3-(5-(1-(3,6-dimethyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 69); 3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 70); 3-(5-(1-(6-chloro-5-methoxy-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 71); 3-(5-(1-(5,6-dichloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 72); N-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-3-methyl-1H-indol-6-yl)acetamide (compound 73); N-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-3-methyl-1H-indol-6-yl)methanesulfonamide (compound 74); 1-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-3-methyl-1H-indol-6-yl)-3-ethylurea (compound 75); 3-(5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)azetidin-3-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 76); 3-(5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)-3-hydroxyazetidin-3-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 77); 3-(5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)pyrrolidin-3-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 78); 3-(5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)-3-hydroxypyrrolidin-3-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 79); 3-(5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)-4-hydroxypiperidin-4-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 80); 6-chloro-2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-1H-indole-3-carbaldehyde (compound 81); 3-(5-(1-(6-chloro-3-(morpholinomethyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 82); 3-(5-(1-(5-bromo-6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 83); 3-(5-(1-(5-chloro-3-methyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 84); 3-(5-(1-(3,5-dimethyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 85); 3-(5-(1-(5-hydroxy-3-methyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 86); 3-(5-(1-(6-chloro-3-((dimethylamino)methyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 87); 3-(5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)ethynyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 88); 3-(5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)ethynyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 89); 3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 90); 3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 91); 5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (compound 92); 3-(6-fluoro-5-(1-(3-methyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 93); 3-(4-fluoro-5-(1-(3-methyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 94); 2-(2,6-dioxopiperidin-3-yl)-5-(1-(3-methyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)isoindoline-1,3-dione (compound 95); 5-((1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)ethynyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (compound 96); 3-(5-(1-(5-methoxy-3-methyl-6-nitro-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 97); 3-(5-(1-(6-chloro-7-fluoro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 98); 3-(5-(1-(6-chloro-7-fluoro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 99); 3-(5-(1-(6-chloro-3,7-dimethyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 100); 3-(5-(1-(6-chloro-5-hydroxy-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 101); 3-(5-(1-(6-chloro-5-fluoro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 102); 3-(5-(1-(6-chloro-3,5-dimethyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 103); 3-(5-(1-(3-methyl-6-morpholino-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 104); 3-(5-(1-(6-chloro-3-(hydroxymethyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 105); 3-(5-(1-(3-methyl-6-(piperazin-1-ylmethyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (compound 106); 3-(5-(1-(4,6-dichloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 107); 3-(5-(1-(6-chloro-5-methoxy-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 108); 3-(5-(1-(6-chloro-3-methyl-5-(piperazin-1-ylmethyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione dihydrochloride (compound 109); 3-(5-(1-(6-methoxy-3-(morpholinomethyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 110); 3-(5-(1-(6-methoxy-3-(morpholinomethyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 111); 3-(5-(1-(6-chloro-5-fluoro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 112); 3-(5-(1-(6-chloro-5-fluoro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 113); 3-(5-(1-(6-chloro-3-((4-methylpiperazin-1-yl)methyl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 114); 3-(5-(1-(6-chloro-5-hydroxy-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 115); 3-(4-fluoro-5-(1-(3-methyl-6-morpholino-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 116); 3-(5-(1-(6-chloro-7-fluoro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 117); 2-(4-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-3-methyl-1H-indole-6-carbonitrile (compound 118); 6-chloro-2-(4-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-3-methyl-1H-indole-5-carbonitrile (compound 119); 2-(4-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-5-fluoro-3-methyl-1H-indole-6-carbonitrile (compound 120); 5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (compound 121); 2-(4-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)piperidine-1-carbonyl)-7-fluoro-3-methyl-1H-indole-6-carbonitrile (compound 122); (3-(5-(1-(6-chloro-3-methyl-1H-indole-2-carbonyl)piperidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl pivalate (compound 123); 3-(4-fluoro-5-(1-(7-fluoro-3-methyl-6-morpholino-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 124); 3-(4-fluoro-5-(1-(5-fluoro-3-methyl-6-morpholino-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 125); 3-(4-fluoro-5-(1-(7-fluoro-3-methyl-6-(4-methylpiperazin-1-yl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 126); and 3-(4-fluoro-5-(1-(5-fluoro-3-methyl-6-(4-methylpiperazin-1-yl)-1H-indole-2-carbonyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 127); 2. The compound of claim 1, its stereoisomer, its solvate, its prodrug, or its pharmaceutically acceptable salt, which is selected from the group consisting of:

9. A composition comprising, as an active ingredient, the compound according to any one of claims 1 to 8, its stereoisomer, its solvate, its prodrug, or its pharmaceutically acceptable salt. A pharmaceutical composition for preventing or treating a disease associated with the regulation of IKZF2 protein level, comprising:

10. The disease associated with the regulation of IKZF2 protein levels is cancer. The pharmaceutical composition for preventing or treating cancer according to claim 9.

11. The cancer is a solid cancer or a blood cancer. The preventive or therapeutic pharmaceutical composition according to claim 10.

12. The solid cancer is selected from the group consisting of non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), prostate cancer, breast carcinoma, lymphoma, leukemia, melanoma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid cancer, nasopharyngeal carcinoma, tongue cancer, pancreatic cancer, esophageal cancer, bile duct carcinoma, gastric cancer, soft tissue sarcoma, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, tubular carcinoma, and Ewing's sarcoma. The pharmaceutical composition for preventing or treating cancer according to claim 11.

13. The hematological cancer is selected from the group consisting of acute myeloid leukemia (AML), chronic myeloid leukemia (CML), Abelson oncogene-associated CML (Bcr-ABL translocation), myelodysplastic syndromes (MDS), acute B-lymphoblastic leukemia (B-ALL), acute T-lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myeloproliferative neoplasms (MPN), Richter's syndrome, hairy cell leukemia (HCL), blastic plasmacytic dendritic cell neoplasm (BPDCN), non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL), Hodgkin's lymphoma, systemic mastocytosis, and Burkitt's lymphoma. The pharmaceutical composition for preventing or treating cancer according to claim 11.

14. The compound represented by formula 1 of claim 1 is administered in combination with an anti-cancer drug. A pharmaceutical composition for preventing or treating cancer, comprising:

15. The anticancer drugs include paclitaxel, docetaxel, cabazitaxel, larotaxel, BMS-184476, BMS-188797, BMS275183, mirataxel, ortaxel, TL-310, docosahexaenoic acid-paclitaxel (DHA-paclitaxel), nab-paclitaxel, EndoTAG+paclitaxel, XRP9881, polymer-mycel paclitaxel, RPR-109881A, nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulan, and mitobromide. Ronitol, Carboquone, Thiotepa, Ranimustine, Nimustine, Temozolomide, Carmustine, Methotrexate, 6-Mercaptopurine Riboside, Mercaptopurine, 5-Fluorouracil, Tegafur, Doxifluridine, Camofur, Cytarabine, Cytarabine octophosphate, Enocitabine, S-1, Gemcitabine, Fludarabine, Pemetrexed Disodium, Actinomycin D, Doxorubicin, Daunorubicin, Neocalcinone Statins, Bleomycin, Peplomycin, Mitomycin C, Aclarubicin thiazol-10, pirarubicin, epirubicin, zinostatin stimalamer, idarubicin, sirolimus, valrubicin, vincristine, vinblastine, vindesine, etoposide, sobuzoxane, docetaxel, paclitaxel, vinorelbine, cisplatin, carboplatin, nedaplatin or oxaliplatin, irinotecan, topotecan, camptothecin, gefitinib, imatinib, erlotinib, cetuximab, bevacizumab, rituximab, bevacizumab, alemtuzumab or trastuzumab, goserelin (gos any one or more selected from the group consisting of cefotaxime, leuprolide, tamoxifen, Imlygic, Avastin, bevacizumab, ramucirumab, aflibercept, cetuximab, panitumumab, regorafenib, sunitinib, sorafenib, pazopanib, vandetanib, axitinib, cediranib, vatalanib, motesanib, lucatinib, intedanib, semaxanib, afatinib, lenvatinib, and cabozantinib. The pharmaceutical composition for preventing or treating cancer according to claim 14.

16. The compound of claim 1 is administered in combination with an immunomodulatory cell therapy agent or an immunomodulatory drug. A pharmaceutical composition for preventing or treating cancer, comprising:

17. The immunomodulatory cell therapeutic agent or immunomodulatory drug includes one or more immunomodulatory cell therapeutic agents or immunomodulatory drugs selected from a PD-1 inhibitor, a PD-L1 inhibitor, a LAG-3 inhibitor, a CTLA-4 antagonist, an A2A antagonist, a GITR agonist, a TIM-3 inhibitor, a STING agonist, and a TLR7 agonist, and is administered in combination with the immunomodulatory cell therapeutic agent or immunomodulator. The pharmaceutical composition for preventing or treating cancer according to claim 16.

18. The PD-1 inhibitors include nivolumab (BMS), pembrolizumab (Merck), BCD-100 (Biocad), cemiplimab (Regeneron Pharmaceuticals Inc.), sintilimab (IBI-308 from Eli Lilly / Innovent Biologics, Inc.), spartalizumab (PDR-001 from Novartis AG), camrelizumab (SHR-1210 from Insight Corporation / Jiangsu Hengrui), tislelizumab (BeiGene Limited), AGEN-2034 (Agenus Inc.), and cisplatin (Tregs). ted), MEDI-0680 (AMP-514; Amplimmune / MedImmune LLC), toripalimab (JS-001 from Shanghai Junshi Bioscience Company Limited), dostarimab (TSR-042 from Tesaro Incorporated), ABBV-181 (AbbVie Incorporated), AK-104 (Akeso BioPharma Incorporated), AK-105 (Akeso BioPharma Incorporated), BAT-1306 (Biothera Solutions Limited), BI754091 (Boehringer Inge GmbH) Brheim Mbha), CBT-501, genolimuzumab (CBT Pharmaceuticals Inc. / Zeno), GLS-010 (Harbin-Lauria / Uxi / Arcus), LZM-009 (Livzon Pharmaceutical Group Inc.), MGA-012 (Insight Corporation / MacroGenics), MGD-013 (MacroGenics Inc.), PF-06801591 (Pfizer Inc.), Sym-021 (Symphogen A / S), CS-1003 (C Stone Pharmaceuticals Company Limited), HLX-10 (Henrix Biotech / Shanghai Henrix Biotech Company Limited), AK-103 (Akeso Biopharmaceuticals Inc.), AM-0001 (Alumo Biosciences Inc.), TILT-123 (Tilt Biotherapeutics Limited), BH-2922 (Beijing Hanmi Pharmaceutical), BH-2941 (Beijing Hanmi Pharmaceutical), BH-2950 (Beijing Hanmi Pharmaceutical),CX-188 (Cytomex Therapeutics, Inc.), ENUM244C8 (Enumeral Biomedical Holdings), ENUM-388D4 (Enumeral Biomedical Holdings), HAB-21 (Suzhou Steinway Biotech, Inc.), HEISCOIII-003 (Sichuan Heisco Pharmaceuticals), IKT-202 (Iselcarex Therapeutics), JS-003 (Shanghai Junshi Bioscience), JTX-4014 (Johns Therapeutics, Inc.), MCLA-134 (Mers NV), MGD-019 (Macrogenics, Inc.), MT-17000 (Molecular Template Twin, Inc.), PEGMP-7 (D5 Pharma Ingredients) Incorporated), PRS-332 (Pieris Pharmaceuticals Inc.), RXI-762 (RXi Pharmaceuticals Corporation), STI-1110 (Res Laboratoire Toilet Servier / Sorrento), VXM-10 (Vexim AG), XmAb-20717 (Gencoin Corporation), XmAb-23104 (Gencoin Corporation), AK-112 (Akeso Biopharma Inc.), HLX-20 (Henrix Biotech / Shanghai Henrix Biotech Co. Ltd.), SSI-361 (Libgen Biopharma Limited), AT-16201 (AIMM Therapeutics BV), and SNA-01 (Fountain Biopharma Inc.); The pharmaceutical composition for preventing or treating cancer according to claim 17.

19. The PD-L1 inhibitors include atezolizumab (Genentech Inc.), avelumab (Merck KGaA / Pfizer), davalumab (AstraZeneca Pharmaceuticals LP / MedImmune), BGB-A333 (BeiGene Limited), CX-072 (Cytomex Therapeutics Inc.), GNS-1480 (Limited Corporation / Xenosco), AMP-224 (MedImmune LLC), and CA-170 (Origin Discovery Lee Technologies Limited), CK-301 (Checkpoint Therapeutics / TG Therapeutics), CS-1001 (C-Stone Pharmaceuticals Company Limited), FAZ-053 (Novartis AG), emvapolimab (ASC22 or KN-035; Suzhou Alfalumab / 3DMed), LY-3300054 (Eli Lilly and Company), M-7824 (Merck KGaA), HTI-1088 (HTI-131, SHR-1316;Atridia and Jiangsu Hengrui Pharmaceutical), MSB-2311 (Mabspace Biosciences (Suzhou) Company Limited), STI-A1014 (Leeds Pharmaceuticals / Sorrento), AK106 (Akeso Biopharmaceuticals, Inc.), AVA-004 (Abacta Life Sciences, Ltd.), BBI-801 (Boston Biomedical, Inc.), CA-327 (Origin / Curis), CBA-0710 (Sorrento Therapeutics, Inc.), CBT-502 (CBT Pharmaceuticals / Ciatai Tianqing Pharmaceuticals), FPT-155 (Five Prime Therapeutics, Inc. Rated), FS-118 (F-Star Biotechnology Limited), IKT-201 (Iselcarex Therapeutics), IKT-703 (Iselcarex Therapeutics), IO-103 (IO Biotech APS), JS-003 (Shanghai Junshi Bioscience), KD-033 (Kadomon Corporation / Jonwa Pharmaceuticals), KY-1003 (Kymab Limited), MCLA-145 (Mers NV / Insight), MT-5050 (Molecular Template Twin Corporation), and SNA-02 (Fountain BioPharma Corporation); The pharmaceutical composition for preventing or treating cancer according to claim 17.

20. The CTLA-4 antagonist is any one or more selected from the group consisting of ipilimumab, tremelimumab, and MEDI5752. The pharmaceutical composition for preventing or treating cancer according to claim 17.

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