BCL-XL / BCL-2 Dual Disintegrants for the Treatment of Cancer

Abstract

Provided herein are compounds (e.g., compounds of Formula (I) or Formula (II)), their mechanisms of action, and methods of modulating proliferative activity, as well as methods of treating diseases and disorders using the compounds provided herein (e.g., compounds of Formula (I) or Formula (II)).

Description

[Technical Field]

[0001] Related Applications This patent application claims priority to U.S. Provisional Patent Application No. 63 / 287962, filed December 9, 2021, which is incorporated herein by reference in its entirety.

[0002] Government support information This invention was made with government support under grant numbers R01 CA242003 and R01 CA241191 awarded by the National Institutes of Health. The government has certain rights in this invention. [Background technology]

[0003] The B-cell lymphoma 2 (Bcl-2) protein family, consisting of pro- and anti-apoptotic members, plays a key role in determining cell fate through regulation of the intrinsic apoptotic pathway. Anti-apoptotic Bcl-2 family proteins, such as Bcl-2, Bcl-xL, Bcl-w, and Mcl-1, are upregulated in many cancers and are associated with tumor initiation, progression, and resistance to chemotherapy and targeted therapies. Therefore, these anti-apoptotic Bcl-2 proteins are attractive targets for the development of novel anticancer drugs (Lessene et al., Nat Rev Drug Discov 7:989-1000, 2008; Vogler et al., Cell Death Differ 2009;16:360-367; Delbridge et al., Nat Rev Cancer 16:99-109, 2016). Numerous Bcl-2 small molecule inhibitors have been reported (Bajwa et al., Expert Opin Ther Patents 22:37-55, 2012; Vogler, Adv Med. 1-14, 2014; Ashkenazi et al., 16:273-284, 2017). The following are some of the Bcl-2 small molecule inhibitors being investigated in various stages of drug development: ABT-737 (U.S. Patent Application Publication No. 20070072860), navitoclax (ABT-263, WO 2009155386), venetoclax (ABT-199, WO 2010138588), obatoclax (GX15-070, WO 2010138588), and vasoclax (GX15-070, WO 2010138588). No. 2004106328), (-)-gossypol (AT-101, WO 2002097053), sabutoclax (BI-97C1, WO 2010120943), TW-37 (WO 2006023778), BM-1252 (APG-1252), and A-1155463 (WO 2010080503).

[0004] Venetoclax, a selective Bcl-2 inhibitor, was approved by the FDA in 2016 for the treatment of chronic lymphocytic leukemia (CLL) with 17p deletion. Venetoclax was designed to be highly selective for Bcl-2 over Bcl-xL to avoid on-target platelet toxicity (Souers et al., Nat Med 19:202-208, 2013). Because platelets depend on Bcl-xL to maintain their viability, dose-limiting thrombocytopenia due to its inhibition of Bcl-xL has been observed in animals and / or humans treated with ABT-737 (Schoenwaelder et al., Blood 118:1663-1674, 2011), ABT-263 (Tse et al., Cancer Res 68:3421-3428, 2008; Roberts et al., Bri J Haematol 170:669-678, 2015), BM-1197 (Bai et al., PLoS ONE 9:e99404, 2014), or A-1155463 (Tao et al., ACS Med Chem Lett 5:1088-1093, 2014). However, many CLL patients are resistant to venetoclax (Roberts et al., N Engl J Med 374:311-322, 2016), and upregulation of Bcl-xL by microenvironmental survival signals has been identified as a key component explaining this resistance, consistent with the high efficacy of the Bcl-2 / Bcl-xL dual inhibitor ABT-263 in killing venetoclax-resistant CLL cells (Oppermann et al., Blood 128:934-947, 2016). Additionally, Bcl-xL is generally overexpressed more frequently than Bcl-2 in solid tumors. Importantly, preclinical and clinical trials of ABT-263 have demonstrated promising results in several solid and hematological malignancies, either as a single agent or in combination with other antitumor agents (Delbridge et al., Nat Rev Cancer 16:99-109, 2016).Therefore, it is highly desirable to develop strategies that can retain the antitumor versatility and efficacy of Bcl-xL / Bcl-2 dual inhibitors while simultaneously sparing their on-target platelet toxicity. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] US Patent Application Publication No. 20070072860 [Patent Document 2] International Publication No. 2009155386 Brochure [Patent Document 3] International Publication No. 2010138588 Brochure [Patent Document 4] International Publication No. 2004106328 Brochure [Patent Document 5] International Publication No. 2002097053 Brochure [Patent Document 6] International Publication No. 2010120943 Brochure [Patent Document 7] International Publication No. 2006023778 Brochure [Patent Document 8] International Publication No. 2010080503 Brochure [Non-patent literature]

[0006] [Non-Patent Document 1] Lessene et al., Nat Rev Drug Discov 7:989-1000,2008 [Non-patent document 2] Vogler et al.,Cell Death Differ 2009;16:360-367 [Non-patent document 3] Delbridge et al., Nat Rev Cancer 16:99-109,2016 [Non-patent document 4] Bajwa et al.,Expert Opin Ther Patents 22:37-55,2012 [Non-Patent Document 5] Vogler,Adv Med.1-14,2014 [Non-patent document 6] Ashkenazi et al.,16:273-284,2017 [Non-Patent Document 7] Souers et al., Nat Med 19:202-208,2013 [Non-patent document 8] Schoenwaelder et al.,Blood 118:1663-1674,2011 [Non-Patent Document 9] Tse et al., Cancer Res 68:3421-3428, 2008 [Non-Patent Document 10] Roberts et al.,Bri J Haematol 170:669-678,2015 [Non-Patent Document 11] Bai et al.,PLoS ONE 9:e99404,2014 [Non-Patent Document 12] Tao et al.,ACS Med Chem Lett 5:1088-1093,2014 [Non-Patent Document 13] Roberts et al.,N Engl J Med 374:311-322,2016 [Non-Patent Document 14] Oppermann et al.,Blood 128:934-947,2016 Summary of the Invention

[0007] Therefore, there is a need to develop compounds that can retain the antitumor versatility and efficacy of dual Bcl-xL / Bcl-2 inhibitors while simultaneously avoiding their on-target platelet toxicity.

[0008] Provided herein are compounds (e.g., compounds of Formula (I) or Formula (II)), their mechanisms of action, and methods of modulating proliferative activity, as well as methods of treating diseases and disorders using the compounds provided herein (e.g., compounds of Formula (I) or Formula (II)). In one embodiment, the disease or disorder is cancer. In another embodiment, the cancer is a Bcl-2-mediated cancer.

[0009] In another aspect, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof: [ka] (Wherein R1 is [ka] and R2 is NO2, SO-2CF3 or SO2CF2Cl; R3 is Cl, F, CF2H, CFH2 or CF3; R4 is H or CH3; L1 is [ka] TIFF2024546095000005.tif215159TIFF2024546095000006.tif231159TIFF2024546095000007.tif216159, L2 is bond, [ka] and each X is independently CH or N; each k is independently 0, 1, 2, 3, 4, 5, or 6; each m is independently 2, 3, 4, 5, 6, or 7; each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each p is independently 0, 1, 2, 3, or 4; each q is independently 1, 2, or 3; each r is independently 1 or 2; R5 is independently H, optionally substituted alkyl or optionally substituted cycloalkyl).

[0010] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof is of formula (IA): [ka]

[0011] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof is of formula (IB): [ka]

[0012] In one aspect, R1 is [ka] is.

[0013] In another embodiment, R1 is [ka] is.

[0014] In another embodiment, R1 is [ka] is.

[0015] In another embodiment, R1 is [ka] is.

[0016] In another embodiment, R1 is [ka] is.

[0017] In another embodiment, R1 is [ka] In another embodiment, R1 is [ka] is.

[0018] In one aspect, R2 is NO2, SO-2CF3, or SO-2CF2Cl. In one aspect, R2 is NO2 or SO-2CF3. In one aspect, R2 is NO2 or SO-2CF2Cl. In one aspect, R2 is SO-2CF3 or SO-2CF2Cl. In one aspect, R2 is NO2. In another aspect, R2 is SO-2CF3. In one aspect, R2 is SO-2CF2Cl.

[0019] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof is of formula (IC): [ka]

[0020] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof is of formula (ID): [ka] (In the formula, R 2’ is CF3 or CF2Cl).

[0021] In one aspect, R3 is Cl, F, CFH2, CF2H, or CF3. In some embodiments, R3 is F, CFH2, CF2H, or CF3. In certain embodiments, R3 is CFH2, CF2H, or CF3. In some embodiments, R3 is Cl, F, or CF3. In certain embodiments, R3 is Cl or F. In some embodiments, R3 is CF3 or F. In certain embodiments, R3 is Cl. In some embodiments, R3 is F. In certain embodiments, R3 is CF3. In some embodiments, R3 is CF2H. In certain embodiments, R3 is CFH2.

[0022] In one aspect, R4 is H or CH3. In some embodiments, R4 is H. In certain embodiments, R4 is CH3.

[0023] In one aspect, R5 is independently H, optionally substituted alkyl, or optionally substituted cycloalkyl. In some embodiments, R5 is independently H or optionally substituted cycloalkyl. In certain embodiments, R5 is independently H or optionally substituted alkyl. In some embodiments, R5 is independently substituted alkyl or substituted cycloalkyl. In certain embodiments, R5 is independently H, unsubstituted alkyl, or unsubstituted cycloalkyl. In some embodiments, R5 is independently H or unsubstituted cycloalkyl. In certain embodiments, R5 is independently H or unsubstituted alkyl. In some embodiments, R5 is independently unsubstituted alkyl or unsubstituted cycloalkyl.

[0024] In certain embodiments, R5 is independently H, optionally substituted C1-C 10 Alkyl or optionally substituted C3-C 10 In some embodiments, R is independently H or an optionally substituted C-C 10In certain embodiments, R5 is independently H or an optionally substituted C1-C 10 In some embodiments, R5 is independently an optionally substituted C1-C 10 Alkyl or optionally substituted C3-C 10 In certain embodiments, R is independently H, unsubstituted C-C 10 Alkyl or unsubstituted C3-C 10 In some embodiments, R is independently H or unsubstituted C-C 10 In certain embodiments, R is independently H or unsubstituted C-C 10 In some embodiments, R is independently an unsubstituted C-C alkyl. 10 Alkyl or unsubstituted C3-C 10 It is cycloalkyl.

[0025] In certain embodiments, R5 is independently H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C7 cycloalkyl. In some embodiments, R5 is independently H or optionally substituted C3-C7 cycloalkyl. In certain embodiments, R5 is independently H or optionally substituted C1-C6 alkyl. In some embodiments, R5 is independently H or optionally substituted C1-C6 alkyl. In some embodiments, R5 is independently optionally substituted C1-C6 alkyl or optionally substituted C3-C7 cycloalkyl. In certain embodiments, R5 is independently H, unsubstituted C1-C6 alkyl, or unsubstituted C3-C7 cycloalkyl. In certain embodiments, R5 is independently H or unsubstituted C3-C7 cycloalkyl. In certain embodiments, R5 is independently H or unsubstituted C1-C6 alkyl. In some embodiments, R5 is independently unsubstituted C1-C6 alkyl or unsubstituted C3-C7 cycloalkyl. In certain embodiments, R5 is H, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, R5 is H, CH3, or CH2CH3. In some embodiments, R5 is H or CH3. In some embodiments, R5 is CH3 or CH2CH3.

[0026] In certain embodiments, R5 is H. In some embodiments, R5 is optionally substituted C1-C6 alkyl. In certain embodiments, R5 is unsubstituted C1-C6 alkyl. In some embodiments, R5 is CH3. In certain embodiments, R5 is CH2CH3. In some embodiments, R5 is optionally substituted C3-C7 cycloalkyl. In certain embodiments, R5 is unsubstituted C3-C7 cycloalkyl.

[0027] In some embodiments, L1 is [ka] In some embodiments, L1 is [ka] is.

[0028] In some embodiments, L1 is [ka] In some embodiments, L1 is [ka] In some embodiments, L1 is [ka] In some embodiments, L1 is [ka] In some embodiments, L1 is [ka] In some embodiments, L1 is [ka] In some embodiments, L1 is [ka] In some embodiments, L1 is [ka] In some embodiments, L1 is [ka] In certain embodiments, L1 is [ka] and in some embodiments, L1 is [ka] In some embodiments, L1 is [ka] is.

[0029] In one aspect, L1 is [ka] where X is N and r is 1.

[0030] In some embodiments, L2 is [ka] In some embodiments, L2 is [ka] is.

[0031] In some embodiments, L1 is [ka] TIFF2024546095000038.tif204159TIFF2024546095000039.tif207159TIFF2024546095000040.tif224159, L2 is a bond, [ka] is.

[0032] In some embodiments, L2 is a bond, [ka] In some embodiments, L2 is [ka] In some embodiments, L2 is [ka] In some embodiments, L2 is [ka] In some embodiments, L2 is [ka] In some embodiments, L2 is [ka] In some embodiments, L1 is [ka] In some embodiments, L2 is a bond. In some embodiments, L2 is [ka] is.

[0033] In some embodiments, L2 is [ka] In some embodiments, L2 is [ka] In some embodiments, L2 is [ka] is.

[0034] In some embodiments, L2 is [ka] is.

[0035] As defined herein, X is independently CH or N. In some embodiments, X is CH. In certain embodiments, X is N.

[0036] As defined herein, each k is independently 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, each k is independently 0, 1, 2, 3, 4, or 5. In some embodiments, each k is independently 0, 1, 2, 3, or 4. In certain embodiments, each k is independently 0, 1, 2, or 3. In some embodiments, each k is independently 0, 1, or 2. In certain embodiments, each k is independently 3, 4, 5, or 6. In some embodiments, each k is independently 1, 2, 3, 4, 5, or 6. In certain embodiments, k is 0. In some embodiments, k is 1. In certain embodiments, k is 2. In some embodiments, k is 3. In certain embodiments, k is 4. In some embodiments, k is 5. In some embodiments, k is 6.

[0037] In one aspect, each m is independently 2, 3, 4, 5, 6, or 7. In some embodiments, each m is independently 2, 3, 4, 5, or 6. In certain embodiments, each m is independently 3, 4, 5, 6, or 7. In some embodiments, each m is independently 2, 3, 4, or 5. In certain embodiments, each m is independently 3, 4, 5, or 6. In some embodiments, each m is independently 4, 5, 6, or 7. In certain embodiments, each m is independently 2, 3, or 4. In some embodiments, each m is independently 3, 4, or 5. In certain embodiments, each m is independently 4, 5, or 6. In some embodiments, each m is 5, 6, or 7. In certain embodiments, each m is independently 2 or 3. In some embodiments, each m is independently 3 or 4. In certain embodiments, each m is independently 4 or 5. In some embodiments, each m is independently 5 or 6. In certain embodiments, each m is independently 6 or 7. In some embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In some embodiments, m is 5. In certain embodiments, m is 6. In some embodiments, m is 7.

[0038] In one aspect, each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9. In certain embodiments, each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, each n is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, each n is independently 1, 2, 3, 4, 5, 6, 7, 8, or 9. In certain embodiments, each n is independently 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, each n is independently 0, 1, 2, 3, 4, or 5. In some embodiments, each n is independently 1, 2, 3, 4, 5, or 6. In certain embodiments, each n is independently 2, 3, 4, 5, 6, or 7. In some embodiments, each n is independently 3, 4, 5, 6, 7, or 8. In certain embodiments, each n is independently 4, 5, 6, 7, 8, or 9. In some embodiments, each n is independently 5, 6, 7, 8, 9, or 10. In certain embodiments, each n is independently 0, 1, 2, 3, or 4. In some embodiments, each n is independently 1, 2, 3, 4, or 5. In some embodiments, each n is independently 2, 3, 4, 5, or 6. In certain embodiments, each n is independently 3, 4, 5, 6, or 7. In some embodiments, each n is independently 0, 1, 2, or 3. In some embodiments, each n is independently 1, 2, 3, or 4. In some embodiments, each n is independently 2, 3, 4, or 5. In certain embodiments, each n is independently 3, 4, 5, or 6. In some embodiments, each n is independently 4, 5, 6, or 7. In certain embodiments, each n is independently 5, 6, 7, or 8. In some embodiments, each n is independently 6, 7, 8, or 9. In certain embodiments, each n is independently 7, 8, 9, or 10. In some embodiments, each n is independently 0, 1, or 2. In certain embodiments, each n is independently 1, 2, or 3.In certain embodiments, each n is independently 2, 3, or 4. In some embodiments, each n is independently 3, 4, or 5. In certain embodiments, each n is independently 4, 5, or 6. In some embodiments, each n is 5, 6, or 7. In certain embodiments, each n is independently 5, 6, or 7. In some embodiments, each n is independently 7, 8, or 9. In certain embodiments, each n is independently 8, 9, or 10. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In certain embodiments, each n is independently 2 or 3. In some embodiments, each n is independently 3 or 4. In certain embodiments, each n is independently 4 or 5. In some embodiments, each n is independently 5 or 6. In certain embodiments, each n is independently 6 or 7. In some embodiments, each n is independently 7 or 8. In certain embodiments, each n is independently 8 or 9. In some embodiments, each n is independently 9 or 10. In certain embodiments, n is 0. In some embodiments, n is 1. In certain embodiments, n is 2. In some embodiments, n is 3. In certain embodiments, n is 4. In some embodiments, n is 5. In certain embodiments, n is 6. In some embodiments, n is 7. In certain embodiments, n is 8. In some embodiments, n is 9. In certain embodiments, n is 10.

[0039] In one aspect, each p is independently 0, 1, 2, 3, or 4. In some embodiments, each p is independently 0, 1, 2, or 3. In certain embodiments, each p is independently 1, 2, 3, or 4. In some embodiments, each p is independently 0, 1, or 2. In certain embodiments, each p is independently 1, 2, or 3. In some embodiments, each p is independently 2, 3, or 4. In certain embodiments, each p is independently 0 or 1. In some embodiments, each p is independently 1 or 2. In certain embodiments, each p is independently 2 or 3. In some embodiments, each p is independently 3 or 4. In certain embodiments, p is 0. In some embodiments, p is 1. In certain embodiments, p is 2. In some embodiments, p is 3. In certain embodiments, p is 4.

[0040] In one aspect, each q is independently 1, 2, or 3. In certain embodiments, each q is independently 1 or 2. In some embodiments, each q is independently 2 or 3. In certain embodiments, q is 1. In some embodiments, q is 2. In certain embodiments, q is 3.

[0041] In one aspect, each r is independently 1 or 2. In some embodiments, r is 1. In certain embodiments, r is 2.

[0042] In one aspect, L1 is [ka] and L2 is a bond or [ka] In another embodiment, L1 is [ka] and L2 is [ka] In another embodiment, L1 is [ka] and L2 is [ka] In another embodiment, L1 is [ka] and L2 is [ka] is.

[0043] In some embodiments, L2 is [ka] (e.g., m is 1), and L1 is [ka] (e.g., r is 1). In some embodiments, L2 is [ka] (e.g., m is 3), and L1 is [ka] (e.g., r is 1). In some embodiments, L2 is [ka] (e.g., m is 2), and L1 is [ka] In some embodiments, L2 is [ka] (e.g., m is 3), and L1 is [ka] In some embodiments, L2 is [ka] (e.g., m is 4), and L1 is [ka] In some embodiments, L2 is [ka] (e.g., p is 2), and L1 is [ka] In some embodiments, L2 is [ka] (e.g., p is 1), and L1 is [ka] (e.g., r is 1). In some embodiments, L2 is [ka] (e.g., m is 3), and L1 is [ka] (e.g., X is CH). In some embodiments, L2 is [ka] (e.g., m is 2), and L1 is [ka] (e.g., X is CH). In some embodiments, L2 is [ka] and L1 is [ka] (e.g., X is CH). In some embodiments, L2 is [ka] (e.g., m is 3), and L1 is [ka] (e.g., X is N). In some embodiments, L2 is [ka] (e.g., m is 3), and L1 is [ka] (e.g., X is N). In another embodiment, the compound of formula (I) is [Table 1] TIFF2024546095000087.tif205159TIFF2024546095000088.tif204159TIFF2024546095000089.tif200159TIFF2024546095000090.tif206159TIFF202 4546095000091.tif206159TIFF2024546095000092.tif203159TIFF2024546 095000093.tif202159TIFF2024546095000094.tif211159TIFF20245460950 00095.tif196159TIFF2024546095000096.tif211159TIFF2024546095000097.tif233159TIFF2024546095000098.tif205159TIFF2024546095000099.t if202159TIFF2024546095000100.tif202159TIFF2024546095000101.tif200159TIFF2024546095000102.tif200159TIFF2024546095000103.tif185159

[0044] In another embodiment, the compound of formula (I) is [Table 2] TIFF2024546095000105.tif235159TIFF2024546095000106.tif177159

[0045] In certain embodiments, the compound is Compound 51, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof). In certain embodiments, the compound is not Compound 51, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof).

[0046] In another aspect, provided herein is a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof: [ka] Formula (II), (In the formula: R2 is NO2, SO-2CF3 or SO2CF2Cl; R3 is Cl, F, CF2H, CFH2 or CF3; R4 is H or CH3; L1 is [ka] TIFF2024546095000109.tif209159TIFF2024546095000110.tif233159TIFF2024546095000111.tif221159, L2 is bond, [ka] and each X is independently CH or N; each k is independently 0, 1, 2, 3, 4, 5, or 6; each m is independently 2, 3, 4, 5, 6, or 7; each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each p is independently 0, 1, 2, 3, or 4; each q is independently 1, 2, or 3; each r is independently 1 or 2; R5 is independently H, optionally substituted alkyl or optionally substituted cycloalkyl; However, R2 is SO-2CF3 and L1 is [ka] If , L2 is a bond, [ka] isn't it).

[0047] In another embodiment, the compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof is of formula (II-A): [ka]

[0048] In another embodiment, the compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof is of formula (II-B): [ka]

[0049] In one aspect, R2 is NO2, SO-2CF3, or SO-2CF2Cl. In one aspect, R2 is NO2 or SO-2CF3. In one aspect, R2 is NO2 or SO-2CF2Cl. In one aspect, R2 is SO-2CF3 or SO-2CF2Cl. In one aspect, R2 is NO2. In another aspect, R2 is SO-2CF3. In one aspect, R2 is SO-2CF2Cl.

[0050] In another embodiment, the compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof is of formula (II-C): [ka]

[0051] In another embodiment, the compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof is of formula (II-D): [ka] (In the formula, R 2’ is CF3 or CF2Cl).

[0052] In one aspect, R3 is Cl, F, CFH2, CF2H, or CF3. In some embodiments, R3 is F, CFH2, CF2H, or CF3. In certain embodiments, R3 is CFH2, CF2H, or CF3. In some embodiments, R3 is Cl, F, or CF3. In certain embodiments, R3 is Cl or F. In some embodiments, R3 is CF3 or F. In certain embodiments, R3 is Cl. In some embodiments, R3 is F. In certain embodiments, R3 is CF3. In some embodiments, R3 is CF2H. In certain embodiments, R3 is CFH2.

[0053] In one aspect, R4 is H or CH3. In some embodiments, R4 is H. In certain embodiments, R4 is CH3.

[0054] In one aspect, R5 is independently H, optionally substituted alkyl, or optionally substituted cycloalkyl. In some embodiments, R5 is independently H or optionally substituted cycloalkyl. In certain embodiments, R5 is independently H or optionally substituted alkyl. In some embodiments, R5 is independently substituted alkyl or substituted cycloalkyl. In certain embodiments, R5 is independently H, unsubstituted alkyl, or unsubstituted cycloalkyl. In some embodiments, R5 is independently H or unsubstituted cycloalkyl. In certain embodiments, R5 is independently H or unsubstituted alkyl. In some embodiments, R5 is independently unsubstituted alkyl or unsubstituted cycloalkyl.

[0055] In certain embodiments, R5 is independently H, optionally substituted C1-C 10 Alkyl or optionally substituted C3-C 10 In some embodiments, R is independently H or an optionally substituted C-C 10In certain embodiments, R5 is independently H or an optionally substituted C1-C 10 In some embodiments, R5 is independently an optionally substituted C1-C 10 Alkyl or optionally substituted C3-C 10 In certain embodiments, R is independently H, unsubstituted C-C 10 Alkyl or unsubstituted C3-C 10 In some embodiments, R is independently H or unsubstituted C-C 10 In certain embodiments, R is independently H or unsubstituted C-C 10 In some embodiments, R is independently an unsubstituted C-C alkyl. 10 Alkyl or unsubstituted C3-C 10 It is cycloalkyl.

[0056] In certain embodiments, R5 is independently H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C7 cycloalkyl. In some embodiments, R5 is independently H or optionally substituted C3-C7 cycloalkyl. In certain embodiments, R5 is independently H or optionally substituted C1-C6 alkyl. In some embodiments, R5 is independently H or optionally substituted C1-C6 alkyl. In some embodiments, R5 is independently optionally substituted C1-C6 alkyl or optionally substituted C3-C7 cycloalkyl. In certain embodiments, R5 is independently H, unsubstituted C1-C6 alkyl, or unsubstituted C3-C7 cycloalkyl. In certain embodiments, R5 is independently H or unsubstituted C3-C7 cycloalkyl. In certain embodiments, R5 is independently H or unsubstituted C1-C6 alkyl. In some embodiments, R5 is independently unsubstituted C1-C6 alkyl or unsubstituted C3-C7 cycloalkyl. In certain embodiments, R5 is H, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, R5 is H, CH3, or CH2CH3. In some embodiments, R5 is H or CH3. In some embodiments, R5 is CH3 or CH2CH3.

[0057] In certain embodiments, R5 is H. In some embodiments, R5 is optionally substituted C1-C6 alkyl. In certain embodiments, R5 is unsubstituted C1-C6 alkyl. In some embodiments, R5 is CH3. In certain embodiments, R5 is CH2CH3. In some embodiments, R5 is optionally substituted C3-C7 cycloalkyl. In certain embodiments, R5 is unsubstituted C3-C7 cycloalkyl.

[0058] In some embodiments, L1 is [ka] In some embodiments, L1 is [ka] is.

[0059] In some embodiments, L1 is [ka] In some embodiments, L1 is [ka] In some embodiments, L1 is [ka] In some embodiments, L1 is [ka] In some embodiments, L1 is [ka] In some embodiments, L1 is [ka] In some embodiments, L1 is [ka] In some embodiments, L1 is [ka] In some embodiments, L1 is [ka] In certain embodiments, L1 is [ka] and in some embodiments, L1 is [ka] In some embodiments, L1 is [ka] is.

[0060] In some embodiments, L1 is [ka] In some embodiments, L1 is not [ka] TIFF2024546095000135.tif238159TIFF2024546095000136.tif218159TIFF2024546095000137.tif73159.

[0061] In one aspect, L1 is [ka] where X is N and r is 1.

[0062] In some embodiments, L1 is [ka] TIFF2024546095000140.tif209159TIFF2024546095000141.tif208159TIFF2024546095000142.tif221159, L2 is a bond, [ka] is.

[0063] In some embodiments, L2 is [ka] In some embodiments, L2 is [ka] is.

[0064] In some embodiments, L2 is a bond, [ka] In some embodiments, L2 is [ka] In some embodiments, L2 is [ka] In some embodiments, L2 is [ka] In some embodiments, L2 is [ka] In some embodiments, L2 is [ka] In some embodiments, L1 is [ka] In some embodiments, L2 is a bond. In some embodiments, L2 is [ka] is.

[0065] In some embodiments, L2 is [ka] In some embodiments, L2 is [ka] In some embodiments, L2 is [ka] is.

[0066] In some embodiments, L2 is [ka] In some embodiments, L2 is not [ka] is.

[0067] In some embodiments, L2 is [ka] is.

[0068] In one aspect, X is independently CH or N. In some embodiments, X is CH. In certain embodiments, X is N.

[0069] As defined herein, each k is independently 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, each k is independently 0, 1, 2, 3, 4, or 5. In some embodiments, each k is independently 0, 1, 2, 3, or 4. In certain embodiments, each k is independently 0, 1, 2, or 3. In some embodiments, each k is independently 0, 1, or 2. In certain embodiments, each k is independently 3, 4, 5, or 6. In some embodiments, each k is independently 1, 2, 3, 4, 5, or 6. In certain embodiments, k is 0. In some embodiments, k is 1. In certain embodiments, k is 2. In some embodiments, k is 3. In certain embodiments, k is 4. In some embodiments, k is 5. In some embodiments, k is 6.

[0070] In one aspect, each m is independently 2, 3, 4, 5, 6, or 7. In some embodiments, each m is independently 2, 3, 4, 5, or 6. In certain embodiments, each m is independently 3, 4, 5, 6, or 7. In some embodiments, each m is independently 2, 3, 4, or 5. In certain embodiments, each m is independently 3, 4, 5, or 6. In some embodiments, each m is independently 4, 5, 6, or 7. In certain embodiments, each m is independently 2, 3, or 4. In some embodiments, each m is independently 3, 4, or 5. In certain embodiments, each m is independently 4, 5, or 6. In some embodiments, each m is 5, 6, or 7. In certain embodiments, each m is independently 2 or 3. In some embodiments, each m is independently 3 or 4. In certain embodiments, each m is independently 4 or 5. In some embodiments, each m is independently 5 or 6. In certain embodiments, each m is independently 6 or 7. In some embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In some embodiments, m is 5. In certain embodiments, m is 6. In some embodiments, m is 7.

[0071] In one aspect, each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9. In certain embodiments, each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, each n is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, each n is independently 1, 2, 3, 4, 5, 6, 7, 8, or 9. In certain embodiments, each n is independently 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, each n is independently 0, 1, 2, 3, 4, or 5. In some embodiments, each n is independently 1, 2, 3, 4, 5, or 6. In certain embodiments, each n is independently 2, 3, 4, 5, 6, or 7. In some embodiments, each n is independently 3, 4, 5, 6, 7, or 8. In certain embodiments, each n is independently 4, 5, 6, 7, 8, or 9. In some embodiments, each n is independently 5, 6, 7, 8, 9, or 10. In certain embodiments, each n is independently 0, 1, 2, 3, or 4. In some embodiments, each n is independently 1, 2, 3, 4, or 5. In some embodiments, each n is independently 2, 3, 4, 5, or 6. In certain embodiments, each n is independently 3, 4, 5, 6, or 7. In some embodiments, each n is independently 0, 1, 2, or 3. In some embodiments, each n is independently 1, 2, 3, or 4. In some embodiments, each n is independently 2, 3, 4, or 5. In certain embodiments, each n is independently 3, 4, 5, or 6. In some embodiments, each n is independently 4, 5, 6, or 7. In certain embodiments, each n is independently 5, 6, 7, or 8. In some embodiments, each n is independently 6, 7, 8, or 9. In certain embodiments, each n is independently 7, 8, 9, or 10. In some embodiments, each n is independently 0, 1, or 2. In certain embodiments, each n is independently 1, 2, or 3.In certain embodiments, each n is independently 2, 3, or 4. In some embodiments, each n is independently 3, 4, or 5. In certain embodiments, each n is independently 4, 5, or 6. In some embodiments, each n is 5, 6, or 7. In certain embodiments, each n is independently 5, 6, or 7. In some embodiments, each n is independently 7, 8, or 9. In certain embodiments, each n is independently 8, 9, or 10. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In certain embodiments, each n is independently 2 or 3. In some embodiments, each n is independently 3 or 4. In certain embodiments, each n is independently 4 or 5. In some embodiments, each n is independently 5 or 6. In certain embodiments, each n is independently 6 or 7. In some embodiments, each n is independently 7 or 8. In certain embodiments, each n is independently 8 or 9. In some embodiments, each n is independently 9 or 10. In certain embodiments, n is 0. In some embodiments, n is 1. In certain embodiments, n is 2. In some embodiments, n is 3. In certain embodiments, n is 4. In some embodiments, n is 5. In certain embodiments, n is 6. In some embodiments, n is 7. In certain embodiments, n is 8. In some embodiments, n is 9. In certain embodiments, n is 10.

[0072] In one aspect, each p is independently 0, 1, 2, 3, or 4. In some embodiments, each p is independently 0, 1, 2, or 3. In certain embodiments, each p is independently 1, 2, 3, or 4. In some embodiments, each p is independently 0, 1, or 2. In certain embodiments, each p is independently 1, 2, or 3. In some embodiments, each p is independently 2, 3, or 4. In certain embodiments, each p is independently 0 or 1. In some embodiments, each p is independently 1 or 2. In certain embodiments, each p is independently 2 or 3. In some embodiments, each p is independently 3 or 4. In certain embodiments, p is 0. In some embodiments, p is 1. In certain embodiments, p is 2. In some embodiments, p is 3. In certain embodiments, p is 4.

[0073] In one aspect, each q is independently 1, 2, or 3. In certain embodiments, each q is independently 1 or 2. In some embodiments, each q is independently 2 or 3. In certain embodiments, q is 1. In some embodiments, q is 2. In certain embodiments, q is 3.

[0074] In one aspect, r is independently 1 or 2. In some embodiments, r is 1. In certain embodiments, r is 2.

[0075] In some embodiments, L1 is [ka] and L2 is a bond or [ka] In certain embodiments, L1 is [ka] and L2 is [ka] is.

[0076] In certain embodiments, L-1 is [ka] TIFF2024546095000165.tif214159TIFF2024546095000166.tif213159TIFF2024546095000167.tif223159, and L2 is [ka] is.

[0077] In certain embodiments, L1 is [ka] TIFF2024546095000170.tif228159TIFF2024546095000171.tif217159TIFF2024546095000172.tif44159, and L2 is combined, [ka] is.

[0078] In another embodiment, the compound of formula (II) is [Table 3] TIFF2024546095000175.tif208159TIFF2024546095000176.tif231159TIFF2024546095000177.tif198159 TIFF2024546095000178.tif189159TIFF2024546095000179.tif230159TIFF2024546095000180.tif151159

[0079] In another embodiment, the compound of formula (II) is [Table 4]

[0080] In another embodiment, the compound is a compound of any of the formulas herein (e.g., Formula (I) or Formula (II)) or a salt thereof, and the compound is not a compound disclosed in International Patent Application Publication No. WO2020 / 163823A8 or a salt thereof. In another embodiment, the compound is a compound of any of the formulas herein (e.g., Formula (I) or Formula (II)) or a salt thereof, and the compound is not a compound provided in Table 1 or a salt thereof. [Table 5] TIFF2024546095000183.tif203159TIFF2024546095000184.tif208159TIFF2024546095000185.tif225159TIFF2024546095000186.t if222159TIFF2024546095000187.tif223159TIFF2024546095000188.tif238159TIFF2024546095000189.tif217159TIFF20245460950 00190.tif229159TIFF2024546095000191.tif216159TIFF2024546095000192.tif196159TIFF2024546095000193.tif195159TIFF202 4546095000194.tif226159TIFF2024546095000195.tif235159TIFF2024546095000196.tif232159TIFF2024546095000197.tif193159

[0081] In another embodiment, the compound is a compound of any of the formulas herein (e.g., Formula (I) or Formula (II)), or a salt thereof, and the compound is not a compound provided in Table 1, or a salt, hydrate, solvate, or prodrug thereof. In another embodiment, the compound is a compound of any of the formulas herein (e.g., Formula (I) or Formula (II)), or a salt thereof, and the compound is not a compound provided in Table 1, or a pharmaceutically acceptable salt thereof.

[0082] In another aspect, provided herein is a pharmaceutical composition comprising a compound provided herein (e.g., a compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier. In another aspect, the pharmaceutical composition further comprises an additional agent. In another aspect, the additional agent is an anti-cancer agent. In another aspect, the anti-cancer agent is an alkylating agent, an antimetabolite, an anti-tumor antibiotic, an anti-cytoskeletal agent, a topoisomerase inhibitor, an anti-hormonal agent, a targeted therapy agent, a photodynamic therapy agent, or a combination thereof.

[0083] In another aspect, provided herein is a method for degrading Bcl-2 protein, comprising administering an effective amount of a compound provided herein (e.g., a compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof. In another aspect, the compound is administered in vitro. In another aspect, the compound is administered in vivo. In another aspect, the method further comprises administering the compound to a subject.

[0084] In another aspect, provided herein is a method of treating a disease or disorder in a subject in need thereof, comprising administering an effective amount of a compound provided herein (e.g., a compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof. In another aspect, the disease is cancer. In another aspect, the cancer is a solid tumor. In another aspect, the cancer is small cell lung cancer. In another aspect, the cancer is chronic lymphocytic leukemia. In another aspect, the cancer is acute lymphoblastic leukemia. In another aspect, the subject is a mammal. In another aspect, the subject is a human.

[0085] In another aspect, provided herein is a method of treating a subject suffering from or susceptible to a disease or disorder, comprising administering an effective amount of a compound provided herein (e.g., a compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof. In another aspect, the disease is cancer. In another aspect, the cancer is a solid tumor. In another aspect, the cancer is small cell lung cancer. In another aspect, the cancer is chronic lymphocytic leukemia. In another aspect, the cancer is acute lymphoblastic leukemia. In another aspect, the subject is a mammal. In another aspect, the subject is a human.

[0086] In another aspect, provided herein is a method for treating a Bcl-2-mediated cancer in a subject in need thereof, comprising administering an effective amount of a compound provided herein (e.g., a compound of Formula (I) or Formula (II)) or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein the platelet toxicity of the compound is less than the platelet toxicity of other Bcl-2 inhibitors. In another aspect, the Bcl-2-mediated cancer is chronic lymphocytic leukemia. In another aspect, the Bcl-2-mediated cancer is a solid tumor. In another aspect, the Bcl-2-mediated cancer is small cell lung cancer. In another embodiment, the other Bcl-2 inhibitor is ABT-737, navitoclax (ABT-263), venetoclax (ABT-199), obatoclax (GX15-070), (-)-gossypol (AT-101), sabutoclax (BI-97C1), TW-37, BM-1252 (APG-1252), or A-1155463. In another embodiment, the other Bcl-2 inhibitor is venetoclax or ABT-263.

[0087] In another aspect, provided herein is a method of treating a subject suffering from or susceptible to a Bcl-2-mediated cancer, the method comprising administering an effective amount of a compound provided herein (e.g., a compound of Formula (I) or Formula (II)) or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein the platelet toxicity of the compound is less than the platelet toxicity of other Bcl-2 inhibitors. In another aspect, the Bcl-2-mediated cancer is chronic lymphocytic leukemia. In another aspect, the Bcl-2-mediated cancer is a solid tumor. In another aspect, the Bcl-2-mediated cancer is small cell lung cancer. In another embodiment, the other Bcl-2 inhibitor is ABT-737, navitoclax (ABT-263), venetoclax (ABT-199), obatoclax (GX15-070), (-)-gossypol (AT-101), sabutoclax (BI-97C1), TW-37, BM-1252 (APG-1252), or A-1155463. In another embodiment, the other Bcl-2 inhibitor is venetoclax or ABT-263.

[0088] In another aspect, a method of treating a Bcl-2 mediated cancer in a subject in need thereof, comprising administering an effective amount of a compound provided herein (e.g., a compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein the anti-cancer activity of the compound (IC 50 ) to human platelet toxicity (IC 50 ) is greater than 1. In another aspect, the Bcl-2-mediated cancer is chronic lymphocytic leukemia. In another aspect, the Bcl-2-mediated cancer is a solid tumor. In another aspect, the Bcl-2-mediated cancer is small cell lung cancer. In another aspect, the anti-cancer activity is measured in MOLT-4 cells. In another aspect, the anti-cancer activity is measured in RS4 cells. In some embodiments, the anti-cancer activity is higher in MOLT-4 cells than in RS4 cells. In certain embodiments, the anti-cancer activity is higher in RS4 cells than in MOLT-4 cells. In another aspect, the ratio is greater than 2.5, greater than 5, greater than 10, greater than 20, greater than 40, greater than 60, greater than 80, greater than 100, greater than 150, greater than 200, greater than 250, greater than 300, greater than 350, greater than 400, greater than 450, or greater than 500. In some embodiments, the ratio is greater than 2.5. In some embodiments, the ratio is greater than 5. In some embodiments, the ratio is greater than 10. In some embodiments, the ratio is greater than 20. In some embodiments, the ratio is greater than 40. In some embodiments, the ratio is greater than 60. In some embodiments, the ratio is greater than 80. In some embodiments, the ratio is greater than 100. In some embodiments, the ratio is greater than 150. In some embodiments, the ratio is greater than 200. In some embodiments, the ratio is greater than 250. In some embodiments, the ratio is greater than 300. In some embodiments, the ratio is greater than 350. In some embodiments, the ratio is greater than 400. In some embodiments, the ratio is greater than 450. In some embodiments, the ratio is greater than 500.

[0089] In another embodiment, a method of treating a subject suffering from or susceptible to a Bcl-2 mediated cancer is provided, comprising: determining the human platelet toxicity (IC) of a compound; 50 ) Anticancer activity (IC 50 Provided herein are methods comprising administering an effective amount of a compound provided herein (e.g., a compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, such that the ratio of Bcl-2-mediated cancer to Bcl-2-mediated cancer is greater than 1. In another aspect, the Bcl-2-mediated cancer is chronic lymphocytic leukemia. In another aspect, the Bcl-2-mediated cancer is a solid tumor. In another aspect, the Bcl-2-mediated cancer is small cell lung cancer. In another aspect, the anti-cancer activity is measured in MOLT-4 cells. In another aspect, the anti-cancer activity is measured in RS4 cells. In some embodiments, the anti-cancer activity is higher in MOLT-4 cells than in RS4 cells. In certain embodiments, the anti-cancer activity is higher in RS4 cells than in MOLT-4 cells. In another aspect, the ratio is greater than 2.5, greater than 5, greater than 10, greater than 20, greater than 40, greater than 60, greater than 80, greater than 100, greater than 150, greater than 200, greater than 250, greater than 300, greater than 350, greater than 400, greater than 450, or greater than 500. In some embodiments, the ratio is greater than 2.5. In some embodiments, the ratio is greater than 5. In some embodiments, the ratio is greater than 10. In some embodiments, the ratio is greater than 20. In some embodiments, the ratio is greater than 40. In some embodiments, the ratio is greater than 60. In some embodiments, the ratio is greater than 80. In some embodiments, the ratio is greater than 100. In some embodiments, the ratio is greater than 150. In some embodiments, the ratio is greater than 200. In some embodiments, the ratio is greater than 250. In some embodiments, the ratio is greater than 300. In some embodiments, the ratio is greater than 350. In some embodiments, the ratio is greater than 400. In some embodiments, the ratio is greater than 450. In some embodiments, the ratio is greater than 500.

[0090] The compounds disclosed herein are bivalent compounds that promote the degradation of anti-apoptotic Bcl-2 family proteins. These bivalent compounds connect Bcl-2 small molecule inhibitors or ligands to E3 ligase binding moieties, such as von Hippel-Landau (VHL) E3 ligase binding moieties (such as HIF-1α-derived (R)-hydroxyproline-containing VHL E3 ligase ligands). VHL is part of the Cullin-2 (CUL2) containing E3 ubiquitin ligase complex elongin BC-CUL2-VHL (known as CRL2VHL), which is responsible for the degradation of the transcription factor HIF-1α. HIF-1α-derived (R)-hydroxyproline-containing VHL E3 ligase ligands have been identified with high affinity. The bivalent compounds can actively recruit anti-apoptotic Bcl-2 family proteins to VHL E3 ligase, resulting in their degradation by the ubiquitin proteasome system.

[0091] Platelets depend on Bcl-xL protein for survival. Therefore, inhibition of Bcl-xL protein in platelets causes thrombocytopenia, limiting the use of Bcl-xL inhibitors as cancer therapeutics. Given the well-documented importance of Bcl-xL in solid tumors and its contribution to drug resistance, strategies devised to minimize on-target platelet toxicity associated with Bcl-xL inhibition could enhance the therapeutic application of drugs such as ABT-263, a dual Bcl-2 / Bcl-xL inhibitor, in cancer. The disclosed compounds were designed to recruit VHL E3 ligase, which is minimally expressed in platelets, for targeted degradation of Bcl-xL.

[0092] Thus, the compounds provided herein (e.g., compounds of Formula (I) or Formula (II)) have reduced platelet toxicity compared to their corresponding Bcl-2 / Bcl-xL inhibitors. Thus, the present disclosure provides compositions and methods for selectively degrading anti-apoptotic Bcl-2 family proteins.

[0093] The invention will now be further described with reference to the following non-limiting examples and with reference to the following figures. [Brief explanation of the drawings]

[0094] [Figure 1] Figures 1A-1D show exemplary degradation of BCL-XL, BCL-2, and MCL-1 by Western blotting analysis in Jurkat cells over a 16-hour period. The word "veh" refers to vehicle. Figure 1A shows exemplary degradation by compound 26. Figure 1B shows exemplary degradation by compound 32. Figure 1C shows exemplary degradation by compound 65. Figure 1D shows exemplary degradation by compound 68. [Figure 2] Figures 2A-2C show that compound 68 (#68) degraded Bcl-xL and Bcl-2 in Jurkat cells in a dose- and time-dependent manner, with long-lasting effects. Figure 2A shows immunoblot analysis of Bcl-xL and Bcl-2 expression in Jurkat cells after treatment with increasing concentrations of compound for 16 hours, as indicated. Figure 2B shows immunoblot analysis of Bcl-xL and Bcl-2 expression in Jurkat cells after treatment with compound (100 nM) for various periods, as indicated. Figure 2C shows immunoblot analysis of Bcl-xL and Bcl-2 expression in Jurkat cells treated with compound for 16 hours, followed by washout and then cultured without compound for 0-48 hours, as indicated. [Figure 3]Figures 3A-3C show that compound 77 (#77) degraded Bcl-xL and Bcl-2 in Jurkat cells in a dose- and time-dependent manner, with long-lasting effects. Figure 3A shows immunoblot analysis of Bcl-xL and Bcl-2 expression in Jurkat cells after treatment with increasing concentrations of compound for 16 hours, as indicated. Figure 3B shows immunoblot analysis of Bcl-xL and Bcl-2 expression in Jurkat cells after treatment with compound (100 nM) for various periods, as indicated. Figure 3C shows immunoblot analysis of Bcl-xL and Bcl-2 expression in Jurkat cells treated with compound for 16 hours, followed by washout, and then cultured without compound from 0 to 48 days, as indicated. [Figure 4] FIG. 4 shows that compounds 68 and 77 have no effect on the expression levels of Bcl-xL and Bcl-2 in human platelets after 16 hours of compound treatment. [Figure 5A] FIG. 5A shows that compounds 77 and 753B formed a ternary complex with the VCB E3 ligase complex and Bcl-xL. [Figure 5B] Figure 5B shows the structure of 753B (Lv et al., Nature Communications, 2021, 12, 6896). DETAILED DESCRIPTION OF THE INVENTION

[0095] definition So that the present invention may be more readily understood, for convenience, certain terms are first defined herein.

[0096] As used herein, the term "treating" a disorder encompasses ameliorating, alleviating, and / or managing the disorder and / or condition that may cause the disorder. The terms "treat" and "treatment" refer to a method of alleviating or alleviating a disease and / or its associated symptoms. As used herein, "treating" includes, for example, blocking, inhibiting, attenuating, modulating, reversing the harmful effects of a disorder, and reducing its occurrence.

[0097] The terms "prevent," "preventing," or "prevention" refer to prophylactic treatment of a subject who does not have the disease, who did not have the disease but is at risk of developing the disease, or who does not have the disease, who does not have the disease but is at risk of regression of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than the average healthy member of the population.

[0098] The terms "condition," "disease," and "disorder" are used interchangeably.

[0099] As used herein, "inhibiting" encompasses reducing and stopping progression.

[0100] The term "modulate" refers to an increase or decrease in cellular activity in response to exposure to a compound provided herein.

[0101] The terms "isolated," "purified," or "biologically pure" refer to material that is substantially or essentially free from components that normally accompany it as found in its native state. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. In particular, in embodiments, the compounds are at least 85% pure, more preferably at least 90% pure, more preferably at least 95% pure, and most preferably at least 99% pure.

[0102] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to a polymer of amino acid residues. The terms apply to amino acid polymers in which one or more amino acid residues are artificial chemical mimetics of the corresponding naturally occurring amino acids, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers.

[0103] A "peptide" is a sequence of at least two amino acids. Peptides can consist of short and long amino acid sequences, including proteins.

[0104] The term "protein" refers to a series of amino acid residues joined one to the other by peptide bonds between the alpha-amino and carboxy groups of adjacent residues.

[0105] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function similarly to naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as amino acids that are subsequently modified, such as hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. An "amino acid analog" refers to a compound that has the same basic chemical structure as a naturally occurring amino acid, i.e., a carbon attached to a hydrogen atom, a carboxyl group, an amino group, and an R group, such as homoserine, norleucine, methionine sulfoxide, or methionine methylsulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. An "amino acid mimetic" refers to a chemical compound that has a structure different from the general chemical structure of an amino acid but functions similarly to a naturally occurring amino acid.

[0106] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission.

[0107] With respect to amino acid sequences, those skilled in the art will recognize that individual substitutions, deletions, or additions to a peptide, polypeptide, or protein sequence that alter, add, or delete a single amino acid or a small percentage of amino acids in the encoded sequence are "conservatively modified variants," in which the modification replaces an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art.

[0108] Macromolecular structures, such as polypeptide structures, can be described in terms of various levels of organization. For general discussions of this organization, see, for example, Alberts et al., Molecular Biology of the Cell (3rd ed., 1994) and Cantor and Schimmel, Biophysical Chemistry Part I: The Conformation of Biological Macromolecules (1980). "Primary structure" refers to the amino acid sequence of a particular peptide. "Secondary structure" refers to the locally ordered three-dimensional structures within a polypeptide. These structures are commonly known as domains. Domains are portions of polypeptides that form compact units of the polypeptide and are typically 50–350 amino acids long. Typical domains are composed of less organized portions, such as stretches of beta-sheet and alpha-helix. "Tertiary structure" refers to the complete three-dimensional structure of a polypeptide monomer. "Quaternary structure" refers to the three-dimensional structure formed by the noncovalent association of independent tertiary units. Anisotropy terms are also known as energy terms.

[0109] The term "administration" or "administering" includes the route of introducing a compound into a subject to perform its intended function. Examples of routes of administration that may be used include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal, and transdermal.

[0110] As used herein, the phrases "systemic administration," "systemically administered," "peripheral administration," and "peripherally administered" refer to the administration of a compound, drug, or other substance so that it enters the patient's system and is therefore susceptible to metabolism and other similar processes.

[0111] The terms "composition" and "formulation" are used interchangeably.

[0112] The term "effective amount" includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result. The effective amount of a compound can vary depending on factors such as the disease state, age, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens can be adjusted to provide an optimal therapeutic response. An effective amount is also an amount in which any toxic or adverse effects (e.g., side effects) are outweighed by the therapeutically beneficial effects. The effective amount of a compound provided herein can vary depending on factors such as the desired biological endpoint, side effects, severity of the disease or disorder, the identity of the specific compound, pharmacokinetics and pharmacodynamics, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age, and health or general condition of the subject. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

[0113] An effective amount of a compound (i.e., an effective dosage) can range from about 0.005 μg / kg to about 200 mg / kg, preferably from about 0.1 mg / kg to about 200 mg / kg, and more preferably from about 10 mg / kg to about 100 mg / kg of body weight. In other embodiments, an effective amount can range from about 1.0 pM to about 500 nM. One of ordinary skill in the art will appreciate that certain factors, including, but not limited to, the severity of the disease or disorder, previous treatments, the subject's general health and / or age, and other diseases present, can affect the dosage required to effectively treat a subject. Furthermore, treatment of a subject with an effective amount of a compound can include a single treatment or, preferably, a series of treatments. In certain embodiments, an effective amount is the amount of a compound provided herein in a single dose. In certain embodiments, an effective amount is the combined amount of a compound provided herein in multiple doses. In certain embodiments, the desired dosage is delivered three times a day, twice a day, once a day, every other day, every three days, weekly, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). In one example, a subject is treated with a compound in the range of about 0.005 μg / kg to about 200 mg / kg body weight once a week for about 1 to 10 weeks, preferably 2 to 8 weeks, more preferably about 3 to 7 weeks, and even more preferably about 4, 5, or 6 weeks. It will also be understood that the effective dosage of the compound used for treatment may increase or decrease over the course of a particular treatment.

[0114] The term "therapeutically effective amount" refers to the amount of compound administered that is sufficient to prevent or alleviate to some extent one or more of the symptoms of the condition or disorder being treated. A therapeutically effective amount of a compound refers to that amount of a therapeutic agent that, alone or in combination with other therapies, provides a therapeutic benefit in treating a condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of a condition, and / or enhances the therapeutic effectiveness of another therapeutic agent.

[0115] A "prophylactically effective amount" of a compound provided herein is an amount sufficient to prevent a condition, or one or more symptoms associated with a condition, or prevent its recurrence. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent that, alone or in combination with other agents, provides a prophylactic benefit in preventing a condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic effectiveness of another prophylactic agent.

[0116] The term "subject" refers to a human (i.e., a male or female of any age, e.g., a pediatric subject (e.g., an infant, a child, or an adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or the elderly)) or a non-human animal. In some embodiments, the term "subject" refers to an animal such as a mammal, including, but not limited to, a primate (e.g., a human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, etc. In certain embodiments, the subject is a human. The term "patient" refers to a human subject in need of treatment for a disease.

[0117] The term "biological sample" refers to any sample, including tissue samples (such as tissue sections and tissue needle biopsies); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); whole organism samples (such as yeast or bacterial samples); or cell fractions, fragments, or organelles (obtained, such as by lysing cells and centrifuging or otherwise separating their components). Other examples of biological samples include blood, serum, urine, semen, feces, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical or needle biopsy), nipple aspirate, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules derived from a first biological sample.

[0118] The term "target tissue" refers to any biological tissue of a subject (including a group of cells, a body part, or an organ) or a portion thereof, including blood and / or lymphatic vessels, to which a compound, particle, and / or composition provided herein is delivered. A target tissue can be an abnormal or unhealthy tissue that may need to be treated. A target tissue can also be a normal or healthy tissue that is at higher than normal risk of becoming abnormal or unhealthy and may need to be prevented. In certain embodiments, the target tissue is the liver. In certain embodiments, the target tissue is the lung. A "non-target tissue" is any biological tissue of a subject (including a group of cells, a body part, or an organ) or a portion thereof, including blood and / or lymphatic vessels, that is not a target tissue.

[0119] The term "chiral" refers to a molecule that has the property of being non-superimposable on its mirror image partner, and the term "achiral" refers to a molecule that is superimposable on its mirror image partner.

[0120] The term "diastereomer" refers to a stereoisomer with two or more centers of dissymmetry and whose molecules are not mirror images of one another.

[0121] The term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. An equimolar mixture of two enantiomers is called a "racemic mixture" or "racemate."

[0122] The term "isomers" or "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0123] Additionally, the compounds provided herein include olefins having either geometry: "Z" refers to what is referred to as the "cis" (same-side) conformation, and "E" refers to what is referred to as the "trans" (opposite-side) conformation. With regard to the nomenclature of chiral centers, the terms "d" and "l" configurations are as defined by the IUPAC Recommendations. With regard to the use of the terms diastereomer, racemate, epimer, and enantiomer, these are used in their usual context to describe the stereochemistry of a preparation.

[0124] The term "tautomer" or "tautomeric" refers to two or more interconvertible compounds resulting from the formal migration of at least one hydrogen atom and at least one change in valence (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization (i.e., the reaction providing the tautomeric pair) can be catalyzed by acid or base. Exemplary tautomerizations include keto-enol, amide-imide, lactam-lactim, enamine-imine, and enamine-(different enamine) tautomerizations.

[0125] As used herein, the term "salt" refers to any and all salts, including pharmaceutically acceptable salts. Salts include ionic compounds resulting from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions), such that the salt is electrically neutral (no net charge). Salts of the compounds provided herein include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods known in the art, such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, and lactic acid. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-2-hydroxybenzoates, such as benzoyl benzoates, benzoates, benzoates, and benzoates. + (C 1-4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0126] The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable carrier" is intended to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents found in the compounds provided herein. When the compounds provided herein contain a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When the compounds provided herein contain a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids such as alginate, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., Journal of Pharmaceutical Science 66:1-19 (1977)).

[0127] The term "solvate" refers to a form of a compound or its salt that is associated with a solvent, typically through solvolysis. This physical association may involve hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds provided herein may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates, further including both stoichiometric and non-stoichiometric solvates. In certain cases, a solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0128] The term "hydrate" refers to a compound associated with water. Typically, the number of water molecules contained in a hydrate of a compound is a fixed ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound can be represented, for example, by the general formula R x HO, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, a monohydrate (x is 1), a lower hydrate (x is a number greater than 0 and less than 1, e.g., a hemihydrate (R 0.5 HO)), and a polyhydrate (x is a number greater than 1, e.g., a dihydrate (R 2 HO) and a hexahydrate (R 6 HO)).

[0129] The term "polymorph" refers to the crystalline form of a compound (or its salt, hydrate, or solvate). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, optical and electrical properties, stability, and solubility. Depending on the recrystallization solvent, crystallization rate, storage temperature, and other factors, one crystalline form may predominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0130] The term "prodrug" includes compounds having a moiety that can be metabolized in vivo. Generally, prodrugs are metabolized in vivo by esterases or other mechanisms to active drugs. Examples of prodrugs and their uses are well known in the art (see, e.g., Berge et al. (1977) "Pharmaceutical Salts," J. Pharm. Sci. 66:1-19). Prodrugs can be prepared in situ during the final isolation and purification of a compound, or by separately reacting its free acid form or a hydroxyl purified compound with a suitable esterifying agent. Hydroxyl groups can be converted to esters by treatment with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted branched or unbranched lower alkyl ester moieties (e.g., propionate esters), lower alkenyl esters, di-lower alkyl-amino lower alkyl esters (e.g., dimethylaminoethyl esters), acylamino lower alkyl esters (e.g., acetyloxymethyl esters), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl esters), aryl esters (phenyl esters), aryl lower alkyl esters (e.g., benzyl esters), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl lower alkyl esters, amides, lower alkyl amides, di-lower alkyl amides, and hydroxyamides. Preferred prodrug moieties are propionate esters and acyl esters. Prodrugs that are converted to active forms in vivo through other mechanisms are also included.

[0131] The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Similarly, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0132] As used herein, the term "alkyl" refers to a straight or branched chain hydrocarbon group containing 1 to 12 carbon atoms. The term "lower alkyl" refers to a C1-C6 alkyl chain. In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1-12 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2-6 alkyl). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl), and hexyl (C6) (e.g., n-hexyl). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), n-dodecyl (C9), and hexyl (C10). 12) and the like. An alkyl group may be optionally substituted with one or more substituents. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents (e.g., halogen, such as F) ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1-12 Alkyl (e.g., unsubstituted C 1-6 Alkyl, for example, -CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C 1-12 Alkyl (substituted C 1-6 alkyl, for example, —CH2F, —CHF2, —CF3, —CH2CH2F, —CH2CHF2, —CH2CF3 or benzyl (Bn), etc.

[0133] The term "haloalkyl" refers to a substituted alkyl group in which one or more of the hydrogen atoms are independently replaced with a halogen, such as fluoro, bromo, chloro, or iodo. "Perhaloalkyl" is a subset of haloalkyl and refers to an alkyl group in which all of the hydrogen atoms are independently replaced with a halogen, such as fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms ("C 1-10 In some embodiments, the haloalkyl moiety has 1 to 9 carbon atoms ("C 1-9 In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms ("C 1-7 In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C 1-6In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms ("C 1-5 In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C 1-4 In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C 1-2 In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with fluoro to provide a "perfluoroalkyl" group. In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with chloro to provide a "perchloroalkyl" group. Examples of haloalkyl groups include -CHF, -CHF, -CF, -CHCF, -CFCF, -CFCF, -CFCFCF, -CCl, -CFCl, -CFCl, and the like.

[0134] The term "heteroalkyl" refers to an alkyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the parent chain (e.g., inserted between adjacent carbon atoms) and / or at one or more terminal positions of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 12 carbon atoms and one or more heteroatoms within the parent chain ("heteroC"). 1-12 In some embodiments, heteroalkyl groups are saturated groups having 1 to 11 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-11 In some embodiments, heteroalkyl groups are saturated groups having 1 to 10 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-10 In some embodiments, heteroalkyl groups are saturated groups having 1 to 9 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-9In some embodiments, heteroalkyl groups are saturated groups having 1 to 8 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-8 In some embodiments, heteroalkyl groups are saturated groups having 1 to 7 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-7 In some embodiments, heteroalkyl groups are saturated groups having 1 to 6 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-6 In some embodiments, heteroalkyl groups are saturated groups having 1 to 5 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1-5 In some embodiments, heteroalkyl groups are saturated groups having 1 to 4 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1-4 In some embodiments, heteroalkyl groups are saturated groups having 1 to 3 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1-3 In some embodiments, heteroalkyl groups are saturated groups having 1 to 2 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1-2 In some embodiments, heteroalkyl groups are saturated groups having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In some embodiments, heteroalkyl groups are saturated groups having 2 to 6 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 2-6 Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl") with one or more substituents. In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1-12 In certain embodiments, the heteroalkyl group is a substituted heteroC 1-12 It is alkyl.

[0135] The term "alkenyl" refers to an unsaturated hydrocarbon chain that may be straight or branched, containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. In some embodiments, an alkenyl group has 1 to 12 carbon atoms ("C 1-12 In some embodiments, an alkenyl group has 1 to 11 carbon atoms ("C 1-11 In some embodiments, an alkenyl group has 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkenyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, an alkenyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, an alkenyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkenyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkenyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkenyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkenyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkenyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, an alkenyl group has one carbon atom ("C1 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C 1-4 Examples of alkenyl groups include methylidenyl (C1), ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 1-6 Examples of alkenyl groups include the above-mentioned C 2-4Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Alkenyl groups may be optionally substituted with one or more substituents. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 1-20 In certain embodiments, the alkenyl group is a substituted C 1-20 In an alkenyl group, a C=C double bond with unspecified stereochemistry (e.g., -CH=CHCH3 or [ka] ) may be in the (E)- or (Z)-configuration.

[0136] The term "alkynyl" refers to an unsaturated hydrocarbon chain that may be straight or branched, containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond (e.g., 1, 2, 3, or 4 triple bonds). In some embodiments, an alkynyl group has 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkynyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, an alkynyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, an alkynyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkynyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkynyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkynyl group has 1 to 4 carbon atoms ("C 1-4In some embodiments, an alkynyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkynyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, the alkynyl group has one carbon atom ("C1 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). C 1-4 Examples of alkynyl groups include, but are not limited to, methylidinyl (C1), ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 1-6 Examples of alkenyl groups include the above-mentioned C 2-4 Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Alkynyl groups may be optionally substituted with one or more substituents. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 1-20 In certain embodiments, the alkynyl group is a substituted C 1-20 It is alkynyl.

[0137] The sp of each of the alkenyl and alkynyl groups 2 The carbon or sp carbon may be the point of attachment of the alkenyl or alkynyl group.

[0138] The term "alkoxy" refers to an --O-alkyl radical.

[0139] As used herein, the terms "halogen," "hal," or "halo" refer to -F, -Cl, -Br, or -I. The term "cycloalkyl" refers to a hydrocarbon 3-8 membered monocyclic or 7-14 membered bicyclic ring system having at least one saturated ring or at least one non-aromatic ring, where the non-aromatic ring may have some degree of unsaturation and zero heteroatoms in the non-aromatic ring system. In some embodiments, a cycloalkyl group has 3 to 14 ring carbon atoms ("C 3-14 In some embodiments, a cycloalkyl group has 3 to 13 ring carbon atoms ("C 3-13 In some embodiments, a cycloalkyl group has 3 to 12 ring carbon atoms ("C 3-12 In some embodiments, a cycloalkyl group has 3 to 11 ring carbon atoms ("C 3-11 In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a cycloalkyl group has 3 to 7 ring carbon atoms ("C 3-7 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 cycloalkyl). Exemplary C 3-6Cycloalkyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C 3-8 The cycloalkyl group includes the above-mentioned C 3-6 Cycloalkyl groups include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3-10 The cycloalkyl group includes the above-mentioned C 3-8 Cycloalkyl groups, and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ) and other examples. 3-8 The cycloalkyl group includes the above-mentioned C 3-10 Cycloalkyl groups, and cycloundecyl (C 11 ), spiro[5.5]undecanyl (C 11 ), cyclododecyl (C 12 ), cyclododecenyl (C 12 ), cyclotridecane (C 13 ), cyclotetradecane (C 14As the foregoing examples illustrate, in certain embodiments, a cycloalkyl group is either monocyclic ("monocyclic cycloalkyl") or polycyclic (e.g., containing fused, bridged, or spiro ring systems such as a bicyclic ring system ("bicyclic cycloalkyl") or a tricyclic ring system ("tricyclic cycloalkyl")), and can be saturated or contain one or more carbon-carbon double or triple bonds. "Cycloalkyl" also includes ring systems in which a cycloalkyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, and the point of attachment is on the cycloalkyl ring; in such cases, the number of carbons continues to designate the number of carbons in the carbocyclic ring system. A cycloalkyl group may be optionally substituted with one or more substituents. Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3-14 In certain embodiments, the cycloalkyl group is a substituted C 3-14 In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of the cycloalkyl group may be substituted by a substituent. Representative examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.

[0140] In some embodiments, "cycloalkyl" is a monocyclic saturated cycloalkyl group having 3 to 14 ring carbon atoms ("C 3-14 In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 Cycloalkyl). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups include the above-mentioned C 5-6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of cycloalkyl groups include the above-mentioned C 3-6 Cycloalkyl groups include cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3-14 In certain embodiments, the cycloalkyl group is a substituted C 3-14 In certain embodiments, a cycloalkyl contains, where valence allows, 0, 1, or 2 C═C double bonds in the carbocyclic ring system.

[0141] The term "heterocycloalkyl" refers to a non-aromatic 3- to 8-membered monocyclic, 7- to 12-membered bicyclic, or 10- to 14-membered tricyclic ring system containing 1 to 3 heteroatoms in the monocyclic ring, 1 to 6 heteroatoms in the bicyclic ring, or 1 to 9 heteroatoms in the tricyclic ring, wherein the heteroatoms are selected from O, N, S, B, P, or Si; non-aromatic ring systems are fully saturated. Heterocycloalkyl polycyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocycloalkyl" also includes ring systems in which a heterocycloalkyl ring, as defined above, is fused to one or more cycloalkyl groups, with the point of attachment being on either the cycloalkyl or heterocycloalkyl ring, or in which a heterocycloalkyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the heterocycloalkyl ring; in such cases, the number of ring members continues to designate the number of ring members in the heterocycloalkyl ring system. Heterocycloalkyl groups may be optionally substituted with one or more substituents. Unless otherwise specified, each instance of heterocycloalkyl is independently unsubstituted (an "unsubstituted heterocycloalkyl") or substituted (a "substituted heterocycloalkyl") with one or more substituents. In certain embodiments, a heterocycloalkyl group is an unsubstituted 3- to 14-membered heterocycloalkyl. In certain embodiments, a heterocycloalkyl group is a substituted 3- to 14-membered heterocycloalkyl. In certain embodiments, a heterocycloalkyl is a substituted or unsubstituted 3- to 7-membered monocyclic heterocycloalkyl, wherein one, two, or three atoms of the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valence permits. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heterocycloalkyl group may be substituted by a substituent.

[0142] In some embodiments, a heterocycloalkyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heterocycloalkyl"). In some embodiments, a heterocycloalkyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heterocycloalkyl"). In some embodiments, a heterocycloalkyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heterocycloalkyl"). In some embodiments, a 5- to 6-membered heterocycloalkyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heterocycloalkyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocycloalkyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0143] Representative heterocycloalkyl groups include piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,3-dioxolane, tetrahydrofuranyl, tetrahydrothienyl, tyrenyl, and the like. Exemplary 3-membered heterocycloalkyl groups containing one heteroatom include aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocycloalkyl groups containing one heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocycloalkyl groups containing one heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocycloalkyl groups containing two heteroatoms include dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocycloalkyl groups containing three heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocycloalkyl groups containing one heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocycloalkyl groups containing two heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocycloalkyl groups containing three heteroatoms include triazinyl. Exemplary 7-membered heterocycloalkyl groups containing one heteroatom include azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocycloalkyl groups containing one heteroatom include azocanyl, oxecanyl, and thiocanyl.Exemplary bicyclic heterocycloalkyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetra-hydro-benzo-thienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromanyl, 1H-benzo[e][1,4]diazepinyl, Examples include 1,4,5,7-tetrahydro-pyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo-[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo-[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-furo[3,2-c]pyridinyl, 4,5,6,7-tetrahydro-thieno[3,2-b]pyridinyl, and 1,2,3,4-tetrahydro-1,6-naphthyridinyl.

[0144] The term "aryl" refers to a hydrocarbon monocyclic, bicyclic, or tricyclic aromatic ring system. In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14"Aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, and the radical or point of attachment is on the aryl ring; in such cases, the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6-14 In certain embodiments, the aryl group is a substituted C 6-14 Aryl. The aryl group may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, 4, 5, or 6 atoms of each ring of the aryl group may be substituted with a substituent. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, etc.

[0145] The term "heteroaryl" refers to an aromatic 5- to 8-membered monocyclic ring system, an 8- to 12-membered bicyclic ring system, or an 11- to 14-membered tricyclic ring system having 1 to 4 ring heteroatoms if monocyclic, 1 to 6 heteroatoms if bicyclic, or 1 to 9 heteroatoms if tricyclic, wherein the heteroatoms are selected from O, N, or S, and the remaining ring atoms are carbon (with appropriate hydrogen atoms unless otherwise specified). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, where valence permits. Heteroaryl polycyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more cycloalkyl or heterocycloalkyl groups, and the point of attachment is on the heteroaryl ring; in such cases, the number of ring members continues to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more aryl groups, and the point of attachment is at either the aryl or heteroaryl ring; in such cases, the number of ring members refers to the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. In polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be at either ring, for example, a ring containing a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl). In certain embodiments, the heteroaryl is a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, and one, two, three, or four atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is a substituted or unsubstituted 9- or 10-membered bicyclic heteroaryl, and one, two, three, or four atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0146] Heteroaryl groups may be optionally substituted with one or more substituents. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl") with one or more substituents. In certain embodiments, a heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5-14 membered heteroaryl. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heteroaryl group may be substituted with a substituent. Examples of heteroaryl groups include pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolylthiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoquinolinyl, indazolyl, and the like.

[0147] In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, a 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0148] Exemplary 5-membered heteroaryl groups containing one heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0149] The term "amino" refers to the group -NH. The term "substituted amino" extends to mono-, di-, or tri-substituted amino. In certain embodiments, a "substituted amino" is a mono- or di-substituted amino group.

[0150] The term "alkylamino" refers to an amino substituent further substituted with one or two alkyl groups. The term "aminoalkyl" refers to an alkyl substituent further substituted with one or more amino groups. The terms "hydroxyalkyl" or "hydroxylalkyl" refer to an alkyl substituent further substituted with one or more hydroxyl groups. The alkyl or aryl portions of alkylamino, aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl may be optionally substituted with one or more substituents.

[0151] In certain embodiments, a substituent on any group (e.g., alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl, etc.) can be at any atom of that group, and any group that can be substituted (e.g., alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl, etc.) can be optionally substituted with one or more substituents (which can be the same or different), each replacing a hydrogen atom. Examples of suitable substituents include alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxyl, hydroxylalkyl, oxo (i.e., carbonyl), carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, and aminoalkyl. , dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, alkoxycarbonylamino, alkylamino, arylamino, diarylamino, alkylcarbonyl or arylamino substituted aryl; arylalkylamino, aralkylaminocarbonyl, amido, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, imino, carbamido, carbamyl, thioureido, thiocyanato, sulfamido, sulfonylalkyl, sulfonylaryl or mercaptoalkoxy.

[0152] Acids and bases useful in the methods herein are known in the art. Acid catalysts are any acidic chemicals that can be inorganic in nature (e.g., hydrochloric acid, sulfuric acid, nitric acid, aluminum trichloride) or organic in nature (e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid, ytterbium triflate). Acids are useful in either catalytic or stoichiometric amounts to promote chemical reactions. Bases are any basic chemicals that can be inorganic in nature (e.g., sodium bicarbonate, potassium hydroxide) or organic in nature (e.g., triethylamine, pyridine). Bases are useful in either catalytic or stoichiometric amounts to promote chemical reactions.

[0153] An alkylating agent is any reagent capable of alkylating the functional group of interest (e.g., the oxygen atom of an alcohol, the nitrogen atom of an amino group). Alkylating agents are known in the art, including the references cited herein, and include alkyl halides (e.g., methyl iodide, benzyl bromide, or chloride), alkyl sulfates (e.g., methyl sulfate), or combinations of other alkyl leaving groups known in the art. A leaving group can be any stable species known in the art, including the references cited herein, that can be eliminated from a molecule during a reaction (e.g., elimination reaction, substitution reaction), and includes halides (e.g., I, Cl, Br, F), hydroxy, alkoxy (e.g., -OMe, -Ot-Bu), acyloxy anions (e.g., -OAc, -OC(O)CF), sulfonates (e.g., mesyl, tosyl), acetamides (e.g., -NHC(O)Me), carbamates (e.g., N(Me)C(O)Ot-Bu), phosphonates (e.g., -OP(O)(OEt)), water or alcohols (protic conditions), and the like.

[0154] As used herein, the term "nucleophile" refers to an ion, atom, or functional group that has a nucleophilic center, i.e., that can probe or react with an electrophilic center. In some embodiments, the nucleophile donates a pair of electrons to form a chemical bond (e.g., by reacting with an electrophile). In some embodiments, the nucleophile is neutral or negatively charged. Non-limiting examples of nucleophiles include uncharged compounds such as water, amines, mercaptans, and alcohols, as well as charged moieties such as alkoxides, thiolates, carbanions, and various organic and inorganic anions. Non-limiting examples of anionic nucleophiles include simple anions such as hydroxide, azide, cyanide, thiocyanate, acetate, formate, or chloroformate, and bisulfite. The nucleophile may also be provided as a salt, such as, but not limited to, an alkali metal salt (i.e., a salt comprising an anionic nucleophile, such as an alkoxide, aryloxide, or thiolate, and an alkali metal cation, such as, but not limited to, sodium (Na), potassium (K), lithium (Li), rubidium (Rb), or cesium (Cs) cation).

[0155] As used herein, the term "electrophile" refers to an ion, atom, or functional group that has an electrophilic center, i.e., that is attracted to electrons. In some embodiments, electrophiles participate in chemical reactions by accepting a pair of electrons to form a chemical bond (e.g., by reacting with a nucleophile). In some embodiments, electrophiles are neutral or positively charged. Exemplary electrophilic groups are halide groups, such as bromide or chloride substituents, halogens (F, Cl, Br, or I); nitriles (CN); carboxylic acid esters where LG is the leaving group (COO(LG)); carboxylic acids; carbonyls (CO); -aldehydes (-CHO), acetaldehyde.

[0156] "Leaving group" (LG) is an art-recognized term and refers to the atom or molecular fragment that starts with an electron pair in a heterolytic bond cleavage, the molecular fragment being an anion or a neutral molecule. As used herein, a leaving group can be an atom or group that can be displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502). Exemplary leaving groups include halo (e.g., fluoro, chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g., -OC(=O)SR aa , -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -OC(=NR bb )N(R bb )2, -OS(=O)R aa , -OSO2R aa , -OP(R cc )2, -OP(R cc )3, -OP(=O)2R aa , -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -OP(=O)2N(R bb )2 and -OP(=O)(NR bb )2(wherein, R aa , R bb and R cc(wherein R is as defined herein). Further examples of suitable leaving groups include, but are not limited to, halogen, alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates. In some embodiments, the leaving group is a sulfonate ester, such as toluenesulfonate (tosylate, -OT), methanesulfonate (mesylate, -OM), p-bromobenzenesulfonyloxy (brosylate, -OB), -OS(=O)2(CF2)3CF3 (nonaflate, -ONf), or trifluoromethanesulfonate (triflate, -OTf). In some embodiments, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In some embodiments, the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. In some embodiments, the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a tosylate group. In some embodiments, the leaving group is a phosphine oxide (e.g., formed during the Mitsunobu reaction) or an internal leaving group such as an epoxide or a cyclic sulfate. Other non-limiting examples of leaving groups are water, ammonia, alcohol, ether moiety, thioether moiety, zinc halide, magnesium moiety, diazonium salt, and copper moiety. "Bcl-2," when used herein alone or as part of a group reference to members of the Bcl-2 family of proteins, includes the following: Bcl-xL, MCL-1, Bcl-W, BFL-1 / A1, Bcl-B, BAX, BAK, and BOK.

[0157] The term "proteolysis-targeting chimera" or "PROTAC" refers to a heterobifunctional molecule capable of inducing intracellular protein degradation. In some embodiments, a PROTAC comprises an E3-ubiquitin ligase-binding molecule covalently linked to a moiety that binds to a protein targeted for degradation.

[0158] The terms "neoplasm" and "tumor" are used interchangeably herein to refer to an abnormal mass of tissue in which the growth of the mass exceeds and is uncoordinated with that of normal tissue. Neoplasms or tumors can be "benign" or "malignant" depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), growth rate, local invasion, and metastasis. "Benign neoplasms" are generally well-differentiated, characteristically slower-growing than malignant neoplasms, and remain localized at the site of origin. In addition, benign neoplasms lack the ability to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipomas, chondromas, adenomas, acrochordons, senile hemangiomas, seborrheic keratoses, lentigines, and sebaceous hyperplasia. In some cases, certain "benign" tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of neoplastic cells in the tumor; these tumors are referred to as "premalignant neoplasms." An exemplary premalignant neoplasm is a teratoma. In contrast, "malignant neoplasms" are generally poorly differentiated (anaplastic) and have characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of surrounding tissues. Furthermore, malignant neoplasms generally have the ability to metastasize to distant sites. The terms "metastasis," "metastatic," or "metastasizing" refer to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue, typically identifiable by the presence of a "secondary tumor" or "secondary cell mass" of the histological type of the primary or original tumor, but not of the organ or tissue in which the secondary (metastatic) tumor is located. For example, prostate cancer that has migrated to bone is said to be metastatic prostate cancer, and includes cancerous prostate cancer cells growing in bone tissue.

[0159] The term "cancer" refers to a class of diseases characterized by the development of abnormal cells that grow uncontrollably and have the ability to invade and destroy normal body tissue. See, e.g., Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990. Exemplary cancers include acoustic neuroma; adenocarcinoma; adrenal carcinoma; anal carcinoma; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, angiosarcoma); appendix cancer; benign monoclonal cytomas; bile duct cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., breast adenocarcinoma, papillary carcinoma, breast adenocarcinoma, medullary breast carcinoma); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial carcinoma; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon carcinoma, rectal carcinoma, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine carcinoma, uterine sarcoma); esophageal Cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familial eosinophilia; gallbladder cancer; gastric cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell carcinoma; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal carcinoma, oropharyngeal carcinoma)); hematopoietic cancer (e.g., leukemia such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML) and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL);Lymphomas, such as Hodgkin's lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin's lymphoma (NHL) (e.g., diffuse large cell lymphoma (DLCL) (e.g., B-cell NHL such as diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoma Plasma cell lymphoma (i.e., Waldenstrom's macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, primary central nervous system (CNS) lymphoma; and T-cell NHL, such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphomas (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma. follicular lymphoma); mixture of one or more of the above leukemias / lymphomas; and multiple myeloma (MM), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharyngeal carcinoma; inflammatory myofibroblastic tumor; immune cell amyloidosis; kidney cancer (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatocellular carcinoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle carcinoma; myelodysplastic syndrome (MD) S); mesothelioma; myeloproliferative disorders (MPDs) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), myelodysplasia of unknown cause (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibromas (e.g., neurofibromatosis (NF) type 1 or 2, schwannomatosis); neuroendocrine carcinomas (e.g., gastroenteropancreatic neuroendocrine tumors (GEP-NETs), carcinoid tumors); osteosarcomas (e.g., bone carcinoma); ovarian cancers (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma);Papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic adenocarcinoma, intrapapillary mucinous neoplasm (IPMN), pancreatic islet cell tumor); penile cancer (e.g., Paget's disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasm; paraneoplastic syndromes; intraepithelial neoplasia; prostate cancer (e.g., prostatic adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small intestine cancer ( For example, appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovium; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).

[0160] Unless the context otherwise requires, singular terms shall include the plural and plural terms shall include the singular. The singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. The use of the words "a" or "an" when used in conjunction with the word "comprising" in the claims and / or specification may mean "one," but is also consistent with the meaning of "one or more," "at least one," and "one or more."

[0161] When a range of values ​​("range") is listed, it encompasses each value and subrange within the range. A range includes both endpoints of the range unless otherwise specified. When ranges are listed in this application, the endpoints of the range are understood to be specifically disclosed as if specifically stated. For example, a range of about 19% to about 99% specifically includes the disclosure of 19% separately and 99% separately.

[0162] Except in the examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood to be modified in all instances by the term "about." "About" and "approximately" are generally intended to mean an acceptable degree of error for the measured amount, given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically within 10%, or more typically within 5%, 4%, 3%, 2%, or 1% of a given value or range of values.

[0163] The recitation of a list of chemical groups in any definition of a variable herein includes a definition of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof.

[0164] compound The compounds depicted herein (e.g., Formula (I) or compounds of Formula (I)) include salts, hydrates, solvates, and prodrugs thereof, including all compounds depicted in the schemes herein, whether intermediate compounds in the process or final compounds.

[0165] The compounds provided herein can be obtained from natural sources or made or modified by means known in the art of organic synthesis. Methods for optimizing reaction conditions, if necessary, to minimize competing by-products, are known in the art. Reaction optimization and scale-up can advantageously utilize high-speed parallel synthesis equipment and computer-controlled microreactors (see, for example, Design and Optimization in Organic Synthesis, 2000). ndEdition, Carlson R, Ed, 2005; Elsevier Science Ltd.; Jahnisch, K et al, Angew.Chem.Int.Ed.Engl.2004 43:406; and references therein). Additional reaction schemes and protocols can be determined by those skilled in the art by using commercially available structure searchable database software, for example, SciFinder® (CAS Division of the American Chemical Society) and CrossFire Beilstein® (Elsevier MDL), or by appropriate keyword searches using Internet search engines such as Google® or keyword databases such as the United States Patent and Trademark Office text database. For example, the compounds of the formulas herein can be prepared using methodologies known in the art, which further include the general principles of organic chemistry and specific functional moieties and reactivity, see Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March's Advanced Organic Chemistry, 7 th Edition, John Wiley&Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley&Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0166] The compounds provided herein may also contain bonds (e.g., carbon-carbon bonds) where bond rotation is restricted around that particular bond, for example, due to the presence of a ring or double bond. Accordingly, all cis / trans and E / Z isomers are expressly included in the present invention. The compounds provided herein may also be represented in multiple tautomeric forms, and in such cases, the present invention expressly includes all tautomeric forms of the compounds provided herein, even if only a single tautomeric form may be represented. All such isomeric forms of the compounds provided herein are expressly included in the present invention. All crystalline forms and polymorphs of the compounds provided herein are expressly included in the present invention. All hydrate and solvate forms of the compounds provided herein are expressly included in the present invention. Extracts and fractions containing the compounds provided herein are also embodied. The term "isomer" is intended to include diastereoisomers, enantiomers, positional isomers, structural isomers, rotamers, tautomers, etc. All such isomers of the compounds provided herein are expressly included in the present invention. In the case of compounds containing one or more stereocenters, e.g., chiral compounds, the methods provided herein can be carried out with enantiomerically enriched compounds, racemates, or mixtures of diastereomers.

[0167] Preferred enantiomerically enriched compounds have an enantiomeric excess of 50% or greater, and more preferably, the compounds have an enantiomeric excess of 60%, 70%, 80%, 90%, 95%, 98%, or 99% or greater. In preferred embodiments, only one enantiomer or diastereomer of the chiral compounds provided herein is administered to a cell or subject.

[0168] The compounds of the formulae herein can be synthesized using methodologies similar to those described in Chen, QY; Liu, Y.; Cai, W.; Luesch, H. Improved Total Synthesis and Biological Evaluation of Potent Apratoxin S4 Based Anticancer Agents with Differential Stability and Further Enhanced Activity. J. Med. Chem. 2014, 57(7): p. 3011-302; and WO 2012 / 158933.

[0169] The present disclosure provides compounds in salt form. In some embodiments, the salt is a pharmaceutically acceptable salt. Certain specific compounds provided herein contain both basic and acidic functional groups, which allow the compound to be converted into either a base addition salt or an acid addition salt. The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salt is equivalent to the parent form of the compound for the purposes of the present invention.

[0170] In addition to salt forms, compounds in prodrug form are provided herein.Prodrugs of the compounds provided herein are compounds that easily undergo chemical changes under physiological conditions to provide the compounds provided herein.Furthermore, prodrugs can be converted to the compounds provided herein by chemical or biochemical methods in an ex vivo environment.For example, prodrugs can be slowly converted to the compounds provided herein when placed in a transdermal patch reservoir with suitable enzymes or chemical reagents.

[0171] Certain compounds provided herein can exist in solvated forms, including non-solvated forms and hydrated forms.In general, solvated forms are equivalent to non-solvated forms and are intended to be included within the scope of the present invention.Certain compounds provided herein can exist in multiple crystalline forms or amorphous forms.In general, all physical forms are equivalent for the use contemplated by the present invention and are intended to be within the scope of the present invention.

[0172] Treatment method In another aspect, provided herein is a method for degrading Bcl-2 protein, comprising administering an effective amount of a compound provided herein (e.g., a compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof. In another aspect, the compound is administered in vitro. In another aspect, the compound is administered in vivo. In another aspect, the method further comprises administering the compound to a subject.

[0173] In another aspect, provided herein is a method of treating a disease or disorder in a subject in need thereof, comprising administering an effective amount of a compound provided herein (e.g., a compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof. In another aspect, the disease is cancer. In another aspect, the cancer is a solid tumor. In another aspect, the cancer is chronic lymphocytic leukemia. In another aspect, the subject is a mammal. In another aspect, the subject is a human.

[0174] In another aspect, provided herein is a method of treating a subject suffering from or susceptible to a disease or disorder, comprising administering an effective amount of a compound provided herein (e.g., a compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof. In another aspect, the disease is cancer. In another aspect, the cancer is a solid tumor. In another aspect, the cancer is chronic lymphocytic leukemia. In another aspect, the subject is a mammal. In another aspect, the subject is a human.

[0175] In another embodiment, provided herein is a method of treating a Bcl-2-mediated cancer in a subject in need thereof, comprising administering an effective amount of a compound provided herein (e.g., a compound of Formula (I) or Formula (II)) or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, such that platelet toxicity is reduced compared to other Bcl-2 inhibitors. In another embodiment, the Bcl-2-mediated cancer is chronic lymphocytic leukemia. In another embodiment, the other Bcl-2 inhibitor is ABT-737, navitoclax (ABT-263), venetoclax (ABT-199), obatoclax (GX15-070), (-)-gossypol (AT-101), sabutoclax (BI-97C1), TW-37, BM-1252 (APG-1252), or A-1155463. In another embodiment, the other Bcl-2 inhibitor is venetoclax or ABT-263.

[0176] In another embodiment, provided herein is a method of treating a subject suffering from or susceptible to a Bcl-2-mediated cancer, comprising administering an effective amount of a compound provided herein (e.g., a compound of Formula (I) or Formula (II)) or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof such that platelet toxicity is reduced compared to other Bcl-2 inhibitors. In another embodiment, the Bcl-2-mediated cancer is chronic lymphocytic leukemia. In another embodiment, the other Bcl-2 inhibitor is ABT-737, navitoclax (ABT-263), venetoclax (ABT-199), obatoclax (GX15-070), (-)-gossypol (AT-101), sabutoclax (BI-97C1), TW-37, BM-1252 (APG-1252), or A-1155463. In another embodiment, the other Bcl-2 inhibitor is venetoclax or ABT-263.

[0177] In another aspect, a method of treating a Bcl-2 mediated cancer in a subject in need thereof comprises administering a human platelet cytotoxic (IC) 50 ) Anticancer activity (IC 50 Provided herein are methods, comprising administering an effective amount of a compound provided herein (e.g., a compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, such that the ratio of Bcl-2 inhibitors to Bcl-2 is lower than the ratio of the other Bcl-2 inhibitor. In another embodiment, the Bcl-2-mediated cancer is chronic lymphocytic leukemia. In another embodiment, the other Bcl-2 inhibitor is venetoclax or ABT-263. In another embodiment, the anticancer activity is measured in MOLT-4 cells. In another embodiment, the ratio is greater than 1. In another embodiment, the ratio is greater than 10. In another embodiment, the ratio is greater than 20. In another embodiment, the ratio is greater than 40.

[0178] In another embodiment, a method of treating a subject suffering from or susceptible to a Bcl-2 mediated cancer is provided, comprising administering to a subject a human platelet cytotoxic (IC) 50 ) Anticancer activity (IC 50Provided herein are methods, comprising administering an effective amount of a compound provided herein (e.g., a compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, such that the ratio of Bcl-2 inhibitors to Bcl-2 is less than the ratio of the other Bcl-2 inhibitor. In another embodiment, the Bcl-2-mediated cancer is chronic lymphocytic leukemia. In another embodiment, the other Bcl-2 inhibitor is venetoclax or ABT-263. In another embodiment, the anticancer activity is measured in MOLT-4 cells. In another embodiment, the ratio is greater than 1. In another embodiment, the ratio is greater than 10. In another embodiment, the ratio is greater than 20. In another embodiment, the ratio is greater than 40.

[0179] The present disclosure includes a method for selectively killing one or more cancer cells in a sample, the method comprising contacting the sample with a composition comprising an effective amount of a compound of Formula (I). In another aspect, the present disclosure includes a method for selectively killing one or more cancer cells in a subject in need thereof, the method comprising administering to the subject a composition comprising a therapeutically effective amount of a compound of Formula (I).

[0180] By "selectively killing one or more cancer cells," it is meant that the compositions provided herein do not appreciably kill non-cancer cells at the same concentration. In one embodiment, the compositions provided herein have reduced platelet toxicity and retained or improved toxicity in cancer cells when compared to other BCL-2 inhibitors. Thus, the median lethal dose (LD50) of an inhibitor in non-cancer cells may be about 5 to about 50 times higher than the LD50 of the inhibitor in cancer cells. As used herein, LD50 is the concentration of inhibitor required to kill half of the cells in a cell sample. For example, the LD50 of an inhibitor in non-cancer cells may be about 5, 6, 7, 8, 9, or 10 times higher than the LD50 of the inhibitor in cancer cells. Alternatively, the LD50 of the inhibitor in non-cancer cells may be about 10-fold, about 15-fold, about 20-fold, about 25-fold, about 30-fold, about 35-fold, about 40-fold, about 45-fold, or about 50-fold greater than the LD50 of the inhibitor in cancer cells. Furthermore, the LD50 of the inhibitor in non-cancer cells may be more than 50-fold greater than the LD50 of the inhibitor in cancer cells. In a specific embodiment, the LD50 of the inhibitor in non-cancer cells is more than 10-fold greater than the LD500 of the inhibitor in cancer cells. In another specific embodiment, the LD50 of the inhibitor in non-cancer cells is more than 20-fold greater than the LD50 of the inhibitor in cancer cells.

[0181] Non-limiting examples of neoplasms or cancers that may be treated include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, appendix cancer, astrocytoma (pediatric cerebellar or cerebral), basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumors (cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, optic pathway and hypothalamic glioma), breast cancer, bronchial adenoma / carcinoid, Burkitt's lymphoma, carcinoid tumor (pediatric, gastrointestinal), carcinoma of unknown primary, central nervous system lymphoma (primary), cerebellar Astrocytoma, Cerebral astrocytoma / malignant glioma, Cervical cancer, Childhood cancer, Choriocarcinoma, Chronic lymphocytic leukemia, Chronic myeloid leukemia, Chronic myeloproliferative disorder, Colon cancer, Cutaneous T-cell lymphoma, Desmoplastic small round cell tumor, Endometrial cancer, Ependymoma, Esophageal cancer, Ewing's sarcoma of the Ewing's tumor family, Extracranial germ cell tumor (childhood), Extragonadal germ cell tumor, Extrahepatic bile duct cancer, Eye cancer (intraocular melanoma, retinoblastoma), Gallbladder cancer, Gastric (stomach) cancer, Gastrointestinal carcinoid tumor, Gastrointestinal stromal tumor, Germ cell tumor (pediatric extracranial, extragonadal, ovarian), Gestational trophoblastic tumor, Glioblastoma, Gliomas (adult, pediatric brainstem, pediatric) Cerebral astrocytoma, childhood visual pathway and hypothalamic), gastric carcinoid, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, Hodgkin's lymphoma, hypopharyngeal cancer, hypothalamic and visual pathway glioma (childhood), intraocular melanoma, pancreatic islet cell carcinoma, Kaposi's sarcoma, kidney cancer (renal cell carcinoma), laryngeal cancer, leukemia (acute lymphoblastic, acute myeloid, chronic lymphocytic, chronic myeloid, hairy cell), lip and oral cavity cancer, liver cancer (primary), lung cancer (non-small cell, small cell), lymphoma (AIDS-related, Burkitt's, cutaneous T-cell, Hodgkin's, non-Hodgkin's, primary central nervous system), macroglobulinemia (Waldensis) ulcerative colitis), malignant fibrous histiocytoma / osteosarcoma of bone, medulloblastoma (childhood), melanoma, intraocular melanoma, Merkel cell carcinoma, mesothelioma (adult malignant, childhood), metastatic squamous cell carcinoma of the neck with unknown primary origin, oral cancer, multiple endocrine neoplasia syndrome (childhood), multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative disorders, myeloid leukemia (chronic), myeloid leukemia (adult acute, childhood acute), multiple myeloma, myeloproliferative disorders (chronic), nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell renal pelvic transitional cell carcinoma, urethral cancer, uterine cancer (endometrium), uterine sarcoma,These include vaginal cancer, visual pathway and hypothalamic glioma (childhood), vulvar cancer, Waldenstrom's macrobullinemia, and Wilms' tumor (childhood). In certain embodiments, the cancer is selected from the group consisting of synovial sarcoma, Burkitt's lymphoma, Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioblastoma, small cell lung cancer, pancreatic cancer, hepatocellular (liver) cancer, endometrial cancer, ovarian cancer, cervical cancer, breast cancer, prostate cancer, bladder cancer, melanoma, rhabdomyosarcoma, osteosarcoma / malignant fibrous histiocytoma of bone, choriocarcinoma, kidney cancer (renal cell carcinoma), thyroid cancer, and leukemia (acute lymphoblastic, acute myeloid, chronic lymphocytic, and chronic myeloid).

[0182] Pharmaceutical Composition In one aspect, provided herein is a pharmaceutical composition comprising a compound of any of the formulae herein (e.g., a compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt hydrate, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.

[0183] In another embodiment, provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt hydrate, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier. In another embodiment, provided herein is a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt hydrate, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier. In another aspect, the composition further comprises an additional agent. In another aspect, the additional agent is an anticancer agent. In another aspect, the anticancer agent is an alkylating agent, an antimetabolite, an antitumor antibiotic, an anti-cytoskeletal agent, a topoisomerase inhibitor, an antihormonal agent, a targeted therapy agent, a photodynamic therapy agent, or a combination thereof.

[0184] Non-limiting examples of suitable alkylating agents include altretamine, benzodopa, busulfan, carboplatin, carboquone, carmustine (BCNU), chlorambucil, chlornaphazine, chlorophosphamide, chlorozotocin, cisplatin, cyclophosphamide, dacarbazine (DTIC), estramustine, fotemustine, ifosfamide, iprosulfan, lipoplatin, lomustine (CCNU), mafosfamide, mannosulfan, mechlorethamine, mechlorethamine oxide hydrochloride, and cyclohexyl benzoate. These include rido, melphalan, metuledopa, mustine (mechlorethamine), mitobronitol, nimustine, nobembine, oxaliplatin, phenesterine, piposulfan, prednimustine, ranimustine, satraplatin, semustine, temozolomide, thiotepa, treosulfan, triaziconazole, triethylenemelamine, triethylenephosphoramide (TEPA), triethylenethiophosphamide (thiotepa), trimethylmelamine, trophosfamide, uracil mustard, and uredopa.

[0185] Suitable antimetabolites include aminopterin, ancitabine, azacitidine, 8-azaguanine, 6-azauridine, capecitabine, carmofur (1-hexylcarbomoyl-5-fluorouracil), cladribine, clofarabine, cytarabine (cytosine arabinoside (Ara-C)), decitabine, denopterin, dideoxyuridine, doxifluridine, enocitabine, floxuridine, fludarabine, and the like. These include, but are not limited to, fluoxetine, 5-fluorouracil, gemcitabine, hydroxyurea (hydroxycarbamide), leucovorin (folinic acid), 6-mercaptopurine, methotrexate, nafoxidine, nelarabine, oblimersen, pemetrexed, pteropterin, raltitrexed, tegofur, tiazofurin, thiamiprine, thioguanine (thioguanine), and trimetrexate.

[0186] Non-limiting examples of suitable antitumor antibiotics include aclacinomycin, aclarubicin, actinomycin, adriamycin, aurostatins (e.g., monomethylauristatin E), ausramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detrevicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, thiazolinone ... These include rubicin, epirubicin, epoxomicin, esorubicin, idarubicin, marcellomycin, mitomycin, mithramycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, plicamycin, potfilomycin, puromycin, queramycin, lorubicin, sparsomycin, streptonigrin, streptozocin, tubercidin, valrubicin, ubenimex, zinostatin, and zorubicin.

[0187] Non-limiting examples of suitable anti-cytoskeletal agents include cabazitaxel, colchicine, demecolcine, docetaxel, epothilones, ixabepilone, macromycin, ometacetaxine mepesuccinate, ortataxel, paclitaxel (e.g., DHA-paclitaxel), taxanes, tesetaxel, vinblastine, vincristine, vindesine, and vinorelbine.

[0188] Suitable topoisomerase inhibitors include, but are not limited to, amsacrine, etoposide (VP-16), irinotecan, mitoxantrone, RFS2000, teniposide, and topotecan.

[0189] Non-limiting examples of suitable antihormonal agents include aminoglutethimide, antiestrogens, aromatase inhibitor 4(5)-imidazole, bicalutamide, finasteride, flutamide, fulvestrant, goserelin, 4-hydroxytamoxifen, keoxifene, leuprolide, LY117018, mitotane, nilutamide, onapristone, raloxifene, tamoxifen, toremifene, and trilostane.

[0190] Examples of targeted therapeutic agents include monoclonal antibodies, such as alemtuzumab, cartumaxomab, edrecolomab, epratuzumab, gemtuzumab, gemtuzumab ozogamicin, grambatumumab vedotin, ibritumomab tiuxetan, reditux, rituximab, tositumomab, and trastuzumab; protein kinase inhibitors, such as bevacizumab, cetuximab, crizonib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, mubritinib, nilotinib, panitumumab, pazopanib, sorafenib, sunitinib, toceranib, and vandetanib; angiogenesis inhibitors, such as angiostatin, bevacizumab, These include, but are not limited to, cyclosporine, denileukin diptitoxin, endostatin, everolimus, genistein, interferon alpha, interleukin-2, interleukin-12, pazopanib, pegaptanib, ranibizumab, rapamycin (sirolimus), temsirolimus, and thalidomide; and growth inhibitory polypeptides such as bortazomib, erythropoietin, interleukins (e.g., IL-1, IL-2, IL-3, IL-6), leukemia inhibitory factor, interferon, romidepsin, thrombopoietin, TNF-α, CD30 ligand, 4-1BB ligand, and Apo-1 ligand.

[0191] Non-limiting examples of photodynamic therapy agents include aminolevulinic acid, methyl aminolevulinate, retinoids (alitretinone, tamibarotene, tretinoin), and temoporfin.

[0192] Other antineoplastic agents include anagrelide, arsenic trioxide, asparaginase, bexarotene, bropirimine, celecoxib, chemically conjugated Fab, efaproxal, etoglucide, ferruginol, lonidamide, masoprocol, miltefosine, mitoguazone, talapanel, trabectin, and vorinostat.

[0193] In one aspect, provided herein is a kit comprising an effective amount of a compound of any of the formulae herein (e.g., a compound of Formula (I) or Formula (II)) or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, in unit dosage form, together with instructions for administering the compound to a subject suffering from or susceptible to cancer. In another aspect, the cancer is a solid tumor. In another aspect, the cancer is chronic lymphocytic leukemia.

[0194] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, is administered to a subject using a pharmaceutically acceptable formulation, e.g., a pharmaceutically acceptable formulation that provides sustained delivery of the compound to the subject for at least 12 hours, 24 hours, 36 hours, 48 ​​hours, 1 week, 2 weeks, 3 weeks, or 4 weeks after the pharmaceutically acceptable formulation is administered to the subject.

[0195] Actual dosage levels and time-course of administration of the active ingredients in the pharmaceutical compositions provided herein may be varied so as to obtain an amount of the active ingredient that is effective to achieve a desired therapeutic response for a particular patient, composition, and mode of administration without being toxic (or unacceptably toxic) to the patient.

[0196] In use, at least one compound provided herein, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, is administered to a subject in need thereof in a pharmaceutical carrier in a pharmaceutically effective amount by intravenous, intramuscular, subcutaneous, or intracerebroventricular injection, or by oral administration or topical application. The compounds provided herein can be administered alone or in combination with a second, different therapy. "In combination with" means substantially simultaneously or sequentially together. In one embodiment, the compounds provided herein are administered acutely. Thus, the compounds provided herein can be administered for short-term treatment, such as from about one day to about one week. In another embodiment, the compounds provided herein can be administered for longer periods to ameliorate chronic disorders, such as from about one week to several months, depending on the condition being treated.

[0197] As used herein, "pharmaceutically effective amount" refers to an amount of a compound provided herein that is high enough to significantly positively modify the condition being treated, but low enough (at a reasonable benefit / risk ratio) to avoid serious side effects, within the scope of sound medical judgment. The pharmaceutically effective amount of a compound provided herein will vary depending on the specific goal to be achieved, the age and physical condition of the patient being treated, the severity of the underlying disease, the duration of treatment, the nature of the concomitant therapy, and the specific apratoxin compound used. For example, the therapeutically effective amount of a compound provided herein administered to a child or neonate will be reduced proportionately according to sound medical judgment. Thus, the effective amount of a compound provided herein is the minimum amount that provides the desired effect.

[0198] The compound or compositions thereof can be administered parenterally or intraperitoneally.Dispersions can also be prepared, for example, in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils.

[0199] Pharmaceutical forms suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage. The carrier can be a solvent or dispersion medium containing, for example, water, DMSO, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained by the use of a coating such as lecithin, or by maintaining the required particle size in the case of dispersions. In many cases, it is preferable to include an isotonic agent, such as sugar or sodium chloride. Prolonged absorption of injectable compositions can be achieved by using agents that delay absorption, such as aluminum monostearate and gelatin in the composition.

[0200] Sterile injectable solution is prepared by incorporating the compound provided herein in the required amount into suitable solvent with various other components as listed above as necessary, and then sterilized by filtration.Generally, dispersion is prepared by incorporating various sterilized compounds into a sterile vehicle that contains basic dispersion medium and other necessary components listed above.For the preparation of sterile powder for sterile injectable solution, the preferred preparation method is vacuum drying and freeze-drying technology, by which the powder of active ingredient and any additional desired ingredients can be obtained from the solution that has been previously sterilized and filtered.

[0201] For oral therapeutic administration, the compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc. The compositions or preparations provided herein are prepared so that an oral dosage unit form contains a concentration of the compound sufficient to treat the disorder of interest.

[0202] Some examples of substances that can serve as pharmaceutical carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; tragacanth powder; malt; gelatin; talc; stearic acid; magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and theobroma oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; agar; alginic acid; pyrogen-free water; isotonic saline; and phosphate buffer; nonfat dry milk; and other non-toxic, compatible substances used in pharmaceutical formulations, such as vitamin C, estrogen, and echinacea. Wetting agents and lubricants, such as sodium lauryl sulfate, as well as colorants, flavorings, lubricants, excipients, tableting agents, stabilizers, antioxidants, and preservatives may also be present. [Example]

[0203] The present invention will now be illustrated using specific examples that should not be construed as limiting.

[0204] Preparation of compounds [ka] The compounds provided herein can be made or modified by various means known in the art of organic synthesis. For example, among various organic synthesis methodologies known in the art, the compounds provided herein can be synthesized according to the above reaction scheme. E represents an electrophile, and Nu represents a nucleophile. R is R1 or morpholine. R1, R2, R3, R4, L1, and L2 are as defined herein. In some embodiments, the nucleophile is an amine, and the electrophile is a carboxylic acid.

[0205] Scheme 1: Preparation of Intermediate A [ka] Preparation of ethyl 4-(4-((4'-chloro-4-formyl-4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoate (A-2): Under an argon atmosphere, to a solution of DMSO (440 μL, 6.21 mmol) in DCM (10 mL) was added oxalyl chloride (351 μL, 4.14 mmol) dropwise with stirring at −78° C. The resulting mixture was stirred at −78° C. for an additional 15 minutes. Then, a solution of A-1 (1 g, 2.07 mmol) in DCM / DMSO (20 mL / 5 mL) was added dropwise. After the addition was complete, the mixture was stirred at −78° C. for an additional 30 minutes. TEA (1.73 mL, 12.42 mmol) was added to the mixture at −78° C., and then the dry ice / acetone bath was removed. The reaction mixture was warmed to room temperature and stirred for an additional 30 minutes. The reaction mixture was added to water and extracted with DCM. The combined organic layers were washed with 10% aqueous NaSO and saturated aqueous NHCl, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (0% to 40% EtOAc in hexanes) to give A-2 (760 mg, 76% yield). 1 H NMR(600MHz,CDCl3)δ9.56(s,1H),7.94-7.91(m,2H),7.31-7.29(m,2H),7.00-6.96(m,2H) ),6.85-6.82(m,2H),4.34(q,J=7.1Hz,2H),3.30(t,J=5.1Hz,4H),2.86(q,J=12.6Hz,2H) ,2.69(dd,J=18.1,1.9Hz,1H),2.47-2.40(m,2H),2.40-2.25(m,4H),2.11-2.04(m,1H),2 .04-1.97(m,1H),1.68-.58(m,1H),1.38(t,J=7.1Hz,3H),1.18(s,3H)ppm.LC / MS(ESI)m / z 481.1;[M+H] + C 28 H 34 ClN2O3 + Calculated value: 481.23.

[0206] Preparation of tert-butyl 4-((4'-chloro-6-((4-(4-(ethoxycarbonyl)phenyl)piperazin-1-yl)methyl)-4-methyl-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazine-1-carboxylate (A-3): NaBH(OAc) (771 mg, 3.64 mmol) was added portionwise to a solution of A-2 (350 mg, 0.727 mmol), 1-Boc-piperazine (162 mg, 0.87 mmol), and TEA (607 μL, 4.37 mmol) in DCM (5 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with saturated aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (0% to 40% EtOAc in hexanes) to give compound A-3 (400 mg, 84% yield). 1 H NMR(600MHz,CDCl3)δ7.94-7.90(m,2H),7.32-7.27(m,2H),7.03-7.00(m, 2H),6.86-6.81(m,2H),4.34(q,J=7.1Hz,2H),3.42(t,J=5.0Hz,4H),3.27( t,J=5.1Hz,4H),2.82(s,2H),2.59-2.11(m,14H),1.95(d,1H),1.67-1.57( m,1H),1.48(s,9H),1.38(t,J=7.1Hz,3H),0.97(s,3H)ppm.LC / MS(ESI)m / z 651.2;[M+H] + C 37 H 52 ClN4O4 + Calculated value: 651.37.

[0207] Preparation of 4-(4-((4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-4'-chloro-4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid (Intermediate A): To a solution of A-3 (400 mg, 0.61 mmol) in MeOH / THF (4 mL / 4 mL) was added a solution of LiOH·HO (129 mg, 3.07 mmol) in water (1 mL), followed by stirring at 45 °C overnight. The reaction mixture was concentrated to remove the organic solvent, then adjusted to pH = 5-6 with 10% aqueous citric acid and extracted with EtOAc. The combined organic layers were washed with water and saturated aqueous brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (0% to 70% EtOAc in hexanes) to give intermediate A (340 mg, 89% yield). 1 H NMR(600MHz,CDCl3)δ7.98-7.92(m,2H),7.33-7.27(m,2H),7.03-7.00(m,2H),6.86-6.81(m,2H),3.41(t,J=4.9Hz,4H),3.30( t,J=5.2Hz,4H),2.85(s,2H),2.59-2.13(m,14H),1.97(d,1H),1.67-1.58(m,1H),1.47(s,9H),0.97(s,3H)ppm.LC / MS(ESI)m / z 623.2;[M+H] + C 35 H 48 ClN4O4 + Calculated value: 623.34.

[0208] Scheme 2: Preparation of intermediate B [ka] Preparation of ethyl (R)-4-(4-((4'-chloro-4-formyl-4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoate (B-2): Preparation was carried out according to the first step in the preparation of intermediate A using B-1 (3 g, 6.21 mmol) as starting material. B-2 (2.3 g) was obtained in 77% yield.1 H NMR(600MHz,chloroform-d)δ9.56(s,1H),7.95-7.89(m,2H),7.33-7.27(m,2H),7.01-6.95( m,2H),6.87-6.81(m,2H),4.34(q,J=7.1Hz,2H),3.30(t,J=5.1Hz,4H),2.86(q,J=12.7H z,2H),2.73-2.66(m,1H),2.48-2.41(m,2H),2.40-2.26(m,4H),2.12-2.04(m,1H),2.05 -1.99(m,1H),1.69-1.60(m,1H),1.38(t,J=7.1Hz,3H),1.18(s,3H)ppm.LC / MS(ESI)m / z 481.2;[M+H] + C 28 H 34 ClN2O3 + Calculated value: 481.23.

[0209] Preparation of (R)-4-(4-((4'-chloro-4-formyl-4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid (B-3): To a solution of B-2 (2.3 g, 4.78 mmol) in MeOH / THF (25 mL / 25 mL) was added a solution of LiOH·HO (602 mg, 14.35 mmol) in water (6 mL), and the resulting mixture was stirred at 40 °C overnight. The reaction mixture was concentrated to remove the organic solvent and then adjusted to pH 5-6 with 10% aqueous citric acid. The precipitate was collected by filtration, washed with water, and dried under vacuum to give B-3 (2.0 g, 92% yield). 1 H NMR (600MHz, methanol-d4) δ9.56(s,1H),7.91(d,J=9.0Hz,2H),7.40-7.37(m,2H),7.11-7.08(m,2H),7.00-6.95(m,2H),3.53-3.42(m,4H),3.04-2 .89(m,3H),2.83(s,2H),2.68(dd,J=17.5,1.9Hz,1H),2.44-2.32(m,3H),2.17-2.06(m,2H),1.78-1.68(m,1H),1.21(s,3H)ppm.LC / MS(ESI)m / z 453.1;[M+H]+ C 26 H 29 ClN2O3 + Calculated value: 452.98.

[0210] Preparation of (R)-4-(4-((4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-4'-chloro-4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid (Intermediate B): NaBH(OAc) (468 mg, 2.21 mmol) was added to a solution of B-3 (500 mg, 1.1 mmol), 1-Boc-piperazine (616 mg, 3.31 mmol), and TEA (768 μL, 5.52 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with saturated aqueous NHCl, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (0% to 40% EtOAc in hexanes) to give intermediate B (530 mg, 77% yield). 1 H NMR(600MHz,MeOD)δ7.90-7.85(m,2H),7.38-7.34(m,2H),7.14-7.10(m,2H),6.96 -6.91(m,2H),3.53-3.40(m,4H),3.37-3.31(m,4H),3.10-3.00(m,2H),2.89-2.72 (m,1H),2.67-2.53(m,8H),2.43-2.23(m,5H),2.01(d,J=17.4Hz,1H),1.72-1.64( m,1H),1.53(dt,J=11.6,5.3Hz,1H),1.47(s,9H),1.05(s,3H)ppm.LC / MS(ESI)m / z 623.2;[M+H] + C 35 H 48 ClF3N4O4 + Calculated value: 623.34.

[0211] Scheme 3: Preparation of Intermediates C and D [ka] Preparation of benzyl (R)-3-amino-4-(phenylthio)butanoate (C-2): HCl in dioxane (4N, 10 mL) was added to a solution of C-1 (1.0 g, 2.49 mmol) in DCM (10 mL) with stirring. After stirring at room temperature for 2 h, the reaction mixture was concentrated to give crude C-2 (950 mg) as the HCl salt, which was used directly in the next step. LC / MS (ESI) m / z 302.1; [M+H] + C 17 H 20 ClF3NO2S + Calculated value: 302.12.

[0212] Preparation of benzyl (R)-3-((2-nitro-4-sulfamoylphenyl)amino)-4-(phenylthio)butanoate (C-4) and benzyl (R)-4-(phenylthio)-3-((4-sulfamoyl-2-((trifluoromethyl)sulfonyl)phenyl)amino)butanoate (D-4): C-3 or D-3 (1.0 equiv.) was added to a solution of C-2 (1.0 equiv.) and DIPEA (8.0 equiv.) in DMSO. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to give C-4 and D-4, respectively. C-4 (140 mg, 56% yield over two steps): 1 H NMR(600MHz,CDCl3)δ8.71-8.65(m,2H),7.74(dd,J=9.0,2.3Hz,1H),7.41-7.25(m,10H),6.67(d,J=9.2Hz,1H),5.15(q,2H),4. 82(s,2H),4.31-4.23(m,1H),3.24-3.17(m,2H),2.96(dd,J=16.3,5.1Hz,1H),2.87(dd,J=16.3,6.8Hz,1H)ppm.LC / MS(ESI)m / z 502.1;[M+H] + C 23 H 24 N3O6S2 + Calculated value: 502.11. D-4 (1.1 g, 75% yield over two steps): 1H NMR(600MHz,CDCl3)δ8.26(d,J=2.2Hz,1H),7.83(dd,J=9.1,2.3Hz,1H),7.44 -7.39(m,2H),7.39-7.29(m,8H),6.55(d,J=9.3Hz,1H),5.16(d,J=12.1Hz,1H ),5.11(d,J=12.1Hz,1H),4.98(s,1H),4.19-4.09(m,1H),3.21-3.07(m,2H), 2.90(dd,J=16.5,5.0Hz,1H),2.81(dd,J=16.5,6.6Hz,1H)ppm.LC / MS(ESI)m / z 589.1;[M+H] + C 24 H 24 N2O6S3 + Calculated value: 589.07.

[0213] tert-Butyl 4-((6-((4-(4-(4-((((R)-4-(benzyloxy)-4-oxo-1-(phenylthio)butan-2-yl)amino)-3-nitrophenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-4'-chloro-4-methyl-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazine-1-carboxylate (C-5) and tert-butyl 4-((6-((4-(4-(((4-(((R)-4-(benzyloxy) Preparation of )-4-oxo-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-4'-chloro-4-methyl-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazine-1-carboxylate (D-5): C-4 or D-4 (1.0 equiv.) was added to a mixture of Intermediate A (1.0 equiv.), DMAP (6.0 equiv.), and EDC (6.0 equiv.) in DCM. The resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with water and saturated aqueous NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to give C-5 and D-5, respectively. C-5 (136 mg, 62% yield):1 H NMR (600MHz, CDCl3) δ8.81(s,1H),8.71(d,J=8.9Hz,1H),8.02(dd,J=9.2,2.3Hz,1H),7.67(d,J=8.5Hz,2H) ,7.37-7.20(m,12H),7.04-6.98(m,2H),6.78(d,J=8.6Hz,2H),6.65(d,J=9.3Hz,1H),5.13(q,2H),4.31-4.2 0(m,1H),3.48-3.38(m,4H),3.28(t,J=5.2Hz,4H),3.23-3.14(m,2H),2.97-2.82(m,4H),2.51(s,4H),2.44- 2.11(m,9H),1.94(d,J=17.4Hz,1H),1.66-1.58(m,1H),1.52-1.43(m,10H),0.96(s,3H)ppm.LC / MS(ESI)m / z 1106.5;[M+H] + C 58 H 69 ClN7O9S2 + Calculated value: 1106.43. D-5 (225 mg, yield 65%): LC / MS (ESI) m / z 1193.2; [M+H] + C 59 H 69 ClF3N6O9S3 + Calculated value: 1193.39

[0214] tert-Butyl 4-((4'-chloro-6-((4-(4-(((4-(((R)-4-hydroxy-1-(phenylthio)butan-2-yl)amino)-3-nitrophenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-4-methyl-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazine-1-carboxylate (C-6) and tert-butyl 4-((4'-chloro-6-((4-(4-(((4-(((R)-4-hydroxy-1-(phenylthio)butan-2-yl)amino)-3-nitrophenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-4-methyl-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazine-1-carboxylate (C-6) Preparation of hydroxy-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-4-methyl-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazine-1-carboxylate (D-6): To a solution of C-5 or D-5 (1.0 equiv.) in THF / MeOH (50 mL / 2.5 mL), NaBH (20.0 equiv.) was added portionwise over 6 hours. The mixture was then stirred overnight at room temperature. Saturated aqueous NH4Cl was added, and the mixture was extracted with DCM (3 times). The combined organic layer was washed with saturated aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to give C-6 and D-6, respectively. C-6 (112 mg, 91% yield): 1H NMR(600MHz, CDCl3)δ8.81(d,J=2.3Hz,1H),8.63(d,J=8.6Hz,1H),8.00(dd,J=9.3,2.3Hz,1H),7.70-7.63(m,2H),7.39- 7.32(m,2H),7.30(d,J=1.8Hz,2H),7.27-7.19(m,3H),7.03-6.98(m,2H),6.77(t,J=9.5Hz,3H),4.20-4.09(m,1H),3.89- 3.75(m,2H),3.41(t,J=5.1Hz,4H),3.28(t,J=5.2Hz,4H),3.20(qd,J=14.1,5.8Hz,2H),2.86(s,2H),2.57-2.45(m,4H), 2.45-2.11(m,11H),2.01-1.90(m,2H),1.63(td,J=16.3,8.8Hz,1H),1.50-1.44(m,10H),0.96(s,3H)ppm.LC / MS(ESI)m / z 1002.3;[M+H] + C 51 H 65 ClN7O8S2 + Calculated value: 1002.40. D-6 (181 mg, yield 88%): LC / MS (ESI) m / z 1089.4; [M+H] + C 52 H 65 ClF3N6O8S3 + Calculated value: 1089.37.

[0215] tert-Butyl 4-((4'-chloro-4-methyl-6-((4-(4-(((3-nitro-4-(((R)-4-oxo-1-(phenylthio)butan-2-yl)amino)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazine-1-carboxylate (Intermediate C) and tert-butyl 4-((4'-chloro-4-methyl-6-((4-(4-(((4 Preparation of -(((R)-4-oxo-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazine-1-carboxylate (Intermediate D): DMP (2.0 equivalents) was added to a solution of compound C-6 or D-6 (1.0 equivalents) in EtOAc, followed by stirring at room temperature for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated to give crude Intermediate C and Intermediate D, respectively, which were used directly in the next step or purified by flash column chromatography. Intermediate C (84 mg, 75% yield): LC / MS (ESI) m / z 1000.4; [M+H] + C 51 H 63 ClN7O8S2 + Calculated for: 1000.39. Intermediate D (155 mg, 86% yield): LC / MS (ESI) m / z 1087.5; [M+H] + C 52 H 63 ClF3N6O8S3 + Calculated value: 1087.35.

[0216] Scheme 4: Preparation of Intermediates E and F [ka] tert-Butyl 4-(((R)-6-((4-(4-(((4-(((R)-4-(benzyloxy)-4-oxo-1-(phenylthio)butan-2-yl)amino)-3-nitrophenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-4'-chloro-4-methyl-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazine-1-carboxylate (E-1) and tert-butyl 4-(((R)-6-((4-(4-(((4-((R)-4-(benzyl Preparation of (trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-4'-chloro-4-methyl-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazine-1-carboxylate (F-1): C-4 or D-4 (1.0 equiv.) was added to a mixture of Intermediate B (1.0 equiv.), DMAP (6.0 equiv.), and EDC (6.0 equiv.) in DCM. The resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with water and saturated aqueous NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to give E-1 and F-1, respectively. E-1 (150mg, yield 84%):LC / MS(ESI)m / z 1106.5;[M+H] + C 58 H 69 ClN7O9S2 + Calculated value: 1106.43. F-1 (220 mg, 57% yield): 1H NMR(600MHz,クロロホルム-d)δ8.39(d,J=2.3Hz,1H),8.14(dd,J=9.2,2.3Hz,1H),7.66(d,J=8.7Hz,2H),7.42-7.37(m,3 H),7.38-7.26(m,10H),7.04-6.97(m,2H),6.79(d,J=8.7Hz,2H),6.52(d,J=9.4Hz,1H),5.19-5.06(m,2H),4.17-4. 07(m,1H),3.46-3.38(m,4H),3.29(t,J=5.3Hz,4H),3.20-3.06(m,2H),2.93-2.76(m,4H),2.52(s,4H),2.45-2.34( m,4H),2.34-2.12(m,5H),1.95(d,J=17.3Hz,1H),1.66-1.58(m,1H),1.47(s,10H),0.96(s,3H)ppm.LC / MS(ESI)m / z 1193.4;[M+H] + C 59 H 69 ClF3N6O9S3 + Calculated value: 1193.39.

[0217] tert-Butyl 4-(((R)-4'-chloro-6-((4-(4-(((4-(((R)-4-hydroxy-1-(phenylthio)butan-2-yl)amino)-3-nitrophenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-4-methyl-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazine-1-carboxylate (E-2) and tert-butyl 4-(((R)-4'-chloro-6-((4-(4-(((4-(((R)-4-hydroxy- Preparation of 1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-4-methyl-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazine-1-carboxylate (F-2): To a solution of E-1 or F-1 (1.0 equiv.) in THF / MeOH (50 mL / 2.5 mL), NaBH4 (20.0 equiv.) was added portionwise over 6 hours and then stirred at room temperature overnight. Saturated aqueous NH4Cl was added to the reaction mixture and extracted with DCM. The combined organic layer was washed with saturated aqueous NH4Cl, then dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to give E-2 and F-2, respectively. E-2 (99 mg, yield 73%): LC / MS (ESI) m / z 1002.3; [M+H] + C 51 H 65 ClN7O8S2 + Calculated value: 1002.40. F-2 (168 mg, 66% yield). 1H NMR(600MHz,クロロホルム-d)δ8.36(s,1H),8.10(s,1H),7.76-7.62(m,2H),7.39(d,J=7.6Hz,2H),7.34-7. 17(m,7H),7.00(d,J=8.2Hz,2H),6.75(s,2H),6.60(d,J=9.3Hz,1H),4.01(s,1H),3.75(d,J=36.2Hz,2 H),3.40(s,5H),3.28(s,4H),3.18-3.05(m,2H),3.01-2.82(m,2H),2.57-2.36(m,9H),2.36-2.08(m, 5H),1.96(d,J=17.4Hz,1H),1.85(s,1H),1.68-1.57(m,1H),1.46(s,9H),0.96(s,3H).LC / MS(ESI)m / z 1089.5;[M+H] + C 52 H 65 ClF3N6O8S3 + Calculated value: 1089.37.

[0218] tert-Butyl 4-(((4R)-4'-chloro-4-methyl-2-((4-(4-(((3-nitro-4-(((R)-4-oxo-1-(phenylthio)butan-2-yl)amino)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-[1,1'-bi(cyclohexane)]-1,1',5'-trien-4-yl)methyl)piperazine-1-carboxylate (Intermediate E) and tert-butyl 4-(((4R)-4'-chloro-4-methyl-2-((4-(4 Preparation of -(((4-(((R)-4-oxo-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-[1,1'-bi(cyclohexane)]-1,1',5'-trien-4-yl)methyl)piperazine-1-carboxylate (Intermediate F): DMP (2.0 equivalents) was added to a solution of compound E-2 or F-2 (1.0 equivalents) in EtOAc, followed by stirring at room temperature for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated to give crude Intermediate E and Intermediate F, which were used directly in the next step or purified by flash column chromatography. Intermediate E (171 mg, crude): LC / MS (ESI) m / z 1000.3; [M+H] + C 51 H 63 ClN7O8S2 + Calculated value: 1000.39. Intermediate F (90 mg, 55% yield): 1H NMR (600MHz, chloroform-d) δ9.74(d,J=2.6Hz,1H),8.40(dd,J=5.2,2.3Hz,1H),8.19(td,J=9.5,8.7,2.3Hz,1H),7.66(dd,J=12.2,8.6H z,2H),7.44-7.39(m,2H),7.37-7.22(m,6H),7.03-6.98(m,2H),6.77(dd,J=19.9,8.7Hz,2H),6.58(dd,J=9.4,2.6Hz,1H),4.26-4.17 (m,1H),3.42(d,J=5.9Hz,4H),3.35-3.26(m,4H),3.21(dd,J=14.2,5.0Hz,1H),3.16-3.09(m,1H),3.07-2.97(m,2H),2.97-2.89(m, 2H),2.64-2.41(m,9H),2.37-2.15(m,5H),2.05-1.93(m,1H),1.70-1.58(m,1H),1.52-1.42(m,10H),0.97(s,3H)ppm.LC / MS(ESI)m / z 1087.4;[M+H] + C 52 H 63 ClF3N6O8S3 + Calculated value: 1087.35.

[0219] Scheme 5: Preparation of intermediates G and H [ka] Preparation of tert-butyl (R)-(4-hydroxy-1-(phenylthio)butan-2-yl)carbamate (G-1): To a solution of C-1 (2.7 g, 6.724 mmol) in THF / MeOH (50 mL / 5 mL) was added NaBH4 (1.49 g, 40.35 mmol) in portions over 6 h. The resulting mixture was then stirred overnight at room temperature. Saturated aqueous NH4Cl was added, and the mixture was extracted with DCM (3 times). The combined organic layers were washed with saturated aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (0% to 70% EtOAc in hexanes) to give G-1 (1.6 g, 80% yield). 1H NMR(600MHz,chloroform-d)δ(ppm):7.43-7.40(m,2H),7.32(t,J=7.8Hz,2H),7.26-7.21(m,1H),4.84(d,J=8.4Hz,1H), 4.07(s,1H),3.67(s,2H),3.22-2.98(m,3H),1.98-1.82(m,1H),1.67-1.49(m,1H),1.46(s,9H)ppm.LC / MS(ESI)m / z 298.1;[M+H] + C 15 H 24 NO3S + Calculated value: 298.15.

[0220] Preparation of tert-butyl (R)-(4-oxo-1-(phenylthio)butan-2-yl)carbamate (G-2): DMP (2.08 g, 4.90 mmol) was added to a solution of G-1 (1.08 g, 3.63 mmol) in EtOAc (25 mL) and stirred at room temperature for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (0% to 70% EtOAc in hexanes) to give G-2 (1.0 g, 93% yield). 1 H NMR(600MHz,chloroform-d)δ9.71(s,1H),7.43-7.40(m,2H),7.35-7.30(m,2H),7.26-7.21(m,1H),5.00(s,1 H),4.22(s,1H),3.33-3.21(m,1H),3.17-3.07(m,1H),2.90-2.72(m,2H),1.44(s,9H)ppm.LC / MS(ESI)m / z 296.1;[M+H] + C 15 H 22 NO3S + Calculated value: 296.13.

[0221] Preparation of tert-butyl ((R)-4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1-(phenylthio)butan-2-yl)carbamate (G-3) and tert-butyl (R)-(4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)carbamate (H-3): NaBH(OAc) (1.2 equiv.) was added to a solution of G-2 (1 equiv.) and an amine (1.1 equiv.) in DCM, followed by stirring overnight at room temperature. The reaction mixture was washed with saturated aqueous NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (50% to 100% EtOAc in hexanes, then 0% to 10% MeOH in DCM) to give G-3 and H-3, respectively. G-3 (360 mg, 56%): 1 H NMR (600MHz, methanol-d4) δ7.44(d,2H),7.33(t,J=7.8Hz,2H),7.25-7.20(m,1H),4.60(s,1H),4.14(s,1H),4.07(d,1H),3. 81-3.68(m,2H),3.21-3.09(m,4H),3.09-2.97(m,2H),2.17-2.01(m,3H),1.84-1.72(m,1H),1.46(s,9H).LC / MS(ESI)m / z 379.2;[M+H] + C 20 H 31 N2O3S + Calculated value: 379.20. H-3 (760 mg, 98% yield): 1 H NMR (600MHz, chloroform-d) δ7.42(d,J=7.6Hz,2H),7.33-7.29(m,2H),7.19(t,J=7.4Hz,1H),3.91(s,1H),3.82(t,J=6.1Hz,2H),3.73(t,2H),3.30 (d,J=13.5Hz,1H),3.07-2.95(m,1H),2.77-2.60(m,4H),2.59-2.52(m,1H),1.95-1.82(m,3H),1.74-1.66(m,1H),1.45(s,9H).LC / MS(ESI)m / z 381.4;[M+H] + C 20 H 33N2O3S + Calculated value: 381.22.

[0222] Preparation of (R)-4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1-(phenylthio)butan-2-amine hydrochloride (G-4) and (R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-amine (H-4): HCl dioxane solution (4N) was added to a solution of G-3 or H-3 in DCM, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated to give G-4 and H-4, respectively, which were used directly in the next step. G-4 (350 mg, quantitative yield): LC / MS (ESI) m / z 279.1; [M+H] + C 15 H 23 N2OS + Calculated value: 279.15. H-4 (750 mg, quantitative yield). LC / MS(ESI)m / z 281.2;[M+H] + C 15 H 25 N2OS + Calculated value: 281.17.

[0223] Preparation of 4-(((R)-4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide (Intermediate G) and (R)-4-((4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide (Intermediate H): D-3 (1.0 equiv.) was added to a solution of G-4 or H-4 (1.2 equiv.) and DIPEA (8.0 equiv.) in DMSO, followed by stirring at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (50% to 100% EtOAc in hexanes, then 0% to 10% MeOH in DCM) to give Intermediate G or Intermediate H, respectively. Intermediate G (480 mg, 89% yield over two steps): 1 H NMR (600MHz, methanol-d4) δ8.15(d,J=2.2Hz,1H),7.88(dd,J=9.2,2.3Hz,1H),7.45-7.38(m,2H),7.34-7.28(m,2H) ),7.28-7.22(m,1H),6.89(d,J=9.3Hz,1H),4.40(s,1H),4.14-4.05(m,1H),3.95(d,J=7.9Hz,1H),3.60(dd,J=7. 8,1.8Hz,1H),3.48(s,1H),3.30(dd,1H),3.19(dd,J=14.2,5.9Hz,1H),2.80(dd,J=10.3,1.8Hz,1H),2.75-2.60( m,2H),2.54(dd,J=10.2,1.5Hz,1H),2.06-1.94(m,1H),1.87-1.75(m,2H),1.75-1.69(m,1H)ppm.LC / MS(ESI)m / z 566.1;[M+H] + C 22 H 27 F3N3O5S3 + Calculated for: 566.11. Intermediate H (900 mg, 83% yield over two steps). 1H NMR(600MHz,chloroform-d)δ8.27(d,J=2.2Hz,1H),7.83(dd,J=9.2,2.3Hz,1H),7.44-7.40(m,2H),7 .37-7.33(m,2H),7.33-7.27(m,1H),7.19(d,J=8.5Hz,1H),6.65(d,J=9.2Hz,1H),5.06(s,2H),4 .01-3.91(m,1H),3.77(t,J=6.0Hz,2H),3.73-3.63(m,2H),3.17-3.03(m,2H),2.75-2.69(m,2H) ,2.68-2.52(m,4H),2.14-2.04(m,1H),1.90-1.82(m,2H),1.76-1.67(m,1H)ppm.LC / MS(ESI)m / z 568.0;[M+H] + C 22 H 29 F3N3O5S3 + Calculated value: 568.12.

[0224] Scheme 6: Preparation of Intermediate I [ka] tert-Butyl 4-((6-((4-(4-(((4-(((R)-4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-4'-chloro-4- Preparation of methyl-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazine-1-carboxylate (I-1): Intermediate G (36 mg, 0.064 mmol) was added to a mixture of Intermediate A (40 mg, 0.064 mmol), EDC (62 mg, 0.32 mmol), and DMAP (39 mg, 0.32 mmol) in DCM (3 mL). The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water and saturated aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (0% to 10% MeOH in DCM) to give I-1 (39 mg, 52% yield).1 H NMR(600MHz,chloroform-d)δ8.34(s,1H),8.03(d,J=8.8,2.5Hz,1H),7.79-7.74(m,2H),7.42-7.35(m,2H),7.34-7.22(m,5H),7.06-6.97(m, 3H),6.78(d,J=8.6Hz,2H),6.57(d,J=9.3Hz,1H),4.46(s,1H),4.03(d,J=8.3Hz,1H),3.97-3.89(m,1H),3.73-3.62(m,2H),3.42(t,J=4.8 Hz,4H),3.28(t,J=5.2Hz,4H),3.13-2.98(m,3H),2.94-2.79(m,3H),2.78-2.65(m,2H),2.56-2.47(m,4H),2.42(s,4H),2.36-2.04(m,6H) ),2.03-1.91(m,2H),1.86-1.73(m,2H),1.61(qd,J=12.0,10.9,8.0Hz,1H),1.51-1.41(m,10H),0.96(d,J=3.3Hz,3H)ppm.LC / MS(ESI)m / z 1170.4;[M+H] + C 57 H 72 ClF3N7O8S3 + Calculated value: 1170.42.

[0225] Preparation of N-((4-(((R)-4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-((4′-chloro-4-methyl-4-(piperazin-1-ylmethyl)-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide hydrochloride (Intermediate I): HCl dioxane solution (4N, 1 mL) was added to a solution of compound I-1 (39 mg, 0.033 mmol) in DCM (1 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated to give crude Intermediate I (37 mg, quantitative yield), which was used directly in the next step. LC / MS(ESI) m / z 1070.4; [M+H] + C 52 H64 ClF3N7O6S3 + Calculated value: 1070.37.

[0226] Scheme 7: Preparation of intermediate J [ka] tert-Butyl 4-(((R)-6-((4-(4-(((4-(((R)-4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-4'-chloro Preparation of I-4-methyl-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazine-1-carboxylate (J-1): Intermediate G (91 mg, 0.16 mmol) was added to a mixture of Intermediate A (100 mg, 0.16 mmol), EDC (154 mg, 0.8 mmol), and DMAP (98 mg, 0.8 mmol) in DCM (7 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with water and saturated aqueous NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (0% to 10% MeOH in DCM) to give I-1 (157 mg, 84% yield). 1H NMR(600MHz,クロロホルム-d)δ8.35(t,J=2.2Hz,1H),8.09-8.02(m,1H),7.76 -7.71(m,2H),7.44-7.37(m,2H),7.36-7.22(m,5H),7.14-7.04(m,1H),7 .03-6.98(m,2H),6.79(d,2H),6.58(d,J=9.5,2.4Hz,1H),4.45(s,1H),4 .05-3.98(m,1H),3.98-3.90(m,1H),3.72-3.56(m,2H),3.42(t,J=4.9Hz ,4H),3.28(t,J=5.2Hz,4H),3.16-3.01(m,2H),3.01-2.92(m,1H),2.90- 2.76(m,3H),2.74-2.60(m,2H),2.57-2.46(m,4H),2.46-2.36(m,4H),2. 35-2.11(m,5H),2.10-2.01(m,1H),1.99-1.88(m,2H),1.85-1.71(m,2H) ,1.69-1.55(m,1H),1.53-1.41(m,10H),0.96(s,3H)ppm.LC / MS(ESI)m / z 1170.5;[M+H] + C 57 H 72 ClF3N7O8S3 + Calculated value: 1170.42.

[0227] Preparation of N-((4-(((R)-4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((R)-4′-chloro-4-methyl-4-(piperazin-1-ylmethyl)-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide hydrochloride (Intermediate J): HCl dioxane solution (4 N, 4 mL) was added to a solution of J-1 (100 mg, 0.086 mmol) in DCM (4 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated, and the residue was triturated with diethyl ether and then dried under vacuum to give intermediate J (103 mg, quantitative yield), which was used directly in the next step. LC / MS (ESI) m / z 1070.4; [M+H] + C 52 H 64 ClF3N7O6S3 + Calculated value: 1070.37.

[0228] Scheme 8: Preparation of intermediates K and L [ka] Preparation of N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((R)-4'-chloro-4-formyl-4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide (Intermediate K): Intermediate H (250 mg, 0.44 mmol) was added to a mixture of B-3 (200 mg, 0.44 mmol), EDC (424 mg, 2.21 mmol), and DMAP (269 mg, 2.21 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with water and saturated aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (0% to 10% MeOH in DCM) to give intermediate K (290 mg, 66% yield). 1 H NMR(600MHz,CDCl3)δ9.54(s,1H),8.37(d,J=2.3Hz,1H),8.08(dd,J=9.2,2.3Hz,1H),7.71(d,J=8.5Hz,2H), 7.39(d,J=7.3Hz,2H),7.37-7.23(m,5H),7.15(d,J=8.9Hz,1H),6.99-6.96(m,2H),6.80(d,J=8.6Hz,2H),6. 61(d,J=9.3Hz,1H),3.93(s,1H),3.82-3.66(m,4H),3.35-3.26(m,4H),3.16-2.99(m,2H),2.94-2.58(m,8H) ,2.51-2.25(m,7H),2.15-1.87(m,6H),1.86-1.72(m,1H),1.69-1.59(m,1H),1.16(s,3H)ppm.LC / MS(ESI)m / z 1002.3;[M+H] + C 48 H 56 ClF3N5O7S3 + Calculated value: 1002.30.

[0229] tert-Butyl 4-(((R)-6-((4-(4-(((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-4'-chloro-4-methyl-2,3,4,5-tetrahydro-[1, Preparation of 1'-biphenyl]-4-yl)methyl)piperazine-1-carboxylate (L-1): NaBH(OAc)3 (106 mg, 0.5 mmol) was added to a solution of intermediate K (250 mg, 0.25 mmol), 1-Boc-piperazine (231 mg, 1.25 mmol), and TEA (208 μL, 1.5 mmol) in DCM (6 mL), followed by stirring overnight at room temperature. The reaction mixture was washed with saturated aqueous NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (0% to 10% MeOH in DCM) to give L-1 (240 mg, 82% yield). 1 H NMR(600MHz,CDCl3)δ8.37(d,J=2.3Hz,1H),8.08(dd,J=9.3,2.3Hz,1H),7.71(d,2H),7.41-7.37(m,2H),7.35-7.24(m,5H) ),7.15(d,J=8.5Hz,1H),7.01(d,2H),6.81-6.76(m,2H),6.60(d,J=9.3Hz,1H),3.93(d,J=9.4Hz,1H),3.83-3.67(m,4H), 3.42(s,4H),3.35-3.24(m,4H),3.14-3.01(m,2H),2.90-2.59(m,8H),2.52(s,4H),2.45-2.35(m,4H),2.34-2.20(m,4H), 2.19-2.07(m,2H),2.01-1.88(m,4H),1.81-1.70(m,1H),1.67-1.57(m,1H),1.48(s,9H),0.96(s,3H)ppm.LC / MS(ESI)m / z 1172.5;[M+H] + C 57 H 74 ClF3N7O8S3 + Calculated value: 1172.44.

[0230] Preparation of N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((R)-4′-chloro-4-methyl-4-(piperazin-1-ylmethyl)-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide hydrochloride (Intermediate L): HCl dioxane solution (4N, 4 mL) was added to a stirred solution of L-1 (240 mg, 0.204 mmol) in DCM (4 mL). After stirring at room temperature for 2 h, the reaction mixture was concentrated. The residue was triturated with diethyl ether and dried under vacuum to give Intermediate L (227 mg, quantitative yield), which was used directly in the next step. LC / MS(ESI) m / z 1072.5; [M+H] + C 52 H 66 ClF3N7O6S3 + Calculated value: 1072.39.

[0231] Scheme 9: Preparation of intermediates M and N [ka] Preparation of 4-(4-((4'-chloro-4-formyl-4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (Intermediate M): N-1 (1.36 g, 2.45 mmol) was added to a mixture of A-3 (1.2 g, 2.65 mmol), DMAP (1.5 g, 12.27 mmol), and EDC (2.35 g, 12.27 mmol) in DCM (50 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with water and saturated aqueous NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (0% to 5% MeOH in DCM) to give intermediate M (1.9 g, 72% yield). 1H NMR(600MHz,クロロホルム-d)δ9.54(d,J=1.5Hz,1H),8.38(d,J=2.3Hz,1H),8.13(dd,J=9.3,2.4Hz,1H),7.68-7.62(m,2H),7.41-7.3 7(m,2H),7.36-7.26(m,4H),7.10(d,J=8.7Hz,1H),6.98-6.94(m,2H),6.81(d,J=8.9Hz,2H),6.63(d,J=9.5Hz,1H),3.93(s,1H), 3.71-3.61(m,6H),3.32(t,J=5.2Hz,4H),3.12(dd,J=13.9,5.1Hz,1H),3.04(dd,J=13.9,7.3Hz,1H),2.88(s,2H),2.69(d,J=17. 6Hz,1H),2.53-2.27(m,10H),2.19-2.10(m,1H),2.09-1.97(m,2H),1.74-1.59(m,2H),1.16(d,J=2.1Hz,3H)ppm.LC / MS(ESI)m / z 988.3;[M+H] + C 47 H 54 ClF3N5O7S3 + Calculated value: 988.28.

[0232] Preparation of tert-butyl 4-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazine-1-carboxylate (N-2): NaBH(OAc) (113 mg, 0.53 mmol) was added in portions to a solution of intermediate M (350 mg, 0.35 mmol), 1-Boc-piperazine (79 mg, 0.43 mmol), and TEA (246 μL, 1.77 mmol) in DCM (6 mL), followed by stirring at room temperature overnight. The reaction mixture was washed with saturated aqueous NH4Cl. The organic layer was dried over NaSO4, filtered, and concentrated. The residue was purified by flash column chromatography (0% to 10% MeOH in DCM) to give N-2 (320 mg, 81% yield). 1 H NMR (600MHz, chloroform-d) δ8.38(d,J=2.3Hz,1H),8.13(dd,J=9.2,2.3Hz,1H),7.66(d,J=8.8Hz,2H),7.42-7.38(m,2H),7.36-7.26(m,4 H),7.09(d,J=8.6Hz,1H),7.03-6.97(m,2H),6.80(d,J=9.1Hz,2H),6.63(d,J=9.4Hz,1H),3.98-3.88(m,1H),3.74-3.62(m,4H),3.42( s,4H),3.29(t,J=5.2Hz,4H),3.12(dd,J=13.9,5.1Hz,1H),3.04(dd,J=13.9,7.3Hz,1H),2.85(s,2H),2.58-2.27(m,17H),2.27-2.20 (m,2H),2.18-2.10(m,2H),1.95(d,J=17.3Hz,1H),1.75-1.66(m,1H),1.66-1.59(m,1H),1.47(s,9H),0.96(s,3H)ppm.LC / MS(ESI)m / z 1158.4;[M+H] + C 56 H 72 ClF3N7O8S3 + Calculated value: 1158.42.

[0233] Preparation of 4-(4-((4'-chloro-4-methyl-4-(piperazin-1-ylmethyl)-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide hydrochloride (Intermediate N): HCl dioxane solution (4N, 5 mL) was added to a stirred solution of N-2 (320 mg, 0.28 mmol) in DCM (5 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated. The residue was triturated with diethyl ether and dried under vacuum to give Intermediate L (305 mg, quantitative yield) as the HCl salt, which was used directly in the next step. LC / MS(ESI) m / z 1058.4; [M+H] + C 51 H 64 ClF3N7O6S3 + Calculated value: 1058.37.

[0234] Scheme 10: Preparation of intermediate P [ka] Preparation of methyl 8-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctanoate (P-1): A solution of VHL ligand (VHL-L, 1.0 g, 2.08 mmol, HCl salt) and TEA (1.45 mL, 10.4 mmol) in DCM (10 mL) was added to a solution of 8-methoxy-8-oxooctanoic acid (469 mg, 2.49 mmol) and HATU (1.2 g, 3.12 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature for 2 hours and then washed with water and saturated aqueous NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (0% to 10% MeOH in DCM) to give P-1 (820 mg, 64% yield). 1 H NMR(600MHz,CDCl3)δ8.69(s,1H),7.47(d,J=7.9Hz,1H),7.44-7.41(m,2H),7.41-7.37(m,2H),6.19(d,J=8.7Hz, 1H),5.10(p,J=7.1Hz,1H),4.74(t,J=7.9Hz,1H),4.58(d,J=8.8Hz,1H),4.55-4.50(m,1H),4.12(d,J=2.0Hz,1H) ,3.67(s,3H),3.62(dd,J=11.3,3.8Hz,1H),2.57-2.49(m,5H),2.31(t,J=7.5Hz,2H),2.21(qd,J=8.1,6.1Hz,2H) ,2.12-2.04(m,1H),1.67-1.58(m,4H),1.50(d,J=7.0Hz,3H),1.37-1.28(m,4H),1.06(s,9H)ppm.LC / MS(ESI)m / z 615.3;[M+H] + C 32 H 47 N4O6S + Calculated value: 615.32.

[0235] Preparation of 8-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctanoic acid (Intermediate P): To a solution of P-1 (820 mg, 1.33 mmol) in MeOH / THF (5 mL / 5 mL) was added a solution of LiOH·HO (168 mg, 4.0 mmol) in water (2 mL). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated to remove the organic solvent and then adjusted to pH 3–4 with 1 N aqueous HCl. The precipitate was collected by filtration, washed with water, and then dried under vacuum to give Intermediate P (730 mg, 91% yield). 1 H NMR(600MHz,DMSO)δ8.99(s,1H),8.38(d,J=7.8Hz,1H),7.79(d,J=9.3Hz,1H),7.46-7.41(m,2H),7.41-7. 36(m,2H),4.92(p,J=7.1Hz,1H),4.52(d,J=9.3Hz,1H),4.43(t,J=8.0Hz,1H),4.30-4.26(m,1H),3.65-3.5 7(m,2H),2.46(s,3H),2.27-2.21(m,1H),2.18(t,J=7.4Hz,2H),2.14-2.07(m,1H),2.05-1.98(m,1H),1.83 -1.76(m,1H),1.56-1.41(m,4H),1.38(d,J=7.0Hz,3H),1.30-1.19(m,4H),0.94(s,9H)ppm.LC / MS(ESI)m / z 601.3;[M+H] + C 31 H 45 N4O6S + Calculated value: 601.31

[0236] Scheme 11: Preparation of intermediate Q [ka] Preparation of (2S,4R)-1-((S)-2-(2-chloroacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Q-1): A solution of 2-chloroacetic acid (294 mg, 3.12 mmol), HATU (1.58 g, 4.16 mmol), VHL-L (1 g, 2.08 mmol, HCl salt), and TEA (1.74 mL, 12.47 mmol) in DCM (40 mL) was stirred at room temperature for 3 h. The reaction mixture was washed with water and saturated aqueous NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (0% to 10% MeOH in DCM) to give Q-1 (870 mg, 81% yield). 1 H NMR(600MHz,CDCl3)δ8.67(s,1H),7.43-7.39(m,2H),7.38-7.33(m,3H),7.23(d,J=8. 6Hz,1H),5.08(p,J=7.1Hz,1H),4.73(t,J=7.7Hz,1H),4.57-4.52(m,2H),4.10-4.03( m,2H),4.00(d,J=2.0Hz,1H),3.64(dd,J=11.3,4.0Hz,1H),2.76-2.71(m,1H),2.59-2 .51(m,4H),2.09-2.02(m,1H),1.49(d,J=7.0Hz,3H),1.07(s,9H)ppm.LC / MS(ESI)m / z 521.2;[M+H] + C 25 H 34 ClN4O4S + Calculated value: 521.20.

[0237] Preparation of tert-butyl 4-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)piperazine-1-carboxylate (Q-2): A solution of Q-1 (380 mg, 0.73 mmol), DIPEA (507 μL, 2.92 mmol), and tert-butyl piperazine-1-carboxylate (203 mg, 1.09 mmol) in DCM (8 mL) was stirred at room temperature for 3 days. The reaction mixture was washed with saturated aqueous NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (0% to 10% MeOH in DCM) to give Q-2 (500 mg, quantitative yield). 1 H NMR(600MHz,CDCl3)δ8.69(s,1H),7.84(d,J=8.2Hz,1H),7.47(d,J=7.8Hz,1H),7.44-7.40(m,2H),7. 40-7.36(m,2H),5.10(p,J=7.1Hz,1H),4.78(t,J=7.8Hz,1H),4.53(s,1H),4.45(d,J=8.2Hz,1H),4.21 -4.16(m,1H),3.61(dd,J=11.4,3.7Hz,1H),3.55-3.42(m,4H),3.14-3.01(m,3H),2.62-2.56(m,1H),2 .55(s,3H),2.54-2.48(m,4H),2.12-2.05(m,1H),1.53-1.46(m,12H),1.09(s,9H)ppm.LC / MS(ESI)m / z 671.3;[M+H] + C 34 H 51 N6O6S + Calculated value: 671.36.

[0238] Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(2-(piperazin-1-yl)acetamido)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (Q-3): HCl dioxane solution (4N, 5 mL) was added to a solution of Q-2 (500 mg, 0.75 mmol) in DCM (5 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated. The residue was triturated with diethyl ether and dried under vacuum to give Q-3 (570 mg, quantitative yield) as the HCl salt, which was used directly in the next step. LC / MS (ESI) m / z 571.3; [M+H] + C 29 H 43 N6O4S + Calculated value: 571.31.

[0239] Preparation of tert-butyl 2-(4-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)piperazin-1-yl)acetate (Q-4): To a solution of Q-3 (570 mg, 0.94 mmol) and DIPEA (1.31 mL, 7.51 mmol) in DCM (20 mL) was added tert-butyl 2-bromoacetate (549 mg, 2.82 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with saturated aqueous NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (0% to 10% MeOH in DCM) to give Q-4 (390 mg, 78% yield over three steps). 1H NMR(600MHz,CDCl3)δ8.70(s,1H),7.88(d,J=8.2Hz,1H),7.48(d,J=7.8Hz,1H),7.45-7.41(m ,2H),7.41-7.37(m,2H),5.10(p,J=7.1Hz,1H),4.79(t,J=7.8Hz,1H),4.53(s,1H),4.45(d,J= 8.2Hz,1H),4.23(d,J=11.4Hz,1H),3.60(dd,J=11.4,3.7Hz,1H),3.20-2.99(m,5H),2.79-2.5 7(m,9H),2.55(s,3H),2.13-2.05(m,1H),1.51-1.48(m,12H),1.09(s,9H)ppm.LC / MS(ESI)m / z 685.4;[M+H] + C 35 H 53 N6O6S + Calculated value: 685.37.

[0240] Preparation of 2-(4-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)piperazin-1-yl)acetic acid (Intermediate Q): HCl dioxane solution (4N, 10 mL) was added to a solution of Q-4 (390 mg, 0.57 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated and triturated with diethyl ether, and the precipitate was collected by filtration and dried under vacuum to give Intermediate Q (352 mg, 98% yield), which was used directly in the next step. LC / MS (ESI) m / z 629.3; [M+H] + C 31 H 45 N6O6S + Calculated value: 629.31.

[0241] Preparation of compounds in Table 1 General Procedure A Step 1: A mixture of halide ester (1.0 equiv.), 1-Boc-piperazine (1.2 equiv.), and DIPEA (3.0 equiv.) or K2CO3 (1.5 equiv.) in DMF or DMSO was heated at 50°C to 120°C overnight. The resulting mixture was cooled to room temperature, diluted with water, and then extracted with EtOAc. The combined organic layers were washed with water and saturated aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to give the corresponding ester intermediate.

[0242] Step 2: To a solution of the ester intermediate from Step 1 (1.0 equiv.) in MeOH / THF, an aqueous solution of LiOH·OH (5 equiv.) was added and then stirred at 40° C. overnight. The reaction mixture was concentrated to remove the organic solvent, then adjusted to pH=5-6 with 10% aqueous citric acid and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give the corresponding carboxylic acid intermediate.

[0243] Step 3: A solution of amine (1.0 equiv.) and DIPEA (5.0 equiv.) in DMF was added to a solution of the carboxylic acid intermediate from Step 2 (1.0 equiv.) and HATU (1.2 equiv.) in DMF. The resulting mixture was stirred at room temperature for 2 hours, then diluted with EtOAc and washed with saturated aqueous NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to give the corresponding amide intermediate.

[0244] Step 4: To a solution of the amide intermediate from step 3 in DCM was added HCl in dioxane (4N). The resulting mixture was stirred at room temperature for 1-2 hours. The reaction mixture was concentrated to give the crude piperazine intermediate as the HCl salt, which was used directly in the next step.

[0245] Step 5: A suspension of aldehyde (1.0 equiv.), piperazine intermediate from Step 4 (1.2-1.6 equiv.), TEA (20.0 equiv.), and NaBH(OAc) (2.0 equiv.) in DCE was stirred at room temperature overnight. The reaction mixture was washed with saturated aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH) to give the corresponding final product.

[0246] General Procedure B To a solution of azide (1.0 equiv.) and alkyne (1.0 equiv.) in THF / t-BuOH / HO, Vc-Na (0.05 equiv.) and CuSO (0.05 equiv.) were added, and the resulting mixture was stirred at 50° C. overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by preparative TLC (DCM / MeOH) to give the desired compound.

[0247] General Procedure C Step 1: A mixture of amine (1 equivalent), halide (1.1 equivalents), and base (2 equivalents) in DMF was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc, then washed with water and saturated aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to give the tert-butyl ester intermediate.

[0248] Step 2: To a solution of the tert-butyl ester intermediate from Step 1 (1.0 equiv.) in DCM was added HCl in dioxane (4N) and then stirred at room temperature overnight. The reaction mixture was concentrated to give the crude carboxylic acid intermediate, which was used directly in the next step.

[0249] Step 3: A solution of VHL-L (1 equivalent, HCl salt) and TEA (5 equivalents) in DCM was added to a solution of the carboxylic acid intermediate from Step 2 (1 equivalent), TEA (5 equivalents), and HATU (1.1 equivalents) in DCM. The resulting mixture was stirred at room temperature for 7 hours. The reaction mixture was washed with saturated aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to give the ethyl ester intermediate.

[0250] Step 4: To a solution of the ethyl ester intermediate from Step 3 (1.0 equiv.) in MeOH / THF, an aqueous solution of LiOH·HO (3.0-5.0 equiv.) was added, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to remove the organic solvent and then adjusted to pH 5-6 with 10% aqueous citric acid. The precipitate was collected by filtration, washed with water, and dried under vacuum to give the carboxylic acid intermediate.

[0251] Step 5: A solution of the carboxylic acid intermediate from Step 4 (1 eq.), HATU (1.1 eq.), intermediate N (1 eq., HCl salt), and TEA (10 eq.) in DMF was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH) to give the desired compound.

[0252] General Procedure D Step 1: A suspension of G-2 (1.0 equiv.), amine (1.2 equiv.), and NaBH(OAc) (2.0 equiv.) in DCM was stirred at room temperature for 3 hours. The reaction mixture was washed with saturated aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to give the Boc-amine intermediate.

[0253] Step 2: To a solution of the Boc-amine intermediate from step 1 (1.0 equiv.) in DCM was added HCl in dioxane (4N) and then stirred at room temperature for 1-2 hours. The reaction mixture was concentrated to give the corresponding amine intermediate as the HCl salt, which was used directly in the next step.

[0254] Step 3: A solution of the amine intermediate from Step 2 (1.0 equiv., HCl salt), DIPEA (8.0 equiv.), and 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide or 4-fluoro-3-nitrobenzenesulfonamide (1.0 equiv.) in DMSO was stirred at room temperature overnight. The resulting mixture was diluted with EtOAc and washed with water and saturated aqueous NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to give the sulfonamide intermediate.

[0255] Step 4: To a solution of intermediate A or B (1.0 equivalent), DMAP (5.0 equivalents), and EDC (5.0 equivalents) in DCM was added the sulfonamide intermediate from step 3 (1.0 equivalents). The resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with water and saturated aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to give the Boc-amine intermediate.

[0256] Step 5: To a solution of the Boc-amine intermediate from step 4 (1.0 equiv.) in DCM was added HCl in dioxane (4N) and then stirred at room temperature for 1-2 hours. The reaction mixture was concentrated to give the amine HCl salt intermediate, which was used directly in the next step.

[0257] Step 6: A solution of the amine HCl salt (1.0 equiv.) from Step 5 and TEA (8.0 equiv.) in DCM (or DMF) was added to a solution of intermediate P (1.2 equiv.) and HATU (1.5 equiv.) in DCM (or DMF). The resulting mixture was stirred at room temperature for 2 hours and then washed with saturated aqueous NH4Cl (or diluted with EtOAc and washed with saturated aqueous NHCl). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH) to give the desired compound.

[0258] General Procedure E Step 1: To a solution of carboxylic acid (1.0 equivalent), DMAP (5.0 equivalents), and EDC (5.0 equivalents) in DCM was added sulfonamide (1.0 equivalents). The resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with water and saturated aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to give the corresponding N-acyl-sulfonamide intermediate bearing a Boc protecting group.

[0259] Step 2: To a solution of the intermediate from step 1 (1.0 equiv.) in DCM was added HCl in dioxane (4N) and then stirred at room temperature for 1-2 hours. The reaction mixture was concentrated to give the corresponding amine-HCl salt intermediate, which was used directly in the next step.

[0260] Step 3: A solution of the amine-HCl salt intermediate from Step 2 (1.0 equiv.) and TEA (8.0 equiv.) in DCM (or DMF) was added to a solution of carboxylic acid (1.2 equiv.) and HATU (1.5 equiv.) in DCM (or DMF). The resulting mixture was stirred at room temperature for 2 hours. It was then washed with saturated aqueous NH4Cl (or diluted with EtOAc and washed with saturated aqueous NHCl). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH) to give the desired compound.

[0261] General Procedure F Step 1: A suspension of aldehyde (1.0 equiv.), amine (1.2–1.5 equiv.), TEA (3.0–5.0 equiv.), and NaBH(OAc) (2.0 equiv.) in DCM was stirred overnight at room temperature. The reaction mixture was washed with saturated aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to give the ethyl ester intermediate.

[0262] Step 2: To a solution of the ethyl ester intermediate from Step 1 (1.0 equiv.) in MeOH / THF, an aqueous solution of LiOH·HO (3.0-5.0 equiv.) was added and stirred at room temperature overnight. The reaction mixture was concentrated to remove the organic solvent and then adjusted to pH 5-6 with 10% aqueous citric acid. The precipitate was collected by filtration, washed with water, and dried under vacuum to give the corresponding carboxylic acid intermediate.

[0263] Step 3: To a solution of the carboxylic acid intermediate from Step 2 (1.0 equivalent), DMAP (5.0 equivalents), and EDC (5.0 equivalents) in DCM was added sulfonamide (1.0 equivalents). The resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with water and saturated aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to give the Boc-protected intermediate.

[0264] Step 4: To a solution of the intermediate from step 3 (1.0 equiv.) in DCM was added HCl in dioxane (4N) and then stirred at room temperature for 1-2 hours. The reaction mixture was concentrated to give the crude amine-HCl salt, which was used directly in the next step.

[0265] Step 5: A solution of the amine-HCl salt (1.0 equiv.) from Step 4 and TEA (8.0 equiv.) in DCM (or DMF) was added to a solution of the carboxylic acid (1.2 equiv.) and HATU (1.5 equiv.) in DCM (or DMF). The resulting mixture was stirred at room temperature for 2 hours and then washed with saturated aqueous NH4Cl (or diluted with EtOAc and washed with saturated aqueous NHCl). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH) to give the desired compound.

[0266] General Procedure G Step 1: A suspension of aldehyde (1.0 equiv.), amine (1.2–1.5 equiv.), TEA (3.0–5.0 equiv.), and NaBH(OAc) (2.0 equiv.) in DCM was stirred at room temperature overnight. The reaction mixture was washed with saturated aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to give the corresponding reductive amination product bearing a Boc protecting group.

[0267] Step 2: To a solution of the product from Step 1 (1.0 equiv.) in DCM was added HCl in dioxane (4N) and then stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the corresponding amine-HCl salt intermediate, which was used directly in the next step.

[0268] Step 3: A solution of the crude amine-HCl salt (1.0 equiv.) from Step 2 and TEA (8.0 equiv.) in DCM (or DMF) was added to a solution of intermediate P (1.2 equiv.) and HATU (1.5 equiv.) in DCM (or DMF). The resulting mixture was stirred at room temperature for 2 hours and then washed with saturated aqueous NH4Cl (or diluted with EtOAc and washed with saturated aqueous NHCl). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH) to give the desired compound.

[0269] General Procedure H A solution of amine (1.0 equiv., HCl salt) and TEA (8.0 equiv.) in DCM (or DMF) was added to a solution of acid (1.2 equiv.) and HATU (1.5 equiv.) in DCM (or DMF). The resulting mixture was stirred at room temperature for 2 hours and then washed with saturated aqueous NH4Cl (or diluted with EtOAc and washed with saturated aqueous NHCl). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH) to give the desired compound.

[0270] General procedure J Step 1: A solution of amine hydrochloride (1.0 equiv.), DIPEA (8.0 equiv.), and 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide or 4-fluoro-3-nitrobenzenesulfonamide (1.0 equiv.) in DMSO was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to give the sulfonamide intermediate.

[0271] Step 2: To a solution of intermediate A or B (1.0 equiv.), DMAP (5.0 equiv.), and EDC (5.0 equiv.) in DCM was added the sulfonamide intermediate from Step 1 (1.0 equiv.). The resulting mixture was stirred at room temperature overnight and then washed with water and saturated aqueous NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to give the corresponding N-acyl-sulfonamide bearing a Boc protecting group.

[0272] Step 3: To a solution of the product from step 2 (1.0 equiv.) in DCM was added HCl in dioxane (4N) and then stirred at room temperature for 1-2 hours. The reaction mixture was concentrated to give the crude amine-HCl salt intermediate, which was used directly in the next step.

[0273] Step 4: A solution of the amine-HCl salt (1.0 equiv.) from Step 3 and TEA (8.0 equiv.) in DCM (or DMF) was added to a solution of intermediate P (1.2 equiv.) and HATU (1.5 equiv.) in DCM (or DMF). The resulting mixture was stirred at room temperature for 2 hours and then washed with saturated aqueous NH4Cl (or diluted with EtOAc and washed with saturated aqueous NHCl). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH) to give the desired compound.

[0274] General Procedure K A mixture of amine (2.0 equiv.), TEA (8.0 equiv.), aldehyde (1.0 equiv.), and NaBH(OAc) (2.0 equiv.) in DCM was stirred overnight at room temperature. The reaction mixture was washed with saturated aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH) to give the desired compound. [Example]

[0275] Preparation of Compounds #1-3 [ka] Compounds #1-3 were prepared according to general procedure A.

[0276] tert-Butyl 4-(5-(methoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylate (1-1) (890 mg, 95% yield). 1 H NMR(600MHz,CDCl3)δ8.82(dd,J=2.3,0.7Hz,1H),8.06(dd,J=9.0,2.4Hz,1H),6.60(dd,J=9.0,0 .7Hz,1H),3.90(s,3H),3.74-3.67(m,4H),3.57(t,J=5.2Hz,4H),1.51(s,9H)ppm.LC / MS(ESI)m / z 322.3;[M+H] + C 16 H 24 N3O4 + Calculated value: 322.18.

[0277] 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)nicotinic acid (1-2) (266 mg, 93% yield). 1 H NMR(600MHz,DMSO)δ8.64(d,J=2.4Hz,1H),7.95(dd,J=9.1,2.4Hz,1H),6.86(d,J=9 .1Hz,1H),3.69-3.60(m,4H),3.43(t,J=5.3Hz,4H),1.43(s,9H)ppm.LC / MS(ESI)m / z 308.2;[M+H] + C 15 H 22 N3O4+ Calculated value: 308.16.

[0278] tert-Butyl 4-(5-((2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)carbamoyl)pyridin-2-yl)piperazine-1-carboxylate (1-4) (18 mg, 57% yield). 1 H NMR (600 MHz, chloroform-d): δ 8.72 (d, J = 2.5 Hz, 1H), 8.67 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.98 (dd, J = 9.0, 2.5 Hz, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.75 (t, J = 4.8 Hz, 1H), 7.36 (s, 4H), 6.57 (d, J = 9.1 Hz, 1H), 5.10 (p, J = 7.1 Hz, 1H), 4.79 (t, J = 8.4 Hz, 1H), 4.69 (d, J = 9.3 Hz, 1H), 4.46-4.35 (m,2H),4.06(dd,J=17.2,4.1Hz,1H),3.84(d,J=11.2Hz,1H),3.71-3.61(m,5H),3.58(dd,J=11.4,3.1Hz,1H),3.53(dd,J=6.7,4.0Hz,4 H),2.51(s,3H),2.24(dd,J=13.6,7.7Hz,1H),2.16(ddd,J=13.3,9.2,4.3Hz,1H),1.52(d,3H),1.49(s,9H),1.04(s,9H).LC / MS(ESI)m / z 791.4;[M+H] + C 40 H 55 N8O7S + Calculated value: 791.39

[0279] tert-Butyl 4-(5-((4-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutyl)carbamoyl)pyridin-2-yl)piperazine-1-carboxylate (2-4): (17 mg, 55% yield). LC / MS (ESI) m / z 819.3; [M+H] + C 42 H 59 N8O7S + Calculated value: 819.42.

[0280] tert-Butyl 4-(5-((6-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexyl)carbamoyl)pyridin-2-yl)piperazine-1-carboxylate (3-4): (19 mg, 61% yield). 1H NMR(600MHz,chloroform-d)δ8.68(s,1H),8.60(d,J=2.4Hz,1H),7.96(dd,J=9.0,2.5Hz,1H),7.51(d,J=7.8Hz,1H),7.40(d,J=8.3Hz,2H),7.36(d,J=8.2Hz, 2H),6.78(t,J=5.8Hz,1H),6.61(d,J=8.9Hz,1H),6.53(d,J=9.0Hz,1H),5.0 8(p,J=7.1Hz,1H),4.67(t,J=8.1Hz,1H),4.60(d,J=9.1Hz,1H),4.48(s,1H), 4.05(d,J=11.3Hz,1H),3.60(dd,J=6.7,3.9Hz,5H),3.52(dd,J=6.7,4.0Hz, 4H),3.40(qd,J=6.8,3.6Hz,2H),2.52(s,3H),2.42-2.35(m,1H),2.31-2.18( m,3H),2.13-2.06(m,1H),1.65(dq,J=14.1,7.3Hz,2H),1.58(p,J=7.0Hz,2H ),1.51-1.45(m,12H),1.37(p,J=7.7Hz,2H),1.03(s,9H)ppm.LC / MS(ESI)m / z 847.4;[M+H] + C 44 H 63 N8O7S + Calculated value: 847.45.

[0281] N-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)-6-(piperazin-1-yl)nicotinamide hydrochloride (1-5): (16 mg, quantitative yield). LC / MS (ESI) m / z 691.2; [M+H] + C 35 H 47 N8O5S + Calculated value: 691.34.

[0282] N-(4-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutyl)-6-(piperazin-1-yl)nicotinamide hydrochloride (2-5): (18 mg, quantitative yield). LC / MS (ESI) m / z 719.2; [M+H] + C 37 H 51 N8O5S + Calculated value: 719.37.

[0283] N-(6-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexyl)-6-(piperazin-1-yl)nicotinamide hydrochloride (3-5): (17 mg, quantitative yield). LC / MS (ESI) m / z 747.6; [M+H] + C 39 H 55 N8O5S + Calculated value: 747.40.

[0284] 6-(4-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)nicotinamide (Compound #1) (7.3 mg, 22% yield). 11H NMR (600 MHz, chloroform-d) δ 8.67 (s, 1H), 8.62 (d, J = 3.7 Hz, 1H), 8.33 (d, J = 2.3 Hz, 1H), 8.08 (d, J = 9.1 Hz, 1H), 7.86 (d, J = 8.9 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 33.6 Hz, 1H), 7.39 - 7.32 (m, 6H), 7.32 - 7.26 (m, 4H), 7.24 (t, J = 7.3 Hz, 1H), 7.04 - 6.96 (m, 2H), 6.75 (d, 2H), 6.59 (d, J = 9.4 Hz, 1H), 6.46 (s, 1H), 5.08 (p, J = 6.9 Hz, 1H), 4.75 (t, J = 8.3 Hz, 1H), 4.61 (s, 1H), 4.46 (s, 1H), 4.20 (d, J = 16.6 Hz, 1H), 4.14 - 4.07 (m, 1H), 3.98 (d, J = 11.2 Hz, 1H), 3.87 (s, 1H), 3.70 - 3.50 (m, 10H), 3.23 (s, 4H), 3.10 (dd, J = 13.8, 4.9 Hz, 1H), 3.01 (dd, J = 13.9, 7.1 Hz, 1H), 2.87 (q, J = 12.6, 12.2 Hz, 2H), 2.72 - 2.57 (m, 4H), 2.51 (s, 3H), 2.47 - 2.16 (m, 21H), 2.10 (t, J = 7.4 Hz, 1H), 1.90 (d, J = 17.3 Hz, 1H), 1.71 - 1.58 (m, 2H), 1.52 - 1.40 (m, 4H), 1.05 (s, 9H), 1.00 (s, 3H) ppm. LC / MS (ESI) m / z 1662.5; [M + H] + C 82 H 100 ClF3N 13 O 11 S4 + Calculated value: 1662.62.

[0285] 6-(4-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl

[0047] Compound #2) (4.7 mg, 20% yield). 1 H NMR(600MHz,chloroform-d)δ8.68(s,1H),8.57-8.51(m,1H),8.36-8.30(m,1H),8.0 9(d,J=9.2Hz,1H),7.93(t,J=9.1Hz,1H),7.73(s,2H),7.46-7.33(m,6H),7.28(s ,4H),7.03-6.96(m,2H),6.87(s,1H),6.74(d,J=8.6Hz,2H),6.59(d,J=9.2Hz,1 H),6.51(s,1H),5.09(p,J=6.9Hz,1H),4.64(dt,J=37.1,8.2Hz,1H),4.55-4.45( m,2H),4.09(d,J=11.0Hz,1H),3.88(s,1H),3.73-3.33(m,12H),3.20(s,4H),3. 10(dd,J=14.1,4.9Hz,1H),3.05-2.97(m,1H),2.84(dd,2H),2.73-2.60(m,4H),2 .51(d,J=1.2Hz,3H),2.47-2.19(m,20H),2.10(s,2H),1.92(s,4H),1.71-1.58( m,2H),1.51-1.43(m,4H),1.05(s,9H),0.99(d,J=4.6Hz,3H)ppm.LC / MS(ESI)m / z 1690.8;[M+H] + C 84 H 104 ClF3N 13 O 11 S4 +Calculated value: 1690.65.

[0286] 6-(4-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl )piperazin-1-yl)-N-(6-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexyl)nicotinamide (compound #3) (5.6 mg, 20% yield). 1H NMR(600MHz,クロロホルム-d)δ8.68(s,1H),8.59(d,J=2.1Hz,1H),8.33(d,J=2.2Hz,1H),8.09(d,J=9.2Hz, 1H),7.93(dd,J=8.8,2.4Hz,1H),7.75(s,2H),7.47(dd,J=41.3,7.8Hz,1H),7.40-7.32(m,6H),7.32- 7.21(m,5H),7.02-6.95(m,2H),6.89-6.82(m,1H),6.75(d,J=8.8Hz,2H),6.56(dd,J=31.0,16.4Hz,3 H),5.07(td,J=7.2,3.4Hz,1H),4.64(dt,J=20.8,8.2Hz,1H),4.57(dd,J=9.1,4.1Hz,1H),4.47(s,1H ),4.05(dd,J=11.3,6.2Hz,1H),3.87(s,1H),3.70-3.60(m,4H),3.60-3.49(m,5H),3.46-3.37(m,2H) ,3.21(s,4H),3.14-3.06(m,1H),3.01(dd,J=13.8,7.2Hz,1H),2.85(p,J=12.5,12.0Hz,2H),2.70-2. 57(m,4H),2.51(s,3H),2.46-2.19(m,20H),2.10(dt,J=13.7,7.4Hz,2H),1.88(d,J=17.3Hz,1H),1.7 3-1.53(m,4H),1.46(t,J=6.9Hz,3H),1.39-1.31(m,1H),1.03(s,9H),0.98(s,3H)ppm.LC / MS(ESI)m / z 1718.5;[M+H] + C 86 H 108 ClF3N 13 O 11 S4 + Calculated value: 1718.68.

Example

[0287] Preparation of compounds #4~6

change

[0288] Compounds #4-6 were prepared from 4-1 by following steps 2-5 of General Procedure A.

[0289] 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)picolinic acid (4-2) (266 mg, 93% yield). LC / MS (ESI) m / z 308.1; [M+H] + C 15 H 22 N3O4 + Calculated value: 308.16.

[0290] tert-Butyl 4-(6-((4-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate (4-4) (54 mg, 67% yield). 1 H NMR(600MHz,CDCl3)δ8.69(s,1H),8.17(d,J=2.9Hz,1H),8.03(dd,J=8.8,1.6Hz,1H),7.99(t,J=6.6Hz,1H),7.62(d,J=7.6Hz,1H), 7.43-7.37(m,4H),7.21(dd,J=8.8,2.9Hz,1H),5.11(p,J=7.1Hz,1H),4.84(t,J=8.1Hz,1H),4.54(d,J=7.9Hz,1H),4.51(s,1H),4. 24(d,J=11.5Hz,1H),3.79-3.68(m,1H),3.66-3.44(m,7H),3.31(t,J=5.2Hz,4H),2.63-2.56(m,1H),2.54(s,3H),2.36-2.24(m,2H) ),2.13(ddt,J=13.6,8.3,1.8Hz,1H),1.91(h,J=7.1Hz,2H),1.82-1.73(m,1H),1.53-1.46(m,12H),1.12(s,9H)ppm.LC / MS(ESI)m / z 819.6;[M+H] + C 42 H 59 N8O7S + Calculated value: 819.42

[0291] tert-Butyl 4-(6-((6-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate (5-4) (59 mg, 71% yield). 1H NMR(600MHz,CDCl3)δ8.69(s,1H),8.17(d,J=2.9Hz,1H),8.03(d,J=8.7Hz,1H),7.86(t,J=6.1Hz,1H),7.56(d,J=7.8Hz,1H),7.41(q,J =8.4Hz,4H),7.22(dd,J=8.8,2.9Hz,1H),6.21(d,J=8.2Hz,1H),5.11(p,J=7.1Hz,1H),4.74(t,J=7.9Hz,1H),4.57-4.50(m,2H),4.13(d d,J=11.6,2.1Hz,1H),3.66-3.57(m,5H),3.44(td,J=12.4,6.8Hz,2H),3.38-3.19(m,5H),2.54(s,3H),2.50(ddt,J=12.1,7.7,3.8Hz,1 LC / MS(ESI)m / z 847.6;[M+H] + C 44 H 63 N8O7S + Calculated value: 847.45

[0292] tert-Butyl 4-(6-((8-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate (6-4) (51 mg, 60% yield). 1H NMR(600MHz,CDCl3)δ8.69(s,1H),8.17(d,J=2.9Hz,1H),8.03(d,J=8.7Hz,1H),7.86(t,J=6.1Hz,1H),7.56(d,J=7.8Hz,1H),7.41(q,J =8.4Hz,4H),7.22(dd,J=8.8,2.9Hz,1H),6.21(d,J=8.2Hz,1H),5.11(p,J=7.1Hz,1H),4.74(t,J=7.9Hz,1H),4.57-4.50(m,2H),4.13(d d,J=11.6,2.1Hz,1H),3.66-3.57(m,5H),3.44(td,J=12.4,6.8Hz,2H),3.38-3.19(m,5H),2.54(s,3H),2.50(ddt,J=12.1,7.7,3.8Hz,1 LC / MS(ESI)m / z 875.5;[M+H] + C 46 H 67 N8O7S + Calculated value: 875.48.

[0293] N-(4-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutyl)-5-(piperazin-1-yl)picolinamide hydrochloride (4-5) (28 mg, quantitative yield). LC / MS (ESI) m / z 719.2; [M+H] + C 37 H 51 N8O5S + Calculated value: 719.37.

[0294] N-(6-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexyl)-5-(piperazin-1-yl)picolinamide hydrochloride (5-5) (37 mg, quantitative yield). LC / MS (ESI) m / z 747.3; [M+H] + C 39 H 55 N8O5S + Calculated value: 747.40.

[0295] N-(8-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctyl)-5-(piperazin-1-yl)picolinamide hydrochloride (6-5) (30 mg, quantitative yield). LC / MS (ESI) m / z 775.3; [M+H] + C 41 H 59 N8O5S + Calculated value: 775.43

[0296] 5-(4-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methicone

[0047] N-(4-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutyl)picolinamide (Compound #4) (3.1 mg, 26% yield). 11H NMR (600 MHz, CDCl3) δ 8.68 (s, 1H), 8.34 (d, J = 2.3 Hz, 1H), 8.17 - 8.10 (m, 2H), 8.00 (t, J = 7.7 Hz, 2H), 7.69 (dd, J = 8.9, 1.8 Hz, 2H), 7.49 (d, J = 7.8 Hz, 1H), 7.42 - 7.36 (m, 6H), 7.35 - 7.24 (m, 5H), 7.18 (d, J = 8.9 Hz, 2H), 7.02 - 6.97 (m, 2H), 6.78 (d, J = 8.6 Hz, 2H), 6.63 (d, J = 9.3 Hz, 1H), 5.09 (p, J = 7.1 Hz, 1H), 4.76 (t, J = 8.1 Hz, 1H), 4.57 (d, J = 8.4 Hz, 1H), 4.49 (s, 1H), 4.17 - 4.11 (m, 1H), 3.91 (s, 1H), 3.66 (d, J = 8.3 Hz, 4H), 3.61 - 3.57 (m, 1H), 3.54 - 3.46 (m, 2H), 3.36 - 3.22 (m, 8H), 3.12 (dd, J = 13.9, 5.1 Hz, 1H), 3.04 (dd, J = 13.9, 7.2 Hz, 1H), 2.85 (s, 2H), 2.79 - 2.68 (m, 4H), 2.56 - 2.17 (m, 22H), 2.12 (dd, J = 13.7, 8.2 Hz, 2H), 1.99 - 1.87 (m, 3H),​​​​​​​​​​​​​​​5-(4-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl )piperazin-1-yl)-N-(6-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexyl)picolinamide (Compound #5) (3.3 mg, 21% yield). 11H NMR (600 MHz, CDCl3) δ 8.69 (s, 1H), 8.34 (d, J = 2.3 Hz, 1H), 8.13 (dd, J = 9.0, 2.5 Hz, 2H), 7.97 (d, J = 8.8 Hz, 1H), 7.87 (t, J = 6.1 Hz, 1H), 7.70 (d, J = 8.6 Hz, 2H), 7.46 (dd, J = 8.0, 6.1 Hz, 1H), 7.43 - 7.36 (m, 6H), 7.35 - 7.23 (m, 5H), 7.18 - 7.12 (m, 1H), 7.02 - 6.98 (m, 2H), 6.78 (d, J = 8.9 Hz, 2H), 6.62 (d, J = 9.3 Hz, 1H), 6.48 (t, J = 8.3 Hz, 1H), 5.09 (p, J = 7.1 Hz, 1H), 4.73 (t, J = 8.1 Hz, 1H), 4.61 (dd, J = 9.1, 1.2 Hz, 1H), 4.49 (s, 1H), 4.08 (d, J = 11.4 Hz, 1H), 3.95 - 3.87 (m, 1H), 3.67 (tt, J = 12.1, 6.1 Hz, 4H), 3.58 (dd, J = 11.4, 3.4 Hz, 1H), 3.47 - 3.41 (m, 2H), 3.28 (dt, J = 18.4, 5.3 Hz, 8H), 3.11 (dd, J = 13.9, 5.1 Hz, 1H), 3.04 (dd, J = 13.9, 7.2 Hz, 1H), 2.85 (s, 2H), 2.74 (h, J = 6.4 Hz, 4H), 2.5 (s, 3H), 2.50 - 2.18 (m, 20H), 2.15 - 2.09 (m, 2H), 1.95 (d, J = 17.0 Hz, 1H), 1.75 - 1.58 (m, 6H), 1.49 (d, J = 6.9 Hz, 3H), 1.44 - 1.36 (m, 3H), 1.03 (s, 9H), 0.99 (s, 3H) ppm. LC / MS (ESI) m / z 1718.7; [M + H] + C 86 H 108 ClF3N 13 O 11 S4 + Calculated value: 1718.68. <(

[0298] 5-(4-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl )piperazin-1-yl)-N-(8-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctyl)picolinamide (compound #6) (3.6 mg, 29% yield). 1H NMR(600MHz, CDCl3)δ8.69(d,J=3.0Hz,1H),8.34(d,J=2.2Hz,1H),8.15-8.09(m,2H),7.97(d,J=8.8H z,1H),7.87(t,J=6.1Hz,1H),7.72(dd,J=9.1,2.1Hz,2H),7.50-7.44(m,1H),7.43-7.35(m,6H),7.35- 7.24(m,5H),7.15(d,J=9.0Hz,1H),7.02-6.97(m,2H),6.78(d,J=9.0Hz,2H),6.61(d,J=9.4Hz,1H),6 .48(t,J=8.8Hz,1H),5.09(p,J=7.1Hz,1H),4.73-4.67(m,1H),4.61(d,J=9.0Hz,1H),4.49(s,1H),4.0 7(d,J=11.4Hz,1H),3.90(s,0H),3.67(q,J=5.9Hz,4H),3.58(dd,J=11.4,3.5Hz,1H),3.47-3.40(m,3 H),3.28(dt,J=23.1,5.3Hz,8H),3.11(dd,J=13.9,5.0Hz,1H),3.03(dd,J=13.9,7.2Hz,1H),2.84(s,2 H),2.79-2.68(m,4H),2.53(d,J=4.9Hz,3H),2.48-2.18(m,18H),2.10(dd,J=13.5,8.2Hz,2H),1.95( d,J=17.8Hz,1H),1.72-1.58(m,8H),1.53-1.30(m,10H),1.04(s,9H),0.99(s,3H)ppm.LC / MS(ESI)m / z 1746.8;[M+H] + C 88 H 112 ClF3N 13 O 11 S4 + Calculated value: 1746.71.

Example

[0299] Preparation of compounds #7~9

change

[0300] Preparation of ethyl 6-(4-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)piperazin-1-yl)nicotinate (7-2): Under an argon atmosphere, to a solution of DMSO (1.22 mL, 17.14 mmol) in DCM (15 mL) was added oxalyl chloride (966 μL, 11.43 mmol) dropwise with stirring at −78° C. The resulting mixture was stirred at −78° C. for an additional 15 minutes. Then, a solution of 7-6 (1 g, 5.71 mmol) in DCM (10 mL) was added dropwise. After the addition was complete, the mixture was stirred at −78° C. for an additional 20 minutes. TEA (4.8 mL, 34.29 mmol) was added to the mixture at −78° C., and then the dry ice / acetone bath was removed. The resulting mixture was allowed to warm to room temperature and stirred for an additional 30 minutes. Water was added to the reaction mixture, which was then extracted with DCM. The combined organic layers were washed with 10% aqueous Na.sub.2S.sub.2O.sub.3 and saturated aqueous NH.sub.4Cl, dried over Na.sub.2SO.sub.4, filtered, and concentrated to give aldehyde 7-7, which was used directly in the next step.

[0301] A suspension of 7-7 (1.0 equiv.), 7-1 (1.2 equiv.), and NaBH(OAc) (2.0 equiv.) in DCM was stirred at room temperature overnight. The reaction mixture was washed with saturated aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to give 7-2 (161 mg, 76% yield). LC / MS (ESI) m / z 379.1; [M+H] + C 19 H 31 N4O4 + Calculated value: 379.23.

[0302] Preparation of 6-(4-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)piperazin-1-yl)nicotinic acid (7-3): To a solution of 7-2 (1.0 equiv.) in MeOH / THF, an aqueous solution of LiOH·HO (5 equiv.) was added and then stirred at 40° C. overnight. The reaction mixture was concentrated to remove the organic solvent, then adjusted to pH=5-6 with 10% aqueous citric acid and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to give 7-3 (135 mg, 93% yield). LC / MS (ESI) m / z 365.1; [M+H] + C 18 H 29 N4O4 + Calculated value: 365.22.

[0303] tert-Butyl(2-(4-(5-((2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)carbamoyl)pyridin-2-yl)piperazine- 1-yl)ethyl)(methyl)carbamate (7-4), tert-butyl(2-(4-(5-((4-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutan tert-butyl(2-(4-(5-((6-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl Preparation of ethyl-1-oxobutan-2-yl)amino)-6-oxohexyl)carbamoyl)pyridin-2-yl)piperazin-1-yl)ethyl)(methyl)carbamate (9-4): A solution of 1-3, 2-3, or 3-3 (1.0 equiv.) and DIPEA (5.0 equiv.) in DMF was added to a solution of 7-3 (1.0 equiv.) and HATU (1.2 equiv.) in DMF. The resulting mixture was stirred at room temperature for 2 hours, then diluted with EtOAc and washed with saturated aqueous NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to give 7-4, 8-4, and 9-4, respectively. 7-4 (24 mg, 71% yield): 1H NMR(600MHz,クロロホルム-d)δ8.75(s,1H),8.68(s,1H),8.20(s,1H),8.03-7.89(m,2H),7.75(s,1H),7.36(s,4H),6.59(d,J= 9.1Hz,1H),5.11(p,J=7.0Hz,1H),4.80(t,J=8.4Hz,1H),4.69(d,J=9.4Hz,1H),4.48-4.36(m,2H),4.03(dd,J=17.3,3.9 Hz,1H),3.76(d,J=11.1Hz,1H),3.69-3.59(m,6H),3.53(d,J=10.7Hz,1H),3.43-3.32(m,2H),2.89(s,3H),2.68-2.53(m ,5H),2.52(s,3H),2.25(dd,J=13.4,7.7Hz,1H),2.18-2.11(m,1H),1.48-1.37(m,12H),1.04(s,9H)ppm.LC / MS(ESI)m / z 848.5;[M+H] + C 43 H 62 N9O7S + Calculated value: 848.45. 8-4 (17.8 mg, yield 53%): 1 H NMR(600MHz,クロロホルム-d)δ8.68(s,1H),8.57(d,J=2.4Hz,1H),7.94(dd,J=8.9,2.5Hz,1H),7.52(s,1H),7.46(d,J=7.8Hz,1H),7. 41-7.33(m,4H),7.05(d,J=8.3Hz,1H),6.62(d,J=9.0Hz,1H),5.08(p,J=7.1Hz,1H),4.66(t,J=8.2Hz,1H),4.53(d,J=8.4Hz,1H ),4.50(p,J=2.0Hz,1H),4.06(d,J=11.1Hz,1H),3.68-3.56(m,5H),3.49-3.32(m,3H),2.95-2.84(m,4H),2.64-2.47(m,10H),2 .43-2.27(m,3H),2.13(ddt,J=13.6,7.9,1.9Hz,1H),1.89(p,J=6.7Hz,2H),1.52-1.42(m,12H),1.05(s,9H)ppm.LC / MS(ESI)m / z 876.3;[M+H] + C 45 H66 N9O7S + Calculated value: 876.48. 9-4 (19.7 mg, yield 61%): 1 H NMR(600MHz,クロロホルム-d)δ8.67(s,1H),8.61(d,J=2.4Hz,1H),7.96(dd,J=9.0,2.5Hz,1H),7.55(d,J=7.8Hz,1H),7.42-7.33(m,4H),6 .63(d,J=9.0Hz,1H),6.58(d,J=9.1Hz,1H),5.07(p,J=7.0Hz,1H),4.66(t,J=8.1Hz,1H),4.60(d,J=9.1Hz,2H),4.51-4.44(m,1H),4 .02(d,J=11.3Hz,1H),3.86-3.49(m,10H),3.39(q,J=6.6Hz,2H),2.90(s,3H),2.76-2.63(m,2H),2.52(s,3H),2.38-2.30(m,1H),2. 30-2.19(m,2H),2.14-2.06(m,1H),1.69-1.55(m,4H),1.45(s,9H),1.41(d,3H),1.40-1.33(m,2H),1.02(s,9H)ppm.LC / MS(ESI)m / z 904.6;[M+H] + C 47 H 70 N9O7S + Calculated value: 904.51.

[0304] N-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)-6-(4-(2-(methylamino)ethyl)piperazin-1-yl)nicotinamide hydrochloride (7-5), N-(4-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxoethyl)-6-(4-(2-(methylamino)ethyl)piperazin-1-yl)nicotinamide hydrochloride (7-6), Preparation of N-(6-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexyl)-6-(4-(2-(methylamino)ethyl)piperazin-1-yl)nicotinamide hydrochloride (9-5): To a solution of 7-4, 8-4, or 9-4 in DCM, HCl in dioxane (4N) was added and then stirred at room temperature for 1-2 hours. The reaction mixture was concentrated to give 7-5, 8-5, and 9-5, respectively, as HCl salts, which were used directly in the next step. 7-5 (15 mg, quantitative yield): LC / MS (ESI) m / z 748.4; [M+H] + C 38 H 54 N9O5S + Calculated for: 748.40. 8-5 (18 mg, quantitative yield): LC / MS (ESI) m / z 776.3; [M+H] + C 40 H 58 N9O5S + Calculated for: 776.43. 9-5 (17 mg, quantitative yield): LC / MS (ESI) m / z 804.4; [M+H] + C 42 H 62 N9O5S + Calculated value: 804.46.

[0305] 6-(4-(2-(((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)ethyl)piperazin-1-yl)-N-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4- (4-Methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)nicotinamide (Compound #7), 6-(4-(2-(((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrafluoromethyl- thiazol-5-yl)phenyl)ethyl)piperazin-1-yl)-N-(4-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutyl)nicotinamide (Compound #8) and 6-(4-(2-(((4'-chloro-4-methyl-6-((4-(4-(((4-((R)-4- morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)ethyl)piperazin-1-yl)-N-(6-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,Preparation of 3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexyl)nicotinamide (Compound #9): A suspension of Intermediate M (1.0 equiv.), 7-5 / 8-5 / 9-5 (1.2-1.6 equiv.), TEA (20.0 equiv.), and NaBH(OAc) (2.0 equiv.) in DCE was stirred overnight at room temperature. The reaction mixture was washed with saturated aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH) to give the desired compound. Compound #7 (3.1 mg, 18% yield): 1 H NMR(600MHz,CDCl3)δ8.67(s,1H),8.54(s,1H),8.33(d,J=2.3Hz,1H),8.05 (d,J=9.2Hz,1H),7.84-7.70(m,3H),7.40-7.31(m,6H),7.31-7.20(m,5H),7 .01-6.96(m,2H),6.70(d,J=8.5Hz,2H),6.58(d,J=9.3Hz,1H),6.30(s,1H) ,5.06(q,J=6.9Hz,1H),4.71(s,1H),4.56(s,1H),4.47(s,1H),4.21-3.99(m ,3H),3.86(s,1H),3.68-3.60(m,6H),3.53(s,4H),3.13(d,J=53.8Hz,5H), 3.01(dd,J=13.8,7.2Hz,1H),2.83(s,2H),2.71(s,2H),2.59(s,6H),2.51(s ,3H),2.47-2.19(m,22H),2.18-2.07(m,2H),1.98(d,J=17.4Hz,1H),1.68-1 .54(m,3H),1.47-1.35(m,4H),1.05(s,9H),0.96(s,3H)ppm.LC / MS(ESI)m / z 1719.8;[M+H] + C 85 H 107 ClF3N 14 O 11 S4 + Calculated value: 1719.68.

[0306] Compound #8 (4.8 mg, 27% yield): 1H NMR (600MHz, CDCl3) δ8.67(s,1H),8.51(s,1H),8.33(s,1H),8.05(d,J=9.2Hz,1H),7.82( d,J=9.2Hz,1H),7.77(d,J=8.3Hz,2H),7.51-7.33(m,7H),7.32-7.20(m,4H),7.01-6.97(m ,2H),6.70(d,J=8.6Hz,2H),6.57(d,J=9.3Hz,1H),6.32(s,1H),5.08(p,J=7.3Hz,1H),4. 66(q,J=8.1Hz,1H),4.50(s,2H),4.08(d,J=11.4Hz,1H),3.86(s,1H),3.69-3.56(m,5H),3 .55-3.42(m,5H),3.39(s,1H),3.17(d,J=5.0Hz,4H),3.10(dd,J=13.9,4.8Hz,1H),3.00( dd,J=13.8,7.2Hz,1H),2.84(t,J=13.0Hz,2H),2.70(d,J=7.5Hz,2H),2.58(d,J=8.1Hz,6H ),2.52(s,4H),2.48-2.20(m,22H),2.16-2.07(m,3H),2.01-1.88(m,2H),1.84-1.55(m,4H ),1.48(dd,J=12.5,6.9Hz,3H),1.39(s,1H),1.05(s,9H),0.96(s,3H)ppm.LC / MS(ESI)m / z 1747.9;[M+H] + C 87 H 111 ClF3N 14 O 11 S4 + Calculated value: 1747.71.

[0307] Compound #9 (4.1 mg, yield 23%): 11H NMR (600 MHz, CDCl3) δ 8.68 (s, 1H), 8.54 (s, 1H), 8.34 (d, J = 2.1 Hz, 1H), 8.07 (d, J = 9.1 Hz, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 6.9 Hz, 1H), 7.42 - 7.33 (m, 6H), 7.33 - 7.22 (m, 5H), 7.00 (d, J = 8.2 Hz, 2H), 6.71 (d, J = 8.6 Hz, 2H), 6.57 (dd, J = 24.8, 9.0 Hz, 2H), 6.36 (s, 1H), 5.07 (p, J = 7.1 Hz, 1H), 4.66 (q, J = 7.9 Hz, 1H), 4.57 (d, J = 8.6 Hz, 1H), 4.47 (s, 1H), 4.05 (d, J = 11.3 Hz, 1H), 3.88 (s, 1H), 3.66 (s, 5H), 3.57 (dd, J = 11.3, 3.3 Hz, 1H), 3.50 (s, 4H), 3.45 - 3.39 (m, 2H), 3.19 (s, 4H), 3.11 (dd, J = 13.9, 4.9 Hz, 1H), 3.01 (dd, J = 13.8, 7.3 Hz, 1H), 2.85 (s, 2H), 2.71 (s, 2H), 2.58 (s, 6H), 2.52 (s, 3H), 2.46 - 2.17 (m, 22H), 2.11 (d, J = 10.4 Hz, 2H), 1.98 (s, 1H), 1.74 - 1.43 (m, 10H), 1.39 (q, J = 7.6 Hz, 2H), 1.03 (s, 9H), 0.97 (s, 3H) ppm. LC / MS (ESI) m / z 1775.5; [M + H] + C 89 H 115 ClF3N 14 O 11 S4 + Calculated value: 1775.74.

Example

[0308] Preparation of Compounds #10 - 12

Chem.

[0309] tert-Butyl 4-(4-(ethoxycarbonyl)phenyl)piperazine-1-carboxylate (10-2) (580 mg, 58% yield). 1 H NMR(600MHz,CDCl3)δ8.00-7.92(m,2H),6.91-6.84(m,2H),4.35(q,J=7.1Hz,2H),3.6 0(t,4H),3.32(t,J=5.1Hz,4H),1.51(s,9H),1.39(t,J=7.1Hz,3H)ppm.LC / MS(ESI)m / z 335.3;[M+H] + C 18 H 27 N2O4 + Calculated value: 335.20.

[0310] 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid (10-3) (250 mg, 91% yield). 1 H NMR(600MHz,DMSO)δ7.82-7.74(m,2H),7.00-6.93(m,2H),3.46(t,J=5.2Hz,4H),3.29(t,4H),1.43(s,9H)ppm.LC / MS(ESI)m / z 307.2;[M+H] + C 16 H 23 N2O4 + Calculated value: 307.17.

[0311] tert-Butyl 4-(4-((2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)carbamoyl)phenyl)piperazine-1-carboxylate (10-4) (23 mg, 74% yield). 1H NMR(600MHz,CDCl3)δ8.68(s,1H),8.06(s,1H),7.96-7.89(m,1H),7.85(d,J=8.4Hz,2H),7.60(s,1H),7.39-7.33(m,4H) ,6.87(d,J=8.6Hz,2H),5.11(p,J=7.1Hz,1H),4.81(t,J=8.5Hz,1H),4.66(d,J=8.9Hz,1H),4.46(d,J=17.0Hz,1H),4.38 (s,1H),3.96(d,J=17.0Hz,1H),3.58(t,J=5.3Hz,4H),3.50(d,J=11.0Hz,1H),3.26(t,J=5.3Hz,4H),2.52(s,3H),2.27( dd,J=13.5,7.6Hz,1H),2.15(t,J=10.8Hz,1H),1.50(s,9H),1.44(dd,J=7.0,3.4Hz,3H),1.05(s,9H)ppm.LC / MS(ESI)m / z 790.3;[M+H] + C 41 H 56 N7O7S + Calculated value: 790.40.

[0312] tert-Butyl 4-(4-((4-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutyl)carbamoyl)phenyl)piperazine-1-carboxylate (11-4) (25 mg, 81% yield). 1H NMR(600MHz,CDCl3)δ8.68(s,1H),7.74-7.71(m,2H),7.47(d,J=7.8Hz,1H),7.42-7.34(m,4H),7.12(d,J=8.5Hz,1H), 6.92(t,J=5.8Hz,1H),6.89-6.86(m,2H),5.08(p,J=7.1Hz,1H),4.69(t,J=8.0Hz,1H),4.54(d,J=8.6Hz,1H),4.48(s, 1H),4.05(dt,J=11.6,1.8Hz,1H),3.63-3.54(m,5H),3.48-3.39(m,2H),3.24(t,J=5.2Hz,4H),2.52(s,3H),2.45-2.3 8(m,1H),2.37-2.28(m,2H),2.16-2.07(m,2H),1.98-1.84(m,2H),1.52-1.46(m,12H),1.05(s,9H)ppm.LC / MS(ESI)m / z 818.4;[M+H] + C 43 H 60 N7O7S + Calculated value: 818.43.

[0313] tert-Butyl 4-(4-((6-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexyl)carbamoyl)phenyl)piperazine-1-carboxylate (12-4) (20 mg, 66% yield). 1H NMR(600MHz,CDCl3)δ8.68(s,1H),7.72-7.67(m,2H),7.44(d,J=7.8Hz,1H),7.40(d,J=8.3Hz,2H),7.36(d,J=8.3Hz,2H),6.90-6.84(m,2H),6.56 (d,J=9.1Hz,1H),6.50(t,J=5.8Hz,1H),5.08(q,J=7.1Hz,1H),4.66(t,J=8.1Hz,1H),4.59(d,J=9.2Hz,1H),4.47(d,J=4.1Hz,1H),4.03(d,J=11). 2Hz,1H),3.57(q,J=4.2Hz,5H),3.40(qd,J=7.0,2.4Hz,2H),3.24(t,J=5 .2Hz,4H),2.53(s,3H),2.40-2.34(m,1H),2.29-2.18(m,2H),2.16(s,1H) ),2.12-2.05(m,1H),1.70-1.62(m,2H),1.58(p,J=7.3Hz,2H),1.51-1.45(m,12H),1.37(qt,J=10.2,4.6Hz,2H),1.03(s,9H)ppm.LC / MS(ESI)m / z 846.5;[M+H] + C 45 H 64 N7O7S + Calculated value: 846.46.

[0314] (2S,4R)-1-((S)-3,3-dimethyl-2-(2-(4-(piperazin-1-yl)benzamido)acetamido)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (10-5) (18 mg, quantitative yield). LC / MS (ESI) m / z 690.5; [M+H] + C 36 H 48 N7O5S + Calculated value: 690.34.

[0315] (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(4-(piperazin-1-yl)benzamido)butanamido)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (11-5) (21 mg, quantitative yield). LC / MS (ESI) m / z 718.3; [M+H] + C 38 H 52 N7O5S + Calculated value: 718.37.

[0316] (2S,4R)-1-((S)-3,3-dimethyl-2-(6-(4-(piperazin-1-yl)benzamido)hexanamido)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (12-5) (20 mg, quantitative yield). LC / MS (ESI) m / z 746.5; [M+H] + C 40 H 56 N7O5S + Calculated value: 746.41.

[0317] (2S,4R)-1-((2S)-2-(2-(4-(4-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazin-1-yl)benzamido)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound #10) (5.4 mg, 16% yield). 1H NMR(600MHz,CDCl3)δ8.68(d,J=6.6Hz,1H),8.34(s,1H),8.08(s,1H),7.74(d ,J=18.7Hz,2H),7.71-7.61(m,3H),7.36(h,J=6.2Hz,7H),7.29(d,J=8.5Hz,4 H),7.03-6.96(m,2H),6.80-6.68(m,3H),6.59(d,J=9.2Hz,1H),5.10(q,J=6. 9Hz,1H),4.79(t,J=8.1Hz,1H),4.61(d,J=11.0Hz,1H),4.48(s,1H),4.17(s,2 H),4.03(s,1H),3.88(s,1H),3.70-3.59(m,6H),3.22(s,9H),3.12-3.08(m,1 H),3.01(dd,J=13.8,7.2Hz,1H),2.90-2.79(m,2H),2.77-2.65(m,4H),2.52( s,3H),2.49-2.16(m,20H),2.10(d,J=9.0Hz,1H),1.88(s,1H),1.71-1.59(m, 2H),1.52-1.30(m,4H),1.06(s,9H),0.98(d,J=2.1Hz,3H)ppm.LC / MS(ESI)m / z 1661.5;[M+H] + C 83 H 101 ClF3N 12 O 11 S4 + Calculated value: 1661.62.

[0318] (2S,4R)-1-((2S)-2-(4-(4-(4-((4'-chloro-4-methyl-6-((4-(4-((4-((4-((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazin-1-yl)benzamido)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound #11) (3.6 mg, 11% yield).1 1H NMR (600 MHz, CDCl3) δ 8.68 (s, 1H), 8.34 (d, J = 2.3 Hz, 1H), 8.12 (d, J = 9.3 Hz, 1H), 7.75 - 7.64 (m, 4H), 7.48 - 7.34 (m, 7H), 7.34 - 7.23 (m, 4H), 7.08 - 6.96 (m, 3H), 6.85 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 8.7 Hz, 2H), 6.62 (d, J = 9.4 Hz, 1H), 5.08 (p, J = 7.1 Hz, 1H), 4.74 - 4.66 (m, 1H), 4.54 (d, J = 8.1 Hz, 1H), 4.48 (s, 1H), 4.06 (d, J = 11.3 Hz, 1H), 3.90 (s, 1H), 3.72 - 3.62 (m, 5H), 3.62 - 3.56 (m, 1H), 3.50 - 3.42 (m, 3H), 3.25 (s, 8H), 3.11 (dd, J = 14.0, 5.0 Hz, 1H), 3.03 (dd, J = 13.9, 7.2 Hz, 1H), 2.85 (s, 2H), 2.77 - 2.65 (m, 4H), 2.52 (s, 3H), 2.50 - 2.21 (m, 20H), 2.10 (dd, J = 13.7, 8.4 Hz, 2H),​​​​​​​​​​​​​​​(2S,4R)-1-((2S)-2-(6-(4-(4-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazin-1-yl)benzamido)hexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound #12) (4.1 mg, 12% yield). 1 H NMR(600MHz,CDCl3)δ8.68(s,1H),8.38-8.31(m,1H),8.10(d,J=9.1Hz,1H),7.75(d,J=8.4H) z,2H),7.67(d,J=8.5Hz,2H),7.43-7.34(m,7H),7.34-7.22(m,4H),7.03-6.96(m,2H),6.81( d,J=8.4Hz,2H),6.75(d,J=8.6Hz,2H),6.59(d,J=9.3Hz,1H),6.53(d,J=8.8Hz,1H),5.07(p ,J=7.0Hz,1H),4.66(t,J=8.2Hz,1H),4.57(d,J=8.9Hz,1H),4.46(s,1H),4.05(d,J=11.6Hz, 1H),3.88(s,1H),3.66(q,J=6.3Hz,5H),3.55(dd,J=10.0,5.6Hz,1H),3.46-3.38(m,2H),3. 22(d,J=5.1Hz,7H),3.11(dd,J=13.8,4.9Hz,1H),3.02(dd,J=13.9,7.2Hz,1H),2.85(p,J=12 .3Hz,2H),2.71(dq,J=11.6,5.7Hz,4H),2.52(s,3H),2.48-2.21(m,22H),2.11(d,J=9.4Hz,2 H),1.88(d,J=17.3Hz,1H),1.78-1.31(m,12H),1.02(s,9H),0.98(s,3H)ppm.LC / MS(ESI)m / z 1717.4;[M+H] + C 87 H109 ClF3N 12 O 11 S4 + Calculated value: 1717.69. [Example]

[0320] Preparation of compounds #13-15 [ka] Compounds #13-15 were prepared following a procedure similar to the preparation of compounds #7-9.

[0321] Ethyl 4-(piperazin-1-yl)benzoate (13-1) (306 mg, quantitative yield). LC / MS (ESI) m / z 235.2; [M+H] + C 13 H 19 N2O2 + Calculated value: 235.14.

[0322] Ethyl 4-(4-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)piperazin-1-yl)benzoate (13-2) (296 mg, 66% yield). LC / MS (ESI) m / z 392.4; [M+H] + C 21 H 34 N3O4 + Calculated value: 392.25.

[0323] 4-(4-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)piperazin-1-yl)benzoic acid (13-3) (180 mg, 97% yield). 1 H NMR(600MHz,DMSO)δ7.79-7.72(m,2H),7.01-6.92(m,2H),3.42-3.24(m,6H),2.80(d,J=1 1.1Hz,3H),2.55(q,J=7.5Hz,4H),2.45(d,J=6.5Hz,2H),1.40(s,9H)ppm.LC / MS(ESI)m / z 364.3;[M+H] + C 19 H 30 N3O4 +Calculated value: 364.22.

[0324] tert-Butyl (2-(4-(4-((2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)carbamoyl)phenyl)piperazin-1-yl)ethyl)(methyl)carbamate (13-4) (25.2 mg, 72% yield). 1 H NMR(600MHz,CDCl3)δ8.67(s,1H),8.16(d,J=7.8Hz,1H),7.93(d,J=9.0Hz,1H),7.81(s,2H),7.73(s,1H),7.39-7.31(m,4 H),6.84(s,2H),5.09(p,J=7.0Hz,1H),4.81(t,J=8.4Hz,1H),4.70(d,J=9.3Hz,1H),4.41(d,J=17.7Hz,2H),4.04(dd,J=17 .3,4.0Hz,1H),3.84-3.73(m,1H),3.57-3.44(m,2H),3.43-3.27(m,5H),2.90(s,3H),2.83(s,2H),2.70(s,2H),2.63-2.55 (m,1H),2.50(s,3H),2.26(dd,J=13.4,7.6Hz,1H),2.18-2.08(m,1H),1.48-1.39(m,12H),1.03(s,9H)ppm.LC / MS(ESI)m / z 847.5;[M+H] + C 44 H 63 N8O7S + Calculated value: 847.45.

[0325] tert-Butyl (2-(4-(4-((4-(((S)-3,3-dimethyl-1-((2S,4R)-4-methyl-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-1-oxobutan-2-yl)amino)-4-oxobutyl)carbamoyl)phenyl)piperazin-1-yl)ethyl)(methyl)carbamate (14-4) (27.7 mg, 77% yield).1 H NMR(600MHz,CDCl3)δ8.69(s,1H),8.55(d,J=4.3Hz,1H),8.22(d,J=8.4Hz,1H),7.74-7.63(m,2H),7.54(s,1H) ,7.38(q,4H),7.30-7.24(m,1H),6.80(s,2H),5.08(p,J=7.0Hz,1H),4.71(t,J=8.0Hz,1H),4.57(d,J=7.6Hz,1H ),4.50(s,1H),4.03(d,J=11.2Hz,1H),3.65-3.31(m,8H),3.10(s,2H),3.05-2.72(m,6H),2.52(s,3H),2.48-2. 20(m,4H),2.12(dd,J=13.5,8.3Hz,1H),1.93-1.83(m,2H),1.53-1.41(m,12H),1.05(s,9H)ppm.LC / MS(ESI)m / z 875.5;[M+H] + C 46 H 67 N8O7S + Calculated value: 875.48.

[0326] tert-Butyl (2-(4-(4-((6-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexyl)carbamoyl)phenyl)piperazin-1-yl)ethyl)(methyl)carbamate (15-4) (25.7 mg, 69% yield). 1H NMR(600MHz,CDCl3)δ8.68(s,1H),7.69(d,J=8.5Hz,2H),7.45(d,J=7.8Hz,1H),7.42-7.34(m,4H),6.86(d,J=8.5Hz,2H),6.56(d,J=9.1Hz, 1H),6.50(t,J=5.8Hz,1H),5.08(p,J=7.1Hz,1H),4.68(t,J=8.1Hz,1H),4.60(d,J=9.1Hz,1H),4.47(d,1H),4.03(d,J=1.8Hz,1H),3.57(dd ,J=11.3,3.5Hz,1H),3.46-3.31(m,4H),3.27(t,J=5.1Hz,4H),2.89(s,3H),2.65(s,4H),2.61-2.51(m,5H),2.41-2.34(m,1H),2.32-2.16( LC / MS(ESI)m / z 903.5;[M+H] + C 48 H 71 N8O7S + Calculated value: 903.52.

[0327] (2S,4R)-1-((S)-3,3-dimethyl-2-(2-(4-(4-(2-(methylamino)ethyl)piperazin-1-yl)benzamido)acetamido)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (13-5) (22 mg, quantitative yield). LC / MS (ESI) m / z 747.5; [M+H] + C 39 H 55 N8O5S + Calculated value: 747.40.

[0328] (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(4-(4-(2-(methylamino)ethyl)piperazin-1-yl)benzamido)butanamido)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (14-5) (18 mg, quantitative yield). LC / MS (ESI) m / z 775.3; [M+H] + C 41 H 59 N8O5S + Calculated value: 775.43.

[0329] (2S,4R)-1-((S)-3,3-dimethyl-2-(6-(4-(4-(2-(methylamino)ethyl)piperazin-1-yl)benzamido)hexanamido)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (15-5) (19 mg, quantitative yield). LC / MS (ESI) m / z 803.5; [M+H] + C 43 H 63 N8O5S + Calculated value: 803.46.

[0330] (2S,4R)-1-((2S)-2-(2-(4-(4-(2-((4'-chloro-4-methyl-6-((4-(4-((4-((4-((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)ethyl)piperazin-1-yl)benzamido)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound #13) (5.5 mg, 32% yield). 11H NMR (600 MHz, CDCl3) δ 8.67 (d, J = 1.0 Hz, 1H), 8.34 (d, J = 2.2 Hz, 1H), 8.08 (d, J = 9.1 Hz, 1H), 7.81 - 7.74 (m, 2H), 7.64 (dd, J = 8.9, 3.6 Hz, 2H), 7.40 - 7.32 (m, 7H), 7.32 - 7.26 (m, 4H), 7.26 - 7.22 (m, 1H), 7.00 (d, J = 8.1 Hz, 2H), 6.71 - 6.62 (m, 3H), 6.60 (d, J = 9.4 Hz, 1H), 5.10 - 5.02 (m, 1H), 4.73 (td, J = 8.1, 3.8 Hz, 1H), 4.61 (s, 1H), 4.47 (s, 1H), 4.16 (s, 2H), 4.03 (d, J = 11.3 Hz, 1H), 3.88 (s, 1H), 3.73 - 3.58 (m, 5H), 3.19 (s, 8H), 3.10 (dd, J = 13.6, 4.7 Hz, 1H), 3.01 (dd, J = 13.8, 7.2 Hz, 1H), 2.94 - 2.77 (m, 3H), 2.70 (s, 6H), 2.57 - 2.21 (m, 25H), 2.20 - 2.01 (m, 3H), 1.70 - 1.50 (m, 4H), 1.44 (t, J = 6.6 Hz, 3H), 1.34 - 1.19 (m, 1H), 1.06 (s, 9H), 1.00 (s, 3H) ppm. LC / MS (ESI) m / z 1718.8; [M + H] + C 86 H 108 ClF3N 13 O 11 S4 + Calculated value: 1718.68.

[0331] (2S,4R)-1-((2S)-2-(4-(4-(4-(2-((4'-chloro-4-methyl-6-((4-(4-((4-((4-((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)ethyl)piperazin-1-yl)benzamido)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound #14) (4.9 mg, 28% yield). 1 H NMR(600MHz,CDCl3)δ8.68(s,1H),8.34(d,J=2.5Hz,1H),8.10-8.05(m,1H),7.78- 7.73(m,2H),7.63(d,J=8.4Hz,2H),7.41-7.32(m,7H),7.33-7.22(m,5H),7.01-6.9 8(m,2H),6.69(dd,J=9.0,5.7Hz,4H),6.59(d,J=9.3Hz,1H),5.07(td,J=6.7,3.0Hz ,1H),4.68(td,J=8.1,3.9Hz,1H),4.53(t,J=4.3Hz,1H),4.48(s,1H),4.05(d,J=11 .3Hz,1H),3.88(s,1H),3.71-3.56(m,5H),3.51-3.42(m,3H),3.24-3.14(m,8H),3 .11(dd,J=13.8,4.9Hz,1H),3.01(dd,J=13.9,7.3Hz,1H),2.84(s,2H),2.79-2.59( m,8H),2.52(s,3H),2.48-2.19(m,22H),2.12(d,J=10.6Hz,2H),2.03-1.96(m,1H), 1.96-1.88(m,2H),1.76-1.27(m,6H),1.05(s,9H),0.98(s,3H)ppm.LC / MS(ESI)m / z 1746.6;[M+H] + C 88 H 112 ClF3N 13 O 11 S4+ Calculated value: 1746.71.

[0332] (2S,4R)-1-((2S)-2-(6-(4-(4-(2-((4'-chloro-4-methyl-6-((4-(4-((4-((4-((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)(methyl)amino)ethyl)piperazin-1-yl)benzamido)hexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound #15) (6.6 mg, 37% yield). 1H NMR(600MHz, CDCl3)δ8.68(s,1H),8.37-8.32(m,1H),8.06-8.00(m,1H),7.83(d,J=8.5Hz,2H),7. 68(d,J=8.4Hz,2H),7.45(d,J=8.0Hz,1H),7.41-7.33(m,6H),7.28(t,J=7.6Hz,4H),7.23(t,J=7.3 Hz,1H),7.01(dd,J=8.4,2.2Hz,2H),6.93-6.79(m,1H),6.71(dd,J=23.6,8.5Hz,4H),6.59(d,J=9. 0Hz,1H),6.55(d,J=9.3Hz,1H),5.07(p,J=7.1Hz,1H),4.67(t,J=8.1Hz,1H),4.60(d,J=9.1Hz,1H) ,4.47(s,1H),4.04(d,J=11.3Hz,1H),3.85(s,1H),3.71-3.61(m,5H),3.57(dd,J=11.5,3.4Hz,1H) ,3.42(d,J=12.0Hz,2H),3.21(t,J=5.2Hz,8H),3.12(q,J=7.3Hz,1H),2.99(dd,J=13.8,7.3Hz,1H) ,2.96-2.83(m,3H),2.71(s,5H),2.58-2.19(m,25H),2.10(dd,J=13.6,8.0Hz,2H),1.71-1.57(m,5 H),1.54(t,J=7.4Hz,1H),1.47(dd,J=10.3,6.8Hz,7H),1.02(d,J=4.4Hz,12H)ppm.LC / MS(ESI)m / z 1774.6;[M+H] + C 90 H 116 ClF3N 13 O 11 S4 + Calculated value: 1774.74.

Example

[0333] Preparation of Compound #16

change

[0334] Preparation of ethyl 2-(4-(piperazin-1-ylmethyl)piperidin-1-yl)acetate hydrochloride (16-2): To a solution of 16-1 in DCM was added HCl in dioxane (4N), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated to give 16-2 as the HCl salt (16 mg, quantitative yield), which was used directly in the next step. LC / MS (ESI) m / z 270.3; [M+H] + C 14 H 28 N3O2 + Calculated value: 270.22.

[0335] Preparation of ethyl 2-(4-((4-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)acetate (16-3): A suspension of 16-2 (1.2 equiv., HCl salt), TEA (10.0 equiv.), Intermediate M (1.0 equiv.), and NaBH(OAc) (2.0 equiv.) in DCM was stirred at room temperature overnight. The reaction mixture was washed with saturated aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to give 16-3 (17 mg, 39% yield). 1 H NMR(600MHz,CDCl3)δ8.34(d,J=2.2Hz,1H),8.01(dd,J=9.1,2.2Hz,1H),7.88(d,J=8.7Hz,2H),7.41-7.36(m,2H),7.34-7.23(m,5H),7.02-6.97( m,2H),6.84(d,J=8.5Hz,1H),6.75(d,J=8.6Hz,2H),6.51(d,J=9.3Hz,1H ),4.19(q,J=7.1Hz,2H),3.84(dt,J=8.4,4.1Hz,1H),3.66(qp,J=6.2,3. 4Hz,5H),3.21(s,3H),3.10(dd,J=13.8,4.8Hz,1H),3.04-2.93(m,3H),2 .84(s,2H),2.60(d,J=45.4Hz,8H),2.49-2.18(m,22H),2.17-2.10(m,1H ),2.07-1.97(m,1H),1.77-1.61(m,4H),1.55(s,1H),1.51-1.46(m,1H), 1.43-1.36(m,1H),1.28(t,J=7.1Hz,3H),1.00(s,3H)ppm.LC / MS(ESI)m / z 1241.4;[M+H] + C 61 H 81 ClF3N8O8S3 + Calculated value: 1241.50.

[0336] Preparation of 2-(4-((4-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)acetic acid (16-4): To a solution of methyl 16-3 (1.0 equiv.) in MeOH / THF, an aqueous solution of LiOH·HO (5 equiv.) was added and stirred at 40 °C overnight. The reaction mixture was concentrated to remove organic solvents, then adjusted to pH = 5-6 with 10% aqueous citric acid and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 16-4 (8 mg, 82% yield), which was used directly in the next step. LC / MS (ESI) m / z 1213.5; [M+H] + C 59 H 77 ClF3N8O8S3 + Calculated value: 1213.47.

[0337] (2S,4R)-1-((2S)-2-(2-(4-((4-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazin-1-yl)methyl Preparation of ((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound #16): A solution of VHL-L (1.0 equiv.), 16-4 (1.0 equiv. from step 4), HATU (1.5 equiv.), and DMAP (5.0 equiv.) in DCM was stirred at room temperature overnight and then washed with saturated aqueous NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH) to give compound #16 (5.7 mg, 53% yield). 1 H NMR(600MHz,CDCl3)δ8.67(d,J=3.7Hz,1H),8.30(s,1H),8.00(s,1H),7.92-7.71(m,2H),7.44-7.20(m,11H),7.06-6.99(m ,2H),6.90(s,0H),6.76(s,2H),6.59(s,1H),5.10-5.00(m,1H),4.71(s,1H),4.48(s,1H),4.37(s,1H),4.15(s,1H),3.87( s,1H),3.66(s,6H),3.58(d,J=10.9Hz,1H),3.32-3.06(m,6H),3.06-2.90(m,3H),2.84-2.56(m,8H),2.52(s,3H),2.47-2. 22(m,20H),2.10(s,3H),2.05-1.95(m,1H),1.91-1.80(m,1H),1.74-1.36(m,12H),1.12-0.93(m,12H)ppm.LC / MS(ESI)m / z 1639.7;[M+H] + C 82 H 107 ClF3N 12 O 10 S4+ Calculated value: 1639.68. [Example]

[0338] Preparation of compounds #17-19 [ka] Preparation of tert-butyl 4-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (17-1): A suspension of benzyl 4-formylpiperidine-1-carboxylate (500 mg, 2.02 mmol), tert-butyl piperazine-1-carboxylate (415 mg, 2.23 mmol), and NaBH(OAc) (645 mg, 3.04 mmol) in DCM (20 mL) was stirred at room temperature overnight. The reaction mixture was washed with saturated aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (0% to 50% EtOAc in hexanes) to give 17-1 (726 mg, 86% yield). 1 H NMR(600MHz,CDCl3)δ7.41-7.36(m,4H),7.35-7.31(m,1H),5.15(s,2H),4.20(s,2H),3.42(dd,J=6.7,3.5Hz,4H),2.79(s,2H),2. 36(t,J=5.0Hz,4H),2.19(d,J=7.2Hz,2H),1.77(d,J=12.9Hz,2H),1.72-1.63(m,1H),1.48(s,9H),1.12(s,2H)ppm.LC / MS(ESI)m / z 418.3;[M+H] + C 23 H 36 N3O4 + Calculated value: 418.27.

[0339] Preparation of tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (17-2): A stirred mixture of 17-1 (150 mg, 0.36 mmol) and 10% Pd(OH) (15 mg) in EtOH (5 mL) was hydrogenated overnight with a hydrogen balloon. The reaction mixture was filtered through celite, and the filtrate was concentrated to give crude 17-2 (103 mg, quantitative yield), which was used directly in the next step. LC / MS (ESI) m / z 284.3; [M+H] + C 15 H 30 N3O2 + Calculated value: 284.23.

[0340] Preparation of tert-butyl 4-((1-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (17-3): A suspension of intermediate M (50 mg, 0.05 mmol), 17-2 (28.8 mg, 0.1 mmol), TEA (35 μL, 0.25 mmol), and NaBH(OAc) (21.3 mg, 0.1 mmol) in DCM (2 mL) was stirred at room temperature overnight. The reaction mixture was washed with saturated aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (0% to 10% MeOH in DCM) to give 17-3 (41 mg, 63% yield). 1H NMR(600MHz,CDCl3)δ8.33(d,J=2.2Hz,1H),8.01(dd,J=9.1,2.2Hz,1H),7.85(d,J=8.5Hz,2H),7.40-7.35(m,2H),7.30(dd,J=7.8,4.6Hz,4H), 7.27-7.21(m,1H),7.02(d,J=8.1Hz,2H),6.84(d,J=8.6Hz,1H),6.66(d,J=8.5Hz,2H),6.55(d,J=9.3Hz,1H),3.85(dt,J=8.6,4.4Hz,1H),3.66 (tp,J=9.0,4.4Hz,4H),3.45-3.06(m,11H),2.98(dd,J=13.7,7.5Hz,2H),2.84-2.48(m,7H),2.47-2.26(m,16H),2.19(d,J=5.4Hz,2H),2.12(d td,J=14.8,7.4,4.0Hz,1H),2.05-1.89(m,1H),1.80(s,2H),1.71-1.58 (m,3H),1.55-1.50(m,1H),1.45(s,9H),1.10(s,3H)ppm.LC / MS(ESI)m / z 1255.5;[M+H] + C 62 H 83 ClF3N8O8S3 + Calculated value: 1255.51.

[0341] Preparation of 4-(4-((4'-chloro-4-methyl-4-((4-(piperazin-1-ylmethyl)piperidin-1-yl)methyl)-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide hydrochloride (17-4): To a solution of 17-3 (35 mg, 0.028 mmol) in DCM (1 mL) was added 4 N HCl in dioxane (1 mL) and then stirred at room temperature for 2 hours. The reaction mixture was concentrated to give crude 17-4 (9.3 mg) as the HCl salt, which was used directly in the next step. LC / MS(ESI) m / z 1155.3; [M+H] + C 57 H 75ClF3N8O6S3 + Calculated value: 1155.46.

[0342] General procedure H was used for the final step preparation of compounds #17-19.

[0343] (2S,4R)-1-((2S)-2-(3-(4-((1-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-oxopropanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound #17) (5.4 mg, 43% yield). 1 H NMR(600MHz,CDCl3)δ8.68(s,1H),8.33(d,J=2.3Hz,1H),8.04(d,J=9.0Hz,1H),7.82(d,J=8.1Hz,2H),7.60(d,J=7.9Hz,1H),7.43-7.34(m,6H),7 .33-7.21(m,5H),7.00(d,J=8.0Hz,2H),6.72(d,J=8.6Hz,2H),6.56(d,J =9.2Hz,1H),5.08(p,J=6.9Hz,1H),4.73(t,J=8.1Hz,1H),4.52(d,J=5.0 Hz,1H),4.48(s,1H),4.07(d,J=11.4Hz,1H),3.86(s,1H),3.70-3.50(m, 8H),3.47-3.37(m,2H),3.32(d,J=10.8Hz,1H),3.27-3.07(m,5H),3.00( dd,J=13.9,7.3Hz,1H),2.92(s,1H),2.43(d,J=117.5Hz,32H),2.22-2.05(m,4H),1.73-1.40(m,8H),1.06(d,J=17.7Hz,12H)ppm.LC / MS(ESI)m / z 1667.4;[M+H] +C 83 H 107 ClF3N 12 O 11 S4 + Calculated value: 1667.67.

[0344] (2S,4R)-1-((2S)-2-(5-(4-((1-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound #18) (4.7 mg, 37% yield). 1 H NMR(600MHz,CDCl3)δ8.68(s,1H),8.33(d,J=2.2Hz,1H),8.04(d,J=9.1Hz, 1H),7.82(d,J=8.4Hz,2H),7.54(s,1H),7.43-7.33(m,7H),7.32-7.21(m,4H ),6.99(d,J=8.2Hz,2H),6.74(d,J=8.6Hz,2H),6.56(d,J=9.3Hz,1H),5.08 (p,J=6.9Hz,1H),4.71(t,J=8.2Hz,1H),4.55(q,J=4.3Hz,1H),4.48(s,1H), 4.09(d,J=11.4Hz,1H),3.85(s,1H),3.71-3.56(m,6H),3.48(s,1H),3.36( s,2H),3.18(s,4H),3.12-2.94(m,3H),2.85(s,2H),2.53(d,J=4.9Hz,3H),2 .49-2.22(m,30H),2.22-2.07(m,4H),2.00-1.86(m,4H),1.76-1.56(m,4H), 1.51-1.42(m,3H),1.36(s,1H),1.03(d,J=25.0Hz,12H)ppm.LC / MS(ESI)m / z 1695.8;[M+H]+ C 85 H 111 ClF3N 12 O 11 S4 + Calculated value: 1695.70.

[0345] (2S,4R)-1-((2S)-2-(7-(4-((1-((4'-chloro-4-methyl-6-((4-(4-(((4-((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound #19) (6.1 mg, 47% yield). 1 H NMR(600MHz,CDCl3)δ8.68(d,J=2.5Hz,1H),8.32(d,J=2.2Hz,1H),8.04(dd,J=9.2,2.2Hz,1H),7.82(d,J=8.5Hz,2H),7.49-7.33(m,8H),7.32-7 .21(m,5H),7.00-6.97(m,2H),6.73(d,J=8.5Hz,2H),6.57(dd,J=15.5,7 .6Hz,2H),5.08(p,J=6.6Hz,1H),4.68(dt,J=19.6,8.2Hz,1H),4.62-4.5 8(m,1H),4.49(s,1H),4.05(dd,J=21.7,11.4Hz,1H),3.86(s,1H),3.71 -3.56(m,6H),3.55-3.32(m,3H),3.18(s,4H),3.13-2.94(m,3H),2.85(s ,2H),2.53(d,J=3.8Hz,3H),2.50-2.07(m,34H),1.74-1.56(m,6H),1.54 -1.42(m,5H),1.42-1.29(m,3H),1.08-0.97(m,12H)ppm.LC / MS(ESI)m / z 1723.7;[M+H] + C87 H 115 ClF3N 12 O 11 S4 + Calculated value: 1723.73. [Example]

[0346] Preparation of Compound #20 [ka] Preparation of methyl 6-(prop-2-yn-1-yloxy)hexanoate (20-2): Under an argon atmosphere, 2-propyn-1-ol (565 μL, 9.57 mmol) was added dropwise to a suspension of 60% NaH (250 mg, 6.22 mmol) in anhydrous DMF (5 mL) at 0-5 °C with stirring. After stirring for an additional 20 min at 0-5 °C, 20-1 (1 g, 4.78 mmol) was added to the mixture. The resulting mixture was then warmed to 50 °C and stirred overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (0%-20% EtOAc in hexanes) to give 20-2 (655 mg, 74% yield). LC / MS (ESI) m / z 185.1; [M+H] + C 10 H 17 O3 + Calculated value: 185.12.

[0347] Preparation of 6-(prop-2-yn-1-yloxy)hexanoic acid (20-3): To a solution of 20-2 (300 mg, 1.63 mmol) in MeOH / THF (1.5 mL / 0.3 mL) was added 1 M aqueous NaOH (0.5 mL) and stirred at room temperature overnight. The reaction mixture was concentrated to remove the organic solvent, then adjusted to pH 4-5 with 10% aqueous citric acid and extracted with EtO. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to give crude 20-3 (289 mg, quantitative yield), which was used directly in the next step. LC / MS (ESI) m / z 171.1; [M+H] + C9H 15 O3+ Calculated value: 171.10.

[0348] Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(6-(prop-2-yn-1-yloxy)hexanamido)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (20-4): A mixture of 20-3 (35 mg, 0.21 mmol), HATU (100 mg, 0.26 mmol), VHL-L (100 mg, 0.2 mmol, HCl salt), and TEA (150 μL, 2.0 mmol) in DCM (2 mL) was stirred at room temperature for 3 h. The reaction mixture was washed with saturated aqueous NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (0% to 5% MeOH in DCM) to give 20-4 (99 mg, 81% yield). 1 H NMR(600MHz,CDCl3)δ8.69(s,1H),7.46(d,J=7.9Hz,1H),7.44-7.36(m,4H),6.28(d,J=8.8Hz,1H),5.10(p,J=7.1Hz,1H) ),4.69(t,J=7.9Hz,1H),4.58(d,J=8.8Hz,1H),4.54-4.49(m,1H),4.12(d,J=2.4Hz,2H),4.07(dt,J=11.4,1.9Hz,1H), 3.88(s,1H),3.63(dd,J=11.3,3.7Hz,1H),3.50(t,J=6.4Hz,2H),2.54(s,3H),2.48-2.41(m,2H),2.19(td,J=7.4,2.5H z,2H),2.12-2.05(m,1H),1.66-1.56(m,4H),1.49(d,J=6.9Hz,3H),1.43-1.33(m,2H),1.05(s,9H)ppm.LC / MS(ESI)m / z 597.3;[M+H] + C 32 H 45 N4O5S + Calculated value: 597.31.

[0349] Preparation of ethyl 4-(4-((4'-chloro-4-methyl-4-(((methylsulfonyl)oxy)methyl)-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoate (20-5): Under an argon atmosphere, to a stirred solution of A-1 (260 mg, 0.54 mmol) and TEA (225 μL, 1.62 mmol) in DCM (3 mL) was added methanesulfonyl chloride (50 μL, 0.65 mmol) dropwise at 0 °C. After the addition was complete, the resulting mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated and purified by flash column chromatography (0% to 50% EtOAc in hexanes) to give 20-5 (270 mg, 89% yield). 1 H NMR(600MHz,CDCl3)δ7.95-7.89(m,2H),7.34-7.29(m,2H),7.04-6.99(m,2H),6.86-6.81(m, 2H),4.07(q,J=9.2Hz,2H),3.28(t,J=4.2Hz,4H),3.06(s,3H),2.83(s,2H),2.37(t,J=5.1Hz, 4H),2.35-2.30(m,2H),2.23(dt,J=17.8,2.3Hz,1H),2.11(dd,J=18.1,1.9Hz,1H),1.71(dt, J=13.6,6.9Hz,1H),1.64-1.56(m,3H),1.38(t,J=7.1Hz,3H),1.12(s,3H)ppm.LC / MS(ESI)m / z 561.2;[M+H] + C 29 H 38 ClN2O5S + Calculated value: 561.22.

[0350] Preparation of ethyl 4-(4-((4-(azidomethyl)-4'-chloro-4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoate (20-6): A mixture of 20-5 (270 mg, 0.48 mmol) and NaN (156 mg, 2.4 mmol) in DMF (3 mL) was heated at 120 °C overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with water and brine. The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (0% to 25% EtOAc in hexanes) to give 20-6 (165 mg, 68% yield). 1 H NMR(600MHz,CDCl3)δ7.94-7.89(m,2H),7.33-7.29(m,2H),7.04-6.99(m,2H),6. 86-6.82(m,2H),4.34(q,J=7.1Hz,2H),3.31-3.23(m,6H),2.83(s,2H),2.37(t,J =5.1Hz,4H),2.35-2.24(m,1H),2.22-2.14(m,1H),2.09-2.02(m,1H),1.68-1.61 (m,1H),1.57-1.50(m,1H),1.38(t,J=7.1Hz,3H),1.06(s,3H)ppm.LC / MS(ESI)m / z 508.1;[M+H] + C 28 H 35 ClN5O2 + Calculated value: 508.25.

[0351] Preparation of 4-(4-((4-(azidomethyl)-4'-chloro-4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid (20-7): To a solution of 20-6 (50 mg, 0.098 mmol) in THF / MeOH (0.5 mL / 0.1 mL), a solution of LiOH·HO (15 mg, 1.19 mmol) in water (0.1 mL) was added and then stirred at 45 °C overnight. The reaction mixture was concentrated to remove the organic solvent, then adjusted to pH = 5-6 with 5% aqueous citric acid and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to give 20-7 (47 mg, quantitative yield). LC / MS (ESI) m / z 480.2; [M+H] + C 26 H 31 ClN5O2 + Calculated value: 480.22.

[0352] Preparation of 4-(4-((4-(azidomethyl)-4'-chloro-4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (20-8): A mixture of 20-7 (47 mg, 0.097 mmol), N-1 (49 mg, 0.088 mmol), EDC (85 mg, 0.44 mmol), and DMAP (54 mg, 0.44 mmol) in DCM (2 mL) was stirred at room temperature overnight. The reaction mixture was washed with water and saturated aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (0% to 5% MeOH in DCM) to give 20-8 (56 mg, 62% yield). LC / MS (ESI) m / z 1015.2; [M+H] + C 47 H 55 ClF3N8O6S3 + Calculated value: 1015.30.

[0353] (2S,4R)-1-((2S)-2-(6-((1-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-bi Preparation of [phenyl]-4-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)hexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound #20): General procedure B was applied to provide compound #20 (17.6 mg, 74% yield). 11H NMR (600 MHz, CDCl3) δ 8.68 (s, 1H), 8.32 (d, J = 2.2 Hz, 1H), 8.09 (dt, J = 9.3, 1.6 Hz, 1H), 7.79 - 7.71 (m, 3H), 7.47 (t, J = 7.8 Hz, 1H), 7.43 - 7.35 (m, 6H), 7.30 (dd, J = 8.2, 6.6 Hz, 4H), 7.27 - 7.23 (m, 1H), 7.04 - 6.97 (m, 3H), 6.76 (d, J = 8.7 Hz, 2H), 6.62 (d, J = 9.4 Hz, 1H), 6.52 (dd, J = 9.1, 3.3 Hz, 1H), 5.10 (p, J = 7.1 Hz, 1H), 4.70 (t, J = 8.2 Hz, 1H), 4.68 - 4.63 (m, 1H), 4.59 (s, 2H), 4.50 (d, J = 4.1 Hz, 1H), 4.34 - 4.26 (m, 2H), 4.11 (d, J = 11.5 Hz, 1H), 3.90 (dp, J = 8.6, 4.1 Hz, ), 3.72 - 3.62 (m, 4H), 3.60 (dd, J = 11.4, 3.4 Hz, 1H), 3.40 (t, J = 6.7 Hz, 2H), 3.22 (t, J = 5.2 Hz, 4H), 3.11 (dd, J = 13.8, 5.1 Hz, 1H), 3.03 (dd, J = 13.9, 7.2 Hz, 1H), 2.88 (d, 1H), 2.82 (d, J = 12.6 Hz, 1H), 2.52 (s, 3H), 2.49 - 2.23 (m, 16H), 2.18 - 2.06 (m, 4H), 2.02 (d, J = 17.4 Hz, 1H), 1.73 - 1.58 (m, 3H), 1.53 - 1.37 (m, 6H), 1.20 (t, J = 7.2 Hz, 2H), 1.05 (s, 9H), 0.99 (d, J = 2.8 Hz, 3H) ppm. LC / MS (ESI) m / z 1611.7; [M + H] + C 79 H 99 ClF3N 12 O<000​​​​​​​​​​​​​​​​

[0355] (2S,4R)-1-((2S)-2-(2-((2-((1-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound #21) (12.5 mg, 57% yield). 1H NMR(600MHz, CDCl3)δ8.70(s,1H),8.34(d,J=2.3Hz,1H),8.11(d,J=9.2Hz,1H),7.78(d,J=7 .7Hz,1H),7.72(d,J=8.4Hz,2H),7.49(s,1H),7.41-7.35(m,7H),7.34-7.22(m,5H),7.05-6 .98(m,2H),6.76(dd,J=9.1,2.9Hz,2H),6.61(d,J=9.4Hz,1H),5.13-5.05(m,1H),4.75-4.6 7(m,3H),4.59-4.48(m,2H),4.30(s,2H),4.12(d,J=11.4Hz,1H),3.90(d,J=8.1Hz,1H),3.86 -3.71(m,2H),3.71-3.58(m,7H),3.53(s,2H),3.21(d,J=7.4Hz,4H),3.11(dd,J=13.9,5.0H z,1H),3.02(dd,J=13.9,7.2Hz,1H),2.88(d,J=12.6Hz,1H),2.82(d,J=12.8Hz,1H),2.51(s ,3H),2.48-2.23(m,16H),2.16-2.07(m,2H),2.04(d,J=17.5Hz,1H),1.72-1.65(m,1H),1.6 2(t,J=6.7Hz,2H),1.49(dd,J=6.9,2.7Hz,3H),1.06(s,9H),0.98(s,3H)ppm.LC / MS(ESI)m / z 1599.6;[M+H] + C 77 H 95 ClF3N 12 O 12 S4 + Calculated value: 1599.57.

Example

[0356] Preparation of Compound #22

change

[0357] Preparation of tert-butyl ((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)carbamate (22-3): A mixture of 22-2 (37 mg, 0.067 mmol), N-1 (34 mg, 0.061 mmol), EDC (60 mg, 0.31 mmol), and DMAP (38 mg, 0.31 mmol) in DCM (1.5 mL) was stirred at room temperature overnight. The reaction mixture was washed with water and saturated aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (0% to 5% MeOH in DCM) to give 22-3 (27 mg, 40% yield). 1H NMR(600MHz,CDCl3)δ8.36(d,J=2.3Hz,1H),8.14-8.07(m,1H),7.70(d,J=8.3Hz,2H),7.39(d,J=7.1Hz,2H),7.35-7.22(m ,6H),7.05-6.98(m,3H),6.74(d,J=8.6Hz,2H),6.60(d,J=9.3Hz,1H),4.84(s,1H),3.90(s,1H),3.75-3.62(m,4H),3.36- 3.23(m,4H),3.13(td,J=13.7,6.0Hz,2H),3.04(td,J=13.6,6.6Hz,2H),2.91(s,2H),2.53-2.23(m,11H),2.15(d,J=18.0 Hz,2H),2.01(d,J=17.7Hz,1H),1.76-1.64(m,1H),1.62-1.54(m,1H),1.54-1.39(m,11H),0.98(s,3H)ppm.LC / MS(ESI)m / z 1089.5;[M+H] + C 52 H 65 ClF3N6O8S3 + Calculated value: 1089.37.

[0358] Preparation of 4-(4-((4-(aminomethyl)-4'-chloro-4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide hydrochloride (22-4): To a solution of 22-3 (12 mg, 0.011 mmol) in DCM (0.2 mL) was added 4 N HCl in dioxane (0.2 mL), then stirred at room temperature for 1 h. The reaction mixture was concentrated to give crude product 22-4 (11 mg, quantitative yield) as the HCl salt, which was used directly in the next step. LC / MS (ESI) m / z 989.2; [M+H] + C 47 H 57 ClF3N6O6S3 + Calculated value: 989.31.

[0359] Preparation of 4-(4-((4-((4-azidobutanamido)methyl)-4'-chloro-4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (22-5): To a solution of 22-4 (12 mg, 0.011 mmol) and TEA (15 μL, 0.2 mmol) in DCM (0.2 mL) was added a solution of 4-azidobutanoic acid (1.7 mg, 0.013 mmol) and HATU (5.5 mg, 0.014 mmol) in DCM (0.2 mL), followed by stirring at room temperature for 3 h. The reaction mixture was washed with saturated aqueous NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (0% to 60% EtOAc in hexanes) to give 22-5 (10 mg, 83% yield). 1 H NMR(600MHz,CDCl3)δ8.37(d,J=2.2Hz,1H),8.05(dd,J=9.1,2.3Hz,1H),7.71(d,J=8.4Hz,2H),7.43-7.38(m,2H),7.38-7.30(m,4H) ,7.31-7.25(m,1H),7.05-7.00(m,2H),6.93(d,J=8.6Hz,1H),6.64(d,J=9.3Hz,1H),6.54(d,J=8.5Hz,2H),3.91(s,1H),3.73-3.63(m ,5H),3.56(s,2H),3.36-3.23(m,4H),3.21-3.16(m,2H),3.13(dd,J=13.7,5.0Hz,1H),3.03(dd,J=13.8,7.3Hz,1H),2.95(d,J=13.1H) z,1H),2.50-2.26(m,16H),2.14(s,1H),1.87(p,J=7.1Hz,2H),1.74-1.64(m,1H),1.60-1.53(m,2H),1.03(s,3H)ppm.LC / MS(ESI)m / z 1100.4;[M+H] + C 51 H 62 ClF3N9O7S3 + Calculated value: 1100.36.

[0360] (2S,4R)-1-((2S)-2-(6-((1-(4-(((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl] Preparation of N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound #22): General procedure B was followed to form compound #22 (8.6 mg, 56% yield). 1 H NMR(600MHz,CDCl3)δ8.68(s,1H),8.33(d,J=2.2Hz,1H),8.08-8.02(m,1H),7.73(d, J=8.4Hz,2H),7.55(s,1H),7.49(d,J=7.6Hz,1H),7.43-7.35(m,6H),7.34-7.22(m,5H ),7.04-6.99(m,2H),6.95(d,J=8.5Hz,1H),6.63(t,J=8.8Hz,3H),6.52(dd,J=9.0,4. 3Hz,1H),5.09(p,J=7.1Hz,1H),4.67(t,1H),4.59(dd,J=8.9,2.0Hz,1H),4.52(d,J=2 .8Hz,2H),4.48(s,1H),4.33(t,J=6.7Hz,2H),4.06(d,J=11.3Hz,1H),3.94-3.85(m, 1H),3.70-3.62(m,4H),3.62-3.57(m,1H),3.47-3.44(m,2H),3.37(s,1H),3.22(s,5H) ),3.16-2.98(m,3H),2.52(s,3H),2.48-2.07(m,22H),1.74-1.51(m,10H),1.48(dd,J =7.0,1.7Hz,3H),1.32(p,J=8.0Hz,2H),1.04(s,9H),1.01(s,3H)ppm.LC / MS(ESI)m / z 1696.7;[M+H]+ C 83 H 106 ClF3N 13 O 12 S4 + Calculated value: 1696.66. [Example]

[0361] Preparation of Compound #23 [ka] Compound #23 was prepared according to general procedure B.

[0362] (2S,4R)-1-((2S)-2-(2-(2-((1-(4-(((4'-chloro-4-methyl-6-((4-(4-(((4-((((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro -[1,1'-biphenyl]-4-yl)methyl)amino)-4-oxobutyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound #23) (9.8 mg, 43% yield). 11H NMR (600 MHz, CDCl3) δ 8.70 (s, 1H), 8.32 (d, J = 2.4 Hz, 1H), 8.08 (d, J = 9.1 Hz, 1H), 7.80 (d, J = 7.0 Hz, 1H), 7.74 (d, J = 7.9 Hz, 2H), 7.66 (d, J = 7.6 Hz, 1H), 7.50 (dd, J = 9.2, 6.7 Hz, 1H), 7.41 - 7.35 (m, 6H), 7.31 (td, J = 7.9, 2.1 Hz, 4H), 7.25 (t, J = 7.3 Hz, 1H), 7.04 - 6.99 (m, 2H), 6.93 (d, J = 8.5 Hz, 1H), 6.63 (d, J = 8.6 Hz, 2H), 5.09 (p, J = 7.1 Hz, 1H), 4.75 - 4.64 (m, 2H), 4.61 (d, 2H), 4.48 (s, 1H), 4.32 (td, J = 13.7, 6.5 Hz, 2H), 4.00 (dd, J = 14.1, 5.0 Hz, 2H), 3.97 - 3.85 (m, 2H), 3.75 - 3.58 (m, 9H), 3.35 (s, 1H), 3.23 (s, 5H), 3.15 - 2.96 (m, 3H), 2.50 (s, 3H), 2.47 - 2.05 (m, 22H), 1.7 (m, 2H), 1.59 - 1.51 (m, 2H), 1.48 (dd, J = 6.9, 1.9 Hz, 3H), 1.35 - 1.22 (m, 1H), 1.05 (s, 9H), 0.99 (d, J = 6.1 Hz, 3H) ppm. LC / MS (ESI) m / z 1684.5; [M + H] + C 81 H 102 ClF3N 13 O 13 S4<​​​​​​​​​​​​​​​​​​(2S,4R)-1-((2S)-2-(2-(4-(2-(4-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound #25). 1 1H NMR (600 MHz, chloroform-d) δ 8.67 (s, 1H), 8.33 (s, 1H), 8.09 (d, J = 10.0 Hz, 1H), 7.79 (d, J = 34.9 Hz, 2H), 7.38 (dt, J = 18.1, 6.8 Hz, 7H), 7.34 - 7.27 (m, 4H), 7.01 (s, 3H), 6.70 (d, J = 57.8 Hz, 2H), 5.13 - 5.05 (m, 1H), 4.75 (d, J = 9.4 Hz, 1H), 4.54 (d, J = 44.8 Hz, 2H), 4.17 (s, 1H), 3.94 (s, 1H), 3.84 - 3.51 (m, 7H), 3.50 - 3.15 (m, 2H), 3.14 - 2.97 (m, 4H), 2.88 (s, 2H), 2.64 (d, J = 15.9 Hz, 5H), 2.55 - 2.44 (m, 13H), 2.32 (s, 10H), 2.2 – 1.86 (m, 4H), 1.73 (s, 1H), 1.47 (d, J = 7.0 Hz, 3H), 1.41 (t, J = 7.3 Hz, 3H), 1.25 (s, 5H), 1.05 (d, J = 5.2 Hz, 9H), 0.97 (s, 4H), 0.88 (d, J = 6.5 Hz, 2H) ppm. LC / MS (ESI) m / z 1668.9; [M+H] + C 82 H 106 ClF3N 13 O 11 S4 + Calculated value: 1668.67.

Example

[0365] Preparation of Compound #26 [ka] Compound #26 was prepared according to general procedure C.

[0366] tert-Butyl 2-(4-(2-ethoxy-2-oxoethyl)piperidin-1-yl)acetate (26-2). 1 H NMR (600MHz, chloroform-d) δ4.12(q,J=7.1Hz,2H),3.09(s,2H),2.92(d,J=11.6Hz,2H),2.22(d,J=7.1Hz,2H),2.20-2.14( m,2H),1.77(ddd,J=11.4,7.6,4.0Hz,1H),1.71-1.66(m,2H),1.45(s,9H),1.42-1.34(m,2H),1.25(t,J=7.1Hz,3H)ppm.

[0367] 2-(4-(2-ethoxy-2-oxoethyl)piperidin-1-yl)acetic acid (26-3). LC / MS (ESI) m / z 230.1; [M+H] + C 11 H 20 No. 4 + Calculated value: 230.14.

[0368] Ethyl 2-(1-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)piperidin-4-yl)acetate (26-4). 1H NMR(600MHz,chloroform-d)δ8.67(s,1H),7.89(d,J=8.0Hz,1H),7.50(d,J=7.8Hz,1H),7.40(d,J=8.3Hz,2H),7.36(d,J=8.3Hz,2H), 5.07(p,J=7.0Hz,1H),4.76(t,J=7.9Hz,1H),4.50(s,1H),4.40(d,J=8.1Hz,1H),4.21(d,J=11.6Hz,1H),4.13(q,J=7.1Hz,2H),3 .57(dd,J=11.4,3.6Hz,1H),3.04-2.94(m,2H),2.84(d,J=11.3Hz,2H),2.59-2.54(m,1H),2.53(s,3H),2.28-2.16(m,4H),2.06( ddt,J=13.6,8.3,2.0Hz,1H),1.84-1.72(m,4H),1.47(d,J=6.9Hz,3H),1.37-1.27(m,2H),1.26(t,J=7.1Hz,3H),1.07(s,9H)ppm.

[0369] 2-(1-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)piperidin-4-yl)acetic acid (26-5). 1H NMR (600MHz, methanol-d4) δ8.80(s,1H),7.35(q,J=8.4Hz,4H),4.93(q,J=5.6,4.6Hz,1H),4.55(s,1H),4.52-4 .43(m,2H),4.36(dt,J=4.1,2.1Hz,1H),3.79(dt,J=11.1,1.8Hz,1H),3.67(dd,J=11.0,3.9Hz,1H),3.55-3. 35(m,1H),3.16-3.09(m,2H),2.58(s,1H),2.40(s,3H),2.20(dd,J=15.3,6.7Hz,2H),2.13(ddt,J=13.2,7.6 ,1.9Hz,1H),1.91-1.79(m,4H),1.51(d,J=7.1Hz,1H),1.44(d,J=7.0Hz,5H),0.98(s,9H)ppm.LC / MS(ESI)m / z 628.3;[M+H] + C 32 H 46 N5O6S + Calculated value: 628.32.

[0370] (2S,4R)-1-((2S)-2-(2-(4-(2-(4-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound #26): 1H NMR (600MHz, chloroform-d) δ8.67(d,J=2.7Hz,1H),8.32(t,J=2.5Hz,1H),8.10(dd,J=8.2,4. 4Hz,1H),7.90(t,J=9.0Hz,1H),7.71(t,J=7.8Hz,2H),7.41-7.35(m,7H),7.32-7.27(m,5H ),7.05(d,J=8.5Hz,1H),7.01-6.96(m,2H),6.77(d,J=8.5Hz,2H),6.60(d,J=9.4Hz,1H), 5.08(p,J=7.0Hz,1H),4.77(t,J=7.9Hz,1H),4.51(d,J=8.7Hz,2H),4.23(d,J=11.5Hz,1H) ,3.90(s,1H),3.69-3.62(m,5H),3.60(d,J=10.8Hz,1H),3.41(s,2H),3.23(s,4H),3.10( dd,J=13.9,5.1Hz,1H),3.01(dd,J=13.8,7.5Hz,2H),2.96(t,J=5.2Hz,1H),2.83(d,J=11. 9Hz,3H),2.78(d,J=12.5Hz,1H),2.51(d,J=0.8Hz,3H),2.41(d,J=10.9Hz,2H),2.34-2.10 (m,17H),1.91-1.57(m,19H),1.47(dd,J=7.0,4.0Hz,4H),1.07(s,9H)ppm.LC / MS(ESI)m / z 1667.7;[M+H] + C 84 H 108 ClF3N 11 O 11 S4 + Calculated value: 1667.67. [Example]

[0371] Preparation of Compound #27 [ka] Compound #27 was prepared according to general procedure C.

[0372] tert-Butyl 2-(1-(2-ethoxy-2-oxoethyl)piperidin-4-yl)acetate (27-2). 1H NMR (600MHz, chloroform-d) δ4.18(q,J=7.2Hz,2H),3.18(s,2H),2.91(d,J=11.6Hz,2H),2.20-2.15(m,2H),2.13(d,J=7 .0Hz,2H),1.74(tt,J=7.2,3.9Hz,1H),1.71-1.67(m,2H),1.44(s,9H),1.41-1.34(m,2H),1.26(t,J=7.1Hz,3H)ppm.

[0373] 2-(1-(2-ethoxy-2-oxoethyl)piperidin-4-yl)acetic acid (27-3). 1 H NMR(600MHz,chloroform-d)δ4.27(q,J=7.1Hz,2H),3.93(s,2H),3.81-3.74(m,2H),3.13(t,J=12.6Hz,2 H),2.42(d,J=6.5Hz,2H),2.04(d,J=14.9Hz,3H),1.87(t,J=13.4Hz,2H),1.29(d,J=7.1Hz,3H)ppm.

[0374] Ethyl 2-(4-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)piperidin-1-yl)acetate (27-4). 1H NMR(600MHz,chloroform-d)δ8.67(s,1H),7.45-7.39(m,3H),7.36(d,J=8.3Hz,2H),6.09(d,J=8.5Hz,1H),5.08(p,J=7.1Hz,1H),4 .74(t,J=7.9Hz,1H),4.52(d,J=8.6Hz,2H),4.17(q,J=7.1Hz,2H),4.14(d,J=11.5Hz,1H),3.58(dd,J=11.4,3.7Hz,1H),3.18( s,2H),2.92(dd,J=10.7,4.3Hz,2H),2.58(ddd,J=13.6,7.5,4.7Hz,1H),2.53(s,3H),2.20-2.13(m,3H),2.13-2.04(m,2H),1. 78(td,J=7.4,3.7Hz,1H),1.70-1.64(m,3H),1.47(d,J=7.0Hz,3H),1.43-1.36(m,3H),1.26(t,J=7.1Hz,3H),1.05(s,9H)ppm.

[0375] 2-(4-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)piperidin-1-yl)acetic acid (27-5). 1H NMR (600MHz, methanol-d4) δ8.79(d,J=1.3Hz,1H),8.48(d,J=7.5Hz,1H),7.86(d,J=8.8Hz,1H),7.38-7.31(m,4H),4.9 2(p,J=7.1Hz,1H),4.53(d,J=8.8Hz,1H),4.47(d,J=4.6Hz,1H),4.35(dt,J=4.4,2.2Hz,1H),3.80(dt,J=11.1,1.8Hz ,1H),3.66(dd,J=11.0,4.0Hz,1H),3.59-3.47(m,4H),2.96(s,2H),2.39(d,J=1.6Hz,3H),2.23(d,J=7.0Hz,2H),2.1 6-2.09(m,1H),1.98(s,1H),1.87(dq,J=13.3,4.5Hz,3H),1.57-1.48(m,2H),1.43(d,J=7.1Hz,3H),0.97(s,9H)ppm.

[0376] (2S,4R)-1-((2S)-2-(2-(1-(2-(4-((4'-chloro-4-methyl-6-((4-(4-(((4-((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)piperidin-4-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound #27). 1H NMR (600 MHz, chloroform-d) δ 8.65 (d, J = 1.7 Hz, 1H), 8.28 (t, J = 2.1 Hz, 1H), 8.06-8.03 (m, 1H), 7.74 (dd, J = 17.3, 8.5 Hz, 2H), 7.51 (d, J = 7.7 Hz, 1H), 7.38-7.31 (m, 7H), 7.26-7.2 0(m,5H),6.96(dt,J=5.9,1.8Hz,3H),6.79(s,1H),6.75(d,J=8.6Hz,2H),6.56(d,J= 9.6Hz,1H),5.04(p,J=7.0Hz,1H),4.60(t,J=8.2Hz,1H),4.57-4.53(m,1H),4.43(s,1 H),3.97(d,J=11.5Hz,1H),3.84(s,1H),3.66-3.59(m,6H),3.57(d,J=11.0Hz,1H),3 .52(s,2H),3.46(s,2H),3.37(p,J=1.7Hz,2H),3.10-3.03(m,2H),2.97(d,J=23.4Hz, 7H),2.90-2.78(m,3H),2.48(d,J=1.7Hz,7H),2.39(s,14H),2.17-2.05(m,7H),1.65 (dd,J=15.1,9.4Hz,5H),1.48-1.38(m,8H),1.00(d,J=1.7Hz,9H)ppm.LC / MS(ESI)m / z 1667.6;[M+H] + C 83 H 107 ClF3N 12 O 11 S4 + Calculated value: 1667.67. [Example]

[0377] Preparation of compounds #28-30 [ka] Preparation of ethyl 4-(4-((4'-chloro-4-methyl-4-(2-oxoethyl)-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoate (28-1). To a stirred solution of A-2 (1 equiv.) and (methoxymethyl)triphenylphosphonium chloride (1.5 equiv.) in DMF was added KO.t- Bu (1.4 equiv.) was added and stirred at room temperature for 5 hours. Once the starting material was consumed, the reaction was quenched with 1N HCl solution, followed by the addition of 3N HCl solution, and the reaction was stirred overnight. Once the enol ether had disappeared, the mixture was diluted with EtOAc and washed with water followed by brine solution. The organic portion was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to give 28-1. 1 H NMR (600MHz, chloroform-d) δ9.93(s,1H),7.89(d,J=9.0Hz,2H),7.29(d,J=8.4Hz,2H),6.99(d, J=8.4Hz,2H),6.81(d,J=9.0Hz,2H),4.32(q,J=7.1Hz,2H),3.25(t,J=5.1Hz,4H),2.80(s,2 H),2.39(d,J=3.1Hz,2H),2.35(t,J=5.1Hz,4H),2.33-2.27(m,2H),2.26(s,1H),2.16-2.10 (m,1H),1.74-1.68(m,1H),1.61(dt,J=13.1,6.5Hz,3H),1.36(t,J=7.1Hz,3H),1.19(s,3H). 13 C NMR (151 MHz, chloroform-d) δ 203.42, 166.84, 154.27, 141.32, 134.96, 132.49, 131.26, 129.79, 129.01, 128.55, 120.06, 113.68, 60.53, 60.46, 53.47, 52.66, 47.70, 40.17, 34.35, 32.31, 30.19, 25.98, 14.61 ppm.

[0378] Compounds #28-30 were prepared according to general procedure F.

[0379] tert-Butyl 4-(2-(4'-chloro-6-((4-(4-(ethoxycarbonyl)phenyl)piperazin-1-yl)methyl)-4-methyl-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)ethyl)piperazine-1-carboxylate (28-2). 1H NMR (600MHz, chloroform-d) δ7.89(d,J=9.0Hz,2H),7.27(d,J=8.0Hz,2H),6.98(d,J=8.4Hz ,2H),6.80(d,J=9.1Hz,2H),4.31(q,J=7.1Hz,2H),3.58(t,J=5.4Hz,1H),3.47-3.38(m ,7H),3.24(t,J=5.1Hz,4H),2.79(s,2H),2.42(d,J=7.6Hz,6H),2.34(t,J=5.2Hz,4H), 2.24(d,J=5.8Hz,2H),2.10(s,2H),1.45(s,9H),1.35(t,J=7.1Hz,3H),0.98(s,3H)ppm.

[0380] 4-(4-((4-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-4'-chloro-4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid (28-3). 1 H NMR (600MHz, chloroform-d) δ7.88(d,J=9.0Hz,2H),7.20(d,J=8.4Hz,2H),6.96(d,J=8.5Hz,2 H),6.73(d,J=9.2Hz,2H),3.60-3.55(m,4H),3.45-3.38(m,2H),3.21(d,J=5.4Hz,4H),2. 83(s,2H),2.69(s,4H),2.65-2.57(m,2H),2.43-2.37(m,2H),2.34-2.27(m,3H),2.22-2. 15(m,2H),2.00-1.96(m,1H),1.77(dt,J=12.6,6.2Hz,1H),1.44(s,9H),0.97(s,3H)ppm.

[0381] tert-Butyl 4-(2-(4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)ethyl)piperazine-1-carboxylate (28-4). 1 H NMR (600MHz, chloroform-d) δ8.28(d,J=2.3Hz,1H),7.98-7.92(m,1H),7.86(d,J=8.4Hz,2H),7.34(d,J=7.1Hz,2H),7.25-7.19(m,4H),7.00(d,J=8.0H) z,2H),6.80(d,J=8.5Hz,1H),6.67(d,J=8.5Hz,2H),6.48(d,J=9.3Hz,1H ),3.81(dt,J=8.7,4.5Hz,1H),3.62(dt,J=11.0,4.9Hz,8H),3.20(t,J=5. 1Hz,4H),3.07(dd,J=13.8,4.7Hz,1H),2.98-2.90(m,3H),2.78(s,5H),2 .54-2.38(m,6H),2.38-2.26(m,6H),2.26-2.16(m,2H),2.13-2.06(m,1H) ,2.01(d,J=17.6Hz,1H),1.73-1.66(m,2H),1.64(dd,J=6.0,2.8Hz,2H),1 .48(dq,J=13.4,6.7Hz,2H),1.43(s,9H),0.95(s,3H)ppm.LC / MS(ESI)m / z 1172.4;[M+H] + C 57 H 73 ClF3N7O8S3 + Calculated value: 1172.44.

[0382] 4-(4-((4'-chloro-4-methyl-4-(2-(piperazin-1-yl)ethyl)-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide hydrochloride (28-5). LC / MS(ESI) m / z 1072.4; [M+H] + C 52 H 66 ClF3N7O6S3 + Calculated value: 1072.39.

[0383] (2S,4R)-1-((2S)-2-(8-(4-(2-(4'-chloro-4-methyl-6-((4-(4-(((4-((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)ethyl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound #28). 1H NMR (600MHz, chloroform-d) δ8.67(s,1H),8.32(dd,J=11.0,2.3Hz,1H),8.08(d,J=9. 3Hz,1H),7.80(d,J=8.2Hz,1H),7.73(d,J=8.5Hz,1H),7.42-7.28(m,11H),7.17( s,2H),6.99(d,J=8.3Hz,1H),6.73(s,1H),6.65-6.36(m,1H),5.08(dt,J=14.1,7 .3Hz,1H),4.72-4.55(m,2H),4.51(s,1H),4.06-3.89(m,4H),3.66(d,J=26.8Hz,6 H),3.60(d,J=11.2Hz,2H),3.44(d,J=50.2Hz,4H),3.35(s,2H),3.12-3.09(m,1H ),3.04-3.01(m,1H),2.96(t,J=7.8Hz,2H),2.57(dd,J=27.0,7.5Hz,2H),2.50(d, J=2.3Hz,4H),2.43-2.19(m,13H),2.17(s,5H),1.76(t,J=7.6Hz,6H),1.56(d,J= 7.3Hz,10H),1.45(dd,J=28.7,6.9Hz,6H),1.04-1.01(m,12H)ppm.LC / MS(ESI)m / z 1654.5;[M+H] + C 83 H 108 ClF3N 11 O 11 S4 + Calculated value: 1654.67.

[0384] (2S,4R)-1-((2S)-2-(9-(4-(2-(4'-chloro-4-methyl-6-((4-(4-(((4-((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)ethyl)piperazin-1-yl)-9-oxononeamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound #29).1 1H NMR (600 MHz, chloroform-d) δ 8.67 (s, 1H), 8.31 (t, J = 2.5 Hz, 1H), 8.06 (dt, J = 7.2, 2.8 Hz, 1H), 7.75 (dd, J = 8.7, 5.7 Hz, 2H), 7.41 - 7.28 (m, 9H), 6.98 (d, J = 8.2 Hz, 3H), 6.74 (d, J = 8.6 Hz, 2H), 6.57 (dd, J = 9.5, 3.1 Hz, 1H), 6.34 (dd, J = 54.7, 8.8 Hz, 1H), 5.07 (dt, J = 14.2, 7.2 Hz, 1H), 4.71 (dt, J = 12.9, 8.0 Hz, 1H), 4.60 (dd, J = 14.9, 8.8 Hz, 1H), 4.50 (s, 1H), 4.14 - 4.05 (m, 1H), 3.90 - 3.82 (m, 1H), 3.70 - 3.56 (m, 8H), 3.52 (s, 2H), 3.21 (s, 4H), 3.10 (dd, J = 13.8, 5.0 Hz, 1H), 2.99 (dd, J = 13.9, 7.4 Hz, 1H), 2.92 (s, 1H), 2.80 (s, 2H), 2.51 (d, J = 2.9 Hz, 8H), 2.46 - 2.33 (m, 8H), 2.28 (ddd, J = 12.0, 8.2, 4.4 Hz, 7H), ②26 - 2.15 (m, 5H), 2.11 (dt, J = 13.2, 7.0 Hz, 2H), 1.69 - 1.50 (m, 10H), 1.45 (dd, J = 18.8, 6.9 Hz, 6H), 1.29 - 1.27 (m, 6H), 1.04 (d, J = 3.1 Hz, 9H), 0.98 - 0.96 (m, 3H) ppm. LC / MS (ESI) m / z 1668.6; [M + H] + C 84 H 110 ClF3N 11 O 11 S4 + Calculated value: 1668.${69}$.

[0385] Note: There seems to be an error in the original text where "②26" in the 1H NMR data part is likely a typo and is left as is in the translation. Also, for the "m / z 1668.${69}" part, the original might have a formatting issue with the decimal point, and it's presented as accurately as possible in the translation.(2S,4R)-1-((2S)-2-(10-(4-(2-(4'-chloro-4-methyl-6-((4-(4-(((4-((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)ethyl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound #30). 11H NMR (600 MHz, chloroform-d) δ 8.67 (s, 1H), 8.31 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 9.1 Hz, 1H), 7.73 (dd, J = 8.8, 1.6 Hz, 2H), 7.39 - 7.34 (m, 6H), 7.30 (d, J = 7.1 Hz, 2H), 7.25 - 7.24 (m, 1H), 6.98 (t, J = 7.6 Hz, 3H), 6.74 (d, J = 8.7 Hz, 2H), 6.60 - 6.56 (m, 1H), 6.23 (dd, J = 16.2, 8.7 Hz, 1H), 5.08 (td, J = 7.3, 4.3 Hz, 1H), 4.72 (q, J = 7.6 Hz, 1H), 4.57 (dd, J = 8.8, 5.4 Hz, 1H), 4.54 - 4.45 (m, 1H), 4.15 - 4.05 (m, 1H), 3.89 (dd, J = 8.6, 4.8 Hz, 1H), 3.73 - 3.63 (m, 6H), 3.63 - 3.51 (m, 4H), 3.21 (t, J = 5.2 Hz, 4H), 3.10 (dd, J = 13.8, 5.0 Hz, 1H), 3.00 (dd, J = 13.8, 7.3 Hz, 1H), 2.81 (s, 2H), 2.55 (d, J = 8.0 Hz, 4H), 2.51 (s, 4H), 2.42 (s, 2H), 2.40 - 2.33 (m, 4H), 2.33 - 2.27 (m, 7H), 2.23 - 2.18 (m, 2H), 1.97 (d, J = 17.5 Hz, 1H), 1.69 - 1.63 (m, 1H), 1.58 (q, J = 7.3 Hz, 6H), 1.52 (t, J = 5.4 Hz, 2H), 1.46 (dd, J = 6.9, 5.7 Hz, 3H), 1.26 - 1.24 (m, 16H), 1.04 (d, J = 1.8 Hz, 9H), 0.97 (s, 3H) ppm. LC / MS (ESI) m / z 1682.6; [M+H] + C 85 H 112 ClF3N 11 O 11 S4 + Calculated value: 1682.71.

Example

[0386] Preparation of Compounds #31 - 32

Chemical formula

[0387] tert-Butyl (1R,5S)-3-(2-ethoxy-2-oxoethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (31-2). 1 H NMR (600MHz, chloroform-d) δ4.17(q,J=7.1Hz,2H),4.05(d,J=26.2Hz,2H),3.39(d,J=3.8Hz,2H),3.36(s,1H),3.21(s,1H) ,3.01(d,J=9.8Hz,2H),2.43(dtt,J=8.1,6.1,1.0Hz,1H),1.61(d,J=8.1Hz,1H),1.44(s,9H),1.27(t,J=7.1Hz,3H)ppm.

[0388] tert-Butyl (1R,5S)-3-(2-ethoxy-2-oxoethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (32-2). 1 H NMR(600MHz,chloroform-d)δ4.20(s,1H),4.15(q,J=7.1Hz,2H),4.13-4.07(m,1H),3.19(d,J=1.5Hz,2H),2.65(d,J= 10.6Hz,2H),2.56(d,J=34.3Hz,2H),1.91(dd,J=7.5,4.7Hz,2H),1.88-1.78(m,2H),1.46(s,9H),1.25(s,3H)ppm.

[0389] tert-Butyl 2-((1R,5S)-3-(2-ethoxy-2-oxoethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)acetate (31-3). 1 H NMR(600MHz,chloroform-d)δ4.19(q,J=7.1Hz,2H),3.73(d,J=5.8Hz,2H),3.45(s,2H),3.40(s,2H),3.26(d,J=10.6Hz,2H), 2.89(dd,J=10.8,1.5Hz,2H),2.56(dt,J=8.0,5.9Hz,1H),1.89(d,J=8.1Hz,1H),1.45(s,10H),1.29(t,J=7.1Hz,3H)ppm.

[0390] tert-Butyl 2-((1R,5S)-3-(2-ethoxy-2-oxoethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)acetate (32-3). 1 H NMR(600MHz,chloroform-d)δ4.14(q,J=7.1Hz,2H),3.24(s,2H),3.16(s,2H),3.14(s, 2H),2.69-2.58(m,4H),1.94-1.82(m,4H),1.45(s,9H),1.26(t,J=7.1Hz,3H)ppm.

[0391] tert-Butyl 2-((1R,5S)-3-(2-ethoxy-2-oxoethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)acetate (31-4). LC / MS (ESI) m / z 299.1; [M+H] + C 15 H 27 N2O4 + Calculated value: 299.20.

[0392] 2-((1R,5S)-3-(2-ethoxy-2-oxoethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)acetic acid (32-4). 1 H NMR (600MHz, methanol-d4) δ4.24-4.18(m,4H),4.10(s,2H),3.72(s,2H),3.64(s,1H),3. 42(d,J=13.2Hz,2H),3.35-3.30(m,2H),2.32-2.27(m,4H),1.27(t,J=7.1Hz,3H)ppm.

[0393] Ethyl 2-((1R,5S)-6-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)acetate (31-5). 1H NMR (600MHz, chloroform-d) δ8.67-8.64(m,1H),8.10(s,1H),7.51(d,J=7.8Hz,1H),7.36(ddd,J=8.8,6.3,3.7Hz ,4H),5.09(d,J=11.8Hz,1H),4.73(d,J=6.3Hz,1H),4.55-4.44(m,2H),4.20-4.02(m,3H),3.58(dd,J=11.4, 3.6Hz,1H),3.45(s,2H),3.32(d,J=20.4Hz,1H),3.11(d,J=2.0Hz,6H),3.03-2.96(m,2H),2.53-2.48(m,4H) ,2.08(dd,J=13.5,8.1Hz,1H),2.05-1.96(m,1H),1.47(dd,J=7.2,3.0Hz,4H),1.21(s,3H),1.06(s,9H)ppm.

[0394] Ethyl 2-((1R,5S)-8-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)acetate (32-5). 1H NMR(600MHz,chloroform-d)δ8.67(s,1H),8.28(s,1H),7.53(d,J=7.7Hz,1H),7.40(d,J=8.0Hz,2H),7.36(d,J=8.2Hz,2H),5.0 7(p,J=7.0Hz,1H),4.78(dt,J=8.0,3.6Hz,1H),4.49(s,1H),4.40(d,J=7.6Hz,1H),4.23(d,J=12.1Hz,1H),4.17-4.13(m,2 H),3.57(d,J=11.4Hz,1H),3.20(s,3H),3.09(s,2H),2.99(d,J=11.5Hz,2H),2.73-2.63(m,3H),2.53(s,3H),2.10-2.05(m ,1H),1.91(d,J=7.9Hz,2H),1.82(q,J=7.7,6.3Hz,2H),1.47(d,J=6.9Hz,3H),1.27(td,J=7.0,1.5Hz,3H),1.09(s,9H)ppm.

[0395] (2S,4R)-1-((2S)-2-(2-(3-(2-(4-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydrofuran N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound #31). 11H NMR (600 MHz, chloroform-d) δ 8.66 (d, J = 1.1 Hz, 1H), 8.32 (dd, J = 6.5, 2.2 Hz, 2H), 8.05 (t, J = 8.7 Hz, 2H), 7.89 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 7.37 (dt, J = 8.1, 1.3 Hz, 6H), 7.29 - 7.27 (m, 5H), 7.01 - 6.98 (m, 3H), 6.89 (d, J = 8.5 Hz, 1H), 6.81 - 6.73 (m, 4H), 6.55 (d, J = 9.2 Hz, 1H), 6.50 (d, J = 9.3 Hz, 1H), 5.08 (q, J = 7.1 Hz, 1H), 4.80 (t, J = 8.2 Hz, 1H), 4.52 (d, J = 8.3 Hz, 1H), 4.46 (s, 1H), 4.13 (d, J = 10.3 Hz, 1H), 3.85 (s, 1H), 3.64 (s, 8H), 3.58 (d, J = 11.1 Hz, 1H), 3.34 (s, 4H), 3.22 (d, J = 35.3 Hz, 5H), 3.12 - 3.07 (m, 1H), 2.96 (d, J = 7.3 Hz, 15H), 2.67 (s, 2H), 2.51 (d, J = 0.7 Hz, 4H), 2.43 (s, 2H), 2.35 (td, J = 16.4, 15.2, 8.6 Hz, 6H), 2.23 (d, J = 19.6 Hz, 1H), 2.16 - 2.07 (m, 1H), 1.73 - 1.52 (m, 4H), 1.48 (d, J = 6.9 Hz, 3H), 1.35 (d, J = 18.6 Hz, 5H), 1.06 (s, 9H) ppm. LC / MS (ESI) m / z 1680.7; [M + H] + C 83 H 106 ClF3N 13 O 11 S4 + Calculated value: 1680.67.

[0396] (2S,4R)-1-((2S)-2-(2-((1R,5S)-3-(2-(4-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5- Tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound #32). 1 H NMR(600MHz,chloroform-d)δ8.67(s,1H),8.32(t,J=2.1Hz,1H),8.15(s,1H),8.09( t,J=9.8Hz,1H),7.69(d,J=8.4Hz,2H),7.47(d,J=8.9Hz,1H),7.42-7.34(m,6H) ,7.32-7.26(m,4H),7.02(d,J=8.6Hz,1H),7.00-6.97(m,2H),6.77(d,J=8.5Hz, 2H),6.63-6.58(m,1H),5.08(p,J=7.2Hz,1H),4.76(td,J=7.9,5.9Hz,1H),4.53 -4.44(m,2H),4.22(s,1H),3.90(s,1H),3.65(td,J=6.4,3.4Hz,5H),3.57(s,4H) ),3.21(d,J=26.3Hz,5H),3.17-2.98(m,6H),2.81(d,J=29.1Hz,4H),2.66-2.54 (m,5H),2.52(s,3H),2.45-2.22(m,19H),2.15-2.03(m,4H),1.90(d,J=16.6Hz, 2H),1.73-1.56(m,7H),1.48(d,J=6.9Hz,3H),1.07(s,10H)ppm.LC / MS(ESI)m / z 1694.6;[M+H] + C 84 H 108 ClF3N 13 O 11 S4 +Calculated value: 1694.68. [Example]

[0397] Preparation of Compound #33 [ka] Compound #33 was prepared according to general procedure E.

[0398] tert-Butyl 4-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-nitrophenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazine-1-carboxylate (33-1) (73 mg, 61% yield). 1 H NMR(600MHz,CDCl3)δ8.75(d,J=2.3Hz,1H),7.99-7.92(m,1H),7.73(d,J=8.6Hz,2H),7.34-7.17(m,8H),7.02-6.94( m,2H),6.74(dd,J=20.2,9.0Hz,3H),3.99(p,J=5.7Hz,1H),3.69(qt,J=10.0,5.0Hz,4H),3.38(d,J=5.2Hz,4H),3.26 (t,J=5.2Hz,4H),3.19-3.08(m,2H),2.87(s,2H),2.56-2.34(m,16H),2.33-2.25(m,1H),2.24-2.17(m,3H),2.17-2. 07(m,2H),1.93(d,J=17.3Hz,1H),1.87-1.77(m,1H),1.62-1.55(m,1H),1.44(s,9H),0.93(s,3H)ppm.LC / MS(ESI)m / z 1071.7;[M+H] + C 55 H 72 ClN8O8S2 + Calculated value: 1071.46.

[0399] 4-(4-((4'-chloro-4-methyl-4-(piperazin-1-ylmethyl)-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-nitrophenyl)sulfonyl)benzamide hydrochloride (33-2) (75 mg, quantitative yield). LC / MS (ESI) m / z 971.4; [M+H] + C 50 H 64 ClN8O6S2 + Calculated value: 971.41.

[0400] (2S,4R)-1-((2S)-2-(8-(4-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-nitrophenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound #33) (29.9 mg, 49% yield). 1H NMR(600MHz,クロロホルム-d)δ8.76(d,J=2.5Hz,1H),8.68(s,1H),7.97(d,J=9. 2,2.5Hz,1H),7.74(d,J=8.5Hz,2H),7.54-7.45(m,1H),7.42-7.31(m,6H) ,7.31-7.18(m,5H),7.02-6.96(m,2H),6.74(d,J=8.1Hz,3H),6.52(d,J=9 .8Hz,1H),5.15-5.04(m,1H),4.74-4.64(m,1H),4.60(dd,J=9.1,4.1Hz,1H ),4.49(s,1H),4.07(d,J=11.3Hz,1H),4.01(s,1H),3.76-3.63(m,5H),3. 64-3.51(m,3H),3.43(s,2H),3.31-3.19(m,5H),3.19-3.09(m,3H),2.87( s,2H),2.66-2.07(m,25H),1.97-1.76(m,3H),1.68-1.53(m,6H),1.53-1. 41(m,4H),1.38-1.24(m,6H),1.04(s,9H),0.96(s,3H)ppm.LC / MS(ESI)m / z 1553.7;[M+H] + C 81 H 106 C1N 12 O 11 S3 + Calculated value: 1553.69.

Example

[0401] Preparation of Compound #34

change

[0402] The last three steps for the preparation of compound #34 were carried out according to general procedure G.

[0403] tert-Butyl 4-((4'-chloro-6-((4-(4-(((4-(((R)-4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino)-3-nitrophenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-4-methyl-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazine-1-carboxylate (34-2) (23 mg, 48% yield). 1H NMR (600 MHz, chloroform-d) δ 8.64 (s, 1H), 7.84 (d, J = 8.5 Hz, 3H), 7.33-7.24 (m, 4H), 7.22-7.11 (m, 3H), 6.99 (dd, J = 8.5, 2.5 Hz, 2H), 6.77-6.70 (m, 2H), 6.67 (s, 1H), 4.05-3.94 (m, 1H), 3.48 (t, J = 5.3 Hz, 1H), 3.46- 3.35(m,4H),3.28-3.17(m,4H),3.11(s,2H),2.83(s,4H),2.65-2.45(m,9H),2.45-2.26(m,5H),2.25-2 .09(m,5H),2.07-1.89(m,3H),1.64-1.54(m,1H),1.46(s,9H),0.95(d,J=2.8Hz,3H)ppm.LC / MS(ESI)m / z 1029.8;[M+H] + C 53 H 70 ClN8O7S2 + Calculated value: 1029.45.

[0404] 4-(4-((4'-chloro-4-methyl-4-(piperazin-1-ylmethyl)-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((R)-4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino)-3-nitrophenyl)sulfonyl)benzamide hydrochloride (34-3) (25 mg, quantitative yield). 1H NMR (600MHz, methanol-d4) δ8.70(d,J=2.3Hz,1H),7.98(dd,J=9.2,2.4Hz,1H),7.80(d,J=8.9Hz,2H),7.43(d,J=8.0Hz,2H ),7.27-7.20(m,4H),7.10-7.05(m,4H),7.02(d,J=8.8Hz,2H),4.23(dq,J=9.8,5.0Hz,1H),3.97-3.82(m,3H),3.82-3.4 1(m,15H),3.37-3.21(m,4H),3.03-2.95(m,1H),2.90(d,J=4.4Hz,6H),2.87-2.70(m,2H),2.51(s,2H),2.41(d,J=16.5H) z,1H),2.36-2.28(m,1H),2.27-2.19(m,1H),2.14-2.04(m,1H),1.68(d,J=10.6Hz,1H),1.27(s,3H)ppm.LC / MS(ESI)m / z 929.7;[M+H] + C 48 H 62 ClN8O5S2 + Calculated value: 929.40.

[0405] (2S,4R)-1-((2S)-2-(8-(4-((4'-chloro-6-((4-(4-(((4-((R)-4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino)-3-nitrophenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-4-methyl-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound #34) (4.9 mg, 17% yield). 1H NMR (600MHz, chloroform-d) δ8.73-8.64(m,2H),7.89(d,1H),7.80(d,J=8.4Hz ,2H),7.56-7.47(m,1H),7.42-7.35(m,4H),7.34-7.25(m,4H),7.24-7.15( m,3H),7.02-6.97(m,2H),6.75(d,J=8.6Hz,2H),6.68(d,J=9.2Hz,1H),6.5 3(d,J=8.9Hz,1H),5.09(p,J=7.1Hz,1H),4.75-4.66(m,1H),4.61(dd,J=9. 1,3.5Hz,1H),4.49(s,1H),4.07(d,J=11.4Hz,1H),3.99(s,1H),3.67-3.5 0(m,3H),3.47-3.37(m,2H),3.21(s,4H),3.12(d,J=5.6Hz,2H),2.89-2.77 (m,2H),2.73-2.06(m,32H),2.02-1.86(m,2H),1.74-1.50(m,6H),1.53-1. 41(m,4H),1.38-1.16(m,5H),1.04(s,9H),0.95(s,3H)ppm.LC / MS(ESI)m / z 1511.4;[M+H] + C 79 H 104 ClN 12 O 10 S3 + Calculated value: 1511.68. [Example]

[0406] Preparation of compounds #35-36 [ka] Compounds #35-36 were prepared according to general procedure D.

[0407] tert-Butyl (R)-(4-(cyclopropyl(methyl)amino)-1-(phenylthio)butan-2-yl)carbamate (35-1) (28 mg, 79% yield). 1H NMR(600MHz,CDCl3)δ7.42(d,J=7.7Hz,2H),7.34-7.26(m,2H),7.19(t,J=7.5Hz,1H),5.52(s,1H),3.83(s,1H),3.25(d,J=13.5Hz,1H),3. 09-2.99(m,1H),2.74-2.59(m,2H),2.36(s,3H),1.96-1.84(m,1H),1.75-1.63(m,2H),1.45(s,9H),0.57-0.43(m,4H)ppm.LC / MS(ESI)m / z 351.2;[M+H] + C 19 H 31 N2O2S + Calculated value: 351.21.

[0408] tert-Butyl (R)-(4-(cyclobutyl(methyl)amino)-1-(phenylthio)butan-2-yl)carbamate (36-1) (32 mg, 86% yield). 1 H NMR(600MHz,MeOD)δ7.44(d,J=7.7Hz,2H),7.33(td,J=7.7,1.7Hz,2H),7.26-7.20(m,1H),3.74-3.63(m,2H),3.19-2.96( m,4H),2.68(s,3H),2.38-2.20(m,3H),2.17-2.08(m,1H),2.00(s,3H),1.91-1.75(m,2H),1.46(s,9H)ppm.LC / MS(ESI)m / z 365.1;[M+H] + C 20 H 33 N2O2S + Calculated value: 365.23.

[0409] (R)-N1-Cyclopropyl-N1-methyl-4-(phenylthio)butane-1,3-diamine hydrochloride (35-2) (25 mg, quantitative yield). LC / MS (ESI) m / z 251.2; [M+H] + C 14 H 23 N2S + Calculated value: 251.16.

[0410] (R)-N1-Cyclobutyl-N1-methyl-4-(phenylthio)butane-1,3-diamine hydrochloride (36-2) (34 mg, quantitative yield). LC / MS (ESI) m / z 265.1; [M+H] + C 15 H 25 N2S + Calculated value: 265.17.

[0411] (R)-4-((4-(cyclopropyl(methyl)amino)-1-(phenylthio)butan-2-yl)amino)-3-nitrobenzenesulfonamide (35-3) (14 mg, 39% yield over two steps). 1 H NMR(600MHz,CDCl3)δ8.70-8.65(m,1H),7.71(dd,J=9.1,2.3Hz,1H),7.40-7.33(m,2 H),7.33-7.23(m,3H),6.63(d,J=9.2Hz,1H),3.92(p,J=6.1Hz,1H),3.18-3.07(m,2H) ,2.79-2.70(m,1H),2.61-2.53(m,1H),2.33(s,3H),2.16-2.08(m,1H),1.94-1.82(m ,1H),1.63(p,J=5.8Hz,1H),0.51-0.38(m,3H),0.28-0.20(m,1H)ppm.LC / MS(ESI)m / z 451.1;[M+H] + C 20 H 27 N4O4S2 + Calculated value: 451.15.

[0412] (R)-4-((4-(cyclobutyl(methyl)amino)-1-(phenylthio)butan-2-yl)amino)-3-nitrobenzenesulfonamide (36-3): (30 mg, 74% yield over two steps). 1H NMR (600 MHz, chloroform-d) δ 8.92 (d, J = 8.3 Hz, 0H), 8.69 (d, J = 2.3 Hz, 1H), 7.74 (dt, J = 9.3, 1.7 Hz, 1H), 7.39 (dq, J = 6.2, 1.2 Hz, 2H), 7.34-7.21 (m, 4H), 6.71 (dd, J = 9.3, 1.6 Hz, 1H), 4.06-3.95 (m, 1H), 3.23-3.3 .10(m,2H),2.78(p,J=8.0Hz,1H),2.56-2.46(m,1H),2.25(dt,J=12.5,5.6Hz,1H),2.16-2.05(m,4H ),2.04-1.95(m,2H),1.95-1.84(m,2H),1.75(p,J=9.8Hz,1H),1.68-1.52(m,2H)ppm.LC / MS(ESI)m / z 465.0;[M+H] + C 21 H 29 N4O4S2 + Calculated value: 465.16.

[0413] tert-Butyl 4-((4'-chloro-6-((4-(4-(((4-(((R)-4-(cyclopropyl(methyl)amino)-1-(phenylthio)butan-2-yl)amino)-3-nitrophenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-4-methyl-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazine-1-carboxylate (35-4) (30 mg, 91% yield). 1H NMR(600MHz,CDCl3)δ8.86-8.78(m,...

Claims

1. Formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein R １ teeth, 【Chemistry 2】 and R ２ No ２ , SO- ２ CF ３ or SO ２ CF ２ Cl, R ３ are Cl, F, and CF ２ H, C.F.H. ２ or CF ３ and R ４ is H or CH ３ and L １ teeth, 【Transformation 3】 【change】 【change】 【change】 and L ２ is a bond, 【Chemistry 4】 and each X is independently CH or N; each k is independently 0, 1, 2, 3, 4, 5, or 6; each m is independently 2, 3, 4, 5, 6, or 7; each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each p is independently 0, 1, 2, 3, or 4; each q is independently 1, 2, or 3; each r is independently 1 or 2; R ５ are independently H, optionally substituted alkyl or optionally substituted cycloalkyl; A compound or a pharmaceutically acceptable salt thereof.

2. L １ but 【Transformation 5】 【change】 【change】 【change】 and L ２ is bonded, 【Transformation 6】 2. The compound of claim 1, wherein:

3. 2. The compound of claim 1, wherein the compound is of the following formula: or a pharmaceutically acceptable salt thereof: 【Transformation 7】

4. L １ but 【Transformation 8】 and L 1 is 【Chemistry 9】 or L 1 may be 【Chemistry 10】 and / or L2 is 【Chemistry 11】 and L2 is 【Chemistry 12】 or L 2 may be 【Chemistry 13】 may be; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

5. R １ but 【Chemistry 14】 and R 1 is 【Chemistry 15】 may be, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

6. L １ but 【Chemistry 16】 and L ２ is combined or 【Chemistry 17】 is; or L 1 is [Chemistry 18] and L 2 is 【Chemistry 19】 is; or L 1 is 【Chemistry 20】 and L 2 is 【Chemistry 21】 is; or L 1 is 【Chemistry 22】 and L 2 is 【Chemistry 23】 is; or L2 is 【Chemistry 24】 and L 1 is 【Chemistry 25】 Or L2 is 【Chemistry 26】 and L 1 is 【Chemistry 27】 Or L2 is 【Chemistry 28】 and L 1 is 【Chemistry 29】 Or L2 is 【Transformation 30】 and L 1 is 【Chemistry 31】 Or L2 is 【Chemistry 32】 and L 1 is 【Transformation 33】 Or L2 is 【Transformation 34】 and L 1 is 【Chemistry 35】 Or L2 is 【Transformation 36】 and L 1 is 【Chemistry 37】 ) or L2 is 【Transformation 38】 and L 1 is 【Chemistry 39】 Or L2 is 【Chemistry 40】 and L 1 is 【Chemistry 41】 Or L2 is 【Chemistry 42】 and L 1 is 【Chemistry 43】 Or L2 is 【Chemistry 44】 and L 1 is 【Chemistry 45】 or L2 is 【Chemistry 46】 and L 1 is 【Chemistry 47】 is; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

7. R ２ But NO ２ or R 2 is SO- 2 CF 3 ; and / or R 3 is F, Cl or CF 3 , where R 3 may be Cl; and / or R 4 is CH 3 or R 4 is H; and / or R 5 is H or R 5 is optionally substituted C 1-6 alkyl, where R 5 may be CH 3 ; and / or X is N or X is CH; and / or r is 1 or r is 2; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

8. 2. The compound of claim 1, wherein the compound is: Table 1 or Table 2

9. Formula (II) or Formula (III): 【Chemistry 48】 or a pharmaceutically acceptable salt thereof, wherein R ２ No ２ , SO- ２ CF ３ or SO ２ CF ２ Cl, R ３ are Cl, F, and CF ２ H, C.F.H. ２ or CF ３ and R ４ is H or CH ３ and L １ teeth, 【Chemistry 49】 【change】 【change】 【change】 and L ２ is a bond, [Transformation 50] and each X is independently CH or N; each k is independently 0, 1, 2, 3, 4, 5, or 6; each m is independently 2, 3, 4, 5, 6, or 7; each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each p is independently 0, 1, 2, 3, or 4; each q is independently 1, 2, or 3; each r is independently 1 or 2; R ５ are independently H, optionally substituted alkyl or optionally substituted cycloalkyl; However, R ２ SO- ２ CF ３ and L １ but 【Chemistry 51】 If L ２ is a bond, 【Chemistry 52】 isn't it; A compound or a pharmaceutically acceptable salt thereof.

10. L １ but 【Chemistry 53】 【change】 【change】 【change】 and L ２ is bonded, 【Chemistry 54】 and / or The compound has the formula: 【Transformation 55】 is of; The compound according to claim 9 or a pharmaceutically acceptable salt thereof.

11. L １ but 【Transformation 56】 and L 1 is 【Chemistry 57】 and / or L2 is 【Chemistry 58】 and L 2 is 【Chemistry 59】 may be; or L 1 is 【Transformation 60】 and L 2 is a bond or 【Chemistry 61】 is; or L 1 is 【Transformation 62】 and L 2 is 【Transformation 63】 is; 10. The compound of claim 9 or a pharmaceutically acceptable salt thereof.

12. L １ but 【Chemistry 64】 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein: X is N and r is 1; L2 is 【Transformation 65】 may be L2 is 【Chemical Formula 66】 may be, A compound or a pharmaceutically acceptable salt thereof.

13. R ２ But NO ２ or R 2 is SO- 2 CF 3 ; and / or R 3 is F, Cl or CF 3 , where R 3 may be Cl; and / or R 4 is CH 3 or R 4 is H; and / or R 5 is H or R 5 is optionally substituted C 1-6 alkyl, where R 5 may be CH 3 ; and / or X is N or X is CH; and / or r is 1 or r is 2; 10. The compound of claim 9 or a pharmaceutically acceptable salt thereof.

14. The compound is Table 3 【change】 【change】 【change】 【change】 【change】 【change】 【change】 is; or The compound is 【Transformation 67】 is; or The compound has the formula: 【Transformation 68】 is a compound of the formula:

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising the compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, The pharmaceutical composition may further comprise an additional agent, The additional agent may be an anti-cancer agent; The anti-cancer agent may be an alkylating agent, an antimetabolite, an anti-tumor antibiotic, an anti-cytoskeletal agent, a topoisomerase inhibitor, an anti-hormonal agent, a targeted therapeutic agent, a photodynamic therapeutic agent, or a combination thereof; Pharmaceutical compositions.

16. An in vitro method for degrading Bcl-2 protein, comprising administering an effective amount of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.

17. A composition for use in degrading Bcl-2 protein, comprising the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, The composition may be administered in vitro or The composition may be administered in vivo or The use may be in degrading Bcl-2 protein in a subject; The subject may be a mammal, or The subject may be a human. composition.

18. A composition for use in treating a disease or disorder in a subject, or for use in treating a subject suffering from or susceptible to a disease or disorder, comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof; The disease may be cancer, or The cancer may be a solid tumor; The cancer may be chronic lymphocytic leukemia; The cancer may be acute lymphoblastic leukemia. composition.

19. A composition for use in treating a Bcl-2 mediated cancer in a subject, or for use in treating a subject suffering from or susceptible to a Bcl-2 mediated cancer, comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof; The Bcl-2 mediated cancer may be chronic lymphocytic leukemia; The Bcl-2 mediated cancer may be a solid tumor; The Bcl-2 mediated cancer may be small cell lung cancer; The subject may be a mammal, or The subject may be a human. composition.

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