Isoquinoline derivatives as protein degraders, e7 degraders, antivirals, tumor therapeutics and immune suppressives

A pharmaceutical composition comprising a combination of a signaling molecule antagonist or agonist and a compound selected from the group consisting of

• rel-(3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• rel-(3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• rel-(3R,4R)-7-methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• rel-(3R,4R)—N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• rel-(3R,4R)—N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3R,4R)-7-methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3R,4R)—N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and
• (3R,4R)—N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3S,4S)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3S,4S)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3S,4S)-7-methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3S,4S)—N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and
• (3S,4S)—N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
• or a pharmaceutically acceptable hydrate, solvate or salt thereof, optionally in combination with a pharmaceutically acceptable carrier, wherein the signaling molecule is a receptor molecule or one or more of its downstream target, such as, EGFR, Ras, Phosphatidylinositol-4,5-bisphosphate 3-kinase alpha 85 kDa regulatory subunit or 110 kDa catalytic subunit (PI3K), Phosphatase and tensin homolog (PTEN), Protein kinase B (PKB, Akt), p70-S6 Kinase 1, mammalian target of rapamycin (mTOR1), FK506-binding protein (FKBP12), mTOR Complex 1 (mTORC1), TGFbeta pathway signaling, and/or NOTCH signaling, especially wherein the signaling molecule is a steroid receptor molecule for estrogen or a signaling molecule antagonist or agonist selected from the group mTOR inhibitor-8 (CAS No.:
• 2489196-70-3), mTOR inhibitor-3 (CAS No.:
• 1207358-59-5), mTOR inhibitor-1 (CAS No.:
• 468747-17-3), mTOR inhibitor-2 (CAS No.:
• 2219323-96-1), HDACs/mTOR Inhibitor 1 (CAS No.:
• 2271413-06-8), PI3K/mTOR Inhibitor-3 (CAS No. 1363338-53-7), PI3K/mTOR Inhibitor-2 (CAS No.:
• 1848242-58-9), PI3K/mTOR Inhibitor-1 (CAS No.:
• 1949802-49-6), MTI-31 (CAS No.:
• 1567915-38-1), Sapanisertib (CAS No.:
• 1224844-38-5), WAY-600 (CAS No.:
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• 1228013-30-6), MHY1485 (CAS No.:
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• 1013098-90-2), PF-04979064 (CAS No.:
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• 27406-31-1), MCX 28 (CAS No.:
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• 1394076-92-6), NSC781406 (CAS No.:
• 1676893-24-5), GDC-0349 (CAS No.:
• 1207360-89-1), Gedatolisib (CAS No.:
• 1197160-78-3), Compound 401 (CAS No.:
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• 1225037-39-7), (+)-Usnic acid (CAS No.:
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• 221877-56-1), AZD-8055 (CAS No.:
• 1009298-09-2), Torin 1 (CAS No.:
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• 1173204-81-3), PKI-402 (CAS No.:
• 1173204-81-3), Chrysophanol (CAS No.:
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• 1032754-93-0), Everolimus (CAS No.:
• 159351-69-6), WYE-687 (CAS No.:
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• 1174428-47-7), WYE-132 (CAS No.:
• 1144068-46-1), Lupiwighteone (CAS No.:
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• 2411853-34-2), SAR405 CAS No.:1523406-39-4), WYE-687 dihydrochloride (CAS No.:
• 1702364-87-1), PI3Kα-IN-5 (CAS No.:
• 2237953-19-2), PQR530 (CAS No.:
• 1927857-61-1), PKI-179 (CAS No.:
• 1197160-28-3),
• WYE-354 (CAS No.:
• 1062169-56-5), BGT226 maleate (CAS No.:
• 1245537-68-1), AKT-IN-10 (CAS No.:
• 2709045-56-5), BGT226 (CAS No.:
• 915020-55-2), AKT-IN-9 (CAS No.:
• 2709045-53-2), PI-103 (CAS No.:
• 371935-74-9), Voxtalisib (CAS No.:
• 934493-76-2), ETP-45658 (CAS No.:
• 1198357-79-7), PF-06843195 (CAS No.:
• 2067281-51-8), (32-Carbonyl)-RMC-5552 (CAS No.:
• 2382768-55-8), BC-LI-0186 (CAS No.:
• 695207-56-8), P7 (CAS No.:
• 1001409-50-2), BX-320 (CAS No.:
• 702676-93-5), BX-517 (CAS No.:
• 850717-64-5), BX517 (CAS No.:
• 850717-64-5), BX795 (CAS No.:
• 702675-74-9), BX-912 (CAS No.:
• 702674-56-4), JX06 (CAS No.:
• 729-46-4), Polyphyllin I (CAS No.:
• 50773-41-6), PS10 (CAS No.:
• 1564265-82-2), PS210 (CAS No.:
• 1221962-86-2), PS423 (CAS No.:
• 1221964-37-9), PDK1-IN-RS2 (CAS No.:
• 1643958-89-7), GSK2334470 (CAS No.:
• 1227911-45-6), PF-AKT400 (CAS. Nr.:
• 1004990-28-6), Capivasertib (CAS. Nr.:
• 1143532-39-1), Afuresertib (CAS. Nr.:
• 1047644-62-1), Borussertib (CAS. Nr.:
• 1800070-77-2), GSK-690693 (CAS. Nr.:
• 937174-76-0), AKT-IN-10 (CAS. Nr.:
• 2709045-56-5), AKT-IN-9 (CAS. Nr.:
• 2709045-53-2), AKT-IN-3 (CAS. Nr.:
• 2374740-21-1), Vevorisertib (CAS. Nr.:
• 1416775-46-6), FPA-124 (CAS. Nr.:
• 902779-59-3), CCT128930 (CAS. Nr.:
• 885499-61-6), AT13148 (CAS. Nr.:
• 1056901-62-2), an anti-CTLA-4 antibody, especially ipilimumab;
• an anti-PD-1 antibody, especially nivolumab, pembrolizumab or tislelizumab;
• and/or an anti-PD-L1 antibody, especially atezolizumab, durvalumab or avelumab.

An antiviral agent comprising a compound selected from the group consisting of

• rel-(3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• rel-(3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• rel-(3R,4R)-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(6-(trifluoromethyl)pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• rel-(3R,4R)-7-methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• rel-(3R,4R)-7-acetamido-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• rel-(3R,4R)-6,7-dimethoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• rel-(3R,4R)-2-(4-methylbenzyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• rel-(3R,4R)-2-(4-methylbenzyl)-N-(3-morpholinophenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• rel-(3R,4R)—N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• rel-(3R,4R)—N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• rel-(3R,4R)—N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-3-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, including all pharmaceutically acceptable salt and ester forms thereof and including all racemates of these compounds and salts, preferably
• (3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3R,4R)-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(6-(trifluoromethyl)pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3R,4R)-7-methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3R,4R)-7-acetamido-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3R,4R)-6,7-dimethoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3R,4R)-2-(4-methylbenzyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3R,4R)-2-(4-methylbenzyl)-N-(3-morpholinophenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3R,4R)—N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3R,4R)—N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3R,4R)—N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-3-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3S,4S)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3S,4S)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3S,4S)-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(6-(trifluoromethyl)pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3S,4S)-7-methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3S,4S)-7-acetamido-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3S,4S)-6,7-dimethoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3S,4S)-2-(4-methylbenzyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3S,4S)-2-(4-methylbenzyl)-N-(3-morpholinophenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3S,4S)—N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3S,4S)—N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and
• (3S,4S)—N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-3-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, especially
• rel-(3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• rel-(3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• rel-(3R,4R)-7-methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• rel-(3R,4R)—N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• rel-(3R,4R)—N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3R,4R)-7-methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3R,4R)—N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and
• (3R,4R)—N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3S,4S)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3S,4S)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3S,4S)-7-methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3S,4S)—N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and
• (3S,4S)—N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide.

A pharmaceutical composition comprising a combination of an anti-CTLA-4 antibody, especially ipilimumab;

• an anti-PD-1 antibody, especially nivolumab, pembrolizumab or tislelizumab;
• and/or an anti-PD-L1 antibody, especially atezolizumab, durvalumab or avelumab and a compound selected from the group consisting of
• (3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3R,4R)-7-methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3R,4R)—N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and
• (3R,4R)—N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3S,4S)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3S,4S)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3S,4S)-7-methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
• (3S,4S)—N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and
• (3S,4S)—N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
• or a pharmaceutically acceptable hydrate, solvate or salt thereof, optionally in combination with a pharmaceutically acceptable carrier.