# US 9,518,022 B2 · Anti-HIV compounds > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 9,518,022 B2 - Document ID: US9518022B2 - Status: Granted - Kind: B2 - Application number: 14/970,393 - Filed: 2015-12-15 - Published: 2016-06-16 - Granted: 2016-12-13 - Earliest claimed: 2014-12-15 - Assignees: Prosetta Antiviral Inc. - Applicants: Prosetta Antiviral, Inc. - Inventors: Andy Atuegbu; Dennis Solas; Clarence R. Hurt; Anatoliy Kitaygorodskyy - Web page: https://patentgrep.com/patent/US9518022B2 ## CPC - A61K 31/472: Non-condensed isoquinolines, e.g. papaverine - A61P 31/18: for HIV - C07D 217/02: with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines - C07D 217/04: with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom - C07D 217/06: with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates - C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) ## Abstract This invention provides, among other things, tetrahydroisoquinolines useful for treating viral infections, pharmaceutical formulations containing such compounds, as well as methods of inhibiting the replication of a virus, such as HIV, or treating a disease, such as AIDS. ## Claims ### Claim 1 A compound which is: in which R1 is phenyl substituted alkoxy; R2 is H or CF3 or unsubstituted alkoxy or phenyl substituted alkoxy; R3 is H or —C(O)OR4 or C(O)R4 or —C(O)NR4R5 wherein R4 and R5 are independently selected from unsubstituted alkyl, unsubstituted phenyl, or unsubstituted pyridinyl; A is substituted or unsubstituted phenyl, or a hydrate, solvate, or salt thereof. ### Claim 2 (depends on 1) The compound of claim 1, which is: or a hydrate, solvate, or salt thereof. ### Claim 3 (depends on 1) The compound of claim 1, which is: or a hydrate, solvate, or salt thereof. ### Claim 4 (depends on 1) The compound of claim 1, which is: or a hydrate, solvate, or salt thereof. ### Claim 5 (depends on 1) A pharmaceutical formulation comprising: a) a compound of claim 1, or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable excipient. ### Claim 6 (depends on 1) A method of inhibiting the replication of HIV in an animal, comprising: administering a compound of claim 1 to the animal, thereby inhibiting the replication of HIV in an animal. ### Claim 7 (depends on 6) The method of any of claims claim 6, wherein the animal is a human. ### Claim 8 (depends on 1) The compound of claim 1, or a hydrate, solvate, or salt thereof, wherein R3 is selected from the group consisting of —C(O)OCH3, —C(O)OC(CH3)3, —C(O)NH2, —C(O)NHC(CH3)3, and —(CH2)nCH3, wherein n is an integer selected from 0-10. ### Claim 9 (depends on 1) The compound of claim 1, or a hydrate, solvate, or salt thereof, wherein R3 is selected from the group consisting of ### Claim 10 (depends on 1) The compound of claim 1, or a hydrate, solvate, or salt thereof, wherein A is wherein each R10, R11, and R12 is independently selected from H or halogen or unsubstituted alkyl or halogen-substituted alkyl or unsubstituted alkoxy or phenyl-substituted alkoxy. ### Claim 11 (depends on 1) The compound of claim 1, or a hydrate, solvate, or salt thereof, wherein A is wherein R10 is C1-C6 unsubstituted alkoxy, R11 is C1-C6 unsubstituted alkoxy and R12 is C1-C6 unsubstituted alkoxy. ### Claim 12 (depends on 1) The compound of claim 1, or a hydrate, solvate, or salt thereof, wherein A is wherein R10 is C1-C3 unsubstituted alkoxy, R11 is methoxy and R12 is methoxy. ### Claim 13 (depends on 1) The compound of claim 1, or a hydrate, solvate, or salt thereof, wherein A is ### Claim 14 (depends on 1) The compound of claim 1, or a hydrate, solvate, or salt thereof, wherein A is wherein R10 is H or halogen or unsubstituted alkyl or halogen-substituted alkyl or unsubstituted alkoxy or phenyl-substituted alkoxy. ### Claim 15 (depends on 1) The compound of claim 1, or a hydrate, solvate, or salt thereof, wherein A is wherein R10 is H. ### Claim 16 (depends on 1) The compound of claim 1, or a hydrate, solvate, or salt thereof, wherein A is ### Claim 17 (depends on 1) The compound of claim 1, or a hydrate, solvate, or salt thereof, wherein A is R12 wherein R12 is substituted or unsubstituted imidazolyl. ### Claim 18 (depends on 1) The compound of claim 1, or a hydrate, solvate, or salt thereof, wherein A is R12 wherein R12 is unsubstituted imidazol-1-yl. ### Claim 19 (depends on 1) The compound of claim 1, or a hydrate, solvate, or salt thereof, wherein A is R12 wherein R12 is substituted pyrimidin-5-yl. ### Claim 20 (depends on 1) The compound of claim 1, or a hydrate, solvate, or salt thereof, wherein A is R12 wherein R12 is unsubstituted pyrimidin-5-yl. ### Claim 21 (depends on 1) The compound of claim 1, or a hydrate, solvate, or salt thereof, wherein A is wherein R10 is H or halogen or unsubstituted alkyl or halogen-substituted alkyl or unsubstituted alkoxy or phenyl-substituted alkoxy. ### Claim 22 (depends on 1) The compound of claim 1, or a hydrate, solvate, or salt thereof, wherein A is wherein R10 is methyl. ### Claim 23 (depends on 1) The compound of claim 1, wherein A is wherein R10 is halogen or unsubstituted alkyl or halogen-substituted alkyl or unsubstituted alkoxy or phenyl-substituted alkoxy. ### Claim 24 (depends on 1) The compound of claim 1, or a hydrate, solvate, or salt thereof, wherein A is wherein R10 is C1-C3 unsubstituted alkyl. ### Claim 25 (depends on 1) The compound of claim 1, or a hydrate, solvate, or salt thereof, wherein the compound is selected from the group consisting of 6-benzyloxy-1-[(E)-2-(4,5-dimethoxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline, 6-Benzyloxy-1-[(E)-2-(2,3-dihydrobenzofuran-5-yl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline, 6-Benzyloxy-7-methoxy-1-[(E)-2-(2,4,5-trimethoxyphenyl)vinyI]-1,2,3,4-tetrahydroisoquinoline, 6-benzyloxy-7-methoxy-1-[(E)-2-(4-methoxy-2-methyl-phenyl)vinyl]-1,2,3,4-tetrahydroisoquinoline, [6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydro-1 H-isoquinolin-2-yl]-(4-pyridyl)methanone, [6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-(3-pyridyl)methanone, 6-Benzyloxy-7-methoxy-1-[(E)-2-(7-methyl-2,3-dihydro-1,4-benzodioxin-6-yl)vinyl]-1 ,2,3,4-tetrahydroisoquinoline, (E)-1 -(4-(1 H-imidazol-1 -yl)styryl)-6-(benzyloxy)-7-methoxy-1 ,2,3,4-tetrahydroisoquinoline, 6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydroisoquinoline, (E)-7-(2-(6-(benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl)quinoline, tert-butyl 6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate, 6-(Benzyloxy)-7-methoxy-1 -[(E)-2-[4-(pyrimidin-5-yl)phenyl]ethenyl]-1,2,3,4-tetrahydroisoquinoline, (6-amino-3-pyridyl)-[6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydro-1 H-isoquinolin-2-yl]methanone, 6-Benzyloxy-1-[(E)-2-(2,4-dimethoxy-5-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline, 6-Benzyloxy-7-methoxy-1 -[(E)-2-(6-methyl-1 ,3-benzodioxol-5-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline, [6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydro-1 H-isoquinolin-2-yl]-(2-pyridyl)methanone, (2-amino-4-pyridyl)-[6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydro-1 H-isoquinolin-2-yl]methanone, and 6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline. ### Claim 26 (depends on 1) The compound of claim 1, or a hydrate, solvate, or salt thereof, wherein the compound is selected from the group consisting of (6-amino-2-pyridyl)-[6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydro-1 H-isoquinolin-2-yl]methanone, [6-Benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydro-1 H-isoquinolin-2-yl]-pyrazin-2-yl-methanone, Methyl 6-benzyloxy-1-[(E)-2-(4,5-dimethoxy-2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydro-1 H-isoquinoline-2-carboxylate, (2-Amino-3-pyridyl)-[6-benzyloxy-1-[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydro-1 H-isoquinolin-2-yl]methanone, 6-benzyloxy-1 -[(E)-2-(5-benzyloxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-3,4-dihydro-1 H-isoquinoline-2-carboxamide, 6-benzyloxy-7-methoxy-1 -[(E)-2-[4-methoxy-2-(trifluoromethyl)phenyl]vinyl]-1,2,3,4-tetrahydroisoquinoline, 6-benzyloxy-1-[(E)-2-(5-benzyloxy-2-ethyl-4-methoxy-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline, 6-benzyloxy-1-[(E)-2-(3-benzyloxy-4-methoxy-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline, 6-benzyloxy-1-[(E)-2-(5-benzyloxy-2-chloro-4-methoxy-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline, 6-benzyloxy-1-[(E)-2-(5-benzyloxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline, 6-Benzyloxy-7-methoxy-1-[(E)-2-(3,4,5-trimethoxyphenyl)vinyl]-1,2,3,4-tetrahydroisoquinoline, 6-Benzyloxy-7-methoxy-1-[(E)-2(7-methoxybenzofuran-4-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline, 6-Benzyloxy-1-[(E)-2-(2,4-dimethoxyphenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline, 6-Benzyloxy-1-[(E)-2-(3-butoxy-4-methoxy-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline, 6-Benzyloxy-1-[(E)-2-(5-fluoro-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline, 6-Benzyloxy-7-methoxy-1 -[(E)-2-(4-methoxyphenyl)vinyl]-1,2,3,4-tetrahydroisoquinoline, 6-Benzyloxy-1-[(E)-2-(5-butoxy-4-methoxy-2-methyl-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline, 1-[(E)-2-(benzofuran-5-yl)vinyl]-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline, 4-[5-[(E)-2-(B-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]-2-methoxy-4-methyl-phenoxy]butanoic acid, 6-Benzyloxy-1-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline, 6-Benzyloxy-1-[(E)-2-(1 H-indazol-6-yl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline, 6-Benzyloxy-1-[(E)-2-(2,6-difluoro-4-methoxy-phenyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline, 6-Benzyloxy-1 -[(E)-2-(2,6-dimethoxy-3-pyridyl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline, 1-[(E)-2-[5-(4-azidobutoxy)-4-methoxy-2-methyl-phenyl]vinyl]-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline, 6-Benzyloxy-7-methoxy-1-[(E)-2-(7-methylchroman-6-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline, 6-Benzyloxy-1-[(E)-2-chroman-8-ylvinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline, 6-Benzyloxy-7-methoxy-1-[(E)-2-(6-methyl-2,3-dihydrobenzofuran-5-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline, tert-Butyl 3-[(E)-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]indole-1-carboxylate, 6-Benzyloxy-1-[(E)-2-(1 H-indol-3-yl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline, tert-Butyl 7-[(E)-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1 -yl)vinyl]indole-1 -carboxylate, 6-Benzyloxy-7-methoxy-1-[(E)-2-(6-methoxy-2,3-dihydro-1,4-benzodioxin-7-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline, 6-Benzyloxy-7-methoxy-1-[(E)-2-(6-methoxy-1,3-benzodioxol -5-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline, 2-[(E)-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]-4,5-dimethoxy-N,N-dimethyl-aniline, 3-[(E)-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyI]-N,N-dimethyl-pyridin-2-amine, Ethyl 4-[5-[(E)-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]-2-methoxy-phenoxy]butanoate, 2-[(E)-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]aniline, (E)-2-(2-(6-(benzyloxy)-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl)-N,N-dimethylamine, (E)-6-(benzyloxy-7-methoxy-1-(4-(pyridine-3-yl)styryl)-1,2,3,4-tetrahydroisoquinoline, (E)-6-(benzyloxy)-7-methoxy-1-(4-(2-methyl-1 H-imidazol-1-yl)styryl)-1,2,3,4-tetrahydroisoquinoline, 6-(Benzyloxy)-7-methoxy-1-[(E)-2-[3-(pyridin-4-yl)phenyl]ethenyl]-1,2,3,4-tetrahydroisoquinoline, 6-Benzyloxy-7-methoxy-1-[(E)-2-(6-methoxybenzofuran-5-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline, 2-[4-[(E)-2-(6-Benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]phenyl]oxazole, 6-Benzyloxy-1-(E)-2-(2,3-dihydrobenzofuran-6-yl)vinyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline, 6-Benzyloxy-7-methoxy-1-[(E)-2-(4-methoxy-3-methyl-phenyl)vinyl]-1,2,3,4-tetrahydroisoquinoline, 6-Benzyloxy-7-methoxy-1-[(E)-2-(4-methoxy-2,3-dimethyl-phenyl)vinyl]-1,2,3,4-tetrahydroisoquinoline, 6-Benzyloxy-7-methoxy-11(E)-214-methoxy-3-[(2-methylimidazol-1-yl)methyl]phenyl]vinyl]-1,2,3,4-tetrahydroisoquinoline, and 6-Benzyloxy-7-methoxy-1-[(E)-2-[4-methoxy-3-(phenoxymethyl)phenyl]vinyl]-1,2,3,4-tetrahydroisoquinoline.