EP-4739393-A1 - TETRAHYDROQUINAZOLINE DERIVATIVES AS SELECTIVE CYTOTOXIC AGENTS

Abstract

The present disclosure is directed to tetrahydroquinazoline derivatives of Formula (I) and their use for selectively killing HIV infected GAG-POL expressing cells without concomitant cytotoxicity to HIV naïve cells, and for the treatment or prophylaxis of infection by HIV, or for the treatment, prophylaxis or delay in the onset or progression of AIDS or AIDS Related Complex (ARC).

Inventors

• BRESLIN, MICHAEL J.
• CONVERSO, ANTONELLA
• EL MARROUNI, Abdellatif
• FORSTER, Ashley
• HUNTER, DAVID N.
• SHAW, ANTHONY W.
• SHIPE, WILLIAM D.
• ZHANG, YUNLONG

Assignees

• Merck Sharp & Dohme LLC

Dates

Publication Date

20260513

Application Date

20240705

Claims (1)

1. 25726 WHAT IS CLAIMED IS: 1. A compound of Formula I: or a pharmaceutically X is N(R 3 ) or C(R 3 ); W is -C 1-6 alkyl-, -(C 0-6 alkyl)O-, -(C 1-6 alkyl)amino-, or -(C 1-6 alkyl)aminocarbonyl-, w herein W is substituted by 0, 1, or 2 R 5 substituents; each R5 independently is halo, C 1-4 alkyl or C 1-4 fluoroalkyl; R1 is halo, C 1-6 alkyl, (C 3-12 )heterocycloalkyl(C 0-4 alkyl), or (C 3-12 )cycloalkyl(C 0-4 alkyl); R2 is hydrogen, halo, or C 1-10 alkyl; R3 is hydrogen, halo, or C 1-10 alkyl; R 4 is selected from: a) a 5-membered heteroaryl having at least one nitrogen atom, b) a mono-, bicyclic- or tricyclic, 7- to 14-membered heteroaryl comprising at least one aromatic heteroatom containing ring, wherein said 7- to 14-member heteroaryl comprises at least one nitrogen atom, or c) a ketone containing ring system selected from triazolinonyl, 2,4-dihydro-3H-1,2,4- triazoly-3-onyl, dihydropyrrolo[3, 4-b]pyrrolonyl, imidazolidinonyl, 1,3-dihydro-2H- benzo[d]imidazole-2-onyl, dihydrobenzo[d]imidazolinonyl, 1,3-dihydroimidazo[4,5- c]pyridinonyl, oxazolo[5,4-c]pyridine-2-onyl, 1,5,6,7-tetrahydro-pyrrolo[3,2- c]pyridin-4-onyl, 1,3-dihydroimidazo[4,5-b]pyridine-2-onyl, isoindolinonyl, 4,5- dihydropyrrolo[3,4-b]pyrrolonyl, 4,5-dihydropyrrolo[3,4-b]pyrrol-6(2H)onyl, benzo[d]oxazolonyl, benzo[d]oxazol-2-onyl, 1,4,5,6- 25726 tetrahydrocyclopenta[c]pyrazolonyl, and 1,5,6,7- tetrahydro-pyrazolo[4,3-c]pyridine- 4-onyl; wherein R 4 is substituted by 0, 1, 2, or 3 R 4a substituents; each R 4a is selected from: C 1-6 alkyl, C 1-10 fluoroalkyl, amino, cyano, halo, hydroxy, ( C 1-10 alkyloxy)C 0-10 alkyl, C 1-10 fluoroalkyloxy, -(C 1-10 alkyl)OH, (C 1-6 alkyl) 1-2 amino(C 0-10 alkyl), amino(C 1-10 alkyl), aminocarbonyl(C 0-10 alkyl), (C 3-12 )cycloalkyl(C 0-6 alkyl), (C 5-6 )heteroaryl(C 0-6 alkyl), (C 6-14 )aryl(C 0-6 alkyl), -(C 0-4 alkyl)carbonyl, and –(C 0-5 alkyl)–(S(=O) 2 NH 2 ); wherein R 4a is substituted by 0, 1, 2, or 3 R 4b substituents; and each R4b independently is C 1-10 alkyloxy, C 1-6 alkyl, C 1-10 fluoroalkyl, amino, hydroxy, halo, or cyano. 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is N(R 3 ). 3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is C(R 3 ). 25726 4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein W is -C 1-6 alkyl-, -(C 1-6 alkyl)amino-, or -(C 1-6 alkyl)aminocarbonyl, wherein W is substituted by 0, 1, or 2 R 5 substituents. 5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein W is -(C 0-6 alkyl)O-, wherein W is substituted by 0, 1, or 2 R5 substituents. 6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is fluoro, chloro, bromo, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmetyl, cyclopentylmethyl, or cyclohexylmethyl. 7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen, fluoro, chloro, bromo, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or neopentyl. 8 . The compound of claim 7 or a pharmaceutically acceptable salt thereof, R 3 is hydrogen, fluoro chloro, methyl, bromo, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or neopentyl. 9. The compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof wherein R 4 is selected from: a) a 5-membered heteroaryl having at least one nitrogen atom, the 5-membered heteroaryl having at least one nitrogen atom, is selected from: triazolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrrolyl, tetrazolyl, furazanyl, 1,2,3- oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, and 1,2,3,5- oxatriazolyl; b) a mono-, bicyclic- or tricyclic, 7- to 14-membered heteroaryl comprising at least one aromatic heteroatom containing ring, wherein said 7- to 14-member heteroaryl comprises at least one nitrogen atom, and the mono-, bicyclic- or tricyclic, 7- to 14- membered heteroaryl comprising at least one aromatic heteroatom containing ring, 25726 wherein said 7- to 14-member heteroaryl comprises at least one nitrogen atom is selected from 2H-pyrazolo [4,3-c]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 6,7- dihydropyrano[4,3-c]pyrazolyl, 2H-pyrazolo[3,4-d]pyrimidinyl, 2H-pyrazolo[3,4- d]pyrimidinyl, indolyl, 2H-pyrazolo[3,4-b]pyridinyl, benzo[d][1,2,3]-triazolyl, benzo[d]imidazolyl, indolizinyl, isoindolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, carbazolyl, phenathridinyl, acridinyl, phenanthrolinyl, phenazinyl, 7H-pyrazino[2,3-c]carbazolyl, 1,3-benzooxazolyl, and 2,1-benzoxazolyl, or c) a ketone containing ring system selected from the ketone containing ring system selected from 2,4-dihydro-3H-1,2,4-triazoly-3-onyl, imidazolidinonyl, 1,3-dihydro- 2H-benzo[d]imidazole-2-onyl, 1,3-dihydroimidazo[4,5-c]pyridinonyl, isoindolinonyl, 4,5-dihydropyrrolo[3,4-b]pyrrol-6(2H)onyl, and benzo[d]oxazol-2onyl, 1,4,5,6- tetrahydrocyclopenta[c]pyrazolonyl, and further wherein R 4 is substituted by 0, 1, 2, or 3 R 4a substituents. 10. The compound of claim 9 or a pharmaceutically acceptable salt thereof wherein each R4a independently is selected from: C 1-4 alkyl, C 1-6 fluoroalkyl, amino, cyano, halo, hydroxy, (C 1-6 alkyloxy)C 0-6 alkyl, C 1-6 fluoroalkyloxy, -(C 1-6 alkyl)OH, (C 1-4 alkyl)1-2 amino(C 0-6 alkyl), amino(C 1-6 alkyl), aminocarbonyl(C 0-6 )alkyl), (C 3-12 )cycloalkyl(C 0-4 alkyl), (C 5-6 )heteroaryl(C 0-4 alkyl), (C 6-14 )aryl(C 0-6 alkyl), -(C 0-4 alkyl)carbonyl, and –(C 0-4 alkyl)–(S(=O)2NH2), wherein R 4a is substituted by 0, 1, 2, or 3 R 4b substituents. 11. The compound of claim 10 or a pharmaceutically acceptable salt thereof wherein each R4b independently is selected from C 1-6 alkyloxy, C 1-4 alkyl, C 1-6 fluoroalkyl, amino, hydroxy, halo, or cyano. 12. The compound of claim 11 or a pharmaceutically acceptable salt thereof wherein each R 5 independently is fluoro, chloro, methyl, ethyl, propyl, trifluoromethyl, 2,2,2- trifluoroethyl, difluoromethyl, or fluoromethyl. 13. The compound of claim 1 that is: 25726 (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methoxy-1H-1,2,4-triazol-1- yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(hydroxymethyl)-1H-pyrazol-1- yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-methoxy-1H-pyrazol-1- yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(hydroxymethyl)-1H-1,2,4- triazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((5-(hydroxymethyl)-1H-pyrazol-1-yl)methyl)-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((3-(hydroxymethyl)-1H-pyrazol-1-yl)methyl)-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3- yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-7-((2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-3-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin- 7-yl)methyl)-1-methylimidazolidine-2,4-dione; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-(pyridin-4-yl)-1H-pyrazol-1- yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-methyl-1H-pyrazol-1-yl)methyl)- 3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-3-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin- 7-yl)methyl)benzo[d]oxazol-2(3H)-one; (S)-3-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)imidazolidine-2,4-dione; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-fluoro-1H-pyrazol-1-yl)methyl)- 3,4-dihydroquinazolin-2(1H)-one; (S)-7-((4-chloro-1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro- 3,4-dihydroquinazolin-2(1H)-one; 25726 (S)-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)-1H-pyrazole-3-carbonitrile; (S)-7-((5-chloro-3-(methoxymethyl)-1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1- difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one; (S)-7-((3-bromo-1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro- 3,4-dihydroquinazolin-2(1H)-one; (S)-7-((1H-1,2,4-triazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4- dihydroquinazolin-2(1H)-one; (S)-7-((2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-7-((6,7-dihydropyrano[4,3-c]pyrazol-1(4H)-yl)methyl)-6-fluoro-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-7-((6,7-dihydropyrano[4,3-c]pyrazol-2(4H)-yl)methyl)-6-fluoro-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-7-((1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-6- fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((3-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4- yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-7-((3-chloro-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1- difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one; (S)-7-((3-chloro-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-4-(cyclopropylethynyl)-6- fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-7-((3-cyclopropyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-4-(cyclopropylethynyl)- 6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methyl-5-oxo-1,5-dihydro-4H- 1,2,4-triazol-4-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1- yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one; 25726 (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((6-oxo-5,6-dihydropyrrolo[3,4- b]pyrrol-1(4H)-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3- yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-3-((4-(cyclopropylethynyl)-6-fluoro-3-methyl-2-oxo-4-(trifluoromethyl)-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)imidazolidine-2,4-dione; (S)-7-((3-amino-1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro- 3,4-dihydroquinazolin-2(1H)-one; (S)-7-((3-amino-5-methyl-1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1- difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one; (S)-7-((3-amino-4-methyl-1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1- difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one; (S)-7-((3-amino-1H-pyrazol-1-yl)methyl)-4-(cyclopropyldifluoromethyl)-4- (cyclopropylethynyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(2-hydroxyethyl)-1H-pyrazol-1- yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-6-chloro-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(hydroxymethyl)-1H-pyrazol-1- yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((2-(hydroxymethyl)-1H-imidazol-1- yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((5-(hydroxymethyl)-1H-imidazol-1- yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-(hydroxymethyl)-1H-imidazol-1- yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-7-(1H,1'H-[3,3'-bipyrazol]-1-ylmethyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6- fluoro-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((1'-methyl-1H,1'H-[3,3'-bipyrazol]- 1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methoxymethyl)-1H-pyrazol-1- yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-7-((1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4- dihydroquinazolin-2(1H)-one; 25726 (S)-7-((1H-imidazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4- dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methoxy-1H-pyrazol-1- yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-((R or S)-1-methoxyethyl)-1H- pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-((S or R)-1-methoxyethyl)-1H- pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-7-((3-amino-5-chloro-1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)- 6-fluoro-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-oxo-3,4,5,6- tetrahydrocyclopenta[c]pyrazol-1(2H)-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-1-((4-(cyclopropyldifluoromethyl)-4-(cyclopropylethynyl)-6-fluoro-2-oxo-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)-1H-imidazole-2-carboxamide; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(difluoromethoxy)-1H-pyrazol-1- yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-(methoxymethyl)-1H-pyrazol-1- yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methoxymethyl)-1H-1,2,4- triazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-7-((4-chloro-3-(methoxymethyl)-1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1- difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-fluoro-3-(hydroxymethyl)-1H- pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(hydroxymethyl)-4-methyl-1H- pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-7-((5-chloro-3-(hydroxymethyl)-1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1- difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-(2-hydroxyethyl)-1H-pyrazol-1- yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-7-((4-chloro-3-(hydroxymethyl)-1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1- difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one; 25726 (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-((S or R)-1-hydroxyethyl)-1H- pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-((R or S)-1-hydroxyethyl)-1H- pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((2-methoxy-1H-imidazol-1- yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methylamino)-1H-pyrazol-1- yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(dimethylamino)-1H-pyrazol-1- yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one; (S)-4-chloro-N-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)-1H-imidazole-5-carboxamide; (S)-4-chloro-N-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)-1H-imidazole-5-carboxamide; (S)-N-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)-1H-imidazole-2-carboxamide; (S)-N-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin- 7-yl)methyl)-1H-imidazole-2-carboxamide; (S)-N-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)-N-methyl-1H-imidazole-2-carboxamide; (S)-N-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)-1-methyl-1H-imidazole-2-carboxamide; (S)-N-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin- 7-yl)methyl)oxazole-2-carboxamide; (S)-2-amino-N-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)-4-methylthiazole-5-carboxamide; (S)-N-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin- 7-yl)methyl)-4H-1,2,4-triazole-3-carboxamide; (S)-N-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin- 7-yl)methyl)-3-methyl-1H-pyrrole-2-carboxamide; (S)-N-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin- 7-yl)methyl)-4-methyl-1H-imidazole-5-carboxamide; 25726 (S)-4-cyano-N-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)-1H-pyrrole-2-carboxamide; (S)-N-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin- 7-yl)methyl)thiazole-2-carboxamide; (S)-7-((2H-indazol-2-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4- dihydroquinazolin-2(1H)-one; (S)-7-((1H-indazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4- dihydroquinazolin-2(1H)-one; (S)-7-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6- fluoro-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methyl-1H-indazol-1-yl)methyl)- 3,4-dihydroquinazolin-2(1H)-one; (S)-7-((1H-benzo[d]imidazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6- fluoro-3,4-dihydroquinazolin-2(1H)-one; (S)-7-((4-chloro-3-methoxy-1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1- difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((1-oxoisoindolin-2-yl)methyl)-4-(trifluoromethyl)-3,4- dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(4-methoxyphenyl)-1H-pyrazol- 1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-1- yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-7-((3-amino-4-methoxy-1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1- difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one; (S)-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin- 7-yl)methyl)-1H-imidazole-2-carboxamide; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((3-methyl-1H-pyrazol-1-yl)methyl)-4-(trifluoromethyl)- 3,4-dihydroquinazolin-2(1H)-one; (S)-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)-1H-pyrazole-3-carbaldehyde; (S)-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)-4-fluoro-1H-pyrazole-5-carboxamide; 25726 (S)-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)-4-fluoro-1H-pyrazole-3-carboxamide; (S)-7-((5-amino-1H-1,2,4-triazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6- fluoro-3,4-dihydroquinazolin-2(1H)-one; (S)-7-((3-amino-1H-1,2,4-triazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6- fluoro-3,4-dihydroquinazolin-2(1H)-one; (S)-7-((3-amino-1H-1,2,4-triazol-1-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4- triazol-4-yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((5-oxo-4,5-dihydro-1H-1,2,4- triazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-3-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)-1-methylimidazolidine-2,4-dione; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((methyl(1H-pyrazol-3- yl)amino)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methoxymethyl)-1H-pyrazol-1- yl)methyl)-3-methyl-3,4-dihydroquinazolin-2(1H)-one; (S)-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)-1H-1,2,4-triazole-3-carboxamide; (S)-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)-1H-1,2,4-triazole-5-carboxamide; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-fluoro-3-methoxy-1H-pyrazol-1- yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin- 7-yl)methyl)-1H-1,2,4-triazole-5-carboxamide; (S)-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin- 7-yl)methyl)-1H-1,2,4-triazole-3-carboxamide; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((5-methyl-2H-tetrazol-2-yl)methyl)-4-(trifluoromethyl)- 3,4-dihydroquinazolin-2(1H)-one; (S)-7-((2H-indazol-3-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4- dihydroquinazolin-2(1H)-one; 25726 (S)-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)-1H-pyrazole-3-sulfonamide; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((4-(difluoromethyl)-1H-pyrazol-1- yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-methyl-5-oxo-4,5-dihydro-1H- 1,2,4-triazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-6-chloro-4-(cyclopropylethynyl)-7-((4-methoxy-1H-pyrazol-1-yl)methyl)-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one; 5-(((S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)-1-methylimidazolidine-2,4-dione; (S)-5-(((S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)-1-methylimidazolidine-2,4-dione; (R)-5-(((S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)-1-methylimidazolidine-2,4-dione; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-((dimethylamino)methyl)-1H-pyrazol-1- yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-7-((3-methyl-1H-pyrazol-1-yl)methyl)-4-(trifluoromethyl)-3,4- dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3,4-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4- triazol-1-yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one; and (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(2-hydroxypropan-2-yl)-1H- pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one, or a pharmaceutically acceptable salt thereof. 14. The compound of claim 1 that is: (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methoxy-1H-1,2,4-triazol-1- yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-7-((1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-6- fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one; (S)-7-((3-amino-1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro- 3,4-dihydroquinazolin-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methoxymethyl)-1H-pyrazol-1- yl)methyl)-3,4-dihydroquinazolin-2(1H)-one; 25726 (S)-7-((5-amino-1H-1,2,4-triazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6- fluoro-3,4-dihydroquinazolin-2(1H)-one; (S)-7-((3-amino-1H-1,2,4-triazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6- fluoro-3,4-dihydroquinazolin-2(1H)-one; (S)-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)-1H-1,2,4-triazole-3-carboxamide; (S)-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)-1H-1,2,4-triazole-5-carboxamide; (S)-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin- 7-yl)methyl)-1H-1,2,4-triazole-5-carboxamide; or (S)-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin- 7-yl)methyl)-1H-1,2,4-triazole-3-carboxamide; or a pharmaceutically acceptable salt thereof. 15. A pharmaceutical composition comprising an effective amount of the compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 16. The pharmaceutical composition of claim 15 further comprising an effective amount of one or more additional nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide reverse transcriptase translocation inhibitors, non- nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors, HIV maturation inhibitors, post-attachment inhibitors and latency reversing agents. 17. A method for the treatment or prophylaxis of infection by HIV, or for the treatment, prophylaxis or delay in the onset or progression of AIDS or ARC in a human subject in need thereof which comprises administering to the subject an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof. 18. A method for eliciting GAG-POL dimerization in HIV-infected cells in a human subject in need thereof which comprises administering to the subject an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof. 25726 19. A method for selectively killing HIV infected GAG-POL expressing cells in a human subject which comprises administering to the subject an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof. 20. A method for selectively killing HIV infected GAG-POL expressing cells without concomitant cytotoxicity to HIV naïve cells in a human subject which comprises administering to the human subject an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof. 21. A method for augmenting the suppression of HIV viremia in a human subject whose viremia is being suppressed by administration of one or more compatible HIV antiviral agents, which comprises additionally administering to the subject an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof. 22. The method of any one of claims 1 to 15 further comprising administering to the human subject an effective amount of one or more additional compatible HIV antiviral agents selected from nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside reverse transcriptase translocation inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors, HIV maturation inhibitors, post-attachment inhibitors and latency reversing agents. 23. The compound according to any one of claims 1 to 14 for use in therapy.

Description

25726 TETRAHYDROQUINAZOLINE DERIVATIVES AS SELECTIVE CYTOTOXIC AGENTS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63/512,403 filed July 7, 2023, the entire contents of which are incorporated by reference herein. BACKGROUND OF THE INVENTION [0002] Human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS). In the absence of viral suppression, people living with HIV exhibit severe immunodeficiency which makes them highly susceptible to debilitating and ultimately fatal opportunistic infections. Multiple clinically approved antiretroviral drugs are available which demonstrate multi-log reductions in viral loads. Treated patients are at risk for acquiring mutations which render the virus in their bodies resistant to available therapies and rapid rebound of viremia is seen when therapy is removed, indicating that current regimens are not curative. [0003] HIV is a retrovirus whose life cycle involves reverse transcription of a viral RNA genome into DNA via an enzyme known as reverse transcriptase and subsequent integration of the DNA copy into the host chromosomal DNA via the virally encoded integrase. Viral RNA is transcribed and viral proteins are translated using the host cellular machinery in conjunction with viral accessory proteins. Many viral proteins are contained within the GAG and GAG-POL polyproteins, with GAG containing structural proteins and GAG-POL resulting from a frameshift near the carboxy-terminus of GAG and containing protease (PR), reverse transcriptase (RT), and integrase (IN) viral enzymes, in addition to the structural proteins. GAG and GAG-POL are cleaved into individual proteins through the process of maturation which occurs during budding of virions from the infected cell. At this time GAG-POL dimerizes and the now dimeric HIV PR within the GAG-POL dimer forms an active enzyme which can cleave itself out of the polyprotein and catalyze further cleavage to form the remaining viral enzymes and structural proteins. [0004] Available antiretroviral drugs act by blocking the virus at different stages in the viral life cycle. For example, reverse transcriptase inhibitors target the viral reverse transcriptase and prevent the RNA genome from being copied into DNA, integrase inhibitors block the ability of the copied DNA from being integrated into the host cell, and protease inhibitors prevent viral maturation so that virions produced from cells treated with protease inhibitors are immature and non-infectious. Once integration has occurred, a cell is infected until it dies through either normal cell death pathways, accelerated death due to viral factors, or is targeted by the immune system. While most infected cells are expected to die within ~2 days of being infected, the rapid rebound of viremia when therapy is removed is an indication that infected cells remain even after years on therapy (See, e.g., J. B. Dinoso et al., Proc. Natl. Acad. Sci. U.S.A., 2009, 106(23): 9403-9408). These latently infected and/or persistently virus-expressing cells that remain even during antiretroviral therapy are collectively termed the HIV reservoir and are the reason that people living with HIV require life-long treatment with a high level of adherence to maintain virus at undetectable levels. Thus, new therapies that can selectively kill the HIV infected cells would provide new treatment options for HIV infection. These targeted activator of cell kill (TACK) molecules bind the reverse transcriptase-p66 domain of monomeric Gag-Pol and act as allosteric modulators to accelerate dimerization, resulting in HIV-1+ cell death through premature intracellular viral protease activation. TACK molecules retain potent antiviral activity and selectively eliminate infected CD4+ T cells isolated from people living with HIV-1, thus supporting an immune-independent clearance strategy (See, e.g., C. J. Balibar, et al., Sci. Transl. Med., 2023, 684 (15):eabn2038) [0005] Treatment with compounds that can accelerate death of HIV infected cells and decrease the overall number of virally infected cells that persist within patients has the potential to decrease residual viremia in HIV suppressed individuals and address co-morbidities associated with chronic viral infection such as chronic inflammation, immune dysfunction, accelerated aging, cardiovascular disease (CVD), central nervous system (CNS) and other tissue and end- organ damage. Furthermore, treatment with compounds that can purge the remaining HIV reservoir may prolong viral remission off therapy and play a role in an HIV cure strategy. SUMMARY OF THE INVENTION [0006] The present disclosure is directed to tetrahydroquinazoline derivatives and their use as HIV-Targeted Activator of Cell Kill agents which accelerate the death of HIV GAG-POL expressing cells without concomitant cytotoxicity to HIV naïve cells. Accordingly, the compounds are us