Tetrahydroquinazoline derivatives as selective cytotoxic agents

Abstract

To provide a method useful for treating or preventing infection by HIV, or treating, preventing or delaying the onset or progression of AIDS or AIDS-related complex (ARC).SOLUTION: Tetrahydroquinazoline derivatives of the formula I and their use for selectively killing HIV-infected GAG-POL-expressing cells without cytotoxic effects on HIV-naive cells and for treating or preventing infection by HIV or for treating, preventing or delaying the onset or progression of AIDS-related complex or acquired immune deficiency syndrome (ARC) are provided.SELECTED DRAWING: None

Description

[Background technology]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 512,403, filed July 7, 2023, the entire contents of which are incorporated herein by reference.

[0002] Human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS). Without viral suppression, HIV-infected individuals exhibit severe immunodeficiency, which renders them extremely debilitating and ultimately highly susceptible to fatal opportunistic infections. Multiple clinically approved antiretroviral drugs are available that demonstrate multi-log reductions in viral load. Treated patients are at risk of acquiring mutations that render the virus resistant to available therapies and experience rapid rebound in viremia upon treatment cessation. These factors indicate that current regimens are not curative.

[0003] HIV is a retrovirus whose life cycle involves reverse transcription of the viral RNA genome into DNA via an enzyme known as reverse transcriptase, followed by integration of the DNA copy into host chromosomal DNA via virally encoded integrase. Viral RNA is transcribed, and viral proteins, along with viral accessory proteins, are translated using the host cellular machinery. Many viral proteins are contained in the GAG ​​and GAG-POL polyproteins, where GAG ​​contains the structural proteins and GAG-POL is derived from a frameshift near the carboxy terminus of GAG and contains the viral enzymes protease (PR), reverse transcriptase (RT), and integrase (IN) in addition to the structural proteins. GAG and GAG-POL are cleaved into individual proteins through a maturation process that occurs during budding of virions from infected cells. At this point, GAG-POL dimerizes, and the newly dimeric HIV PR within the GAG-POL dimer forms an active enzyme that can cleave itself from the polyprotein and catalyze further cleavages to form the remaining viral enzymes and structural proteins.

[0004] Available antiretroviral drugs act by blocking the virus at various stages of its 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 to integrate into the host cell; and protease inhibitors prevent viral maturation, such that virions produced from cells treated with protease inhibitors are immature and noninfectious. Once integrated, the cell becomes infected and either dies through normal cell death pathways or accelerated death due to viral factors, or is targeted by the immune system. Although most infected cells are expected to die within approximately two days of infection, the rapid rebound of viremia upon discontinuation of treatment indicates that infected cells persist even after years of treatment (see, e.g., J.B. Dinoso et al., Proc. Natl. Acad. Sci. USA, 2009, 106(23): 9403-9408). These latently infected cells and persistently virus-expressing cells that persist during antiretroviral therapy are collectively referred to as the HIV reservoir, and these cells are the reason HIV-infected individuals require lifelong, highly compliant treatment to maintain undetectable levels of virus. Therefore, new therapies that can selectively kill HIV-infected cells would provide new treatment options for HIV infection. These targeted activating cell killing (TACK) molecules bind to the reverse transcriptase-p66 domain of monomeric Gag-Pol and function as allosteric modulators, promoting dimerization. This allows the early activation of intracellular viral proteases, resulting in the death of HIV-1 + TACK molecules possess potent antiviral activity and inhibit the growth of infected CD4 cells isolated from HIV-1-infected humans. +It selectively eliminates T cells, thus supporting an immune-independent clearance strategy (see, e.g., CJ Balibar, et al., Sci. Transl. Med., 2023, 684 (15):eabn2038). [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] JB Dinoso et al., Proc. Natl. Acad. Sci. USA, 2009, 106(23): 9403-9408 [Non-patent document 2] CJ Balibar, et al., Sci. Transl. Med., 2023, 684 (15):eabn2038 Summary of the Invention [Problem to be solved by the invention]

[0006] Treatment with compounds that can accelerate the death of HIV-infected cells and reduce the total number of virally infected cells that persist in a patient's body has the potential to reduce residual viremia in individuals with HIV suppression and address comorbidities associated with chronic viral infection (e.g., chronic inflammation, immune dysfunction, accelerated aging, cardiovascular disease (CVD), damage to the central nervous system (CNS) and other tissues and peripheral organs). Furthermore, treatment with compounds that can eliminate residual HIV reservoirs can prolong viral remission after treatment and may also play a role in HIV treatment strategies. [Means for solving the problem]

[0007] The present disclosure is directed to tetrahydroquinazoline derivatives and their use as HIV-targeted activators of cell kill agents that accelerate the death of HIV GAG-POL-expressing cells without cytotoxicity to HIV-naive cells. These compounds are therefore useful for selectively killing HIV-infected GAG-POL-expressing cells in HIV-infected subjects. The compounds disclosed herein are therefore useful for treating or preventing infection by HIV, or for treating, preventing, or delaying the onset or progression of AIDS or AIDS-related complex (ARC). Compositions and methods of use comprising the disclosed compounds are also provided.

[0008] In one aspect, the present disclosure provides a compound of formula (I): [ka] and pharmaceutically acceptable salts thereof. DETAILED DESCRIPTION OF THE INVENTION

[0009] The present disclosure is directed to tetrahydroquinazoline derivative compounds and their use to accelerate the death of HIV GAG-POL-expressing cells without cytotoxicity to naive HIV cells. In the absence of compounds such as those from the present disclosure, protease (PR) activation occurs during viral maturation, and the concentration of mature PR in the cytoplasm is limiting. In contrast, compounds of the present invention promote the desired phenotype by binding to the immature RT binding site and inducing premature activation of the HIV PR enzyme in infected host cells prior to budding, thereby catalyzing GAG-POL dimerization within the infected cell. As a result, PR cleaves host substrates within the cell, causing cytotoxicity and cell death. This effect can be blocked in the presence of HIV protease inhibitors such as indinavir or darunavir, indicating a role for HIV protease in this process.

[0010] The compounds presently disclosed herein also possess activity as non-nucleoside reverse transcriptase inhibitors (NNRTIs) due to the homology between the mature and immature RT pockets in HIV, which allows the compounds to bind to the mature hydrophobic pocket near the active site of the viral RT enzyme. Binding to mature RT inhibits enzymatic activity and produces a DNA provirus, thereby preventing infection of naive CD4+ T cells.

[0011] Although the effects of NNRTIs on RT and GAG-POL dimerization have been documented (Tachedjian et al. Proc. Natl. Acad. Sci. USA 2001, 98(13):7188; Tachedjian et al. FEBS Lett. 2005, 579:379; Figueiredo et al. PLOS Path. 2006, 2(11):1051; Sudo et al. J. Virol. 2013, 87(6):3348), selective killing of HIV-infected cells as a result of enhanced dimerization was first reported by Jochmans et al. (Jochmans et al. Retrovirology 2010, 7:89), who generated data demonstrating these effects in chronically infected MT-4 cells, PBMCs, and CD4+ cells. Based on the efficacy of the tested molecules, they concluded, "These data provide proof of concept for targeted drug-induced elimination of HIV-producing cells. While NNRTIs themselves may not be sufficiently potent for therapeutic applications, the results provide a basis for the development of drugs that utilize this mechanism of action." Recently, Zerbato et al. (Zerbato et al. Antimicrob. Agents Chemother. 2017, 61(3)) measured the activity of NNRTIs in a primary cell model of HIV latency. They observed a significant reduction in viral production with certain NNRTIs compared with other classes of antiretroviral drugs and speculated that this was due to the ability of these compounds to eliminate cells expressing the HIV GAG-POL protein. Recently, Trinite et al. (Trinite et al., Retrovirology, 2019, 16(17)) demonstrated in their paper how NNRTI-induced PR activation triggers apoptotic cell death of resting or activated T cells productively infected with HIV.

[0012] The present disclosure provides a compound of formula (I) [ka] [During the ceremony, X is N(R 3 ) or C(R 3 ) and; W is -C 1-6 Alkyl-, -(C 0-6 alkyl)O-, -(C 1-6 alkyl)amino- or -(C 1-6 alkyl)aminocarbonyl-, where W is 0, 1, or 2 R 5 is substituted with a substituent; Each R 5 independently, halo, C 1-4 Alkyl or C 1-4 is a fluoroalkyl; R 1 Ha, Halo, C 1-6 Alkyl, (C 3-12 )Heterocycloalkyl(C 0-4 alkyl) or (C 3-12 ) Cycloalkyl(C 0-4 alkyl); R 2 is hydrogen, halo or C 1-10 is alkyl; R 3 is hydrogen, halo or C 1-10 is alkyl; R 4 teeth, (a) a 5-membered heteroaryl having at least one nitrogen atom; (b) a monocyclic, bicyclic, or tricyclic 7- to 14-membered heteroaryl containing at least one aromatic heteroatom-containing ring, wherein the 7- to 14-membered heteroaryl contains at least one nitrogen atom; or (c) Triazolinonyl, 2,4-dihydro-3H-1,2,4-triazolin-3-onyl, dihydropyrrolo[3,4-b]pyrrololonyl, imidazolidinonyl, 1,3-dihydro-2H-benzo[d]imidazol-2-onyl, dihydrobenzo[d]imidazolinonyl, 1,3-dihydroimidazo[4,5-c]pyridinonyl, oxazolo[5,4-c]pyridin-2-onyl, 1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-onyl, 1,3 a ketone-containing ring system selected from dihydroimidazo[4,5-b]pyridin-2-onyl, isoindolinonyl, 4,5-dihydropyrrolo[3,4-b]pyrrololonyl, 4,5-dihydropyrrolo[3,4-b]pyrrol-6(2H)onyl, benzo[d]oxazolonyl, benzo[d]oxazol-2-onyl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolonyl and 1,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-4-onyl, Selected from; where R 4 is 0, 1, 2 or 3 R 4a is substituted with a substituent; Each R 4a is, independently, C 1-6 Alkyl, C 1-10 fluoroalkyl, amino, Cyano, Hello, 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(C0-6 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)2NH2) Selected from; where R 4a is 0, 1, 2 or 3 R 4b is substituted with a substituent; and Each R 4b independently, C 1-10 Alkyloxy, C 1-6 Alkyl, C 1-10 fluoroalkyl, amino, hydroxy, halo, or cyano. or a pharmaceutically acceptable salt thereof.

[0013] In a first embodiment of the present invention, X is NR 3 where R 3 is hydrogen, halo or C 1-10 In one variation of this embodiment, X is NR 3 where R 3 is hydrogen, methyl, ethyl, propyl, or isopropyl, and the other groups are as set forth in general formula (I) above. In another variation of this embodiment, X is NR 3 where R 3 is hydrogen or methyl, and the other groups are as shown in general formula (I) above.

[0014] In a second embodiment of the present invention, X is C(R 3 ), where R 3 is hydrogen, halo or C 1-10alkyl, and the other groups are as shown in general formula (I) above.

[0015] In a third embodiment of the present invention, W is -C 1-6 Alkyl-, -(C 1-6 alkyl)amino- or -(C 1-6 alkyl)aminocarbonyl-, where W is 0, 1, or 2 R 5 It is substituted with a substituent, and other groups are as shown in the above general formula (I) or as shown in the first and second embodiments.

[0016] In a fourth embodiment of the present invention, W is -C 1-6 alkyl-, where W is 0, 1 or 2 R 5 It is substituted with a substituent, and other groups are as shown in the above general formula (I) or as shown in the first to third embodiments.

[0017] In a fifth embodiment of the present invention, W is -(C 1-6 alkyl)amino- or -(C 1-6 alkyl)aminocarbonyl-, where W is 0, 1, or 2 R 5 It is substituted with a substituent, and other groups are as shown in the above general formula (I) or as shown in the first to third embodiments.

[0018] In a sixth embodiment of the present invention, W is -(C 0-6 alkyl)O—, where W is 0, 1, or 2 R 5 It is substituted with a substituent, and other groups are as shown in the above general formula (I) or as shown in the first to third embodiments.

[0019] In a seventh embodiment, W is methyl, -methyl(aminocarbonyl)- or -methylamino-, where W is 0, 1 or 2 R 5It is substituted with a substituent, and other groups are as shown in the above general formula (I) or as shown in the first to third embodiments.

[0020] In the eighth embodiment, each R 5 are independently fluoro, chloro, methyl, ethyl, propyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl or fluoromethyl, and the other groups are as shown in general formula (I) above or as shown in the first to seventh embodiments.

[0021] In a ninth embodiment of the present invention, each R 5 are independently fluoro, chloro, methyl, ethyl, propyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl or fluoromethyl, and the other groups are as shown in general formula (I) above or as shown in the first to seventh embodiments.

[0022] In a tenth embodiment of the present invention, R 5 is methyl, and the other groups are as shown in general formula (I) above or as shown in the first to seventh embodiments.

[0023] In an eleventh embodiment of the present invention, R 1 Ha, Halo, C 1-6 Alkyl, (C 3-7 )Heterocycloalkyl(C 0-4 alkyl) or (C 3-7 ) Cycloalkyl(C 0-4 alkyl), and the other groups are as shown in general formula (I) above or as shown in the first to tenth embodiments.

[0024] In a twelfth embodiment of the present invention, R 1is fluoro, chloro, bromo, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl, and the other groups are as set forth in general formula (I) above or as set forth in the first to tenth embodiments.

[0025] In a thirteenth embodiment of the present invention, R 1 is fluoro, methyl or cyclopropyl, and the other groups are as shown in general formula (I) above or as shown in the first to tenth embodiments.

[0026] In a fourteenth embodiment of the present invention, R 2 is hydrogen, fluoro, chloro, bromo, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or neopentyl, and the other groups are as shown in general formula (I) above or as shown in the first to thirteenth embodiments.

[0027] In a fifteenth embodiment of the present invention, R 2 is hydrogen, fluoro or chloro, and the other groups are as shown in general formula (I) above or as shown in the first to thirteenth embodiments.

[0028] In a sixteenth embodiment of the present invention, R 3 is hydrogen, fluoro, chloro, methyl, bromo, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or neopentyl, and the other groups are as shown in general formula (I) above or as shown in the first to fifteenth embodiments.

[0029] In a seventeenth embodiment of the present invention, R 3 is hydrogen, and the other groups are as shown in general formula (I) above or as shown in the first to fifteenth embodiments.

[0030] In an eighteenth embodiment of the present invention, R 3 is methyl, and the other groups are as shown in general formula (I) above or as shown in the first to fifteenth embodiments.

[0031] In a nineteenth embodiment of the present invention, R 4 wherein the 5-membered heteroaryl having at least one nitrogen atom is selected from triazolyl (e.g., 1,2,4-triazolyl, 1,2,3-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, wherein R 4 is 0, 1, 2 or 3 R 4a It is substituted with the substituents, and other groups are as shown in the above general formula (I) or as shown in the first to eighteenth embodiments.

[0032] In a twentieth embodiment of the present invention, R 4 wherein the 5-membered heteroaryl having at least one nitrogen atom is selected from 1,2,3-triazolyl, 1,2,4-triazolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyrrolyl, and tetrazolyl, wherein R 4 is 0, 1, 2 or 3 R 4a It is substituted with the substituents, and other groups are as shown in the above general formula (I) or as shown in the first to eighteenth embodiments.

[0033] In a 21st embodiment of the present invention, R 4 In the formula (I), the monocyclic, bicyclic or tricyclic 7- to 14-membered heteroaryl containing a ring containing at least one aromatic heteroatom (wherein the 7- to 14-membered heteroaryl contains at least one nitrogen atom) is 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, quinolidinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, carbazolyl, phenatridinyl, acridinyl, phenanthrolinyl, phenazinyl, 7H-pyrazino[2,3-c]carbazolyl, 1,3-benzoxazolyl, and 2,1-benzoxazolyl, wherein R 4 is 0, 1, 2 or 3 R 4a It is substituted with the substituents, and other groups are as shown in the above general formula (I) or as shown in the first to eighteenth embodiments.

[0034] In a 22nd embodiment of the present invention, R 4 wherein the monocyclic, bicyclic or tricyclic 7- to 14-membered heteroaryl containing a ring containing at least one aromatic heteroatom, wherein the 7- to 14-membered heteroaryl contains 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 and benzo[d]imidazolyl, 4 is 0, 1, 2 or 3 R 4aIt is substituted with the substituents, and other groups are as shown in the above general formula (I) or as shown in the first to eighteenth embodiments.

[0035] In a 23rd embodiment of the present invention, R 4 wherein the ketone-containing ring system is selected from 2,4-dihydro-3H-1,2,4-triazol-3-onyl, imidazolidinonyl, 1,3-dihydro-2H-benzo[d]imidazol-2-onyl, 1,3-dihydroimidazo[4,5-c]pyridinonyl, isoindolinonyl, 4,5-dihydropyrrolo[3,4-b]pyrrol-6(2H)onyl, and benzo[d]oxazol-2-onyl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolonyl, wherein R 4 is 0, 1, 2 or 3 R 4a It is substituted with the substituents, and other groups are as shown in the above general formula (I) or as shown in the first to eighteenth embodiments.

[0036] In a 24th embodiment of the present invention, R 4 teeth, (a) a 5-membered heteroaryl having at least one nitrogen atom, wherein the 5-membered heteroaryl having at least one nitrogen atom is selected from triazolyl, 1,2,4-triazolyl, 1,2,3-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) Monocyclic, bicyclic, or tricyclic 7- to 14-membered heteroaryls containing at least one ring containing an aromatic heteroatom, wherein the 7- to 14-membered heteroaryl contains at least one nitrogen atom, and monocyclic, bicyclic, or tricyclic 7- to 14-membered heteroaryls containing at least one ring containing an aromatic heteroatom, wherein the 7- to 14-membered heteroaryl containing at least one nitrogen atom is 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, quinolidinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, carbazolyl, phenatridinyl, acridinyl, phenanthrolinyl, phenazinyl, 7H-pyrazino[2,3-c]carbazolyl, 1,3-benzoxazolyl, and 2,1-benzoxazolyl; or (c) a ketone-containing ring system selected from the ketone-containing ring systems selected from 2,4-dihydro-3H-1,2,4-triazol-3-onyl, imidazolidinonyl, 1,3-dihydro-2H-benzo[d]imidazol-2-onyl, 1,3-dihydroimidazo[4,5-c]pyridinonyl, isoindolinonyl, 4,5-dihydropyrrolo[3,4-b]pyrrol-6(2H)onyl, and benzo[d]oxazol-2-onyl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolonyl; where R 4 is 0, 1, 2 or 3 R 4a It is substituted with the substituents, and other groups are as shown in the above general formula (I) or as shown in the first to eighteenth embodiments.

[0037] In a 25th embodiment of the present invention, each R 4a independently, C 1-6 Alkyl, C1-10 Fluoroalkyl, amino, cyano, halo, hydroxy, (C 1-6 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 3-7 ) 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)2NH2), where R 4a is 0, 1, 2 or 3 R 4b It is substituted with the substituents, and other groups are as shown in the general formula (I) above, or as shown in the first to twenty-fourth embodiments.

[0038] In a 26th embodiment of the present invention, each R 4a independently, 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 3-7 ) 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), where R 4a is 0, 1, 2 or 3 R 4b It is substituted with the substituents, and other groups are as shown in the general formula (I) above, or as shown in the first to twenty-fourth embodiments.

[0039] In a 27th embodiment of the present invention, each R 4a is independently selected from hydroxymethyl, methoxy, phenyl, pyridyl, oxomethyl, aminosulfonyl, methyl, 2-hydroxypropyl, fluoro, chloro, cyano, difluoromethyl, (dimethylamino)methyl, methoxymethyl, bromo, amino, hydroxyethyl, pyrazolyl, (methoxy)ethyl, aminocarbonyl, difluoromethoxy, 2-hydroxyethyl, methylamino, and dimethylamino; 4a is 0, 1, 2 or 3 R 4b It is substituted with the substituents, and other groups are as shown in the general formula (I) above, or as shown in the first to twenty-fourth embodiments.

[0040] In a 28th embodiment, each R 4b independently, C 1-6 Alkyloxy, C 1-4 Alkyl, C 1-6 selected from fluoroalkyl, amino, hydroxy, halo, or cyano, and other groups are as shown in general formula (I) above or as shown in the first to twenty-seventh embodiments.

[0041] In a 29th embodiment, each R 4b independently, C 1-4 Alkyloxy, C 1-4 Alkyl, C 1-4selected from fluoroalkyl or halo, and other groups are as shown in general formula (I) above or as shown in the first to twenty-seventh embodiments.

[0042] In a 30th embodiment of the present invention, each R 4b are independently selected from methyl and methoxy, and the other groups are as shown in general formula (I) above or as shown in the first to twenty-seventh embodiments.

[0043] In one embodiment of the present disclosure, the present disclosure provides a compound of formula (I): [ka] [During the ceremony, X is N(R 3 ) or C(R 3 ) and; W is -C 1-6 Alkyl-, -(C 1-6 alkyl)amino- or -(C 1-6 alkyl)aminocarbonyl-, where W is 0 or 1. 5 is substituted with a substituent; Each R 5 is methyl; R 1 is F, methyl or cyclopropyl; R 2 is hydrogen, fluoro or chloro; R 3 is hydrogen or methyl; R 4 teeth, (a) a 5-membered heteroaryl having at least one nitrogen atom, which is selected from triazolyl, 1,2,4-triazolyl, 1,2,3-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) monocyclic, bicyclic, or tricyclic 7- to 14-membered heteroaryls containing at least one ring containing an aromatic heteroatom, such as 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]pyridinyl, benzo[d]pyridinyl, benzo[b ... [1,2,3]-triazolyl, benzo[d]imidazolyl, indolizinyl, isoindolyl, purinyl, quinolidinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, carbazolyl, phenatridinyl, acridinyl, phenanthrolinyl, phenazinyl, 7H-pyrazino[2,3-c]carbazolyl, 1,3-benzoxazolyl, and 2,1-benzoxazolyl), or (c) a ketone-containing ring system selected from 2,4-dihydro-3H-1,2,4-triazol-3-onyl, imidazolidinonyl, 1,3-dihydro-2H-benzo[d]imidazol-2-onyl, 1,3-dihydroimidazo[4,5-c]pyridinonyl, isoindolinonyl, 4,5-dihydropyrrolo[3,4-b]pyrrol-6(2H)onyl and benzo[d]oxazol-2-onyl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolonyl; where R 4 is 0, 1, 2 or 3 R 4a is substituted with a substituent; Each R 4a is independently selected from hydroxymethyl, methoxy, phenyl, pyridyl, oxomethyl, aminosulfonyl, methyl, 2-hydroxypropyl, fluoro, chloro, cyano, difluoromethyl, (dimethylamino)methyl, methoxymethyl, bromo, amino, hydroxyethyl, pyrazolyl, (methoxy)ethyl, aminocarbonyl, difluoromethoxy, 2-hydroxyethyl, methylamino, and dimethylamino; 4a is 0, 1, 2 or 3 R 4b is substituted with a substituent; and Each R 4bare independently selected from methyl and methoxy. or a pharmaceutically acceptable salt thereof.

[0044] One embodiment of the present invention is a compound of formula (Ia) [ka] [During the ceremony, W is -C 1-6 Alkyl-, -(C 1-6 alkyl)amino- or -(C 1-6 alkyl)aminocarbonyl-, where W is 0, 1, or 2 R 5 is substituted with a substituent; Each R 5 independently, halo, C 1-4 Alkyl or C 1-4 is a fluoroalkyl; R 1 Ha, Halo, C 1-6 Alkyl, (C 3-12 )Heterocycloalkyl(C 0-4 alkyl) or (C 3-12 ) Cycloalkyl(C 0-4 alkyl); R 2 is hydrogen, halo or C 1-10 is alkyl; R 4 is a 5-membered heteroaryl having at least one nitrogen atom; where R 4 is 0, 1, 2 or 3 R 4a is substituted with a substituent; Each R 4a is, independently, C 1-6 Alkyl, C 1-10 fluoroalkyl, amino, Cyano, Hello, Hydroxy, (C 1-10 Alkyloxy)C 0-10 Alkyl, C 1-10fluoroalkyloxy, -(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)2NH2) Selected from; where R 4a is 0, 1, 2 or 3 R 4b is substituted with a substituent; and Each R 4b independently, C 1-10 Alkyloxy, C 1-6 Alkyl, C 1-10 fluoroalkyl, amino, hydroxy, halo, or cyano. or a pharmaceutically acceptable salt thereof.

[0045] Another embodiment of the present invention is a compound of formula (Ia) [ka] [During the ceremony, R 1 is F, methyl or cyclopropyl; R 2 is hydrogen, fluoro or chloro; R 4 is selected from 5-membered heteroaryl having at least one nitrogen atom, where R4 is selected from 1,2,4-triazolyl, 1,2,3-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; Furthermore, where R 4 is 0, 1, 2 or 3 R 4a is substituted with a substituent; Each R 4a is, independently, C 1-6 Alkyl, C 1-10 fluoroalkyl, amino, Cyano, Hello, 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)2NH2) Selected from: where R4a is 0, 1, 2 or 3 R 4b is substituted with a substituent; and Each R 4b independently, C 1-10 Alkyloxy, C 1-6 Alkyl, C 1-10 fluoroalkyl, amino, hydroxy, halo, or cyano. or a pharmaceutically acceptable salt thereof.

[0046] Non-limiting examples of compounds represented by formula (I) include Compounds 1 to 129 described in the Examples and pharmaceutically acceptable salts thereof: (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; (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; (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; (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; (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; (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; (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; (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.

[0047] One embodiment of the present invention is a selected compound of formula (I) or a pharmaceutically acceptable salt thereof, encompassed below: (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; (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; and (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.

[0048] In one variation of this embodiment, the compound or a pharmaceutically acceptable salt thereof 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.

[0049] In another variation, the compound or a pharmaceutically acceptable salt thereof is (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.

[0050] In another variation, the compound or a pharmaceutically acceptable salt thereof is (S)-7-((3-amino-1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one.

[0051] In yet another variation, the compound or a pharmaceutically acceptable salt thereof is (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methoxymethyl)-1H-pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one.

[0052] In another variation, the compound or a pharmaceutically acceptable salt thereof is (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.

[0053] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is (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.

[0054] In another variation, the compound or a pharmaceutically acceptable salt thereof is (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.

[0055] In another variation, the compound or a pharmaceutically acceptable salt thereof is (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.

[0056] In another variation, the compound or a pharmaceutically acceptable salt thereof is (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.

[0057] In another variation, the compound or a pharmaceutically acceptable salt thereof is (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.

[0058] The present invention is directed to compounds of formula I herein and all embodiments, examples, classes and subclasses thereof, and includes the compounds of the Examples herein. The present invention is further directed to compounds of formula I, which are neutral compounds or salts thereof, where salts are possible, including pharmaceutically acceptable salts.

[0059] The term "eg" means "for example." When the terms "eg" or "for example" are used herein, the examples given are intended to be illustrative and not an exhaustive list of all relevant examples. The term "ie" means "that is."

[0060] As used herein, "alkyl" refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms in the specified range. For example, "C 1-8 "Alkyl" refers to an alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, respectively, including straight or branched chain isomers thereof. 1-8 Alkyl" is "C 1-6 "Alkyl" groups include straight-chain and branched-chain alkyl groups having 7 or 8 carbons in the chain.

[0061] The term "alkyl," as well as other groups having the prefix "alk" (e.g., alkoxy, dialkylamino, and trialkylamine), refers to an aliphatic hydrocarbon group that has one of its hydrogen atoms replaced with a bond.

[0062] "Amino" means -NH- or -NH2-, in which one or more hydrogen atoms may be replaced as described below.

[0063] "Aminocarbonyl" means -C(=O)NH.

[0064] "Aryl" means a monocyclic, bicyclic, or tricyclic carbocyclic aromatic ring or carbocyclic aromatic ring system containing 5 to 14 carbon atoms, wherein at least one of the rings is aromatic. Examples of aryl include phenyl, biphenyl, and naphthyl. In one embodiment of the present invention, aryl is phenyl.

[0065] A "bicyclic ring" or "bicyclic ring system" refers to two linked rings, which may be fused (i.e., may share two adjacent atoms) or "spirocyclic" (i.e., may share only a single atom).

[0066] "Celite®" (Fluka) diatomite is a diatomaceous earth and may be referred to as "celite."

[0067] "Carbonyl" refers to a functional group composed of a carbon atom double bonded to an oxygen atom (C=O).

[0068] "Carboxy" means a -CO2H group. The bond to the parent group is through the carbon atom of the carbonyl moiety.

[0069] "Cycloalkyl" or "C 3-12"Cycloalkyl" means a monovalent non-aromatic radical derived from a monocyclic, bicyclic, tricyclic, or tetracyclic ring system having 3 to 12 ring carbon atoms. These non-aromatic radicals have 3, 4, 5, 6, 7, 8, or up to 12 ring carbon atoms and may be fully saturated or partially unsaturated. Unless expressly stated otherwise in the specification, the cycloalkyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and it can include fused or bridged ring systems, where the point of attachment of "cycloalkyl" to the rest of the molecule is on the saturated ring. Bicyclic cycloalkyl ring systems include fused ring systems in which two rings share two atoms (e.g., decalin), spiro ring systems in which two rings share one atom (e.g., spiro[4.5]decanyl), and bridging groups (e.g., norbornyl).

[0070] Additional examples within the above meaning include, but are not limited to, monovalent radicals of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.2]octanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, [1.1.1]-bicyclopentane, bicyclo[3.1.0]hexanyl, cyclohexenyl, cyclopentenyl, 1-decalinyl, spiro[2.4]heptyl, spiro[2.2]pentyl, and norbornyl.

[0071] The term “C 3-8 "Cycloalkyl" (or "C-C cycloalkyl" or "C cycloalkyl") means an alkane ring structure having three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl). 3-7 cycloalkyl," "C 3-6 cycloalkyl," "C 5-7 "Cycloalkyl", etc. have a similar meaning.

[0072] "Fluoroalkyl" refers to the above alkyl group in which one or more hydrogen atoms (particularly 1 to 10 hydrogen atoms) have been replaced with fluorine atoms, and includes the case in which all hydrogen atoms have been completely replaced with halo groups. 1-6 Haloalkyl includes, for example, -CH2F, -CHF2, -CF3, -CF4, -CF2CF3, -CHFCH3, and the like.

[0073] "Halo" or "halogen" refers to chloro, fluoro, bromo and / or iodo, with chloro, fluoro and bromo being important classes of halogens, and in particular fluoro and chloro being important classes of halogens.

[0074] The term "heteroaryl," as used herein, refers to a stable monocyclic, bicyclic, or tricyclic ring system containing 5 to 14 carbon atoms and at least one ring heteroatom selected from N, S, and O, wherein at least one of the heteroatom-containing rings is aromatic. Bicyclic heteroaryl ring systems include fused ring systems in which two rings share two atoms and spiro ring systems in which two rings share one atom.

[0075] Heteroaryl groups within this definition include, but are not limited to, azaindolyl, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiazolyl, benzo[d]isothiazolyl, benzoxazolyl, carbazolyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthopyridinyl, oxadiazolyl, oxazolyl, oxazolinyl, isoxazolinyl, pyranyl, pyrazinyl, pyrazolyl, pyrrolyl, pyrazolopyrimidinyl, pyridazinyl, pyridyl, pyrimidyl, pyrimidinyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyri Diazolyl, thiadiazolyl, 5H-pyrrolo[3,4-b]pyridine, thiazolyl, thienyl, triazolyl, triazinyl, benzothiazolyl, benzothienyl, quinolinyl, quinazolinyl, isoquinolinyl, 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, 2H-pyrazolo[3,4-b]pyridinyl, benzo[d][1,2,3]-triazolyl, benzo[d]imidazolyl, indolizinyl, purinyl, quinolizinyl, phthalazinyl, naphthyridinyl, carbazolyl, phenathridinyl, acridinyl, phenanthrolinyl, phenazinyl, 7H-pyrazino[2,3-c]carbazolyl, 1,3-benzoxazolyl, and 2,1-benzoxazolyl. If the heteroaryl contains a nitrogen atom, it is understood that the corresponding N-oxide is also encompassed by this definition.

[0076] As used herein, the term "heterocycloalkyl" refers to a stable non-aromatic (including those that are not fully aromatic, e.g., have one double bond) 3- to 12-membered ring (i.e., C 3-12In some embodiments, it is a 5- to 10-ring heterocycloalkyl. In some embodiments, it is a 4- to 10-ring heterocycloalkyl. In some embodiments, it is a 3- to 10-ring heterocycloalkyl. In some embodiments, it is a 3- to 7-ring heterocycloalkyl. Unless expressly stated otherwise in the specification, the heterocycloalkyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems. The prefix "aza," "oxa," or "thia" before the heterocyclyl root name means that at least a nitrogen, oxygen, or sulfur atom, respectively, is present as a ring atom. The heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl may be attached to the remainder of the molecule through any atom of the ring.

[0077] In one embodiment, a heterocycloalkyl group is monocyclic and has from about 3 to about 7 ring atoms. In another embodiment, a heterocycloalkyl group is monocyclic and has from about 5 to about 8 ring atoms. In another embodiment, a heterocycloalkyl group is bicyclic and has from about 8 to about 11 ring atoms. In yet another embodiment, a heterocycloalkyl group is monocyclic and has 5 or 6 ring atoms. In one embodiment, a heterocycloalkyl group is monocyclic. In another embodiment, a heterocycloalkyl group is bicyclic. In another embodiment, a heterocycloalkyl group is tricyclic. There are no adjacent oxygen and / or sulfur atoms within the ring system.

[0078] Non-limiting examples of heterocycloalkyl rings include decahydroisoquinoline, dioxaspiro[4.5]decane, 2,5-diazabicyclo[2.2.1]heptyl, quinuclidinyl, oxetanyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, 2-azabicyclo[2.1.1]hexyl, 6-azaspiro[2.5]octanyl, azetidinyl, 3a,5,6,6a-tetrahydro-4H-pyrrolo[3,4-d]isoxazole, diazabicyclo[3.3.2]decanyl, 2,3,4,5,6,7-hexahydroisothiazolin ... thiazolo[5,4-c]pyridyl, hexahydro-2H-pyrrolo[3,4-d]isothiazolyl, 3,9-diazabicyclo[3.3.2]decanyl, 2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinazoline], octahydropyrrolo[3,4-b][1,4]oxazinyl, (diazabicyclo[2.2.1]heptanyl), 2,5-diazabicyclo[2.2.1]heptanyl, tetrahydrobenzo[d]thiazolyl, 2,3-dihydrobenzofuranyl, oxabicyclo[2.1.1]hexyl, dihydrothiazolo[5,4-c]pyridin-5(4H)-yl, diazaspiro[4.4]nonanyl, and 2,7-diazaspiro[4.4]nonanyl, and all isomers thereof. In one embodiment of the present invention, heterocycloalkyl rings include the following: piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azelidinyl, azetidinyl.

[0079] The term "ketone" refers to --(C.dbd.O)--R, where R is another carbon atom or a hydrocarbon radical.

[0080] "HIV naive cell(s)" are cells that are not infected with HIV.

[0081] "Compatible anti-HIV agent(s)" are anti-HIV agents other than HIV protease inhibitors.

[0082] A "latency reversing agent" (LRA) is a drug that can reactivate latent HIV (e.g., HIV-1) in cells (e.g., human cells) infected with HIV (e.g., HIV-1).

[0083] A "stable" compound is one that can be prepared and isolated, and whose structure and properties remain essentially unchanged or can remain essentially unchanged for a period of time sufficient to allow the compound to be used for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject). The compounds of the present disclosure are limited to stable compounds encompassed by Formula I and its embodiments. For example, a particular moiety defined in Formula I can be unsubstituted or substituted, where the latter is intended to encompass substitution patterns (i.e., number and type of substituents) that are chemically possible for that moiety and result in a stable compound.

[0084] The present disclosure encompasses individual diastereomers, particularly epimers, i.e., compounds that have the same chemical formula but differ in spatial arrangement around a single atom. The present disclosure also encompasses mixtures of diastereomers, particularly mixtures of epimers, in all ratios. The present disclosure encompasses compounds of Formula I having either the (R) or (S) configuration at one asymmetric center and at any additional asymmetric centers that may be present in compounds of Formula I, as well as stereoisomeric mixtures thereof. Embodiments of the present disclosure also encompass mixtures of enantiomers that are 51% or more enriched in one enantiomer (e.g., containing 60% or more, 70% or more, 80% or more, or 90% or more of one enantiomer). Single epimers are preferred. Individual or single enantiomers refer to enantiomers obtained by chiral synthesis and / or using commonly known separation and purification techniques, which may be 100% of one enantiomer or may contain small amounts (e.g., 10% or less) of the opposite enantiomer. Thus, individual enantiomers in pure form (as both levorotatory and dextrorotatory enantiomers), in the form of racemates, and in the form of mixtures of the two enantiomers in all ratios are subject of the present invention. In the case of cis / trans isomerism, the present disclosure encompasses both the cis and trans forms and mixtures of these forms in all ratios.

[0085] Individual stereoisomers can be prepared, if necessary, by separating mixtures by conventional methods (e.g., chromatography or crystallization), by using stereochemically uniform starting materials in the synthesis, or by stereoselective synthesis. In some cases, derivatization can be carried out prior to separation of stereoisomers. Separation of stereoisomeric mixtures can be carried out at the intermediate stage during the synthesis of compounds of Formula I, or on the final racemic product. Absolute stereochemistry can be confirmed by X-ray crystallography of crystalline products or crystalline intermediates, which are derivatized, if necessary, with a reagent containing a stereocenter of known configuration. Alternatively, absolute stereochemistry can be confirmed by vibrational circular dichroism (VCD) spectroscopy. The present disclosure encompasses all such isomers, as well as salts, solvates (including hydrates) and solvated salts of such racemates, enantiomers, diastereomers, and tautomers, and mixtures thereof.

[0086] As will be understood by those skilled in the art, certain compounds of the present disclosure may exist as tautomers. All tautomeric forms of such compounds, whether isolated individually or in mixtures, are within the scope of the present disclosure. For example, if an oxo (=O) substituent is possible on a heterocyclic ring and keto-enol tautomerism is possible, it is understood that the substituent may actually exist in whole or in part in the -OH and oxo forms. Examples of tautomers of the compounds herein include, but are not limited to, the following: [ka]

[0087] Atoms in the compounds of formula I may be represented by their natural isotopic abundance, or one or more atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present disclosure is intended to encompass all suitable isotopic variations of the compounds of general formula I. For example, various isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H). Protium is the predominant isotope of hydrogen found in nature. Enrichment with deuterium may confer certain therapeutic advantages, such as increased in vivo half-life or reduced required dosage, or may provide compounds useful as standards for characterizing biological samples. Isotopically enriched compounds of Formula I can be prepared without undue experimentation by conventional methods well known to those skilled in the art, or by methods similar to those described in the schemes and examples herein using appropriate isotopically enriched reagents and / or intermediates.

[0088] The compound can be administered in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to a salt that has the effectiveness of the parent compound and is not biologically or otherwise undesirable (e.g., is not toxic or otherwise harmful to the recipient). When a compound of Formula I contains one or more acidic or basic groups, the present invention encompasses the corresponding pharmaceutically acceptable salts.

[0089] Thus, compounds of Formula I containing an acidic group (e.g., —COOH) can be used in accordance with the present invention, for example, but not limited to, as alkali metal, alkaline earth metal, or ammonium salts. Examples of such salts include, but are not limited to, sodium, potassium, calcium, magnesium, or salts with ammonia or organic amines (e.g., ethylamine, ethanolamine, triethanolamine, or amino acids). Compounds of Formula I containing one or more basic groups (i.e., groups that can be protonated) can be used in accordance with the present invention in the form of their acid addition salts with inorganic or organic acids, such as, but not limited to, salts with hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, trifluoroacetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, etc. When a compound of Formula I contains both an acidic group and a basic group in its molecule, the present invention also encompasses internal salts or betaines (zwitterions) in addition to the above salt forms. Salts can be obtained from compounds of formula I by conventional methods known to those skilled in the art, for example by combining them in a solvent or dispersant with an organic or inorganic acid or base, or by anion or cation exchange from another salt. The present invention also covers all salts of compounds of formula I which are not directly suitable for use in medicine because of their poor physiological compatibility, but which can be used, for example, as intermediates for chemical reactions or for preparing pharmaceutically acceptable salts.

[0090] The present disclosure encompasses any composition comprised of a compound represented by Formula I or a salt thereof, including, for example, but not limited to, compositions comprised of the compound in association with one or more additional molecular and / or ionic components, which may be referred to as a "co-crystal." As used herein, the term "co-crystal" refers to a solid phase (which may or may not be crystalline) in which two or more different molecular and / or ionic components (generally in stoichiometric ratios) are held together by non-ionic interactions, including, but not limited to, hydrogen bonding, dipole-dipole interactions, dipole-quadrupole interactions, or dispersion forces (van der Waals). There is no proton transfer between the heterogeneous components, and the solid phase is not a simple salt or solvate. A discussion of co-crystals can be found, for example, in S. Aitipamula et al., Crystal Growth and Design, 2012, 12(5), pp. 2147-2152.

[0091] Additionally, the compounds of the present disclosure may exist in amorphous form and / or one or more crystalline forms, and therefore, all amorphous and crystalline forms, and mixtures thereof, of the compounds represented by Formula I and their salts are intended to be included within the scope of the present disclosure. Additionally, some of the compounds of the present disclosure may form solvates (i.e., hydrates) with water or common organic solvents. Such solvates and hydrates (particularly pharmaceutically acceptable solvates and hydrates) of the compounds of the present disclosure, along with unsolvated and anhydrous forms of such compounds, are similarly encompassed within the scope of the compounds defined by Formula I and their pharmaceutically acceptable salts.

[0092] Accordingly, the present invention is directed to compounds of Formula I or salts thereof (including pharmaceutically acceptable salts thereof), embodiments thereof, and the specific compounds described and claimed herein, including all possible stereoisomers, tautomers, physical forms (e.g., amorphous and crystalline forms), co-crystal forms, solvates and hydrates, and any combination of said forms, where such forms are possible.

[0093] Another embodiment of the present disclosure is a composition comprising a compound of Formula I, wherein the compound or a salt thereof is present in the composition in substantially pure form. As used herein, "substantially pure" means that a composition or product comprising a compound of Formula I or a salt thereof (e.g., a product isolated from a reaction mixture yielding the compound or salt) is suitably at least about 60% by weight, typically at least about 70% by weight, preferably at least about 80% by weight, more preferably at least about 90% by weight (e.g., about 90% to about 99% by weight), even more preferably at least about 95% by weight (e.g., about 95% to about 99% by weight, or about 98% to 100% by weight), and most preferably at least about 99% by weight (e.g., 100% by weight) of the compound or salt. The purity level of the compounds and salts can be determined using standard analytical methods, such as high-performance liquid chromatography and / or mass spectrometry or NMR techniques. When two or more analytical methods are used and the methods result in an experimentally significant difference in the measured purity level, preference is given to the method providing the highest level of purity. A composition containing a 100% pure compound or salt is one that contains no detectable impurities as determined by standard analytical methods. For compounds of the invention that have one or more asymmetric centers and can exist as a mixture of stereoisomers, a composition containing a substantially pure compound can be a substantially pure mixture of stereoisomers or can be a substantially pure individual stereoisomer.

[0094] The compounds of formula I herein and their pharmaceutically acceptable salts are useful for inducing GAG-POL dimerization in HIV-infected cells, thereby selectively killing HIV-infected GAG-POL-expressing cells without cytotoxicity to HIV-naive cells, which is referred to herein as TAK (Targeted Activator of Cell Kill) activity, or more specifically, as HIV TACK activity. HIV TACK or TACK was previously also referred to as Small Molecule Activated Cell Kill (SMACK). Thus, the compounds of formula I and their pharmaceutically acceptable salts are useful for: (i) a method for treating or preventing infection by HIV, or treating, preventing, or delaying the onset or progression of AIDS or ARC, in a human subject in need thereof, comprising administering to said human subject an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof; and / or (ii) a method for inducing GAG-POL dimerization in HIV-infected cells in a human subject in need thereof, the method comprising administering to the human subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof; and / or (iii) a method for selectively killing HIV-infected GAG-POL-expressing cells in a human subject without cytotoxicity to HIV-naive cells, comprising administering to the human subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof; and / or (iv) A method for enhancing suppression of HIV viremia in a human subject whose HIV viremia has been suppressed by administration of one or more compatible HIV antiviral drugs, comprising further administering to the human subject an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0095] Additionally, compounds of Formula I and pharmaceutically acceptable salts thereof are useful in any of the above methods (i), (ii), (iii), or (iv), which further comprise administering to the human subject an effective amount of one or more 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 reversal agents. In the above methods (i), (ii), (iii), or (iv), the human subject can be treated with a compound of Formula I or a pharmaceutically acceptable salt thereof in addition to treatment with one or more compatible HIV antiviral agents.

[0096] The compounds of formula I and pharmaceutically acceptable salts thereof are also useful in methods of enhancing suppression of HIV viremia in a human subject whose HIV viremia has been suppressed by administration of one or more compatible HIV antiviral agents, the method comprising further administering to the human subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0097] Another embodiment of the present disclosure includes the following: (a) a pharmaceutical composition comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; (b) a pharmaceutical composition comprising the product prepared by combining (e.g., mixing) an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; (c) the pharmaceutical composition of (a) or (b), further comprising an effective amount of one or more compatible anti-HIV drugs selected from the group consisting of HIV antivirals, immunomodulatory agents, anti-infective agents, and latency reversal agents; (d) the pharmaceutical composition of (c), wherein the compatible anti-HIV drug is selected from one or more antiviral drugs selected from the group consisting of nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside HIV 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 reversal agents; (e) a combination comprising (i) a compound of Formula I or a pharmaceutically acceptable salt thereof, and (ii) one or more compatible anti-HIV agents selected from the group consisting of HIV antivirals, immunomodulators, anti-infectives, and latency reversal agents; wherein the compound and the compatible anti-HIV agents are each used in amounts that render the combination effective for treating or preventing infection by HIV, or for treating, preventing, or delaying the onset or progression of AIDS or ARC; (f) the combination of (e), wherein the compatible anti-HIV drug is an antiviral drug selected from the group consisting of 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 reversal agents; (g) a method for inducing GAG-POL dimerization in HIV-infected cells, a method for selectively killing HIV-infected GAG-POL-expressing cells without cytotoxicity to HIV-naive cells, and / or a method for treating or preventing infection by HIV or treating, preventing, or delaying the onset or progression of AIDS or ARC, comprising administering to a subject in need of such treatment an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof; (h) the method of (g), wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is administered in combination with an effective amount of at least one other compatible HIV antiviral agent selected from a nucleoside or nucleotide HIV reverse transcriptase inhibitor, a nucleoside reverse transcriptase translocation inhibitor, a non-nucleoside HIV reverse transcriptase inhibitor, an HIV integrase inhibitor, an HIV fusion inhibitor, an HIV entry inhibitor, an HIV maturation inhibitor, a post-attachment inhibitor, and a latency reversal agent; (i) the method of (g) or (h), comprising administering to said subject a pharmaceutical composition of (a), (b), (c), or (d), or a combination of (e) or (f); (j) use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for (1) inducing GAG-POL dimerization in HIV-infected cells in a subject; (2) selectively killing HIV-infected GAG-POL-expressing cells in a subject without cytotoxicity to HIV-naive cells; (3) treating or preventing infection by HIV in a subject; (4) treating, preventing, or delaying the onset or progression of AIDS or ARC in a subject; (5) enhancing suppression of HIV viremia in a subject being treated with a compatible anti-HIV drug; and / or (6) enhancing suppression of HIV viremia in a subject whose HIV viremia has been suppressed by administration of one or more compatible HIV antiviral drugs; (k) A compound of formula I or a pharmaceutically acceptable salt thereof for use in (1) inducing GAG-POL dimerization in HIV-infected cells, (2) selectively killing HIV-infected GAG-POL-expressing cells without cytotoxicity to HIV-naive cells, (3) treating or preventing infection by HIV, (4) treating, preventing, or delaying the onset or progression of AIDS or ARC, (5) enhancing suppression of HIV viremia in a subject receiving treatment with a compatible anti-HIV drug, and / or (6) enhancing suppression of HIV viremia in a subject whose HIV viremia has been suppressed by administration of one or more compatible HIV antiviral drugs.

[0098] Further embodiments of the present invention include each of the pharmaceutical compositions, methods, and uses described in the preceding paragraphs, wherein the compound of formula I or a salt thereof used therein is substantially pure. With respect to a pharmaceutical composition comprising a compound of formula I or a salt thereof and a pharmaceutically acceptable carrier, and optionally one or more excipients, it is understood that the term "substantially pure" refers to the compound of formula I or a salt thereof per se.

[0099] Another embodiment of the present disclosure is the pharmaceutical compositions, methods, medicaments, uses, and combinations described herein, wherein the HIV of interest is HIV-1. Thus, for example, in any of the pharmaceutical compositions, methods, medicaments, uses, and combinations employing a compound of Formula I or a pharmaceutically acceptable salt thereof, the compound or salt thereof is used in an amount effective against HIV-1; and, when used in combination with one or more compatible anti-HIV drugs, each such additional agent is a compatible HIV antiviral drug, for example, but not limited to, one or more of a nucleoside or nucleotide HIV reverse transcriptase inhibitor, a nucleoside reverse transcriptase translocation inhibitor, a non-nucleoside HIV reverse transcriptase inhibitor, an HIV integrase inhibitor, an HIV fusion inhibitor, an HIV entry inhibitor, an HIV maturation inhibitor, a post-attachment inhibitor, and a latency reversal agent.

[0100] With respect to a compound of Formula I, the term "administration" and variations thereof (e.g., "administering" a compound) means providing the compound to an individual in need of treatment or prevention, and includes both self-administration and administration to a patient by another person or any other means. When a compound is provided in combination with one or more other active agents (e.g., antiviral agents useful in the treatment or prevention of HIV infection or AIDS), "administration" and variations thereof are understood to include providing the compound and the other agent(s) at the same time or at different times, respectively. When agents of a combination are administered simultaneously, they can be administered together in a single composition, or they can be administered separately.

[0101] As used herein, the term "composition" is intended to encompass products containing the specified ingredients, as well as any product obtained by combining the specified ingredients. Ingredients suitable for inclusion in a pharmaceutical composition are "pharmaceutically acceptable" ingredients, meaning that the ingredients must be compatible with each other and not deleterious to the recipient thereof.

[0102] As used herein, the terms "subject" or "patient" refer to a human (or "person") who has been the object of treatment, observation, or experiment. Examples of patients treated with an HIV TACK agent include, but are not limited to, patients infected with HIV and / or whose HIV viral load is considered suppressed and / or undetectable at the time of HIV TACK treatment. Patients treated with an HIV TACK agent also include, but are not limited to, patients using an HIV TACK agent for the prevention of HIV infection or for post-exposure prophylaxis after potential exposure to HIV to prevent infection.

[0103] "Prevention" includes both pre-exposure prophylaxis (PrEP), i.e., the use of a compound of Formula I or a pharmaceutically acceptable salt thereof to prevent HIV infection in uninfected humans, and post-exposure prophylaxis (PEP), i.e., the use of a compound of Formula I or a pharmaceutically acceptable salt thereof after potential exposure to HIV to prevent HIV infection.

[0104] As used herein, the term "effective amount" refers to an amount of a compound sufficient to induce GAG-POL dimerization in HIV-infected cells and selectively kill HIV-infected, GAG-POL-expressing cells without cytotoxicity to HIV-naive cells; and / or an amount of a compound sufficient to exert a therapeutic effect and / or an amount of a compound sufficient to exert a prophylactic effect after administration. One embodiment of an "effective amount" is a "therapeutically effective amount," which is an amount of a compound effective to selectively kill HIV-infected, GAG-POL-expressing cells, effective for treating HIV infection, or effective for treating, preventing, or delaying the onset or progression of AIDS or ARC in HIV-infected patients. Another embodiment of an "effective amount" is a "prophylactically effective amount," which is an amount of a compound effective for preventing HIV infection or effective for preventing AIDS or ARC in HIV-infected patients. It is understood that an effective amount can simultaneously be both a therapeutically effective amount (e.g., a therapeutically effective amount for treating HIV infection) and a prophylactically effective amount (e.g., a prophylactically effective amount for preventing or reducing the risk of developing AIDS or ARC in a subject infected with HIV).

[0105] In the combination therapies of the present invention, an effective amount can be for each individual agent or for the combination as a whole, where the amounts of all agents administered in the combination are effective as a whole, but the component agents of the combination may or may not be present in individually effective amounts with respect to what would be effective for that component agent if it were administered alone.

[0106] In the methods of the invention (i.e., selectively killing HIV-infected GAG-POL-expressing cells, treating infection by HIV, preventing HIV infection, or treating, preventing, or delaying the onset or progression of AIDS or ARC, and other methods described herein), the compounds of the invention or salts thereof can be administered by any means that results in contact of the active agent with its site of action. They can be administered by any conventional means available for use in combination with pharmaceuticals, either as individual therapeutic agents or in a therapeutic combination. The compounds can be administered by themselves, but are typically administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. The compounds of the invention can be administered orally (e.g., by tablet or capsule), parenterally (which includes subcutaneous injection, intravenous, intramuscular, or intrasternal injection or infusion techniques), by inhalation spray, or rectally, for example, in the form of a unit dose of a pharmaceutical composition comprising an effective amount of the compound and conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles. The compounds can also be administered via implantable drug delivery devices adapted to provide effective amounts of the compound or a pharmaceutical composition of the compound over an extended period of time.

[0107] formulation Solid preparations suitable for oral administration (e.g., powders, pills, capsules, and tablets) can be prepared according to techniques known in the art, and solid excipients such as starch, sugar, kaolin, lubricants, binders, disintegrants, etc. can be used. Liquid preparations suitable for oral administration (e.g., suspensions, syrups, elixirs, etc.) can be prepared according to techniques known in the art, and any of the usual vehicles, such as water, glycols, oils, alcohols, etc., can be used. Parenteral compositions can be prepared according to techniques known in the art, and typically use sterile water as the carrier, and optionally other ingredients such as a solubilizing agent. Injectable solutions can be prepared according to methods known in the art, where the carrier comprises saline, glucose solution, or a solution containing a mixture of saline and glucose. Implantable compositions can be prepared according to methods known in the art, where the carrier comprises the active chemical ingredient together with a polymer and suitable excipients, or utilize implantable devices for drug delivery. Further description of methods suitable for use in preparing pharmaceutical compositions for use in the present invention and ingredients suitable for use in such compositions is provided in Remington - The Science and Practice of Pharmacy, 22nd Edition, published by Pharmaceutical Press and Philadelphia College of Pharmacy at University of the Sciences, 2012, ISBN 978 0 85711-062-6 and previous editions.

[0108] Formulations of compounds of Formula I that result in drug supersaturation and / or rapid dissolution can be used to enhance oral drug absorption. Formulation approaches for achieving drug supersaturation and / or rapid dissolution include, but are not limited to, nanoparticle systems, amorphous systems, solid solutions, solid dispersions, and lipid systems. Such formulation approaches and techniques for their preparation are known in the art. For example, solid dispersions can be prepared using excipients and processes as described in reviews (e.g., ATM Serajuddin, J Pharm Sci, 88:10, pp. 1058-1066 (1999)). Nanoparticle systems based on both milling and direct synthesis are also described in reviews such as Wu et al. (F. Kesisoglou, S. Panmai, Y. Wu, Advanced Drug Delivery Reviews, 59:7, pp. 631-644 (2007)).

[0109] The compound of Formula I can be administered, for example, in a dosage range of 1 to 20 mg, or 1 to 10 mg, or about 5 mg per kg of mammalian (e.g., human) body weight per day, or at other time intervals, as appropriate, in a single dose or in divided doses. The compound of Formula I can be administered in a dosage range of 0.001 to 2000 mg per day, in a single dose or in divided doses. Exemplary dosage ranges are 0.01 to 1500 mg per day, or 0.1 to 1000 mg per day, administered orally or via another route of administration, in a single dose or in divided doses.

[0110] For oral administration (e.g., tablet or capsule) or another route of administration, the dosage unit can contain 100-1500 mg of active ingredient, including, but not limited to, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, or 1500 mg of active ingredient, to symptomatically adjust the dosage to the patient being treated. Furthermore, the compound can be formulated into oral dosage forms for immediate or modified release (e.g., sustained or controlled release). When a compound of Formula I is administered as a salt, references to the amount of the compound in milligrams or grams are based on the free form (i.e., non-salt form) of the compound.

[0111] Daily administration can be via any suitable route of administration, but is preferably via oral administration, and can be a single dose or multiple doses staggered within each 24-hour period (divided daily doses). Each dose can be administered using one or more dosage units, as needed.

[0112] The specific dose level and frequency of administration for any particular patient can vary and will depend upon a variety of factors, such as the activity of the particular compound used, the metabolic stability and length of action of that compound, age, body weight, general health, sex, diet, method and time of administration, rate of excretion, drug combination, severity of the particular condition, and the host being treated. In some cases, it may be necessary to deviate upward or downward from a given dose depending on the efficacy of the compounds or individual response. The amount and frequency of administration will be regulated according to the judgment of the attending clinician, taking such factors into consideration.

[0113] An "anti-HIV drug" is any drug that is directly or indirectly effective in inhibiting HIV, treating or preventing HIV infection, and / or treating, preventing, or delaying the onset or progression of AIDS or ARC. An anti-HIV drug is understood to be effective in treating, preventing, or delaying the onset or progression of HIV infection or AIDS and / or diseases or conditions resulting therefrom or related thereto. The present disclosure is further directed to the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, together with one or more compatible anti-HIV drugs (i.e., anti-HIV drugs other than HIV protease inhibitors) (also referred to as "compatible HIV antivirals"). For example, a compound of Formula I can be administered in combination with an effective amount of one or more compatible anti-HIV drugs selected from HIV antivirals, immunomodulators, anti-infectives, or vaccines useful in the treatment of HIV infection or AIDS. Compatible HIV antivirals suitable for use in combination with the compounds of the present disclosure include, but are not limited to, those listed in Table A below: [Table 1] TIFF2026021308000008.tif196165

[0114] The TACK effect induced by HIV-TACK agents depends on the expression of viral Gag-Pol. Therefore, when used in conjunction with HIV-TACK therapy, additional active agents (e.g., latency reversal agents ("LRAs" or "LRAs")) that promote the production of Gag-Pol in infected cells and / or activate viral expression in cells that constitute latent HIV reservoirs may potentiate the TACK effect. The present disclosure is further directed to the combination of a compound of Formula I, or a pharmaceutically acceptable salt thereof, with one or more LRAs. For example, a compound of Formula I can be administered in combination with an effective amount of one or more LRAs to treat HIV infection or AIDS.Examples of LRAs that may be used in combination with the compounds of the present disclosure include, but are not limited to, epigenetic modifiers such as histone deacetylase (HDAC) inhibitors, DNA methyltransferase (DNMT) inhibitors, and histone methyltransferase (HMT) inhibitors; protein kinase C (PKC) agonists such as prostratin, bryostatin, or ingenol; P-TEFb release inducers such as BET inhibitors (e.g., JQ1, or Bromodomain and Extra-Terminal Motif inhibitors); These include drugs that bind reversibly to the bromodomains of the BET (brain exchange transcriptional (BET) motif) proteins BRD2, BRD3, BRD4, and / or BRDT (a class of drugs that reversibly bind to the bromodomains of BET proteins BRD2, BRD3, BRD4, and / or BRDT), antagonists of CC chemokine receptor type 5 (CCR5), inducers of the non-canonical NF-κB pathway (e.g., second mitochondrial-derived activator of caspases (SMAC) mimetics or inhibitor of apoptosis protein (IAP) antagonists, proteasome inhibitors, Toll-like receptor (TLR) agonists, mitogen-activated protein kinase (MAPK) agonists, AKT / protein kinase B (AKT / PKB) pathway activators, cytokines, and immunomodulatory agents (e.g., immune checkpoint inhibitors), as well as other therapeutic agents described in the literature (e.g., Bullen et al., Nature Medicine, 20:425-429 (2014); Ait-Ammar et al., Frontiers in Microbiology, 10:3060 (2019); and Fujinaga et al., Viruses). 12:11 (2020)).

[0115] Examples of HDAC inhibitors that can be used as latency reversals include, but are not limited to, vorinostat, panabinostat, romidepsin, and valproic acid. Examples of DNMT inhibitors that can be used as latency reversals include, but are not limited to, 5-aza-2'-cytidine and 5-aza-2'-deoxycytidine. Examples of HMT inhibitors that can be used as latency reversal agents include, but are not limited to, chaetocin, 3-deazaneplanocin A, tazemetostat (EPZ-6438), N-[(1,2-dihydro-6-methyl-2-oxo-4-propyl-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[2-(4-methyl-1-piperazinyl)-4-pyridinyl]-1H-indazole-4-carboxamide (GSK-343), and 2-cyclohexyl-6-methoxy-N-[1-(1-methylethyl)-4-piperidinyl]-7-[3-(1-pyrrolidinyl)propoxy]-4-quinazolinamine (UNC-0638). Examples of PKC agonists that can be used as latency reversals include, but are not limited to, phorbol esters such as prostratin and phorbol myristate acetate (PMA), bryostatin-1, and ingenol. Examples of BET inhibitors that can be used as latency reversals include, but are not limited to, JQ1 ((S)-tert-butyl 2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetate), iBET, and N-cyclohexyl-2-(4-(3,5-dimethylisoxazol-4-yl)-2-methoxyphenyl)imidazo[l,2-a]pyrazin-3-amine (UMB-136). Examples of CCR5 antagonists that can be used as latency reversal agents include, but are not limited to, maraviroc and vicriviroc.Examples of inducers of the non-canonical NF-κB pathway and SMAC mimetics / IAP inhibitors that can be used as latency reversals include, but are not limited to, 3,3'-[2,4-hexadiyn-1,6-diylbis[oxy[(1S,2R)-2,3-dihydro-1H-indene-2,1-diyl]]]bis[N-methyl-L-alanyl-(2S)-2-cyclohexylglycyl-L-prolinamide (AZD5582), ciapavir, birinapant, LCL161, and DEBIO1143 / AT-406. Examples of proteasome inhibitors that can be used as latency reversals include, but are not limited to, bortezomib and ixazomib. Examples of TLR agonists that can be used as latency reversal agents include, but are not limited to, the TLR2 agonist Pam3CSK4, the TLR7 agonist vesatolimod, and the TLR9 agonists lefitolimod (MGN1703) and CPG7909.

[0116] Examples of MAPK agonists that can be used as latency reversals include, but are not limited to, procyanidin trimer C1. Examples of AKT pathway activators that can be used as latency reversals include, but are not limited to, disulfiram. Examples of immunomodulatory cytokines that can be used as latency reversals include, but are not limited to, IL-2, IL-7, and IL-15 (including the IL-15 superagonist N-803). Examples of immune checkpoint inhibitors include, but are not limited to, programmed cell death protein 1 (PD-1) inhibitors, programmed death-ligand 1 (PD-L1) inhibitors, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), lymphocyte-activation gene 3 (LAG3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and CD24Fc, a recombinant fusion protein composed of the extracellular domain of the mature human glycoprotein cluster of differentiation 24 (CD24) linked to the human immunoglobulin G1 (IgG1) Fc domain.

[0117] Non-limiting examples of anti-HIV drugs, HIV integrase inhibitors, are disclosed in International Patent Application Publication WO2018 / 102485, which is incorporated herein by reference in its entirety, and [ka] etc.

[0118] Non-limiting examples of non-nucleoside reverse transcriptase inhibitors that are anti-HIV drugs are disclosed in International Patent Application Publication WO2014 / 058747, which is incorporated herein by reference in its entirety, and include the following: 3-chloro-5-((6-oxo-1-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)methyl)-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (uronivrine); 3-chloro-5-((6-oxo-1-((3-oxo-2,3-dihydropyridazin-4-yl)methyl)-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile; 3-chloro-5-((1-((4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile; and 3-chloro-5-((1-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

[0119] Non-limiting examples of nucleoside reverse transcriptase inhibitors that are anti-HIV drugs are disclosed in International Patent Application Publication WO2015 / 148746, which is incorporated herein by reference in its entirety, and include the following: 3-chloro-5-((6-oxo-1-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)methyl)-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (UNIVIRINE); 3-chloro-5-((6-oxo-l-((3-oxo-2,3-dihydropyridazin-4-yl)methyl)-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile; 3-chloro-5-((1-((4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile; and 3-chloro-5-((1-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

[0120] Thus, compounds of formula I or pharmaceutically acceptable salts thereof, when used in conjunction with a latency reversal agent, may be useful for: (i) a method for reactivating latent HIV and inducing GAG-POL dimerization in HIV-infected cells (e.g., CD4 T cells) in a human subject, comprising administering to the subject an effective amount of a compound of Formula I or a pharmaceutically acceptable derivative thereof; and / or (ii) A method for reactivating latent HIV and selectively killing HIV-infected GAG-POL-expressing cells (e.g., latently HIV-infected CD4 T cells or central memory CD4 T cells) in a human subject without cytotoxicity to naive HIV cells, comprising administering to the subject an effective amount of a compound of formula I or a pharmaceutically acceptable derivative thereof.

[0121] The compounds of the present invention may be used in combination with any one or more antiviral agents (such as, but not limited to, those listed in Table A) and / or any one or more LRAs (such as, but not limited to, those LRAs described herein).

[0122] It is understood that the scope of combinations of the compounds of the present invention with compatible anti-HIV drugs is not limited to the HIV antivirals listed in Table A, but includes, in principle, any combination with any pharmaceutical composition useful for the treatment or prevention of HIV, AIDS, or ARC (with the exception of HIV protease inhibitors). The compatible HIV antiviral drug and another active drug are typically used in these combinations in their customary dosage ranges and regimens reported in the art, e.g., dosages described in the current "Physicians' Desk Reference, Thomson PDR, 70th edition (2016), Montvale, NJ: PDR Network" or previous editions. The dosage ranges of the compounds of the present disclosure in these combinations can be the same as those described above.

[0123] The compounds of the present invention are also useful in preparing and performing screening assays for antiviral compounds. For example, the compounds of the present invention are useful for isolating enzyme mutants, which are excellent screening tools for more potent antiviral compounds. Furthermore, the compounds of the present invention are useful for establishing or confirming the binding site of other antiviral drugs to the reverse transcriptase domain within GAG-POL, for example, by competitive inhibition. [Table 2] TIFF2026021308000011.tif42165

[0124] Bromine-containing compounds include 79 Br and 81It has two masses in a ratio of approximately 1:1 due to the two bromine isotopes of Br. [Example]

[0125] Intermediate A Section Intermediate A01: 7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-1-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (A01) [ka]

[0126] Step 1: 1-(4-bromo-2,5-difluorophenyl)-2,2-difluoropropan-1-one (A01-a) To a stirred mixture of 1,4-dibromo-2,5-difluorobenzene (500 g, 1838.99 mmol) in ether (5 L) under a N atmosphere, 2.5 M n-BuLi (809.16 mL, 2022.89 mmol) was added dropwise at −78°C. The resulting mixture was stirred at −78°C for an additional 1.0 h. Subsequently, ethyl 2,2-difluoropropanoate (253.99 g, 1838.99 mmol) was added dropwise to the mixture over 40 min at −78°C. The resulting mixture was stirred at −78°C for an additional 1 h. The reaction was quenched with saturated aqueous NH4Cl (2 L). The quenched mixture was then extracted with ether / EtOAc (3 × 2 L). The combined organic extracts were washed with brine (3×500 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to isolate compound A01-a, which was used directly in Step 2.

[0127] 1 H NMR (500 MHz, chloroform-d) δ 7.70–7.59 (m, 1H), 7.45 (dd, J = 9.3, 5.3 Hz, 1H), 1.88 (t, J = 19.3 Hz, 3H).

[0128] Step 2: 1-(4-bromo-5-fluoro-2-{[(4-methoxyphenyl)methyl]amino}phenyl)-2,2-difluoropropan-1-one (A01-b) A solution of 1-(4-bromo-2,5-difluorophenyl)-2,2-difluoropropan-1-one (A01-a, 460 g, 1613.83 mmol) in toluene (4600 mL) was treated with 1-(4-methoxyphenyl)methanamine (332.08 g, 2420.74 mmol) and KCO (223.04 g, 1613.83 mmol) and then stirred at 115 °C under a nitrogen atmosphere for 10 h. The mixture was cooled to ambient temperature. The precipitated solid was collected by filtration and washed with toluene (3 × 200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash silica chromatography eluting with PE:EtOAc (95:5) to give compound A01-b.

[0129] 1 H NMR (500 MHz, chloroform-d) δ 8.89 (s, 1H), 7.82 (d, J = 10.0 Hz, 1H), 7.25 (s, 2H), 6.97 (d, J = 5.6 Hz, 1H), 6.91 (d, J = 7.5 Hz, 2H), 4.36 (d, J = 5.1 Hz, 2H), 3.86 - 3.78 (m, 3H), 1.86 (t, J = 19.5 Hz, 3H).

[0130] Step 3: 7-Bromo-4-(1,1-difluoroethyl)-6-fluoro-4-hydroxy-1-[(4-methoxyphenyl)methyl]-3H-quinazolin-2-one (A01-c) To a stirred solution of 1-(4-bromo-5-fluoro-2-{[(4-methoxyphenyl)methyl]amino}phenyl)-2,2-difluoropropan-1-one (A01-b, 430 g, 1069.1 mmol) in AcOH (4.3 L) under a N atmosphere, sodium isocyanate (903.48 g, 13898.2 mmol) was added portionwise at ambient temperature. The resulting mixture was stirred at 110 °C for an additional 10 h. The mixture was cooled to ambient temperature. The mixture was adjusted to pH 8-9 with NaHCO. The resulting mixture was extracted with EtOAc (3 × 3 L). The combined organic layers were washed with brine (3 × 1 L), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by trituration with PE:EtOAc (5:1) to give compound A01-c.

[0131] MS (ESI) m / z 445, 447 [M+1].

[0132] Step 4: 7-Bromo-4-(1,1-difluoroethyl)-6-fluoro-1-[(4-methoxyphenyl)methyl]quinazolin-2-one (A01-d) A mixture of 7-bromo-4-(1,1-difluoroethyl)-6-fluoro-4-hydroxy-1-[(4-methoxyphenyl)methyl]-3H-quinazolin-2-one (A01-c, 410 g, 920.86 mmol) in toluene (8200 mL) was stirred at 120° C. for 24 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure to isolate compound A01-d, which was used without further purification.

[0133] 1 H NMR (500 MHz, DMSO-d6) δ 7.97 (dd, J = 14.9, 7.4 Hz, 2H), 7.25 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 5.45 (s, 2H), 3.72 (s, 3H), 2.10 (t, J = 20.0 Hz, 3H).

[0134] Step 5: 7-Bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-1-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (A01) To a room temperature solution of ethynylcyclopropane (139.26 g, 2106.63 mmol) in toluene (1.4 L) was added dropwise 1 M LiHMDS in THF (1685.31 mL, 1685.31 mmol) at −5° C. under a nitrogen atmosphere. The resulting mixture was stirred for an additional 120 minutes at 10° C. To this mixture was added a solution of 7-bromo-4-(1,1-difluoroethyl)-6-fluoro-1-[(4-methoxyphenyl)methyl]quinazolin-2-one (A01-d, 360 g, 842.65 mmol, 1.0 equiv.) in THF (4 L). This was added dropwise over 40 minutes at −15° C. The resulting mixture was stirred for an additional 120 minutes at room temperature. The reaction was quenched with saturated aqueous NH4Cl at room temperature. The resulting mixture was extracted with EtOAc (3 × 3000 mL). The combined organic layers were washed with brine (2×1000 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash silica column chromatography eluting with PE:EtOAc (80:20) to give compound A01.

[0135] MS (ESI) m / z 493, 495 [M+1].

[0136] Intermediate A02: (S)-7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one and (R)-7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one (A02) [ka]

[0137] A mixture of 7-bromo-4-(2-cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-1-[(4-methoxyphenyl)methyl]-3H-quinazolin-2-one (A01, 300 g, 608.12 mmol) and CAN (1171.13 g, 2128.42 mmol) in acetonitrile (6 L) and water (600 mL) was stirred at room temperature for 10 h. The resulting mixture was diluted with HO (20 L). The precipitated solid was collected by filtration and washed with HO (3 × 300 mL). The residue was purified by flash silica column chromatography eluting with PE:EtOAc (80:20). The racemic product was separated by Pre-SFC (Amylose-C Neo 100 × 4.6 mm 3.0 μm Co Solvent:MeOH (20 mM NH)) to isolate isomer A02-A (fast eluting) and isomer A02-B (slow eluting).

[0138] For both isomers, MS (ESI) m / z 373, 375 [M+1]

[0139] Intermediate A03: (S)-7-Bromo-4-(cyclopropyldifluoromethyl)-4-(cyclopropylethynyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one and (R)-7-bromo-4-(cyclopropyldifluoromethyl)-4-(cyclopropylethynyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one (A03) [ka]

[0140] Step 1: 1-(4-bromo-2,5-difluorophenyl)-2-cyclopropyl-2,2-difluoroethan-1-one (A03-a) To a solution of 1,4-dibromo-2,5-difluorobenzene (18.86 g, 69.4 mmol) in diethyl ether (347 mL) was added dropwise 1.6 M nBuLi in hexanes (47.7 mL, 76 mmol) at −78 °C. The reaction was stirred at −78 °C for 30 min under a N atmosphere. Ethyl 2-cyclopropyl-2,2-difluoroacetate (15 g, 91 mmol) was dissolved in toluene (20 mL) and added dropwise over 10 min. The solution was stirred at −78 °C for an additional 1 h and quenched by the addition of 10% NH Cl (100 mL). The mixture was diluted with EtOAc (200 mL), washed with water (2 × 100 mL), brine (100 mL), and dried over Na SO . The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash chromatography (SiO 2 ; 0-60% EtOAc:hexanes) to isolate compound (A03-a).

[0141] 1 H NMR (500 MHz, DMSO-d6) δ 9.97 - 9.57 (m, 1H), 8.32 (m, 1H), 1.48 (s, 1H), 0.87 (bs, 2H), 0.73 (bs, 2H).

[0142] Step 2: 7-Bromo-4-(cyclopropyldifluoromethyl)-6-fluoro-4-hydroxy-3,4-dihydroquinazolin-2(1H)-one (A03-b) Urea (8.61 g, 143 mmol) was dissolved in NMP (47.8 mL) and added to 1-(4-bromo-2,5-difluorophenyl)-2-cyclopropyl-2,2-difluoroethan-1-one (A03-a, 14.86 g, 47.8 mmol) in NMP (47.8 mL). The mixture was heated to 140° C. for 16 hours. The reaction mixture was cooled and added to water (500 mL) and then extracted with EtOAc (3×200 mL). The combined organics were washed with water (3×300 mL), brine (3×300 mL), and dried over MgSO. The organic layer was concentrated under reduced pressure to isolate compound A03-b.

[0143] MS (ESI) m / z 351, 353 [M+1]

[0144] Step 3: 7-Bromo-4-(cyclopropyldifluoromethyl)-6-fluoroquinazolin-2(1H)-one (A03-c) 7-Bromo-4-(cyclopropyldifluoromethyl)-6-fluoro-4-hydroxy-3,4-dihydroquinazolin-2(1H)-one (A03-b, 13.683 g, 39.0 mmol) was added to the flask, followed by toluene (195 mL) and heated to reflux for 72 hours. The reaction was cooled to 0° C., and the resulting slurry was filtered to isolate compound A03-c.

[0145] 1H NMR (500 MHz, methanol-d4) δ 7.95 (d, J = 9.2 Hz, 1H), 7.72 (d, J = 5.9 Hz, 1H), 1.93 (ddd, J = 13.3, 8.0, 5.2 Hz, 1H), 0.94–0.75 (m, 4H).

[0146] Step 4: (S)-7-Bromo-4-(cyclopropyldifluoromethyl)-4-(cyclopropylethynyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one and (R)-7-Bromo-4-(cyclopropyldifluoromethyl)-4-(cyclopropylethynyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one (A03-A and A03-B) Cyclopropylacetylene (4.70 mL, 55.5 mmol) was dissolved in THF (69.4 mL) and cooled to 0 °C. To the solution was added 2.5 M nBuLi (22.20 mL, 55.5 mmol) in hexanes and stirred for 30 min. 7-Bromo-4-(cyclopropyldifluoromethyl)-6-fluoroquinazolin-2(1H)-one (A03-c, 4.62 g, 13.88 mmol) was added to the reaction, which was allowed to warm to ambient temperature and stir for 16 h. The reaction was quenched with water. To the solution was added EtOAc (200 mL). The solution was extracted with water (2 × 50 mL), brine (50 mL), dried over MgSO, filtered, and the organics were concentrated under reduced pressure. The residue was purified by flash chromatography (SiO; 0-100% EtOAc:hexanes) to isolate A03 as a racemic mixture. The racemic mixture was resolved by prep SFC using a Daicel ChiralPak® IG (30 mm x 250 mm (5 microns), Daicel Chiral Technologies, West Chester, PA); elution with 25% MeOH (0.1% DEA); 80 mL / min; 100 bar).

[0147] Isomer A03-A (fast eluting) and Isomer A03-B (slow eluting): MS (ESI) m / z 399, 401 [M+1] for both isomers

[0148] Intermediate A04: (S)-7-Bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3-methyl-3,4-dihydroquinazolin-2(1H)-one and (R)-7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3-methyl-3,4-dihydroquinazolin-2(1H)-one (A04) [ka]

[0149] Step 1: 7-Bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-1-(4-methoxybenzyl)-3-methyl-3,4-dihydroquinazolin-2(1H)-one (A04-a) To a solution of (S)-7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-1-(4-methoxybenzyl)-3-methyl-3,4-dihydroquinazolin-2(1H)-one (A01, 2000 mg, 4.05 mmol) in anhydrous 1,4-dioxane (20.3 mL) was added NaH (324 mg, 8.11 mmol), and the mixture was stirred at room temperature for 1 h. MeI (760 μL, 12.16 mmol) was added dropwise and stirred for an additional 16 h. The mixture was cooled to 0 °C, quenched with NH Cl (saturated aqueous, 20 mL), and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over Na SO , filtered, and the organics were concentrated under reduced pressure. The residue was used crude to isolate A04-a.

[0150] MS (ESI) m / z 507, 509 [M+1]

[0151] Step 2: (S)-7-Bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3-methyl-3,4-dihydroquinazolin-2(1H)-one and (R)-7-Bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3-methyl-3,4-dihydroquinazolin-2(1H)-one (A04-A and A04-B) A solution of 7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-1-(4-methoxybenzyl)-3-methyl-3,4-dihydroquinazolin-2(1H)-one (A04-a, 2.057 g, 4.05 mmol) in anhydrous TFA (8.11 mL) was heated to 60° C. for 1 h. The reaction was concentrated under reduced pressure and purified by flash silica chromatography eluting with 0-100% EtOAc in hexanes to isolate the racemate. The material was further purified by SFC (Daicel ChiralPak® IG, 20% MeOH / 0.1% DEA, 100 mL / min, 100 bar) to isolate the fast-eluting isomer A04-A and the slow-eluting isomer A04-B.

[0152] For both isomers, MS (ESI) m / z 387, 389 [M+1]

[0153] Intermediate A05 to Intermediate A07 shown in Table 1 were synthesized using the process disclosed in International Patent Application Publication WO2022 / 046844. [Table 3]

[0154] Intermediate A08: (S)-7-Bromo-4-(cyclopropylethynyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (A08) [ka]

[0155] Step 1: (2-Bromo-6-fluorophenyl)trimethylsilane (A08-a) To a solution of 1-bromo-3-fluorobenzene (1200 g, 6857 mmol) and TMSCl (1638 g, 15085 mmol) in THF (10 L) was added 2 M LDA in THF (7.54 L, 15085 mmol) at −70° C. The resulting solution was stirred at −75° C. for 30 min and hydrolyzed with dilute aqueous HSO. The organic layer was separated, and the aqueous phase was extracted with ether. The organics were concentrated, and the oil was distilled under reduced pressure to give the crude product as a colorless oil. Methanol (1 L) was added, and the solution was placed in a freezer at −20° C. overnight. The mixture was filtered to isolate A08-a.

[0156] Step 2: 1-(4-bromo-2-fluoro-3-(trimethylsilyl)phenyl)-2,2,2-trifluoroethan-1-one (A08-b) To a solution of 2,2,6,6-tetramethylpiperidine (426.5 g, 3020 mmol, 1.1 equiv.) in 2500 mL of THF was added dropwise 2.5 M nBuLi (1207 mL, 3020 mmol) in hexanes at −20° C. After stirring for 30 minutes, the mixture was cooled to −70° C., and a solution of (2-bromo-6-fluorophenyl)(trimethyl)silane (678 g, 2745 mmol) in 700 mL of THF was added. The solution was stirred for 1 hour, followed by the dropwise addition of ethyl trifluoroacetate (428 g, 3020 mmol) at −70° C. The mixture was then slowly warmed to room temperature and stirred for 1 hour. Saturated aqueous NH4Cl was then added, and the mixture was extracted twice with ethyl acetate. The combined ethyl acetate phases were washed with brine, dried over MgSO4, filtered, and concentrated to isolate A08-b, which was used directly in Step 3.

[0157] Step 3: 1-(4-bromo-2-fluorophenyl)-2,2,2-trifluoroethan-1-one (A08-c) To a solution of A08-b (658 g, 1918 mmol) in 2 L of THF was added 1 M TBAF in THF (2301 mL, 2301 mmol) at room temperature. After stirring for 30 min, the solution was diluted with ethyl acetate and washed with water. The aqueous phase was extracted again with ethyl acetate. The combined organic layers were then washed with brine, dried over MgSO4, filtered, and concentrated. The resulting residue was purified by flash chromatography (silica gel, mobile phase cyclohexane / ethyl acetate 95:5) to isolate A08-c.

[0158] Step 4: 1-(4-bromo-2-((4-methoxybenzyl)amino)phenyl)-2,2,2-trifluoroethan-1-one (A08-d) 1-(4-Bromo-2-fluorophenyl)-2,2,2-trifluoroethan-1-one (A08-c, 260 g, 959 mmol) was added to a flask, followed by 1-(4-methoxyphenyl)methanamine (262.7 g, 1918 mmol), K2CO3 (158.8 g, 1150.8 mmol), and toluene (2080 mL). The resulting solution was stirred in an oil bath at 115 °C for 2 h. The mixture was diluted with 1 L of water. The resulting solution was extracted with ethyl acetate (3 × 500 mL), and the organic layers were combined, dried over Na2SO4, and concentrated. The residue was purified by normal phase chromatography (SiO2, PE:EA = 5:1) to isolate the title compound A08-d.

[0159] Step 5: 1-(2-amino-4-bromophenyl)-2,2,2-trifluoroethan-1-one and N-(5-bromo-2-(2,2,2-trifluoroacetyl)phenyl)-2,2,2-trifluoroacetamide (A08-e) 1-(4-Bromo-2-((4-methoxybenzyl)amino)phenyl)-2,2,2-trifluoroethan-1-one (A08-d, 281 g, 724 mmol) was added to a round-bottom flask, followed by TFA (840 mL). The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was concentrated to isolate the title material (A08-e) as a mixture, which was used directly in Step 6.

[0160] Step 6: 1-(2-amino-4-bromophenyl)-2,2,2-trifluoroethan-1-one (A08-f) A flask purged with nitrogen and maintained under an inert nitrogen atmosphere was charged with a mixture of 1-(2-amino-4-bromophenyl)-2,2,2-trifluoroethan-1-one and N-[5-bromo-2-(2,2,2-trifluoroacetyl)phenyl]-2,2,2-trifluoroacetamide (A08-e, 105 g, 290 mmol), MeOH (530 mL), NHOH (53 mL), and DCM (530 mL). The resulting solution was stirred at room temperature for 5 h. The resulting solution was diluted with water (500 mL) and extracted with DCM (3 × 500 mL). The organic layer was washed with brine (500 mL), dried over NaSO, and concentrated. The residue was purified by normal phase chromatography (SiOPE:EtOAc = 50:1 → 5:1) to isolate the title material A08-f.

[0161] Step 7: 1-(2-amino-4-bromophenyl)-2,2,2-trifluoroethane-1,1-diol.HCl (A08-g) A 500 mL three-necked round-bottom flask was charged with 1-(2-amino-4-bromophenyl)-2,2,2-trifluoroethan-1-one (A08-f, 70 g, 261.16 mmol), acetic acid (210 mL), and 12 N HCl (70 mL). The resulting solution was stirred at 65° C. for 10 hours. The solid was collected by filtration to isolate the title compound A08-g.

[0162] Step 8: 7-Bromo-4-hydroxy-3-((R)-1-phenylethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (A08-h) To a round-bottom flask was added 1-(2-amino-4-bromophenyl)-2,2,2-trifluoroethane-1,1-diol·HCl (A08-g, 78 g, 243.38 mmol), [(1R)-1-isocyanatoethyl]benzene (71.6 g, 486.75 mmol), THF (1450 mL), and 1 N HCl (110 mL, 3620.31 mmol). The resulting solution was stirred in a water / ice bath at 0 °C for 2 h and then at 17 °C for an additional 48 h. The reaction was then stirred at 60 °C for 1 h. The resulting mixture was concentrated. The residue was diluted with 500 mL of water and extracted with ethyl acetate (3 × 1 L). The combined organic layers were concentrated and purified by reverse-phase chromatography (C18 column; eluent: 50%-70% MeCN in water) to isolate the title compound A08-h.

[0163] Step 9: (S)-7-Bromo-4-(cyclopropylethynyl)-3-((R)-1-phenylethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (A08-i) A 500 mL three-necked round-bottom flask was charged with butyl(chloro)magnesium (378 mL, 756.40 mmol, 2 M in THF) and ethynylcyclopropane (50 g, 756.40 mmol) was added slowly at room temperature. The resulting solution was stirred at 18° C. for 2 hours. The resulting intermediate was used directly.

[0164] A round-bottom flask was charged with 7-bromo-4-hydroxy-3-[(1R)-1-phenylethyl]-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-2-one (A08-h, 70 g, 168.59 mmol), and toluene (700 mL) and TEA (85.3 g, 842.95 mmol) were added. SOCl2 (21.1 g, 177.02 mmol) was then added slowly while maintaining the temperature at -5 to 0 °C. The resulting solution was stirred at 0 °C in a water / ice bath for 1 h. The reaction was then cooled to -70 °C, and in situ generated magnesium chloride solution was added dropwise over 30 min. The mixture was quenched with 12% aqueous citric acid (700 mL) and extracted with ethyl acetate (3 × 1 L), the combined organics were dried over NaSO, concentrated, and the residue was purified by Prep-SFC (conditions: column, Daicel ChiralPak® OD-H 5 × 25 cm, 5 μm (Daicel Chiral Technologies, West Chester, PA); mobile phase, mobile phase A: CO: 80%, mobile phase B: MeOH (NH / MeOH, 20 mmol).

[0165] Step 10: (S)-7-Bromo-4-(cyclopropylethynyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (A08) To a round-bottom flask purged with nitrogen and maintaining an inert atmosphere of nitrogen was added (4S)-7-bromo-4-(2-cyclopropylethynyl)-3-[(1R)-1-phenylethyl]-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-2-one (A08-i, 23 g, 49.64 mmol) and TFA (69 mL, 928.95 mmol). The resulting solution was stirred at 18 °C for 1 hour. The reaction was then quenched by adding 100 mL of water. The resulting solution was extracted with DCM (3 × 100 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to isolate the title compound A08.

[0166] MS (ESI) m / z 359, 361 [M+1]

[0167] Intermediate A09: (S)-7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-3,4-dihydroquinazolin-2(1H)-one and (R)-7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (A09) [ka]

[0168] Step 1: (2-Bromo-6-fluorophenyl)trimethylsilane (A09-a) To a solution of 1-bromo-3-fluorobenzene (50 g, 286 mmol) and TMS-Cl (73.0 mL, 571 mmol) in THF (450 mL) was added 2 M LDA in THF (286 mL, 571 mmol) at −70° C. The reaction was stirred at −70° C. for 2 h. The reaction was hydrolyzed with dilute aqueous HSO. The organic layer was separated and the aqueous phase was extracted with EtOAc. The organics were dried over MgSO and filtered. The organics were concentrated under reduced pressure to isolate the title compound A09-a, which was used directly in Step 2.

[0169] 1 H NMR (400 MHz, chloroform-d) δ ppm 7.35 (d, J=7.82 Hz, 1 H) 7.16 (td, J=7.95, 6.36 Hz, 1 H) 6.94 (t, J=8.80 Hz, 1 H) 0.46 (d, J=2.45 Hz, 9 H).

[0170] Step 2: 1-(4-bromo-2-fluoro-3-(trimethylsilyl)phenyl)-2,2-difluoropropan-1-one (A09-b) To a solution of 2,2,6,6-tetramethylpiperidine (18.86 g, 134 mmol) in THF (125 mL) was added 2.5 M nBuLi (53.4 mL, 134 mmol) in hexanes at −20° C. After stirring at −20° C. for 30 min, the mixture was further cooled to a bath temperature of −70° C., and a solution of (2-bromo-6-fluorophenyl)trimethylsilane (A09-a, 30 g, 121 mmol) in THF (35 mL) was added. After stirring at −70° C. for 1 h, ethyl 2,2-difluoropropanoate (18.44 g, 134 mmol) was added dropwise. The mixture was then slowly warmed to 20° C. and stirred at 20° C. for an additional 1 h. Saturated aqueous NH4Cl (300 mL) was then added, and the mixture was extracted with ethyl acetate (3 × 300 mL). The combined organic layers were washed with brine (300 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated to isolate the title compound A09-b.

[0171] Step 3: 1-(4-bromo-2-fluorophenyl)-2,2-difluoropropan-1-one (A09-c) To a solution of 1-(4-bromo-2-fluoro-3-(trimethylsilyl)phenyl)-2,2-difluoropropan-1-one (A09-b, 45 g, 133 mmol) in THF (200 mL) was added 1 M TBAF in THF (34.7 g, 133 mmol) at 20 °C and stirred for 0.5 h. The reaction was concentrated and purified by flash silica gel (PE:EA = 1:0 to 95:5) to isolate the title compound A09-c.

[0172] Step 4: 1-(4-bromo-2-((4-methoxybenzyl)amino)phenyl)-2,2-difluoropropan-1-one (A09-d) To a solution of 1-(4-bromo-2-fluorophenyl)-2,2-difluoropropan-1-one (A09-c, 20 g, 74.9 mmol) in toluene (200 mL) was added (4-methoxyphenyl)methanamine (20.55 g, 150 mmol) and K2CO3 (12.42 g, 90 mmol). The reaction was stirred at 115 °C for 2 h. The reaction was filtered, concentrated, and purified by flash silica gel (PE:EA = 1:0 to 10:1) to isolate the title compound A09-d.

[0173] Step 5: 7-Bromo-4-(1,1-difluoroethyl)-4-hydroxy-1-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (A09-e) To a solution of 1-(4-bromo-2-((4-methoxybenzyl)amino)phenyl)-2,2-difluoropropan-1-one (A09-d, 20 g, 52.1 mmol) in AcOH (400 mL) was added sodium cyanate (33.8 g, 521 mmol). The reaction was stirred at 110 °C for 16 h. The reaction was adjusted to pH = 8 with saturated aqueous NaHCO. The mixture was extracted with EtOAc (3 × 500 mL). The organic layer was washed with brine (500 mL), dried (NaSO), filtered, and concentrated. The residue was purified on flash silica gel (PE:EA = 1:0 to 4:1) to isolate the title compound A09-e.

[0174] 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.33 (s, 1H) 7.50 (d, J=2.32 Hz, 1H), 7.38 (dd, J=8.31, 1.83 Hz, 1H), 7.21 (dd, J=8.31, 1.59 Hz, 1H), 7.15 (d, J=8.56 Hz, 2H), 7.02 (d, J=1.59 Hz, 1H), 6.84 - 6.91 (m, 2H), 4.86 - 5.25 (m, 2H), 3.71 (s, 3H), 1.68 (t, J=19.20 Hz, 3H).

[0175] Step 6: 7-Bromo-4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)quinazolin-2(1H)-one (A09-f) To a solution of 7-bromo-4-(1,1-difluoroethyl)-4-hydroxy-1-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (A09-e, 10 g, 23.41 mmol) in ACN (200 mL) was added phosphorus pentoxide (3.99 g, 28.1 mmol). The reaction was stirred at 90 °C under N for 3 h. The reaction was adjusted to pH = 8 with saturated aqueous NaHCO. The residue was extracted with EtOAc (3 x 500 mL). The organic layer was washed with brine (500 mL), dried (NaSO), filtered, and concentrated to isolate the title compound (A09-f), which was used directly in Step 7.

[0176] 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.07 (d, J=8.80 Hz, 1H), 7.81 (d, J=1.59 Hz, 1H), 7.56 (dd, J=8.80, 1.59 Hz, 1H), 7.22 - 7.27 (m, 2H), 6.88 - 6.90 (m, 2H), 5.44 (s, 2H), 3.71 (s, 3H), 2.01 - 2.16 (m, 3H).

[0177] Step 7: 7-Bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (A09-g) To a solution of ethynylcyclopropane (4.36 g, 66.0 mmol) in toluene (50 mL) was added 1 M LiHMDS in THF (55.0 mL, 55.0 mmol) at 0 °C. The reaction was stirred at 85 °C for 15 minutes. To the reaction was then added a solution of 7-bromo-4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)quinazolin-2(1H)-one (A09-f, 9 g, 11.00 mmol) in THF (50.0 mL) at 0 °C. The reaction was stirred at 15 °C for 0.5 hours. The reaction was quenched with saturated aqueous NH4Cl (100 mL). The solution was extracted with EtOAc (3 × 100 mL). The organic layer was washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by flash silica gel chromatography (PE:EA=1:0→3:1) to isolate the title compound A09-g.

[0178] MS (ESI) m / z 475, 477 [M+1].

[0179] Step 8: (S)-7-Bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-3,4-dihydroquinazolin-2(1H)-one and (R)-7-Bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (A09-A and A09-B) To a mixture of 7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (A09-g, 3 g, 6.31 mmol) in ACN (40 mL) and water (15 mL) was added CAN (17.30 g, 31.6 mmol). The reaction was stirred at 15 °C for 2 h. The reaction was extracted with EtOAc (3 × 50 mL). The organic layer was washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to isolate a residue. The residue was purified by flash silica gel chromatography (PE:EA = 1:0 → 1:3) to isolate A09. The white solid was subjected to chiral separation by prep SFC (column: Daicel ChiralPak® AD, 250 × 50 mm id10u (Daicel Chiral Technologies, West Chester, PA); mobile phase A: CO and mobile phase B: MeOH (0.1% NH3HO); gradient: B% = 45%), resulting in the isolation of a fast-eluting peak A09-A and a slow-eluting isomer A09-B.

[0180] Faster eluting isomer A09-A: 1 H NMR (400 MHz, chloroform-d) δ ppm 8.39 (s, 1 H) 7.37 (d, J=8.16 Hz, 1 H) 7.17 (dd, J=8.38, 1.76 Hz, 1 H) 6.93 (d, J=1.76 Hz, 1 H) 5.65 (s, 1 H) 1.65 (t, J=18.30 Hz, 3 H) 1.29 - 1.36 (m, 1 H) 0.83 - 0.89 (m, 2 H) 0.72 - 0.79 (m, 3 H); MS (ESI) m / z 355, 357 [M+1]. Slow-eluting isomer A09-B: 1H NMR (400 MHz, chloroform-d) δ ppm 8.55 (br s, 1 H) 7.36 (d, J=8.44 Hz, 1 H) 7.16 (dd, J=8.38, 1.77 Hz, 1 H) 6.94 (d, J=1.83 Hz, 1 H) 5.78 (br s, 1 H) 1.64 (t, J=18.34 Hz, 3 H) 1.30 - 1.36 (m, 1 H) 0.83 - 0.89 (m, 2 H) 0.72 - 0.79 (m, 3 H); MS (ESI) m / z 355, 357 [M+1].

[0181] Intermediate B Section Intermediate B01: (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-(hydroxymethyl)-3,4-dihydroquinazolin-2(1H)-one (B01) [ka]

[0182] Step 1: (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-(((4-methoxybenzyl)oxy)methyl)-3,4-dihydroquinazolin-2(1H)-one (B01-a) (S)-7-Bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one (A02-B, 10 g, 26.8 mmol), potassium (4-methoxy)benzyloxymethyltrifluoroborate (17.29 g, 67.0 mmol), and Pd(dppf)Cl (1.961 g, 2.68 mmol) were dissolved in 1,4-dioxane (121 mL), followed by the addition of CsCO (52.4 g, 161 mmol). The reaction was heated to 150 °C in a sealed tube for 1 h. The reaction was cooled, filtered through Celite, and washed with EtOAc (100 mL). The filtrate was diluted with saturated aqueous NaHCO and extracted with EtOAc (3 × 50 mL). The combined organics were dried over MgSO, filtered, and concentrated under reduced pressure to isolate the crude material, which was purified by flash silica chromatography eluting with 0-100% EtOAc in hexanes to isolate the title compound B01-a.

[0183] MS (ESI) m / z 445 [M+1].

[0184] Step 2: (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-(hydroxymethyl)-3,4-dihydroquinazolin-2(1H)-one (B01) (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-(((4-methoxybenzyl)oxy)methyl)-3,4-dihydroquinazolin-2(1H)-one (B01-a, 11.93 g, 26.8 mmol) was dissolved in DCM (134 mL). 4 M HCl in dioxane (33.6 mL, 134 mmol) was added to the reaction mixture and the mixture was stirred at ambient temperature for 3 hours. The reaction was concentrated under reduced pressure to isolate the crude product. The crude product was taken up in 1:1 DCM:hexane and sonicated for 15 minutes to form a slurry. The slurry was filtered to isolate compound B01.

[0185] MS (ESI) m / z 325 [M+1].

[0186] Intermediate B02: (S)-4-(cyclopropyldifluoromethyl)-4-(cyclopropylethynyl)-6-fluoro-7-(hydroxymethyl)-3,4-dihydroquinazolin-2(1H)-one (B02) [ka]

[0187] The following intermediate was prepared from intermediate B01 in an analogous manner, replacing A02-B with A03-A, and the title compound B02 was isolated.

[0188] MS (ESI) m / z 351 [M+1].

[0189] Intermediate B03: (S)-4-(cyclopropylethynyl)-7-(hydroxymethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (B03) [ka]

[0190] The following intermediate was prepared from intermediate B01 in an analogous manner, replacing A02-B with A08, and the title compound B03 was isolated. MS (ESI) m / z 311 [M+1].

[0191] Intermediate B04: (S)-4-(cyclopropylethynyl)-7-(hydroxymethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (B04) [ka]

[0192] The following intermediate was prepared from intermediate B01 in an analogous manner, replacing A02-B with A09-A, resulting in the isolation of the title compound B04.

[0193] MS (ESI) m / z 307 [M+1]

[0194] Intermediate B05: (S)-6-chloro-4-(cyclopropylethynyl)-7-(hydroxymethyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one and (R)-6-chloro-4-(cyclopropylethynyl)-7-(hydroxymethyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (B05-A and B05-B) [ka]

[0195] Step 1: 6-chloro-4-(cyclopropylethynyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)-7-vinyl-3,4-dihydroquinazolin-2(1H)-one (B05-a) To a solution of 7-bromo-6-chloro-4-(cyclopropylethynyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (A06, 14 g, 27.3 mmol) and potassium vinyltrifluoroborate (5.48 g, 40.9 mmol) in 1,4-dioxane (140 mL) and water (14 mL) was added KCO (11.30 g, 82 mmol) and PdCl(dppf) (1.994 g, 2.73 mmol). The reaction mixture was stirred at 100 °C under N for 3 h. The reaction was concentrated under reduced pressure and purified by flash chromatography (SiO; 0-20% EtOAc:PE) to isolate compound B05-a.

[0196] Step 2: 6-chloro-4-(cyclopropylethynyl)-7-(hydroxymethyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (B05-b) Ozone (0.854 g, 17.79 mmol) was bubbled through a solution of 6-chloro-4-(cyclopropylethynyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)-7-vinyl-3,4-dihydroquinazolin-2(1H)-one (B05-a, 8.2 g, 17.79 mmol) in MeOH (30 mL) and DCM (150 mL) at −60° C. for 30 minutes. NaBH(OAc) (22.63 g, 107 mmol) was added to the solution, and the reaction mixture was stirred at 20° C. for 30 minutes. The reaction mixture was dissolved in water (100 mL) and extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure to isolate product B05-b, which was used directly in Step 3.

[0197] MS (ESI) m / z 465 [M+1].

[0198] Step 3: (S)-6-chloro-4-(cyclopropylethynyl)-7-(hydroxymethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one and (R)-6-chloro-4-(cyclopropylethynyl)-7-(hydroxymethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (B05-A and B05-B) To a solution of 6-chloro-4-(cyclopropylethynyl)-7-(hydroxymethyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (B05-b, 8.5 g, 18.28 mmol) in MeCN (200 mL) and water (70 mL) was added CAN (50.1 g, 91 mmol). The mixture was stirred at 20 °C for 16 h. The reaction was dissolved in water (100 mL) and extracted with EtOAc (150 mL × 3). The combined organic layers were washed with brine (200 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by prep HPLC (water / MeCN (containing 0.1% TFA)) to isolate compound B05 as a racemic mixture. This was resolved by SFC (Daicel ChiralPak® AD, 30% EtOH / CO2, 200 g / min, 40°C, 100 bar) to isolate isomer B05-A (fast eluting) and isomer B05-B (slow eluting).

[0199] Isomer B05-A (fast eluting) : 1H NMR (400 MHz, MeOH-d4) δ 7.44 (s, 1H), 7.14 (s, 1H), 4.71 - 4.60 (m, 2H), 1.53 - 1.38 (m, 1H), 1.00 - 0.85 (m, 2H), 0.83 - 0.70 (m, 2H) ppm. Isomer B05-B (slow eluting) : 1 H NMR (400 MHz, MeOH-d4) δ 7.44 (s, 1H), 7.14 (s, 1H), 4.71 - 4.62 (m, 2H), 1.47 - 1.45 (m, 1H), 0.99 - 0.85 (m, 2H), 0.82 - 0.69 (m, 2H) ppm. For both isomers, MS (ESI) m / z 345 [M+1]

[0200] Intermediate B05 shown in Table 3 was synthesized using the method disclosed in International Patent Application Publication WO2022 / 046844 (WO22 / 046844). [Table 4]

[0201] Intermediate B07: (S)-7-(chloromethyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one (B07) [ka]

[0202] Intermediate B01 (0.578 g, 1.782 mmol) was dissolved in DCE (8.91 mL) and thionyl chloride (0.650 mL, 8.91 mmol) was added to the reaction and stirred at 50 °C for 1 h. The reaction was neutralized with NaHCO (saturated aqueous) until pH 10. The aqueous mixture was extracted with DCM (2 × 10 mL) and the combined organic layers were dried over MgSO and concentrated under reduced pressure to isolate compound B07.

[0203] MS (ESI) m / z 343 [M+1]

[0204] Intermediates B08 to B11 were prepared in a manner similar to that described for the preparation of Intermediate B07, using the listed starting intermediate in place of B01, as shown in Table 4. [Table 5]

[0205] Intermediate B12: (S)-6-chloro-7-(chloromethyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (B12) [ka]

[0206] Step 1: (S)-6-chloro-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-(hydroxymethyl)-3,4-dihydroquinazolin-2(1H)-one (B12-a) To a solution of (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-(hydroxymethyl)-3,4-dihydroquinazolin-2(1H)-one (B04, 260 mg, 0.849 mmol) in anhydrous DMF (5 mL) was added NCS (113 mg, 0.849 mmol). The resulting reaction mixture was stirred at 40° C. for 16 hours. The reaction mixture was diluted with EtOAc, washed with water (3×), dried over MgSO4, filtered, and concentrated under reduced pressure to isolate compound B12-a, which was used directly in Step 2.

[0207] MS (ESI) m / z 341 [M+1].

[0208] Step 2: (S)-6-chloro-7-(chloromethyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (B12) To a solution of (S)-6-chloro-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-(hydroxymethyl)-3,4-dihydroquinazolin-2(1H)-one (B12-a, 289 mg, 0.848 mmol) in anhydrous DCE (8.5 mL) was added thionyl chloride (1.2 mL, 16.96 mmol). The reaction was stirred at 60° C. for 90 minutes. The reaction mixture was concentrated under reduced pressure and azeotroped with EtO to isolate compound B12, which was used without further purification.

[0209] MS (ESI) m / z 359 [M+1].

[0210] Intermediate B13: (S)-4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-carbaldehyde (B13) [ka]

[0211] To a mixture of (S)-4-(cyclopropylethynyl)-6-fluoro-7-(hydroxymethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (B06, 150 mg, 0.457 mmol) in DCM (10 mL) and THF (1 mL) was added PDC (344 mg, 0.914 mmol). The reaction was stirred at 25 °C under N for 16 h. The reaction mixture was filtered and purified by flash chromatography (SiO, 50% EtOAc:PE) to isolate B13.

[0212] MS (ESI) m / z 327 [M+1].

[0213] Intermediate B14: (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carbaldehyde (B14) [ka]

[0214] To a mixture of (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-(hydroxymethyl)-3,4-dihydroquinazolin-2(1H)-one (B01, 140 mg, 0.432 mmol) in DCM (2.5 mL) was added manganese(IV) oxide (375 mg, 4.32 mmol), and the mixture was stirred at 25° C. for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to isolate product B14, which was used directly in the next reaction.

[0215] MS (ESI) m / z 323 [M+1].

[0216] Intermediate B15: (S)-7-(chloromethyl)-4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-3-methyl-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (B15) [ka]

[0217] Step 1: (S)-7-Bromo-4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (B15-a) To a solution of (S)-7-bromo-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (A07-A, 2 g, 5.30 mmol) and CsCO (2.073 g, 6.36 mmol) in DMF (26.5 mL) was added PMBCl (0.794 mL, 5.83 mmol). The reaction mixture was stirred at 25 °C for 16 h. The reaction was quenched with water (200 mL) and extracted with EtO (2 × 300 mL). The resulting organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO, 0-100% EtOAc:hexanes) to give compound B15-a.

[0218] MS (ESI) m / z 497, 499 [M+1].

[0219] Step 2: (S)-7-Bromo-4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-3-methyl-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (B15-b) To a solution of (S)-7-bromo-4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (B15-a, 580 mg, 1.166 mmol) in anhydrous 1,4-dioxane (12 mL) was added 60% NaH (93 mg, 2.333 mmol). Subsequently, MeI (0.219 mL, 3.50 mmol) was added to the solution and stirred at 25 °C for 16 h. The mixture was quenched with saturated aqueous NH Cl and extracted with EtOAc (3x). The organic layer was dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO, 0-100% EtOAc:hexanes) to give compound B15-b.

[0220] Step 3: (S)-4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-7-(((4-methoxybenzyl)oxy)methyl)-3-methyl-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (B15-c) A mixture of (S)-7-bromo-4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-3-methyl-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (B15-b, 440 mg, 0.861 mmol), potassium (4-methoxy)benzyloxymethyl trifluoroborate (489 mg, 1.893 mmol), and PdCl(dppf)-CHCl adduct (70.3 mg, 0.086 mmol) in anhydrous 1,4-dioxane (8605 μL) was purged with N. 3 M aqueous CsCO solution (1721 μL, 5.16 mmol) was added, and the resulting mixture was irradiated at 150 °C for 1 h in a Biotage® Initiator microwave oven (Biotage, LLC, Charlotte, NC). The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (3x). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0-100% EtOAc:hexanes) to give compound B15-c.

[0221] MS (ESI) m / z 583 [M+1].

[0222] Step 4: (S)-4-(cyclopropylethynyl)-6-fluoro-7-(hydroxymethyl)-1-(4-methoxybenzyl)-3-methyl-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (B15-d) To a solution of (S)-4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-7-(((4-methoxybenzyl)oxy)methyl)-3-methyl-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (B15-c, 318 mg, 0.546 mmol) in DCM (1 mL) was added 4 M HCl in 1,4-dioxane (1.365 mL). The reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was then concentrated under reduced pressure and purified by flash chromatography (SiO, 0-7% MeOH:DCM) to provide compound B15-d.

[0223] Step 5: (S)-7-(chloromethyl)-4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-3-methyl-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (B15) To a solution of (S)-4-(cyclopropylethynyl)-6-fluoro-7-(hydroxymethyl)-1-(4-methoxybenzyl)-3-methyl-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (B15-d, 230 mg, 0.497 mmol) in DCM (1 mL) was added thionyl chloride (0.036 mL, 0.497 mmol). The reaction was stirred at 45° C. for 16 hours. The reaction was then cooled and concentrated under reduced pressure to isolate compound B15, which was used without further purification.

[0224] MS (ESI) m / z 481 [M+1].

[0225] Intermediate B16: (S)-7-(aminomethyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one (B16) [ka]

[0226] To a vial containing intermediate B07 (0.1 g, 0.292 mmol) was added ammonia in MeOH (7 M, 5 mL, 35.0 mmol) and stirred at 70° C. for 16 h. The reaction was concentrated under reduced pressure to isolate compound B16, which was used directly in the next step.

[0227] MS (ESI) m / z 324 [M+1].

[0228] Intermediates B17-B18 were prepared in a manner similar to that described for the preparation of Intermediate B16, using the listed starting intermediate in place of B07 and using the analogous amine reagent, as shown in Table 5. [Table 6]

[0229] Intermediate C-section Intermediate C01: tert-butyl 2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridine-3-carboxylate (C01) [ka]

[0230] 1H-Imidazo[4,5-C]pyridin-2(3H-one) (C01-a, 500 mg, 3.70 mmol) was dissolved in DMF (18.5 mL) and NaH (154 mg, 3.85 mmol) was added. The mixture was stirred at 0 °C for 30 min. BocO (880 mg, 4.03 mmol) was added and the reaction was allowed to warm to room temperature and stirred for 48 h. The reaction mixture was diluted with saturated NaHCO and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with water (10 mL), then brine (10 mL), and then dried over MgSO. The resulting mixture was then filtered and concentrated under reduced pressure. Compound C01 was isolated and used directly without further treatment.

[0231] Intermediate CO2 was prepared in a manner similar to that described for the preparation of intermediate CO1, using the listed starting material in place of CO1-a, as shown in Table 6. [Table 7]

[0232] Intermediate C03: 2,5-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (C03) [ka]

[0233] Step 1: 4-amino-3-methyl-1H-1,2,4-triazol-5(4H)-one (C03-b) Carbohydrazine (C03-a, 10 g, 111 mmol) was suspended in 1,1,1-triethoxyethane (9.16 mL, 50.0 mmol). The mixture was stirred at 90° C. for 1 hour and then refluxed at 145° C. for 16 hours. The reaction was cooled and concentrated under reduced pressure. The crude solid was recrystallized from EtOH to give compound C03-b.

[0234] MS (ESI) m / z 115 [M+1].

[0235] Step 2: 4-amino-1,3-dimethyl-1H-1,2,4-triazol-5(4H)-one (C03-c) To a mixture of 4-amino-3-methyl-1H-1,2,4-triazol-5(4H)-one (C03-b, 1 g, 8.76 mmol) and NaOH (0.421 g, 10.52 mmol) in water (2 mL) was added dimethyl sulfate (0.829 mL, 8.76 mmol). The reaction was stirred at 15 °C for 30 minutes. The reaction was concentrated under reduced pressure to isolate compound C03-c, which was used without further purification.

[0236] MS (ESI) m / z 129 [M+1].

[0237] Step 3: 2,5-Dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (C03) To a solution of 4-amino-1,3-dimethyl-1H-1,2,4-triazol-5(4H)-one (C03-c, 1.1 g, 8.58 mmol) in HCl (40.6 mL, 487 mmol, 12 mol / L) was added 0.5 M aqueous sodium nitrite (17.2 mL, 8.58 mmol) dropwise at 0° C. The mixture was stirred at 15° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the crude solid was purified by sublimation (0.1 atm, 160° C.) to give compound C03.

[0238] MS (ESI) m / z 114 [M+1].

[0239] Intermediate C04: 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-1H-pyrazole (C04) [ka]

[0240] Step 1: (4-methyl-1H-pyrazol-3-yl)methanol (C04-b) To a solution of ethyl 4-methyl-1H-pyrazole-3-carboxylate (C04-a, 0.5 g, 3.24 mmol) in THF (6 mL) under N was added 1 M LiAlH (0.150 g, 3.96 mmol) in THF at 0 °C. The reaction was stirred at 20 °C for 2 h. The reaction mixture was quenched with saturated NH Cl (20 mL) and extracted with EtOAc (3 × 15 mL). The organic layer was dried over Na SO , filtered, and concentrated under reduced pressure to isolate compound C04-b, which was used without further purification.

[0241] MS (ESI) m / z 113 [M+1].

[0242] Step 2: 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-1H-pyrazole (C04) To a solution of (4-methyl-1H-pyrazol-3-yl)methanol (C04-b, 100 mg, 0.892 mmol) in DMF (2 mL) was added imidazole (182 mg, 2.68 mmol) and TBSCl (269 mg, 1.784 mmol). The reaction was stirred at 20 °C for 16 h. The reaction was diluted with water (10 mL) and extracted with EtOAc (2 × 15 mL). The combined organic layers were washed with brine (5 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO, 50% EtOAc:PE) to provide compound C04.

[0243] MS (ESI) m / z 227 [M+1]

[0244] Intermediates C05 to C08 were prepared in a manner similar to that described for the preparation of Intermediate C04, using the listed starting material in place of C04-a, as shown in Table 7. [Table 8]

[0245] Intermediate C09: 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole (C09) [ka]

[0246] Step 1: 3-(diethoxymethyl)-2-ethoxytetrahydrofuran (C09-a) Iron(III) chloride (0.231 g, 1.427 mmol) was added to a flask containing triethoxymethane (2.326 g, 15.69 mmol) and cooled to 10° C. for 30 minutes. 2,3-Dihydrofuran (C09-a, 1 g, 14.27 mmol) was added dropwise over 30 minutes, and the resulting mixture was stirred at 10° C. for 1 hour. The reaction was diluted with DCM (50 mL), filtered through Celite®, and concentrated under reduced pressure to isolate compound C09-a, which was used directly in Step 2.

[0247] Step 2: 2-(1H-pyrazol-4-yl)ethan-1-ol (C09-b) To a solution of hydrazine dihydrochloride (500 mg, 4.76 mmol) in water (10 mL) was added a solution of 3-(diethoxymethyl)-2-ethoxytetrahydrofuran (C09-b, 800 mg, 3.66 mmol) in EtOH (5 mL) at 0 °C. The reaction mixture was stirred at 15 °C for 2 h. The reaction mixture was filtered and purified by prep HPLC (water:MeCN (containing 0.05% NH3HO)) to give compound C09-c.

[0248] MS (ESI) m / z 113 [M+1].

[0249] Step 3: 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole (C09) To a solution of 2-(1H-pyrazol-4-yl)ethan-1-ol (C09-c, 120 mg, 1.070 mmol) in DMF (1 mL) was added imidazole (109 mg, 1.605 mmol) at 0 °C. TBSCl (194 mg, 1.284 mmol) was added to the mixture, and the mixture was stirred at 20 °C for 12 hours. The solution was poured into water (5 mL) and extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with water (2 × 5 mL), brine (2 × 5 mL), dried over NaSO, filtered, and then concentrated under reduced pressure to isolate compound C09, which was used without further purification.

[0250] MS (ESI) m / z 227 [M+1].

[0251] Intermediate C10: 5-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one (C10) [ka]

[0252] To a stirred solution of hydrazinecarboxamide hydrochloride (5000 mg, 44.8 mmol) in DCM (100 mL) was added TEA (13.75 mL, 99 mmol). The mixture was stirred at −10° C. for 30 min. Cyclopropanecarbonyl chloride (5155 mg, 49.3 mmol) was added at −10° C., and the mixture was stirred at 20° C. for 15 h. The mixture was concentrated under reduced pressure, and the residue was diluted with MeCN (100 mL). The mixture was stirred for 30 min, filtered, and the solid was collected. The solid was dissolved in 1 M NaOH (20 mL) and stirred at 100° C. for 2 h. The solution was cooled, and the pH was adjusted to 4-5 with concentrated HCl. The mixture was filtered to isolate compound C10, which was used without further purification.

[0253] MS (ESI) m / z 124 [M-1].

[0254] Intermediate C11: 4-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-1H-pyrazole (C11) [ka]

[0255] A mixture of (3-methyl-1H-pyrazol-4-yl)methanol (C11-a, 50 mg, 0.446 mmol), TBSCl (101 mg, 0.669 mmol), and imidazole (91 mg, 1.338 mmol) in DCM (1 mL) was stirred at 25 °C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (2 × 15 mL). The combined organic layers were washed with brine (5 mL), dried over NaSO, filtered, and concentrated under reduced pressure to provide compound C11, which was used without further purification.

[0256] MS (ESI) m / z 227 [M+1].

[0257] Intermediate C12: 3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chloro-1H-pyrazole (C12) [ka]

[0258] Step 1: Methyl 5-chloro-1H-pyrazole-3-carboxylate (C12-b) To a solution of 5-chloro-1H-pyrazole-3-carboxylic acid (C12-a, 200 mg, 1.365 mmol) in MeOH (5 mL) was added thionyl chloride (0.259 mL, 3.55 mmol) at 0 °C. The mixture was stirred at 65 °C for 3 h. The reaction was concentrated under reduced pressure, and the resulting residue was diluted with saturated aqueous NaHCO (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give compound C12-b, which was used in the next step without purification.

[0259] MS (ESI) m / z 161 [M+1].

[0260] Step 2: (5-chloro-1H-pyrazol-3-yl)methanol (C12-c) To a solution of methyl 5-chloro-1H-pyrazole-3-carboxylate (C12-b, 150 mg, 0.934 mmol) in THF (3 mL) was added LiAlH (42.6 mg, 1.121 mmol) at 0 °C. The mixture was stirred at 15 °C for 12 h. Water (0.4 mL) was added at 0 °C, followed by 15% NaOH (0.4 mL), and finally water (1.3 mL). The mixture was stirred for 30 min. The solution was then dried over NaSO, filtered, and concentrated under reduced pressure to give compound C12-c, which was used in the next step without purification.

[0261] MS (ESI) m / z 133 [M+1].

[0262] Step 3: 3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chloro-1H-pyrazole (C12) To a solution of (5-chloro-1H-pyrazol-3-yl)methanol (C12-c, 100 mg, 0.754 mmol) in DMF (1.5 mL) was added imidazole (77 mg, 1.132 mmol) at 0 °C. To the reaction mixture was added TBSCl (125 mg, 0.83 mmol), and the mixture was stirred at 15 °C for 12 h. The solution was poured into water (5 mL) and extracted with EtOAc (2 × 5 mL). The organic layer was washed with water (2 × 5 mL), brine (2 × 5 mL), dried over NaSO, filtered, and then concentrated under reduced pressure. The resulting residue was purified by prep TLC (SiO, 20% EtOAc:PE) to give product C12.

[0263] MS (ESI) m / z 247 [M+1].

[0264] Intermediate C13: 5-chloro-3-(methoxymethyl)-1H-pyrazole (C13) [ka]

[0265] Step 1: Methyl 5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (C13-b) To a solution of methyl 5-chloro-1H-pyrazole-3-carboxylate (C13-a, 100 mg, 0.623 mmol) in THF (5 mL) was added NaH (37.4 mg, 0.934 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 min. SEMCl (0.166 mL, 0.934 mmol) was added, and the reaction was stirred at 15 °C for 2 h. The reaction was diluted with water (10 mL) and extracted with EtOAc (3 × 10 mL). The organic layer was washed with brine (10 mL), dried (NaSO), filtered, and concentrated under reduced pressure. The resulting residue was purified by prep TLC (SiO, EtOAc:PE, 1:5) to provide compound C13-b.

[0266] Step 2: (5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methanol (C13-c) To a solution of methyl 5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (C13-b, 120 mg, 0.413 mmol) in THF (5 mL) was added LiAlH (18.79 mg, 0.495 mmol) at 0 °C. The mixture was stirred at 15 °C for 2 h. The reaction was dissolved in saturated aqueous NH Cl (10 mL) and extracted with EtOAc (3 × 10 mL). The organic layer was washed with brine (10 mL), dried over Na SO , filtered, and concentrated under reduced pressure to give compound C13-c, which was used directly in the next step without purification.

[0267] MS (ESI) m / z 263 [M+1].

[0268] Step 3: 5-chloro-3-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (C13-d) To a solution of (5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methanol (C13-c, 100 mg, 0.381 mmol) in DMF (5 mL) was added NaH (22.83 mg, 0.571 mmol) at 0 °C. The mixture was stirred at 15 °C for 30 min. MeI (0.119 mL, 1.903 mmol) was added and the reaction was stirred at 15 °C for 1.5 h. The reaction was diluted with water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the product C13-d, which was used directly without purification.

[0269] MS (ESI) m / z 277 [M+1].

[0270] Step 4: 5-chloro-3-(methoxymethyl)-1H-pyrazole (C13) A solution of 5-chloro-3-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (C13-d, 100 mg, 0.361 mmol) was stirred in DCM (3 mL) and TFA (1 mL) at 15 °C for 12 h. The reaction was concentrated under reduced pressure, dissolved in saturated aqueous NaHCO (10 mL), and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep HPLC (water:MeCN (with 0.1% TFA)) to provide compound C13. MS (ESI) m / z 147 [M+1].

[0271] Intermediate C14: tert-butyl 6-oxo-5,6-dihydropyrrolo[3,4-b]pyrrole-1(4H)-carboxylate (C14) [ka]

[0272] To a suspension of 4,5-dihydropyrrolo[3,4-b]pyrrol-6(1H)-one (C14-a, 1 g, 8.19 mmol), TEA (2.286 mL, 16.38 mmol), and BOCO (2.091 mL, 9.01 mmol) in DCM (20 mL) was added N,N-dimethylpyridin-4-amine (0.050 g, 0.409 mmol). The resulting solution was stirred at 20 °C for 2 h. The reaction mixture was evaporated and purified by flash silica chromatography (SiO, EtOAc:heptane, 7:3) to isolate compound C14.

[0273] 1 H NMR (400 MHz, DMSO-d6) δ = 7.93 (s, 1H), 7.50 (d, J = 2.7 Hz, 1H), 6.34 (d, J = 3.1 Hz, 1H), 4.07 (d, J = 0.7 Hz, 2H), 1.56 (s, 9H).

[0274] Intermediate C15: 3-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methoxy-1H-pyrazole (C15) [ka]

[0275] To a solution of 4-methoxy-1H-pyrazol-3-amine (C15-a, 50 mg, 0.442 mmol) in acetic acid (2 mL) was added hexane-2,5-dione (50.5 mg, 0.442 mmol). The mixture was stirred at 120 °C for 3 h. The mixture was concentrated under reduced pressure and purified by prep-TLC (SiO, PE: EtOAc = 1:2) to isolate compound C15.

[0276] MS (ESI) m / z 192 [M+1].

[0277] Intermediate C16: 2-(3-(methoxymethyl)-1H-pyrazol-1-yl)acetic acid (C16) [ka]

[0278] Step 1: Benzyl 2-(3-(methoxymethyl)-1H-pyrazol-1-yl)acetate (C16-b) To a vial containing 3-(methoxymethyl)-1H-pyrazole (C16-a, 1 g, 8.92 mmol) and K2CO3 (3.70 g, 26.8 mmol), acetonitrile (22.3 mL) was added, followed by benzyl-2-bromoacetate (2.451 g, 10.70 mmol). The reaction was heated to 65 °C for 16 h. After cooling to ambient temperature, the crude reaction mixture was added to water and extracted with CHCl2. The organic layer was concentrated under reduced pressure, and the residue was purified by flash silica chromatography (SiO2, PE:EtOAc = 1:2) to give compound C16-b.

[0279] MS (ESI) m / z 261 [M+1].

[0280] Step 2: 2-(3-(methoxymethyl)-1H-pyrazol-1-yl)acetic acid (C16) Benzyl 2-(3-(methoxymethyl)-1H-pyrazol-1-yl)acetate (C16-b, 312 mg, 1.199 mmol) and Pd / C (128 mg, 0.120 mmol) were added to a flask, followed by MeOH (10 mL). The vessel was evacuated alternately with vacuum and hydrogen three times and then stirred under H for 16 h. The reaction was filtered through Celite® and the organics were concentrated under reduced pressure to isolate compound C16.

[0281] 1 H NMR (500 MHz, chloroform-d) δ 7.44 (d, J = 1.8 Hz, 1H), 6.37 (d, J = 1.8 Hz, 1H), 4.98 (s, 2H), 4.50 (s, 2H), 3.40 (s, 3H).

[0282] Intermediate C17: 4-Fluoro-3-methoxy-1H-pyrazole (C17) [ka]

[0283] To a solution of 3-methoxy-1H-pyrazole (C17-a, 300 mg, 3.06 mmol) in acetonitrile (10 mL) was added 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium ditetrafluoroborate (1083 mg, 3.06 mmol). The reaction was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure, dissolved in EtOAc (10 mL), and then 1 M HCl was added to pH = 4. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by pre-TLC (SiO2, PE:EtOAc = 1:1) to isolate compound C17.

[0284] 1 H NMR (400 MHz, DMSO-d6) δ = 11.78 (br s, 1H), 7.70 (d, J = 4.3 Hz, 1H), 3.82 (s, 3H).

[0285] Intermediate C18: 4-chloro-3-methoxy-1H-pyrazole (C18) [ka]

[0286] Step 1: tert-Butyl 3-methoxy-1H-pyrazole-1-carboxylate (C18-b) To a solution of 3-methoxy-1H-pyrazole (C18-a, 200 mg, 2.04 mmol) and EtN (1.4 mL, 10.2 mmol) in CHCl (10 mL) was added BOC-anhydride (710 μL, 3.06 mmol). Subsequently, DMAP (24.9 mg, 0.204 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. Water (10 mL) was added to the reaction mixture. The organic layer was extracted and concentrated under reduced pressure. The residue was purified by flash silica chromatography (SiO, hexane:EtOAc = 1:1) to isolate compound C18-b.

[0287] 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J = 2.9 Hz, 1H), 5.86 (d, J = 2.9 Hz, 1H), 3.99 (s, 3H), 1.62 (s, 9H).

[0288] Step 2: tert-Butyl 4-chloro-3-methoxy-1H-pyrazole-1-carboxylate (C18-c) tert-Butyl 3-methoxy-1H-pyrazole-1-carboxylate (C18-b, 275 mg, 1.387 mmol) was dissolved in EtOAc (6.9 mL) and NCS (371 mg, 2.8 mmol) was added. The resulting mixture was stirred at 50 °C for 48 h. Water (10 mL) was added to the reaction, and the organic layer was extracted, dried over MgSO and filtered. The organics were concentrated under reduced pressure, and the residue was purified by flash silica chromatography (SiO, hexane: EtOAc = 1:3) to isolate compound C18-c.

[0289] 1 H NMR (500 MHz, CDCl3) δ 7.85 (s, 1H), 4.06 (s, 3H), 1.61 (s, 9H).

[0290] Step 3: 4-chloro-3-methoxy-1H-pyrazole (C18) tert-Butyl 4-chloro-3-methoxy-1H-pyrazole-1-carboxylate (C18-c, 275 mg, 1.182 mmol) was dissolved in 4 M HCl in dioxane (2.9 mL, 11.82 mmol) and stirred at ambient temperature for 16 hours. Over time, the solution became cloudy. The reaction was concentrated under reduced pressure to isolate compound C18, which was used without further purification.

[0291] 1 H NMR (500 MHz, DMSO-d6) δ 7.78 (s, 1H), 3.83 (s, 3H).

[0292] Intermediate C19: 3-(1-methoxyethyl)-1H-pyrazole (C19) [ka]

[0293] Step 1: 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)ethan-1-one (C19-b) To a mixture of (2-(chloromethoxy)ethyl)trimethylsilane (7.27 g, 43.6 mmol) in THF (80 mL) was added sodium hydride (3.20 g, 80 mmol) at 0 °C. The reaction was then stirred at 0 °C for 0.5 h. 1-(1H-pyrazol-3-yl)ethan-1-one (C19-a, 4 g, 36.3 mmol) was then added. The reaction was stirred at 20 °C for 5.5 h. The reaction was slowly quenched with saturated aqueous NH Cl (40 mL) at 0 °C and extracted with EtOAc (130 mL × 2). The combined organic layers were washed with brine (130 mL), dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by flash silica chromatography (SiO , PE: EtOAc = 9:1) to isolate compound C19-b.

[0294] MS (ESI) m / z 241 [M+1].

[0295] Step 2: 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)ethan-1-ol (C19-c) To 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)ethan-1-one (C19-b, 4 g, 16.6 mmol) in anhydrous MeOH (80 mL) was added NaBH (1.89 g, 50 mmol) at 0 °C under N and then stirred at 25 °C for 2 h. Saturated aqueous NH Cl (50 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (2 × 80 mL). The combined organic layers were washed with brine (100 mL), dried over Na SO , filtered, and concentrated under reduced pressure to isolate compound C19-c, which was used without further purification.

[0296] MS (ESI) m / z 243 [M+1].

[0297] Step 3: 3-(1-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (C19-d) To a mixture of 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)ethan-1-ol (C19-c, 3.2 g, 13.20 mmol) in THF (50 mL) was added 60% NaH (1.056 g, 26.4 mmol) at 0 °C. The reaction was stirred at 0 °C for 0.5 h. Then, iodomethane (1.644 mL, 26.4 mmol) was added. The reaction was stirred at 20 °C for 6 h. The reaction mixture was cooled to 0 °C and quenched with saturated aqueous NH Cl (50 mL). The mixture was extracted with EtOAc (2 × 80 mL). The combined organic layers were washed with brine (100 mL), dried over Na SO , filtered, and concentrated under reduced pressure to isolate compound C19-d.

[0298] MS (ESI) m / z 257 [M+1].

[0299] Step 4: 3-(1-methoxyethyl)-1H-pyrazole (C19) 3-(1-Methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (C19-d, 1 g, 3.90 mmol) was dissolved in DCM (20 mL). TFA (4 mL) was added dropwise at 0 °C, and the mixture was stirred at 25 °C for 6 h. The reaction was concentrated under reduced pressure, and the residue was dissolved in EtOAc (20 mL), followed by dropwise addition of saturated aqueous NaHCO (20 mL). The mixture was extracted with EtOAc (5 × 20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to isolate compound C19, which was not further purified.

[0300] MS (ESI) m / z 127 [M+1].

[0301] Intermediate C20: 4-chloro-3-(methoxymethyl)-1H-pyrazole (C20) [ka]

[0302] Step 1: Methyl 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (C20b) To a mixture of methyl 4-chloro-1H-pyrazole-3-carboxylate (C20-a, 400 mg, 2.491 mmol) in THF (10 mL) was added NaH (299 mg, 7.47 mmol) at 0 °C. The reaction was stirred at 15 °C for 0.5 h. Then, (2-(chloromethoxy)ethyl)trimethylsilane (1246 mg, 7.47 mmol) was added, and the reaction was stirred at 40 °C for 2 h. The residue was extracted with EtOAc (3 × 10 mL). The organic layer was washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to isolate compound C20-b, which was used directly in Step 2.

[0303] MS (ESI) m / z 291 [M+1].

[0304] Step 2: (4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methanol (C20-c) To a mixture of methyl 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (C20-b, 700 mg, 2.407 mmol) in THF (20 mL) was added LiBH4 (157 mg, 7.22 mmol). The reaction was stirred at 65 °C for 4 h. The reaction was poured into HO (10 mL). The residue was extracted with EtOAc (3 × 10 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to isolate compound C20-c, which was used without further purification.

[0305] MS (ESI) m / z 263 [M+1].

[0306] Step 3: 4-chloro-3-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (C20-d) To a mixture of (4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methanol (C20-c, 15 mg, 0.057 mmol) in DMF (1 mL) was added NaH (2.74 mg, 0.114 mmol) at 0 °C. The reaction was stirred at 15 °C for 0.5 h. Iodomethane (40.5 mg, 0.285 mmol) was then added. The reaction was stirred at 15 °C for 3 h. The reaction was dissolved in water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to isolate compound C20-d, which was used directly in Step 4.

[0307] MS (ESI) m / z 277 [M+1].

[0308] Step 4: 4-chloro-3-(methoxymethyl)-1H-pyrazole (C20) A solution of 4-chloro-3-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (C20-d, 10 mg, 0.036 mmol) in 4 M HCl in MeOH (1 mL) was stirred for 2 h at 15° C. The reaction was concentrated under reduced pressure, and the residue was purified by prep HPLC (water:MeCN (with 0.1% TFA)) to give compound C20.

[0309] MS (ESI) m / z 147 [M+1]

[0310] Intermediate C21: 3-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (C21) [ka]

[0311] To a solution of 3-bromo-2H-indazole (C21-a, 0.3 g, 1.523 mmol) in DMF (8 mL) was added NaH (0.122 g, 3.05 mmol). The reaction was stirred at 20 °C for 0.2 h. SEMCl (0.324 mL, 1.83 mmol) was then added. The reaction was stirred at 20 °C for 16 h. The reaction was dissolved in water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica chromatography to isolate compound C21.

[0312] MS (ESI) m / z 327, 329 [M+1].

[0313] Intermediate C22: 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylic acid (C22) [ka]

[0314] Step 1: 4,5-Dichloro-1H-imidazole (C22-b) A 50 L four-neck round-bottom flask purged with nitrogen and maintained under an inert nitrogen atmosphere was charged with HO (30 L) and imidazole (C22-a, 1.5 kg, 22.03 mol). Subsequently, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (4.91 kg, 24.89 mol, 1.13 equiv.) was added at 0 °C. To the mixture was then added HSO (8.643 kg, 88.12 mmol) at 0 °C over 30 min. The resulting solution was stirred at room temperature for 2 h. The reaction was then quenched by the addition of NaOH (40 L, 3.8 M). The mixture was acidified to pH 3 with AcOH. The resulting solution was extracted with ethyl acetate (3 × 15 L), and the organic layers were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 6% EtOAc / PE to give compound C22-b.

[0315] Step 2: 4,5-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (C22-c) A 50 L four-necked round-bottom flask purged with nitrogen and maintained under an inert nitrogen atmosphere was charged with tetrahydrofuran (23.4 L) and 4,5-dichloro-1H-imidazole (C22-b, 2.34 kg, 17.08 mol, 1.00 equiv.). NaH (1.033 kg, 25.62 mol, 60%) was then added over 30 minutes at 0 °C. The resulting solution was stirred at 0 °C for 1 hour. SEMCl (3.42 kg, 20.50 mol) was then added over 30 minutes at 0 °C. The resulting solution was stirred at room temperature overnight. The reaction was then quenched by the addition of NH4Cl solution (40 L). The resulting solution was extracted with ethyl acetate (3 × 15 L). The organic layers were combined and concentrated under reduced pressure to provide compound C22-c, which was used directly in Step 3.

[0316] Step 3: 2-Bromo-4,5-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (C22-d) A 50 L four-neck round-bottom flask purged with nitrogen and maintained under an inert nitrogen atmosphere was charged with CHCl (26 L), 4,5-dichloro-1-{[2-(trimethylsilyl)ethoxy]methyl}imidazole (C22-c, 2.6 kg, 9.72 mol), NBS (2.60 kg, 14.59 mol), and AIBN (0.05 kg, 291.88 mmol). The resulting solution was stirred at room temperature overnight. The reaction was then quenched by the addition of NH4Cl solution (40 L). The resulting solution was extracted with DCM (3 × 15 L). The organic layers were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 10% EtOAc / PE to give compound C22-d.

[0317] Step 4: 4,5-Dichloro-2-(trimethylsilyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (C22-e) A 50 L four-neck round-bottom flask, purged with nitrogen and maintaining an inert nitrogen atmosphere, was charged with tetrahydrofuran (25 L) and 2-bromo-4,5-dichloro-1-{[2-(trimethylsilyl)ethoxy]methyl}imidazole (C22-d, 2.5 kg, 7.22 mol). Subsequently, n-butyllithium (3.178 L, 7.94 mol, 2.5 M) was added dropwise over 1 h with stirring at −78 °C. The resulting solution was stirred at −78 °C for 30 min. Subsequently, chlorotrimethylsilane (0.86 kg, 7.94 mol, 1.10 equiv.) was added dropwise over 20 min with stirring at −78 °C. The resulting solution was stirred at room temperature for 2 h. The reaction was then quenched by the addition of NH4Cl solution (50 L). The resulting solution was extracted with ethyl acetate (3 x 15 L) and the organic layers were combined, dried and concentrated under reduced pressure to isolate compound C22-e.

[0318] Step 5: 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carbaldehyde (C22-f) A 50 L four-neck round-bottom flask, purged with nitrogen and maintaining an inert nitrogen atmosphere, was charged with 4,5-dichloro-2-(trimethylsilyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}imidazole (C22-e, 2 kg, 5.89 mol) and tetrahydrofuran (20 L). Subsequently, n-butyllithium (2.35 L, 2.5 M) was added dropwise over 30 minutes with stirring at −78°C. The resulting solution was stirred at −78°C for 1 hour. Subsequently, DMF (276.81 g, 3.60 mol, 7.00 equiv.) was added dropwise over 5 minutes with stirring at −78°C. The resulting solution was stirred at room temperature for 1 hour. The reaction was then quenched by the addition of HCl (50 L, 1 N). The resulting solution was extracted with ethyl acetate (3 × 15 L). The organic layers were combined and concentrated under reduced pressure to isolate compound C22-f.

[0319] Step 6: 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylic acid (C22) A 50 L four-neck round-bottom flask purged with nitrogen and maintained under an inert nitrogen atmosphere was charged with 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carbaldehyde (C22-f, 980 g, 3.75 mol), tetrahydrofuran (9.8 L), 2-methyl-2-butene (2.319 kg, 33.06 mol), and 2-methyl-2-propanol (3.92 L). Sodium chlorite (1.699 kg, 18.78 mol) was then added at 0° C. To the mixture was added NaH2PO4 (2.254 kg, 18.78 mol) at 0° C. Water (5.88 L) was then added at 0° C. The resulting solution was stirred at room temperature for 2 hours. The solution was then extracted with ethyl acetate (3×15 L), and the organic layers were combined, dried, and concentrated under reduced pressure. The resulting crude solid was purified by trituration with PE (500 mL) and then filtered to collect the filter cake. This gave compound C22.

[0320] MS (ESI) m / z 277 [M+1]

[0321] The non-commercially available intermediates used in the preparation of Examples 1-130 were prepared as described above in Intermediate Sections A-C. Such intermediates are identified in the INT column in Tables 8-16, respectively.

[0322] Example 1 (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 (1) [ka]

[0323] Step 1: (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one (1-a) To a solution of intermediate B07 (40 mg, 0.117 mmol) in DMF (1 mL) was added KCO (48.4 mg, 0.350 mmol) and 3-nitro-1H-1,2,4-triazole (19.97 mg, 0.175 mmol). The mixture was stirred at 50 °C for 4 h. The solution was poured into water (5 mL) and extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with water (5 mL), brine (5 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give compound 1-a, which was used in Step 2 without purification.

[0324] MS (ESI) m / z 421 [M+1].

[0325] Step 2: (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 (1-b) To a solution of (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one (1-a, 40 mg, 0.095 mmol) in MeOH (0.5 mL) was added sodium methoxide (30.8 mg, 0.571 mmol). The mixture was stirred at 60° C. for 16 h. The mixture was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to give compound 1-b.

[0326] 1 H NMR (400 MHz, acetonitrile-d3) δ 8.05 - 8.01 (m, 1H), 7.87 - 7.68 (m, 1H), 7.28 (d, J = 10.26 Hz, 1H), 6.63 (br t, J = 6.38 Hz, 1H), 6.41 - 6.20 (m, 1H), 5.23 (s, 2H), 3.90 (s, 3H), 1.67 (t, J = 18.89 Hz, 3H), 1.37 - 1.35 (m, 1H), 0.88 - 0.84 (m, 2H), 0.73 - 0.72 (m, 2H) ppm. MS (ESI) m / z 406 [M+1] .

[0327] Example 2 (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(hydroxymethyl)-1H-pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one (2) [ka]

[0328] To a solution of intermediate B07 (41.2 mg, 0.120 mmol) and (1H-pyrazol-3-yl)methanol (2-a, 28.3 mg, 0.288 mmol) in DMA (1.2 mL) was added KCO (58.1 mg, 0.404 mmol). The reaction was stirred at 60 °C for 16 h. The mixture was filtered and purified by prep HPLC (water:MeCN (with 0.1% TFA)) followed by flash chromatography (SiO, 0-70% (3:1 EtOAc:EtOH):hexanes) to give compound 2.

[0329] 1 H NMR (500 MHz, CDCl3) δ 9.23 (s, 1H), 7.39 (d, J = 2.1 Hz, 1H), 7.16 (d, J = 10.0 Hz, 1H), 6.33 (d, J = 2.2 Hz, 1H), 6.30 (s, 1H), 6.25 (d, J = 6.3 Hz, 1H), 5.30 (q, J = 16.3 Hz, 2H), 4.68 (s, 2H), 1.63 (t, J = 18.3 Hz, 3H), 1.36 - 1.28 (m, 1H), 0.87 - 0.83 (m, 2H), 0.78 - 0.72 (m, 2H) ppm. MS (ESI) m / z 405 [M+1].

[0330] Example 3 (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-methoxy-1H-pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one (3) [ka]

[0331] To a solution of intermediate B07 (25 mg, 0.073 mmol) and 4-methoxy-1H-pyrazole (3-a, 7.16 mg, 0.073 mmol) in DMA (0.73 mL) was added KCO (35.3 mg, 0.255 mmol). The reaction was stirred at 60 °C for 16 h. The solution was purified by prep HPLC (water:MeCN (with 0.1% TFA)) to give compound 3.

[0332] 1 H NMR (500 MHz, chloroform-d) δ 8.01 (s, 1H), 7.27 (s, 1H), 7.23 (d, J = 9.8 Hz, 1H), 7.12 (s, 1H), 6.46 (d, J = 6.1 Hz, 1H), 5.71 (s, 1H), MS (ESI) m / z 405 [M+1].

[0333] Example 4 (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 (4) [ka]

[0334] To a solution of intermediate B07 (50 mg, 0.146 mmol) in DMF (0.5 mL) was added KCO (40.3 mg, 0.292 mmol), (1H-1,2,4-triazol-3-yl)methanol (4-a, 72.3 mg, 0.292 mmol), and KI (48.4 mg, 0.292 mmol). The mixture was stirred at 25 °C for 3 h. The mixture was then filtered and purified by prep HPLC (water:MeCN (containing 10 mM NHHCO)) to give compound 4.

[0335] 1H NMR (400 MHz, acetonitrile d3) δ 8.25 (s, 1H), 7.76 (br s, 1H), 7.28 (d, J = 10.1 Hz, 1H), 6.62 (d, J = 6.4 Hz, 1H), 6.20 (br s, 1H), 5.35 (s, 2H), 4.53 (d, J = 5.7 Hz, 2H), 3.30 (t, J = 5.9 Hz, 1H), 1.67 (t, J = 18.8 Hz, 3H), 1.37 - 1.34 (m, 1H), 0.87 - 0.84 (m, 2H), 0.73 - 0.71 (m, 2H) ppm. MS (ESI) m / z 406 [M+1].

[0336] The compounds of Examples 5 through 31 shown in Table 8 were prepared in a manner similar to that described for Example 4, except for using the appropriate intermediate starting material as indicated in the INT column. The compounds were purified by prep HPLC (water:MeCN (containing 0.1% TFA or 0.05% NH4OH), flash chromatography, or a combination of both. [Table 9] TIFF2026021308000057.tif207165 TIFF2026021308000058.tif230165 TIFF2026021308000059.tif218165 TIFF2026021308000060.tif209166 TIFF2026021308000061.tif128165

[0337] Example 32 (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 (32) [ka]

[0338] To a stirred mixture of Intermediate B08 in KCO (399 mg, 2.88 mmol) in DMF (4.0 mL) was added Intermediate C03 (326 mg, 1.731 mmol). The resulting mixture was stirred at 40 °C for 16 h. The mixture was filtered and the solution was purified by prep HPLC (water:ACN (with NHHCO modifier)) to give Compound 32.

[0339] 1 H NMR (400 MHz, DMSO-d6) δ = 9.65 (s, 1H), 8.44 (s, 1H), 7.22 (d, J = 10.1 Hz, 1H), 6.68 (d, J = 6.5 Hz, 1H), 4.88 - 4.75 (m, 2H), 3.29 (s, 3H), 2.12 (s, 3H), 1.51 - 1.42 (m, 1H), 0.94 - 0.83 (m, 2H), 0.76 - 0.66 (m, 2H) ppm. MS (ESI) m / z 424 [M+1].

[0340] Example 33 (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 (33) [ka]

[0341] A mixture of intermediate B08 (24.1 mg, 0.070 mmol), 1,2-dihydro-5-methyl-1,2,4-triazol-3-one (33-a, 8.27 mg, 0.083 mmol), KCO (19.21 mg, 0.139 mmol), and KI (2.308 mg, 0.014 mmol) in MeCN (0.22 mL) was stirred at 85 °C for 45 min. The reaction mixture was cooled, diluted with MeOH / DCM (10% v / v), and washed with water (3 × 5 mL) followed by brine (5 mL). The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to give compound 33.

[0342] 1 H NMR (500 MHz, DMSO-d6) δ 11.54 (s, 1H), 9.67 (s, 1H), 8.44 (s, 1H), 7.23 (d, J = 9.9 Hz, 1H), 6.67 (d, J = 6.5 Hz, 1H), 4.79 (s, 2H), 2.10 (s, 3H), 1.57 - 1.40 (m, 1H), 0.89 - 0.87 (m, 2H), 0.80 - 0.67 (m, 2H) ppm. MS (ESI) m / z 410 [M+1].

[0343] The compounds of Examples 34 to 38 shown in Table 9 were prepared in a manner similar to that described for Example 33, except using the appropriate intermediate starting material as indicated in the INT column. [Table 10] TIFF2026021308000065.tif52165

[0344] Example 39 (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 (39) [ka]

[0345] Step 1: tert-butyl (S)-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridine-3-carboxylate (39-a) To a solution of Intermediate CO1 (40.7 mg, 0.173 mmol) in DMF (1 mL) was added KCO (35.9 mg, 0.260 mmol), LiBr (7.51 mg, 0.087 mmol), and Intermediate B08 (30 mg, 0.087 mmol). The mixture was stirred at 40 °C for 16 h. The reaction mixture was concentrated under reduced pressure and diluted with water (10 mL) and EtOAc (20 mL). The mixture was washed with water (10 mL), brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to isolate compound 39-a, which was used without further purification.

[0346] MS (ESI) m / z 546 [M+1].

[0347] Step 2: (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 (39) A solution of 39-a (50 mg, 0.092 mmol) in DCM (1 mL) and TFA (1 mL) was stirred for 1 h at 15° C. The solution was cooled, concentrated under reduced pressure, and purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to give compound 39.

[0348] 1 H NMR (400 MHz, MeOH-d4) δ 8.26 (s, 1H), 8.20 (d, J = 5.4 Hz, 1H), 7.29 (d, J = 10.0 Hz, 1H), 7.16 (d, J = 5.5 Hz, 1H), 6.72 (d, J = 6.4 Hz, MS (ESI) m / z 446 [M+1].

[0349] Example 40 (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 (40) [ka]

[0350] Example 40 was prepared using a procedure similar to that of Example 39, except Intermediate B08 and Intermediate C01 were replaced with Intermediate B07 and Intermediate C14, respectively.

[0351] 1 H NMR (400 MHz, DMSO-d6)= 9.48 (s, 1H), 7.94 (s, 1H), 7.86 (br s, 1H), 7.12 (d, J = 10.0 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.51 (d, J = 6.6 Hz, 1H), 6.12 (d, J = 2.4 Hz, 1H), 5.35 - 5.19 (m, 2H), 4.06 (s, 2H), 1.67 (t, J = 18.8 Hz, 3H), 1.48 - 1.36 (m, 1H), 0.84 (dd, J = 2.8, 8.3 Hz, 2H), 0.74 - 0.63 (m, 2H). MS (ESI) m / z 429 [M+1].

[0352] Example 41 (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 (41) [ka]

[0353] Step 1: tert-butyl (S)-(3-(((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)amino)pyridin-4-yl)carbamate (41-a) A mixture of intermediate B13 (60 mg, 0.184 mmol) and intermediate CO2 (46.2 mg, 0.221 mmol) in EtOH (5 mL) and AcOH (0.05 mL) was stirred at 55 °C for 16 h. The reaction was cooled to 15 °C, and NaBHCN (11.56 mg, 0.184 mmol) was added. The resulting mixture was stirred at 15 °C for 4 h. The reaction was purified by prep HPLC (water:MeCN (containing 10 mM NHHCO)) to give compound 41-a.

[0354] Step 2: (S)-7-(((4-aminopyridin-3-yl)amino)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (41-b) A mixture of tert-butyl (S)-(3-(((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)amino)pyridin-4-yl)carbamate (41-a, 40 mg, 0.077 mmol) in 4 M HCl / MeOH (10 mL) was stirred at 15° C. for 2 h. The reaction was concentrated under reduced pressure to isolate compound 41-b, which was used without further purification.

[0355] Step 3: (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 (41) A mixture of (S)-7-(((4-aminopyridin-3-yl)amino)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (41-b, 30 mg, 0.072 mmol) and DIPEA (0.050 mL, 0.286 mmol) in THF (2 mL) was cooled to 0 °C. To the mixture was added triphosgene (42.5 mg, 0.143 mmol) in THF (0.5 mL) dropwise. The reaction was allowed to warm to 15 °C and stirred for 2 h. The mixture was quenched with saturated aqueous NaHCO (5 mL) and washed with water (2 × 5 mL). The organic layer was washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by prep HPLC (water:MeCN (with 0.1% TFA)) to give compound 41.

[0356] 1H NMR (400 MHz, MeOH-d4) δ 8.53 (s, 1H), 8.43 (d, J = 6.3 Hz, 1H), 7.57 (d, J = 6.4 Hz, 1H), 7.32 (d, J = 10.0 Hz, 1H), 6.86 (d, J = 6.3 Hz, MS (ESI) m / z 446 [M+1].

[0357] Example 42 (S)-3-((4-(cyclopropylethynyl)-6-fluoro-3-methyl-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)imidazolidine-2,4-dione (42) [ka]

[0358] Step 1: (S)-3-((4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-3-methyl-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)imidazolidine-2,4-dione (42-a) A mixture of intermediate B15 (19 mg, 0.040 mmol), K2CO3 (10.92 mg, 0.079 mmol), and imidazolidine-2,4-dione (5.54 mg, 0.055 mmol) in DMF (0.5 mL) was stirred at 45 °C for 16 h. The reaction was added to water (10 mL) and extracted with EtOAc (2 × 5 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to isolate compound 42-a, which was used without further purification.

[0359] MS (ESI) m / z 545 [M+1].

[0360] Step 2: (S)-3-((4-(cyclopropylethynyl)-6-fluoro-3-methyl-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)imidazolidine-2,4-dione (42) (S)-3-((4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-3-methyl-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)imidazolidine-2,4-dione (42-a, 20 mg, 0.037 mmol) was dissolved in ACN (0.75 mL) / water (0.25 mL). CAN (44.3 mg, 0.081 mmol) was added, and the reaction mixture was stirred at 65° C. for 48 hours. The reaction mixture was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to give compound 42.

[0361] 1 H NMR (500 MHz, chloroform-d) δ 10.00 (s, 1H), 8.55 (s, 1H), 4.85 (d, J = 14.2 Hz, 1H), 4.68 (d, J = 14.4 Hz, 1H), 4.12 - 3.90 (m, 2H), 3.25 (s, 3H), 1.50 - 1.36 (m, 1H), 0.99 - 0.90 (m, 2H), 0.85 (dt, J = 4.5, 3.1 Hz, 2H). MS (ESI) m / z 425 [M+1].

[0362] Example 43 (S)-7-((3-amino-1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one (43) [ka]

[0363] Step 1: (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-nitro-1H-pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one (43-a) To a solution of intermediate B07 (30 mg, 0.088 mmol) and 3-nitro-1H-pyrazole (14.85 mg, 0.131 mmol) in DMF (0.5 mL) was added KCO (36.3 mg, 0.263 mmol) and LiBr (11.40 mg, 0.131 mmol). The reaction mixture was stirred at 50 °C for 2 h. The mixture was then diluted with water (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to isolate compound 43-a, which was used directly in Step 2.

[0364] MS (ESI) m / z 420 [M+1].

[0365] Step 2: (S)-7-((3-amino-1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one (43) To a solution of (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-nitro-1H-pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one (43-a, 30 mg, 0.072 mmol) in EtOH (1 mL) and water (0.2 mL) was added NH4Cl (77 mg, 1.431 mmol). Iron powder (40.0 mg, 0.715 mmol) was then added and the reaction was stirred at 90 °C for 2 h. The reaction was diluted with water (10 mL) and then extracted with EtOAc (2 × 15 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to give compound 43.

[0366] 1H NMR (400 MHz, MeOH-d4) δ 7.76 (d, J = 2.08 Hz, 1H), 7.22 (d, J = 9.90 Hz, 1H), 6.66 (d, J = 6.36 Hz, 1H), 6.13 (d, J = 2.20 Hz, 1H), 5.31 (s, 2H), 1.68 (t, J = 18.52 Hz, 3H), 1.39 - 1.37 (m, 1H), 0.89 - 0.86 (m, 2H), 0.74 - 0.72 (m, 2H) ppm. MS (ESI) m / z 390 [M+1].

[0367] The compounds of Examples 44 to 46 shown in Table 10 were prepared in a manner similar to that described for Example 43, except using the appropriate intermediate starting material as indicated in the INT column. [Table 11]

[0368] Example 47 (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(2-hydroxyethyl)-1H-pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one (47) [ka]

[0369] To a solution of Intermediate B07 (20 mg, 0.058 mmol) and Intermediate C05 (15.85 mg, 0.070 mmol) in DMF (0.2 mL) was added KOH (9.82 mg, 0.175 mmol). The reaction was stirred at 25 °C for 3 h. The reaction was diluted with water (10 mL) and extracted with EtOAc (2 × 15 mL). The combined organic layers were washed with brine (5 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep HPLC (water:MeCN (with 0.1% TFA)) to isolate product 47.

[0370] 1H NMR (400 MHz, acetonitrile-d3) δ 7.64 (s, 1H), 7.54 (d, J = 2.20 Hz, 1H), 7.28 (d, J = 10.15 Hz, 1H), 6.52 (d, J = 6.36 Hz, 1H), 6.18 (d, J = 2.20 Hz, 1H), 6.11 (br s, 1H), 5.29 (s, 2H), 3.75 (t, J = 6.66 Hz, 2H), 2.78 (t, J = 6.66 Hz, 2H), 1.69 (t, J = 18.83 Hz, 3H), 1.43 - 1.38 (m, 1H), 0.92 - 0.90 (m, 2H), 0.77 - 0.73 (m, 2H) ppm. MS (ESI) m / z 419 [M+1].

[0371] Example 48 (S)-6-chloro-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(hydroxymethyl)-1H-pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one (48) [ka]

[0372] Step 1: (S)-1-((6-chloro-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1H-pyrazole-3-carbaldehyde (48-a) To a solution of intermediate B12 (100 mg, 0.278 mmol) in DMF (1 mL) was added 1H-pyrazole-3-carbaldehyde (32.1 mg, 0.334 mmol) and K2CO3 (77 mg, 0.557 mmol). The reaction was stirred at 40 °C for 16 h. The reaction was concentrated under reduced pressure, diluted with NaHCO3 (20 mL), and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to isolate compound 48-a, which was used directly in Step 2.

[0373] Step 2: (S)-6-chloro-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(hydroxymethyl)-1H-pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one (48) To a solution of (S)-1-((6-chloro-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1H-pyrazole-3-carbaldehyde (48-a, 90 mg, 0.215 mmol) in MeOH (1 mL) was added NaBH (3.25 mg, 0.086 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure, diluted with NaHCO (20 mL), and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to give compound 48.

[0374] 1 H NMR (400 MHz, MeOH-d4) δ 7.71 (d, J = 2.20 Hz, 1H), 7.46 (s, 1H), 6.40 (d, J = 2.20 Hz, 1H), 6.33 (s, 1H), 5.40 (s, 2H), 4.59 (s, 2H), 1.67 (t, J = 18.52 Hz, 3H), 1.41 - 1.39 (m, 1H), 0.92 - 0.83 (m, 2H), 0.76 - 0.73 (m, 2H) ppm. MS (ESI) m / z 421 [M+1].

[0375] The compounds of Examples 49 to 51 shown in Table 11 were prepared in a manner similar to that described for Example 48, except using the appropriate intermediate starting material as indicated in the INT column. [Table 12]

[0376] Example 52 (S)-7-(1H,1'H-[3,3'-bipyrazol]-1-ylmethyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one (52) [ka]

[0377] To a solution of the compound from Example 19 (60 mg, 0.132 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (38.5 mg, 0.199 mmol), and Brettphos Pd G3 (12.00 mg, 0.013 mmol) in EtOH (2 mL) was added K3PO4 (28.1 mg, 0.132 mmol) in water (0.5 mL). The reaction was stirred at 80 °C for 4 h. The reaction was concentrated under reduced pressure, diluted with NaHCO3 (20 mL), and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to provide compound 52.

[0378] 1 H NMR (400 MHz, acetonitrile-d3) δ 7.85 - 7.73 (m, 1H), 7.70 (s, 1H), 7.65 (br s, 1H), 7.30 (d, J = 10.27 Hz, 1H), 6.67 (s, 1H), 6.62 (br s, 1H), 6.54 (br s, 1H), 6.21 (br s, 1H), 5.41 (s, 2H), 1.66 (t, J = 18.83 Hz, 3H), 1.41 - 1.38 (m, 1H), 0.90 - 0.87 (m, 2H), 0.76 - 0.74 (m, 2H) ppm. MS (ESI) m / z 441 [M+1].

[0379] Example 53 (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 (53) [ka]

[0380] Example 53 was prepared in a manner similar to that of Example 52, except 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

[0381] 1 H NMR (400 MHz, acetonitrile-d3) δ 7.69 (s, 1H), 7.63 (d, J = 2.08 Hz, 1H), 7.49 (d, J = 1.96 Hz, 1H), 7.26 (d, J = 10.27 Hz, 1H), 6.59 (d, J = 2.08 Hz, 1H), 6.50 - 6.46 (m, 2H), 6.14 (s, 1H), 5.36 (s, 2H), 3.86 (s, 3H), 1.66 (t, J = 18.83 Hz, 3H), 1.38 - 1.35 (m, 1H), 0.87 - 0.83 (m, 2H), 0.74 - 0.72 (m, 2H) ppm. MS (ESI) m / z 455 [M+1].

[0382] Example 54 (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methoxymethyl)-1H-pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one (54) [ka]

[0383] To a solution of 3-(methoxymethyl)-1H-pyrazole (54-a, 30 mg, 0.161 mmol) in DMF (1 mL) was added NaH (25.7 mg, 0.642 mmol). The reaction mixture was stirred at 0 °C for 30 min. Intermediate B07 (55.0 mg, 0.161 mmol) was added and stirred at 15 °C for 1.5 h. The solution was poured into NH Cl (5 mL) and extracted with EtOAc (2 × 5 mL). The organic layer was washed with brine (2 × 5 mL), dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by prep HPLC (water:MeCN (containing 10 mM NH HCO)) to give compound 54.

[0384] 1 H NMR (400 MHz, MeOH-d4) δ 7.70 (d, J = 2.26 Hz, 1H), 7.22 (d, J = 10.04 Hz, 1H), 6.50 (d, J = 6.40 Hz, 1H), 6.36 (d, J = 2.26 Hz, 1H), 5.37 MS, MS (ESI) m / z 419 [M+1]

[0385] The compounds of Examples 55 to 66 shown in Table 12 were prepared in a manner similar to that described for Example 54, except using the appropriate intermediate starting material as indicated in the INT column. [Table 13] TIFF2026021308000079.tif214165 TIFF2026021308000080.tif113165

[0386] Example 67 (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 (67) [ka]

[0387] Step 1: (S)-7-((3-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluoro-1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one (67-a) To a solution of intermediate C06 (67.2 mg, 0.292 mmol) in DMF (2 mL) was added NaH (10.50 mg, 0.438 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. Intermediate B07 (50 mg, 0.146 mmol) was added, and the mixture was stirred at 20 °C for 1.5 h. The solution was poured into water (10 mL) and extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give product 67-a, which was used without further purification.

[0388] MS (ESI) m / z 537 [M+1]

[0389] Step 2: (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 (67) A mixture of (S)-7-((3-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluoro-1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one (67-a, 80 mg, 0.149 mmol) in DCM (1 mL) and TFA (0.3 mL) was stirred at 20° C. for 1 h. The reaction mixture was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to give compound 67.

[0390] 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 7.98 (s, 1H), 7.90 (d, J = 4.82 Hz, 1H), 7.12 (d, J = 9.65 Hz, 1H), 6.60 (d, J = 6.58 Hz, 1H), MS (ESI) m / z 423 [M+1].

[0391] Example 68 (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 (68) [ka]

[0392] Step 1: (S)-7-((3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one (68-a) To a solution of intermediate C04 (30 mg, 0.133 mmol) in DMF (2 mL) was added NaH (3.50 mg, 0.088 mmol). The reaction was stirred at 20 °C for 30 min. Intermediate B07 (30 mg, 0.088 mmol) was added to the reaction mixture, which was stirred at 20 °C for 1.5 h. The mixture was quenched with saturated aqueous NH4Cl (10 mL) at 0 °C and extracted with EtOAc (3 × 15 mL). The organic layer was washed with brine (3 × 9 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to isolate compound 68-a, which was used without further purification.

[0393] MS (ESI) m / z 533 [M+1].

[0394] Step 2: (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 (68) To a solution of (S)-7-((3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one (68-a, 36 mg, 0.068 mmol) in MeOH (1 mL) was added 3 M HCl / MeOH (0.2 mL, 0.600 mmol). The reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was purified by prep HPLC (water:MeCN (with 0.1% TFA)) to give compound 68.

[0395] 1 H NMR (400 MHz, acetonitrile-d3) δ 8.13 (br s, 1H), 7.36 (s, 1H), 7.23 (d, J = 10.1 Hz, 1H), 6.51 (d, J = 6.4 Hz, 1H), 6.47 (s, 1H), 5.23 (s, MS (ESI) m / z 419 [M+1].

[0396] The compounds of Examples 69 to 71 shown in Table 13 were prepared in a manner similar to that described for Example 68, except using the appropriate intermediate starting material as indicated in the INT column. [Table 14]

[0397] Example 72 and Example 73 (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 and (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 (72 and 73) [ka]

[0398] Step 1: (S)-7-((3-acetyl-1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one (72 / 73-a) To a solution of 1-(1H-pyrazol-3-yl)ethanone (28.9 mg, 0.263 mmol) in DMF (3 mL) was added NaH (42.0 mg, 1.050 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Subsequently, intermediate B07 (90 mg, 0.263 mmol) was added, and the resulting mixture was stirred at 15 °C for 4 h. The mixture was poured into saturated aqueous NH Cl (5 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over Na SO , filtered, and concentrated under reduced pressure. The resulting residue was purified by prep TLC (SiO , 66% EtOAc:PE) to give compound 72 / 73-a as a racemic mixture.

[0399] MS (ESI) m / z 417 [M+1]

[0400] Step 2: (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 and (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 (72 and 73) To a solution of (S)-7-((3-acetyl-1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one (72 / 73-a, 20 mg, 0.048 mmol) in MeOH (1 mL) was added NaBH (1.817 mg, 0.048 mmol) at 0 °C. The mixture was stirred at 15 °C for 1 h. The mixture was purified by prep HPLC (water:MeCN (with 0.05% NH HO + 10 mM NH HCO ) and SFC (Chiralcel OD, 30% iPrOH (0.1% NH HO) / CO , 65 g / min, 150 bar, 35 °C) to give the following compounds:

[0401] 72 (fast eluting) : 11H NMR (400 MHz, MeOH-d4) δ 7.66 (d, J = 2.20 Hz, 1H), 7.22 (d, J = 10.15 Hz, 1H), 6.51 (d, J = 6.36 Hz, 1H), 6.35 (d, J = 2.32 Hz, 1H), 5.38 - 5.30 (m, 2H), 4.36-4.32 (q, J =6.4 Hz, 1H), 1.68 (t, J = 18.52 Hz, 3H), 1.48 (d, J = 6.48 Hz, 3H), 1.44 - 1.37 (m, 1H), 0.89 - 0.86 (m, 2H), 0.74 - 0.73 (m, 2H) ppm 73 (late eluting) : 1 1H NMR (400 MHz, MeOH-d4) δ 7.65 (d, J = 2.32 Hz, 1H), 7.22 (d, J = 10.27 Hz, 1H), 6.51 (d, J = 6.36 Hz, 1H), 6.35 (d, J = 2.32 Hz, 1H), 5.38 - 5.30 (m, 2H), 4.36-4.32 (q, J=6.4 Hz, 1H), 1.67 (t, J = 18.52 Hz, 3H), 1.48 (d, J = 6.60 Hz, 3H), 1.43 - 1.37 (m, 1H), 0.89 - 0.86 (m, 2H), 0.74 - 0.73 (m, 2H) ppm. For both isomers, MS (ESI) m / z 419 [M+1]

[0402] Example 74 (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((2-methoxy-1H-imidazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one (74)

Chem.

[0403] Step 1: (S)-7-((2-bromo-1H-imidazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one (74-a) To a solution of 2-bromo-1H-imidazole (75 mg, 0.510 mmol) in THF (1.5 mL) was added NaH (40.8 mg, 1.021 mmol). The reaction solution was stirred at 60° C. for 1 h. Intermediate B07 in THF (1 mL) was added, and the reaction was stirred at 60° C. for 6 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (35 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep TLC (SiO, 10% MeOH:EtOAc) to provide compound 74-a.

[0404] MS (ESI) m / z 453, 455 [M+1]

[0405] Step 2: (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((2-methoxy-1H-imidazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one (74) To a solution of (S)-7-((2-bromo-1H-imidazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one (74-a, 140 mg, 0.309 mmol) in MeOH (0.5 mL) was added sodium methoxide (0.1 mL, 0.100 mmol) and CuI (11.76 mg, 0.062 mmol) under N. The reaction mixture was stirred at 120 °C for 7 h. The mixture was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to give compound 74.

[0406] 1H NMR (400 MHz, acetonitrile-d3) δ 8.27 (br s, 1H), 7.30 (d, J = 10.1 Hz, 1H), 6.97 (br s, 1H), 6.90 (br s, 1H), 6.67 (d, J = 6.2 Hz, 1H), 6.51 (br s, 1H), 5.03 (s, 2H), 4.24 (s, 3H), 1.68 (t, J = 18.9 Hz, 3H), 1.38 - 1.34 (m, 1H), 0.87 - 0.84 (m, 2H), 0.73 - 0.71 (m, 2H) ppm. MS (ESI) m / z 405 [M+1].

[0407] Example 75 (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methylamino)-1H-pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one (75) [ka]

[0408] A solution of Example 43 (20 mg, 0.051 mmol) and 37% aqueous formaldehyde (8.06 mg, 0.103 mmol) in DMF (1 mL) and AcOH (0.01 mL) was stirred at 15° C. for 1 h. NaBHCN (6.46 mg, 0.103 mmol) was added at 15° C., and the resulting solution was stirred for 1 h. The mixture was filtered and purified by prep-HPLC (water:MeCN (containing 0.1% TFA)) to give compound 75.

[0409] 1H NMR (400 MHz, acetonitrile-d3) δ 7.84 (br s, 1H), 7.46 (br s, 1H), 7.25 (br d, J = 10.3 Hz, 1H), 6.56 (br s, 1H), 6.23 (br s, 1H), 5.71 (br s, MS (ESI) m / z 404 [M+1].

[0410] Example 76 (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(dimethylamino)-1H-pyrazol-1-yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one (76) [ka]

[0411] Compound 76 was prepared using a procedure similar to that of Example 75, except that 2 eq of 37% aqueous formaldehyde was replaced with 5 eq of 37% aqueous formaldehyde and MeOH was used instead of DMF / AcOH as the solvent.

[0412] 1 H NMR (400 MHz, acetonitrile-d3) δ 7.85 (br s, 1H), 7.53 (s, 1H), 7.25 (d, J = 10.3 Hz, 1H), 6.54 (br d, J = 6.2 Hz, 1H), 6.22 (br s, 1H), 5.87 (br s, 1H), 5.22 (br s, 2H), 2.90 (br s, 6H), 1.67 (t, J = 18.8 Hz, 3H), 1.38 - 1.35 (m, 1H), 0.87 - 0.84 (m, 2H), 0.73 - 0.72 (m, 2H) ppm. MS (ESI) m / z 418 [M+1].

[0413] Example 77 (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 (77) [ka]

[0414] Step 1: (S)-4-chloro-N-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxamide (77-a) Intermediate C22 (60 mg, 0.217 mmol), HATU (82 mg, 0.217 mmol) were added to a vial, followed by DIPEA (114 μL, 0.650 mmol). The mixture was stirred for 10 minutes, and then intermediate B16 (84 mg, 0.260 mmol) in DMF (1084 μL) was added. The solution was stirred at ambient temperature for 16 hours. The reaction mixture was added to EtOAc (40 mL), extracted with water (2 × 10 mL), brine (10 mL), dried over MgSO4, and concentrated under reduced pressure. The resulting residue was purified by flash silica chromatography (elution gradient 0 → 100% EtOAc in hexanes) to isolate compound 77-a.

[0415] MS (ESI) m / z 582 [M+1].

[0416] Step 2: (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 (77) (S)-4-chloro-N-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxamide (77-a, 97.6 mg, 0.168 mmol) was taken up in DCM (1524 μL):TFA (152 μL) at 40° C. for 2 h. The reaction was concentrated under reduced pressure, and the residue was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to give compound 77.

[0417] 1H NMR (500 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.20 (s, 1H), 7.92 (s, 1H), 7.79 (s, 1H), 7.09 (d, J = 9.9 Hz, 1H), 6.81 (d, J = 6.6 Hz, 1H), 4.45 (d, J = 3.5 Hz, 2H), 1.68 (t, J = 18.8 Hz, 3H), 1.51 - 1.36 (m, 1H), 0.94 - 0.78 (m, 2H), 0.69 (tt, J = 5.0, 2.3 Hz, 2H). MS (ESI) m / z 452 [M+1].

[0418] Example 78 (S)-4-Chloro-N-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1H-imidazole-5-carboxamide (78) [ka]

[0419] Compound 78 was prepared using a procedure similar to that described in Example 77, except intermediate B16 was replaced with intermediate B17.

[0420] 1 H NMR (500 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.38 (s, 1H), 8.19 (t, J = 6.0 Hz, 1H), 7.70 (s, 1H), 7.16 (d, J = 9.9 Hz, 1H), 6.88 (d, J = 6.5 MS (ESI) m / z 456 [M+1].

[0421] Example 79 (S)-N-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1H-imidazole-2-carboxamide (79) [ka]

[0422] 1H-Imidazole-2-carboxylic acid (30 mg, 0.268 mmol), EDC (56.4 mg, 0.294 mmol), and HOAt (40.1 mg, 0.294 mmol) were added to a vial, followed by DMF (1.3 mL) and DIPEA (140 μL, 0.803 mmol). The resulting mixture was stirred for 60 minutes, and then Intermediate B16 (85 mg, 0.263 mmol) was added. The mixture was stirred at ambient temperature for 16 hours. The reaction was concentrated under reduced pressure, and the residue was purified by prep HPLC (water:MeCN (with 0.1% TFA)). The fraction was added to saturated aqueous NaHCO3 (15 mL) and then extracted with DCM (3 × 15 mL). The combined organic layers were washed with water (15 mL) and concentrated under reduced pressure. The residue was dissolved in an ACN:water mixture and lyophilized to isolate compound 79.

[0423] 1 H NMR (500 MHz, DMSO-d6) δ 9.44 (s, 1H), 8.94 (s, 1H), 7.90 (s, 1H), 7.29 (s, 1H), 7.08 (d, J = 9.0 Hz, 2H), 6.80 (d, J = 6.1 Hz, 1H), 4.43 (d, J = 5.8 Hz, 2H), 1.67 (t, J = 18.6 Hz, 3H), 1.43 (s, 1H), 0.84 (d, J = 5.5 Hz, 2H), 0.69 (s, 2H). MS (ESI) m / z 418 [M+1].

[0424] The compounds of Examples 80 to 89 shown in Table 14 were prepared in a manner similar to that described for Example 79, except using the appropriate intermediate starting material as indicated in the INT column. [Table 15] TIFF2026021308000092.tif199166

[0425] Example 90 and Example 91 (S)-7-((2H-indazol-2-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one and (S)-7-((1H-indazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one (90 and 91) [ka]

[0426] 1H-Indazole (50 mg, 0.423 mmol) was dissolved in DMF (394 μL) at 0° C., and NaH (25.2 mg, 0.630 mmol) was added. The mixture was stirred for 30 min. B07 (27 mg, 0.079 mmol) was added at 0° C. and stirred at room temperature for 16 h. The reaction was brought to 0° C., and water was added dropwise. The reaction mixture was stirred for 10 min. EtOAc (20 mL) was added, and the organic layer was extracted, washed with water (2×5 mL), brine (5 mL), and dried over MgSO4. The solution was concentrated under reduced pressure and purified by prep HPLC (water:MeCN (with 0.1% TFA)) to give Compound 90 and Compound 91.

[0427] Faster eluting isomer (90) : 1 H NMR (500 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.48 (s, 1H), 7.96 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H), 7.27 - 7.21 (m, 1H), 7.15 (d, J = 10.0 Hz, 1H), 7.08 - 7.01 (m, 1H), 6.64 (d, J = 6.5 Hz, 1H), 5.67 (d, J = 3.1 Hz, 2H), 1.68 (t, J = 18.8 Hz, 3H), 1.46 - 1.39 (m, 1H), 0.88 - 0.80 (m, 2H), 0.69 (tt, J = 4.8, 2.1 Hz, 2H) Slow-eluting isomer (91) : 1H NMR (500 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.20 - 7.10 (m, 2H), 6.51 (d, J = 6.4 Hz, 1H), 5.65 (d, J = 3.7 Hz, 2H), 1.66 (t, J = 18.8 Hz, 3H), 1.46 - 1.39 (m, 1H), 0.84 (dd, J = 8.2, 2.8 Hz, 2H), 0.68 (tt, J = 4.9, 2.3 Hz, 2H) ppm. For both isomers, MS (ESI) m / z 425 [M+1]

[0428] The compounds of Examples 92 to 98 shown in Table 15 were prepared in a manner similar to that described for Example 90, except using the appropriate intermediate starting material as indicated in the INT column. [Table 16] TIFF2026021308000095.tif76165

[0429] Example 99 (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 (99) [ka]

[0430] Step 1: (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methoxy-1H-pyrazol-1-yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one (99-a) To a solution of intermediate C15 (24.55 mg, 0.128 mmol) in DMF (2 mL) was added NaH (7.00 mg, 0.175 mmol) at 0 °C under N. The mixture was stirred at 20 °C for 0.5 h. Intermediate B07 (40 mg, 0.117 mmol) was added, and the mixture was stirred at 20 °C for 1 h. The mixture was poured into water (10 mL) and extracted with EtOAc (2 × 8 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried over NaSO, filtered, and concentrated under reduced pressure to isolate compound 99-a, which was used without further purification.

[0431] MS (ESI) m / z 498 [M+1].

[0432] Step 2: (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 (99) To a solution of (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methoxy-1H-pyrazol-1-yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one (99-a, 50 mg, 0.100 mmol) in EtOH (6 mL) and water (2 mL) was added hydroxylamine hydrochloride (384 mg, 5.53 mmol) and KOH (197 mg, 3.52 mmol). The mixture was stirred at 90° C. for 2 h. The mixture was poured into water (20 mL) and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine (2×20 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by prep HPLC (water:MeCN (with 0.1% TFA)) to give compound 99.

[0433] 1H NMR (400 MHz, acetonitrile-d3) δ = 7.80 (br s, 1H), 7.23-7.21 (br d, J = 10.1 Hz, 1H), 7.12 (s, 1H), 6.44-6.42 (d, J = 6.4 Hz, 1H), 6.24 (br s, 1H), 5.00 (s, 2H), 3.73 (br s, 2H), 3.68 (s, 3H), 1.70-1.61 (t, J = 18.7 Hz, 3H), 1.39 - 1.36 (m, 1H), 0.87- 0.83 (m, 2H), 0.72 - 0.72 (m, 2H) ppm. MS (ESI) m / z 420 [M+1].

[0434] Example 100 (S)-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1H-imidazole-2-carboxamide (100) [ka]

[0435] Step 1: Ethyl (S)-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1H-imidazole-2-carboxylate (100-a) To a solution of ethyl 1H-imidazole-2-carboxylate (50 mg, 0.357 mmol) in DMF (1442 μL) was added NaH (34.6 mg, 0.865 mmol) at 0° C. and stirred for 30 minutes. Subsequently, intermediate B08 (100 mg, 0.288 mmol) was added. The resulting mixture was stirred at 0° C. for 2 hours and then warmed to ambient temperature for 16 hours. The reaction was quenched with water (dropwise). The mixture was added to EtOAc (10 mL) and washed with water (2×3 mL) and brine (3 mL). The organic layer was dried over MgSO and concentrated under reduced pressure to isolate compound 100-a, which was used directly in the next reaction.

[0436] MS (ESI) m / z 451 [M+1].

[0437] Step 2: (S)-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1H-imidazole-2-carboxamide (100) Ethyl (S)-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1H-imidazole-2-carboxylate (100-a, 130 mg, 0.288 mmol) was dissolved in 7N ammonia in MeOH (3 mL, 21.0 mmol) and heated to 50° C. for 16 hours. The solution was concentrated under reduced pressure. The residue was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to give compound 100.

[0438] 1 H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.39 (s, 1H), 7.80 (s, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 9.9 Hz, 1H), 7.08 (s, 1H), 6.38 (d, J = 6.4 Hz, 1H), 5.78 - 5.63 (m, 2H), 1.48 (tt, J = 8.6, 5.1 Hz, 1H), 0.87 (dt, J = 7.4, 3.7 Hz, 2H), 0.81 - 0.66 (m, 2H) ppm. MS (ESI) m / z 422 [M+1].

[0439] Example 101 (S)-4-(cyclopropylethynyl)-6-fluoro-7-((3-methyl-1H-pyrazol-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (101) [ka]

[0440] To a solution of intermediate B08 in DMF (2 mL) was added K2CO3 (63.6 mg, 0.46 mmol) and 3-methyl-1H-pyrazole (25.2 mg, 0.31 mmol) and stirred at 15 °C for 3 h. The reaction was added to water (10 mL) and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep HPLC (water:MeCN (with 0.1% TFA)) to give compound 101.

[0441] 1 H NMR (400 MHz, acetonitrile-d3) δ 7.97 (br s, 1H) 7.49 (d, J=1.98 Hz, 1H) 7.28 (d, J=9.92 Hz, 1H) 6.42 - 6.52 (m, 2H) 6.07 (d, J=1.98 Hz, 1H) 5.25 (s, 2H) 2.18 (s, 3H) 1.38 (tt, J=8.32, 4.91 Hz, 1 H) 0.83 - 0.91 (m, 2H) 0.71 - 0.80 (m, 2H) ppm. MS (ESI) m / z 393 [M+1].

[0442] Example 102 (S)-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1H-pyrazole-3-carbaldehyde (102) [ka]

[0443] Compound 102 was prepared using a procedure similar to that outlined in Example 101, except intermediate B08 was replaced with intermediate B07.

[0444] 1 H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 9.51 (br s, 1H), 8.18 - 7.86 (m, 2H), 7.15 (br d, J=9.9 Hz, 1H), 6.83 (s, 1H), 6.62 (br d, J=6.2 MS (ESI) m / z 403 [M+1].

[0445] Examples 103 and 104 (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 (103) and (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 (104). [ka]

[0446] Step 1: Ethyl (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-carboxylate (103-a) and ethyl (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-carboxylate (104-a) To a solution of intermediate B07 (10 mg, 0.029 mmol) and ethyl 4-fluoro-1H-pyrazole-3-carboxylate (6.92 mg, 0.044 mmol) in DMF (1 mL) was added LiBr (3.80 mg, 0.044 mmol) and KCO (12.10 mg, 0.088 mmol). The resulting mixture was stirred at 50 °C for 2 h, then water (5 mL) was added and the solution was extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with water (5 mL), brine (2 × 5 mL), dried over NaSO, filtered, and concentrated under reduced pressure to isolate compounds 103-a and 104-a, which were used without further purification.

[0447] MS (ESI) m / z 465 [M+1].

[0448] Step 2: (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 (103) and (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 (104) Ethyl (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-carboxylate (103-a, 80 mg, 0.172 mmol) was treated with 7N NH / MeOH (2 mL) and stirred at 60° C. for 16 h. The mixture was concentrated under reduced pressure and purified by prep HPLC (water:MeCN (with 0.1% TFA)) to provide the title compound.

[0449] 103 (faster eluting isomer): 1 H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 7.95 - 7.95 (m, 1H), 7.85 (br s, 1H), 7.71 (d, J=4.4 Hz, 1H), 7.52 (br s, 1H), 7.09 (d, J=10.1 Hz, 1H), 6.42 (d, J=6.5 Hz, 1H), 5.73 - 5.54 (m, 2H), 1.67 (br t, J=18.8 Hz, 3H), 1.47 - 1.35 (m, 1H), 0.87 - 0.81 (m, 2H), 0.74 - 0.63 (m, 2H) 104 (slower eluting isomer): 1 H NMR (400 MHz, DMSO-d6) δ = 9.48 (s, 1H), 8.08 (d, J=4.4 Hz, 1H), 7.98 (s, 1H), 7.36 (br s, 2H), 7.15 (br d, J=10.0 Hz, 1H), 6.52 (d, J=6.5 Hz, 1H), 5.42 - 5.26 (m, 2H), 1.68 (br t, J=18.9 Hz, 3H), 1.51 - 1.37 (m, 1H), 0.84 (br dd, J=2.8, 8.2 Hz, 2H), 0.72 - 0.63 (m, 2H) 103 and 104For both, MS (ESI) m / z 436 [M+1]

[0450] Example 105 and Example 106 (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 (105) and (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 (106) [ka]

[0451] To a solution of intermediate B07 (50 mg, 0.146 mmol) and 1H-1,2,4-triazol-3-amine (18.40 mg, 0.219 mmol) in DMF (3 mL) was added KCO (60.5 mg, 0.438 mmol) and LiBr (12.67 mg, 0.146 mmol). The mixture was stirred at 40 °C for 8 h. The reaction was added to water (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by prep HPLC (water:MeCN (with 0.1% TFA)) to give a mixture of isomers. The mixture was purified using SFC (DAICEL CHIRALCEL OZ, 30% MeOH, 100 bar, column temperature 40 °C) to give the title compound.

[0452] 105 (faster eluting isomer) : 1 H NMR (400 MHz, DMSO-d6) δ = 9.49 (s, 1H), 7.95 (s, 1H), 7.40 (s, 1H), 7.11 (d, J=9.8 Hz, 1H), 6.45 (d, J=6.6 Hz, 1H), 6.39 (s, 2H), 5.17 - 5.05 (m, 2H), 1.68 (t, J=18.8 Hz, 3H), 1.50 - 1.38 (m, 1H), 0.89 - 0.81 (m, 2H), 0.72 - 0.65 (m, 2H) 106 (slow-eluting isomer) : 1H NMR (400 MHz, DMSO-d6) δ = 9.56 (s, 1H), 8.47 (s, 1H), 7.98 (d, J=1.1 Hz, 1H), 7.13 (d, J=9.9 Hz, 1H), 6.70 (d, J=6.6 Hz, 1H), 5.27 - 5.12 (m, 2H), 1.68 (t, J=18.9 Hz, 3H), 1.43 (tt, J=5.0, 8.3 Hz, 1H), 0.89 - 0.80 (m, 2H), 0.73 - 0.62 (m, 2H). For both isomers, MS (ESI) m / z 391 [M+1]

[0453] Example 107 (S)-7-((3-amino-1H-1,2,4-triazol-1-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (107) [ka]

[0454] A mixture of 3-amino-1,2,4-triazole (485 mg, 5.77 mmol), LiBr (551 mg, 6.35 mmol), and KCO (877 mg, 6.35 mmol) in DMF (10 mL) was stirred at 20 °C for 10 min. Intermediate B08 (200 mg, 0.577 mmol) was then added, and the reaction was stirred at 40 °C for 12 h. The mixture was filtered and purified by prep HPLC (water:MeCN with 0.1% TFA), and the second eluting peak was isolated as compound 107.

[0455] 1 H NMR (400 MHz, DMSO-d6) δ = 9.79 (s, 1H), 8.44 (d, J = 1.3 Hz, 1H), 8.31 (s, 1H), 7.21 (d, J = 9.8 Hz, 1H), 6.74 (d, J = 6.5 Hz, 1H), 1.60 - 1.37 (m, 1H), 0.92 - 0.83 (m, 2H), 0.77 - 0.66 (m, 2H). MS (ESI) m / z 395 [M+1].

[0456] The compounds of Examples 108 to 111 shown in Table 16 were prepared in a manner similar to that described for Example 107, except using the appropriate intermediate starting material as indicated in the INT column.

[0457] [Table 17]

[0458] Example 112 (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 (112) [ka]

[0459] To an oven-dried 2-dram vial equipped with a stir bar was added Intermediate A04-A (50 mg, 0.129 mmol), Intermediate C16 (33.0 mg, 0.194 mmol), phthalimide (9.50 mg, 0.065 mmol), [Ir(dtbbpy)[dF(CF3)ppy]2]PF6 (1.449 mg, 1.291 μmol), and [Ni(dtbbpy)(HO)4]Cl2 (6.07 mg, 0.013 mmol). To the vial was added DMA (1291 μL), followed by 1,1,3,3-tetramethylguanidine (24.30 μL, 0.194 mmol), which was then sparged with N2 for 5 minutes. The reaction was sealed and irradiated with a blue LED (PennOC M2, 450 nm, 100% intensity, 5200 rpm fan, 1000 rpm stirring) for 24 hours, filtered, and purified by prep HPLC (water:MeCN (with 0.1% TFA)) to isolate compound 112.

[0460] 1H NMR (500 MHz, DMSO-d6) δ 9.81 (s, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.23 (d, J = 10.2 Hz, 1H), 6.59 (d, J = 6.5 Hz, 1H), 6.25 (d, J = 1.9 Hz, 1H), 5.41 - 5.23 (m, 2H), 4.31 (s, 2H), 3.23 (s, 3H), 3.07 (s, 3H), 1.67 - 1.41 (m, 4H), 0.89 (dd, J = 8.2, 2.8 Hz, 2H), 0.76 (s, 2H). MS (ESI) m / z 433 [M+1].

[0461] Example 113 and Example 114 (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 (113) and (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 (114). [ka]

[0462] To a solution of intermediate B07 (100 mg, 0.292 mmol) in DMF (1 mL) was added LiBr (25.3 mg, 0.292 mmol), K2CO3 (81 mg, 0.584 mmol), and 1H-1,2,4-triazole-3-carboxamide (49.1 mg, 0.438 mmol) at 25 °C. The reaction was stirred at 40 °C for 2 h. Water (40 mL) was added to the reaction mixture, and the mixture was then extracted with EtOAc (40 mL). The organic layer was washed with brine (30 mL), then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep HPLC (water:MeCN (with 0.1% TFA)) to isolate 113 (as the faster eluting isomer) and 114 (as the slower eluting isomer).

[0463] 113 (fast-eluting isomer) : 11H NMR (400 MHz, acetonitrile-d3) δ = 8.36 (s, 1H), 7.64 (br s, 1H), 7.29 (d, J = 10.5 Hz, 1H), 7.07 (br s, 1H), 6.64 (d, J = 6.4 Hz, 1H), 6.25 - 6.05 (m, 2H), 5.44 (s, 2H), 1.67 (t, J = 18.8 Hz, 3H), 1.43 - 1.29 (m, 1H), 0.93 - 0.78 (m, 2H), 0.76 - 0.58 (m, 2H). MS (ESI) m / z 419 [M+1]. 114 (slow-eluting isomer) : 1 1H NMR (400 MHz, acetonitrile-d3) δ = 7.95 (s, 1H), 7.60 (br s, 1H), 7.34 (br s, 1H), 7.26 (d, J = 10.3 Hz, 1H), 6.53 (d, J = 6.4 Hz, 1H), 6.42 (br s, 1H), 6.14 (br s, 1H), 5.86 (s, 2H), 1.66 (t, J = 18.8 Hz, 3H), 1.42 - 1.32 (m, 1H), 0.93 - 0.80 (m, 2H), 0.72 (qd, J = 3.2, 4.8 Hz, 2H). For both isomers, MS (ESI) m / z 419 [M+1]

[0464] Example 115 (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 (115)

Chemical Structure

[0465] To C17 (67.7 mg, 0.584 mmol) in DMF (5 mL) was added NaH (58.3 mg, 1.459 mmol) at 0 °C. The mixture was stirred at 20 °C for 0.5 h. Then, B07 (100 mg, 0.292 mmol) was added, and the reaction mixture was stirred at 40 °C for 4 h. The mixture was added to water (15 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (15 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by prep HPLC (water:MeCN (with 0.1% TFA)) to isolate compound 115.

[0466] 1 H NMR (400 MHz, DMSO-d6) δ = 9.48 (s, 1H), 7.97 (d, J = 1.1 Hz, 1H), 7.88 (d, J = 4.3 Hz, 1H), 7.12 (d, J = 9.9 Hz, 1H), 6.51 (d, J = 6.6 Hz, 1H), 5.11 (d, J = 3.0 Hz, 2H), 3.83 (s, 3H), 1.68 (t, J = 18.8 Hz, 3H), 1.43 (tt, J = 5.0, 8.3 Hz, 1H), 0.88 - 0.81 (m, 2H), 0.72 - 0.66 (m, 2H) ppm. MS (ESI) m / z 423 [M+1].

[0467] Examples 116 and 117 (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 (116) and (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 (117) [ka]

[0468] Compounds 116 and 117 were prepared using a method similar to that described for the preparation of compounds 113 and 114, except that intermediate B08 was used instead of intermediate B07. Compound 116 was isolated as the faster eluting isomer. Compound 117 was isolated as the slower eluting isomer.

[0469] compound 116 : 1 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.42 (s, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.21 (d, J = 9.8 Hz, 1H), 6.59 (d, J = 6.5 Hz, 1H), 6.01 - 5.76 (m, 2H), 1.47 (tt, J=5.0, 8.3 Hz, 1H), 0.96 - 0.82 (m, 2H), 0.78 - 0.58 (m, 2H) Compound 117 : 1 1H NMR (400 MHz, DMSO-d6) δ 9.78 (br s, 1H), 8.77 (s, 1H), 8.46 (br s, 1H), 7.78 (s, 1H), 7.59 (s, 1H), 7.24 (d, J = 10.0 Hz, 1H), 6.70 (d, J = 6.4 Hz, 1H), 5.52 (d, J = 2.1 Hz, 2H), 1.52 - 1.42 (m, 1H), 0.90 - 0.83 (m, 2H), 0.78 - 0.69 (m, 2H) For both isomers, MS (ESI) m / z 423 [M+1]

[0470] Example 118 (S)-4-(cyclopropylethynyl)-6-fluoro-7-((5-methyl-2H-tetrazol-2-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (118)

Chemical Structure

[0472] 1 H NMR (500 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.58 - 8.41 (m, 1H), 7.27 (d, J = 9.7 Hz, 1H), 6.87 (d, J = 6.3 Hz, 1H), 5.98 - 5.85 (m, 2H), 2.45 (s, 3H), 1.53 - 1.43 (m, 1H), 0.87 (dd, J = 8.3, 3.2 Hz, 2H), 0.73 (dd, J = 7.4, 4.6 Hz, 2H). MS (ESI) m / z 395 [M+1].

[0473] Example 119 (S)-7-((2H-indazol-3-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (119) [ka]

[0474] Step 1: (S)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-7-((2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-3-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one (119-a) In a glove box, to a mixture of Intermediate C21 (47.2 mg, 0.144 mmol) and Intermediate B08 (20 mg, 0.058 mmol) in DMA (2 mL) was added NiCl(DME) (3.17 mg, 0.014 mmol), picolinimidamide (1.747 mg, 0.014 mmol), zinc (9.43 mg, 0.144 mmol), and NaI (8.65 mg, 0.058 mmol). The reaction was moved outside the glove box and stirred at 80 °C for 40 min. The reaction was diluted with water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by prep HPLC (water:MeCN (with 0.1% TFA)) to isolate compound 119-a.

[0475] MS (ESI) m / z 559 [M+1].

[0476] Step 2: (S)-7-((2H-indazol-3-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (119) A solution of (S)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-7-((2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-3-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one (119-a, 30 mg, 0.054 mmol) in 1 M HCl / EtOAc (2 mL) was stirred for 4 h at 35° C. The reaction was concentrated under reduced pressure and the residue was purified by prep HPLC (water:MeCN (with 0.1% TFA)) to isolate compound 119.

[0477] 1H NMR (400 MHz, acteonitrile-d3) δ ppm 10.97 (br s, 1H) 7.64 (br d, J = 8.07 Hz, 2H) 7.51 (d, J = 8.44 Hz, 1H) 7.36 (t, J = 7.64 Hz, 1H) 7.27 (d, J = 9.78 Hz, 1H) 7.12 (t, J = 7.52 Hz, 1H) 6.71 (d, J = 6.48 Hz, 1H) 6.34 (br s, 1 H) 4.31 (s, 2H) 1.32 - 1.43 (m, 1H) 0.82 - 0.92 (m, 2H) 0.69 - 0.77 (m, 2H). MS (ESI) m / z 428 [M+1].

[0478] Example 120 (S)-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1H-pyrazole-3-sulfonamide (120) [ka]

[0479] To a mixture of intermediate B07 (100 mg, 0.292 mmol), 1H-pyrazole-3-sulfonamide (47.2 mg, 0.321 mmol), and KCO (81 mg, 0.584 mmol), DMA (912 μL) was added and stirred for 30 min at 80° C. The reaction mixture was cooled, filtered, and purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to isolate compound 120. 1H NMR (500 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.04 - 7.94 (m, 2H), 7.39 (s, 2H), 7.15 (d, J = 9.9 Hz, 1H), 6.70 (d, J = 6.5 Hz, 1H), 6.63 (d, J = 2.3 Hz, 1H), 5.42 (d, J = 5.1 Hz, 2H), 1.68 (t, J = 18.8 Hz, 3H), 1.52 - 1.36 (m, 1H), 0.84 (dq, J = 9.8, 3.9, 3.2 Hz, 2H), 0.69 (ddt, J = 7.3, 5.2, 2.6 Hz, 2H). MS (ESI) m / z 454 [M+1].

[0480] Example 121 (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((4-(difluoromethyl)-1H-pyrazol-1-yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one (121) [ka]

[0481] Compound 121 was prepared using a procedure similar to that of Example 120, except 1H-pyrazole-3-sulfonamide was replaced with 4-(difluoromethyl)-1H-pyrazole.

[0482] 1 H NMR (500 MHz, methanol-d4) δ 8.00 (s, 1H), 7.71 (s, 1H), 7.23 (d, J = 9.9 Hz, 1H), 6.81 (t, J = 56.3 Hz, 1H), 6.58 (d, J = 6.3 Hz, 1H), 5.41 MS (ESI) m / z 425 [M+1].

[0483] Example 122 (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 (122) [ka]

[0484] 4-Methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (24.86 mg, 0.251 mmol), Intermediate B07 (43 mg, 0.125 mmol), NaI (18.81 mg, 0.125 mmol), and KCO (69.4 mg, 0.502 mmol) were added to a vial, followed by DMF (627 μL). The reaction was heated to 50° C. for 16 hours. The mixture was cooled and filtered, and the solution was purified by prep HPLC (water:MeCN (with 0.1% TFA)) to isolate compound 122.

[0485] 1 H NMR (500 MHz, DMSO-d6) δ 9.46 (s, 1H), 7.96 (s, 2H), 7.11 (d, J = 9.8 Hz, 1H), 6.69 (d, J = 6.5 Hz, 1H), 4.85 (s, 2H), 3.19 (s, 3H), 1.68 (t, J = 18.8 Hz, 3H), 1.50 - 1.36 (m, 1H), 0.90 - 0.80 (m, 2H), 0.69 (tt, J = 4.9, 2.2 Hz, 2H) ppm. MS (ESI) m / z 406 [M+1].

[0486] Example 123 (S)-6-chloro-4-(cyclopropylethynyl)-7-((4-methoxy-1H-pyrazol-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (123) [ka]

[0487] Intermediate B10 (30 mg, 0.083 mmol), 4-methoxy-1H-pyrazole (8.1 mg, 0.083 mmol), and KCO (40 mg, 0.289 mmol) were dissolved in DMA (826 μL) and heated to 60° C. for 16 h. The reaction was cooled, filtered, and the solution was purified by prep HPLC (water:MeCN (with 0.1% TFA)) to isolate compound 123.

[0488] 1 H NMR (500 MHz, Chloroform-d3) δ 8.02 (s, 1H), 7.51 (s, 1H), 7.30 (s, 1H), 7.15 (s, 1H), 6.28 (s, 1H), 5.92 (s, 1H), 5.35 - 5.21 (m, 2H), 3.76 (s, 3H), 1.33 (td, J = 8.3, 4.2 Hz, 1H), 0.88 (dd, J = 7.4, 4.8 Hz, 2H), 0.85 - 0.74 (m, 2H). MS (ESI) m / z 425 [M+1].

[0489] Example 124 and Example 125 (S or 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 (124) and (R or 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 (125). [ka]

[0490] Step 1: (S,E)-5-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methylene)-1-methylimidazolidine-2,4-dione (124-a) To a mixture of intermediate B14 (140 mg, 0.434 mmol) and 2-aminoethan-1-ol (13.27 mg, 0.217 mmol) in EtOH (1.3 mL) and water (1.3 mL) was added 1-methylimidazolidine-2,4-dione (149 mg, 1.303 mmol). The mixture was stirred at 120 °C for 48 h. The solution was filtered and the precipitate was washed with EtOH (5 mL) to isolate compound 124-a.

[0491] MS (ESI) m / z 419 [M+1].

[0492] Step 2: (S or 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 (124) and (R or 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 (125) To a solution of (S,E)-5-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methylene)-1-methylimidazolidine-2,4-dione (124-a, 80 mg, 0.198 mmol) in AcOH (3 mL) was added Zn (1643 mg, 25.1 mmol). The mixture was stirred at 25° C. for 12 h. The reaction was filtered and the solution concentrated under reduced pressure. The residue was purified by prep HPLC (water:MeCN (with 0.1% TFA)) to isolate a racemic mixture of products. The material was separated by SFC (Daicel ChiralPak® AS, MeOH 40%, 100 psi) to isolate compounds 124 and 125.

[0493] Faster eluting isomer 124 : 1 H NMR (400 MHz, methanol-d4) δ 7.17 (d, J = 10.26 Hz, 1H) 6.74 (d, J = 6.38 Hz, 1H) 4.30 (t, J = 4.88 Hz, 1H) 3.23 - 3.29 (m, 1H) 3.09 - 3.16 (m, 1H) 2.90 (s, 3H) 1.64 (t, J = 18.45 Hz, 3H) 1.36 - 1.45 (m, 1H) 0.84 - 0.91 (m, 2H) 0.70 - 0.77 (m, 2H) Slow-eluting isomer 125 : 1H NMR (400 MHz, methanol-d4) δ 7.17 (d, J = 10.01 Hz, 1H) 6.74 (d, J = 6.38 Hz, 1H) 4.31 (t, J = 4.75 Hz, 1H) 3.34 (d, J = 5.13 Hz, 1H) 3.08 (dd, J = 14.57, 4.06 Hz, 1H) 2.89 - 2.93 (m, 3H) 1.66 (t, J = 18.45 Hz, 3H) 1.38-1.41 (m, 1H) 0.84 - 0.92 (m, 2H) 0.73-0.75 (m, 2H) For both isomers, MS (ESI) m / z 421 [M+1]

[0494] Example 126 (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-((dimethylamino)methyl)-1H-pyrazol-1-yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one (126) [ka]

[0495] To a mixture of compound 102 (20 mg, 0.050 mmol) in DCM (1 mL) was added dimethylamine hydrochloride (6.08 mg, 0.075 mmol), followed by AcOH (0.1 mL). The resulting mixture was stirred at 15° C. for 0.5 h. Sodium triacetoxyborohydride (21.07 mg, 0.099 mmol) was then added and stirred at 30° C. for 16 h. The reaction mixture was filtered and purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to isolate compound 126.

[0496] 1H NMR (400 MHz, methanol-d4) δ 7.84 -7.85 (d, J = 2.25 Hz, 1H), 7.21 - 7.24 (dd, J = 9.20 Hz, 0.80 Hz, 1H), 6.61 - 6.63 (d, J = 6.25 Hz, 1H), 6.49 - 6.51 (d, J = 2.25 Hz, 1H), 5.43 (s, 2H), 4.30 (s, 2H), 2.86 (s, 6H), 1.69 (t, J = 18.51 Hz, 3H), 1.36 - 1.44 (m, 1H), 0.85 - 0.91 (m, 2H), 0.71 - 0.76 (m, 2H). MS (ESI) m / z 432 [M+1].

[0497] Example 127 (S)-4-(cyclopropylethynyl)-7-((3-methyl-1H-pyrazol-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (127) [ka] 3-Methyl-1H-pyrazole (40.0 mg, 0.487 mmol) and CsCO (39.6 mg, 0.122 mmol) were combined in DMA (487 μL) in a vial and heated at 80° C. for 0.5 h. Intermediate B09 (16 mg, 0.049 mmol) was added in DMA (100 μL) and stirring was continued at 80° C. for 16 h. The reaction was filtered through a syringe filter and the solution was purified by prep HPLC (water:MeCN with 0.1% TFA) to isolate compound 127.

[0498] 1H NMR (600 MHz, methanol-d4) δ 7.57 (s, 1H), 7.45 (d, J = 7.9 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.61 (s, 1H), 6.11 (s, 1H), 5.23 (s, 2H), 2.22 (s, 3H), 1.43 - 1.34 (m, 1H), 0.86 (dd, J = 8.2, 3.4 Hz, 2H), 0.73 (t, J = 5.8 Hz, 2H). MS (ESI) m / z 375 [M+1].

[0499] Example 128 (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 (128) [ka]

[0500] 4,5-Dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (28.4 mg, 0.251 mmol), Intermediate B07 (43 mg, 0.125 mmol), NaI (18.81 mg, 0.125 mmol), and KCO (69.4 mg, 0.502 mmol) were added to a vial, followed by DMF (627 μL). The reaction was heated to 50° C. for 16 hours. The mixture was filtered and purified by prep HPLC (water:MeCN (with 0.1% TFA)) to isolate compound 128.

[0501] 1H NMR (500 MHz, DMSO-d6) δ 9.46 (s, 1H), 7.96 (s, 1H), 7.10 (d, J = 10.0 Hz, 1H), 6.70 (d, J = 6.5 Hz, 1H), 4.81 (d, J = 3.1 Hz, 2H), 3.14 (d, J = 3.5 Hz, 3H), 2.15 (s, 3H), 1.68 (t, J = 18.8 Hz, 3H), 1.54 - 1.35 (m, 1H), 0.84 (dd, J = 8.3, 2.8 Hz, 2H), 0.69 (dt, J = 4.8, 2.7 Hz, 2H) ppm. MS (ESI) m / z 420 [M+1].

[0502] Example 129 (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 (129) [ka]

[0503] Step 1: (S)-7-((3-acetyl-1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one (129-a) To a solution of 1-(1H-pyrazol-3-yl)ethanone (9.64 mg, 0.088 mmol) in DMF (1 mL) was added NaH (14.00 mg, 0.350 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Intermediate B07 (30 mg, 0.088 mmol) was added, and the mixture was stirred at 15 °C for 1.5 h. The solution was poured into saturated aqueous NH Cl (5 mL) and extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over Na SO , filtered, and concentrated under reduced pressure to isolate compound 129-a, which was used without further purification.

[0504] MS (ESI) m / z 417 [M+1].

[0505] Step 2: (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 (129) To a solution of (S)-7-((3-acetyl-1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one (129-a) (15 mg, 0.036 mmol) in THF (1 mL) was added 3 M MeMgBr in THF (0.018 mL, 0.054 mmol) at 0 °C. The mixture was stirred at 10 °C for 10 min. The reaction was poured into saturated aqueous NH Cl (10 mL) and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by prep HPLC (water:MeCN with 0.1% TFA) to isolate compound 129.

[0506] 1 H NMR (400 MHz, acetonitrile-d3) δ ppm 7.81 (br s, 1H), 7.50-7.51 (d, J = 2.20 Hz, 1H), 7.24-7.27 (d, J = 10.15 Hz, 1H), 6.44-6.46 (d, J = 6.48 Hz, 1H), 6.26-6.27 (d, J = 2.20 Hz, 1H), 6.20 (br s, 1H), 5.27 (s, 2H), 3.13 (s, 1H), 1.62-1.71 (t, J = 18.77 Hz, 3H), 1.48 (s, 6H), 1.32-1.40 (m, 1H), 0.83- 0.88 (m, 2H), 0.69 - 0.74 (m, 2H). MS (ESI) m / z 433 [M+1].

[0507] Measurement of cell killing (HIV-TACK) activity: PBMCs from healthy donors were cultured at approximately 2.5 × 10 in complete medium (RPMI 1640 with L-glutamine; 10% heat-inactivated fetal bovine serum; 100 U / mL penicillin-streptomycin) containing 5 μg / mL phytohemagglutinin at 5% CO , 37°C, and 90% humidity. 6On day 4, PHA-stimulated cells were washed and plated in complete medium containing IL-2 (10 U / mL) containing a VSV-G pseudotyped HIV virus stock (VSV-G / pNLG1-P2A-ΔEnv-20 μg / mL p24) at approximately 20 × 10 cells / mL for 3 days. 6 Resuspend cells / mL and incubate at 37°C, 5% CO 2 The infected cells were then incubated at 200 × g for 4 hours at 90% humidity. VSV-G / pNLG1-P2A-ΔEnv is a VSV-G pseudotype derived from pNL43, in which eGFP is inserted 5' of nef, resulting in eGFP expression overtaking the normally spliced ​​RNA transcript. The virus contains Vif truncated by 50 amino acids due to a single-nucleotide deletion that causes a frameshift, and does not express Nef due to a stop codon after gfp. Due to the frameshift resulting in multiple stop codons, HIV Env is not expressed. The infected cells were then washed three times with complete medium + 10 U / mL IL-2 and centrifuged at 200 × g for 3 minutes at 22°C. The cells were then resuspended in complete medium + 10 U / mL IL-2 for 5 × 10 6 For compound treatment, infected PBMCs were resuspended at 4 × 10 cells / mL and incubated overnight at 37°C, 5% CO2, and 90% humidity. For compound treatment, infected PBMCs were cultured at 4 × 10 cells / mL in RPMI 1640 containing L-glutamine, 50% normal human serum (NHS), 100 U / mL penicillin-streptomycin, and IL-2 (10 U / mL). 5 The compounds were diluted to 1000 cells / mL, and 20,000 cells were transferred to each well of a compound-containing 384-well poly-D-lysine-coated compound plate with a final DMSO concentration of less than 0.5%. Compounds were tested in 10-point, 3-fold titrations. Plates were analyzed on an Acumen ex3 imager using a Blue Laser at 488 nm, and the number of GFP-positive objects with loss of GFP, representing infected cell death, was collected. Titration curves and EC50 values ​​were calculated using a four-parameter logistic fit. Results are shown in Table 17. [Table 18] TIFF2026021308000120.tif63166

Claims

1. Formula (I) 【Chemistry 1】 [During the ceremony, X is N(R ３ ) or C(R ３ ) and W is -C １－６ Alkyl-, -(C ０－６ alkyl)O-, -(C １－６ alkyl)amino- or -(C １－６ alkyl)aminocarbonyl-, where W is 0, 1, or 2 R ５ is substituted with a substituent; Each R ５ are independently halo, C １－４ Alkyl or C １－４ is fluoroalkyl; R １ Ha, Halo, C １－６ Alkyl, (C ３－１２ ) heterocycloalkyl (C ０－４ alkyl) or (C ３－１２ ) cycloalkyl (C ０－４ alkyl); R ２ is hydrogen, halo or C １－１０ is alkyl; R ３ is hydrogen, halo or C １－１０ is alkyl; R ４ teeth, (a) a 5-membered heteroaryl having at least one nitrogen atom; (b) a monocyclic, bicyclic, or tricyclic 7- to 14-membered heteroaryl containing a ring containing at least one aromatic heteroatom, wherein the 7- to 14-membered heteroaryl contains at least one nitrogen atom; or (c) triazolinonyl, 2,4-dihydro-3H-1,2,4-triazolin-3-onyl, dihydropyrrolo[3,4-b]pyrrololonyl, imidazolidinonyl, 1,3-dihydro-2H-benzo[d]imidazol-2-onyl, dihydrobenzo[d]imidazolinonyl, 1,3-dihydroimidazo[4,5-c]pyridinonyl, oxazolo[5,4-c]pyridin-2-onyl, 1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-onyl, 1,3 - a ketone-containing ring system selected from dihydroimidazo[4,5-b]pyridin-2-onyl, isoindolinonyl, 4,5-dihydropyrrolo[3,4-b]pyrrololonyl, 4,5-dihydropyrrolo[3,4-b]pyrrol-6(2H)onyl, benzo[d]oxazolonyl, benzo[d]oxazol-2-onyl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolonyl and 1,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-4-onyl, Selected from: Here, R ４ is 0, 1, 2 or 3 R ４ａ is substituted with a substituent; Each R ４ａ is, independently, C １－６ Alkyl, C １－１０ fluoroalkyl, amino, Cyano, Hello, 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 ) Selected from: Here, R ４ａ is 0, 1, 2 or 3 R ４ｂ is substituted with a substituent; and Each R ４ｂ are independently １－１０ Alkyloxy, C １－６ Alkyl, C １－１０ fluoroalkyl, amino, hydroxy, halo, or cyano. or a pharmaceutically acceptable salt thereof.

2. X is N(R ３ 2. The compound of claim 1, wherein R is 1 or 2; or a pharmaceutically acceptable salt thereof.

3. X is C(R ３ 2. The compound of claim 1, wherein R is 1 or 2; or a pharmaceutically acceptable salt thereof.

4. W is -C １－６ Alkyl-, -(C １－６ alkyl)amino- or -(C １－６ alkyl)aminocarbonyl, where W is 0, 1, or 2 R ５ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is substituted with a substituent.

5. W is -(C ０－６ alkyl)O—, where W is 0, 1, or 2 R ５ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is substituted with a substituent.

6. 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, cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl, or a pharmaceutically acceptable salt thereof.

7. R ２ 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein is hydrogen, fluoro, chloro, bromo, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or neopentyl.

8. R ３ The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein is hydrogen, fluoro, chloro, methyl, bromo, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or neopentyl.

9. R ４ but, (a) a 5-membered heteroaryl having at least one nitrogen atom, wherein 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) Monocyclic, bicyclic, or tricyclic 7- to 14-membered heteroaryls containing a ring containing at least one aromatic heteroatom, wherein the 7- to 14-membered heteroaryl contains at least one nitrogen atom, and the monocyclic, bicyclic, or tricyclic 7- to 14-membered heteroaryls containing a ring containing at least one aromatic heteroatom, wherein the 7- to 14-membered heteroaryl containing at least one nitrogen atom is 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, quinolidinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, carbazolyl, phenatridinyl, acridinyl, phenanthrolinyl, phenazinyl, 7H-pyrazino[2,3-c]carbazolyl, 1,3-benzoxazolyl, and 2,1-benzoxazolyl; or (c) a ketone-containing ring system selected from 2,4-dihydro-3H-1,2,4-triazol-3-onyl, imidazolidinonyl, 1,3-dihydro-2H-benzo[d]imidazol-2-onyl, 1,3-dihydroimidazo[4,5-c]pyridinonyl, isoindolinonyl, 4,5-dihydropyrrolo[3,4-b]pyrrol-6(2H)onyl, and benzo[d]oxazol-2-onyl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolonyl; and Furthermore, where R ４ is 0, 1, 2 or 3 R ４ａ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, which is substituted with a substituent.

10. Each R ４ａ But independently, 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) ２ NH ２ ) wherein R ４ａ is 0, 1, 2 or 3 R ４ｂ 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, which is substituted with a substituent.

11. Each R ４ｂ But independently, C １－６ Alkyloxy, C １－４ Alkyl, C １－６ 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the group is selected from fluoroalkyl, amino, hydroxy, halo, or cyano.

12. Each R ５ or a pharmaceutically acceptable salt thereof, according to claim 11, wherein is independently fluoro, chloro, methyl, ethyl, propyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, or fluoromethyl.

13. below, (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; (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; (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; (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; (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; (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; (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; (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 2. The compound of claim 1, wherein:

14. below, (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; (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 2. The compound of claim 1, wherein:

15. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

16. 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 reversal agents.

17. A method for treating or preventing infection by HIV, or treating, preventing, or delaying the onset or progression of AIDS or ARC in a human subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

18. A method for inducing GAG-POL dimerization in HIV-infected cells in a human subject in need thereof, comprising administering to the subject an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

19. A method for selectively killing HIV-infected GAG-POL-expressing cells in a human subject, comprising administering to the subject an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

20. A method for selectively killing HIV-infected GAG-POL-expressing cells in a human subject without cytotoxicity to HIV-naive cells, the method comprising administering to the human subject an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

21. 10. A method for enhancing suppression of HIV viremia in a human subject whose HIV viremia has been suppressed by administration of one or more compatible HIV antiviral drugs, the method comprising further administering to the subject an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

22. 16. 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 reversal agents.

23. A compound according to any one of claims 1 to 14 for use in therapy.

Images