Tetrahydroquinazoline derivatives as selective cytotoxic agents

Abstract

This disclosure relates to tetrahydroquinazoline derivatives represented by Formula I, and their use for selectively killing HIV-infected GAG-POL-expressing cells without cytotoxicity to HIV-naive cells, and for treating or preventing HIV infection, or for treating, preventing or delaying the onset or progression of AIDS or AIDS-related syndromes (ARC). [Formula 1] TIFF2026516541000123.tif46141

Description

[Background technology]

[0001] Cross-reference with related applications This application claims the interests of U.S. Provisional Patent Application No. 63 / 512,403, filed on 7 July 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, individuals infected with HIV exhibit severe immunodeficiency, leading to extreme debilitation and ultimately making them highly susceptible to fatal opportunistic infections. Several clinically approved antiretroviral drugs are available that demonstrate multi-log reduction of viral load. However, treated patients are at risk of developing mutations that make the virus resistant to available treatments, and a rapid rebound in viremia occurs upon discontinuation of treatment. These factors indicate that current regimens are not curative.

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

[0004] Available antiretroviral drugs act by blocking the virus at various stages of its life cycle. For example, reverse transcriptase inhibitors target viral reverse transcriptase and prevent the RNA genome from being copied into DNA; integrase inhibitors block the ability of copied DNA to be integrated into host cells; and protease inhibitors prevent viral maturation, thereby resulting in virions produced from cells treated with protease inhibitors being immature and non-infectious. Once integration occurs, cells become infected and die either through normal cell death pathways or accelerated death due to viral factors, or they are targeted by the immune system. While 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, for example, "JB Dinoso et al., Proc. Natl. Acad. Sci. USA, 2009, 106(23): 9403-9408"). These latent infected cells and persistently virus-expressing cells that remain during antiretroviral therapy are collectively referred to as the HIV reservoir, and these cells are the reason why HIV-infected individuals require lifelong, high-adherence treatment to maintain undetectable levels of the virus. Therefore, novel therapies that can selectively kill HIV-infected cells would offer new treatment options for HIV infection. These targeted cell-killing activation (TACK) molecules bind to the reverse transcriptase-p66 domain of the monomer Gag-Pol and function as allosteric modulators to promote dimerization. This allows HIV-1 to be activated early through intracellular viral proteases. + Cell death is triggered. The TACK molecule possesses potent antiviral activity, and infected CD4 isolated from HIV-1 infected humans. +It selectively eliminates T cells and therefore supports an immune-independent clearance strategy (see, for example, "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 [Overview of the project] [Problems that the invention aims to solve]

[0006] Therapies with compounds capable of accelerating the death of HIV-infected cells and reducing the total number of virus-infected cells remaining in a patient's body have the potential to reduce residual viremia in individuals in an HIV-suppressed state and address comorbidities associated with chronic viral infection (e.g., chronic inflammation, immune dysfunction, accelerated aging, cardiovascular disease (CVD), central nervous system (CNS) and other tissue and peripheral organ damage). Furthermore, therapies with compounds capable of eliminating residual HIV stores can prolong post-treatment viral remission and may play a role in HIV treatment strategies. [Means for solving the problem]

[0007] This disclosure focuses on 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. Therefore, these compounds are useful for selectively killing HIV-infected GAG-POL-expressing cells in HIV-infected subjects. Accordingly, the compounds disclosed herein are useful for the treatment or prevention of HIV infection, or for the treatment, prevention, or delay of the onset or progression of AIDS or AIDS-related syndromes (ARC). Compositions and methods of use containing the compounds of this disclosure are also provided.

[0008] In one embodiment, this disclosure relates to formula (I) [ka] The present invention provides compounds represented by and pharmaceutically acceptable salts thereof. [Modes for carrying out the invention]

[0009] This disclosure relates to tetrahydroquinazoline derivative compounds and their use to accelerate the death of HIV GAG-POL-expressing cells without cytotoxicity to HIV-naive cells. In the absence of compounds such as those derived from this disclosure, protease (PR) activation occurs during viral maturation, and the concentration of mature PR in the cytoplasm is limited. In contrast, the compounds of the present invention promote the desired phenotype by catalyzing GAG-POL dimerization in infected cells by binding to immature RT binding sites and inducing premature activation of the HIV PR enzyme in host-infected cells before budding. 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. This indicates the role of HIV proteases in this process.

[0010] The compounds currently disclosed herein also possess activity as non-nucleoside reverse transcriptase inhibitors (NNRTIs) due to 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. By binding to the mature RT, enzyme activity is inhibited, leading to the production of a DNA provirus, which prevents infection of naive CD4+ T cells.

[0011] While the effects of NNRTI 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 death of HIV-infected cells as a result of enhanced dimerization was first reported by Jochmans et al. (Jochmans et al. Retrovirology 2010, 7:89). Their authors generated data demonstrating these effects in chronically infected MT-4 cells, PBMCs, and CD4+ cells. Based on the potency of the molecules tested, they concluded that "these data demonstrate the concept of targeted drug-induced elimination of HIV-producing cells. While NNRTIs themselves may not be sufficiently potent for therapeutic application, the results provide a basis for the development of drugs that utilize this mechanism of action." More recently, Zerbato et al. (Antimicrob. Agents Chemother. 2017, 61(3)) measured the activity of NNRTIs in a primary cell model of HIV latency. They found a significant reduction in viral production with certain NNRTIs compared to another class of antiretroviral drugs, and speculated that this was due to the ability of these compounds to eliminate cells expressing the HIV GAG-POL protein. More recently, Trinite et al. (Retrovirology, 2019, 16(17)) showed in their paper how NNRTI-induced PR activation induces apoptotic cell death of productively HIV-infected resting or activated T cells.

[0012] This disclosure relates to formula (I) [ka] [In the formula, X is N(R 3 ) or C(R 3 ); W is -C 1-6 alkyl-, -(C 0-6 alkyl)O-, -(C 1-6 alkyl)amino- or -(C 1-6 alkyl)aminocarbonyl-, where W is substituted with 0, 1 or 2 R 5 substituents; Each R 5 is independently halo, C 1-4 alkyl or C 1-4 fluoroalkyl; R 1 is 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 alkyl; R 3 is hydrogen, halo or C 1-10 alkyl; R 4 is (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, where the 7- to 14-membered heteroaryl contains at least one nitrogen atom, or (c) Triazolinonyl, 2,4-dihydro-3H-1,2,4-triazoli-3-onyl, dihydropyrrolo[3,4-b]pyrrolonyl, imidazolidinonyl, 1,3-dihydro-2H-benzo[d]imidazole-2-onyl, dihydrobenzo[d]imidazolinonyl, 1,3-dihydroimidazo[4,5-c]pyridinonyl, oxazolo[5,4-c]pyridine-2-onyl, 1,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-onyl, 1,3 - A ketone-containing ring system selected from dihydroimidazo[4,5-b]pyridine-2-onyl, isoindolinonyl, 4,5-dihydropyrrolo[3,4-b]pyrrolonyl, 4,5-dihydropyrrolo[3,4-b]pyrrole-6(2H)onyl, benzo[d]oxazolonyl, benzo[d]oxazole-2-onyl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolonyl, and 1,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-4-onyl, Selected from; Here, R 4 R is 0, 1, 2, or 3 4a Substituting with a substituent; Each R 4a 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; Here, R 4a R is 0, 1, 2, or 3 4b Substituting with substituents; and, Each R 4b Independently, C 1-10 Alkyloxy, C 1-6 Alkyl, C 1-10 [Fluoroalkyl, amino, hydroxy, halo, or cyano] The target is the compound represented by or its pharmaceutically acceptable salt.

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

[0014] In a second embodiment of the present invention, X is C(R 3 ) and here, R 3 is hydrogen, halo, or C 1-10The alkyl group and other groups are as shown in the 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 It is an alkyl)aminocarbonyl-, where W is 0, 1 or 2 R. 5 Substituents are present, and other groups are as shown in the general formula (I) above, or as shown in the first and second embodiments.

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

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

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

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

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

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

[0023] In the 11th embodiment of the present invention, R 1 Hello, C 1-6 Alkyl, (C 3-7 ) Heterocycloalkyl (C 0-4 (Alkyl) or (C 3-7 )Cycloalkyl(C 0-4 The group is alkyl, and the other groups are as shown in the general formula (I) above, or as shown in the 1st to 10th embodiments.

[0024] In the twelfth embodiment of the present invention, R 1The group 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, and the other groups are as shown in the above general formula (I) or as shown in the 1st to 10th embodiments.

[0025] In the thirteenth embodiment of the present invention, R 1 The group is fluoro, methyl, or cyclopropyl, and the other groups are as shown in the general formula (I) above, or as shown in the 1st to 10th embodiments.

[0026] In the fourteenth embodiment of the present invention, R 2 The group 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 the above general formula (I) or as shown in the 1st to 13th embodiments.

[0027] In the 15th embodiment of the present invention, R 2 The group is hydrogen, fluoro, or chloro, and the other groups are as shown in the general formula (I) above, or as shown in the 1st to 13th embodiments.

[0028] In the sixteenth embodiment of the present invention, R 3 The group 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 the above general formula (I) or as shown in the 1st to 15th embodiments.

[0029] In the 17th embodiment of the present invention, R 3 is hydrogen, and the other groups are as shown in the above general formula (I) or as shown in the 1st to 15th embodiments.

[0030] In the 18th embodiment of the present invention, R 3 is methyl, and the other groups are as shown in the above general formula (I) or as shown in the 1st to 15th embodiments.

[0031] In the 19th embodiment of the present invention, in R 4 , 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, where R 4 is substituted with 0, 1, 2 or 3 R 4a substituents, and the other groups are as shown in the above general formula (I) or as shown in the 1st to 18th embodiments.

[0032] In the 20th embodiment of the present invention, in R 4 , 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, where R 4 is substituted with 0, 1, 2 or 3 R 4a substituents, and the other groups are as shown in the above general formula (I) or as shown in the 1st to 18th embodiments.

[0033] In the 21st embodiment of the present invention, R 4 In, the monocyclic, bicyclic or tricyclic 7- to 14-membered heteroaryl containing a ring containing at least one aromatic heteroatom (where 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, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, 7H-pyrazino[2,3-c]carbazolyl, 1,3-benzoxazolyl and 2,1-benzoxazolyl, where R 4 is substituted with 0, 1, 2 or 3 R 4a substituents, and the other groups are as shown in the above general formula (I) or as shown in the 1st to 18th embodiments.

[0034] In the 22nd embodiment of the present invention, R 4 In, the monocyclic, bicyclic or tricyclic 7- to 14-membered heteroaryl containing a ring containing at least one aromatic heteroatom (where 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 and benzo[d]imidazolyl, where R 4 is substituted with 0, 1, 2 or 3 R 4aSubstituents are present, and other groups are as shown in the general formula (I) above, or as shown in the 1st to 18th embodiments.

[0035] In the 23rd embodiment of the present invention, R 4 In this, the ketone-containing ring system is selected from 2,4-dihydro-3H-1,2,4-triazoli-3-onyl, imidazolidinonyl, 1,3-dihydro-2H-benzo[d]imidazole-2-onyl, 1,3-dihydroimidazo[4,5-c]pyridinonyl, isoindolinonyl, 4,5-dihydropyrrolo[3,4-b]pyrrole-6(2H)onyl and benzo[d]oxazole-2-onyl, and 1,4,5,6-tetrahydrocyclopenta[c]pyrazolonyl, where R 4 R is 0, 1, 2, or 3 4a Substituents are present, and other groups are as shown in the general formula (I) above, or as shown in the 1st to 18th embodiments.

[0036] In the 24th embodiment of the present invention, R 4 teeth, (a) A five-membered heteroaryl having at least one nitrogen atom, wherein the five-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, flazanyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, and 1,2,3,5-oxatriazolyl; (b) A monocyclic, bicyclic or tricyclic 7- to 14-membered heteroaryl comprising a ring containing at least one aromatic heteroatom, wherein the 7- to 14-membered heteroaryl comprises at least one nitrogen atom, and the monocyclic, bicyclic or tricyclic 7- to 14-membered heteroaryl comprising a ring containing at least one aromatic heteroatom, wherein the 7- to 14-membered heteroaryl comprising 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, Selected from 4-d]pyrimidinyl, 2H-pyrazolo[3,4-d]pyrimidinyl, indolyl, 2H-pyrazolo[3,4-b]pyrimidinyl, benzo[d][1,2,3]-triazolyl, benzo[d]imidazolyl, indolidinyl, isoindolyl, prinyl, quinolidinyl, isoquinolyl, quinolyl, phthalazinyl, naphthylidinyl, quinoxalinyl, cinnolinyl, carbazolyl, phenatolidinyl, acridinyl, phenanthrolinyl, phenadinyl, 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-triazoli-3-onyl, imidazolidinonyl, 1,3-dihydro-2H-benzo[d]imidazole-2-onyl, 1,3-dihydroimidazo[4,5-c]pyridinonyl, isoindolinonyl, 4,5-dihydropyrrolo[3,4-b]pyrrole-6(2H)onyl and benzo[d]oxazole-2-onyl, and 1,4,5,6-tetrahydrocyclopenta[c]pyrazolonyl; Selected from, here, R 4 R is 0, 1, 2, or 3 4a Substituents are present, and other groups are as shown in the general formula (I) above, or as shown in the 1st to 18th embodiments.

[0037] In the 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 Selected from alkyl)-(S(=O)2NH2), where R 4a R is 0, 1, 2, or 3 4b Substituents are present, and other groups are as shown in the general formula (I) above, or as shown in the 1st to 24th embodiments.

[0038] In the 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 Selected from alkyl)-(S(=O)2NH2), where R 4a R is 0, 1, 2, or 3 4b Substituents are present, and other groups are as shown in the general formula (I) above, or as shown in the 1st to 24th embodiments.

[0039] In the 27th embodiment of the present invention, each R 4a R 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, where R 4a R is 0, 1, 2, or 3 4b Substituents are present, and other groups are as shown in the general formula (I) above, or as shown in the 1st to 24th embodiments.

[0040] In the 28th embodiment, each R 4b Independently, C 1-6 Alkyloxy, C 1-4 Alkyl, C 1-6 The group is selected from fluoroalkyl, amino, hydroxy, halo, or cyano, and the other group is as shown in the general formula (I) above, or as shown in the first to 27 embodiments.

[0041] In the 29th embodiment, each R 4b Independently, C 1-4 Alkyloxy, C 1-4 Alkyl, C 1-4The group is selected from fluoroalkyl or halo, and other groups are as shown in the general formula (I) above, or as shown in the first to 27 embodiments.

[0042] A 30th embodiment of the present invention, each R 4b The group is independently selected from methyl and methoxy, and the other group is as shown in the general formula (I) above, or as shown in the first to 27 embodiments.

[0043] In one embodiment of the present invention, this disclosure relates to 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 It is an alkyl)aminocarbonyl-, where W is 0 or R is 1. 5 Substituting with a substituent; Each R 5 It 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 five-membered heteroaryl having at least one nitrogen atom (wherein this is selected from triazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrrolyl, tetrazolyl, flazanyl, 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 comprising a ring containing at least one aromatic heteroatom (wherein this 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, indolidinyl, isoindolyl, prinyl, quinolidinyl, isoquinolyl, quinolyl, phthalazinyl, naphthylidinyl, quinoxalinyl, cinnolinyl, carbazolyl, phenatolidinyl, acridinyl, phenanthrolinyl, phenadinyl, 7H-pyrazino[2,3-c]carbazolyl, selected from 1,3-benzoxazolyl and 2,1-benzoxazolyl), or, (c) Ketone-containing ring systems selected from 2,4-dihydro-3H-1,2,4-triazoli-3-onyl, imidazolidinonyl, 1,3-dihydro-2H-benzo[d]imidazole-2-onyl, 1,3-dihydroimidazo[4,5-c]pyridinonyl, isoindolinonyl, 4,5-dihydropyrrolo[3,4-b]pyrrole-6(2H)onyl and benzo[d]oxazole-2-onyl, and 1,4,5,6-tetrahydrocyclopenta[c]pyrazolonyl; Selected from, here, R 4 R is 0, 1, 2, or 3 4a Substituting with a substituent; Each R 4a R 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, where R 4a R is 0, 1, 2, or 3 4b Substituting with substituents; and, Each R 4b[These are independently selected from methyl and methoxy.] The target is the compound represented by or its pharmaceutically acceptable salt.

[0044] One embodiment of the present invention is given by equation (Ia) [ka] [During the ceremony, W is -C 1-6 Alkyl-,-(C 1-6 Alkyl)amino- or -(C 1-6 It is an alkyl)aminocarbonyl-, where W is 0, 1 or 2 R. 5 Substituting with a substituent; Each R 5 It is independently, Halo, C 1-4 Alkyl or C 1-4 It is a fluoroalkyl group; R 1 Hello, C 1-6 Alkyl, (C 3-12 ) Heterocycloalkyl (C 0-4 (Alkyl) or (C 3-12 )Cycloalkyl(C 0-4 Alkyl) is; R 2 is hydrogen, halo, or C 1-10 It is alkyl; R 4 is a five-membered heteroaryl compound having at least one nitrogen atom; Here, R 4 R is 0, 1, 2, or 3 4a Substituting with a substituent; Each R 4a 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; Here, R 4a R is 0, 1, 2, or 3 4b Substituting with substituents; and, Each R 4b Independently, C 1-10 Alkyloxy, C 1-6 Alkyl, C 1-10 [Fluoroalkyl, amino, hydroxy, halo, or cyano] The target is the compound represented by or its pharmaceutically acceptable salt.

[0045] Another embodiment of the present invention is formula (Ia) [ka] [During the ceremony, R 1 is F, methyl, or cyclopropyl; R 2 is hydrogen, fluoro, or chloro; R 4 R is selected from a 5-membered heteroaryl having at least one nitrogen atom, where R4 The following are selected from 1,2,4-triazolyl, 1,2,3-triazolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrrolyl, tetrazolyl, flazanyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, and 1,2,3,5-oxatriazolyl; Furthermore, here, R 4 R is 0, 1, 2, or 3 4a Substituting with a substituent; Each R 4a 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: Here, R4a R is 0, 1, 2, or 3 4b Substituting with substituents; and, Each R 4b Independently, C 1-10 Alkyloxy, C 1-6 Alkyl, C 1-10 [Fluoroalkyl, amino, hydroxy, halo, or cyano] The target is the compound represented by or its pharmaceutically acceptable salt.

[0046] Non-limiting examples of compounds represented by formula (I) include compounds 1 to 129 described in the examples, or their pharmaceutically acceptable salts: (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methoxy-1H-1,2,4-triazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(hydroxymethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-methoxy-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(hydroxymethyl)-1H-1,2,4-triazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((5-(hydroxymethyl)-1H-pyrazole-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((3-(hydroxymethyl)-1H-pyrazole-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-7-((2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-3-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1-methylimidazolidin-2,4-dione; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-(pyridine-4-yl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-methyl-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-3-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)benzo[d]oxazole-2(3H)-one; (S)-3-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)imidazolidin-2,4-dione; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-fluoro-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((4-chloro-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-pyrazole-3-carbonitrile; (S)-7-((5-chloro-3-(methoxymethyl)-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((3-bromo-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((1H-1,2,4-triazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((2H-pyrazolo[4,3-c]pyridine-2-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-7-((6,7-dihydropyrano[4,3-c]pyrazole-1(4H)-yl)methyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-7-((6,7-dihydropyrano[4,3-c]pyrazole-2(4H)-yl)methyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-7-((1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((3-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((5-oxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((3-chloro-5-oxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((3-chloro-5-oxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((3-cyclopropyl-5-oxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((6-oxo-5,6-dihydropyrrolo[3,4-b]pyrrole-1(4H)-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridine-3-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-3-((4-(cyclopropylethynyl)-6-fluoro-3-methyl-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)imidazolidin-2,4-dione; (S)-7-((3-amino-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((3-amino-5-methyl-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((3-amino-4-methyl-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((3-amino-1H-pyrazole-1-yl)methyl)-4-(cyclopropyldifluoromethyl)-4-(cyclopropylethynyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(2-hydroxyethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-6-chloro-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(hydroxymethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((2-(hydroxymethyl)-1H-imidazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((5-(hydroxymethyl)-1H-imidazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-(hydroxymethyl)-1H-imidazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-7-(1H,1'H-[3,3'-bipyrazole]-1-ylmethyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((1'-methyl-1H,1'H-[3,3'-bipyrazole]-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methoxymethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((1H-imidazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methoxy-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-((R or S)-1-methoxyethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-((S or R)-1-methoxyethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((3-amino-5-chloro-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-oxo-3,4,5,6-tetrahydrocyclopenta[c]pyrazole-1(2H)-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-1-((4-(cyclopropyldifluoromethyl)-4-(cyclopropylethynyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-imidazole-2-carboxamide; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(difluoromethoxy)-1H-pyrazole-1-yl)methyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-(methoxymethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methoxymethyl)-1H-1,2,4-triazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((4-chloro-3-(methoxymethyl)-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-fluoro-3-(hydroxymethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(hydroxymethyl)-4-methyl-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((5-chloro-3-(hydroxymethyl)-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-(2-hydroxyethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((4-chloro-3-(hydroxymethyl)-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-((S or R)-1-hydroxyethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-((R or S)-1-hydroxyethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((2-methoxy-1H-imidazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methylamino)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(dimethylamino)-1H-pyrazole-1-yl)methyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-Chloro-N-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-imidazole-5-carboxamide; (S)-4-chloro-N-((4-(cyclopropylethinyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-imidazole-5-carboxamide; (S)-N-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-imidazole-2-carboxamide; (S)-N-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-imidazole-2-carboxamide; (S)-N-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-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-tetrahydroquinazoline-7-yl)methyl)-1-methyl-1H-imidazole-2-carboxamide; (S)-N-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)oxazole-2-carboxamide; (S)-2-amino-N-((4-(cyclopropylethinyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-4-methylthiazole-5-carboxamide; (S)-N-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-4H-1,2,4-triazole-3-carboxamide; (S)-N-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-3-methyl-1H-pyrrole-2-carboxamide; (S)-N-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-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-tetrahydroquinazoline-7-yl)methyl)-1H-pyrrole-2-carboxamide; (S)-N-((4-(cyclopropylethinyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)thiazole-2-carboxamide; (S)-7-((2H-indazole-2-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((1H-indazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((1H-benzo[d][1,2,3]triazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methyl-1H-indazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((1H-benzo[d]imidazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((4-chloro-3-methoxy-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((1-oxoisoindolin-2-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(4-methoxyphenyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((3-amino-4-methoxy-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-1-((4-(cyclopropylethinyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-imidazole-2-carboxamide; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((3-methyl-1H-pyrazole-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-pyrazole-3-carbaldehyde; (S)-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-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-tetrahydroquinazoline-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-dihydroquinazoline-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-dihydroquinazoline-2(1H)-one; (S)-7-((3-amino-1H-1,2,4-triazol-1-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methyl)-6-fluoro-3,4-dihydroquinazoline-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-dihydroquinazoline-2(1H)-one; (S)-3-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1-methylimidazolidin-2,4-dione; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((methyl(1H-pyrazole-3-yl)amino)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methoxymethyl)-1H-pyrazole-1-yl)methyl)-3-methyl-3,4-dihydroquinazoline-2(1H)-one; (S)-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-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-tetrahydroquinazoline-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-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-1-((4-(cyclopropylethinyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-1,2,4-triazole-5-carboxamide; (S)-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-1,2,4-triazole-3-carboxamide; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((5-methyl-2H-tetrazole-2-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((2H-indazole-3-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazoline-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-pyrazole-1-yl)methyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-6-chloro-4-(cyclopropylethynyl)-7-((4-methoxy-1H-pyrazole-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; 5-(((S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1-methylimidazolidin-2,4-dione; (S)-5-(((S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1-methylimidazolidin-2,4-dione; (R)-5-(((S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1-methylimidazolidin-2,4-dione; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-((dimethylamino)methyl)-1H-pyrazole-1-yl)methyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-7-((3-methyl-1H-pyrazole-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3,4-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl)methyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; and, (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(2-hydroxypropan-2-yl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one.

[0047] One embodiment of the present invention is a selected compound represented by formula (I) encompassed below, or a pharmaceutically acceptable salt thereof: (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methoxy-1H-1,2,4-triazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-7-((1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((3-amino-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methoxymethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-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-dihydroquinazoline-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-dihydroquinazoline-2(1H)-one; (S)-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-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-tetrahydroquinazoline-7-yl)methyl)-1H-1,2,4-triazole-5-carboxamide; (S)-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-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-tetrahydroquinazoline-7-yl)methyl)-1H-1,2,4-triazole-3-carboxamide.

[0048] In one variant 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-triazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one.

[0049] In another variant, 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-triazole-4-yl)methyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one.

[0050] In another variant, the compound or its pharmaceutically acceptable salt is (S)-7-((3-amino-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one.

[0051] In yet another variant, the compound or its pharmaceutically acceptable salt is (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methoxymethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one.

[0052] In another variant, the compound or its pharmaceutically acceptable salt is (S)-7-((5-amino-1H-1,2,4-triazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one.

[0053] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is (S)-7-((3-amino-1H-1,2,4-triazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one.

[0054] In another variant, the compound or its pharmaceutically acceptable salt is (S)-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-1,2,4-triazole-3-carboxamide.

[0055] In another variant, the compound or its pharmaceutically acceptable salt is (S)-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-1,2,4-triazole-5-carboxamide.

[0056] In another variant, the compound or its pharmaceutically acceptable salt is (S)-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-1,2,4-triazole-5-carboxamide.

[0057] In another variant, the compound or a pharmaceutically acceptable salt thereof is (S)-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-1,2,4-triazole-3-carboxamide.

[0058] The present invention covers the compounds represented by formula I as described herein, as well as all embodiments, examples, classes, and subclasses thereof, and includes the compounds of the examples described herein. The present invention further covers the compounds represented by formula I, which are neutral compounds or, if salts are possible, salts thereof (including pharmaceutically acceptable salts).

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

[0060] Where used herein, “alkyl” refers to both branched and linear saturated aliphatic hydrocarbon groups having a specified number of carbon atoms within a specified range. For example, “C 1-8 "Alkyl" refers to each alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, and includes its linear or branched isomers. 1-8 "Alkyl" is "C 1-6 This includes alkyl groups, as well as linear and branched alkyl groups having 7 or 8 carbon atoms in the chain.

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

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

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

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

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

[0066] "Celite (registered trademark)" (Fluka) diatomite is diatomaceous earth and can also be referred to as "Celite".

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

[0068] "Carboxylate" refers to the -CO2H group. Bonding to the parent group is done via the carbon atom of the carbonyl component.

[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 otherwise expressly stated herein, the cycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and it may encompass fused or bridging ring systems, where the "cycloalkyl" bond to the remainder of the molecule lies on a saturated ring. Bicyclic cycloalkyl ring systems include fused ring systems where two rings share two atoms (e.g., decalin), spiro-ring systems where two rings share one atom (e.g., spiro[4,5]decanyl), and bridging groups (e.g., norbornyl).

[0070] Additional examples within the scope of the above meaning include, but are not limited to, 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 monovalent radicals.

[0071] The term “C 3-8 The term "cycloalkyl" (or "C3-C8 cycloalkyl" or "C3-8 cycloalkyl") refers to a cyclic structure of alkanes having a total of 3 to 8 carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl). 3-7 Cycloalkyl, C 3-6 Cycloalkyl, C 5-7 "Cycloalkyl," for example, has a similar meaning.

[0072] "Fluoroalkyl" refers to the alkyl group in which one or more hydrogen atoms (especially 1 to 10 hydrogen atoms) are replaced by fluorine atoms, and includes the case where all hydrogen atoms are completely replaced by a halo group. 1-6 Examples of haloalkyl groups include -CH2F, -CHF2, -CF3, -CF4, -CF2CF3, and -CHFCH3.

[0073] "Halo" or "halogen" refers to chloro, fluoro, bromo, and / or iodine. Chloro, fluoro, and bromo are important classes of halogens, and in particular, fluoro and chloro are 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 rings containing the heteroatom 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, the following: azaindolyl, benzimidazolyl, benzoisoxazolyl, benzofuranil, benzofuranil, benzopyrazolyl, benzotriazolyl, benzothiazolyl, benzo[d]isothiazolyl, benzoxazolyl, carbazolyl, cinnolinyl, furanil, imidazolyl, indolinyl, indolyl, indazinyl, indazolyl, isobenzofuranil, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphtopyridinyl, oxadiazolyl, oxazolyl, oxazolinyl, isoxazolinyl, pyranyl, pyrazinyl, pyrazolyl, pyrrolyl, pyrazolopyrimidinyl, pyridadinyl, pyridyl, pyrimidyl, pyrimidinyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyrimidinyl Dil, 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]pyrimidinyl, benzo[d][1,2,3]-triazolyl, benzo[d]imidazolyl, indolidinyl, purinyl, quinolidinyl, phthalazinyl, naphthylidinyl, carbazolyl, phenatridinyl, acridinyl, phenanthrolinyl, phenadinyl, 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 included in this definition.

[0076] As used herein, the term "heterocycloalkyl" refers to a stable, non-aromatic (including those that are not fully aromatic, e.g., those with one double bond) 3-12 membered ring (i.e., C) containing 2-12 ring carbon atoms and 1-6 ring heteroatoms selected from nitrogen, oxygen, and sulfur. 3-12This refers to a heterocycloalkyl radical. Wherever it is described herein, a numerical range (e.g., "3 to 12" or "3-12") refers to each integer within that range. For example, "3 to 12 ring atoms" means that the heterocycloalkyl group consists of 3 ring atoms, 4 ring atoms, 5 ring atoms, and so on, up to a maximum of 12 ring atoms (including 12 ring atoms). In some embodiments, it is a 5 to 10 ring heterocycloalkyl group. In some embodiments, it is a 4 to 10 ring heterocycloalkyl group. In some embodiments, it is a 3 to 10 ring heterocycloalkyl group. In some embodiments, it is a 3 to 7 ring heterocycloalkyl group. Unless otherwise expressly indicated herein, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridging ring systems. The prefixes "aza," "oxa," or "thia" preceding the heterocycloalkyl root name indicate the presence of at least one nitrogen, oxygen, or sulfur atom as a ring atom, respectively. The heterocycloalkyl radical is partially or completely saturated. The heterocycloalkyl can be bonded to the remainder of the molecule via any atom of its ring.

[0077] In one embodiment, the heterocycloalkyl group is monocyclic and has about 3 to about 7 ring atoms. In another embodiment, the heterocycloalkyl group is monocyclic and has about 5 to about 8 ring atoms. In yet another embodiment, the heterocycloalkyl group is bicyclic and has about 8 to about 11 ring atoms. In yet another embodiment, the heterocycloalkyl group is monocyclic and has 5 or 6 ring atoms. In one embodiment, the heterocycloalkyl group is monocyclic. In another embodiment, the heterocycloalkyl group is bicyclic. In yet another embodiment, the heterocycloalkyl group is tricyclic. There are no adjacent oxygen and / or sulfur atoms in 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, tetrahydrofuranil, 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-hexahydroisothia Zoro[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]pyridine-5(4H)-yl, diazaspiro[4.4]nonanyl, and 2,7-diazaspiro[4.4]nonanyl, and all their isomers. In one embodiment of the present invention, the heterocycloalkyl ring includes: piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azelidinyl, and azetidinyl.

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

[0080] "HIV naive cells" are cells that are not infected with HIV.

[0081] "Compatible anti-HIV agents" are anti-HIV drugs 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 infected with HIV (e.g., HIV-1) (especially human cells).

[0083] A “stable” compound is one that can be prepared and isolated and whose structure and properties remain essentially unchanged or can be kept essentially unchanged for a period of time sufficient to enable its use for purposes described herein (e.g., therapeutic or prophylactic administration to a subject). The compounds of this disclosure are limited to stable compounds encompassed in Formula I and its embodiments. For example, certain parts defined in Formula I may or may not be substituted, where the latter is intended to encompass substitution patterns (i.e., the number and type of substituents) that are chemically possible with respect to that part and result in a stable compound.

[0084] This disclosure includes individual diastereomers, in particular epimers, i.e., compounds represented by the same chemical formula but with different spatial configurations around a single atom. This disclosure further includes mixtures of diastereomers in all proportions, in particular mixtures of epimers. This disclosure includes compounds represented by formula I having either the (R) configuration or the (S) configuration at one chiral center and at any additional chiral centers that may be present in the compound represented by formula I, as well as mixtures of their stereoisomers. Embodiments of this disclosure further include mixtures of enantiomers concentrated with 51% or more of one type of enantiomer (e.g., including 60% or more, 70% or more, 80% or more or 90% or more of one type of enantiomer). A single epimer is 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 type of enantiomer or may contain small amounts (e.g., less than 10%) of the opposite enantiomer. Thus, individual enantiomers in pure form (as both levorotatory and dextrorotatory enantiomers), individual enantiomers in racemic compound form, and individual enantiomers in the form of mixtures of two enantiomers in all proportions are the subject of the present invention. In the case of cis / trans isomerism, this disclosure includes both cis and trans forms, as well as mixtures of these forms in all proportions.

[0085] The preparation of individual stereoisomers may be carried out, as necessary, by separating the mixture by conventional methods (e.g., chromatography or crystallization), by using stereochemically homogeneous starting materials in synthesis, or by stereoselective synthesis. Derivatization may be carried out prior to the separation of stereoisomers. Separation of a mixture of stereoisomers may be carried out at the intermediate stage during the synthesis of the compound represented by formula I, or on the final racemic product. Absolute stereochemistry can be confirmed by subjecting the crystalline product or crystalline intermediate (which, if necessary, are derivatized using reagents containing stereocenters of known configuration) to X-ray crystallography. Alternatively, absolute stereochemistry may be confirmed by vibrational circular dichroism (VCD) spectroscopy. This disclosure encompasses all such isomers, as well as salts, solvates (including hydrates), and solvated salts of such racemic compounds, enantiomers, diastereomers, and tautomers, and mixtures thereof.

[0086] As those skilled in the art will understand, certain compounds of this disclosure may exist as tautomers. All tautomer forms of such compounds, whether isolated individually or in mixtures, are within the scope of this 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 partially in -OH and oxo forms. Examples of tautomers of compounds herein, but not limited to, include: [ka]

[0087] The atoms within the compounds represented by Formula I may exhibit their natural isotopic abundances, or one or more atoms may be artificially enriched in specific isotopes having the same number of atoms but different atomic masses or mass numbers than those predominantly found in nature. This disclosure is intended to encompass all suitable isotopic variations of the compounds represented by General Formula I. For example, various isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H), among others. Protium is the main isotope of hydrogen found in nature. Enriching deuterium may result in certain therapeutic advantages, such as an increase in the in vivo half-life or a reduction in the required dosage, or may provide a compound useful as a standard for the characterization of biological samples. Isotope-enriched compounds represented by 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 suitable isotope-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 salts that have the effectiveness of the parent compound and are not biologically or otherwise undesirable (e.g., not toxic to its recipient and not otherwise harmful). When the compound represented by Formula I contains one or more acidic or basic groups, the present invention encompasses its corresponding pharmaceutically acceptable salts.

[0089] Thus, compounds represented by formula I, which include an acidic group (e.g., -COOH), can be used in accordance with the present invention, for example, but not limited to, alkali metal salts, alkaline earth metal salts, or ammonium salts. Examples of such salts, but not limited to, include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines (e.g., ethylamine, ethanolamine, triethanolamine, or amino acids). Compounds represented by formula I, which contain one or more basic groups (i.e., protonable groups), can be used in accordance with the present invention in the form of acid addition salts thereof with inorganic or organic acids, for example, but not limited to, 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. If a compound represented by formula I contains both an acidic group and a basic group in its molecule, the present invention also includes intramolecular salts or betaines (amphoteric ions) in addition to the above salt forms. Salts can be obtained from the compound represented by formula I by conventional methods known to those skilled in the art, for example, by combining it with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange from another salt. The present invention also encompasses all salts of the compound represented by formula I that are not directly suitable for pharmaceutical use due to their poor physiological compatibility, but can be used, for example, as intermediates for chemical reactions or as intermediates for preparing pharmaceutically acceptable salts.

[0090] The present disclosure encompasses any composition comprising a compound represented by Formula I or a salt thereof, including compositions composed of the compound associated with one or more additional molecular components and / or ionic components that may be referred to, for example but not limited 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 components and / or ionic components 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)) (generally in stoichiometric ratios). There is no proton transfer between the heterogenous components, and the solid phase is neither a simple salt nor a solvate. Considerations regarding co-crystals can be found, for example, in "S. Aitipamula et al., Crystal Growth and Design, 2012, 12(5), pp.2147-2152".

[0091] Furthermore, the compounds of the present disclosure can exist in amorphous form and / or one or more crystalline forms, and thus 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 with common organic solvents. Such solvates and hydrates (especially pharmaceutically acceptable solvates and hydrates) of the compounds of the present disclosure are likewise included within the scope of the compounds defined by Formula I and their pharmaceutically acceptable salts, together with the non-solvated and anhydrous forms of such compounds.

[0092] Accordingly, the present invention covers compounds represented by formula I or salts thereof (this includes pharmaceutically acceptable salts thereof), embodiments thereof, and specific compounds described and claimed herein, and encompasses all possible stereoisomers, tautomers, physical forms (e.g., amorphous and crystalline forms), cocrystalline forms, solvates and hydrates, and any combination thereof, where such forms are possible.

[0093] Another embodiment of the present disclosure is a composition comprising a compound represented by formula I, wherein the compound or a salt thereof is present in the composition in a substantially pure form. Where used herein, “substantially pure” means that the composition or product comprising the compound or a salt thereof (e.g., a product isolated from a reaction mixture yielding the compound or salt) is composed of the compound or salt, preferably 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). The level of purity of the compound and salt can be measured using standard analytical methods such as high-performance liquid chromatography and / or mass spectrometry or NMR techniques. If two or more analytical methods are used and they yield experimentally significant differences in the measured level of purity, the method that yields the highest level of purity should be preferred. A composition containing a compound or salt of 100% purity is a composition that does not contain any impurities detectable by standard analytical methods. With respect to the compounds of the present invention that have one or more chiral centers and can exist as a mixture of stereoisomers, a composition containing a substantially pure compound may be a substantially pure mixture of stereoisomers or substantially pure individual stereoisomers.

[0094] The compound represented by Formula I as described herein and its 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 herein as TAK (Targeted Activator of Cell Kill) activity, and more specifically, as HIV TACK activity. HIV TACK or TACK was previously also referred to as Small Molecule Activated Cell Kill (SMACK). Thus, the compound represented by Formula I and its pharmaceutically acceptable salts are useful for the following: (i) A method for treating or preventing HIV infection, or for treating, preventing or delaying the onset or progression of AIDS or ARC, in a human subject who needs to be treated or prevented from being infected with HIV, or who needs to be treated, prevented or delayed from being treated or the progression of AIDS or ARC, comprising administering to the human subject an effective amount of a compound represented by 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 requiring induction of GAG-POL dimerization in HIV-infected cells, comprising administering to the human subject an effective amount of a compound represented by 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 causing cytotoxicity to HIV-naive cells, comprising administering to the human subject an effective amount of a compound represented by formula I or a pharmaceutically acceptable salt thereof; and / or (iv) A method for enhancing the suppression of HIV viremia in a human subject whose HIV viremia is suppressed by the administration of one or more compatible HIV antiviral drugs, comprising further administering to the human subject an effective amount of a compound represented by formula I or a pharmaceutically acceptable salt thereof.

[0095] Furthermore, the compound represented by formula I and its pharmaceutically acceptable salts are useful in any of the above methods (i), (ii), (iii), or (iv), and further comprise administering to a 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-adhesion inhibitors, and latency reversal agents. In the above methods (i), (ii), (iii), or (iv), the human subject may be treated with the compound represented by formula I or its pharmaceutically acceptable salts in addition to treatment with one or more compatible HIV antiviral agents.

[0096] The compound represented by formula I and its pharmaceutically acceptable salts are also useful for a method of enhancing the suppression of HIV viremia in human subjects whose HIV viremia is suppressed by the administration of one or more compatible HIV antiviral drugs, wherein the method comprises further administering to the human subject an effective amount of the compound represented by formula I or its pharmaceutically acceptable salt.

[0097] Other embodiments of this disclosure include: (a) A pharmaceutical composition comprising an effective amount of a compound represented by formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; (b) A pharmaceutical composition comprising a product prepared by combining (e.g., mixing) an effective amount of a compound represented by formula I or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier; (c) The pharmaceutical composition of (a) or (b), further comprising an effective amount of one or more suitable anti-HIV drugs selected from the group consisting of HIV antiviral drugs, immunomodulators, anti-infective drugs and latency reversal drugs; (d) The pharmaceutical composition of (c), wherein the suitable anti-HIV agent is selected from one or more antiviral agents 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-adhesion inhibitors, and latent reversal agents; (e) a combination of (i) a compound represented by formula I or a pharmaceutically acceptable salt thereof, and (ii) one or more compatible anti-HIV drugs selected from the group consisting of HIV antiviral drugs, immunomodulatory drugs, anti-infective drugs and latency reversal drugs; wherein the compound and the compatible anti-HIV drug are used in amounts that make the combination effective for the treatment or prevention of HIV infection, or for the treatment, prevention or delay of the onset or progression of AIDS or ARC; (f) The combination of (e) wherein the suitable 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-adhesion inhibitors, and latent 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 HIV infection or for treating, preventing or delaying the onset or progression of AIDS or ARC, comprising administering an effective amount of a compound represented by formula I or a pharmaceutically acceptable salt thereof to a subject in need of such treatment; (h) The method of (g), wherein a compound represented by formula I or a pharmaceutically acceptable salt thereof is administered in combination with at least one other suitable HIV antiviral agent 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-adhesion inhibitors, and latency reversal agents in an effective amount; (i) The method of (g) or (h), comprising administering to the subject a pharmaceutical composition of (a), (b), (c), or (d) or a combination of (e) or (f); (j) Use in the manufacture of pharmaceuticals a compound represented by formula I or a pharmaceutically acceptable salt thereof for (1) to induce GAG-POL dimerization in HIV-infected cells in subjects, (2) to selectively kill HIV-infected GAG-POL-expressing cells without cytotoxicity to HIV-naive cells in subjects, (3) to treat or prevent HIV infection in subjects, (4) to treat, prevent or delay the onset or progression of AIDS or ARC in subjects, (5) to enhance the suppression of HIV viremia in subjects receiving treatment with a compatible anti-HIV drug, and / or (6) to enhance the suppression of HIV viremia in subjects whose HIV viremia has been suppressed by administration of one or more compatible antiviral drugs; (k) A compound represented by 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 HIV infection, (4) treating, preventing or delaying the onset or progression of AIDS or ARC, (5) enhancing the suppression of HIV viremia in subjects receiving treatment with a suitable anti-HIV drug, and / or (6) enhancing the suppression of HIV viremia in subjects whose HIV viremia is suppressed by administration of one or more suitable antiviral drugs.

[0098] Further embodiments of the present invention encompass each of the pharmaceutical compositions, methods, and uses described in the preceding paragraphs, wherein the compound represented by formula I or a salt thereof used therein is substantially pure. With respect to pharmaceutical compositions comprising the compound represented by 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 represented by formula I or a salt thereof itself.

[0099] Another embodiment of the present disclosure is the pharmaceutical compositions, methods, pharmaceuticals, uses and combinations described herein, where the important HIV is HIV-1. Thus, in any of the pharmaceutical compositions, methods, pharmaceuticals, uses and combinations using, for example, a compound represented by 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 agents, such additional agents are compatible antiviral agents selected from, for example, but not limited to, one or more 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-adhesion inhibitors and latency reversal agents.

[0100] With respect to the compound represented by Formula I, the term “administer” and its variation (e.g., “administering” the 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 the compound is provided in combination with one or more other active agents (e.g., antiviral agents useful for the treatment or prevention of HIV infection or AIDS), “administer” and its variation are understood to include providing the compound and the other agents simultaneously or at different times. When a combination of agents is administered simultaneously, they may be included in a single composition and administered together, or they may be administered separately.

[0101] Where used herein, the term “composition” is intended to encompass products containing the specified components, and any products obtained by combining the specified components. Components suitable for inclusion in a pharmaceutical composition are “pharmaceutically acceptable” components, meaning that the components must be compatible with one another and must not be harmful to the recipient.

[0102] As used herein, the terms "subject" or "patient" refer to a human (or "person") who has been the subject of treatment, observation, or experimentation. Examples of patients treated with HIV TACK include, but are not limited to, patients infected with HIV, and / or patients with HIV infection whose HIV viral load is suppressed and / or is considered undetectable at the time of HIV TACK treatment. Patients treated with HIV TACK also include, but are not limited to, patients using HIV TACK 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 represented by formula I or a pharmaceutically acceptable salt thereof to prevent HIV infection in a person who is not infected with HIV] and post-exposure prophylaxis (PEP) [i.e., the use of a compound represented by formula I or a pharmaceutically acceptable salt thereof after potential exposure to HIV to prevent infection with HIV].

[0104] As used herein, the term “effective dose” means an amount of the 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 the compound sufficient to exert a therapeutic effect, and / or an amount sufficient to exert a prophylactic effect after administration. One embodiment of “effective dose” is a “therapeutic effective dose,” which is an amount of the compound effective in selectively killing HIV-infected GAG-POL-expressing cells, effective in treating HIV infection, or effective in treating, preventing, or delaying the onset or progression of AIDS or ARC in HIV-infected patients. Another embodiment of “effective dose” is a “preventive effective dose,” which is an amount of the compound effective in preventing HIV infection, or effective in preventing AIDS or ARC in HIV-infected patients. It is understood that an effective dose can simultaneously be both a therapeutic effective dose (e.g., a therapeutic effective dose for treating HIV infection) and a prophylactic effective dose (e.g., a prophylactic effective dose for preventing or reducing the risk of developing AIDS or ARC in an HIV-infected person).

[0105] In the combination therapy of the present invention, the effective dose may be for each individual drug or for the combination as a whole. Here, the total amount of all drugs administered in the combination is effective, but the individual components of the drug in the combination may be present in an effective dose or not present in an effective dose, insofar as they are considered effective when administered individually.

[0106] In the methods of the present invention (i.e., selectively killing GAG-POL-expressing cells infected with HIV, treating HIV infection, 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 present invention or salts thereof can be administered by means that bring the active agent into contact with the site of action of the agent. They can be administered by conventional means available for use in combination with pharmaceuticals, either as individual therapeutic agents or in combinations of therapeutic agents. The compounds can be administered by themselves, but are typically administered together with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. The compounds of the present invention can be administered, for example, orally (e.g., by tablets or capsules), parenterally (which includes subcutaneous injection, intravenous, intramuscular or intracardiac injection or infusion techniques), by inhalation spray, or rectally, in unit dosage form of a pharmaceutical composition containing an effective amount of the compound and a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and vehicle. The compounds can also be administered via an implantable drug delivery device adapted to provide an effective amount of the compound or pharmaceutical composition of the compound over a long 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, and disintegrants 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 common media such as water, glycol, oil, and alcohol can be used. Parenteral compositions can be prepared according to techniques known in the art, and typically use sterile water as a carrier, and optionally other components such as solubilizers. Injectable solutions can be prepared according to methods known in the art, wherein the carrier comprises a solution containing physiological saline, a glucose solution, or a mixture of physiological saline and glucose. Implantable compositions can be prepared according to methods known in the art, wherein the carrier contains the activating chemical component together with a polymer and appropriate excipients, or utilize an implantable device for drug delivery. Further descriptions of suitable methods for preparing pharmaceutical compositions for use in the present invention and suitable components for use in such compositions are 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] The absorption of oral drugs can be enhanced by utilizing formulations of compounds represented by formula I that result in drug supersaturation and / or rapid dissolution. Formulation approaches for inducing 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 preparing them are known in the art. For example, solid dispersions can be prepared using excipients and processes as described in the overview (e.g., "ATM Serajuddin, J Pharm Sci, 88:10, pp. 1058-1066 (1999)"). Nanoparticle systems based on both grinding and direct synthesis are also described in overviews such as "Wu et al (F. Kesisoglou, S. Panmai, Y. Wu, Advanced Drug Delivery Reviews, 59:7 pp. 631-644 (2007))".

[0109] The compound represented by formula I can be administered, for example, in a single dose or divided doses, in a dosage range of 1 to 20 mg, 1 to 10 mg, or about 5 mg per kg of body weight in a mammal (e.g., human) per day, or at appropriate intervals. The compound represented by formula I can be administered in a single dose or divided doses, in a dosage range of 0.001 to 2000 mg per day. Examples of dosage ranges include 0.01 to 1500 mg per day, or 0.1 to 1000 mg per day, which can be administered orally or via another route of administration in a single dose or divided doses.

[0110] For oral administration routes (e.g., tablets or capsules) or other routes of administration, the dosage unit may contain 100 to 1500 mg of the active ingredient, and may contain, but is 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 the active ingredient, for example, to adjust the dosage for patients being treated according to their symptoms. Furthermore, the compound may be formulated into oral formulations for immediate release or modified release (e.g., sustained release or controlled release). When the compound represented by 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 may be via any suitable route of administration, but is preferably by oral administration and may be a single dose or multiple doses spaced out within each 24-hour period (divided daily dose). Each dose may be administered using one or more dosing units as needed.

[0112] Specific dose levels and administration frequencies for any particular patient can vary and depend on various factors (e.g., the activity of the particular compound used, its metabolic stability and duration of action, age, weight, general health, sex, diet, method and timing of administration, elimination rate, drug combinations, 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 potency of the compound or the individual response. Dosage and administration frequencies are adjusted at the discretion of the attending clinician, taking such factors into consideration.

[0113] "Anti-HIV drugs" are any agents that are 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. Anti-HIV drugs are understood to be effective in treating, preventing, or delaying the onset or progression of HIV infection or AIDS and / or diseases or conditions resulting from or associated therewith. This disclosure further covers the use of a compound represented by formula I or a pharmaceutically acceptable salt thereof in combination with one or more compatible anti-HIV drugs (i.e., anti-HIV drugs other than HIV protease inhibitors) (also referred to as "compatible HIV antiviral drugs"). For example, a compound represented by formula I may be administered in combination with one or more compatible anti-HIV drugs selected from HIV antiviral drugs, immunomodulators, anti-infective drugs, or vaccines useful for treating HIV infection or AIDS in an effective amount. Suitable compatible HIV antiviral drugs for use in combination with the compounds of this disclosure include, but are not limited to, those listed in Table A below: [Table 1] TIFF2026516541000009.tif185156

[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 activators (e.g., latent reversal agents ("LRAs" or "LRAs")) that promote Gag-Pol production in infected cells and / or activate intracellular viral expression constituting the latent HIV storage may enhance the TACK effect. This disclosure also covers the combination of one or more LRAs of the compound represented by Formula I or its pharmaceutically acceptable salts. For example, the compound represented by Formula I may be administered in combination with one or more LRAs in an effective dose to treat HIV infection or AIDS.Examples of LRAs used in combination with the compounds of this disclosure include, but are not limited to, the following: epigenetic modifiers, e.g., histone deacetylase (HDAC) inhibitors, DNA methyltransferase (DNMT) inhibitors, and histone methyltransferase (HMT) inhibitors; protein kinase C (PKC) agonists, e.g., prostratin, briostatin, or ingenol; P-TEFb release inducers, e.g., BET inhibitors (e.g., JQ1, or bromodomain and extra-terminal motifs); (Drugs of the class that reversibly bind to the bromodomain of the BRD2, BRD3, BRD4 and / or BRDT motif)(BET), CC chemokine receptor 5 (CCR5) antagonists, non-canonical NF-κB pathway inducers (e.g., mitochondrial caspase activator (SMAC) mimetic or apoptosis protein inhibitor (IAP) antagonists, proteasome inhibitors, Toll-like receptor (TLR) agonists, mitogen-activated protein kinase (MAPK) agonists, AK strain mutant / protein kinase B (AKT / PKB) pathway activators, cytokines and immunomodulators (e.g., immune checkpoint inhibitors), and other 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). As described in 12:11 (2020).

[0115] Examples of HDAC inhibitors that can be used as latent reversal agents include, but are not limited to, vorinostat, panabinostat, romidepsin, and valproic acid. Examples of DNMT inhibitors that can be used as latent reversal agents include, but are not limited to, 5-aza-2'-cytidine and 5-aza-2'-deoxycytidine. Examples of HMT inhibitors that can be used as latent reversal agents include, but are not limited to, chaetosin, 3-deazanepranosin 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 latent reversal agents include, but are not limited to, forbor esters, such as prostratin and forbormyrislate acetate (PMA), briostatin-1 and ingenol. Examples of BET inhibitors that can be used as latent reversal agents 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]diazepine-6-yl)acetate), iBET and N-cyclohexyl-2-(4-(3,5-dimethylisoxazole-4-yl)-2-methoxyphenyl)imidazo[1,2-a]pyrazine-3-amine (UMB-136). Examples of CCR5 antagonists that can be used as latent reversal agents include, but are not limited to, maraviroc and bicriviroc.Examples of non-canonical NF-κB pathway inducers and SMAC mimetic / IAP inhibitors that can be used as latent reversal agents include, but are not limited to, 3,3'-[2,4-hexadiin-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, virinapant, LCL161, and DEBIO1143 / AT-406. Examples of proteasome inhibitors that can be used as latent reversal agents include, but are not limited to, bortezomib and ixazomib. Examples of TLR agonists that can be used as latent reversal agents include, but are not limited to, the TLR2 agonist Pam3CSK4, the TLR7 agonist besatrimod, and the TLR9 agonists refitrimod (MGN1703) and CPG7909.

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

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

[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-dihydropyridazine-3-yl)methyl)-4-(trifluoromethyl)-1,6-dihydropyrimidine-5-yl)oxy)benzonitrile (uronibilin); 3-Chloro-5-((6-oxo-1-((3-oxo-2,3-dihydropyridazine-4-yl)methyl)-4-(trifluoromethyl)-1,6-dihydropyrimidine-5-yl)oxy)benzonitrile; 3-Chloro-5-((1-((4-methyl-5-oxo-4,5-dihydropyrazine-2-yl)methyl)6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidine-5-yl)oxy)benzonitrile; and, 3-Chloro-5-((1-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyridazine-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidine-5-yl)oxy)benzonitrile.

[0119] Non-limiting examples of nucleoside reverse transcriptase inhibitors, which 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-dihydropyridazine-3-yl)methyl)-4-(trifluoromethyl)-1,6-dihydropyrimidine-5-yl)oxy)benzonitrile (UNIVIRINE); 3-Chloro-5-((6-oxo-l-((3-oxo-2,3-dihydropyridazine-4-yl)methyl)-4-(trifluoromethyl)-1,6-dihydropyrimidine-5-yl)oxy)benzonitrile; 3-Chloro-5-((1-((4-methyl-5-oxo-4,5-dihydropyrazine-2-yl)methyl)6-oxo-4-(trifluoromethyl)-l,6-dihydropyrimidine-5-yl)oxy)benzonitrile; and, 3-Chloro-5-((1-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyridazine-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidine-5-yl)oxy)benzonitrile.

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

[0121] The compounds of the present invention can be used in combination with any one or more antiviral agents (e.g., antiviral agents listed in Table A, but not limited to them) and / or any one or more LRAs (e.g., LRAs listed herein, but not limited to them).

[0122] It is understood that the range of combinations of the compounds of the present invention with compatible anti-HIV agents is not limited to the HIV antiviral agents listed in Table A, but in principle includes any combination with any pharmaceutical composition useful for the treatment or prevention of HIV, AIDS, or ARC (except for HIV protease inhibitors). The compatible HIV antiviral agents and other active agents are typically used in these combinations in their conventional dosage ranges and regimens reported in the art, for example, in the dosages described in the current "Physicians' Desk Reference, Thomson PDR, 70th edition (2016), Montvale, NJ: PDR Network" or earlier editions. The dosage ranges of the compounds of this disclosure in these combinations may be the same as the dosage ranges described above.

[0123] The compounds of the present invention are also useful in the preparation and execution of screening assays for antiviral compounds. For example, the compounds of the present invention are useful for isolating enzyme variants, 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 another antiviral drug to the reverse transcriptase region within GAG-POL, for example, by competitive inhibition. [Table 2] TIFF2026516541000012.tif42165

[0124] Compounds containing bromine are 79 Br and 81Due to the two bromine isotopes of Br, it has two masses in a ratio of approximately 1:1. [Examples]

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

[0126] Stage 1: 1-(4-bromo-2,5-difluorophenyl)-2,2-difluoropropan-1-one (A01-a) Under an N2 atmosphere, 2.5 M n-BuLi (809.16 mL, 2022.89 mmol) was added dropwise to a stirred mixture of 1,4-dibromo-2,5-difluorobenzene (500 g, 1838.99 mmol) in ether (5 L) at -78°C. The resulting mixture was stirred for a further 1.0 hour at -78°C. Subsequently, ethyl 2,2-difluoropropanoate (253.99 g, 1838.99 mmol) was added dropwise to the mixture over 40 minutes at -78°C. The resulting mixture was stirred for a further 1 hour at -78°C. The reaction product was quenched with saturated aqueous solution NH4Cl (2 L). The quenched mixture was then extracted with ether / SiO2 (3 × 2 L). The combined organic extracts were washed with brine (3 × 500 mL), dehydrated with anhydrous Na₂SO₄, and concentrated under reduced pressure to isolate compound A01-a. A01-a was used directly in step 2.

[0127] 1 ¹H 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] Stage 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)methaneamine (332.08 g, 2420.74 mmol) and K2CO3 (223.04 g, 1613.83 mmol), and then stirred at 115°C for 10 hours under a nitrogen atmosphere. 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 using PE:siRNA (95:5) to obtain 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] Stage 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), sodium isocyanate (903.48 g, 13898.2 mmol) was added in small amounts at ambient temperature under a N2 atmosphere. The resulting mixture was stirred at 110°C for a further 10 hours. The mixture was cooled to ambient temperature. The pH of the mixture was adjusted to 8-9 with NaHCO3. The resulting mixture was extracted with ELISA (3 × 3 L). The combined organic layers were washed with brine (3 × 1 L), dehydrated with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by grinding with PE:ELISA (5:1) to obtain compound A01-c.

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

[0132] Stage 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] Stage 5: 7-Bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-1-(4-methoxybenzyl)-3,4-dihydroquinazoline-2(1H)-one (A01) To a solution of ethinylcyclopropane (139.26 g, 2106.63 mmol) in toluene (1.4 L) at room temperature, 1 M LiHMDS (1685.31 mL, 1685.31 mmol) in THF was added dropwise at -5°C under a nitrogen atmosphere. The resulting mixture was stirred for a further 120 minutes at 10°C. To this mixture, 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 equivalent) in THF (4 L) was added dropwise over 40 minutes at -15°C. The resulting mixture was stirred for a further 120 minutes at room temperature. The reaction product was quenched with saturated aqueous solution NH4Cl at room temperature. The resulting mixture was extracted with ELISA (3 × 3000 mL). The combined organic layers were washed with brine (2 × 1000 mL) and dehydrated with anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash silica column chromatography using PE:siRNA (80:20) to obtain 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 hours. The resulting mixture was diluted with H2O (20 L). The precipitated solid was collected by filtration and washed with H2O (3 × 300 mL). The residue was purified by flash silica column chromatography using PE:ELISA (80:20) elution. The racemic product was separated by Pre-SFC (Amylose-C Neo 100×4.6mm 3.0um Co Solvent:MeOH(20mM NH3)), and isomer A02-A (rapidly eluting) and isomer A02-B (slowly eluting) were isolated.

[0138] For both isomers, MS (ESI) m / z values ​​are 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] Stage 1: 1-(4-bromo-2,5-difluorophenyl)-2-cyclopropyl-2,2-difluoroethane-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), 1.6 M nBuLi (47.7 mL, 76 mmol) in hexane was added dropwise at -78°C. The reaction mixture was stirred at -78°C for 30 minutes under an N2 atmosphere. Ethyl 2-cyclopropyl-2,2-difluoroacetate (15 g, 91 mmol) was dissolved in toluene (20 mL) and added dropwise over 10 minutes. The solution was stirred at -78°C for a further 1 hour, and quenched with 10% NH4Cl (100 mL). The mixture was diluted with SiO2 (200 mL), washed with water (2 × 100 mL) and brine (100 mL), and dehydrated with Na2SO4. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash chromatography (SiO2; 0-60% siRNA: hexane) 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] Stage 2: 7-Bromo-4-(cyclopropyldifluoromethyl)-6-fluoro-4-hydroxy-3,4-dihydroquinazoline-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-difluoroethane-1-one (A03-a, 14.86 g, 47.8 mmol) in NMP (47.8 mL). The mixture was heated at 140°C for 16 hours. The reaction mixture was cooled and added to water (500 mL), then extracted with ELISA (3 × 200 mL). The combined organic matter was washed with water (3 × 300 mL) and brine (3 × 300 mL) and dehydrated with MgSO4. The organic layer was concentrated under reduced pressure to isolate compound A03-b.

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

[0144] Stage 3: 7-Bromo-4-(cyclopropyldifluoromethyl)-6-fluoroquinazoline-2(1H)-one(A03-c) 7-Bromo-4-(cyclopropyldifluoromethyl)-6-fluoro-4-hydroxy-3,4-dihydroquinazoline-2(1H)-one (A03-b, 13.683 g, 39.0 mmol) was added to a flask, followed by the addition of toluene (195 mL), and the mixture was heated under reflux for 72 hours. The reaction product 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] Stage 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. 2.5 M nBuLi (22.20 mL, 55.5 mmol) in hexane was added to the solution and stirred for 30 minutes. 7-Bromo-4-(cyclopropyldifluoromethyl)-6-fluoroquinazoline-2(1H)-one (A03-c, 4.62 g, 13.88 mmol) was added to the reaction mixture, and the mixture was heated to ambient temperature and stirred for 16 hours. The reaction mixture was quenched with water. ELISA (200 mL) was added to the solution. The solution was extracted with water (2 × 50 mL) and brine (50 mL), dehydrated with MgSO4, filtered, and the organic matter was concentrated under reduced pressure. The resulting residue was purified by flash chromatography (SiO2; 0-100% ELISA: hexane), and A03 was isolated as a racemic mixture. The racemic mixture was divided using prep SFC with Daicel ChiralPak® IG (30 mm × 250 mm (5 microns), Daicel Chiral Technologies, West Chester, PA); eluted with 25% MeOH (0.1% DEA); 80 mL / min; 100 bar).

[0147] Isomer A03-A (fast elution) and isomer A03-B (slow elution): MS (ESI) m / z values ​​of 399 and 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] Stage 1: 7-Bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-1-(4-methoxybenzyl)-3-methyl-3,4-dihydroquinazoline-2(1H)-one (A04-a) (S)-7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-1-(4-methoxybenzyl)-3-methyl-3,4-dihydroquinazoline-2(1H)-one (A01, 2000 mg, 4.05 mmol) was dissolved in anhydrous 1,4-dioxane (20.3 mL) and NaH (324 mg, 8.11 mmol) was added. The mixture was stirred at room temperature for 1 hour. MeI (760 μL, 12.16 mmol) was added dropwise and the mixture was stirred for a further 16 hours. The mixture was cooled to 0°C, quenched with NH4Cl (20 mL saturated aqueous solution), and extracted with ELISA (3 × 20 mL). The combined organic layers were dehydrated with Na2SO4, filtered, and the organic matter was concentrated under reduced pressure. A04-a was isolated using the crude residue.

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

[0151] Stage 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-dihydroquinazoline-2(1H)-one (A04-a, 2.057 g, 4.05 mmol) in anhydrous TFA (8.11 mL) was heated to 60°C for 1 hour. The reaction product was concentrated under reduced pressure and purified by flash silica chromatography using elution with 0-100% siRNA in hexane to isolate the racemic compound. The substance was further purified by SFC (Daicel ChiralPak® IG, 20% MeOH / 0.1% DEA, 100 mL / min, 100 bar) to isolate the rapidly eluting isomer A04-A and the slowly eluting isomer A04-B.

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

[0153] Intermediates A05 to 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-dihydroquinazoline-2(1H)-one (A08) [ka]

[0155] Stage 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), 2 M LDA (7.54 L, 15085 mmol) in THF was added at -70°C. The resulting solution was stirred at -75°C for 30 minutes and hydrolyzed with dilute aqueous H2SO4. The organic layer was separated, and its aqueous phase was extracted with ether. The organic matter was concentrated, and the oily substance was distilled under reduced pressure to obtain a crude product as a colorless oil. Methanol (1 L) was added, and the solution was left overnight in a freezer at -20°C. The mixture was filtered, and A08-a was isolated.

[0156] Stage 2: 1-(4-bromo-2-fluoro-3-(trimethylsilyl)phenyl)-2,2,2-trifluoroethane-1-one (A08-b) To a solution of 2,2,6,6-tetramethylpiperidine (426.5 g, 3020 mmol, 1.1 equivalents) in 2500 mL of THF, 2.5 M nBuLi (1207 mL, 3020 mmol) in hexane was added dropwise 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) dissolved in 700 mL of THF was added. The solution was stirred for 1 hour, and then trifluoroethyl acetate (428 g, 3020 mmol) was added dropwise at -70°C. The mixture was then slowly raised to room temperature and stirred for 1 hour. A saturated aqueous solution of NH4Cl was then added, and the mixture was extracted twice with ethyl acetate. The combined ethyl acetate phase was washed with brine, dehydrated with MgSO4, filtered, and concentrated to isolate A08-b, which was used directly in step 3.

[0157] Stage 3: 1-(4-bromo-2-fluorophenyl)-2,2,2-trifluoroethane-1-one (A08-c) To a solution of A08-b (658 g, 1918 mmol) in 2 L of THF, 1 M TBAF (2301 mL, 2301 mmol) in THF was added at room temperature. After stirring for 30 minutes, 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, dehydrated with 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] Stage 4: 1-(4-bromo-2-((4-methoxybenzyl)amino)phenyl)-2,2,2-trifluoroethane-1-one(A08-d) 1-(4-bromo-2-fluorophenyl)-2,2,2-trifluoroethane-1-one (A08-c, 260 g, 959 mmol) was added to a flask, followed by the addition of 1-(4-methoxyphenyl)methaneamine (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 hours. The resulting mixture was diluted with 1 L of water. The resulting solution was extracted with (3 × 500 mL) of ethyl acetate, the organic layers were combined, dehydrated with Na2SO4, and concentrated. The residue was purified by normal-phase chromatography (SiO2, PE:EA = 5:1) to isolate the title compound A08-d.

[0159] Stage 5: 1-(2-amino-4-bromophenyl)-2,2,2-trifluoroethane-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-trifluoroethane-1-one (A08-d, 281 g, 724 mmol) was added to a round-bottom flask, followed by the addition of TFA (840 mL). The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was concentrated, and the title substance (A08-e) was isolated as a mixture. This was used directly in step 6.

[0160] Stage 6: 1-(2-amino-4-bromophenyl)-2,2,2-trifluoroethane-1-one (A08-f) A mixture of 1-(2-amino-4-bromophenyl)-2,2,2-trifluoroethane-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), NH4OH (53 mL), and DCM (530 mL) were placed in a flask purged with nitrogen to maintain an inert nitrogen atmosphere. The resulting solution was stirred at room temperature for 5 hours. 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), dehydrated with Na2SO4, and concentrated. The residue was purified by normal-phase chromatography (SiO2PE:Â=50:1 → 5:1) to isolate the title substance A08-f.

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

[0162] Step 8: 7-Bromo-4-hydroxy-3-((R)-1-phenylethyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one(A08-h) In a round-bottom flask, 1-(2-amino-4-bromophenyl)-2,2,2-trifluoroethane-1,1-diol·HCl (A08-g, 78g, 243.38 mmol), [(1R)-1-isocyanatoethyl]benzene (71.6g, 486.75 mmol), THF (1450 mL), and 1N HCl (110 mL, 3620.31 mmol) were added. The resulting solution was stirred in a water / ice bath at 0°C for 2 hours, and then stirred at 17°C for a further 48 hours. The reaction product was then stirred at 60°C for 1 hour. The resulting mixture was concentrated. The resulting 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 (column, C18; 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-dihydroquinazoline-2(1H)-one(A08-i) In a 500 mL three-necked round-bottom flask, butyl(chloro)magnesium (378 mL, 756.40 mmol, 2 M in THF) was added, and ethinylcyclopropane (50 g, 756.40 mmol) was slowly added at room temperature. The resulting solution was stirred at 18°C ​​for 2 hours. The resulting intermediate was used directly.

[0164] 7-bromo-4-hydroxy-3-[(1R)-1-phenylethyl]-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-2-one (A08-h, 70 g, 168.59 mmol) was placed in a round-bottom flask, and toluene (700 mL) and TEA (85.3 g, 842.95 mmol) were added. Then, while maintaining the temperature at -5 to 0°C, SOCl2 (21.1 g, 177.02 mmol) was slowly added. The resulting solution was stirred at 0°C for 1 hour in a water / ice bath. The reaction mixture was then cooled to -70°C, and the magnesium chloride solution generated in situ was added dropwise over 30 minutes. The mixture was quenched with 12% aqueous citric acid (700 mL), extracted with ethyl acetate (3 × 1 L), the organic matter was combined and dehydrated with Na₂SO₄, concentrated, and the residue was purified using Prep-SFC (conditions as follows: column, Daicel ChiralPak® OD-H 5 × 25 cm, 5 μm (Daicel Chiral Technologies, West Chester, PA); mobile phase, mobile phase A: CO₂: 80%, mobile phase B: MeOH (NH₃ / MeOH, 20 mmol)).

[0165] Step 10: (S)-7-bromo-4-(cyclopropylethynyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one(A08) (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) were added to a round-bottom flask purged with nitrogen and maintaining an inert nitrogen atmosphere. The resulting solution was stirred at 18°C ​​for 1 hour. The reaction product was then quenched by adding 100 mL of water. The resulting solution was extracted with DCM (3 × 100 mL), the organic layer was dehydrated with 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] Stage 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), 2M LDA (286 mL, 571 mmol) in THF was added at -70°C. The reaction mixture was stirred at -70°C for 2 hours. The reaction mixture was hydrolyzed with dilute aqueous H2SO4. The organic layer was separated, and the aqueous phase was extracted with siRNA. The organic matter was dehydrated with MgSO4 and filtered. The organic matter was 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] Stage 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), 2.5 M nBuLi (53.4 mL, 134 mmol) in hexane was added at -20°C. After stirring at -20°C for 30 minutes, 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 hour, ethyl 2,2-difluoropropanoate (18.44 g, 134 mmol) was added dropwise. The mixture was then slowly heated to 20°C and stirred at 20°C for another 1 hour. Saturated aqueous solution 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), dehydrated with Na2SO4, filtered, and concentrated to isolate the title compound A09-b.

[0171] Stage 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), 1 M TBAF (34.7 g, 133 mmol) in THF was added at 20°C and the mixture was stirred for 0.5 hours. The reaction product was concentrated and purified using flash silica gel (PE:EA = 1:0 to 95:5) to isolate the title compound A09-c.

[0172] Stage 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), (4-methoxyphenyl)methaneamine (20.55 g, 150 mmol) and K2CO3 (12.42 g, 90 mmol) were added. The reaction mixture was stirred at 115 °C for 2 hours. The reaction mixture was filtered, concentrated, and purified over flash silica gel (PE:EA = 1:0 to 10:1) to isolate the title compound A09-d.

[0173] Stage 5: 7-Bromo-4-(1,1-difluoroethyl)-4-hydroxy-1-(4-methoxybenzyl)-3,4-dihydroquinazoline-2(1H)-one(A09-e) Sodium cyanate (33.8 g, 521 mmol) was added 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). The reaction mixture was stirred at 110 °C for 16 hours. The reaction mixture was adjusted to pH=8 using saturated aqueous solution NaHCO3. The mixture was extracted with ELISA (3 × 500 mL). The organic layer was washed with brine (500 mL), dehydrated (Na2SO4), filtered, and concentrated. The residue was purified over flash silica gel (PE:EA = 1:0~4:1) 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] Stage 6: 7-Bromo-4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)quinazoline-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), phosphorus pentoxide (3.99 g, 28.1 mmol) was added. The reaction mixture was stirred under N2 at 90°C for 3 hours. The reaction mixture was adjusted to pH=8 using saturated aqueous solution NaHCO3. The residue was extracted with ELISA (3 × 500 mL). The organic layer was washed with brine (500 mL), dehydrated (Na2SO4), 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] Stage 7: 7-Bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinazoline-2(1H)-one(A09-g) A solution of ethinylcyclopropane (4.36 g, 66.0 mmol) in toluene (50 mL) was added to 1 M LiHMDS (55.0 mL, 55.0 mmol) in THF at 0°C. The reaction mixture was stirred at 85°C for 15 minutes. Next, 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) was added to the reaction mixture at 0°C. The reaction mixture was stirred at 15°C for 0.5 hours. The reaction mixture was quenched with saturated aqueous solution NH4Cl (100 mL). The solution was extracted with ELISA (3 × 100 mL). The organic layer was washed with brine (100 mL), dehydrated (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) A mixture of 7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinazoline-2(1H)-one (A09-g, 3g, 6.31 mmol) in ACN (40 mL) and water (15 mL) was mixed with CAN (17.30 g, 31.6 mmol). The reaction mixture was stirred at 15°C for 2 hours. The reaction mixture was extracted with ELISA (3 × 50 mL). The organic layer was washed with brine (50 mL), dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure to isolate the residue. The residue was purified by flash silica gel chromatography (PE:EA = 1:0 → 1:3) to isolate A09. The white solid was chiral-resolved using prep SFC (column: Daicel ChiralPak® AD, 250×50mm id10u (Daicel Chiral Technologies, West Chester, PA); mobile phase A: CO2 and mobile phase B: MeOH (0.1% NH3H2O); gradient: B%=45%), and the rapidly eluting peak A09-A and the slowly eluting isomer A09-B were isolated.

[0180] Rapidly 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]. Slowly 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 section B Intermediate B01: (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-(hydroxymethyl)-3,4-dihydroquinazoline-2(1H)-one (B01) [ka]

[0182] Step 1: (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-(((4-methoxybenzyl)oxy)methyl)-3,4-dihydroquinazoline-2(1H)-one(B01-a) (S)-7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one (A02-B, 10 g, 26.8 mmol), potassium (4-methoxy)benzyloxymethyl trifluoroborate (17.29 g, 67.0 mmol), and Pd(dppf)Cl2 (1.961 g, 2.68 mmol) were dissolved in 1,4-dioxane (121 mL), followed by the addition of Cs2CO3 (52.4 g, 161 mmol). The reaction mixture was heated in a sealed tube at 150°C for 1 hour. The reaction mixture was cooled, filtered through Celite, and washed with SiO2 (100 mL). The filtrate was diluted with saturated aqueous NaHCO3 and extracted with SiO2 (3 × 50 mL). The combined organic matter was dehydrated with MgSO4, filtered, and concentrated under reduced pressure to isolate the crude substance. This crude substance was purified by flash silica chromatography using (0-100%) siRNA in hexane 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-dihydroquinazoline-2(1H)-one (B01) (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-(((4-methoxybenzyl)oxy)methyl)-3,4-dihydroquinazoline-2(1H)-one (B01-a, 11.93 g, 26.8 mmol) was dissolved in DCM (134 mL). 4M 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 product was concentrated under reduced pressure, and the crude product was isolated. The crude product was placed in a 1:1 DCM:hexane mixture and sonicated for 15 minutes to form a slurry. The slurry was filtered, and compound B01 was isolated.

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

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

[0187] The following intermediates were prepared from intermediate B01 by replacing A02-B with A03-A using a similar method, 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-dihydroquinazoline-2(1H)-one (B03) [ka]

[0190] The following intermediates were prepared from intermediate B01 by replacing A02-B with A08 using a similar method, 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-dihydroquinazoline-2(1H)-one (B04) [ka]

[0192] The following intermediate was prepared from intermediate B01 by replacing A02-B with A09-A using a similar method, and the title compound B04 was isolated.

[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] Stage 1: 6-Chloro-4-(cyclopropylethynyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)-7-vinyl-3,4-dihydroquinazoline-2(1H)-one (B05-a) 7-Bromo-6-chloro-4-(cyclopropylethynyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one (A06, 14 g, 27.3 mmol) and potassium vinyl trifluoroborate (5.48 g, 40.9 mmol) were dissolved in 1,4-dioxane (140 mL) and water (14 mL). K2CO3 (11.30 g, 82 mmol) and PdCl2 (dppf) (1.994 g, 2.73 mmol) were added to this solution. The reaction mixture was stirred under N2 at 100°C for 3 hours. The reaction product was concentrated under reduced pressure and purified by flash chromatography (SiO2; 0-20% siRNA:PE) to isolate compound B05-a.

[0196] Stage 2: 6-Chloro-4-(cyclopropylethynyl)-7-(hydroxymethyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one(B05-b) A solution of 6-chloro-4-(cyclopropylethynyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)-7-vinyl-3,4-dihydroquinazoline-2(1H)-one (B05-a, 8.2 g, 17.79 mmol) in MeOH (30 mL) and DCM (150 mL) was aerated with ozone (0.854 g, 17.79 mmol) at -60°C for 30 minutes. NaBH(OAc)3 (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 x 3). The resulting organic layers were combined, washed with brine (100 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to isolate product B05-b. This was used directly in step 3.

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

[0198] Stage 3: (S)-6-chloro-4-(cyclopropylethynyl)-7-(hydroxymethyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one, and (R)-6-chloro-4-(cyclopropylethynyl)-7-(hydroxymethyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one (B05-A and B05-B) 6-chloro-4-(cyclopropylethynyl)-7-(hydroxymethyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one (B05-b, 8.5 g, 18.28 mmol) was dissolved in MeCN (200 mL) and water (70 mL), to which CAN (50.1 g, 91 mmol) was added. The mixture was stirred at 20°C for 16 hours. The reaction product was dissolved in water (100 mL) and extracted with ELISA (150 mL x 3). The combined organic layer was washed with brine (200 mL), dehydrated with Na2SO4, 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 divided using SFC (Daicel ChiralPak® AD, 30% EtOH / CO2, 200 g / min, 40°C, 100 bar) to isolate isomer B05-A (rapidly eluting) and isomer B05-B (slowly eluting).

[0199] Isomer B05-A (elutes quickly) : 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 elution) : 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-dihydroquinazoline-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 product. The mixture was stirred at 50°C for 1 hour. The reaction product was neutralized with NaHCO3 (saturated aqueous solution) until the pH reached 10. The aqueous mixture was extracted with DCM (2 × 10 mL), and the combined organic layers were dehydrated with MgSO4. Compound B07 was isolated by concentration under reduced pressure.

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

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

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

[0206] Step 1: (S)-6-chloro-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-(hydroxymethyl)-3,4-dihydroquinazoline-2(1H)-one(B12-a) (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-(hydroxymethyl)-3,4-dihydroquinazoline-2(1H)-one (B04, 260 mg, 0.849 mmol) was dissolved in anhydrous DMF (5 mL) to which NCS (113 mg, 0.849 mmol) was added. The resulting reaction mixture was stirred at 40 °C for 16 hours. The reaction product was diluted with ELISA, washed with water (3 ×), dehydrated with MgSO4, filtered, and concentrated under reduced pressure to isolate compound B12-a. This 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-dihydroquinazoline-2(1H)-one(B12) (S)-6-chloro-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-(hydroxymethyl)-3,4-dihydroquinazoline-2(1H)-one (B12-a, 289 mg, 0.848 mmol) was dissolved in anhydrous DCE (8.5 mL) to which thionyl chloride (1.2 mL, 16.96 mmol) was added. The reaction mixture was stirred at 60°C for 90 minutes. The reaction mixture was concentrated under reduced pressure and azeotropically reacted with Et2O to isolate compound B12. This 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] A mixture of (S)-4-(cyclopropylethynyl)-6-fluoro-7-(hydroxymethyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one (B06, 150 mg, 0.457 mmol) in DCM (10 mL) and THF (1 mL) was mixed with PDC (344 mg, 0.914 mmol). The reaction mixture was stirred under N2 at 25°C for 16 hours. The reaction mixture was filtered and purified by flash chromatography (SiO2, 50% HCl: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] A mixture of (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-(hydroxymethyl)-3,4-dihydroquinazoline-2(1H)-one (B01, 140 mg, 0.432 mmol) in DCM (2.5 mL) was mixed with 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. This was used directly in the following 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-dihydroquinazoline-2(1H)-one (B15) [ka]

[0217] Step 1: (S)-7-bromo-4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one(B15-a) (S)-7-bromo-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (A07-A, 2g, 5.30 mmol) and Cs2CO3 (2.073g, 6.36 mmol) were dissolved in DMF (26.5 mL) to which PMBCl (0.794 mL, 5.83 mmol) was added. The reaction mixture was stirred at 25°C for 16 hours. The reaction product was quenched with water (200 mL) and extracted with Et2O (2 × 300 mL). The resulting organic layer was dehydrated with MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 0-100% siRNA:hexane) to obtain 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-dihydroquinazoline-2(1H)-one(B15-b) (S)-7-bromo-4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one (B15-a, 580 mg, 1.166 mmol) was dissolved in anhydrous 1,4-dioxane (12 mL), to which 60% NaH (93 mg, 2.333 mmol) was added. Subsequently, MeI (0.219 mL, 3.50 mmol) was added to the solution, and the mixture was stirred at 25°C for 16 hours. The mixture was quenched with saturated aqueous solution NH4Cl and extracted with ethylethanol (3×). The organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0-100% ethylethanol:hexane) to obtain 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-dihydroquinazoline-2(1H)-one(B15-c) A mixture of (S)-7-bromo-4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-3-methyl-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one (B15-b, 440 mg, 0.861 mmol), potassium (4-methoxy)benzyloxymethyl trifluoroborate (489 mg, 1.893 mmol), and PdCl2(dppf)-CH2Cl2 adduct (70.3 mg, 0.086 mmol) in anhydrous 1,4-dioxane (8605 μL) was purged with N2. 3M Cs2CO3 aqueous solution (1721 μL, 5.16 mmol) was added, and the resulting mixture was irradiated at 150°C for 1 hour in a Biotage® Initiator microwave oven (Biotage, LLC, Charlotte, NC). The reaction mixture was quenched with saturated aqueous solution (NH4Cl) and extracted with toluene (3×). The combined organic layer was dehydrated with anhydrous sodium (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0-100% toluene:hexane) to obtain compound B15-c.

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

[0222] Stage 4: (S)-4-(cyclopropylethynyl)-6-fluoro-7-(hydroxymethyl)-1-(4-methoxybenzyl)-3-methyl-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one(B15-d) (S)-4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-7-(((4-methoxybenzyl)oxy)methyl)-3-methyl-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one (B15-c, 318 mg, 0.546 mmol) was dissolved in DCM (1 mL) and 4 M HCl in 1,4-dioxane (1.365 mL) was added. The reaction mixture was stirred at 25°C for 3 hours. Subsequently, the reaction mixture was concentrated under reduced pressure and purified by flash chromatography (SiO2, 0-7% MeOH: DCM) to obtain compound B15-d.

[0223] Stage 5: (S)-7-(chloromethyl)-4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-3-methyl-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one(B15) (S)-4-(cyclopropylethynyl)-6-fluoro-7-(hydroxymethyl)-1-(4-methoxybenzyl)-3-methyl-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one (B15-d, 230 mg, 0.497 mmol) was dissolved in DCM (1 mL) and thionyl chloride (0.036 mL, 0.497 mmol) was added. The reaction mixture was stirred at 45°C for 16 hours. The reaction mixture was then cooled and concentrated under reduced pressure to isolate compound B15. This compound 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-dihydroquinazoline-2(1H)-one (B16) [ka]

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

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

[0228] Intermediates B17 and B18 were prepared in a manner similar to that described for the preparation of intermediate B16, using the starting intermediate listed in place of B07 and similar amine reagents, 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]pyridine-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 minutes. Boc2O (880 mg, 4.03 mmol) was added, and the reaction mixture was heated to room temperature and stirred for 48 hours. The reaction mixture was diluted with saturated NaHCO3 and extracted with RINKAN (3 × 15 mL). The combined organic layers were washed with water (10 mL), then with brine (10 mL), and then dehydrated with MgSO4. The resulting mixture was then filtered and concentrated under reduced pressure. Compound C01 was isolated and used without further processing.

[0231] Intermediate C02 was prepared using the starting materials listed in place of C01-a, as shown in Table 6, in a manner similar to that described for the preparation of intermediate C01. [Table 7]

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

[0233] Stage 1: 4-amino-3-methyl-1H-1,2,4-triazole-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 product was cooled and concentrated under reduced pressure. The crude solid was recrystallized from EtOH to obtain compound C03-b.

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

[0235] Stage 2: 4-amino-1,3-dimethyl-1H-1,2,4-triazole-5(4H)-one(C03-c) To a mixture of 4-amino-3-methyl-1H-1,2,4-triazole-5(4H)-one (C03-b, 1 g, 8.76 mmol) and NaOH (0.421 g, 10.52 mmol) in water (2 mL), dimethyl sulfate (0.829 mL, 8.76 mmol) was added. The reaction mixture was stirred at 15°C for 30 minutes. The reaction mixture 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] Stage 3: 2,5-Dimethyl-2,4-dihydro-3H-1,2,4-triazole-3-one (C03) To a solution of 4-amino-1,3-dimethyl-1H-1,2,4-triazole-5(4H)-one (C03-c, 1.1 g, 8.58 mmol) in HCl (40.6 mL, 487 mmol, 12 mol / L), 17.2 mL of 0.5 M sodium nitrite aqueous solution (8.58 mmol) was added dropwise at 0°C. The mixture was stirred at 15°C for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude solid was purified by sublimation (0.1 atm, 160°C) to obtain 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-pyrazole-3-yl)methanol(CO4-b) To a solution of ethyl 4-methyl-1H-pyrazole-3-carboxylate (C04-a, 0.5 g, 3.24 mmol) in THF (6 mL), 1 M LiAlH4 (0.150 g, 3.96 mmol) in THF was added at 0°C under N2. The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was quenched with saturated NH4Cl (20 mL) and extracted with ELISA (3 × 15 mL). The organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to isolate compound C04-b. This compound was used without further purification.

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

[0242] Stage 2: 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-1H-pyrazole(C04) To a solution of (4-methyl-1H-pyrazole-3-yl)methanol (C04-b, 100 mg, 0.892 mmol) in DMF (2 mL), imidazole (182 mg, 2.68 mmol) and TBSCl (269 mg, 1.784 mmol) were added. The reaction mixture was stirred at 20°C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with SiO2 (2 × 15 mL). The combined organic layer was washed with brine (5 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 50% SiO2:PE) to obtain compound C04.

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

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

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

[0246] Stage 1: 3-(diethoxymethyl)-2-ethoxytetrahydrofuran(C09-a) To a flask containing triethoxymethane (2.326 g, 15.69 mmol), iron(III) chloride (0.231 g, 1.427 mmol) was added 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 product was diluted with DCM (50 mL), filtered through Celite®, and concentrated under reduced pressure to isolate compound C09-a. This compound was used directly in step 2.

[0247] Stage 2: 2-(1H-pyrazole-4-yl)ethane-1-ol(C09-b) A solution of hydrazine dihydrochloride (500 mg, 4.76 mmol) in water (10 mL) was added to 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 hours. The reaction mixture was filtered and purified by prep HPLC (water:MeCN (containing 0.05% NH3H2O)) to obtain 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-pyrazole-4-yl)ethane-1-ol (C09-c, 120 mg, 1.070 mmol) in DMF (1 mL), imidazole (109 mg, 1.605 mmol) was added 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 SiO (2 × 5 mL). The combined organic layers were washed with water (2 × 5 mL) and brine (2 × 5 mL), dehydrated with Na₂SO₄, filtered, and then concentrated under reduced pressure to isolate compound C09. This 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-triazole-3-one (C10) [ka]

[0252] To a stirred solution of hydrazine carboxamide hydrochloride (5000 mg, 44.8 mmol) in DCM (100 mL), TEA (13.75 mL, 99 mmol) was added. The mixture was stirred at -10°C for 30 minutes. Cyclopropane carbonyl chloride (5155 mg, 49.3 mmol) was added at -10°C, and the mixture was stirred at 20°C for 15 hours. The mixture was concentrated under reduced pressure, and the residue was diluted with MeCN (100 mL). The mixture was stirred for 30 minutes, filtered, and the solid was collected. The solid was dissolved in 1 M NaOH (20 mL) and stirred at 100°C for 2 hours. The solution was cooled, and the pH was adjusted to 4-5 using concentrated HCl. The mixture was filtered, and compound C10 was isolated. This 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-pyrazole-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 hours. The reaction mixture was diluted with water (10 mL) and extracted with DCM (2 × 15 mL). The combined organic layer was washed with brine (5 mL), dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure to obtain compound C11. This compound 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) A solution of 5-chloro-1H-pyrazole-3-carboxylic acid (C12-a, 200 mg, 1.365 mmol) in MeOH (5 mL) was mixed with thionyl chloride (0.259 mL, 3.55 mmol) at 0°C. The mixture was stirred at 65°C for 3 hours. The reaction product was concentrated under reduced pressure, and the resulting residue was diluted with saturated NaHCO3 aqueous solution (10 mL) and extracted with RINKAN (2 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain compound C12-b. This compound was used in the next step without purification.

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

[0260] Stage 2: (5-Chloro-1H-pyrazole-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), LiAlH4 (42.6 mg, 1.121 mmol) was added at 0°C. The mixture was stirred at 15°C for 12 hours. 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 minutes. The solution was then dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain compound C12-c. This was used in the next step without purification.

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

[0262] Stage 3: 3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chloro-1H-pyrazole(C12) A solution of (5-chloro-1H-pyrazole-3-yl)methanol (C12-c, 100 mg, 0.754 mmol) in DMF (1.5 mL) was mixed with imidazole (77 mg, 1.132 mmol) at 0°C. TBSCl (125 mg, 0.83 mmol) was added to the reaction mixture, and the mixture was stirred at 15°C for 12 hours. The solution was poured into water (5 mL) and extracted with SiO (2 × 5 mL). The organic layer was washed with water (2 × 5 mL) and brine (2 × 5 mL), dehydrated with Na₂SO₄, filtered, and then concentrated under reduced pressure. The resulting residue was purified by prep TLC (SiO₂, 20% SiO:PE) to obtain 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) A solution of methyl 5-chloro-1H-pyrazole-3-carboxylate (C13-a, 100 mg, 0.623 mmol) in THF (5 mL) was mixed with NaH (37.4 mg, 0.934 mmol) at 0°C. The mixture was stirred at 0°C for 10 minutes. SEMCl (0.166 mL, 0.934 mmol) was added, and the reaction mixture was stirred at 15°C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with HCl (3 × 10 mL). The organic layer was washed with brine (10 mL), dehydrated (Na₂SO₄), filtered, and concentrated under reduced pressure. The resulting residue was purified by prep TLC (SiO₂, HCl:PE, 1:5) to obtain compound C13-b.

[0266] Stage 2: (5-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)methanol(C13-c) 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 mixed with LiAlH4 (18.79 mg, 0.495 mmol) at 0°C. The mixture was stirred at 15°C for 2 hours. The reaction product was dissolved in saturated NH4Cl aqueous solution (10 mL) and extracted with SiO4 (3 × 10 mL). The organic layer was washed with brine (10 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain compound C13-c. This was used directly in the next step without purification.

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

[0268] Stage 3: 5-Chloro-3-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(C13-d) (5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)methanol (C13-c, 100 mg, 0.381 mmol) was dissolved in DMF (5 mL) and NaH (22.83 mg, 0.571 mmol) was added at 0°C. The mixture was stirred at 15°C for 30 minutes. MeI (0.119 mL, 1.903 mmol) was added and the reaction mixture was stirred at 15°C for 1.5 hours. The reaction mixture was diluted with water (10 mL) and extracted with  (3 × 10 mL). The combined organic layer was washed with brine (10 mL), dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure to obtain product C13-d. This was used directly without purification.

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

[0270] Stage 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 hours. The reaction product was concentrated under reduced pressure, dissolved in saturated NaHCO3 aqueous solution (10 mL), and extracted with DCM (3 × 10 mL). The combined organic layer was washed with brine (10 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to obtain 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] N,N-dimethylpyridine-4-amine (0.050 g, 0.409 mmol) was added to a suspension of 4,5-dihydropyrrolo[3,4-b]pyrrole-6(1H)-one (C14-a, 1 g, 8.19 mmol) in DCM (20 mL), TEA (2.286 mL, 16.38 mmol), and BOC2O (2.091 mL, 9.01 mmol). The resulting solution was stirred at 20°C for 2 hours. The reaction mixture was evaporated and purified by flash silica chromatography (SiO2, siRNA: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-pyrrole-1-yl)-4-methoxy-1H-pyrazole(C15) [ka]

[0275] To a solution of 4-methoxy-1H-pyrazole-3-amine (C15-a, 50 mg, 0.442 mmol) in acetic acid (2 mL), hexane-2,5-dione (50.5 mg, 0.442 mmol) was added. The mixture was stirred at 120 °C for 3 hours. The mixture was concentrated under reduced pressure and purified by prep-TLC (SiO2, PE:Â=1:2) to isolate compound C15.

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

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

[0278] Stage 1: Benzyl 2-(3-(methoxymethyl)-1H-pyrazole-1-yl)acetate(C16-b) A 22.3 mL acetonitrile was added to a vial containing 3-(methoxymethyl)-1H-pyrazole (C16-a, 1 g, 8.92 mmol) and K2CO3 (3.70 g, 26.8 mmol), followed by the addition of benzyl-2-bromoacetate (2.451 g, 10.70 mmol). The reaction mixture was heated at 65°C for 16 hours. After cooling to ambient temperature, the crude reaction mixture was added to water and extracted with CH2Cl2. The organic layer was concentrated under reduced pressure, and the residue was purified by flash silica chromatography (SiO2, PE:siRNA=1:2) to obtain compound C16-b.

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

[0280] Step 2: 2-(3-(methoxymethyl)-1H-pyrazole-1-yl)acetic acid (C16) Benzyl 2-(3-(methoxymethyl)-1H-pyrazole-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 the addition of MeOH (10 mL). The container was evacuated by alternating vacuum and hydrogen three times, and then stirred under H2 for 16 hours. The reaction product was filtered through Celite®, and the organic matter was concentrated under reduced pressure to isolate compound C16.

[0281] 1 ¹H 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), 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium ditetrafluoroborate (1083 mg, 3.06 mmol) was added. The reaction mixture was stirred at 20°C for 16 hours. The reaction mixture was concentrated under reduced pressure, dissolved in HCl (10 mL), and then 1 M HCl was added to adjust the pH to 4. The organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by pre-TLC (SiO2, PE:HCl = 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 Et3N (1.4 mL, 10.2 mmol) in CH2Cl2 (10 mL), BOC-anhydrous (710 μL, 3.06 mmol) was added. Subsequently, DMAP (24.9 mg, 0.204 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. 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 (SiO2, hexane:Â=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] Stage 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 SiO2 (6.9 mL), and NCS (371 mg, 2.8 mmol) was added. The resulting mixture was stirred at 50°C for 48 hours. Water (10 mL) was added to the reaction product, and the organic layer was extracted, dehydrated with MgSO4, and filtered. The organic matter was concentrated under reduced pressure, and the residue was purified by flash silica chromatography (SiO2, hexane:SiO2 = 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] Stage 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 4M HCl (2.9 mL, 11.82 mmol) in dioxane and stirred at ambient temperature for 16 hours. Over time, the solution became turbid. The reaction product was concentrated under reduced pressure to isolate compound C18. This compound 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] Stage 1: 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)ethane-1-one(C19-b) A mixture of (2-(chloromethoxy)ethyl)trimethylsilane (7.27 g, 43.6 mmol) in THF (80 mL) was mixed with sodium hydride (3.20 g, 80 mmol) at 0°C. The reaction mixture was then stirred at 0°C for 0.5 hours. Next, 1-(1H-pyrazole-3-yl)ethane-1-one (C19-a, 4 g, 36.3 mmol) was added. The reaction mixture was stirred at 20°C for 5.5 hours. The reaction mixture was slowly quenched with saturated NH4Cl aqueous solution (40 mL) at 0°C and extracted with siRNA (130 mL x 2). The combined organic layer was washed with brine (130 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica chromatography (SiO2, PE:siRNA = 9:1) to isolate compound C19-b.

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

[0295] Stage 2: 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)ethane-1-ol(C19-c) 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)ethane-1-one (C19-b, 4g, 16.6 mmol) was added to 80 mL of anhydrous MeOH under N2 conditions with 1.89 g, 50 mmol of NaBH4 at 0°C, and the mixture was then stirred at 25°C for 2 hours. 50 mL of saturated NH4Cl aqueous solution was added to the reaction mixture, and the mixture was extracted with ELISA (2 × 80 mL). The combined organic layers were washed with brine (100 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to isolate compound C19-c. This compound was used without further purification.

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

[0297] Stage 3: 3-(1-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(C19-d) A mixture of 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)ethane-1-ol (C19-c, 3.2g, 13.20 mmol) in THF (50 mL) was mixed with 60% NaH (1.056 g, 26.4 mmol) at 0°C. The reaction mixture was stirred at 0°C for 0.5 hours. Then, iodomethane (1.644 mL, 26.4 mmol) was added. The reaction mixture was stirred at 20°C for 6 hours. The reaction mixture was cooled to 0°C and quenched with saturated NH4Cl aqueous solution (50 mL). The mixture was extracted with ELISA (2 × 80 mL). The combined organic layers were washed with brine (100 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to isolate compound C19-d.

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

[0299] Stage 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 hours. The reaction product was concentrated under reduced pressure, and the residue was dissolved in ELISA (20 mL), then saturated aqueous NaHCO3 (20 mL) was added dropwise. The mixture was extracted with ELISA (5 × 20 mL), dehydrated with Na2SO4, 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) A mixture of methyl 4-chloro-1H-pyrazole-3-carboxylate (C20-a, 400 mg, 2.491 mmol) in THF (10 mL) was mixed with NaH (299 mg, 7.47 mmol) at 0°C. The reaction mixture was stirred at 15°C for 0.5 hours. Then, (2-(chloromethoxy)ethyl)trimethylsilane (1246 mg, 7.47 mmol) was added, and the reaction mixture was stirred at 40°C for 2 hours. The residue was extracted with siRNA (3 × 10 mL). The organic layer was washed with brine (10 mL), dehydrated with Na₂SO₄, 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] Stage 2: (4-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)methanol(C20-c) 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 mixed with LiBH4 (157 mg, 7.22 mmol). The reaction mixture was stirred at 65 °C for 4 hours. The reaction mixture was poured into H2O (10 mL). The residue was extracted with RINKAN (3 × 10 mL). The organic layer was washed with brine (10 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to isolate compound C20-c. This was used without further purification.

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

[0306] Stage 3: 4-Chloro-3-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(C20-d) A mixture of (4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)methanol (C20-c, 15 mg, 0.057 mmol) in DMF (1 mL) was mixed with NaH (2.74 mg, 0.114 mmol) at 0°C. The reaction mixture was stirred at 15°C for 0.5 hours. Then, iodomethane (40.5 mg, 0.285 mmol) was added. The reaction mixture was stirred at 15°C for 3 hours. The reaction mixture was dissolved in water (10 mL) and extracted with ELISA (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure to isolate compound C20-d. This was used directly in step 4.

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

[0308] Stage 4: 4-Chloro-3-(methoxymethyl)-1H-pyrazole(C20) A 1 mL 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 was stirred at 15°C for 2 hours. The reaction product was concentrated under reduced pressure, and the residue was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to obtain 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), NaH (0.122 g, 3.05 mmol) was added. The reaction mixture was stirred at 20°C for 0.2 hours. Then, SEMCl (0.324 mL, 1.83 mmol) was added. The reaction mixture was stirred at 20°C for 16 hours. The reaction mixture was dissolved in water (20 mL) and extracted with RINKAN (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dehydrated with Na₂SO₄, 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] Stage 1: 4,5-Dichloro-1H-imidazole (C22-b) In a 50 L four-necked round-bottom flask purged with nitrogen and maintaining an inert nitrogen atmosphere, H2O (30 L) and imidazole (C22-a, 1.5 kg, 22.03 mol) were added. Subsequently, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (4.91 kg, 24.89 mol, 1.13 equivalents) was added at 0°C. Then, H2SO4 (8.643 kg, 88.12 mmol) at 0°C was added to the mixture over 30 minutes. The resulting solution was stirred at room temperature for 2 hours. The reaction product was then quenched by adding NaOH (40 L, 3.8 M). The mixture was acidified with AcOH to pH 3. The resulting solution was extracted with ethyl acetate (3 × 15 L), the organic layers were combined, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 6% siRNA / PE to obtain compound C22-b.

[0315] Stage 2: 4,5-Dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole(C22-c) In a 50 L four-necked round-bottom flask purged with nitrogen and maintaining an inert nitrogen atmosphere, tetrahydrofuran (23.4 L) and 4,5-dichloro-1H-imidazole (C22-b, 2.34 kg, 17.08 mol, 1.00 equivalent) were added. Subsequently, NaH (1.033 kg, 25.62 mol, 60%) was added at 0°C for 30 minutes. The resulting solution was stirred at 0°C for 1 hour. Then, SEMCl (3.42 kg, 20.50 mol) at 0°C was added over 30 minutes. The resulting solution was stirred at room temperature overnight. The reaction product was then quenched by adding 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 obtain compound C22-c, which was used directly in step 3.

[0316] Stage 3: 2-bromo-4,5-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole(C22-d) In a 50 L four-necked round-bottom flask purged with nitrogen and maintaining an inert nitrogen atmosphere, CHCl3 (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) were added. The resulting solution was stirred overnight at room temperature. The reaction product was then quenched by adding 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 eluted with 10% Â / PE to obtain compound C22-d.

[0317] Stage 4: 4,5-Dichloro-2-(trimethylsilyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole(C22-e) In a 50 L four-necked round-bottom flask purged with nitrogen and maintaining an inert nitrogen atmosphere, tetrahydrofuran (25 L) and 2-bromo-4,5-dichloro-1-{[2-(trimethylsilyl)ethoxy]methyl}imidazole (C22-d, 2.5 kg, 7.22 mol) were added. Subsequently, n-butyllithium (3.178 L, 7.94 mol, 2.5 M) was added dropwise over 1 hour while stirring at -78°C. The resulting solution was stirred at -78°C for 30 minutes. Subsequently, chlorotrimethylsilane (0.86 kg, 7.94 mol, 1.10 equivalents) was added dropwise over 20 minutes while stirring at -78°C. The resulting solution was stirred at room temperature for 2 hours. The reaction product was then quenched by adding NH4Cl solution (50 L). The resulting solution was extracted with ethyl acetate (3 × 15 L), the organic layer was combined, dehydrated, and concentrated under reduced pressure to isolate compound C22-e.

[0318] Stage 5: 4-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carbaldehyde(C22-f) 4,5-dichloro-2-(trimethylsilyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}imidazole (C22-e, 2 kg, 5.89 mol) and tetrahydrofuran (20 L) were added to a 50 L four-necked round-bottom flask purged with nitrogen and maintaining an inert nitrogen atmosphere. Subsequently, n-butyllithium (2.35 L, 2.5 M) was added dropwise over 30 minutes while 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 equivalents) was added dropwise over 5 minutes while stirring at -78°C. The resulting solution was stirred at room temperature for 1 hour. The reaction product was then quenched by adding 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] Stage 6: 4-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylic acid (C22) In a 50 L four-necked round-bottom flask purged with nitrogen and maintaining an inert nitrogen atmosphere, 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) were added. Then, sodium chlorite (1.699 kg, 18.78 mol) was added at 0°C. To this mixture, NaH2PO4 (2.254 kg, 18.78 mol) at 0°C was added. Next, water (5.88 L) at 0°C was added to this mixture. The resulting solution was stirred at room temperature for 2 hours. Next, the solution was extracted with ethyl acetate (3 × 15 L), the organic layer was combined, dehydrated, and concentrated under reduced pressure. The resulting crude solid was purified by grinding with PE (500 mL), and then filtered to collect the filter cake. Compound C22 was obtained.

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

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

[0322] Example 1 (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methoxy-1H-1,2,4-triazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one(1) [ka]

[0323] Step 1: (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-nitro-1H-1,2,4-triazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one(1-a) To a solution of intermediate B07 (40 mg, 0.117 mmol) in DMF (1 mL), K2CO3 (48.4 mg, 0.350 mmol) and 3-nitro-1H-1,2,4-triazole (19.97 mg, 0.175 mmol) were added. The mixture was stirred at 50°C for 4 hours. The solution was poured into water (5 mL) and extracted with SiO2 (2 × 5 mL). The combined organic layers were washed with water (5 mL) and brine (5 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain compound 1-a. This compound 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-triazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one(1-b) (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-nitro-1H-1,2,4-triazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one (1-a, 40 mg, 0.095 mmol) was dissolved in MeOH (0.5 mL) and sodium methoxide (30.8 mg, 0.571 mmol) was added. The mixture was stirred at 60°C for 16 hours. The mixture was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to obtain 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-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one(2) [ka]

[0328] To a solution of intermediate B07 (41.2 mg, 0.120 mmol) and (1H-pyrazole-3-yl)methanol (2-a, 28.3 mg, 0.288 mmol) in DMA (1.2 mL), K2CO3 (58.1 mg, 0.404 mmol) was added. The reaction mixture was stirred at 60°C for 16 hours. The mixture was filtered and purified by prep HPLC (water:MeCN (containing 0.1% TFA)), followed by flash chromatography (SiO2, 0-70% (3:1 Â:EtOH):hexane) to obtain 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-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-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), K2CO3 (35.3 mg, 0.255 mmol) was added. The reaction mixture was stirred at 60°C for 16 hours. The solution was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to obtain 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-triazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one(4) [ka]

[0334] To a solution of intermediate B07 (50 mg, 0.146 mmol) in DMF (0.5 mL), K2CO3 (40.3 mg, 0.292 mmol), (1H-1,2,4-triazole-3-yl)methanol (4-a, 72.3 mg, 0.292 mmol), and KI (48.4 mg, 0.292 mmol) were added. The mixture was stirred at 25°C for 3 hours. The mixture was then filtered and purified by prep HPLC (water: MeCN (containing 10 mM NH4HCO3)) to obtain 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 to 31 shown in Table 8 were prepared in a manner similar to that described for Example 4, except that appropriate intermediate starting materials listed in the INT column were used. 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] TIFF2026516541000058.tif207165 TIFF2026516541000059.tif230165 TIFF2026516541000060.tif218165 TIFF2026516541000061.tif209166 TIFF2026516541000062.tif128165

[0337] Example 32 (S)-4-(cyclopropylethynyl)-7-((1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one(32) [ka]

[0338] Intermediate C03 (326 mg, 1.731 mmol) was added to a stirred mixture of intermediate B08 in DMF (4.0 mL) and K2CO3 (399 mg, 2.88 mmol). The resulting mixture was stirred at 40°C for 16 hours. The mixture was filtered, and the solution was purified by prep HPLC (water:ACN (containing NH4HCO3 adjusting agent)) to obtain 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-triazole-4-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one(33) [ka]

[0341] A mixture of intermediate B08 (24.1 mg, 0.070 mmol) in MeCN (0.22 mL), 1,2-dihydro-5-methyl-1,2,4-triazole-3-one (33-a, 8.27 mg, 0.083 mmol), K2CO3 (19.21 mg, 0.139 mmol), and KI (2.308 mg, 0.014 mmol) was stirred at 85°C for 45 minutes. The reaction mixture was cooled, diluted with MeOH / DCM (10% v / v), washed with water (3 × 5 mL), and then washed with brine (5 mL). The organic layer was dehydrated with MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to obtain 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 that appropriate intermediate starting materials listed in the INT column were used. [Table 10] TIFF2026516541000066.tif52165

[0344] Example 39 (S)-4-(cyclopropylethynyl)-6-fluoro-7-((2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-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 C01 (40.7 mg, 0.173 mmol) in DMF (1 mL), K2CO3 (35.9 mg, 0.260 mmol), LiBr (7.51 mg, 0.087 mmol), and intermediate B08 (30 mg, 0.087 mmol) were added. The mixture was stirred at 40°C for 16 hours. The reaction mixture was concentrated under reduced pressure and diluted with water (10 mL) and SiO2 (20 mL). The mixture was washed with water (10 mL) and brine (10 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to isolate compound 39-a. This compound was used without further purification.

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

[0347] Stage 2: (S)-4-(cyclopropylethynyl)-6-fluoro-7-((2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one(39) A solution of 39-a (50 mg, 0.092 mmol) in DCM (1 mL) and TFA (1 mL) was stirred at 15°C for 1 hour. The solution was cooled, concentrated under reduced pressure, and purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to obtain 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]pyrrole-1(4H)-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one(40) [ka]

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

[0351] 1H 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]pyridine-3-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one(41) [ka]

[0353] Step 1: tert-butyl (S)-(3-(((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)amino)pyridine-4-yl)carbamate(41-a) A mixture of intermediate B13 (60 mg, 0.184 mmol) and intermediate C02 (46.2 mg, 0.221 mmol) was stirred in EtOH (5 mL) and AcOH (0.05 mL) at 55°C for 16 hours. The reaction mixture was cooled to 15°C, and NaBH3CN (11.56 mg, 0.184 mmol) was added. The resulting mixture was stirred at 15°C for 4 hours. The reaction mixture was purified by prep HPLC (water: MeCN (containing 10 mM NH4HCO3)) to obtain compound 41-a.

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

[0355] Stage 3: (S)-4-(cyclopropylethynyl)-6-fluoro-7-((2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridine-3-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one(41) A mixture of (S)-7-(((4-aminopyridine-3-yl)amino)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazoline-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 this mixture, triphosgene (42.5 mg, 0.143 mmol) in THF (0.5 mL) was added dropwise. The reaction mixture was heated to 15°C and stirred for 2 hours. The mixture was quenched with saturated NaHCO3 aqueous solution (5 mL) and washed with water (2 × 5 mL). The organic layer was washed with brine (10 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to obtain compound 41.

[0356] 1 H 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-tetrahydroquinazoline-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-tetrahydroquinazoline-7-yl)methyl)imidazolidin-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 hours. The reaction product was added to water (10 mL) and extracted with SiO2 (2 × 5 mL). The combined organic layer was dehydrated with MgSO4 and concentrated under reduced pressure to isolate compound 42-a. This compound was used without further purification.

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

[0360] Stage 2: (S)-3-((4-(cyclopropylethynyl)-6-fluoro-3-methyl-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-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-tetrahydroquinazoline-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 obtain compound 42.

[0361] 1H 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-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one(43) [ka]

[0363] Step 1: (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-nitro-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-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), K2CO3 (36.3 mg, 0.263 mmol) and LiBr (11.40 mg, 0.131 mmol) were added. The reaction mixture was stirred at 50°C for 2 hours. The mixture was then diluted with water (5 mL) and extracted with RINKAN (3 × 10 mL). The combined organic layer was washed with brine (10 mL), dehydrated with Na2SO4, 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-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one(43) (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-nitro-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one (43-a, 30 mg, 0.072 mmol) was dissolved in EtOH (1 mL) and water (0.2 mL), to which NH4Cl (77 mg, 1.431 mmol) was added. Then, iron powder (40.0 mg, 0.715 mmol) was added, and the reaction mixture was stirred at 90°C for 2 hours. The reaction mixture was diluted with water (10 mL) and then extracted with ELISA (2 × 15 mL). The combined organic layers were washed with brine (5 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to obtain compound 43.

[0366] 1 H 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 that appropriate intermediate starting materials listed in the INT column were used. [Table 11]

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

[0369] To a solution of intermediates B07 (20 mg, 0.058 mmol) and C05 (15.85 mg, 0.070 mmol) in DMF (0.2 mL), KOH (9.82 mg, 0.175 mmol) was added. The reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with SiO (2 × 15 mL). The combined organic layer was washed with brine (5 mL), dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to isolate product 47.

[0370] 1 H 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-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one(48) [ka]

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

[0373] Step 2: (S)-6-chloro-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(hydroxymethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one(48) (S)-1-((6-chloro-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-pyrazole-3-carbaldehyde (48-a, 90 mg, 0.215 mmol) was dissolved in MeOH (1 mL) and NaBH4 (3.25 mg, 0.086 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure, diluted with NaHCO3 (20 mL), and extracted with ELISA (3 × 10 mL). The combined organic layers were dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to obtain 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 that appropriate intermediate starting materials listed in the INT column were used. [Table 12]

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

[0377] 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) were dissolved in EtOH (2 mL), to which K3PO4 (28.1 mg, 0.132 mmol) in water (0.5 mL) was added. The reaction mixture was stirred at 80°C for 4 hours. The reaction mixture was concentrated under reduced pressure, diluted with NaHCO3 (20 mL), and extracted with siRNA (3 × 10 mL). The combined organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to obtain compound 52.

[0378] 1H 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'-bipyrazole]-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one(53) [ka]

[0380] Example 53 was prepared in a manner similar to that of Example 52, except that 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] 1¹H 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-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-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), NaH (25.7 mg, 0.642 mmol) was added. The reaction mixture was stirred at 0°C for 30 minutes. Intermediate B07 (55.0 mg, 0.161 mmol) was added, and the mixture was stirred at 15°C for 1.5 hours. The solution was poured into NH4Cl (5 mL) and extracted with RINKAN (2 × 5 mL). The organic layer was washed with brine (2 × 5 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep HPLC (water: MeCN (containing 10 mM NH4HCO3)) to obtain compound 54.

[0384] 1H 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 that appropriate intermediate starting materials listed in the INT column were used. [Table 13] TIFF2026516541000080.tif214165 TIFF2026516541000081.tif113165

[0386] Example 67 (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-fluoro-3-(hydroxymethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one(67) [ka]

[0387] Step 1: (S)-7-((3-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluoro-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one(67-a) To a solution of intermediate C06 (67.2 mg, 0.292 mmol) in DMF (2 mL), NaH (10.50 mg, 0.438 mmol) was added at 0°C. The mixture was stirred at 0°C for 30 minutes. Intermediate B07 (50 mg, 0.146 mmol) was added, and the mixture was stirred at 20°C for 1.5 hours. The solution was poured into water (10 mL) and extracted with SiO (2 × 5 mL). The combined organic layers were washed with brine (2 × 5 mL), dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure to obtain product 67-a. This product 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-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one(67) A mixture of (S)-7-((3-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluoro-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-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 hour. The reaction mixture was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to obtain compound 67.

[0390] 1 H 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-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one(68) [ka]

[0392] Step 1: (S)-7-((3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one(68-a) To a solution of intermediate C04 (30 mg, 0.133 mmol) in DMF (2 mL), NaH (3.50 mg, 0.088 mmol) was added. The reaction mixture was stirred at 20°C for 30 minutes. Intermediate B07 (30 mg, 0.088 mmol) was added to the reaction mixture and stirred at 20°C for 1.5 hours. The mixture was quenched with saturated NH4Cl aqueous solution (10 mL) at 0°C and extracted with RINKAN (3 × 15 mL). The organic layer was washed with brine (3 × 9 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to isolate compound 68-a. This 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-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one(68) (S)-7-((3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one (68-a, 36 mg, 0.068 mmol) was dissolved in MeOH (1 mL), to which 3 M HCl / MeOH (0.2 mL, 0.600 mmol) was added. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to obtain compound 68.

[0395] 1H 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 that appropriate intermediate starting materials listed in the INT column were used. [Table 14]

[0397] Examples 72 and 73 (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-((S or R)-1-hydroxyethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one, and (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-((R or S)-1-hydroxyethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one (72 and 73) [ka]

[0398] Step 1: (S)-7-((3-acetyl-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one(72 / 73-a) To a solution of 1-(1H-pyrazole-3-yl)etanone (28.9 mg, 0.263 mmol) in DMF (3 mL), NaH (42.0 mg, 1.050 mmol) was added at 0°C. The mixture was stirred at 0°C for 0.5 hours. Subsequently, intermediate B07 (90 mg, 0.263 mmol) was added, and the resulting mixture was stirred at 15°C for 4 hours. The mixture was poured into a saturated NH4Cl aqueous solution (5 mL) and extracted with siRNA (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep TLC (SiO2, 66% siRNA:PE) to obtain 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-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one, and (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-((R or S)-1-hydroxyethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one (72 and 73) (S)-7-((3-acetyl-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one (72 / 73-a, 20 mg, 0.048 mmol) was dissolved in MeOH (1 mL), to which NaBH4 (1.817 mg, 0.048 mmol) was added at 0°C. The mixture was stirred at 15°C for 1 hour. The mixture was purified by prep HPLC (water: MeCN (containing 0.05% NH3H2O ​​+ 10 mM NH4HCO3)) and SFC (Chiralcel OD, 30% iPrOH (0.1% NH3H2O) / CO2, 65 g / min, 150 bar, 35°C) to obtain the following compounds.

[0401] 72 (Fast dissolution) : 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 (Slowly dissolves) : 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-imidazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one(74)

Chem.

[0403] Step 1: (S)-7-((2-bromo-1H-imidazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one(74-a) 2-bromo-1H-imidazole (75 mg, 0.510 mmol) was dissolved in THF (1.5 mL) and NaH (40.8 mg, 1.021 mmol) was added. The reaction solution was stirred at 60°C for 1 hour. Intermediate B07 in THF (1 mL) was added, and the reaction product was stirred at 60°C for 6 hours. The reaction mixture was diluted with water (20 mL) and extracted with SiO2 (3 × 15 mL). The combined organic layers were washed with brine (35 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep TLC (SiO2, 10% MeOH: SiO2) to obtain 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-imidazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one(74) (S)-7-((2-bromo-1H-imidazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one (74-a, 140 mg, 0.309 mmol) was dissolved in MeOH (0.5 mL), to which sodium methoxide (0.1 mL, 0.100 mmol) and CuI (11.76 mg, 0.062 mmol) were added under N2 conditions. The reaction mixture was stirred at 120°C for 7 hours. The mixture was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to obtain 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-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one(75) [ka]

[0408] The solution of Example 43 (20 mg, 0.051 mmol) and 37% formaldehyde aqueous solution (8.06 mg, 0.103 mmol) in DMF (1 mL) and AcOH (0.01 mL) was stirred at 15°C for 1 hour. NaBH3CN (6.46 mg, 0.103 mmol) was added at 15°C, and the resulting solution was stirred for 1 hour. The mixture was filtered and purified by prep-HPLC (water:MeCN (containing 0.1% TFA)) to obtain 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-pyrazole-1-yl)methyl)-6-fluoro-3,4-dihydroquinazoline-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% formaldehyde aqueous solution was replaced with 5 eq of 37% formaldehyde aqueous solution and MeOH was used as the solvent instead of DMF / AcOH.

[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-Tetrahydroquinazoline-7-yl)methyl)-1H-Imidazole-5-Carboxamide(77) [ka]

[0414] Stage 1: (S)-4-chloro-N-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxamide(77-a) Intermediate C22 (60 mg, 0.217 mmol) and HATU (82 mg, 0.217 mmol) were added to a vial, followed by the addition of 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. This solution was stirred at ambient temperature for 16 hours. The reaction mixture was added to SiO2 (40 mL), extracted with water (2 × 10 mL) and brine (10 mL), dehydrated with MgSO4, and concentrated under reduced pressure. The resulting residue was purified by flash silica chromatography (elution gradient 0 → 100% SiO2 in hexane) to isolate compound 77-a.

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

[0416] Stage 2: (S)-4-chloro-N-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-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-tetrahydroquinazoline-7-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxamide (77-a, 97.6 mg, 0.168 mmol) was incorporated into DCM (1524 μL):TFA (152 μL) at 40°C for 2 hours. The reaction product was concentrated under reduced pressure, and the residue was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to obtain 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-tetrahydroquinazoline-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 that 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-tetrahydroquinazoline-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 the addition of 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 product was concentrated under reduced pressure, and the residue was purified by prep HPLC (water: MeCN (containing 0.1% TFA)). The fraction was added to saturated NaHCO3 aqueous solution (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 freeze-dried 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 that appropriate intermediate starting materials listed in the INT column were used. [Table 15] TIFF2026516541000093.tif199166

[0425] Examples 90 and 91 (S)-7-((2H-indazole-2-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one, and (S)-7-((1H-indazole-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 minutes. B07 (27 mg, 0.079 mmol) was added at 0°C, and the mixture was stirred at room temperature for 16 hours. The reaction product was brought to 0°C, and water was added dropwise. The reaction mixture was stirred for 10 minutes. HCl (20 mL) was added, and the organic layer was extracted, washed with water (2 × 5 mL) and brine (5 mL), and dehydrated with MgSO4. The solution was concentrated under reduced pressure and purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to obtain compounds 90 and 91.

[0427] Rapidly eluting isomers (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) Slowly eluting isomers (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 that appropriate intermediate starting materials listed in the INT column were used. [Table 16] TIFF2026516541000096.tif76165

[0429] Example 99 (S)-7-((3-amino-4-methoxy-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one(99) [ka]

[0430] Step 1: (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(2,5-dimethyl-1H-pyrrole-1-yl)-4-methoxy-1H-pyrazole-1-yl)methyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one(99-a) To a solution of intermediate C15 (24.55 mg, 0.128 mmol) in DMF (2 mL), NaH (7.00 mg, 0.175 mmol) was added at 0°C under N2. The mixture was stirred at 20°C for 0.5 hours. Intermediate B07 (40 mg, 0.117 mmol) was added, and the mixture was stirred at 20°C for 1 hour. The mixture was poured into water (10 mL) and extracted with SiO (2 × 8 mL). The combined organic layers were washed with water (15 mL) and brine (15 mL), dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure to isolate compound 99-a. This compound was used without further purification.

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

[0432] Step 2: (S)-7-((3-amino-4-methoxy-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one(99) (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(2,5-dimethyl-1H-pyrrole-1-yl)-4-methoxy-1H-pyrazole-1-yl)methyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one (99-a, 50 mg, 0.100 mmol) was dissolved in EtOH (6 mL) and water (2 mL), to which hydroxylamine hydrochloride (384 mg, 5.53 mmol) and KOH (197 mg, 3.52 mmol) were added. The mixture was stirred at 90°C for 2 hours. The mixture was poured into water (20 mL) and extracted with ELISA (2 × 15 mL). The combined organic layers were washed with brine (2 × 20 mL), dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to obtain 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-tetrahydroquinazoline-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-tetrahydroquinazoline-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), NaH (34.6 mg, 0.865 mmol) was added at 0°C and the mixture was 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 heated to ambient temperature for 16 hours. The reaction product was quenched with water (dropwise). The mixture was added to RINKAN (10 mL) and washed with water (2 × 3 mL) and brine (3 mL). The organic layer was dehydrated with MgSO4 and concentrated under reduced pressure to isolate compound 100-a. This was used directly in the following reaction.

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

[0437] Stage 2: (S)-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-imidazole-2-carboxamide(100) Ethyl (S)-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-imidazole-2-carboxylate (100-a, 130 mg, 0.288 mmol) was dissolved in 7N ammonia (3 mL, 21.0 mmol) in MeOH and heated at 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 obtain 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-pyrazole-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one(101) [ka]

[0440] To a solution of intermediate B08 in DMF (2 mL), K2CO3 (63.6 mg, 0.46 mmol) and 3-methyl-1H-pyrazole (25.2 mg, 0.31 mmol) were added, and the mixture was stirred at 15°C for 3 hours. The reaction product was added to water (10 mL) and extracted by DCM. The organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to obtain 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-tetrahydroquinazoline-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 that 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), LiBr (3.80 mg, 0.044 mmol) and K2CO3 (12.10 mg, 0.088 mmol) were added. The resulting mixture was stirred at 50°C for 2 hours, then water (5 mL) was added, and the solution was extracted with RINKAN (2 × 5 mL). The combined organic layers were washed with water (5 mL) and brine (2 × 5 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to isolate compounds (103-a and 104-a). These 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-tetrahydroquinazoline-7-yl)methyl)-4-fluoro-1H-pyrazole-3-carboxylate (103-a, 80 mg, 0.172 mmol) was treated with 7N NH3 / MeOH (2 mL) and stirred at 60°C for 16 hours. The mixture was concentrated under reduced pressure and purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to obtain the title compound.

[0449] 103 (Fast-eluting isomers): 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 (Slowly eluting isomers): 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 104 For both, MS (ESI) m / z 436 [M+1]

[0450] Examples 105 and 106 (S)-7-((5-amino-1H-1,2,4-triazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one (105), and (S)-7-((3-amino-1H-1,2,4-triazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one (106) [ka]

[0451] To a solution of intermediate B07 (50 mg, 0.146 mmol) and 1H-1,2,4-triazole-3-amine (18.40 mg, 0.219 mmol) in DMF (3 mL), K2CO3 (60.5 mg, 0.438 mmol) and LiBr (12.67 mg, 0.146 mmol) were added. The mixture was stirred at 40°C for 8 hours. The reaction product was added to water (10 mL), extracted with RINKAN (2 × 10 mL), and the combined organic layer was concentrated under reduced pressure. The residue was purified by prep HPLC (water: MeCN (containing 0.1% TFA)) to obtain a mixture of isomers. This mixture was purified using SFC (DAICEL CHIRALCEL OZ, 30% MeOH, 100 bar, column temperature 40°C) to obtain the title compound.

[0452] 105 (Fast-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-triazole-1-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazoline-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 K2CO3 (877 mg, 6.35 mmol) was stirred in DMF (10 mL) at 20°C for 10 minutes. Intermediate B08 (200 mg, 0.577 mmol) was then added, and the reaction mixture was stirred at 40°C for 12 hours. The mixture was filtered and purified by prep HPLC (water:MeCN (containing 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 that appropriate intermediate starting materials listed in the INT column were used.

[0457] [Table 17]

[0458] Example 112 (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methoxymethyl)-1H-pyrazole-1-yl)methyl)-3-methyl-3,4-dihydroquinazoline-2(1H)-one(112) [ka]

[0459] 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)(H2O)4]Cl2 (6.07 mg, 0.013 mmol) were added to two oven-dried drum vials fitted with stirring rods. DMA (1291 μL) was added to the vials, followed by 1,1,3,3-tetramethylguanidine (24.30 μL, 0.194 mmol), and then N2 was spurged for 5 minutes. The reaction mixture was sealed and irradiated with a blue LED (PennOC M2, 450 nm, 100% intensity, 5200 rpm fan, 1000 rpm stirring) for 24 hours. The reaction mixture was filtered and purified by prep HPLC (water:MeCN (containing 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] Examples 113 and 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), 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) were added at 25°C. The reaction mixture was stirred at 40°C for 2 hours. Water (40 mL) was added to the reaction mixture, and the mixture was then extracted with SiO2 (40 mL). The organic layer was washed with brine (30 mL), then dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to isolate 113 (as a rapidly eluting isomer) and 114 (as a slowly 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-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one(115) [Chemical Structure]

[0465] NaH (58.3 mg, 1.459 mmol) was added to C17 (67.7 mg, 0.584 mmol) in DMF (5 mL) at 0°C. The mixture was stirred at 20°C for 0.5 hours. Next, B07 (100 mg, 0.292 mmol) was added, and the reaction mixture was stirred at 40°C for 4 hours. The mixture was added to water (15 mL) and extracted with SiO2 (3 × 15 mL). The combined organic layers were washed with brine (15 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep HPLC (water: MeCN (containing 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 a rapidly eluting isomer. Compound 117 was isolated as a slowly eluting isomer.

[0469] compound 116 : 1 H 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 H 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-tetrazole-2-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one(118) [ka]

[0471] A mixture of 5-methyl-2H-tetrazole (29.1 mg, 0.346 mmol), LiBr (30.1 mg, 0.346 mmol), and intermediate B08 (60 mg, 0.173 mmol) was mixed with K2CO3 (71.8 mg, 0.519 mmol). The mixture was stirred for 16 hours. The mixture was then filtered and purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to isolate compound 118.

[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-indazole-3-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one(119) [ka]

[0474] Step 1: (S)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-7-((2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-3-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one(119-a) In a glove box, NiCl2(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) were added to a mixture of intermediates C21 (47.2 mg, 0.144 mmol) and B08 (20 mg, 0.058 mmol) in DMA (2 mL). The reaction mixture was transferred out of the glove box and stirred at 80°C for 40 minutes. The reaction mixture was diluted with water (30 mL) and extracted with SiO2 (3 × 30 mL). The combined organic layer was washed with brine (30 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The crude substance was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to isolate compound 119-a.

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

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

[0477] 1 H 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-tetrahydroquinazoline-7-yl)methyl)-1H-pyrazole-3-sulfonamide(120) [ka]

[0479] A mixture of intermediate B07 (100 mg, 0.292 mmol), 1H-pyrazole-3-sulfonamide (47.2 mg, 0.321 mmol), and K2CO3 (81 mg, 0.584 mmol) was mixed with DMA (912 μL) and stirred at 80°C for 30 minutes. The reaction mixture was cooled, filtered, and purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to isolate compound 120. 1 H 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-pyrazole-1-yl)methyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one(121) [ka]

[0481] Compound 121 was prepared using a procedure similar to that of Example 120, except that 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-triazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one(122) [ka]

[0484] 4-Methyl-2,4-dihydro-3H-1,2,4-triazole-3-one (24.86 mg, 0.251 mmol), intermediate B07 (43 mg, 0.125 mmol), NaI (18.81 mg, 0.125 mmol), and K2CO3 (69.4 mg, 0.502 mmol) were added to a vial, followed by the addition of DMF (627 μL). The reaction mixture was heated at 50°C for 16 hours. The mixture was cooled, filtered, and the solution was purified by prep HPLC (water:MeCN (containing 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-pyrazole-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one(123) [ka]

[0487] Intermediate B10 (30 mg, 0.083 mmol), 4-methoxy-1H-pyrazole (8.1 mg, 0.083 mmol), and K2CO3 (40 mg, 0.289 mmol) were dissolved in DMA (826 μL) and heated at 60°C for 16 hours. The reaction product was cooled, filtered, and the solution was purified by prep HPLC (water:MeCN (containing 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] Examples 124 and 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-methylimidazolidin-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-methylimidazolidin-2,4-dione (125) [ka]

[0490] Stage 1: (S,E)-5-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methylene)-1-methylimidazolidin-2,4-dione(124-a) A mixture of intermediate B14 (140 mg, 0.434 mmol) and 2-aminoethane-1-ol (13.27 mg, 0.217 mmol) in EtOH (1.3 mL) and water (1.3 mL) was mixed with 1-methylimidazolidined-2,4-dione (149 mg, 1.303 mmol). The mixture was stirred at 120 °C for 48 hours. 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-methylimidazolidin-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-methylimidazolidin-2,4-dione (125) (S,E)-5-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methylene)-1-methylimidazolidin-2,4-dione (124-a, 80 mg, 0.198 mmol) was dissolved in AcOH (3 mL) and Zn (1643 mg, 25.1 mmol) was added. The mixture was stirred at 25°C for 12 hours. The reaction product was filtered and the solution was concentrated under reduced pressure. The residue was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to isolate a racemic mixture of products. The substance was separated by SFC (Daicel ChiralPak® AS, MeOH 40%, 100 psi) to isolate compounds 124 and 125.

[0493] Rapidly 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) Slowly eluting isomer 125 : 1 H 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-pyrazole-1-yl)methyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one(126) [ka]

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

[0496] 1 H 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-pyrazole-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one(127) [ka] In a vial, 3-methyl-1H-pyrazole (40.0 mg, 0.487 mmol) and Cs2CO3 (39.6 mg, 0.122 mmol) were combined in DMA (487 μL) and heated at 80°C for 0.5 hours. Intermediate B09 (16 mg, 0.049 mmol) was added to DMA (100 μL) and stirring was continued at 80°C for 16 hours. The reaction product was filtered through a syringe filter, and the solution was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to isolate compound 127.

[0498] 1 H 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-triazole-1-yl)methyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one(128) [ka]

[0500] 4,5-dimethyl-2,4-dihydro-3H-1,2,4-triazole-3-one (28.4 mg, 0.251 mmol), intermediate B07 (43 mg, 0.125 mmol), NaI (18.81 mg, 0.125 mmol), and K2CO3 (69.4 mg, 0.502 mmol) were added to a vial, followed by the addition of DMF (627 μL). The reaction mixture was heated at 50°C for 16 hours. The mixture was filtered and purified by prep HPLC (water:MeCN (containing 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-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one(129) [ka]

[0503] Step 1: (S)-7-((3-acetyl-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one(129-a) To a solution of 1-(1H-pyrazole-3-yl)etanone (9.64 mg, 0.088 mmol) in DMF (1 mL), NaH (14.00 mg, 0.350 mmol) was added at 0°C. The mixture was stirred at 0°C for 0.5 hours. Intermediate B07 (30 mg, 0.088 mmol) was added, and the mixture was stirred at 15°C for 1.5 hours. The solution was poured into a saturated aqueous solution of NH4Cl (5 mL) and extracted with RINKAN (2 × 5 mL). The combined organic layers were washed with brine (2 × 5 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to isolate compound 129-a. This compound 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-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one(129) (S)-7-((3-acetyl-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one (129-a) (15 mg, 0.036 mmol) was dissolved in THF (1 mL) and 3 M MeMgBr (0.018 mL, 0.054 mmol) in THF was added at 0°C. The mixture was stirred at 10°C for 10 minutes. The reaction product was poured into saturated NH4Cl aqueous solution (10 mL) and extracted with ELISA (2 × 30 mL). The combined organic layer was washed with brine (20 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep HPLC (water:MeCN (containing 0.1% TFA)) to isolate compound 129.

[0506] 1 ¹H 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 cytotoxic (HIV-TACK) activity: PBMCs derived from healthy donors were incubated in complete medium containing 5 μg / mL phytohemagglutinin (RPMI 1640 containing L-glutamine; 10% heat-inactivated fetal bovine serum; 100 U / mL penicillin-streptomycin) at 5% CO2, 37°C, and 90% humidity for approximately 2.5 × 10⁶ days. 6The cells were grown at a rate of cells / mL for 3 days. On the 4th day, the PHA-stimulated cells were washed and placed in complete medium containing IL-2 (10U / mL) with a VSV-G pseudo-HIV virus stock (VSV-G / pNLG1-P2A-ΔEnv-20μg / mL p24), with approximately 20 × 10⁶ cells. 6 Resuspend cells / mL, and store at 37°C in 5% CO2. 2 The cells were incubated at 90% humidity for 4 hours. VSV-G / pNLG1-P2A-ΔEnv is a VSV-G pseudovirus derived from pNL43, in which egfp is inserted at 5' of nef, and eGFP expression overrides the normally spliced ​​RNA transcript. The virus contains a Vif truncated to 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 a 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 22°C at 200 × g for 3 minutes. The cells were then placed in complete medium + 10 U / mL IL-2 for 5 × 10⁶ days. 6 The cells were resuspended at 37°C, 5% CO2, and 90% humidity overnight. For compound treatment, infected PBMCs were treated with RPMI 1640 containing L-glutamine, 50% normal human serum (NHS), 100 U / mL penicillin-streptomycin + IL-2 (10 U / mL) for 4 × 10⁶ days. 5 The compound was diluted to cells / mL, and 20,000 cells were transferred to each well of a 384-well poly-D-lysine coated compound plate containing the compound, with a final DMSO content of less than 0.5%. The compound was tested by 3x titration to 10 points. The plates were analyzed using an Acumen ex3 imager with a Blue Laser 488nm, and the number of GFP-positive objects where GFP was lost, representing the death of infected cells, was collected. Titration curves and EC50 values ​​were calculated using 4-parameter logistic fit. The results are shown in Table 17. [Table 18] TIFF2026516541000121.tif63166

Claims

1. Equation (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 It is an alkyl)aminocarbonyl-, where W is R = 0, 1, or 2. ５ Substituting with a substituent; Each R ５ is, independently, halo, C １－４ alkyl or C １－４ fluoroalkyl; R １ Hello, C １－６ Alkyl, (C ３－１２ ) Heterocycloalkyl (C ０－４ (Alkyl) or (C ３－１２ ) Cycloalkyl (C ０－４ It is alkyl; R ２ is hydrogen, halo, or C １－１０ It is alkyl; R ３ is hydrogen, halo, or C １－１０ It is alkyl; R ４ teeth, (a) A five-membered heteroaryl having at least one nitrogen atom, (b) A monocyclic, bicyclic, or tricyclic 7- to 14-membered heteroaryl comprising 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-triazoli-3-onyl, dihydropyrrolo[3,4-b]pyrrolonyl, imidazolidinonyl, 1,3-dihydro-2H-benzo[d]imidazole-2-onyl, dihydrobenzo[d]imidazolinonyl, 1,3-dihydroimidazo[4,5-c]pyridinonyl, oxazolo[5,4-c]pyridine-2-onyl, 1,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-onyl, 1,3 A ketone-containing ring system selected from -dihydroimidazo[4,5-b]pyridine-2-onyl, isoindolinonyl, 4,5-dihydropyrrolo[3,4-b]pyrrolonyl, 4,5-dihydropyrrolo[3,4-b]pyrrole-6(2H)onyl, benzo[d]oxazolonyl, benzo[d]oxazole-2-onyl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolonyl, and 1,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-4-onyl, Selected from; Here, R ４ R is 0, 1, 2, or 3 ４ａ Substituting with a substituent; Each R ４ａ 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 R is 0, 1, 2, or 3 ４ｂ Substituting with substituents; and, Each R ４ｂ Independently, C １－１０ Alkyloxy, C １－６ Alkyl, C １－１０ [Fluoroalkyl, amino, hydroxy, halo, or cyano] A compound represented by or a pharmaceutically acceptable salt thereof.

2. X is N(R ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. X is C(R ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. W is -C １－６ Alkyl-,-(C １－６ Alkyl)amino- or -(C １－６ It is an alkyl)aminocarbonyl, where W is 0, 1, or 2 R. ５ A compound according to claim 1, or a pharmaceutically acceptable salt thereof, substituted with a substituent.

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

6. R １ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound 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.

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

9. R ４ but, (a) A five-membered heteroaryl having at least one nitrogen atom, wherein the five-membered heteroaryl having at least one nitrogen atom is selected from triazolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrrolyl, tetrazolyl, flazanyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl and 1,2,3,5-oxatriazolyl; (b) A monocyclic, bicyclic, or tricyclic 7- to 14-membered heteroaryl comprising a ring containing at least one aromatic heteroatom, wherein the 7- to 14-membered heteroaryl comprises at least one nitrogen atom, and the monocyclic, bicyclic, or tricyclic 7- to 14-membered heteroaryl comprising a ring containing at least one aromatic heteroatom, wherein the 7- to 14-membered heteroaryl comprising 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 Selected from [4-d]pyrimidinyl, 2H-pyrazolo[3,4-d]pyrimidinyl, indolyl, 2H-pyrazolo[3,4-b]pyrimidinyl, benzo[d][1,2,3]-triazolyl, benzo[d]imidazolyl, indolidinyl, isoindolyl, purinyl, quinolidinyl, isoquinolyl, quinolyl, phthalazinyl, naphthylidinyl, quinoxalinyl, cinnolinyl, carbazolyl, phenatolidinyl, acridinyl, phenanthrolinyl, phenadinyl, 7H-pyrazino[2,3-c]carbazolyl, 1,3-benzoxazolyl and 2,1-benzoxazolyl; or, (c) Ketone-containing ring systems selected from ketone-containing ring systems selected from 2,4-dihydro-3H-1,2,4-triazoli-3-onyl, imidazolidinonyl, 1,3-dihydro-2H-benzo[d]imidazole-2-onyl, 1,3-dihydroimidazo[4,5-c]pyridinonyl, isoindolinonyl, 4,5-dihydropyrrolo[3,4-b]pyrrole-6(2H)onyl and benzo[d]oxazole-2-onyl, and 1,4,5,6-tetrahydrocyclopenta[c]pyrazolonyl; Selected from, and, Furthermore, here, R ４ R is 0, 1, 2, or 3 ４ａ A 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 However, 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 ) is selected, and here, R ４ａ R is 0, 1, 2, or 3 ４ｂ A compound according to claim 9 or a pharmaceutically acceptable salt thereof, substituted with a substituent.

11. Each R ４ｂ is independently C １－６ alkyloxy, C １－４ alkyl, C １－６ fluoroalkyl, amino, hydroxy, halo or cyano, a compound according to claim 10 or a pharmaceutically acceptable salt thereof.

12. Each R ５ The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein the compounds are 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-triazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(hydroxymethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-methoxy-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(hydroxymethyl)-1H-1,2,4-triazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((5-(hydroxymethyl)-1H-pyrazole-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((3-(hydroxymethyl)-1H-pyrazole-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-7-((2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-3-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1-methylimidazolidin-2,4-dione; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-(pyridine-4-yl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-methyl-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-3-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)benzo[d]oxazole-2(3H)-one; (S)-3-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)imidazolidin-2,4-dione; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-fluoro-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((4-chloro-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-pyrazole-3-carbonitride; (S)-7-((5-chloro-3-(methoxymethyl)-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((3-bromo-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((1H-1,2,4-triazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((2H-pyrazolo[4,3-c]pyridine-2-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-7-((6,7-dihydropyrano[4,3-c]pyrazole-1(4H)-yl)methyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-7-((6,7-dihydropyrano[4,3-c]pyrazole-2(4H)-yl)methyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-7-((1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((3-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((5-oxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((3-chloro-5-oxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((3-chloro-5-oxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((3-cyclopropyl-5-oxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((6-oxo-5,6-dihydropyrrolo[3,4-b]pyrrole-1(4H)-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridine-3-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-3-((4-(cyclopropylethynyl)-6-fluoro-3-methyl-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)imidazolidin-2,4-dione; (S)-7-((3-amino-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((3-amino-5-methyl-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((3-amino-4-methyl-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((3-amino-1H-pyrazole-1-yl)methyl)-4-(cyclopropyldifluoromethyl)-4-(cyclopropylethynyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(2-hydroxyethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-6-chloro-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(hydroxymethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((2-(hydroxymethyl)-1H-imidazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((5-(hydroxymethyl)-1H-imidazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-(hydroxymethyl)-1H-imidazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-7-(1H,1'H-[3,3'-bipirazole]-1-ylmethyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((1'-methyl-1H,1'H-[3,3'-bipirazole]-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methoxymethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((1H-imidazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methoxy-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-((R or S)-1-methoxyethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-((S or R)-1-methoxyethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((3-amino-5-chloro-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-oxo-3,4,5,6-tetrahydrocyclopenta[c]pyrazole-1(2H)-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-1-((4-(cyclopropyldifluoromethyl)-4-(cyclopropylethynyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-imidazole-2-carboxamide; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(difluoromethoxy)-1H-pyrazole-1-yl)methyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-(methoxymethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methoxymethyl)-1H-1,2,4-triazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((4-chloro-3-(methoxymethyl)-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-fluoro-3-(hydroxymethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(hydroxymethyl)-4-methyl-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((5-chloro-3-(hydroxymethyl)-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-(2-hydroxyethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((4-chloro-3-(hydroxymethyl)-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-((S or R)-1-hydroxyethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-((R or S)-1-hydroxyethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((2-methoxy-1H-imidazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methylamino)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(dimethylamino)-1H-pyrazole-1-yl)methyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-chloro-N-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-imidazole-5-carboxamide; (S)-4-chloro-N-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-imidazole-5-carboxamide; (S)-N-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-imidazole-2-carboxamide; (S)-N-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-imidazole-2-carboxamide; (S)-N-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-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-tetrahydroquinazoline-7-yl)methyl)-1-methyl-1H-imidazole-2-carboxamide; (S)-N-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)oxazole-2-carboxamide; (S)-2-amino-N-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-4-methylthiazole-5-carboxamide; (S)-N-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-4H-1,2,4-triazole-3-carboxamide; (S)-N-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-3-methyl-1H-pyrrole-2-carboxamide; (S)-N-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-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-tetrahydroquinazoline-7-yl)methyl)-1H-pyrrole-2-carboxamide; (S)-N-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)thiazole-2-carboxamide; (S)-7-((2H-indazole-2-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((1H-indazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((1H-benzo[d][1,2,3]triazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methyl-1H-indazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((1H-benzo[d]imidazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((4-chloro-3-methoxy-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((1-oxoisoindorin-2-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(4-methoxyphenyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((3-amino-4-methoxy-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-imidazole-2-carboxamide; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((3-methyl-1H-pyrazole-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-pyrazole-3-carbaldehyde; (S)-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-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-tetrahydroquinazoline-7-yl)methyl)-4-fluoro-1H-pyrazole-3-carboxamide; (S)-7-((5-amino-1H-1,2,4-triazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((3-amino-1H-1,2,4-triazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((3-amino-1H-1,2,4-triazole-1-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-3-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1-methylimidazolidin-2,4-dione; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((methyl(1H-pyrazole-3-yl)amino)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methoxymethyl)-1H-pyrazole-1-yl)methyl)-3-methyl-3,4-dihydroquinazoline-2(1H)-one; (S)-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-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-tetrahydroquinazoline-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-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-1,2,4-triazole-5-carboxamide; (S)-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-1,2,4-triazole-3-carboxamide; (S)-4-(cyclopropylethynyl)-6-fluoro-7-((5-methyl-2H-tetrazole-2-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((2H-indazole-3-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1H-pyrazole-3-sulfonamide; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((4-(difluoromethyl)-1H-pyrazole-1-yl)methyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-6-chloro-4-(cyclopropylethynyl)-7-((4-methoxy-1H-pyrazole-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; 5-(((S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1-methylimidazolidin-2,4-dione; (S)-5-(((S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1-methylimidazolidin-2,4-dione; (R)-5-(((S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)-1-methylimidazolidin-2,4-dione; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-((dimethylamino)methyl)-1H-pyrazole-1-yl)methyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-7-((3-methyl-1H-pyrazole-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3,4-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl)methyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; And, (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(2-hydroxypropan-2-yl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

14. below, (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methoxy-1H-1,2,4-triazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-7-((1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((3-amino-1H-pyrazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methoxymethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((5-amino-1H-1,2,4-triazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-7-((3-amino-1H-1,2,4-triazole-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazoline-2(1H)-one; (S)-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazoline-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-tetrahydroquinazoline-7-yl)methyl)-1H-1,2,4-triazole-5-carboxamide; (S)-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-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-tetrahydroquinazoline-7-yl)methyl)-1H-1,2,4-triazole-3-carboxamide The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

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

16. The pharmaceutical composition according to 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-adhesion inhibitors, and latency reversal agents.

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

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

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

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

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

22. The method according to 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-adhesion inhibitors, and latent reversal agents.

23. A compound according to any one of claims 1 to 14, for use in therapeutic purposes.

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