Tetrahydroquinazoline derivatives as selective cytotoxic agents

Abstract

The present disclosure relates to tetrahydroquinazoline derivatives of formula (I) and their use for selectively killing GAG-POL expressing cells infected by HIV without accompanying cytotoxicity on HIV primordial cells, and for treating or preventing HIV infection, or for treating, preventing or delaying the onset or progression of AIDS or AIDS-related syndrome (ARC). (I).

Description

Cross-references to related applications

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 512,403, filed July 7, 2023, the entire contents of which are incorporated herein by reference. Background Technology

[0002] Human immunodeficiency virus (HIV) is the pathogen of acquired immunodeficiency syndrome (AIDS). In the absence of viral suppression, HIV carriers exhibit severe immunodeficiency, making them extremely susceptible to opportunistic infections that can lead to debilitating and ultimately fatal infections. Several clinically approved antiretroviral drugs are available, which have shown multi-log reduction in viral load. Patients receiving treatment are at risk of acquiring mutations that can cause the virus in their bodies to develop resistance to existing therapies, and a rapid rebound of viremia is seen after treatment is discontinued, indicating that current treatment 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 called reverse transcriptase, followed by the integration of the DNA copy into the host's chromosomal DNA via a virally encoded integrase. Viral RNA is transcribed using host cell mechanisms along with viral accessory proteins, and viral proteins are translated. Many viral proteins are contained in the GAG ​​and GAG-POL polyproteins, where GAG ​​contains structural proteins, and GAG-POL is generated by a frameshift near the C-terminus of GAG and, in addition to structural proteins, contains proteases (PR), reverse transcriptase (RT), and integrase (IN) virases. GAG and GAG-POL cleave into individual proteins during the maturation process that occurs during virion budding from infected cells. At this point, GAG-POL dimers, and the dimerized HIV PR within the GAG-POL dimer forms an active enzyme that cleaves itself from the polyprotein and catalyzes further cleavage to form the remaining virases and structural proteins.

[0004] Available antiretroviral drugs work by blocking the virus at different 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 prevent the ability of replicated DNA to integrate into host cells; and protease inhibitors prevent viral maturation, resulting in immature and non-infectious virions produced by cells treated with protease inhibitors. Once integration occurs, the cell becomes infected until it dies through normal cell death pathways, accelerated death caused by viral factors, or targeted death by the immune system. While most infected cells are expected to die within about two days of infection, the rapid rebound of viremia after treatment withdrawal suggests that infected cells may persist even years after treatment. See For example, JB Dinoso et al. ,Proc. Natl. Acad. Sci. USA, 2009, 106(23): 9403-9408). These cells, which remain latently infected and / or persistently express the virus even during antiretroviral therapy, are collectively referred to as HIV reservoirs and are the reason why HIV carriers require highly adherent lifelong treatment to maintain the virus at undetectable levels. Therefore, novel therapies that selectively kill HIV-infected cells will provide new treatment options for HIV infection. These targeted activator of cell kill (TACK) molecules bind to the reverse transcriptase-p66 domain of the monomer Gag-Pol and act as allosteric regulators to accelerate dimerization, thereby leading to premature activation of intracellular viral proteases and resulting in HIV-1. + Cell death. TACK molecules retain potent antiviral activity and selectively eliminate infected CD4 cells isolated from HIV-1 carriers. + T cells, thereby supporting immune-independent clearance strategies ( See For example, CJ Balibar et al. , Sci. Transl. Med., 2023, 684 (15):eabn2038).

[0005] Treatment with compounds that can accelerate the death of HIV-infected cells and reduce the total number of persistent viral-infected cells in patients holds promise for reducing residual viremia in HIV-suppressed individuals and addressing comorbidities associated with chronic viral infection such as chronic inflammation, immune dysfunction, accelerated aging, cardiovascular disease (CVD), central nervous system (CNS) damage, and damage to other tissues and distal organs. Furthermore, treatment with compounds that can clear residual HIV reservoirs can prolong viral remission off-the-the-dose therapy and play a role in HIV cure strategies. Summary of the Invention

[0006] This disclosure relates to a tetrahydroquinazoline derivative and its use as a cell-killing HIV-targeting activator, which accelerates the death of HIV GAG-POL-expressing cells without affecting HIV primary cells (HIV na). The compounds exhibit cytotoxicity against HIV-infected GAG-POL-expressing cells. Therefore, these compounds can be used to selectively kill HIV-infected GAG-POL-expressing cells in HIV-infected subjects. Additionally, the compounds disclosed herein can be used to treat or prevent HIV infection, or to treat or prevent AIDS or AIDS-related syndromes (ARC), or to delay the onset or progression of AIDS or AIDS-related syndromes (ARC). Compositions comprising the compounds of this disclosure and methods of use are also provided.

[0007] In one aspect, this disclosure provides compounds of formula (I). (I), and its pharmaceutically acceptable salts. Detailed Implementation

[0008] This disclosure relates to tetrahydroquinazoline derivative compounds and their use in accelerating the death of HIV GAG-POL-expressing cells without cytotoxicity to HIV primary cells. In the absence of compounds such as those 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 catalyze intracellular GAG-POL dimerization of infected cells by binding to immature RT binding sites and triggering premature activation of the HIV PR enzyme in infected host cells before budding, thereby promoting the desired phenotype. As a result, PR cleaves the host substrate intracellularly, leading to cytotoxicity and cell death. This effect can be blocked in the presence of HIV protease inhibitors such as indinavir or darunavir, demonstrating the role of HIV protease in this process.

[0009] Because the homology between mature and immature RT bags in HIV allows the compound to bind to the mature hydrophobic bag near the active site of the viral RT enzyme, the compound disclosed herein also possesses activity as a non-nucleoside reverse transcriptase inhibitor (NNRTI). Binding to mature RT inhibits enzyme activity and the production of DNA proviruses, thereby preventing infection of primordial CD4+ T cells.

[0010] While the effects of NNRTI on the dimerization of RT and GAG-POL have been reported (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), Jochmans et al. first reported the selective killing of HIV-infected cells due to enhanced dimerization (Jochmans et al., Retrovirology 2010, 7:89). The authors generated data demonstrating these effects in chronically infected MT-4 cells, PBMCs, and CD4+ cells. Based on the potency of the tested molecules, they concluded: "These data provide proof of concept for targeted drugs to induce the elimination of HIV-producing cells. While NNRTI alone may not be sufficient for effective therapeutic applications, the results provide a foundation for drug development based on this mechanism of action." Recently, Zerbato... et al. (Zerbato et al. Trinité, Antimicrob. Agents Chemother. 2017, 61(3)) measured the activity of NNRTIs in a primary cell model of HIV latency. Compared with other classes of antiretroviral drugs, they found that some NNRTIs significantly reduced viral production and inferred that this was due to the ability of these compounds to eliminate cells expressing the HIV GAG-POL protein. Recently, Trinité et al. (Trinité et al. In their article, Retrovirology, 2019, 16(17), they proposed that NNRTI-induced PR activation triggers apoptotic cell death in resting or activated T cells that are effectively infected with HIV.

[0011] This disclosure relates to compounds of formula I. (I) Or its pharmaceutically acceptable salt, wherein: 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-, wherein W is surrounded by 0, 1 or 2 R 5 Substituents; Each R 5 Independent of halogen, C 1-4 Alkyl or C 1-4 Fluorinated alkyl groups; R 1 Halogen, C 1-6 Alkyl, (C 3-12 Heterocyclic alkyl (C 0-4 alkyl) or (C 3-12 )cycloalkyl (C 0-4 alkyl); R 2 It is hydrogen, halogen or C 1-10 alkyl; R 3 It is hydrogen, halogen or C 1-10 alkyl; R 4 Selected from: a) A 5-membered heteroaryl group having at least one nitrogen atom b) A monocyclic, bicyclic, or tricyclic 7- to 14-membered heteroaryl group comprising at least one heteroatom-containing aromatic ring, wherein the 7- to 14-membered heteroaryl group comprises at least one nitrogen atom, or c) Selected from the following ketone-containing ring systems: triazolinone, 2,4-dihydro-3 H -1,2,4-triazolyl-3-one, dihydropyrrolo[3,4-] b ]pyrrolidone, imidazolidinone, 1,3-dihydro-2H-benzo[d]imidazolidinone, dihydrobenzo[d]imidazolinone, 1,3-dihydroimidazo[4,5- c ]Pyridone group, oxazolo[5,4- c ]pyridin-2-one, 1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one, 1,3-dihydroimidazo[4,5- b ]Pyridin-2-one, isoindolinone, 4,5-dihydropyrrolo[3,4- b ]pyrrolidone, 4,5-dihydropyrrolo[3,4- b ]Pyrrole-6( 2H )keto, benzo[ d Oxazolone, benzo[ dOxazol-2-keto, 1,4,5,6-tetrahydrocyclopentanol c ]pyrazolone group and 1,5,6,7-tetrahydro-pyrazolo[4,3- c ]Pyridin-4-keto; Where R 4 By 0, 1, 2 or 3 R 4a Substituents; Each R 4a Selected independently from: C 1-6 alkyl, C 1-10 Fluoroalkyl, amino, Cyano, halogen, hydroxyl group (C 1-10 Alkoxy)C 0-10 alkyl, C 1-10 Fluoroalkoxy, -(C 1-10 alkyl)OH, (C 1-6 alkyl) 1-2 amino (C 0-10 alkyl), amino (C 1-10 alkyl), amino carbonyl (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); Where R 4a By 0, 1, 2 or 3 R 4b Substituents; and Each R 4b Independently for C 1-10 Alkoxy, C 1-6 Alkyl, C 1-10 Fluorinated alkyl, amino, hydroxyl, halogen or cyano groups.

[0012] In the first embodiment of the present invention, X is NR. 3, where R 3 It is hydrogen, halogen or C 1-10 Alkyl groups and other groups are provided as in general formula (I) above. In a variant of this embodiment, X is NR. 3 , where R 3 X is hydrogen, methyl, ethyl, propyl, or isopropyl, and other groups are provided as in general formula (I) above. In another variation of this embodiment, X is NR. 3 , where R 3 It is hydrogen or methyl, and other groups are provided as in general formula (I) above.

[0013] In the second embodiment of the present invention, X is C(R) 3 ), where R 3 It is hydrogen, halogen or C 1-10 Alkyl groups, and other groups as provided in general formula (I) above.

[0014] In the third embodiment of the present invention, W is -C 1-6 Alkyl-, -(C 1-6 alkyl)amino- or -(C 1-6 alkyl)aminocarbonyl-, wherein W is surrounded by 0, 1 or 2 R 5 The substituents are replaced, and the other groups are as in general formula (I) above or as provided in the first to second embodiments.

[0015] In the fourth embodiment of the present invention, W is -C 1-6 Alkyl-, wherein W is surrounded by 0, 1 or 2 R 5 The substituents are replaced, and the other groups are provided as in general formula (I) above or as in the first to third embodiments.

[0016] In the fifth embodiment of the present invention, W is -(C 1-6 alkyl)amino- or -(C 1-6 alkyl)aminocarbonyl-, wherein W is surrounded by 0, 1 or 2 R 5 The substituents are replaced, and the other groups are provided as in general formula (I) above or as in the first to third embodiments.

[0017] In the sixth embodiment of the present invention, W is -(C 0-6 Alkyl)O-, wherein W is surrounded by 0, 1 or 2 R 5 The substituents are replaced, and the other groups are provided as in general formula (I) above or as in the first to third embodiments.

[0018] In the seventh embodiment, W is methyl, -methyl(aminocarbonyl)- or -methylamino-, wherein W is surrounded by 0, 1 or 2 R- groups. 5The substituents are replaced, and the other groups are provided as in general formula (I) above or as in the first to third embodiments.

[0019] In the eighth implementation scheme, each R 5 The group is independently fluorine, chlorine, methyl, ethyl, propyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl or fluoromethyl, and other groups are provided as in general formula (I) above or as in the first to seventh embodiments.

[0020] In the ninth embodiment of the present invention, each R 5 The group is independently fluorine, chlorine, methyl, ethyl, propyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl or fluoromethyl, and other groups are provided as in general formula (I) above or as in the first to seventh embodiments.

[0021] In the tenth embodiment of the present invention, R 5 It is methyl, and the other groups are as in general formula (I) above or as provided in the first to seventh embodiments.

[0022] In the eleventh embodiment of the present invention, R 1 Halogen, C 1-6 Alkyl, (C 3-7 Heterocyclic alkyl (C 0-4 alkyl) or (C 3-7 )cycloalkyl (C 0-4 Alkyl groups, and other groups are those provided in general formula (I) above or in the first to tenth embodiments.

[0023] In the twelfth embodiment of the present invention, R 1 For fluorine, chlorine, bromine, methyl, ethyl, just -propyl, isopropyl, butyl, isobutyl Zhong -Butyl, Uncle -Butyl, pentyl, isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl, and other groups are provided as in general formula (I) above or as in the first to tenth embodiments.

[0024] In the thirteenth embodiment of the present invention, R 1 It is fluorine, methyl or cyclopropyl, and other groups are as in general formula (I) above or as provided in the first to tenth embodiments.

[0025] In the fourteenth embodiment of the present invention, R 2 For hydrogen, fluorine, chlorine, bromine, methyl, ethyl, just -propyl, isopropyl, butyl, isobutyl Zhong -Butyl, Uncle-Butyl, pentyl, isopentyl or neopentyl, and other groups are provided as in general formula (I) above or as in embodiments one through thirteen.

[0026] In the fifteenth embodiment of the present invention, R 2 It is hydrogen, fluorine or chlorine, and other groups are provided as in general formula (I) above or as in embodiments one through thirteen.

[0027] In the sixteenth embodiment of the present invention, R 3 For hydrogen, fluorine, chlorine, methyl, bromine, ethyl, just -propyl, isopropyl, butyl, isobutyl Zhong -Butyl, Uncle -Butyl, pentyl, isopentyl or neopentyl, and other groups are provided as in general formula (I) above or as in embodiments one through fifteen.

[0028] In the seventeenth embodiment of the present invention, R 3 It is hydrogen, and other groups are as in general formula (I) above or as provided in the first to fifteenth embodiments.

[0029] In the eighteenth embodiment of the present invention, R 3 It is methyl, and the other groups are those provided in general formula (I) above or in the first to fifteenth embodiments.

[0030] In the nineteenth embodiment of the present invention, in R 4 In this context, the 5-membered heteroaryl group having at least one nitrogen atom is selected from: triazolyl (such as 1,2,4-triazolyl, 1,2,3-triazolyl), pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrroleyl, tetrazolyl, furazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, and 1,2,3,5-oxtriazolyl, wherein R 4 By 0, 1, 2 or 3 R 4a The substituents are replaced, and the other groups are provided as in general formula (I) above or as in the first to eighteenth embodiments.

[0031] In the twentieth embodiment of the present invention, in R 4 In this context, the 5-membered heteroaryl group having at least one nitrogen atom is selected from: 1,2,3-triazolyl, 1,2,4-triazolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyrroleyl, and tetrazolyl, wherein R 4 By 0, 1, 2 or 3 R 4a The substituents are replaced, and the other groups are provided as in general formula (I) above or as in the first to eighteenth embodiments.

[0032] In the twenty-first embodiment of the present invention, in R 4 Among them, a monocyclic, bicyclic, or tricyclic 7- to 14-membered heteroaryl group containing at least one heteroatom aromatic ring ( wherein the 7- to 14-membered heteroaryl group contains at least one nitrogen atom) is selected from 2 H -pyrazolo[4,3- c ]pyridyl, 1 H -pyrazolo[3,4- c ]pyridyl, 6,7-dihydropyrano[4,3-c]pyrazolyl, 2 H -pyrazolo[3,4- d ]Pyrimidinyl, 2 H -pyrazolo[3,4- d ]Pyrimidinyl, indoleyl, 2 H -pyrazolo[3,4- b ]pyridyl, benzo[ d [1,2,3]-triazolyl, benzo[ d Imidazolyl, indoleazinyl, isoindoleyl, purine, quinazinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthidyl, quinoxalinyl, cenolinyl, carbazolyl, phenanthridineyl, acridineyl, phenanthroxalinyl, phenazinyl, 7 H -pyrazino[2,3-c]carbazole, 1,3-benzoxazolyl and 2,1-benzoxazolyl, wherein R 4 By 0, 1, 2 or 3 R 4a The substituents are replaced, and the other groups are provided as in general formula (I) above or as in the first to eighteenth embodiments.

[0033] In the twenty-second embodiment of the present invention, in R 4 Among them, a monocyclic, bicyclic, or tricyclic 7- to 14-membered heteroaryl group containing at least one heteroatom aromatic ring ( wherein the 7- to 14-membered heteroaryl group contains at least one nitrogen atom) is selected from 2 H -pyrazolo[4,3- c ]pyridyl, 1 H -pyrazolo[3,4- c ]pyridyl, 6,7-dihydropyrano[4,3-c]pyrazolyl, 2 H -pyrazolo[3,4- d ]Pyrimidinyl, 2 H -pyrazolo[3,4- d ]Pyrimidinyl, indoleyl, 2 H -pyrazolo[3,4- b ]pyridyl, benzo[ d [1,2,3]-triazolyl and benzo[ d Imidazole group, wherein R 4a By 0, 1, 2 or 3 R 4aThe substituents are replaced, and the other groups are provided as in general formula (I) above or as in the first to eighteenth embodiments.

[0034] In the twenty-third embodiment of the present invention, in R 4 In this context, the ketone-containing ring system is selected from 2,4-dihydro-3- H -1,2,4-triazolyl-3-one, imidazolylone, 1,3-dihydro-2 H -Benz[d]imidazol-2-keto, 1,3-dihydroimidazol[4,5-] c ]Pyridone group, isoindolinone group, 4,5-dihydropyrrolo[3,4- b ]Pyrrole-6( 2H ) Ketone and benzo[ d Oxazol-2-keto, 1,4,5,6-tetrahydrocyclopentanol c ]Pyrazolone group, wherein R 4 By 0, 1, 2 or 3 R 4a The substituents are replaced, and the other groups are provided as in general formula (I) above or as in the first to eighteenth embodiments.

[0035] In the twenty-fourth embodiment of the present invention, R 4 Selected from: a) a 5-membered heteroaryl group having at least one nitrogen atom, wherein the 5-membered heteroaryl group having at least one nitrogen atom is selected from: triazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrroleyl, tetrazolyl, furazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl and 1,2,3,5-oxtriazolyl; b) A monocyclic, bicyclic, or tricyclic 7- to 14-membered heteroaryl group comprising at least one heteroatom-containing aromatic ring ( wherein the 7- to 14-membered heteroaryl group comprises at least one nitrogen atom), and the monocyclic, bicyclic, or tricyclic 7- to 14-membered heteroaryl group comprising at least one heteroatom-containing aromatic ring ( wherein the 7- to 14-membered heteroaryl group comprises at least one nitrogen atom) is selected from 2 H -pyrazolo[4,3- c ]pyridyl, 1 H -pyrazolo[3,4- c ]pyridyl, 6,7-dihydropyrano[4,3-c]pyrazolyl, 2 H -pyrazolo[3,4- d ]Pyrimidinyl, 2 H -pyrazolo[3,4- d ]Pyrimidinyl, indoleyl, 2 H -pyrazolo[3,4- b]pyridyl, benzo[ d [1,2,3]-triazolyl, benzo[ d Imidazolyl, indoleazinyl, isoindoleyl, purine, quinazinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthidyl, quinoxalinyl, cenolinyl, carbazolyl, phenanthridineyl, acridineyl, phenanthroxalinyl, phenazinyl, 7 H -pyrazino[2,3-c]carbazole, 1,3-benzoxazolyl and 2,1-benzoxazolyl; or c) A ketone-containing ring system, wherein the ketone-containing ring system is selected from 2,4-dihydro-3- H -1,2,4-triazolyl-3-one, imidazolyl ketone, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 1,3-dihydroimidazol[4,5- c ]Pyridone group, isoindolinone group, 4,5-dihydropyrrolo[3,4- b ]Pyrrole-6( 2H ) Ketone and benzo[ d Oxazol-2-keto, 1,4,5,6-tetrahydrocyclopentanol c ]Pyrazolone group; Where R 4 By 0, 1, 2 or 3 R 4a The substituents are replaced, and the other groups are provided as in general formula (I) above or as in the first to eighteenth embodiments.

[0036] In the twenty-fifth embodiment of the present invention, each R 4a Selected independently from: C 1-6 Alkyl, C 1-10 Fluorinated alkyl, amino, cyano, halogen, hydroxyl, (C 1-6 Alkoxy)C 0-10 Alkyl, C 1-10 Fluoroalkoxy, -(C 1-10 alkyl)OH, (C 1-6 alkyl) 1-2 amino (C 0-10 alkyl), amino (C 1-10 alkyl), aminocarbonyl (C 0-10 Alkyl), (C 3-7 )cycloalkyl (C 0-6 Alkyl), (C 5-6 ) heteroaryl (C 0-6 Alkyl), (C 6-14 )Aryl(C 0-6 alkyl), -(C 0-4 alkyl)carbonyl and –(C 0-5 alkyl)–(S(=O)2NH2), where R 4a By 0, 1, 2 or 3 R 4bThe substituents are replaced, and the other groups are those provided in general formula (I) above or in the first to twenty-fourth embodiments.

[0037] In the twenty-sixth embodiment of the present invention, each R 4a Selected independently from: C 1-4 Alkyl, C 1-6 Fluorinated alkyl, amino, cyano, halogen, hydroxyl, (C 1-6 Alkoxy)C 0-6 Alkyl, C 1-6 Fluoroalkoxy, -(C 1-6 alkyl)OH, (C 1-4 alkyl) 1-2 amino (C 0-6 alkyl), amino (C 1-6 alkyl), aminocarbonyl (C 0-6 )alkyl), (C 3-7 )cycloalkyl (C 0-4 Alkyl), (C 5-6 ) heteroaryl (C 0-4 Alkyl), (C 6-14 )Aryl(C 0-6 alkyl), -(C 0-4 alkyl)carbonyl and –(C 0-4 alkyl)–(S(=O)2NH2), where R 4a By 0, 1, 2 or 3 R 4b The substituents are replaced, and the other groups are those provided in general formula (I) above or in the first to twenty-fourth embodiments.

[0038] In the twenty-seventh embodiment of the present invention, each R 4a Independently selected from: hydroxymethyl, methoxy, phenyl, pyridyl, oxomethyl, aminosulfonyl, methyl, 2-hydroxypropyl, fluorine, chlorine, cyano, difluoromethyl, (dimethylamino)methyl, methoxymethyl, bromine, amino, hydroxyethyl, pyrazolyl, (methoxy)ethyl, aminocarbonyl, difluoromethoxy, 2-hydroxyethyl, methylamino, and dimethylamino, wherein R 4a By 0, 1, 2 or 3 R 4b The substituents are replaced, and the other groups are those provided in general formula (I) above or in the first to twenty-fourth embodiments.

[0039] In the twenty-eighth implementation scheme, each R 4b Selected independently from C 1-6 Alkoxy, C 1-4 Alkyl, C 1-6 Fluoroalkyl, amino, hydroxyl, halogen or cyano groups, and other groups are provided as in general formula (I) above or as in the first to twenty-seventh embodiments.

[0040] In the twenty-ninth implementation scheme, each R 4b Selected independently from C 1-4 Alkoxy, C 1-4 Alkyl, C 1-4 Fluoroalkyl or halogen, and other groups are provided as in general formula (I) above or as in embodiments one through twenty-seven.

[0041] In the thirtieth embodiment of the present invention, each R 4b The groups are independently selected from methyl and methoxy groups, and the other groups are those provided in general formula (I) above or in the first to twenty-seventh embodiments.

[0042] In one embodiment of the invention, this disclosure relates to compounds of formula I. (I) Or its pharmaceutically acceptable salt, wherein: X is N(R) 3 ) or C(R 3 ); W is -C 1-6 Alkyl-, -(C 1-6 alkyl)amino- or -(C 1-6 alkyl)aminocarbonyl-, wherein W is surrounded by 0 or 1 R 5 Substituents; Each R 5 It is methyl; R 1 It is F, methyl, or cyclopropyl; R 2 It can be hydrogen, fluorine, or chlorine; R 3 It can be hydrogen or methyl; R 4 Selected from: a) A 5-membered heteroaryl group having at least one nitrogen atom, selected from: triazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrroleyl, tetrazolyl, furazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl and 1,2,3,5-oxtriazolyl; b) A monocyclic, bicyclic, or tricyclic 7- to 14-membered heteroaryl group comprising at least one heteroatom-containing aromatic ring, selected from 2 H -pyrazolo[4,3- c ]pyridyl, 1 H -pyrazolo[3,4- c ]pyridyl, 6,7-dihydropyrano[4,3-c]pyrazolyl, 2 H -pyrazolo[3,4-d ]Pyrimidinyl, 2 H -pyrazolo[3,4- d ]Pyrimidinyl, indoleyl, 2 H -pyrazolo[3,4- b ]pyridyl, benzo[ d [1,2,3]-triazolyl, benzo[ d Imidazolyl, indoleazinyl, isoindoleyl, purine, quinazinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthidyl, quinoxalinyl, cenolinyl, carbazolyl, phenanthridineyl, acridineyl, phenanthroxalinyl, phenazinyl, 7 H -pyrazino[2,3-c]carbazole, 1,3-benzoxazolyl and 2,1-benzoxazolyl, or c) Ketone-containing ring systems selected from 2,4-dihydro-3- H -1,2,4-triazolyl-3-one, imidazolylone, 1,3-dihydro-2 H -benzo[ d Imidazole-2-keto, 1,3-dihydroimidazole[4,5-] c ]Pyridone group, isoindolinone group, 4,5-dihydropyrrolo[3,4- b ]Pyrrole-6(2 H ) Ketone and benzo[ d Oxazol-2-keto, 1,4,5,6-tetrahydrocyclopentanol c ]Pyrazolone group; Where R 4 By 0, 1, 2 or 3 R 4a Substituents; Each R 4a Independently selected from: hydroxymethyl, methoxy, phenyl, pyridyl, oxomethyl, aminosulfonyl, methyl, 2-hydroxypropyl, fluorine, chlorine, cyano, difluoromethyl, (dimethylamino)methyl, methoxymethyl, bromine, amino, hydroxyethyl, pyrazolyl, (methoxy)ethyl, aminocarbonyl, difluoromethoxy, 2-hydroxyethyl, methylamino, and dimethylamino, wherein R 4a By 0, 1, 2 or 3 R 4b Substituents; and Each R 4b It is independently selected from methyl and methoxy.

[0043] One embodiment of the present invention relates to a compound of formula (Ia). (Ia) Or its pharmaceutically acceptable salt, wherein: W is -C 1-6 Alkyl-, -(C 1-6 alkyl)amino- or -(C 1-6alkyl)aminocarbonyl-, wherein W is surrounded by 0, 1 or 2 R 5 Substituents; Each R 5 Independent of halogen, C 1-4 Alkyl or C 1-4 Fluorinated alkyl groups; R 1 Halogen, C 1-6 Alkyl, (C 3-12 Heterocyclic alkyl (C 0-4 alkyl) or (C 3-12 )cycloalkyl (C 0-4 alkyl); R 2 It is hydrogen, halogen or C 1-10 alkyl; R 4 It is a 5-membered heteroaryl group having at least one nitrogen atom. Where R 4 By 0, 1, 2 or 3 R 4a Substituents; Each R 4a Selected independently from: C 1-6 alkyl, C 1-10 Fluoroalkyl, amino, Cyano, halogen, hydroxyl group (C 1-10 Alkoxy)C 0-10 alkyl, C 1-10 Fluoroalkoxy, -(C 1-10 alkyl)OH, (C 1-6 alkyl) 1-2 amino (C 0-10 alkyl), amino (C 1-10 alkyl), amino carbonyl (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); Where R 4a By 0, 1, 2 or 3 R 4b Substituents; and Each R 4b Independently for C 1-10 Alkoxy, C 1-6 Alkyl, C 1-10 Fluorinated alkyl, amino, hydroxyl, halogen or cyano groups.

[0044] Another embodiment of the present invention relates to a compound of formula (Ia). (Ia) Or its pharmaceutically acceptable salt, wherein: R 1 It is F, methyl, or cyclopropyl; R 2 It can be hydrogen, fluorine, or chlorine; R 4 Selected from: 5-membered heteroaryl R having at least one nitrogen atom 4 , where R 4 Selected from: 1,2,4-triazolyl, 1,2,3-triazolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrroleyl, tetrazolyl, furazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl and 1,2,3,5-oxtriazolyl; Furthermore, R 4 By 0, 1, 2 or 3 R 4a Substituents; Each R 4a Selected independently from: C 1-6 alkyl, C 1-10 Fluoroalkyl, amino, Cyano, halogen, hydroxyl group (C 1-10 Alkoxy)C 0-10 alkyl, C 1-10 Fluoroalkoxy, -(C 1-10 alkyl)OH, (C 1-6 alkyl) 1-2 amino (C 0-10 alkyl), amino (C 1-10 alkyl), amino carbonyl (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); Where R 4a By 0, 1, 2 or 3 R 4b Substituents; and Each R 4b Independently for C 1-10 Alkoxy, C 1-6 Alkyl, C 1-10 Fluorinated alkyl, amino, hydroxyl, halogen or cyano groups.

[0045] Non-limiting examples of compounds of Formula I include compounds 1 to 129 or pharmaceutically acceptable salts thereof, as illustrated in the examples: ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methoxy-1 H -1,2,4-triazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(hydroxymethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-methoxy-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(hydroxymethyl)-1 H-1,2,4-triazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((5-(hydroxymethyl)-1 H -pyrazol-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((3-(hydroxymethyl)-1 H -pyrazol-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((2-oxo-1,2-dihydro-3-) H -imidazo[4,5- b ]pyridin-3-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-7-((2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1 H )-ketone; ( S )-3-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1-methylimidazolidine-2,4-dione; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-(pyridin-4-yl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-methyl-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((2-oxo-2,3-dihydro-1) H -Benz[d]imidazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-3-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)benzo[d]oxazol-2(3 H )-ketone; ( S )-3-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)imidazolidine-2,4-dione; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-fluoro-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((4-chloro-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -Pyrazole-3-carboxynitrile; ( S )-7-((5-chloro-3-(methoxymethyl)-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((3-bromo-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((1 H-1,2,4-triazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((2 H -pyrazolo[4,3-c]pyridin-2-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-7-((6,7-dihydropyrano[4,3-c]pyrazole-1(4 H )-yl)methyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-7-((6,7-dihydropyrano[4,3-c]pyrazole-2(4 H )-yl)methyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((2-oxo-2,3-dihydro-1) H -Benz[d]imidazol-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-7-((1,3-dimethyl-5-oxo-1,5-dihydro-4- H -1,2,4-triazol-4-yl)methyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((3-methyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((3-chloro-5-oxo-1,5-dihydro-4 H -1,2,4-triazol-4-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((3-chloro-5-oxo-1,5-dihydro-4 H -1,2,4-triazol-4-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((3-Cyclopropyl-5-oxo-1,5-dihydro-4- H -1,2,4-triazol-4-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((2-oxo-2,3-dihydro-1) H -imidazo[4,5- c ]pyridin-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((6-oxo-5,6-dihydropyrrolo[3,4-b]pyrrole-1(4 H )-methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((2-oxo-1,2-dihydro-3-) H -imidazo[4,5- c ]pyridin-3-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1 H )-ketone; (S )-3-((4-(cyclopropylethynyl)-6-fluoro-3-methyl-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)imidazolidine-2,4-dione; ( S )-7-((3-amino-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((3-amino-5-methyl-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((3-amino-4-methyl-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((3-amino-1 H -pyrazol-1-yl)methyl)-4-(cyclopropyldifluoromethyl)-4-(cyclopropylethynyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(2-hydroxyethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-6-chloro-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(hydroxymethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((2-(hydroxymethyl)-1 H -imidazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((5-(hydroxymethyl)-1 H -imidazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-(hydroxymethyl)-1 H -imidazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-(1 H ,1' H -[3,3'-Bipyrazole]-1-ylmethyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((1'-methyl-1 H ,1' H -[3,3'-Bipyrazole]-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methoxymethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((1 H -imidazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methoxy-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-( R or S )-1-methoxyethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-( S or R )-1-Methoxyethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((3-amino-5-chloro-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-oxo-3,4,5,6-tetrahydrocyclopentan[c]pyrazole-1(2 H )-methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-1-((4-(cyclopropyldifluoromethyl)-4-(cyclopropylethynyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -Imidazole-2-formamide; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(difluoromethoxy)-1 H -pyrazol-1-yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-(methoxymethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methoxymethyl)-1 H -1,2,4-triazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((4-chloro-3-(methoxymethyl)-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-fluoro-3-(hydroxymethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(hydroxymethyl)-4-methyl-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((5-chloro-3-(hydroxymethyl)-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-(2-hydroxyethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; (S)-7-((4-chloro-3-(hydroxymethyl)-1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-( S or R )-1-hydroxyethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H)-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-( R or S )-1-hydroxyethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((2-methoxy-1 H -imidazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methylamino)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(dimethylamino)-1 H -pyrazol-1-yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-chloro- N -((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -Imidazole-5-formamide; ( S )-4-chloro- N -((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -Imidazole-5-formamide; ( S )- N -((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -Imidazole-2-formamide; ( S )- N-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -Imidazole-2-formamide; ( S )- N -((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)- N -Methyl-1 H -Imidazole-2-formamide; ( S )- N -((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1-methyl-1 H -Imidazole-2-formamide; ( S )- N -((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)oxazol-2-carboxamide; ( S )-2-amino- N -((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-4-methylthiazolyl-5-carboxamide; ( S )- N -((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-4 H -1,2,4-triazole-3-carboxamide; ( S )- N -((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-3-methyl-1 H -Pyrrole-2-carboxamide; ( S )- N -((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-4-methyl-1 H -Imidazole-5-formamide; ( S)-4-cyano-N-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -Pyrrole-2-carboxamide; ( S )- N -((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)thiazolyl-2-carboxamide; ( S )-7-((2 H -Indazol-2-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((1 H -Indazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((1 H -Benz[d][1,2,3]triazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methyl-1 H -indazole-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((1 H -Benz[d]imidazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((4-chloro-3-methoxy-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S)-4-(cyclopropylethynyl)-6-fluoro-7-((1-oxoisoindoline-2-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(4-methoxyphenyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((4-oxo-4,5,6,7-tetrahydro-1 H -pyrrolo[3,2-c]pyridin-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; (S )-7-((3-amino-4-methoxy-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -Imidazole-2-formamide; ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((3-methyl-1 H -pyrazol-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -Pyrazole-3-carboxaldehyde; ( S )-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-4-fluoro-1 H -Pyrazole-5-carboxamide; ( S)-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-4-fluoro-1 H -Pyrazole-3-carboxamide; ( S )-7-((5-amino-1 H -1,2,4-triazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((3-amino-1 H -1,2,4-triazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((3-amino-1 H -1,2,4-triazol-1-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((5-oxo-4,5-dihydro-1) H -1,2,4-triazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-3-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1-methylimidazolidine-2,4-dione; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((methyl(1 H -pyrazol-3-yl)amino)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methoxymethyl)-1 H -pyrazol-1-yl)methyl)-3-methyl-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -1,2,4-triazole-3-carboxamide; ( S )-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -1,2,4-triazole-5-carboxamide; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-fluoro-3-methoxy-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -1,2,4-triazole-5-carboxamide; ( S )-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -1,2,4-triazole-3-carboxamide; ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((5-methyl-2-) H -Tetrazol-2-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((2 H -Indazol-3-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S)-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -Pyrazole-3-sulfonamide; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((4-(difluoromethyl)-1H-pyrazol-1-yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-methyl-5-oxo-4,5-dihydro-1) H -1,2,4-triazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-6-chloro-4-(cyclopropylethynyl)-7-((4-methoxy-1 H -pyrazol-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; 5-((( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1-methylimidazolidine-2,4-dione; ( S )-5-((( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1-methylimidazolidine-2,4-dione; ( R )-5-((( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1-methylimidazolidine-2,4-dione; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-((dimethylamino)methyl)-1 H -pyrazol-1-yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-7-((3-methyl-1H-pyrazol-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3,4-dimethyl-5-oxo-4,5-dihydro-1 H -1,2,4-triazol-1-yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; and ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(2-hydroxypropyl-2-yl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone.

[0046] In one embodiment of the invention, the compound of formula I includes the following compounds or pharmaceutically acceptable salts thereof. ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methoxy-1 H -1,2,4-triazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-7-((1,3-dimethyl-5-oxo-1,5-dihydro-4- H -1,2,4-triazol-4-yl)methyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((3-amino-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methoxymethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((5-amino-1 H -1,2,4-triazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((3-amino-1 H -1,2,4-triazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -1,2,4-triazole-3-carboxamide; ( S )-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -1,2,4-triazole-5-carboxamide; ( S )-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -1,2,4-triazol-5-carboxamide; and ( S )-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -1,2,4-triazole-3-carboxamide.

[0047] In a variation of this embodiment, the compound or a pharmaceutically acceptable salt thereof is ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methoxy-1 H -1,2,4-triazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone.

[0048] In another variant, the compound or its pharmaceutically acceptable salt is ( S )-4-(cyclopropylethynyl)-7-((1,3-dimethyl-5-oxo-1,5-dihydro-4- H -1,2,4-triazol-4-yl)methyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone.

[0049] In another variant, the compound or its pharmaceutically acceptable salt is ( S)-7-((3-amino-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone.

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

[0051] In another variant, the compound or its pharmaceutically acceptable salt is ( S )-7-((5-amino-1 H -1,2,4-triazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone.

[0052] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is ( S )-7-((3-amino-1 H -1,2,4-triazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone.

[0053] 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-tetrahydroquinazolin-7-yl)methyl)-1 H -1,2,4-triazole-3-carboxamide.

[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-tetrahydroquinazolin-7-yl)methyl)-1 H -1,2,4-triazole-5-carboxamide.

[0055] 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-tetrahydroquinazolin-7-yl)methyl)-1 H -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-tetrahydroquinazolin-7-yl)methyl)-1 H -1,2,4-triazole-3-carboxamide.

[0057] This invention relates to compounds of Formula I herein, and all embodiments, examples, categories, and subcategories thereof, including compounds described in the examples herein. The invention also relates to compounds of Formula I, which are neutral compounds or salts thereof (where such salts are possible), including pharmaceutically acceptable salts.

[0058] The term "such as (eg)" means "for example." When the terms "such as (eg)" or "for example" are used in this document, the examples described are intended to be illustrative and not to be an exhaustive list of all relevant examples. The term "that is (ie)" means "in other words (that is)."

[0059] As used herein, "alkyl" refers to a branched or straight-chain saturated aliphatic hydrocarbon group having a specified number of carbon atoms within a specified range. For example, "C 1-8 "Alkyl" refers to each of the alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, including its straight-chain and branched isomers. "C" 1-8 "alkyl" includes "C 1-6 "alkyl" groups and straight-chain and branched alkyl groups having 7 or 8 carbons in the chain.

[0060] The term "alkyl" and other groups prefixed with "alkane," such as alkoxy, dialkylamino, and trialkylammonium, refer to aliphatic hydrocarbon groups in which one of their hydrogen atoms is replaced by a bond.

[0061] “Amino” refers to -NH- or -NH2-, in which one or more hydrogen atoms may be substituted, as further described herein.

[0062] "Amino carbonyl" refers to -C(=O)NH.

[0063] "Aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic aromatic ring or ring system containing 5-14 carbon atoms, wherein at least one ring is aromatic. Examples of aryl groups include phenyl, biphenyl, and naphthyl. In one embodiment of the invention, the aryl group is phenyl.

[0064] A “double-ring” or “double-ring system” refers to two connected rings. The rings can be fused, meaning they share two adjacent atoms, or they can be “spiral rings,” meaning they share only one atom.

[0065] “Celite ® (Fluka) Diatomite is diatomaceous earth and can also be called "diatomite".

[0066] "Carbonyl" refers to a functional group (C=O) formed by the double bond between a carbon atom and an oxygen atom.

[0067] "Carboxyl group" refers to the -CO2H group. 。 The bonding with the parent group is achieved through the carbon atoms of the carbonyl component.

[0068] “Cycloalkyl” or “C” 3-12 “Cycloalkyl” refers to any monovalent non-aromatic group derived from a monocyclic, bicyclic, tricyclic, or tetracyclic ring system having 3 to 12 carbon atoms. These non-aromatic groups, having 3, 4, 5, 6, 7, 8, or up to 12 carbon ring atoms, may be fully saturated or partially unsaturated. Unless otherwise specified in the specification, cycloalkyl groups may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused or bridged ring systems. Here, the connection point between “cycloalkyl” and the rest of the molecule is on a saturated ring. Bicyclic cycloalkyl ring systems include fused ring systems (where two rings share two atoms (e.g., decahydronaphthalene)), spirocyclic ring systems (where two rings share one atom (e.g., spiro[4.5]decyl)), and bridged ring groups (e.g., norbornyl).

[0069] Additional examples within the foregoing meaning include, but are not limited to, monovalent groups of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.2]octyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, [1.1.1]-bicyclopentane, bicyclo[3.1.0]hexyl, cyclohexenyl, cyclopentenyl, 1-decahydronaphthyl, spiro[2.4]heptyl, spiro[2.2]pentyl, and norbornyl.

[0070] Term "C" 3-8"Cycloalkyl" (or "C3-C8 cycloalkyl" or "C3-8 cycloalkyl") refers to a cyclic ring of an alkane having a total of three to eight carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl). The term "C" 3-7 cycloalkyl, C 3-6 cycloalkyl, C 5-7 "Cycloalkyl" and similar terms have similar meanings.

[0071] "Fluoroalkyl" refers to an alkyl group as described above, wherein one or more (particularly, 1 to 10) hydrogen atoms have been replaced with fluorine atoms, and at most all hydrogen atoms have been completely replaced by halogen groups. C 1-6 Halogenated alkyl groups, for example, include -CH2F, -CHF2, -CF3, -CF4, -CF2CF3, -CHFCH3, etc.

[0072] "Halogen" or "halogen" refers to chlorine, fluorine, bromine, and / or iodine. Chlorine, fluorine, and bromine are a class of halogens of interest, with fluorine and chlorine being particularly noteworthy.

[0073] As used herein, the term "heteroaryl" refers to a stable monocyclic, bicyclic, or tricyclic ring system containing 5-14 carbon atoms and at least one cyclic heteroatom selected from N, S, and O, wherein at least one heteroatom-containing ring is aromatic. Bicyclic heteroaryl ring systems include fused ring systems (where two rings share two atoms) and spirocyclic systems (where two rings share one atom).

[0074] The heteroaryl groups defined herein include, but are not limited to: azaindolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiazolyl, benzo[ d Isothiazolyl, benzoxazolyl, carbazole, cenyl, furanyl, imidazolyl, indololinyl, indolyl, indolazinyl, indazole, isobenzofuranyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, oxazolinyl, isoxazolinyl, pyranyl, pyrazinyl, pyrazolyl, pyrroleyl, pyrazolopyrimidyl, pyridazinyl, pyrimidyl, pyrimidinyl, quinazolinyl, quinolinyl, quinoxalolinyl, tetrazolyl, tetrazoolopyridinyl, thiadiazolyl, 5 H -pyrrolo[3,4- b Pyridine, thiazolyl, thiophene, triazolyl, triazine, benzothiazolyl, benzothiaphene, quinolinyl, quinazolinyl, isoquinolinyl, 2 H -pyrazolo[4,3- c ]pyridyl, 1 H -pyrazolo[3,4- c]pyridyl, 6,7-dihydropyrano[4,3-c]pyrazolyl, 2 H -pyrazolo[3,4- d ]Pyrimidinyl, 2 H -pyrazolo[3,4- d ]Pyrimidinyl, 2 H -pyrazolo[3,4- b ]pyridyl, benzo[ d [1,2,3]-triazolyl, benzo[ d Imidazolyl, indoleazinyl, purinyl, quinazinyl, phthalazinyl, naphridinyl, carbazole, phenanthridine, acridineyl, phenanthrolinel, phenazinyl, 7H-pyrazino[2,3-c]carbazole, 1,3-benzoxazolyl, and 2,1-benzoxazolyl. If the heteroaryl group contains a nitrogen atom, it should be understood that its corresponding... N -Oxides are also included in this definition.

[0075] As used herein, the term "heterocyclic alkyl" refers to a stable and non-aromatic (including incompletely aromatic, e.g., one double bond) 3- to 12-membered ring (i.e., C12-). 3-12 A heterocyclic alkyl group comprises two to twelve cyclic carbon atoms and one to six cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. Whenever it appears herein, numerical ranges such as “3 to 12” or “3-12” refer to each integer within the given range. For example, “3 to 12 cyclic atoms” means that the heterocyclic alkyl group may consist of 3, 4, 5, etc., up to and including 12 cyclic atoms. In some embodiments, it is a 5- to 10-cyclic heterocyclic alkyl. In some embodiments, it is a 4- to 10-cyclic heterocyclic alkyl. In some embodiments, it is a 3- to 10-cyclic heterocyclic alkyl. In some embodiments, it is a 3- to 7-cyclic heterocyclic alkyl. Unless otherwise specifically stated in the specification, the heterocyclic alkyl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. The prefixes nitro, oxo, or thio before the root name of heterocyclic alkyl indicate the presence of at least one nitrogen, oxygen, or sulfur atom as a ring atom, respectively. The heterocyclic alkyl group is partially or fully saturated. Heterocyclic alkyl groups can be attached to the rest of the molecule by any atom of the ring.

[0076] In one embodiment, the heterocyclic alkyl group is monocyclic and has about 3 to about 7 ring atoms. In another embodiment, the heterocyclic alkyl group is monocyclic and has about 5 to about 8 ring atoms. In another embodiment, the heterocyclic alkyl group is bicyclic and has about 8 to about 11 ring atoms. In yet another embodiment, the heterocyclic alkyl group is monocyclic and has 5 or 6 ring atoms. In one embodiment, the heterocyclic alkyl group is monocyclic. In another embodiment, the heterocyclic alkyl group is bicyclic. In another embodiment, the heterocyclic alkyl group is tricyclic. Adjacent oxygen and / or sulfur atoms are absent in the ring system.

[0077] Non-limiting examples of heterocyclic alkyl rings include decahydroisoquinoline, dioxaspiro[4.5]decane, 2,5-diazabicyclo[2.2.1]heptyl, quininecycloyl, oxacyclobutyl, piperidinyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolyl, 1,4-dioxane, tetrahydrofuranyl, tetrahydrothiopheneyl, piperidinyl, 2-azabicyclo[2.1.1]hexyl, 6-azaspiro[2.5]octyl, azabicyclobutyl, 3a,5,6,6a-tetrahydro-4 H -pyrrolo[3,4- d Isoxazole, diazabicyclo[3.3.2]decyl, 2,3,4,5,6,7-hexahydroisothiazo[5,4- c ]Pyridyl, hexahydro-2 H -pyrrolo[3,4- d Isothiazolyl, 3,9-diazabicyclo[3.3.2]decyl, 2',3'-dihydro-1' H -spiro[piperidine-4,4'-quinazolin], octahydropyrrolo[3,4- b [1,4]oxazinyl, (diazabicyclo[2.2.1]heptyl), 2,5-diazabicyclo[2.2.1]heptyl, tetrahydrobenzo[ d ]Thiazolyl, 2,3-dihydrobenzofuranyl, oxabicyclo[2.1.1]hexyl, dihydrothiazo[5,4- c ]Pyridine-5(4 H )-yl, diazaspiro[4.4]nonyl and 2,7-diazaspiro[4.4]nonyl and all their isomers. In one embodiment of the invention, the heterocyclic alkyl ring includes piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azeridinyl, and azeridinyl.

[0078] The term "ketone" refers to -(C=O)-R, where R is another carbon atom or hydrocarbon group.

[0079] "HIV primary cells" are cells that are not infected with HIV.

[0080] "Compatible anti-HIV agents" are anti-HIV agents that do not contain HIV protease inhibitors.

[0081] "Lateness reversal agents" (LRAs) are agents that can reactivate HIV (e.g., HIV-1) that are latent in HIV-infected cells (especially in humans).

[0082] A "stable" compound is one that can be prepared and isolated, and whose structure and properties remain substantially unchanged or can remain substantially unchanged for a period of time sufficient to allow the compound to be used for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject). The compounds disclosed herein are limited to stable compounds covered by Formula I and its embodiments. For example, certain portions as defined in Formula I may be unsubstituted or substituted, the latter intended to cover substitution patterns (i.e., the number and type of substituents) that are chemically possible and result in a stable compound for that portion.

[0083] This disclosure includes individual diastereomers, particularly epimers, i.e., compounds having the same chemical formula but with different spatial arrangements around a single atom. This disclosure also includes mixtures of diastereomers in all ratios, particularly mixtures of epimers. This disclosure covers the presence of asymmetric centers that may be present in compounds of Formula I, as well as any additional asymmetric centers having ( R )or( S Compounds of Formula I with stereoisomers and mixtures of their stereoisomers. Embodiments of this disclosure also include mixtures of enantiomers rich in 51% or more of one enantiomer (including, for example, 60% or more, 70% or more, 80% or more, or 90% or more of one enantiomer). A single enantiomer is preferred. A single or mono-enantiomer refers to an enantiomer obtained by chiral synthesis and / or using known separation and purification techniques, and it may be 100% a single enantiomer or contain a small amount (e.g., 10% or less) of the opposite enantiomer. Therefore, the subject matter of this disclosure includes single enantiomers in pure form (including both levorotatory and dextrorotatory enantiomers), racemic forms, and mixtures of two enantiomers in all ratios. In the case of cis / trans isomers, this disclosure includes cis and trans forms and mixtures of these forms in all ratios.

[0084] If desired, the mixture can be separated by conventional methods (e.g., by chromatography or crystallization), and the individual stereoisomers can be prepared by using stereochemically consistent synthetic starting materials or by stereoselective synthesis. Optionally, derivatization can be performed prior to the separation of stereoisomers. The separation of the stereoisomer mixture can be carried out as an intermediate step during the synthesis of the compound of Formula I, or from the final racemic product. The absolute stereochemistry can be determined by X-ray crystallography of the crystalline product or crystalline intermediate, if necessary, by derivatization of the crystalline product or crystalline intermediate with a reagent containing a stereocenter of known configuration. Alternatively, the absolute stereochemistry can be determined by vibrational circular dichroism (VCD) spectroscopy. This disclosure includes all such isomers of racemates, enantiomers, diastereomers, and tautomers, as well as salts, solvates (including hydrates), and solvated salts and mixtures thereof.

[0085] As will be understood by those skilled in the art, certain compounds of this disclosure may be able to exist as tautomers. All tautomer forms of such compounds, whether isolated or in mixtures, are within the scope of this disclosure. For example, where an oxo (=O) substituent is permitted on a heterocyclic ring and keto-enol tautomerism is possible, it should be understood that the substituent may be present virtually entirely or partially in the -OH and oxo form. Examples of tautomers of the compounds herein include, but are not limited to, the following:

[0086] The atoms in compounds of Formula I may exhibit their natural isotopic abundances, or one or more atoms may be artificially enriched with specific isotopes having the same number of atoms but different atomic masses or mass numbers from those that are predominantly found in nature. This disclosure is intended to include all suitable isotopic variants of compounds of Formula I; for example, different isotopic forms of hydrogen (H) include protium (… 1 H) and deuterium ( 2 H). Protium is the dominant hydrogen isotope found in nature. Deuterium enrichment can provide certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or can provide compounds that can be used as standards for characterizing biological samples. Isotope-enriched compounds of Formula I can be prepared without excessive experimentation using conventional techniques well known to those skilled in the art or using methods similar to those described in the schemes and examples herein, using suitable isotope-enriching reagents and / or intermediates.

[0087] The compounds may be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt that has the efficacy of the parent compound and has no undesirable properties (e.g., is neither toxic nor otherwise harmful to the recipient). When a compound of Formula I contains one or more acidic or basic groups, the present invention includes the corresponding pharmaceutically acceptable salt.

[0088] Therefore, Formula I compounds containing acidic groups (e.g., -COOH) can be used according to the invention as, for example, but not limited to, alkali metal salts, alkaline earth metal salts, or as ammonium salts. Examples of such salts include, but are not limited to, sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines (such as, for example, ethylamine, ethanolamine, triethanolamine, or amino acids). Formula I compounds containing one or more basic groups (i.e., groups that can be protonated) can be used according to the invention as acid addition salts with inorganic or organic acids, for example, but not limited to, salts with hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, trifluoroacetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, neopentanoic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, aminosulfonic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, etc. If a compound of Formula I contains both acidic and basic groups in its molecule, the invention also includes, in addition to the salt forms mentioned, internal salts or betaine (zwitterions). Salts can be obtained from compounds of Formula I by methods known to those skilled in the art, for example by combining with an organic or inorganic acid or base in a solvent or dispersant, or by anion or cation exchange from other salts. The invention also includes all salts of compounds of Formula I that are not directly suitable for use in pharmaceuticals due to their low physiological compatibility, but can be used, for example, as intermediates in chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0089] This disclosure covers any composition consisting of a compound of Formula I or a salt thereof, including, but not limited to, compositions consisting of said compound together with one or more other molecular and / or ionic components, which may be referred to as a “eutectic.” As used herein, the term “eutectic” refers to a solid phase (which may or may not be crystalline) in which two or more distinct molecular and / or ionic components (typically in stoichiometric proportions) are bound together by nonionic interactions, including but not limited to hydrogen bonds, dipole-dipole interactions, dipole-quadrupole interactions, or dispersion forces (van der Waals forces). There is no proton transfer between dissimilar components, and the solid phase is neither a simple salt nor a solvate. Discussions of eutectics can be found, for example, in S. Aitipamula et al. Crystal Growth and Design , 2012, 12(5), pp. 2147-2152.

[0090] Furthermore, the compounds of this disclosure may exist in amorphous and / or one or more crystalline forms, and therefore all amorphous and crystalline forms of the compounds of Formula I and their salts, and mixtures thereof, are intended to be included within the scope of this disclosure. Additionally, some of the compounds of this disclosure may form solvates (i.e., hydrates) with water or with common organic solvents. Such solvates and hydrates of the compounds of this disclosure, particularly pharmaceutically acceptable solvates and hydrates, as well as unsolvated and anhydrous forms of such compounds, are also covered within the scope of the compounds and their pharmaceutically acceptable salts as defined by Formula I.

[0091] Therefore, the present invention relates to compounds of formula I or salts thereof, including pharmaceutically acceptable salts thereof, embodiments thereof described and claimed herein, and specific compounds thereof, and covers all possible stereoisomers, tautomers, physical forms (e.g., amorphous and crystalline forms), eutectic forms, solvates and hydrates, and any combination of the foregoing forms (where such forms are possible).

[0092] Another embodiment of this disclosure is a composition comprising a compound of formula I, wherein the compound or a salt thereof is present in the composition in a substantially pure form. As used herein, “substantially pure” means that the composition or product containing the compound of formula I or a salt thereof (e.g., a product isolated from a reaction mixture providing the compound or salt) suitably comprises 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% by weight to about 99% by weight), even more preferably at least about 95% by weight (e.g., about 95% by weight to about 99% by weight or about 98% by weight to 100% by weight), and most preferably at least about 99% by weight (e.g., 100% by weight). The purity level of the compound and salt can be determined using standard analytical methods such as high performance liquid chromatography and / or mass spectrometry or NMR techniques. If more than one analytical method is used and these methods provide experimentally significant differences in the measured purity levels, the method providing the highest purity level shall prevail. A composition containing a compound or salt of 100% purity is a composition that is free of detectable impurities as determined by standard analytical methods. For compounds of the present invention having one or more asymmetric centers and existing as a mixture of stereoisomers, a substantially pure composition containing said compound can be a substantially pure mixture of stereoisomers or a substantially pure individual stereoisomer.

[0093] The compounds of Formula I and their pharmaceutically acceptable salts described herein can be used to induce GAG-POL dimerization in HIV-infected cells, thereby selectively killing HIV-infected GAG-POL-expressing cells without cytotoxicity to HIV-native cells. This is referred to herein as TACK (cell-killing targeted activator) activity, or more specifically, HIV TACK activity. HIV TACK or TACK was previously also referred to as small molecule activated cell killing (SMACK). Therefore, the compounds of Formula I and their pharmaceutically acceptable salts can be used for: (i) A method for treating or preventing HIV infection, or treating, preventing AIDS or ARC, or delaying the onset or progression of AIDS or ARC in a human subject in need, said method comprising administering to a human subject an effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof; and / or (ii) A method for inducing GAG-POL dimerization in HIV-infected cells of a human subject in need of this, said method comprising administering to the human subject an effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof; and / or (iii) A method for selectively killing HIV-infected GAG-POL-expressing cells in human subjects without cytotoxicity to HIV primary cells, said method comprising administering to a human subject an effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof; and / or (iv) A method for enhancing the suppression of HIV viremia in human subjects by administration of one or more compatible HIV antiviral agents, the method comprising administering to the human subject an effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof.

[0094] Additionally, compounds of Formula I and pharmaceutically acceptable salts thereof may be used in any of the methods (i), (ii), (iii), or (iv) described above, further comprising 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-attachment inhibitors, and latency reversal agents. In the methods immediately preceding (i), (ii), (iii), or (iv) above, in addition to treatment with one or more compatible HIV antiviral agents, human subjects may also be treated with compounds of Formula I or pharmaceutically acceptable salts thereof.

[0095] Compounds of Formula I and pharmaceutically acceptable salts thereof may also be used in a method of enhancing the suppression of HIV viremia in human subjects who have been suppressed by administration of one or more compatible HIV antiviral agents, the method comprising additionally administering to the human subject an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0096] Other embodiments of this disclosure include the following: (a) A pharmaceutical composition comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier thereof.

[0097] (b) A pharmaceutical composition comprising a product prepared by combining (e.g., mixing) an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.

[0098] (c) The pharmaceutical composition of (a) or (b) further comprises an effective amount of one or more compatible anti-HIV agents selected from HIV antiviral agents, immunomodulators, anti-infective agents and latency reversal agents.

[0099] (d) and (c) are pharmaceutical compositions wherein the compatible anti-HIV agent is selected from one or more antiviral agents, and the antiviral agent is selected from nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase translocation inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors, HIV maturation inhibitors, post-attachment inhibitors, and latency reversal agents.

[0100] (e) A combination comprising (i) a compound of formula I or a pharmaceutically acceptable salt thereof and (ii) one or more compatible anti-HIV agents selected from HIV antiviral agents, immunomodulators, anti-infective agents and latency reversal agents; wherein the compound and the compatible anti-HIV agent are each used in an amount that makes the combination effective for treating or preventing HIV infection, or for treating or preventing AIDS or ARC, or for delaying the onset or progression of AIDS or ARC.

[0101] (f) and (e) are combinations thereof, wherein the compatible anti-HIV agent is an 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-attachment inhibitors, and latency reversal agents.

[0102] (g) Methods for inducing GAG-POL dimerization in HIV-infected cells, methods for selectively killing HIV-infected GAG-POL-expressing cells without cytotoxicity to HIV primary cells, and / or methods for treating or preventing HIV infection, or treating or preventing AIDS or ARC, or delaying the onset or progression of AIDS or ARC, including administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a subject in need of such treatment.

[0103] (h) (g) method, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered in combination with an effective amount of at least one other compatible HIV antiviral agent, said HIV antiviral agent being selected from nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside reverse transcriptase translocation inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors, HIV maturation inhibitors, post-attachment inhibitors, and latency reversal agents.

[0104] (i) (g) or (h) methods, including administering to a subject the pharmaceutical composition of (a), (b), (c) or (d) or a combination of (e) or (f).

[0105] (j) Use of a compound of Formula I or a pharmaceutically acceptable salt thereof in the manufacture of an agent for (1) inducing GAG-POL dimerization in HIV-infected cells of a subject; (2) selectively killing HIV-infected GAG-POL-expressing cells in a subject without cytotoxicity to HIV primary cells; (3) treating or preventing HIV infection in a subject; (4) treating or preventing AIDS or ARC in a subject or delaying the onset or progression of AIDS or ARC; (5) enhancing suppression of HIV viremia in a subject receiving treatment with a compatible anti-HIV agent; and / or (6) enhancing suppression of HIV viremia in a subject whose HIV viremia has been suppressed by administration of one or more compatible HIV antiviral agents.

[0106] (k) A compound of Formula I or a pharmaceutically acceptable salt thereof, for (1) inducing GAG-POL dimerization in HIV-infected cells; (2) selectively killing HIV-infected GAG-POL-expressing cells without cytotoxicity to HIV primary cells; (3) treating or preventing HIV infection; (4) treating or preventing AIDS or ARC or delaying the onset or progression of AIDS or ARC; and / or (5) enhancing the suppression of HIV viremia in subjects receiving treatment with compatible anti-HIV agents; and / or (6) enhancing the suppression of HIV viremia in subjects whose HIV viremia has been suppressed by administration of one or more compatible HIV antiviral agents.

[0107] Further embodiments of the invention include the pharmaceutical compositions, methods, and uses set forth in the foregoing paragraphs, wherein the compound of formula I or a salt thereof used therein is substantially pure. With respect to pharmaceutical compositions comprising a compound of formula I or a salt thereof and a pharmaceutically acceptable carrier and optionally one or more excipients, it should be understood that the term "substantially pure" refers to the compound of formula I or a salt thereof itself.

[0108] In another embodiment of this disclosure are the pharmaceutical compositions, methods, agents, uses, and combinations set forth herein, wherein the HIV of interest is HIV-1. Thus, for example, in any pharmaceutical composition, method, agent, use, and combination using a compound of Formula I or a pharmaceutically acceptable salt thereof, the compound or a salt thereof is used in an amount effective against HIV-1; and when used in combination with one or more compatible anti-HIV agents, each of these additional agents is a compatible HIV-1 antiviral agent selected, for example but not limited to, nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside reverse transcriptase translocation inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors, HIV maturation inhibitors, post-attachment inhibitors, and latency reversal agents.

[0109] The term “application” and its variations (e.g., “application of the compound”) for compounds of Formula I refer to providing the compound to an individual in need of treatment or prevention, and include self-application 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 that can be used to treat or prevent HIV infection or AIDS), “application” and its variations should each be understood to include providing the compound and other agents simultaneously or at different times. When the combined agents are administered simultaneously, they may be administered together in a single composition or they may be administered separately.

[0110] As used herein, the term "composition" is intended to cover products containing the specified ingredients, as well as any products resulting from the combination of the specified ingredients. Ingredients suitable for inclusion in a pharmaceutical composition are pharmaceutically acceptable, meaning that these ingredients must be compatible with each other and harmless to their recipients.

[0111] As used herein, the terms “subject” or “patient” refer to a human being (or “person”) who has become the subject of treatment, observation, or experimentation. Examples of patients awaiting HIV TACK treatment include, but are not limited to, patients already infected with HIV and / or whose HIV viral load has been suppressed and / or is considered undetectable at the time of HIV TACK treatment. Patients awaiting HIV TACK treatment also include, but are not limited to, those using HIV TACK to prevent HIV infection or undergoing post-exposure prophylaxis after potential exposure to HIV to prevent infection.

[0112] "Prevention" includes each of pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP), wherein pre-exposure prophylaxis is the use of a compound of 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 is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof to prevent HIV infection after possible exposure to HIV.

[0113] As used herein, the term "effective amount" refers to an amount of compound sufficient to induce GAG-POL dimerization in HIV-infected cells and selectively kill HIV-infected GAG-POL-expressing cells without cytotoxicity to HIV-native cells; and / or to exert a therapeutic and / or preventive effect upon administration. One embodiment of "effective amount" is a "therapeutic effective amount," which is an amount of 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 amount" is a "preventive effective amount," which is an amount of compound effective in preventing HIV infection or preventing AIDS or ARC in HIV-infected patients. It should be understood that an effective amount can be both a therapeutically effective amount (e.g., for treating HIV infection) and a preventive effective amount (e.g., for preventing HIV-infected subjects from developing AIDS or ARC or reducing the risk of developing AIDS or ARC).

[0114] In the combination therapy of the present invention, the effective amount may refer to each individual agent or the combination as a whole, wherein the amounts of all agents administered in the combination are effective together, but wherein the component agents of the combination may or may not be present individually in an effective amount, the effective amount being referenced to the amount of the component agent that is considered effective when administered alone.

[0115] In the methods of the present invention (i.e., selectively killing HIV-infected GAG-POL-expressing cells, treating HIV infection, preventing HIV infection, or treating or preventing AIDS or ARC, or delaying the onset or progression of AIDS or ARC, and other methods described herein), the compounds of the present invention or salts thereof may be administered by contacting the active agent with the site of action of the agent. They may be administered in conventional ways that can be used in combination with medicaments, as a single therapeutic agent or in combination of therapeutic agents. The compound may be administered on its own, but is generally administered with a drug carrier selected based on the chosen route of administration and standard pharmaceutical practice. The compounds of the present invention may be administered, for example, orally (e.g., via tablets or capsules), parenterally (including subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques), by inhalation spray, or rectally, in the form of a unit-dose pharmaceutical composition containing an effective amount of the compound and a conventionally non-toxic, pharmaceutically acceptable carrier, adjuvant, and mediator. The compound may also be administered via an implantable drug delivery device suitable for delivering an effective amount of the compound or a pharmaceutical composition of the compound over an extended period of time.

[0116] preparation Solid dosage forms (e.g., powders, pills, capsules, and tablets) suitable for oral administration can be prepared according to techniques known in the art and can employ solid excipients such as starch, sugar, kaolin, lubricants, binders, disintegrants, etc. Liquid dosage forms (e.g., suspensions, syrups, elixirs, etc.) suitable for oral administration can be prepared according to techniques known in the art and can employ any commonly used medium such as water, glycols, oils, alcohols, etc. 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 dissolving agents. Injectable solutions can be prepared according to methods known in the art, wherein the carrier comprises a saline solution, a glucose solution, or a solution containing a mixture of saline and glucose. Implantable compositions can be prepared according to methods known in the art, wherein the carrier comprises an active chemical component as well as a polymer and suitable excipients, or drug delivery is performed using an implantable device. Further descriptions of methods for preparing pharmaceutical compositions for use in the present invention and of components suitable for said 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 earlier editions.

[0117] Formulations of Formula I compounds that cause drug supersaturation and / or rapid dissolution can be used to promote the absorption of orally administered drugs. Formulation methods that cause 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 methods and techniques for preparing them are known in the art. For example, solid dispersions can be prepared using excipients and methods described in reviews (e.g., ATM Serajuddin, J Pharm Sci, 88:10, pp. 1058-1066 (1999)). Nanoparticle systems based on milling and direct synthesis are also described in reviews such as Wu et al. (F. Kesisoglou, S. Panmai, Y. Wu, Advanced Drug Delivery Reviews, 59:7 pp. 631-644 (2007)).

[0118] Compounds of Formula I may be administered, for example, in dose ranges of 1 to 20 mg / kg, or 1 to 10 mg / kg, or about 5 mg / kg of mammalian (e.g., human) body weight per day, or at other time intervals, as appropriate, as a single dose or in fractions. Compounds of Formula I may be administered, in dose ranges of 0.001 to 2000 mg / day, as a single dose or in fractions, as a single dose or in fractions, as a single dose or in fractions, as a single dose or in fractions, via other routes of administration. Examples of dose ranges are 0.01 to 1500 mg / day, or 0.1 to 1000 mg / day, administered orally or via other routes of administration.

[0119] For oral (e.g., tablets or capsules) or other routes of administration, the dosage unit may contain 100 mg to 1500 mg of the active ingredient, such as, but not limited to, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, or 1500 mg of the active ingredient, for symptomatic dose adjustment to the patients being treated. Furthermore, the compound may be formulated into oral formulations for immediate or modified release, such as prolonged or controlled release. When a compound of Formula I is administered as a salt, the amounts of the compound mentioned in milligrams or grams are based on the free form of the compound (i.e., the non-salt form).

[0120] Daily administration can be via any suitable route of administration, but oral administration is preferred, and can be a single dose or more doses interspersed throughout a 24-hour period (daily fractions). Each dose may be administered using one or more dose units, as appropriate.

[0121] The specific dose level and frequency of administration for any given patient can vary and will depend on a variety of factors, including the activity of the specific compound used, its metabolic stability and duration of action, age, weight, general health condition, sex, diet, route and timing of administration, excretion rate, drug combination, severity of the specific condition, and the host being treated. In some cases, depending on the potency of the compound or individual response, it may be necessary to deviate from the given dose upwards or downwards. The amount and frequency of administration will be adjusted based on the attending clinician's judgment, taking these factors into account.

[0122] "Anti-HIV agent" is any agent that is directly or indirectly effective in inhibiting HIV, treating or preventing HIV infection and / or treating or preventing AIDS or ARC, or delaying the onset or progression of AIDS or ARC. It should be understood that an anti-HIV agent is effective in treating or preventing HIV infection or AIDS and / or the disease or condition caused by or associated with it, or delaying its onset or progression. This disclosure further relates to the use of compounds of Formula I or pharmaceutically acceptable salts thereof in conjunction with one or more compatible anti-HIV agents, i.e., anti-HIV agents that do not include HIV protease inhibitors (also referred to as "compatible HIV antiviral agents"). For example, a compound of Formula I may be administered in combination with an effective amount of one or more compatible anti-HIV agents selected from HIV antiviral agents, immunomodulators, anti-infective agents, or vaccines that can be used to treat HIV infection or AIDS. Suitable compatible HIV antiviral agents for use in combination with compounds of this disclosure include, but are not limited to, those listed in Table A below: Table A: Antiviral agents used to treat HIV infection or AIDS

[0123] AI = attachment inhibitor; EI = entry inhibitor; FI = fusion inhibitor; InSTI = integrase inhibitor; NRTI = nucleoside or nucleotide reverse transcriptase inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTTI = nucleoside reverse transcriptase translocation inhibitor. Some of the drugs listed in Table A are used in salt form, such as abacavir sulfate and delavudine mesylate.

[0124] The TACK effect induced by HIV-TACK agents depends on viral Gag-Pol expression. Therefore, additional active agents (such as latency reversal agents (“LRAs” or “LRAs”)) that enhance Gag-Pol production in infected cells and / or activate viral expression in cells containing a reservoir of latent HIV when used in conjunction with HIV-TACK therapy may enhance the TACK effect. This disclosure also relates to the use of compounds of Formula I or pharmaceutically acceptable salts thereof with one or more LRAs. For example, a compound of Formula I may be administered in combination with an effective amount of one or more LRAs for the treatment of HIV infection or AIDS. Examples of LRAs used in combination with the compounds disclosed herein include, but are not limited to, epigenetic modifiers such as histone deacetylase (HDAC) inhibitors, DNA methyltransferase (DNMT) inhibitors, and histone methyltransferase (HMT) inhibitors; protein kinase C (PKC) agonists such as prostratin, lichenin, or gentianol; P-TEFb release inducers such as BET inhibitors (e.g., JQ1 or a class of drugs that reversibly bind the bromine domain and the bromine domain of the terminal outer motif (BET) proteins BRD2, BRD3, BRD4, and / or BRDT); type 5 CC chemokine receptor (CCR5) antagonists; atypical NF-κB pathway inducers (e.g., second mitochondrial-derived caspase activator (SMAC) mimics or apoptosis protein inhibitor (IAP) antagonists, proteasome inhibitors, toll-like receptor (TLR) agonists, mitogen-activated protein kinase (MAPK) agonists, Ak strain transformation / protein kinase B... (AKT / PKB) pathway activators, cytokines, and immunomodulators such as immune checkpoint inhibitors, as well as those described elsewhere, such as those described in Bullen et al., Nature Medicine, 20:425-429 (2014); Ait-Ammar et al., Frontiers in Microbiology, 10:3060 (2019); and Fujinaga et al., Viruses. 12:11 (2020).

[0125] Examples of HDAC inhibitors that can be used as latency reversal agents include, but are not limited to, vorinostat, pabisostat, romidesin, and valproic acid. Examples of DNMT inhibitors that can be used as latency 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 latency reversal agents include, but are not limited to, trachomatis, 3-deadenine A, and tazestat (EPZ-6438). N-[(1,2-dihydro-6-methyl-2-oxo-4-propyl-3-pyridyl)methyl]-1-(1-methylethyl)-6-[2-(4-methyl-1-piperazinyl)-4-pyridyl]-1 H -Indazole-4-carboxamide (GSK-343) and 2-cyclohexyl-6-methoxy- N -[1-(1-methylethyl)-4-piperidinyl]-7-[3-(1-pyrrolidinyl)propoxy]-4-quinazolinamine (UNC-0638). Examples of PKC agonists that can be used as latency reversal agents include, but are not limited to, phorbol esters such as prostaglandins and myristoyl phorbol acetate (PMA), lichenin-1, and gentamicin. Examples of BET inhibitors that can be used as latency reversal agents include, but are not limited to, JQ1 (( S 2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thiopheno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diaza-6-yl)tert-butyl acetate), iBET and N -cyclohexyl-2-(4-(3,5-dimethylisoxazol-4-yl)-2-methoxyphenyl)imidazo[1,2-a]pyrazin-3-amine (UMB-136). Examples of CCR5 antagonists that can be used as latency reversal agents include, but are not limited to, maraviro and vicvirol. Examples of atypical NF-κB pathway inducers and SMAC mimics / IAP inhibitors that can be used as latency reversal agents include, but are not limited to, 3,3'-[2,4-hexadiyne-1,6-diylbis[oxy[(1 S ,2 R )-2,3-dihydro-1 H -indene-2,1-dimethyl]]]bi[ N -Methyl-L-alanyl-(2 S 2-Cyclohexylglycyl-L-prolinedamide (AZD5582), Ciapvir, Birinapant, LCL161, and DEBIO1143 / AT-406. Examples of proteasome inhibitors that can be used as latency reversal agents include, but are not limited to, bortezomib and ixazomib. Examples of TLR agonists that can be used as latency reversal agents include, but are not limited to, the TLR2 agonist Pam3CSK4, the TLR7 agonist vesamimod, and the TLR9 agonists lefemod (MGN1703) and CPG 7909.

[0126] Examples of MAPK agonists that can be used as latency reversal agents include, but are not limited to, proanthocyanidin trimer C1. Examples of AKT pathway activators that can be used as latency reversal agents include, but are not limited to, disulfiram. Examples of immunomodulatory cytokines that can be used as latency reversal agents include, but are not limited to, IL-2, IL-7, and IL-15, including the IL-15 superagonist N-803. Examples of immune checkpoint inhibitors include, but are not limited to, programmed cell death protein 1 (PD1) inhibitors, programmed death ligand 1 (PD-L1) inhibitors, cytotoxic T lymphocyte-associated protein 4 (CTLA-4), lymphocyte activation gene 3 (LAG3), T cell immune receptor with Ig and ITIM domains (TIGIT), and CD24Fc (a recombinant fusion protein consisting of the extracellular domain of mature human glycoprotein differentiation cluster 24 (CD24) linked to the Fc domain of human immunoglobulin G1 (IgG1)).

[0127] Non-limiting examples of HIV integrase inhibitors as anti-HIV agents are disclosed in International Patent Application Publication WO2018 / 102485 (incorporated herein by reference in its entirety), and include: , , , , and .

[0128] Non-limiting examples of non-nucleoside reverse transcriptase inhibitors for anti-HIV agents are disclosed in International Patent Application Publication WO2014 / 058747 (incorporated herein by reference in its entirety), and include: 3-Chloro-5-((6-oxo-1-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)methyl)-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (ulonivirine); 3-Chloro-5-((6-oxo-l-((3-oxo-2,3-dihydropyridazin-4-yl)methyl)-4-(trifluoromethyl)-1,6-di-hydroxypyrimidin-5-yl)oxy)benzonitrile; 3-Chloro-5-((1-((4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile; and 3-Chloro-5-((1-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

[0129] Non-limiting examples of nucleoside reverse transcriptase inhibitors for anti-HIV agents are disclosed in International Patent Application Publication WO2015 / 148746 (incorporated herein by reference in its entirety), and include: 3-Chloro-5-((6-oxo-1-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)methyl)-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (UNIVIRINE); 3-Chloro-5-((6-oxo-l-((3-oxo-2,3-dihydropyridazin-4-yl)methyl)-4-(trifluoromethyl)-1,6-di-hydroxypyrimidin-5-yl)oxy)benzonitrile; 3-Chloro-5-((1-((4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile; and 3-Chloro-5-((1-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

[0130] Therefore, compounds of formula I or pharmaceutically acceptable salts thereof, when used in conjunction with latency reversal agents, can be used for: (i) A method for reactivating latent HIV and inducing GAG-POL dimerization in HIV-infected cells (e.g., CD4 T cells) of a human subject, said method comprising administering to the subject an effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof, and a latency reversal agent; and / or (ii) A method for reactivating latent HIV in a human subject and selectively killing HIV-infected GAG-POL-expressing cells (e.g., latent HIV-infected CD4 T cells or central memory CD4 T cells) without cytotoxicity to HIV primary cells, said method comprising administering to the subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, along with a latency reversal agent.

[0131] The compounds of the present invention can be used in combination with any one or more antiviral agents (e.g., but not limited to those listed in Table A) and / or any one or more LRAs (e.g., but not limited to the LRAs described herein).

[0132] It should be understood that the scope 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 that can be used to treat or prevent HIV AIDS or ARC, except for HIV protease inhibitors. Compatible HIV antiviral agents and other active agents are generally used in these combinations at their conventional dosage ranges and regimens reported in the art, including, for example, the dosages described in the current Physicians' Desk Reference, Thomson PDR, 70th edition (2016), Montvale, NJ: PDR Network, or earlier editions. In these combinations, the dosage ranges of the compounds of this disclosure may be the same as those set forth above.

[0133] The compounds of this invention can also be used to prepare and perform screening assays for antiviral compounds. For example, the compounds of this invention can be used to isolate enzyme mutants, which are excellent screening tools for more potent antiviral compounds. Furthermore, the compounds of this invention can be used to establish or determine binding sites of other antiviral agents to the reverse transcriptase region within GAG-POL, for example, through competitive inhibition.

[0134] The abbreviations and acronyms used in this article include the following:

[0135] Compounds containing bromine have two bromine isotopes in a ratio of approximately 1:1. 79 Br and 81 Br has two qualities.

[0136] Intermediate A part Intermediate A01: 7-Bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-1-(4-methoxybenzyl) 3,4-Dihydroquinazolin-2(1H)-one (A01) Step 1: 1-(4-Bromo-2,5-difluorophenyl)-2,2-difluoroprop-1-one (A01-a) Under a nitrogen 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 diethyl ether (5 L) at -78 °C. The resulting mixture was stirred at -78 °C for 1.0 h. Subsequently, ethyl 2,2-difluoropropionate (253.99 g, 1838.99 mmol) was added dropwise to the mixture at -78 °C over 40 minutes. The resulting mixture was stirred at -78 °C for 1 h. The reaction was quenched with a saturated aqueous solution of NH4Cl (2 L). The quenched mixture was then extracted with diethyl ether / EtOAc (3 x 2 L). The organic extracts were combined, washed with brine (3 x 500 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to separate compound A01-a. A01-a is used directly in step 2. 1 H NMR (500 MHz, chloroform-) d ) δ 7.70 – 7.59 (m, 1H), 7.45 (dd, J = 9.3, 5.3 Hz, 1H), 1.88 (t, J = 19.3 Hz, 3H).

[0137] Step 2: 1-(4-bromo-5-fluoro-2-{[(4-methoxyphenyl)methyl]amino}phenyl)-2,2-difluoroprop-1-one (A01-b) A solution of 1-(4-bromo-2,5-difluorophenyl)-2,2-difluoroprop-1-one (A01-a, 460 g, 1613.83 mmol) in toluene (4600 mL) was treated with 1-(4-methoxyphenyl)methylamine (332.08 g, 2420.74 mmol) and K₂CO₃ (223.04 g, 1613.83 mmol) and then stirred at 115 °C for 10 h under a nitrogen atmosphere. The mixture was allowed to cool to ambient temperature. The precipitated solid was collected by filtration and washed with toluene (3 x 200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography, eluting with PE:EtOAc (95:5) to give compound A01-b. 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 = 5.6Hz, 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).

[0138] Step 3: 7-Bromo-4-(1,1-difluoroethyl)-6-fluoro-4-hydroxy-1-[(4-methoxyphenyl)methyl]-3 H - Quinine Azoline-2-one (A01-c) Sodium isocyanate (903.48 g, 13898.2 mmol) was added in portions to a stirred solution of 1-(4-bromo-5-fluoro-2-{[(4-methoxyphenyl)methyl]amino}phenyl)-2,2-difluoroprop-1-one (A01-b, 430 g, 1069.1 mmol) in AcOH (4.3 L) under a nitrogen atmosphere at ambient temperature. The resulting mixture was stirred at 110 °C for 10 hours. The mixture was then cooled to ambient temperature. The pH of the mixture was adjusted to 8–9 with NaHCO3. The mixture was extracted with EtOAc (3 x 3 L). The organic layers were combined, washed with brine (3 x 1 L), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by grinding with PE:EtOAc (5:1) to give compound A01-c. MS (ESI) m / z 445, 447 [M+1].

[0139] Step 4: 7-Bromo-4-(1,1-difluoroethyl)-6-fluoro-1-[(4-methoxyphenyl)methyl]quinazolin-2-one (A01-d) 7-bromo-4-(1,1-difluoroethyl)-6-fluoro-4-hydroxy-1-[(4-methoxyphenyl)methyl]-3 H A mixture of 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 then cooled to room temperature. The resulting mixture was concentrated under reduced pressure, and compound A01-d was isolated and used without further purification. 1 H NMR (500 MHz, DMSO- d 6) δ 7.97 (dd, J = 14.9, 7.4 Hz, 2H), 7.25 (d, J = 8.7Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 5.45 (s, 2H), 3.72 (s, 3H), 2.10 (t, J = 20.0Hz, 3H).

[0140] Step 5: 7-Bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-1-(4-methoxybenzyl)-3, 4-Dihydroquinazoline-2(1 H )-Ketone (A01) Under a nitrogen atmosphere at -5°C, 1 M LiHMDS / THF (1685.31 mL, 1685.31 mmol) was added dropwise to a solution of ethynylcyclopropane (139.26 g, 2106.63 mmol) in toluene (1.4 L) at room temperature. The resulting mixture was stirred at 10°C for 120 minutes. 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 at -15°C over 40 minutes. The resulting mixture was stirred at room temperature for 120 minutes. The reaction was quenched at room temperature with a saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc (3 x 3000 mL). The organic layers were combined, washed with brine (2 x 1000 mL), and dried over anhydrous Na₂SO₄. The filtrate was concentrated under reduced pressure after filtration. The residue was purified by rapid silica gel column chromatography, eluting with PE:EtOAc (80:20) to give compound A01. MS (ESI) m / z 493, 495 [M+1].

[0141] Intermediate A02: ( S 7-Bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinone Azoline-2(1 H )-ketone and ( R 7-Bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazole porphyrin-2(1) H )-Ketone (A02) 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 x 300 mL). The residue was purified by rapid silica gel column chromatography, eluting with PE:EtOAc (80:20). Racemic products were separated using a preparative SFC (Amylose-C Neo 100×4.6mm 3.0µm cosolvent: MeOH (20 mM NH3)), resulting in the separation of isomer A02-A (faster elution) and isomer A02-B (slower elution). MS (ESI) analysis of both isomers was performed. m / z Both are 373 and 375 [M+1].

[0142] Intermediate A03: ( S 7-Bromo-4-(cyclopropyldifluoromethyl)-4-(cyclopropylethynyl)-6-fluoro-3,4-dihydro Quinazoline-2(1 H )-ketone and ( R 7-Bromo-4-(cyclopropyldifluoromethyl)-4-(cyclopropylethynyl)-6-fluoro-3,4-dihydroquinolineAzoline-2(1 H )-Ketone (A03) Step 1: 1-(4-Bromo-2,5-difluorophenyl)-2-cyclopropyl-2,2-difluoroethyl-1-one (A03-a) 1.6 M nBuLi / hexane (47.7 mL, 76 mmol) was added dropwise to a solution of 1,4-dibromo-2,5-difluorobenzene (18.86 g, 69.4 mmol) in diethyl ether (347 mL) at -78 °C. The reaction mixture was stirred at -78 °C for 30 min under a nitrogen atmosphere. Ethyl 2-cyclopropyl-2,2-difluoroacetate (15 g, 91 mmol) was dissolved in toluene (20 mL) and added dropwise over 10 min. The solution was stirred at -78 °C for another 1 h and quenched with 10% NH4Cl (100 mL). The mixture was diluted with EtOAc (200 mL), washed with water (2 x 100 mL) and brine (100 mL), and dried over Na2SO4. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by rapid chromatography (SiO2; 0 – 60 % EtOAc: hexane) to separate the compound (A03-a). 1 H NMR (500 MHz, DMSO- d 6) δ 9.97 – 9.57 (m, 1H), 8.32 (m, 1H), 1.48 (s, 1H), 0.87 (bs, 2H), 0.73 (bs, 2H).

[0143] Step 2: 7-Bromo-4-(cyclopropyldifluoromethyl)-6-fluoro-4-hydroxy-3,4-dihydroquinazolin-2(1 H )-ketone (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-difluoroethyl-1-one (A03-a, 14.86 g, 47.8 mmol) in NMP (47.8 mL). The mixture was heated to 140 °C and maintained for 16 hours. The reaction mixture was cooled and added to water (500 mL), then extracted with EtOAc (3 x 200 mL). The organic layers were combined, washed with water (3 x 300 mL) and brine (3 x 300 mL), and dried over MgSO4. The organic layer was concentrated under reduced pressure to separate compound A03-b. MS (ESI) m / z 351, 353 [M+1].

[0144] Step 3: 7-Bromo-4-(cyclopropyldifluoromethyl)-6-fluoroquinazoline-2(1 H )-Ketone(A03-c) 7-bromo-4-(cyclopropyldifluoromethyl)-6-fluoro-4-hydroxy-3,4-dihydroquinazolin-2(1H )-ketone (A03-b, 13.683 g, 39.0 mmol) was added to a flask, followed by toluene (195 mL), and the mixture was heated to reflux and maintained for 72 hours. The reaction mixture was cooled to 0°C and the resulting slurry was filtered to separate compound A03-c. 1 H NMR (500 MHz, methanol-d4) δ7.95 (d, J = 9.2 Hz, 1H), 7.72 (d, J = 5.9 Hz, 1H), 1.93 (ddd, J = 13.3, 8.0, 5.2Hz, 1H), 0.94 - 0.75 (m, 4H).

[0145] Step 4: ( S 7-Bromo-4-(cyclopropyldifluoromethyl)-4-(cyclopropylethynyl)-6-fluoro-3,4-dihydroquinazole porphyrin-2(1) H )-ketone and ( R 7-Bromo-4-(cyclopropyldifluoromethyl)-4-(cyclopropylethynyl)-6-fluoro-3,4-dihydroquinazole porphyrin-2(1) H )-Ketones (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 / hexane (22.20 mL, 55.5 mmol) was added to the solution and stirred for 30 minutes. 7-Bromo-4-(cyclopropyldifluoromethyl)-6-fluoroquinazoline-2 (1... H )-ketone (A03-c, 4.62 g, 13.88 mmol) was heated to ambient temperature and stirred for 16 hours. The reaction was quenched with water. EtOAc (200 mL) was added to the solution. The solution was extracted with water (2 x 50 mL) and brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by rapid chromatography (SiO2; 0 – 100% EtOAc:hexane) to separate the racemic mixture of A03. This racemic mixture was analyzed by preparative SFC using Daicel ChiralPak. ® Separation was performed using IG (30 mm x 250 mm (5 μm), Daicel Chiral Technologies, West Chester, PA); eluted with 25% MeOH (0.1% DEA); 80 mL / min; 100 bar). Isomer A03-A (faster elution) and isomer A03-B (slower elution): MS (ESI) for both. m / z Both are 399,401 [M+1].

[0146] Intermediate A04: ( S )-7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3-methyl-3,4- dihydroquinazolin-2(1) H )-ketone and( R )-7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3-methyl- 3,4-Dihydroquinazoline-2(1 H )-Ketone (A04) Step 1: 7-Bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-1-(4-methoxybenzyl)-3- Methyl-3,4-dihydroquinazoline-2(1 H )-Ketone(A04-a) To a solution of (S)-7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-1-(4-methoxybenzyl)-3-methyl-3,4-dihydroquinazolin-2(1H)-one (A01, 2000 mg, 4.05 mmol) in anhydrous 1,4-dioxane (20.3 mL), NaH (324 mg, 8.11 mmol) was added and 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 another 16 hours. The mixture was cooled to 0 °C and quenched with NH4Cl (20 mL saturated aqueous solution), and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was used as crude to separate A04-a. MS (ESI) m / z 507, 509 [M+1].

[0147] Step 2: ( S 7-Bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3-methyl-3,4-dihydro Quinazoline-2(1 H )-ketone and ( R )-7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3-methyl-3,4- dihydroquinazolin-2(1) H )-Ketones (A04-A and A04-B) 7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-1-(4-methoxybenzyl)-3-methyl-3,4-dihydroquinazolin-2(1 H A solution of α-keto (A04-a, 2.057 g, 4.05 mmol) in anhydrous TFA (8.11 mL) was heated to 60 °C and held for 1 hour. The reactants were concentrated under reduced pressure and purified by rapid silica gel chromatography, eluting with 0-100% EtOAc / hexane to separate the racemic mixture. This substance was then purified by SFC (Daicel Chiral Pak). ® Further purification was performed using IG (20% MeOH / 0.1% DEA, 100 mL / min, 100 bar) to separate isomer A04-A (faster elution) and isomer A04-B (slower elution). MS (ESI) of both was then analyzed. m / z Both are 387 and 389 [M+1].

[0148] Intermediates A05 to A07, as shown in Table 1, were synthesized using the method disclosed in International Patent Application Publication WO2022 / 046844.

[0149] Table 1.

[0150] Intermediate A08: (S)-7-bromo-4-(cyclopropylethynyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2 (1H)-Keto(A08) Step 1: (2-Bromo-6-fluorophenyl)trimethylsilane (A08-a) 2 M LDA / THF (7.54 L, 15085 mmol) was added to a solution of 1-bromo-3-fluorobenzene (1200 g, 6857 mmol) and TMSCl (1638 g, 15085 mmol) in THF (10 L) at -70 °C. The resulting solution was stirred at -75 °C for 30 min and hydrolyzed with dilute aqueous H2SO4. The organic phase was separated, and the aqueous phase was extracted with diethyl ether. The organic matter was concentrated, and the oil was distilled under vacuum to give a crude product as a colorless oil. Methanol (1 L) was added, and the solution was allowed to stand overnight at -20 °C. The mixture was filtered to separate A08-a.

[0151] Step 2: 1-(4-bromo-2-fluoro-3-(trimethylsilyl)phenyl)-2,2,2-trifluoroethyl-1-one (A08-b) 2.5 M nBuLi / hexane (1207 mL, 3020 mmol) was added dropwise at -20 °C to a solution of 2,2,6,6-tetramethylpiperidine (426.5 g, 3020 mmol, 1.1 equivalence) in 2500 mL THF. After stirring for 30 min, the mixture was cooled to -70 °C, and a solution of (2-bromo-6-fluorophenyl)(trimethyl)silane (678 g, 2745 mmol) in 700 mL THF was added. The solution was stirred for 1 h, followed by the dropwise addition of ethyl trifluoroacetate (428 g, 3020 mmol) at -70 °C. The mixture was then slowly warmed to room temperature and stirred for 1 h. A saturated aqueous NH4Cl solution was then added, and the mixture was extracted twice with ethyl acetate. The combined ethyl acetate phases were washed with brine, dried over MgSO4, filtered, and concentrated to separate A08-b, which was then used directly in step 3.

[0152] Step 3: 1-(4-Bromo-2-fluorophenyl)-2,2,2-trifluoroethyl-1-one (A08-c) At room temperature, 1 M TBAF / THF (2301 mL, 2301 mmol) was added to a solution of A08-b (658 g, 1918 mmol) in 2 L THF. After stirring for 30 min, the solution was diluted with ethyl acetate and washed with water. The aqueous phase was extracted again with ethyl acetate. The organic phases were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by rapid chromatography (silica gel, mobile phase cyclohexane / ethyl acetate 95:5) to separate A08-c.

[0153] Step 4: 1-(4-bromo-2-((4-methoxybenzyl)amino)phenyl)-2,2,2-trifluoroethyl-1-one (A08-d) 1-(4-bromo-2-fluorophenyl)-2,2,2-trifluoroethyl-1-one (A08-c, 260 g, 959 mmol) was added to a flask, followed by 1-(4-methoxyphenyl)methylamine (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 mixture was diluted with 1 L of water. The solution was extracted with (3 x 500 mL) ethyl acetate, the organic layers were combined, dried over Na₂SO₄, and concentrated. The residue was purified by normal-phase chromatography (SiO₂, PE:EA = 5:1), separating the title compound A08-d.

[0154] Step 5: 1-(2-amino-4-bromophenyl)-2,2,2-trifluoroethyl-1-one and N-(5-bromo-2-(2,2,2-trifluoroethyl) Acyl)phenyl)-2,2,2-trifluoroacetamide (A08-e) 1-(4-bromo-2-((4-methoxybenzyl)amino)phenyl)-2,2,2-trifluoroethyl-1-one (A08-d, 281 g, 724 mmol) was added to a round-bottom flask, followed by TFA (840 mL). The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was concentrated, and the title substance (A08-e) in the mixture was separated and used directly in step 6.

[0155] Step 6: 1-(2-Amino-4-bromophenyl)-2,2,2-trifluoroethyl-1-one (A08-f) 1-(2-amino-4-bromophenyl)-2,2,2-trifluoroethyl-1-one and [other ingredients] were placed in a flask that had been purged with and maintained under an inert nitrogen atmosphere. N A mixture of -[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) was prepared. The resulting solution was stirred at room temperature for 5 hours. The solution was diluted with water (500 mL) and extracted with DCM (3 x 500 mL). The organic phase was washed with brine (500 mL), dried over Na2SO4, and concentrated. The residue was purified by normal-phase chromatography (SiO2PE:EtOAc = 50:1 to 5:1) to separate the title compound A08-f.

[0156] Step 7: 1-(2-Amino-4-bromophenyl)-2,2,2-trifluoroethane-1,1-diol . HCl (A08-g) 1-(2-amino-4-bromophenyl)-2,2,2-trifluoroethyl-1-one (A08-f, 70 g, 261.16 mmol), acetic acid (210 mL), and 12 N HCl (70 mL) were added to a 500-mL three-necked round-bottom flask. The resulting solution was stirred at 65 °C for 10 hours. The solid was collected by filtration, and the title compound A08-g was separated.

[0157] Step 8: 7-Bromo-4-hydroxy-3-((R)-1-phenylethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2 (1H)-Ketone(A08-h) Add 1-(2-amino-4-bromophenyl)-2,2,2-trifluoroethane-1,1-diol to a round-bottom flask . HCl (A08-g, 78 g, 243.38 mmol), [(1R)-1-isocyanoethyl]benzene (71.6 g, 486.75 mmol), THF (1450 mL), 1 N HCl (110 mL, 3620.31 mmol). The resulting solution was stirred at 0 °C for 2 h in a water / ice bath, followed by stirring at 17 °C for 48 h. The reaction mixture was then stirred at 60 °C for 1 h. The resulting mixture was concentrated. The residue was diluted with 500 mL of water and extracted with ethyl acetate (3 x 1 L). The organic phases were combined, concentrated, and purified by reversed-phase chromatography (column, C18; eluent, 50%–70% MeCN / water) to separate the title compound A08-h.

[0158] Step 9: ( S )-7-bromo-4-(cyclopropylethynyl)-3-( R )-1-Phenylacetyl)-4-(trifluoromethyl)-3,4- dihydroquinazolin-2(1) H )-Ketone(A08-i) Add 378 mL of butyl(chloro)magnesium (756.40 mmol, 2 M, in THF) to a 500 mL three-necked round-bottom flask and slowly add 50 g of ethynylpropane (756.40 mmol) at room temperature. Stir the resulting solution at 18 °C for 2 hours. The resulting intermediate is used directly.

[0159] 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, SOCl2 (21.1 g, 177.02 mmol) was slowly added, maintaining the temperature at -5 to 0°C. The resulting solution was stirred at 0°C for 1 hour in a water / ice bath. The reaction was then lowered to -70°C, and the magnesium chloride solution generated in situ was added dropwise over 30 minutes. The mixture was quenched with 12% citric acid aqueous solution (700 mL) and extracted with ethyl acetate (3 x 1 L). The organic matter was combined, dried over Na2SO4, concentrated, and the residue was purified by preparative SFC under the following conditions: column, Daicel Chiral Pak. ® 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).

[0160] Step 10: ( S )-7-bromo-4-(cyclopropylethynyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1 H )-ketone (A08) Add (4) to a round-bottom flask that has been purged with and maintained under an inert nitrogen atmosphere. S )-7-bromo-4-(2-cyclopropylethynyl)-3-[(1 R [1-Phenylacetyl]-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-2-one (A08-i, 23 g, 49.64 mmol) and TFA (69 mL, 928.95 mmol). The resulting solution was stirred at 18 °C for 1 hour. The reaction was then quenched by adding 100 mL of water. The resulting solution was extracted with DCM (3 x 100 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum to separate the title compound A08. MS (ESI) m / z 359, 361 [M+1].

[0161] Intermediate A09: ( S )-7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-3,4-dihydroquinazolin-2 (1 H )-ketone and ( R )-7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-3,4-dihydroquinazolin-2(1 H )-ketone (A09) Step 1: (2-Bromo-6-fluorophenyl)trimethylsilane (A09-a) 2 M LDA / THF (286 mL, 571 mmol) was added to a solution of 1-bromo-3-fluorobenzene (50 g, 286 mmol) and TMS-Cl (73.0 mL, 571 mmol) in THF (450 mL) 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 phase was separated, and the aqueous phase was extracted with EtOAc. The organic matter was dried over 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. 1 H NMR (400MHz, 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).

[0162] Step 2: 1-(4-Bromo-2-fluoro-3-(trimethylsilyl)phenyl)-2,2-difluoroprop-1-one (A09-b) 2.5 M nBuLi / hexane (53.4 ml, 134 mmol) was added to a solution of 2,2,6,6-tetramethylpiperidine (18.86 g, 134 mmol) in THF (125 mL) at -20 °C. After stirring at -20 °C for 30 min, the mixture was further cooled to a bath temperature of -70 °C, and a solution of (2-bromo-6-fluorophenyl)trimethylsilane (A09-a, 30 g, 121 mmol) in THF (35 mL) was added. After stirring at -70 °C for 1 hour, ethyl 2,2-difluoropropionate (18.44 g, 134 mmol) was added dropwise. The mixture was then slowly warmed to 20 °C and stirred at 20 °C for another 1 hour. A saturated aqueous solution of NH4Cl (300 mL) was then added, and the mixture was extracted with ethyl acetate (3 x 300 mL). The organic layers were combined, washed with brine (300 mL), dried over Na2SO4, filtered and concentrated to separate the title compound A09-b.

[0163] Step 3: 1-(4-bromo-2-fluorophenyl)-2,2-difluoroprop-1-one (A09-c) At 20 °C, 1 M TBAF (34.7 g, 133 mmol) / THF was added to a solution of 1-(4-bromo-2-fluoro-3-(trimethylsilyl)phenyl)-2,2-difluoroprop-1-one (A09-b, 45 g, 133 mmol) in THF (200 mL) and the mixture was stirred for 0.5 h. The reaction mixture was concentrated and purified by rapid silica gel chromatography (PE:EA = 1:0~95:5) to isolate the title compound A09-c.

[0164] Step 4: 1-(4-bromo-2-((4-methoxybenzyl)amino)phenyl)-2,2-difluoroprop-1-one (A09-d) To a solution of 1-(4-bromo-2-fluorophenyl)-2,2-difluoroprop-1-one (A09-c, 20 g, 74.9 mmol) in toluene (200 mL), (4-methoxyphenyl)methylamine (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 mixture was filtered, concentrated, and purified by rapid silica gel chromatography (PE:EA = 1:0~10:1) to isolate the title compound A09-d.

[0165] Step 5: 7-Bromo-4-(1,1-Difluoroethyl)-4-hydroxy-1-(4-methoxybenzyl)-3,4-dihydroquinazolin-2 (1 H )-Ketone(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-difluoroprop-1-one (A09-d, 20 g, 52.1 mmol) in AcOH (400 mL). The reaction mixture was stirred at 110 °C for 16 h. The pH of the reaction mixture was adjusted to 8 with a saturated aqueous solution of NaHCO3. The mixture was extracted with EtOAc (3 x 500 mL). The organic layer was washed with brine (500 mL), dried (with Na2SO4), filtered, and concentrated. The residue was purified by rapid silica gel chromatography (PE:EA = 1:0~4:1) to isolate the title compound A09-e. 1 H NMR (400 MHz, DMSO- d 6) 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).

[0166] Step 6: 7-Bromo-4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)quinazolin-2-(1 H )-Ketone(A09-f) To 7-bromo-4-(1,1-difluoroethyl)-4-hydroxy-1-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1 H Phosphorus pentoxide (3.99 g, 28.1 mmol) was added to a solution of ketone (A09-e, 10 g, 23.41 mmol) in ACN (200 mL). The reaction mixture was stirred at 90 °C for 3 hours under N2. The pH of the reaction mixture was adjusted to 8 with a saturated aqueous solution of NaHCO3. The residue was extracted with EtOAc (3 x 500 mL). The organic layer was washed with brine (500 mL), dried (with Na2SO4), filtered, and concentrated to separate the title compound (A09-f), which was used directly in step 7. 1 H NMR (400 MHz, DMSO- d 6 ) 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).

[0167] Step 7: 7-Bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)-3,4- dihydroquinazolin-2(1) H )-ketone (A09-g) 1 M LiHMDS (55.0 mL, 55.0 mmol) / THF was added to a solution of ethynylpropane (4.36 g, 66.0 mmol) in toluene (50 mL) at 0 °C. The reaction mixture was stirred at 85 °C for 15 min. Then, 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 h. The reaction was quenched with saturated NH4Cl aqueous solution (100 mL). The solution was extracted with EtOAc (3 x 100 mL). The organic layer was washed with brine (100 mL), dried (after Na2SO4), filtered, and concentrated. The residue was purified by rapid silica gel chromatography (PE:EA = 1:0 to 3:1), separating the title compound A09-g. MS (ESI) m / z 475, 477 [M+1].

[0168] Step 8: ( S )-7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-3,4-dihydroquinazolin-2 (1 H )-ketone and ( R )-7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-3,4-dihydroquinazolin-2(1 H )-ketone (A09-A and A09-B) Add CAN (17.30 g, 31.6 mmol) to a mixture of 7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (A09-g, 3 g, 6.31 mmol) in ACN (40 mL) and water (15 mL). Stir the reaction mixture at 15 °C for 2 hours. Extract the reaction mixture with EtOAc (3 x 50 mL). Wash the organic layer with brine (50 mL), dry to Na2SO4, filter, and concentrate under reduced pressure to separate the residue. Purify the residue by rapid silica gel chromatography (PE:EA = 1:0 to 1:3) to separate A09. Chiral separation of the white solid by preparative SFC: Column: Daicel ChiralPak ® AD, 250 50mm id 10u (Daicel Chiral Technologies, West Chester, PA); Mobile phase: A is CO2, B is MeOH (0.1% NH3H2O); Gradient: B% = 45%, separating the faster elution peak A09-A and the slower elution isomer A09-B. Faster elution isomer A09-A: 1 H NMR (400 MHz, chloroform-) d ) δppm 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, 1H) 0.83 - 0.89 (m, 2 H) 0.72 - 0.79 (m, 3 H); MS (ESI) m / z 355, 357 [M+1]. Slower elution isomer A09-B: 1 H NMR (400 MHz, chloroform-) d ) δ ppm 8.55 (br s, 1 H) 7.36 (d, J =8.44Hz, 1 H) 7.16 (dd, J =8.38, 1.77 Hz, 1 H) 6.94 (d, J =1.83 Hz, 1H) 5.78 (br s, 1H) 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].

[0169] Intermediate B part Intermediate B01: (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-(hydroxymethyl)-3,4- Dihydroquinazoline-2(1H)-one (BO1) Step 1: ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-(((4-methoxybenzyl)oxy )methyl)-3,4-dihydroquinazolin-2(1 H )-Ketone (B01-a) Will( S )-7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H(A02-B, 10 g, 26.8 mmol), potassium (4-methoxy)benzyloxymethyltrifluoroborate (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 was heated to 150 °C in a sealed tube and maintained for 1 hour. After cooling, the mixture was filtered through diatomaceous earth and washed with EtOAc (100 mL). The filtrate was diluted with a saturated aqueous solution of NaHCO3 and extracted into EtOAc (3 x 50 mL). The organic compounds were combined, dried over MgSO4, filtered, and concentrated under vacuum to separate the crude compound. This crude compound was purified by rapid silica gel chromatography, eluting with (0-100%) EtOAc / hexane to separate the title compound B01-a. MS (ESI) m / z 445 [M+1].

[0170] Step 2: ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-(hydroxymethyl)-3,4-dihydro Quinazoline-2(1 H )-ketone (B01) Will( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-(((4-methoxybenzyl)oxy)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone (BO1-a, 11.93 g, 26.8 mmol) was dissolved in DCM (134 mL). 4 M HCl / 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 mixture was concentrated under vacuum under reduced pressure to separate the crude product. This crude product was added to a 1:1 DCM:hexane mixture and sonicated for 15 minutes to form a slurry. The slurry was filtered to separate compound BO1. MS (ESI) m / z 325 [M+1].

[0171] Intermediate B02: ( S )-4-(cyclopropyldifluoromethyl)-4-(cyclopropylethynyl)-6-fluoro-7-(hydroxymethyl)-3, 4-Dihydroquinazoline-2(1 H )-ketone (B02) The following intermediates were prepared using a similar method to intermediate B01, except that A03-A was used instead of A02-B, and the title compound B02 was isolated. MS (ESI) m / z 351 [M+1].

[0172] Intermediate B03: ( S 3,4-(cyclopropylethynyl)-7-(hydroxymethyl)-4-(trifluoromethyl)-3,4-dihydroquinazole porphyrin-2(1) H )-ketone (B03) The following intermediates were prepared using a similar method to intermediate B01, except that A08 was used instead of A02-B, and the title compound B03 was isolated. MS (ESI) m / z 311 [M+1].

[0173] Intermediate B04: ( S 3,4-(cyclopropylethynyl)-7-(hydroxymethyl)-4-(trifluoromethyl)-3,4-dihydroquinazole porphyrin-2(1) H )-ketone (B04) The following intermediates were prepared using a similar method to intermediate B01, except that A09-A was used instead of A02-B, and the title compound B04 was isolated. MS (ESI) m / z 307 [M+1].

[0174] Intermediate B05: ( S )-6-chloro-4-(cyclopropylethynyl)-7-(hydroxymethyl)-1-(4-methoxybenzyl)-4-(trichloro-4 ... fluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone and ( R )-6-chloro-4-(cyclopropylethynyl)-7-(hydroxymethyl)-1-(4-methyl) oxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone( (B05-A and B05-B) Step 1: 6-Chloro-4-(cyclopropylethynyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)-7-vinyl-3, 4-Dihydroquinazoline-2(1 H )-Ketone (B05-a) K₂CO₃ (11.30 g, 82 mmol) and PdCl₂(dppf) (1.994 g, 2.73 mmol) were added to a solution of 7-bromo-6-chloro-4-(cyclopropylethynyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (A06, 14 g, 27.3 mmol) and potassium vinyltrifluoroborate (5.48 g, 40.9 mmol) in 1,4-dioxane (140 mL) and water (14 mL). The reaction mixture was stirred at 100 °C for 3 hours under N₂. The reactants were concentrated under vacuum and purified by rapid chromatography (SiO₂; 0–20% EtOAc:PE) to isolate compound B05-a.

[0175] Step 2: 6-Chloro-4-(cyclopropylethynyl)-7-(hydroxymethyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)- 3,4-Dihydroquinazoline-2(1 H )-Ketone(B05-b) At -60℃, 6-chloro-4-(cyclopropylethynyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)-7-vinyl-3,4-dihydroquinazoline-2(1 HA solution of β-ketone (B05-a, 8.2 g, 17.79 mmol) in MeOH (30 mL) and DCM (150 mL) was bubbled with ozone (0.854 g, 17.79 mmol) for 30 min. NaBH(OAc)3 (22.63 g, 107 mmol) was added to the solution, and the reaction mixture was stirred at 20 °C for 30 min. The reaction mixture was dissolved in water (100 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum to separate product B05-b, which was used directly in step 3. MS (ESI) m / z 465 [M+1].

[0176] Step 3: ( S 6-Chloro-4-(cyclopropylethynyl)-7-(hydroxymethyl)-4-(trifluoromethyl)-3,4-dihydroquinazole porphyrin-2(1) H )-ketone and ( R 6-Chloro-4-(cyclopropylethynyl)-7-(hydroxymethyl)-4-(trifluoromethyl)-3,4-dihydroquinazole porphyrin-2(1) H )-ketones (BO5-A and BO5-B) Add CAN (50.1 g, 91 mmol) to 6-chloro-4-(cyclopropylethynyl)-7-(hydroxymethyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1 H )-ketone (B05-b, 8.5 g, 18.28 mmol) was dissolved in a solution of MeCN (200 mL) and water (70 mL). The mixture was stirred at 20 °C for 16 hours. The reactants were dissolved in water (100 mL) and extracted with EtOAc (150 mL x 3). The organic layers were combined, washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC (water / (MeCN + 0.1 % TFA)) to separate compound B05 as a racemic mixture, which was then analyzed by SFC (Daicel Chiral Pak). ® Resolution was achieved using AD (30% EtOH / CO2, 200 g / min, 40 ℃, 100 bar), separating isomer B05-A (eluted more quickly). 1 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 (slower elution): 1¹H 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. MS (ESI) for both. m / z Both are 345 [M+1].

[0177] Intermediate B05, as shown in Table 3, was synthesized using the method disclosed in International Patent Application Publication WO2022 / 046844 (WO22 / 046844).

[0178] Table 3.

[0179] Intermediate B07: ( S )-7-(chloromethyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4- dihydroquinazolin-2(1) H )-Ketone (B07) Intermediate B01 (0.578 g, 1.782 mmol) was dissolved in DCE (8.91 mL). Thionyl chloride (0.650 mL, 8.91 mmol) was added to the reaction mixture, and the mixture was stirred at 50 °C for 1 hour. The reaction was neutralized with NaHCO3 (saturated aqueous solution) until pH 10. The aqueous mixture was extracted with DCM (2 x 10 mL), the organic layers were combined, dried over MgSO4, and concentrated under vacuum to separate compound B07. MS (ESI) m / z 343 [M+1].

[0180] As shown in Table 4, intermediates B08 to B11 were prepared in a similar manner to that described for preparing intermediate B07, wherein the noted starting intermediate was used instead of B01.

[0181] Table 4.

[0182] Intermediate B12: ( S )-6-chloro-7-(chloromethyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-3,4- dihydroquinazolin-2(1) H )-Keto(B12) Step 1: ( S 6-Chloro-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-(hydroxymethyl)-3,4-dihydro Quinazoline-2(1 H )-keto(B12-a) NCS (113 mg, 0.849 mmol) was added to a solution of (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-(hydroxymethyl)-3,4-dihydroquinazolin-2(1H)-one (BO4, 260 mg, 0.849 mmol) in anhydrous DMF (5 mL). The resulting reaction mixture was stirred at 40 °C for 16 hours. The reaction mixture was diluted with EtOAc, washed with water (3x), dried over MgSO4, filtered, and concentrated under vacuum to separate compound B12-a, which was used directly in step 2. MS (ESI) m / z 341[M+1].

[0183] Step 2: ( S 6-Chloro-7-(chloromethyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-3,4-dihydro Quinazoline-2(1 H )-Keto(B12) Add thionyl chloride (1.2 mL, 16.96 mmol) to ( S )-6-chloro-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-(hydroxymethyl)-3,4-dihydroquinazolin-2(1 H )-ketone (B12-a, 289 mg, 0.848 mmol) was in a solution of anhydrous DCE (8.5 mL). The reaction mixture was stirred at 60 °C for 90 min. The reaction mixture was concentrated under vacuum and azeotropically reacted with Et₂O to isolate compound B12, which was used without further purification. MS (ESI) m / z 359 [M+1].

[0184] Intermediate B13: ( S )-4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydro Quinazoline-7-carboxaldehyde (B13) PDC (344 mg, 0.914 mmol) was added to a mixture of (S)-4-(cyclopropylethynyl)-6-fluoro-7-(hydroxymethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (B06, 150 mg, 0.457 mmol) in DCM (10 mL) and THF (1 mL). The reaction mixture was stirred at 25 °C under N2 for 16 hours. The reaction mixture was filtered and purified by rapid chromatography (SiO2, 50% EtOAc:PE) to separate B13. MS (ESI) m / z 327 [M+1].

[0185] Intermediate B14: ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4- Tetrahydroquinazoline-7-carboxaldehyde (B14) Add manganese oxide (IV) (375 mg, 4.32 mmol) to (S 3,4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-(hydroxymethyl)-3,4-dihydroquinazolin-2(1H)-one (BO1, 140 mg, 0.432 mmol) was added to a mixture in DCM (2.5 mL) and the mixture was stirred at 25 °C for 12 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum to separate product B14, which was used directly in the next reaction. MS (ESI) m / z 323 [M+1].

[0186] Intermediate B15: ( S 7-(chloromethyl)-4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-3-methyl 4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-Keto (B15) Step 1: ( S )-7-bromo-4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-3, 4-Dihydroquinazoline-2(1 H )-Ketone (B15-a) PMBCl (0.794 mL, 5.83 mmol) was added to a solution of (S)-7-bromo-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (A07-A, 2 g, 5.30 mmol) and Cs₂CO₃ (2.073 g, 6.36 mmol) in DMF (26.5 mL). The reaction mixture was stirred at 25 °C for 16 hours. The reaction was quenched with water (200 mL) and extracted with Et₂O (2 x 300 mL). The resulting organic layer was dried over MgSO₄, filtered, and concentrated under vacuum. The crude product was purified by rapid chromatography (SiO₂, 0–100% EtOAc:hexane) to give compound B15-a. MS (ESI) m / z 497, 499[M+1].

[0187] Step 2: ( S 7-Bromo-4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-3-methyl-4-(trifluoro) methyl)-3,4-dihydroquinazoline-2(1 H )-Ketone (B15-b) Add 60% NaH (93 mg, 2.333 mmol) to ( S )-7-bromo-4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 HThe 1,4-dioxane (B15-a, 580 mg, 1.166 mmol) was dissolved in anhydrous 1,4-dioxane (12 mL). MeI (0.219 mL, 3.50 mmol) was then added to the solution, and the mixture was stirred at 25 °C for 16 hours. The mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (3x). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography (SiO2, 0-100% EtOAc:hexane) to give compound B15-b.

[0188] Step 3: ( S )-4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-7-(((4-methoxybenzyl)oxy (1)-3-methyl-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1) H )-Ketone (B15-c) Will( S )-7-bromo-4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-3-methyl-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1 H A mixture of (4-methoxy)benzyloxymethyltrifluoroborate potassium (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. 3 M Cs2CO3 (1721 µl, 5.16 mmol) in aqueous solution was added, and the resulting mixture was irradiated in a Biotage® Initiator microwave oven (Biotage, LLC, Charlotte, NC) at 150 °C for 1 h. The reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc (3x). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography (SiO2, 0-100% EtOAc:hexane) to give compound B15-c. MS (ESI) m / z 583 [M+1].

[0189] Step 4: ( S )-4-(cyclopropylethynyl)-6-fluoro-7-(hydroxymethyl)-1-(4-methoxybenzyl)-3-methyl-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone (B15-d ) Add 1.365 mL of 4M HCl / 1,4-dioxane to ( S )-4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-7-(((4-methoxybenzyl)oxy)methyl)-3-methyl-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H)-ketone (B15-c, 318 mg, 0.546 mmol) was in a solution of DCM (1 mL). The reaction mixture was stirred at 25 °C for 3 hours. Subsequently, the reaction mixture was concentrated under vacuum and purified by rapid chromatography (SiO2, 0-7% MeOH:DCM) to give compound B15-d.

[0190] Step 5: ( S )-7-(chloromethyl)-4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-3-methyl-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-Ketone (B15) ) Add thionyl chloride (0.036 mL, 0.497 mmol) to ( S )-4-(cyclopropylethynyl)-6-fluoro-7-(hydroxymethyl)-1-(4-methoxybenzyl)-3-methyl-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1 H )-ketone (B15-d, 230 mg, 0.497 mmol) was in a solution of DCM (1 mL). The reaction mixture was stirred at 45 °C for 16 hours. The reaction was then cooled and concentrated under vacuum to isolate compound B15, which was used without further purification. MS (ESI) m / z 481 [M+1].

[0191] Intermediate B16: ( S )-7-(aminomethyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3, 4-Dihydroquinazoline-2(1 H )-Keto (B16) Ammonia (7M, 5 mL, 35.0 mmol) in MeOH was added to a vial containing intermediate B07 (0.1 g, 0.292 mmol) and stirred at 70 °C for 16 hours. The reaction mixture was concentrated under vacuum, and compound B16 was isolated and used as is in the next process. MS (ESI) m / z 324 [M+1].

[0192] As shown in Table 5, intermediates B17 to B18 were prepared in a similar manner to that described for the preparation of intermediate B16, wherein the noted starting intermediate was used instead of B07 and similar amine reagents.

[0193] Table 5.

[0194] Intermediate C part Intermediate C01: 2-O-1,2-dihydro-3H-imidazo[4,5-c]pyridine-3-carboxylic acid tert-butyl ester (C01) 1 H -Imidazolo[4,5-C]pyridine-2(3 HThe ketone (C01-a, 500 mg, 3.70 mmol) was dissolved in DMF (18.5 mL), and NaH (154 mg, 3.85 mmol) was added. The mixture was stirred at 0 °C for 30 min. Boc₂O (880 mg, 4.03 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for 48 h. The reaction mixture was diluted with saturated NaHCO₃ and extracted with EtOAc (3 x 15 mL). The organic layers were combined, washed with water (10 mL), then brine (10 mL), and then dried over MgSO₄. The resulting mixture was then filtered and concentrated under vacuum. Compound C01 was isolated and used as is without further processing.

[0195] As shown in Table 6, intermediate CO2 was prepared in a similar manner to that described for the preparation of intermediate CO1, wherein the noted starting material was used instead of CO1-a.

[0196] Table 6.

[0197] Intermediate C03: 2,5-Dimethyl-2,4-dihydro-3 H -1,2,4-triazol-3-one (CO3) Step 1: 4-Amino-3-methyl-1 H -1,2,4-triazole-5(4 H )-ketone(CO3-b) Carbonyl hydrazine (CO3-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 h, and then refluxed at 145 °C for 16 h. The reaction mixture was cooled and concentrated under vacuum. The crude solid was recrystallized from EtOH to give compound CO3-b. MS (ESI) m / z 115 [M+1].

[0198] Step 2: 4-Amino-1,3-dimethyl-1H-1,2,4-triazol-5(4H)-one (CO3-c) Dimethyl sulfate (0.829 mL, 8.76 mmol) was added to 4-amino-3-methyl-1-ethylhexyl sulfate. H -1,2,4-triazole-5(4 H The ketone (CO3-b, 1 g, 8.76 mmol) and NaOH (0.421 g, 10.52 mmol) were reacted in a mixture of water (2 mL). The reaction mixture was stirred at 15 °C for 30 min. The reaction mixture was concentrated under vacuum to isolate compound CO3-c, which was used without further purification. MS (ESI) m / z 129 [M+1].

[0199] Step 3: 2,5-Dimethyl-2,4-dihydro-3 H -1,2,4-triazol-3-one (CO3) A 0.5 M aqueous solution of sodium nitrite (17.2 mL, 8.58 mmol) at 0 °C was added dropwise to a solution of 4-amino-1,3-dimethyl-1H-1,2,4-triazol-5(4H)-one (CO3-c, 1.1 g, 8.58 mmol) in HCl (40.6 mL, 487 mmol, 12 mol / L). The mixture was stirred at 15 °C for 30 min. The reaction mixture was concentrated under vacuum, and the crude solid was purified by sublimation (0.1 atm, 160 °C) to give compound CO3. MS (ESI) m / z 114 [M+1].

[0200] Intermediate C04: 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-1 H -Pyrazole (CO4) Step 1: (4-methyl-1) H -pyrazole-3-yl)methanol(CO4-b) 1 M LiAlH4 / THF (0.150 g, 3.96 mmol) was added to 4-methyl-1-hydroxyl group at 0 °C under N2. H Ethyl pyrazole-3-carboxylate (CO4-a, 0.5 g, 3.24 mmol) was reacted in a solution of THF (6 mL). The reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was quenched with saturated NH4Cl (20 mL) and extracted with EtOAc (3 x 15 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to separate compound CO4-b, which was used without further purification. MS (ESI) m / z 113 [M+1].

[0201] Step 2: 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-1 H -Pyrazole (CO4) Imidazole (182 mg, 2.68 mmol) and TBSCl (269 mg, 1.784 mmol) were added to (4-methyl-1 H 3-pyrazole-3-yl)methanol (CO4-b, 100 mg, 0.892 mmol) was reacted in a solution of DMF (2 mL). The reaction mixture was stirred at 20 °C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by rapid chromatography (SiO2, 50% EtOAc:PE) to give compound CO4. MS (ESI) m / z 227 [M+1].

[0202] As shown in Table 7, intermediates C05 to C08 were prepared in a manner similar to that described for the preparation of intermediate C04, wherein the indicated starting material was used instead of C04-a.

[0203] Table 7.

[0204] Intermediate C09: 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1 H -Pyrazole (C09) Step 1: 3-(diethoxymethyl)-2-ethoxytetrahydrofuran (C09-a) Ferric chloride (III) (0.231 g, 1.427 mmol) was added to a flask containing triethoxymethane (2.326 g, 15.69 mmol) and cooled to 10°C for 30 minutes. 2,3-Dihydrofuran (C09-a, 1 g, 14.27 mmol) was added dropwise over 30 minutes, and the resulting mixture was stirred at 10°C for 1 hour. The reaction mixture was diluted with DCM (50 mL), filtered through a Celite® filter, and concentrated under vacuum to isolate compound C09-a, which was used directly in step 2.

[0205] Step 2: 2-(1 H -pyrazol-4-yl)ethyl-1-ol (C09-b) A solution of 3-(diethoxymethyl)-2-ethoxytetrahydrofuran (C09-b, 800 mg, 3.66 mmol) in EtOH (5 mL) was added to a solution of hydrazine dihydrochloride (500 mg, 4.76 mmol) in water (10 mL) at 0 °C. The reaction mixture was stirred at 15 °C for 2 hours. The reaction mixture was filtered and purified by preparative HPLC (water:(MeCN + 0.05 % NH3H2O)) to give compound C09-c. MS (ESI) m / z 113 [M+1].

[0206] Step 3: 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1 H -Pyrazole (C09) Imidazole (109 mg, 1.605 mmol) was added to 2-(1) at 0 °C. H(-pyrazol-4-yl)ethyl-1-ol (C09-c, 120 mg, 1.070 mmol) was dissolved in DMF (1 mL). TBSCl (194 mg, 1.284 mmol) was added to the mixture, and the mixture was stirred at 20 °C for 12 hours. The solution was poured into water (5 mL) and extracted with EtOAc (2 x 5 mL). The organic layers were combined, washed with water (2 x 5 mL) and brine (2 x 5 mL), dried over Na₂SO₄, filtered, and then concentrated under vacuum to separate compound C09, which was used without further purification. MS (ESI) m / z 227 [M+1].

[0207] Intermediate C10: 5-Cyclopropyl-2,4-Dihydro-3 H -1,2,4-triazol-3-one (C10) TEA (13.75 mL, 99 mmol) was added to a stirred solution of hydrazine formamide hydrochloride (5000 mg, 44.8 mmol) in DCM (100 mL). The mixture was stirred at -10 °C for 30 min. Cyclopropaneformyl chloride (5155 mg, 49.3 mmol) was added at -10 °C, and the mixture was stirred at 20 °C for 15 h. The mixture was concentrated under vacuum, and the residue was diluted with MeCN (100 mL). The mixture was stirred for 30 min, filtered, and the solid was collected. The solid was dissolved in 1 M NaOH (20 mL) and stirred at 100 °C for 2 h. The solution was cooled, and the pH was adjusted to 4-5 with concentrated HCl. The mixture was filtered to separate compound C10, which was used directly without purification. MS (ESI) m / z 124 [M-1].

[0208] Intermediate C11: 4-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-1 H -Pyrazole (C11) 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 layers were washed with brine (5 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to give compound C11, which was used directly without further purification. MS (ESI) m / z 227[M+1].

[0209] Intermediate C12:3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chloro-1 H -Pyrazole (C12) Step 1: 5-Chloro-1 H 3-Pyrazole-3-carboxylic acid methyl ester (C12-b) Thionyl chloride (0.259 mL, 3.55 mmol) was added to 5-chloro-1 at 0 °C. H 3-Pyrazole-3-carboxylic acid (C12-a, 200 mg, 1.365 mmol) was dissolved in MeOH (5 mL). The mixture was stirred at 65 °C for 3 hours. The reaction mixture was concentrated under vacuum, and the resulting residue was diluted with saturated NaHCO3 aqueous solution (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give compound C12-b, which was used in the next step without purification. MS (ESI) m / z 161 [M+1].

[0210] Step 2: (5-chloro-1) H -pyrazole-3-yl)methanol(C12-c) LiAlH4 (42.6 mg, 1.121 mmol) was added to 5-chloro-1 at 0 °C. H Methyl pyrazole-3-carboxylate (C12-b, 150 mg, 0.934 mmol) was dissolved in THF (3 mL). 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 dried over Na₂SO₄ and filtered, and concentrated under vacuum to give compound C12-c, which was used in the next step without purification. MS (ESI) m / z 133 [M+1].

[0211] Step 3: 3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chloro-1 H -Pyrazole (C12) Imidazole (77 mg, 1.132 mmol) was added to (5-chloro-1) at 0°C. HA solution of pyrazole-3-yl)methanol (C12-c, 100 mg, 0.754 mmol) in DMF (1.5 mL) was added. 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 EtOAc (2 x 5 mL). The organic layer was washed with water (2 x 5 mL) and brine (2 x 5 mL), dried over Na2SO4, filtered, and then concentrated under vacuum. The resulting residue was purified by preparative TLC (SiO2, 20% EtOAc:PE) to give product C12. MS (ESI) m / z 247 [M+1].

[0212] Intermediate C13: 5-Chloro-3-(methoxymethyl)-1 H -Pyrazole (C13) Step 1: 5-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H methyl pyrazole-3-carboxylate (C13- b) NaH (37.4 mg, 0.934 mmol) was added to 5-chloro-1 at 0 °C. H Methyl pyrazole-3-carboxylate (C13-a, 100 mg, 0.623 mmol) was added to a solution of THF (5 mL). The mixture was stirred at 0 °C for 10 min. SEMCl (0.166 mL, 0.934 mmol) was added and the reaction mixture was stirred at 15 °C for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The organic layer was washed with brine (10 mL), dried over (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by preparative TLC (SiO2, EtOAc:PE, 1:5) to give compound C13-b.

[0213] Step 2: (5-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazole-3-yl)methanol (C13- c) LiAlH4 (18.79 mg, 0.495 mmol) was added at 0 °C to 5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H Methyl pyrazole-3-carboxylate (C13-b, 120 mg, 0.413 mmol) was dissolved in THF (5 mL). The mixture was stirred at 15 °C for 2 hours. The reactants were dissolved in saturated NH4Cl aqueous solution (10 mL) and extracted with EtOAc (3 x 10 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give compound C13-c, which was used directly in the next step without purification. MS (ESI) m / z 263 [M+1].

[0214] Step 3: 5-Chloro-3-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -Pyrazole (C13-d) NaH (22.83 mg, 0.571 mmol) was added at 0 °C to (5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H 3-Pyrazol-3-yl)methanol (C13-c, 100 mg, 0.381 mmol) was added to a solution of DMF (5 mL). The mixture was stirred at 15 °C for 30 min. MeI (0.119 mL, 1.903 mmol) was added and the reaction mixture was stirred at 15 °C for 1.5 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The organic layers were combined, washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give product C13-d, which was used directly without purification. MS (ESI) m / z 277 [M+1].

[0215] Step 4: 5-Chloro-3-(methoxymethyl)-1 H -Pyrazole (C13) 5-chloro-3-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H A solution of pyrazole (C13-d, 100 mg, 0.361 mmol) in DCM (3 mL) and TFA (1 mL) was stirred at 15 °C for 12 h. The reactants were concentrated under vacuum, dissolved in saturated NaHCO3 aqueous solution (10 mL), and extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to give compound 13. MS (ESI) m / z 147 [M+1].

[0216] Intermediate C14: 6-Oxo-5,6-dihydropyrrolo[3,4-b]pyrrolo-1(4H)-carboxylic acid tert-butyl ester (C14) Will N , N -Dimethylpyridine-4-amine (0.050 g, 0.409 mmol) was added to 4,5-dihydropyrrolo[3,4-b]pyrrole-6 (1 H)-ketone (C14-a, 1 g, 8.19 mmol), TEA (2.286 mL, 16.38 mmol), and BOC2O (2.091 mL, 9.01 mmol) were in suspension in DCM (20 mL). The resulting solution was stirred at 20 °C for 2 hours. The reaction mixture was evaporated and purified by rapid silica gel chromatography (SiO2, EtOAc:heptane, 7:3) to isolate compound C14. 1 H NMR(400 MHz, DMSO-d6) δ = 7.93 (s, 1H), 7.50 (d, J = 2.7 Hz, 1H), 6.34 (d, J = 3.1Hz, 1H), 4.07 (d, J = 0.7 Hz, 2H), 1.56 (s, 9H).

[0217] Intermediate C15: 3-(2,5-Dimethyl-1H-pyrrolo-1-yl)-4-methoxy-1H-pyrazole (C15) Hexane-2,5-dione (50.5 mg, 0.442 mmol) was added to 4-methoxy-1 H 3-Pyrazole-3-amine (C15-a, 50 mg, 0.442 mmol) was dissolved in acetic acid (2 mL). The mixture was stirred at 120 °C for 3 hours. The mixture was concentrated under vacuum and purified by preparative TLC (SiO2, PE:EtOAc = 1:2) to isolate compound C15. MS (ESI) m / z 192[M+1].

[0218] Intermediate C16: 2-(3-(methoxymethyl)-1 H 1-Pyrazol-1-yl)acetic acid (C16) Step 1: 2-(3-(methoxymethyl)-1 H 1-Pyrazole-1-yl)benzyl acetate (C16-b) Add acetonitrile (22.3 mL) to a container containing 3-(methoxymethyl)-1 H In a vial containing pyrazole (C16-a, 1 g, 8.92 mmol) and K₂CO₃ (3.70 g, 26.8 mmol), benzyl 2-bromoacetate (2.451 g, 10.70 mmol) was added. The reaction mixture was heated to 65 °C and maintained 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 vacuum, and the residue was purified by rapid silica gel chromatography (SiO₂, PE:EtOAc = 1:2) to give compound C16-b. MS (ESI) m / z 261 [M+1].

[0219] Step 2: 2-(3-(methoxymethyl)-1 H 1-Pyrazol-1-yl)acetic acid (C16) 2-(3-(methoxymethyl)-1 H 1,1-pyrazol-1-yl)benzyl acetate (C16-b, 312 mg, 1.199 mmol) and Pd / C (128 mg, 0.120 mmol) were added to a flask, followed by MeOH (10 mL). The vessel was evacuated three times with alternating vacuum and hydrogen gas and then stirred under H2 for 16 hours. The mixture was then analyzed by Celite. ® The reactants were filtered and the organic matter was concentrated under vacuum to separate compound C16. 1 H NMR (500 MHz, chloroform-) d ) δ 7.44 (d, J = 1.8 Hz, 1H), 6.37 (d, J = 1.8Hz, 1H), 4.98 (s, 2H), 4.50 (s, 2H), 3.40 (s, 3H).

[0220] Intermediate C17: 4-Fluoro-3-methoxy-1 H -Pyrazole (C17) 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-dionium ditetrafluoroborate (1083 mg, 3.06 mmol) was added to 3-methoxy-1 H β-pyrazole (C17-a, 300 mg, 3.06 mmol) was dissolved in acetonitrile (10 mL). The reaction mixture was stirred at 20 °C for 16 hours. The reaction mixture was concentrated under vacuum and dissolved in EtOAc (10 mL), then 1 M HCl was added to pH 4. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by preparative TLC (SiO2, PE:EtOAc = 1:1) to isolate compound C17. 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).

[0221] Intermediate C18: 4-Chloro-3-methoxy-1 H -Pyrazole (C18) Step 1: 3-Methoxy-1 H 1-Pyrazole-1-carboxylic acid tert-butyl ester (C18-b) BOC-anhydride (710 µL, 3.06 mmol) was added to 3-methoxy-1 H -Pyrazole (C18-a, 200 mg, 2.04 mmol) and Et3N (1.4 mL, 10.2 mmol) were added to a solution of CH2Cl2 (10 mL). 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 the mixture was concentrated under vacuum. The residue was purified by rapid silica gel chromatography (SiO2, hexane:EtOAc = 1:1), separating compound C18-b. 1 H 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).

[0222] Step 2: 4-Chloro-3-methoxy-1 H 1-Pyrazole-1-carboxylic acid tert-butyl ester (C18-c) 3-methoxy-1 H 1,387 mmol tert-butyl pyrazole-1-carboxylate (C18-b, 275 mg, 1.387 mmol) was dissolved in EtOAc (6.9 mL) and NCS (371 mg, 2.8 mmol) was added. The resulting mixture was stirred at 50 °C for 48 hours. Water (10 mL) was added to the reaction mixture, the organic layer was extracted, dried over MgSO4, and filtered. The organic matter was concentrated under vacuum and the residue was purified by rapid silica gel chromatography (SiO2, hexane:EtOAc = 1:3) to isolate compound C18-c. 1 H NMR (500 MHz, CDCl3) δ7.85 (s, 1H), 4.06 (s, 3H), 1.61 (s, 9H).

[0223] Step 3: 4-Chloro-3-methoxy-1 H -Pyrazole (C18) 4-chloro-3-methoxy-1 H 1,18-pyrazole-1-carboxylic acid tert-butyl ester (C18-c, 275 mg, 1.182 mmol) was dissolved in 4M HCl / dioxane (2.9 mL, 11.82 mmol) and stirred at ambient temperature for 16 hours. Over time, the solution became cloudy. The reactants were concentrated under vacuum, and compound C18 was isolated and used without further purification. 1 H NMR (500MHz, DMSO- d6) δ 7.78 (s, 1H), 3.83 (s, 3H).

[0224] Intermediate C19: 3-(1-Methoxyethyl)-1 H -Pyrazole (C19) Step 1: 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazol-3-yl)ethyl-1-one (C19- b) Sodium hydride (3.20 g, 80 mmol) was added to a mixture of (2-(chloromethoxy)ethyl)trimethylsilane (7.27 g, 43.6 mmol) in THF (80 mL) at 0 °C. The reaction mixture was then stirred at 0 °C for 0.5 h. Then, 1-(1... H (-pyrazol-3-yl)ethyl-1-one (C19-a, 4 g, 36.3 mmol). The reaction mixture was stirred at 20 °C for 5.5 h. The reaction was slowly quenched at 0 °C with saturated NH4Cl aqueous solution (40 mL), and extracted with EtOAc (130 mL x 2). The combined organic phases were washed with brine (130 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (SiO2, PE:EtOAc = 9:1), separating compound C19-b. MS (ESI) m / z 241 [M+1].

[0225] Step 2: 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazol-3-yl)ethyl-1-ol (C19- c) NaBH4 (1.89 g, 50 mmol) was added to anhydrous MeOH (80 mL) at 0 °C under N2 conditions, along with 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H 3-pyrazol-3-yl)ethyl-1-one (C19-b, 4 g, 16.6 mmol) was added to the reaction mixture and stirred at 25 °C for 2 hours. A saturated aqueous solution of NH₄Cl (50 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (2 x 80 mL). The organic phases were combined, washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to separate compound C19-c, which was used without further purification. MS (ESI) m / z 243 [M+1].

[0226] Step 3: 3-(1-Methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -Pyrazole (C19-d) 60% NaH (1.056 g, 26.4 mmol) was added to 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 at 0 °C. H(-pyrazol-3-yl)ethyl-1-ol (C19-c, 3.2 g, 13.20 mmol) was added to a mixture in THF (50 mL). The reaction mixture was stirred at 0 °C for 0.5 h. Then, iodomethane (1.644 mL, 26.4 mmol) was added. The reaction mixture was stirred at 20 °C for 6 h. The reaction mixture was cooled to 0 °C and quenched with a saturated aqueous solution of NH4Cl (50 mL). The mixture was extracted with EtOAc (2 x 80 mL). The organic phases were combined, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum to separate compound C19-d. MS (ESI) m / z 257 [M+1].

[0227] Step 4: 3-(1-Methoxyethyl)-1H-pyrazole (C19) 3-(1-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H β-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 mixture was concentrated under vacuum, and the residue was dissolved in EtOAc (20 mL), followed by dropwise addition of a saturated aqueous solution of NaHCO3 (20 mL). The mixture was extracted with EtOAc (5 x 20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to separate compound C19, which was not further purified. MS (ESI) m / z 127 [M+1].

[0228] Intermediate C20: 4-Chloro-3-(methoxymethyl)-1 H -Pyrazole (C20) Step 1: 4-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H methyl pyrazole-3-carboxylate (C20b) NaH (299 mg, 7.47 mmol) was added to 4-chloro-1 at 0 °C. H methyl pyrazole-3-carboxylate (C20-a, 400 mg, 2.491 mmol) was added to a mixture in THF (10 mL). The reaction mixture was stirred at 15 °C for 0.5 h. Then, (2-(chloromethoxy)ethyl)trimethylsilane (1246 mg, 7.47 mmol) was added and the reaction mixture was stirred at 40 °C for 2 h. The residue was extracted with EtOAc (3 x 10 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to separate compound C20-b, which was used directly in step 2. MS (ESI) m / z 291 [M+1].

[0229] Step 2: (4-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazole-3-yl)methanol (C20- c) LiBH4 (157 mg, 7.22 mmol) was added to a mixture of methyl 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (C20-b, 700 mg, 2.407 mmol) in THF (20 mL). The reaction mixture was stirred at 65 °C for 4 hours. The mixture was poured into H2O (10 mL). The residue was extracted with EtOAc (3 x 10 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to separate compound C20-c, which was used without further purification. MS (ESI) m / z 263 [M+1].

[0230] Step 3: 4-Chloro-3-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (C20-d) NaH (2.74 mg, 0.114 mmol) was added at 0 °C to a mixture of (4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methanol (C20-c, 15 mg, 0.057 mmol) in DMF (1 mL). The reaction mixture was stirred at 15 °C for 0.5 h. Then, iodomethane (40.5 mg, 0.285 mmol) was added. The reaction mixture was stirred at 15 °C for 3 h. The reaction mixture was dissolved in water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to separate compound C20-d, which was used directly in step 4. MS (ESI) m / z 277 [M+1].

[0231] Step 4: 4-Chloro-3-(methoxymethyl)-1 H -Pyrazole (C20) 4-chloro-3-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H A solution of pyrazole (C20-d, 10 mg, 0.036 mmol) in 4M HCl / MeOH (1 mL) was stirred at 15 °C for 2 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to give compound C20. MS (ESI) m / z 147 [M+1].

[0232] Intermediate C21:3-Bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2 H -Indazole (C21) Add NaH (0.122 g, 3.05 mmol) to 3-bromo-2 H -Indazole (C21-a, 0.3 g, 1.523 mmol) was dissolved in DMF (8 mL). The reaction mixture was stirred at 20 °C for 0.2 h. Then, SEMCl (0.324 mL, 1.83 mmol) was added. The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was dissolved in water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography to isolate compound C21. MS (ESI) m / z 327, 329 [M+1].

[0233] Intermediate C22: 4-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-carboxylic acid (C22) Step 1: 4,5-Dichloro-1H-imidazole (C22-b) H₂O (30 L) and imidazole (C22-a, 1.5 kg, 22.03 mol) were placed in a 50 L four-necked round-bottom flask purged with and maintained under an inert nitrogen atmosphere. Then, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (4.91 kg, 24.89 mol, 1.13 equivalents) was added at 0 °C. H₂SO₄ (8.643 kg, 88.12 mmol) was then added to the mixture at 0 °C over 30 minutes. The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched by adding NaOH (40 L, 3.8 M). The mixture was acidified to pH 3 with AcOH. The resulting solution was extracted with ethyl acetate (3 x 15 L), the organic layers were combined, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with 6% EtOAc / PE, to give compound C22-b.

[0234] Step 2: 4,5-Dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (C22-c) Tetrahydrofuran (23.4 L) and 4,5-dichloro-1H-imidazole (C22-b, 2.34 kg, 17.08 mol, 1.00 equivalent) were placed in a 50 L four-necked round-bottom flask purged with and maintained under an inert nitrogen atmosphere. NaH (1.033 kg, 25.62 mol, 60%) was then added at 0 °C over 30 minutes. The resulting solution was stirred at 0 °C for 1 hour. Then, SEMCl (3.42 kg, 20.50 mol) was added at 0 °C over 30 minutes. The resulting solution was stirred at room temperature overnight. The reaction was then quenched by adding NH4Cl solution (40 L). The resulting solution was extracted with ethyl acetate (3 x 15 L). The organic layers were combined and concentrated under vacuum to give compound C22-c, which was used directly in step 3.

[0235] Step 3: 2-Bromo-4,5-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (C22-d) 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 placed in a 50 L four-necked round-bottom flask purged with and maintained under an inert nitrogen atmosphere. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by adding NH4Cl solution (40 L). The resulting solution was extracted with DCM (3 x 15 L). The organic layers were combined and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with 10% EtOAc / PE, to give compound C22-d.

[0236] Step 4: 4,5-Dichloro-2-(trimethylsilyl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-Imidazole (C22-e) Tetrahydrofuran (25 L) and 2-bromo-4,5-dichloro-1-{[2-(trimethylsilyl)ethoxy]methyl}imidazole (C22-d, 2.5 kg, 7.22 mol) were placed in a 50 L four-necked round-bottom flask purged with and maintained under an inert nitrogen atmosphere. Then, n-butyllithium (3.178 L, 7.94 mol, 2.5 M) was added dropwise at -78 °C with stirring over 1 hour. The resulting solution was stirred at -78 °C for 30 minutes. Then, trimethylchlorosilane (0.86 kg, 7.94 mol, 1.10 equivalents) was added dropwise at -78 °C with stirring over 20 minutes. The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched by adding 50 L of NH4Cl solution. The solution was extracted with ethyl acetate (3 x 15 L), the organic layers were combined, dried and concentrated under vacuum to separate compound C22-e.

[0237] Step 5: 4-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-carboxaldehyde (C22-f) 4,5-Dichloro-2-(trimethylsilyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}imidazolium (C22-e, 2 kg, 5.89 mol) and tetrahydrofuran (20 L) were placed in a 50 L four-necked round-bottom flask purged with and maintained under an inert nitrogen atmosphere. Then, n-butyllithium (2.35 L, 2.5 M) was added dropwise at -78 °C with stirring over 30 minutes. The resulting solution was stirred at -78 °C for 1 hour. Then, DMF (276.81 g, 3.60 mol, 7.00 equivalents) was added dropwise at -78 °C with stirring over 5 minutes. The resulting solution was stirred at room temperature for 1 hour. The reaction was then quenched by adding HCl (50 L, 1 N). The resulting solution was extracted with ethyl acetate (3 x 15 L). The organic layers were combined and concentrated under vacuum to isolate compound C22-f.

[0238] Step 6: 4-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-carboxylic acid (C22) 4-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-carboxaldehyde (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 placed in a 50 L four-necked round-bottom flask purged with and maintained under an inert nitrogen atmosphere. Sodium chlorite (1.699 kg, 18.78 mol) was then added at 0 °C. NaH₂PO₄ (2.254 kg, 18.78 mol) was added to the mixture at 0 °C. Water (5.88 L) was then added to the mixture at 0 °C. The resulting solution was stirred at room temperature for 2 hours. The solution was then extracted with ethyl acetate (3 x 15 L), the organic layers were combined, dried, and concentrated under vacuum. The resulting crude solid was purified by grinding with PE (500 mL) and then the filter cake was collected by filtration. This yielded compound C22. MS (ESI) m / z 277 [M+1].

[0239] The non-commercially available intermediates used in the preparation of Examples 1 to 130 were prepared as described in Intermediates A to C above and are noted in the INT. column in each of Tables 8-16.

[0240] Example 1 ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methoxy-1 H-1,2,4-triazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-Keto(1) Step 1: ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-nitro-1H-1,2,4- Triazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1H)-one (1-a) K2CO3 (48.4 mg, 0.350 mmol) and 3-nitro-1 H -1,2,4-triazole (19.97 mg, 0.175 mmol) was added to a solution of intermediate B07 (40 mg, 0.117 mmol) in DMF (1 mL). The mixture was stirred at 50 °C for 4 hours. The solution was poured into water (5 mL) and extracted with EtOAc (2 x 5 mL). The organic layers were combined, washed with water (5 mL) and brine (5 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give compound 1-a, which was used in step 2 without purification. MS (ESI) m / z 421 [M+1].

[0241] Step 2: ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methoxy-1 H -1,2, 4-Triazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-Keto(1-b) Sodium methoxide (30.8 mg, 0.571 mmol) was added to ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-nitro-1 H -1,2,4-triazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone (1-a, 40 mg, 0.095 mmol) was in a solution of MeOH (0.5 mL). The mixture was stirred at 60 °C for 16 hours. The mixture was purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to give compound 1-b. 1 ¹H 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].

[0242] Example 2 ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(hydroxymethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-Keto(2) K₂CO₃ (58.1 mg, 0.404 mmol) was added to intermediate B₀₇ (41.2 mg, 0.120 mmol) and (1... H 2-pyrazole-3-yl)methanol (2-a, 28.3 mg, 0.288 mmol) in DMA (1.2 mL). The reaction mixture was stirred at 60 °C for 16 h. The mixture was filtered and purified by preparative HPLC (water:(MeCN + 0.1 % TFA)) followed by rapid chromatography (SiO2, 0 – 70 % (3:1 EtOAc:EtOH):hexane) to give compound 2. 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].

[0243] Example 3 (S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-methoxy-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(3) K₂CO₃ (35.3 mg, 0.255 mmol) was added to intermediate B07 (25 mg, 0.073 mmol) and 4-methoxy-1 H -Pyrazole (3-a, 7.16 mg, 0.073 mmol) was in a solution of DMA (0.73 mL). The reaction mixture was stirred at 60 °C for 16 hours. The solution was purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to give compound 3. 1 ¹H NMR (500 MHz, chloroform-d) δ 8.01 (s, ¹H), 7.27 (s, ¹H), 7.23 (d, ¹H) J = 9.8 Hz, 1H), 7.12(s, 1H), 6.46 (d, J = 6.1 Hz, 1H), 5.71 (s, 1H), 5.26 – 5.15 (m, 2H), 3.74 (s,3H), 1.63 (t, J = 18.3 Hz, 3H), 1.35 – 1.28 (m, 1H), 0.89 – 0.82 (m, 2H), 0.78 – 0.72 (m, 2H) ppm. MS(ESI) m / z 405 [M+1].

[0244] Example 4 ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(hydroxymethyl)-1 H -1,2,4-triazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(4) K2CO3 (40.3 mg, 0.292 mmol), (1 H-1,2,4-triazol-3-yl)methanol (4-a, 72.3 mg, 0.292 mmol) and KI (48.4 mg, 0.292 mmol) were added to a solution of intermediate B07 (50 mg, 0.146 mmol) in DMF (0.5 mL). The mixture was stirred at 25 °C for 3 hours. The mixture was then filtered and purified by preparative HPLC (water: (MeCN + 10 mM NH4HCO3)) to give compound 4. 1 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].

[0245] The compounds of Examples 5 to 31 illustrated in Table 8 were prepared in a manner similar to that described for Example 4, but using suitable intermediate starting materials as indicated in the INT. column. The compounds were purified by preparative HPLC (water: (MeCN + 0.1% TFA or 0.05% NH4OH)), rapid chromatography, or a combination of both.

[0246] Table 8.

[0247] Example 32 ( S)-4-(cyclopropylethynyl)-7-((1,3-dimethyl-5-oxo-1,5-dihydro-4- H -1,2,4-triazol-4-yl)methyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(32) Intermediate CO3 (326 mg, 1.731 mmol) was added to a stirred mixture of intermediate B08 and K2CO3 (399 mg, 2.88 mmol) in DMF (4.0 mL). The resulting mixture was stirred at 40 °C for 16 hours. The mixture was filtered and the solution was purified by preparative HPLC (water:(ACN + NH4HCO3 modifier)) to give compound 32. 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].

[0248] Example 33 ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((3-methyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(33) A mixture of intermediate B08 (24.1 mg, 0.070 mmol), 1,2-dihydro-5-methyl-1,2,4-triazol-3-one (33-a, 8.27 mg, 0.083 mmol), K₂CO₃ (19.21 mg, 0.139 mmol), and KI (2.308 mg, 0.014 mmol) in MeCN (0.22 mL) was stirred at 85 °C for 45 min. The reaction mixture was cooled, diluted with MeOH / DCM (10% v / v), and washed with water (3 x 5 mL), then with brine (5 mL). The organic layer was dried over MgSO₄, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to give compound 33. 1 H NMR (500MHz, 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].

[0249] The compounds of Examples 34 to 38 illustrated in Table 9 were prepared in a similar manner to that described for Example 33, but using suitable intermediate starting materials as noted in the INT. column.

[0250] Table 9.

[0251] Example 39 ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((2-oxo-2,3-dihydro-1) H -imidazo[4,5- c ]pyridin-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1 H )-Ketone(39) Step 1: ( S )-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydro Quinazolin-7-yl)methyl)-2-oxo-1,2-dihydro-3 H -imidazo[4,5- c 39-a tert-butyl pyridine-3-carboxylate K₂CO₃ (35.9 mg, 0.260 mmol), LiBr (7.51 mg, 0.087 mmol), and intermediate B08 (30 mg, 0.087 mmol) were added to a solution of intermediate C01 (40.7 mg, 0.173 mmol) in DMF (1 mL). The mixture was stirred at 40 °C for 16 hours. The reaction mixture was concentrated under vacuum and diluted with water (10 mL) and EtOAc (20 mL). The mixture was washed with water (10 mL) and brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to separate compound 39-a, which was used without further purification. MS (ESI) m / z 546 [M+1].

[0252] Step 2: ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((2-oxo-2,3-dihydro-1) H -imidazo[4,5- c ] Pyridin-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(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 vacuum, and purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to give compound 39. 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, 1H), 5.17 (s, 2H), 1.47 – 1.39 (m, 1H), 0.94 – 0.87 (m, 2H), 0.80 – 0.75 (m, 2H) ppm. MS(ESI) m / z 446 [M+1].

[0253] Example 40 ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((6-oxo-5,6-dihydropyrrolo[3,4-b]pyrrole-1(4 H )-methyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(40) 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. 1 H NMR (400 MHz, DMSO-d6)= 9.48 (s, 1H), 7.94 (s, 1H), 7.86(br s, 1H), 7.12 (d, J = 10.0 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.51 (d, J = 6.6Hz, 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].

[0254] Example 41 ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((2-oxo-1,2-dihydro-3-) H -imidazo[4,5- c ]pyridin-3-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1 H )-Ketone(41) Step 1: ( S )-(3-(((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrafluoromethyl 41-a) tert-butyl carbamate (41-a) A mixture of intermediates B13 (60 mg, 0.184 mmol) and CO2 (46.2 mg, 0.221 mmol) was stirred at 55 °C for 16 h in EtOH (5 mL) and AcOH (0.05 mL). 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 h. The reaction mixture was purified by preparative HPLC (water:(MeCN + 10 mM NH4HCO3)) to give compound 41-a.

[0255] Step 2: ( S )-7-(((4-aminopyridin-3-yl)amino)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(tri-)fluoromethyl)-3,4-dihydroquinazolin-2(1 H )-Keto(41-b) Will( S A mixture of tert-butyl carbamate (41-a, 40 mg, 0.077 mmol) in 4M HCl / MeOH (10 mL) was stirred at 15 °C for 2 hours. The reaction mixture was then concentrated under vacuum to isolate compound 41-b, which was used without further purification.

[0256] Step 3: ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((2-oxo-1,2-dihydro-3-) H -imidazo[4,5- c ] Pyridin-3-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(41) Will( S )-7-(((4-aminopyridin-3-yl)amino)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1 H A mixture of 41-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. Triphosgene (42.5 mg, 0.143 mmol) in THF (0.5 mL) was added dropwise to the mixture. The reaction mixture was heated to 15 °C and stirred for 2 hours. The mixture was quenched with a saturated aqueous solution of NaHCO3 (5 mL) and washed with water (2 x 5 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to give compound 41. 1 HNMR (400 MHz, MeOH-d4) δ 8.53 (s, 1H), 8.43 (d, J = 6.3 Hz, 1H), 7.57 (d, J = 6.4Hz, 1H), 7.32 (d, J = 10.0 Hz, 1H), 6.86 (d, J = 6.3 Hz, 1H), 5.24 (s, 2H), 1.44– 1.41 (m, 1H), 0.92 – 0.89 (m, 2H), 0.77 – 0.75 (m, 2H) ppm. MS(ESI) m / z 446[M+1].

[0257] Example 42 ( S)-3-((4-(cyclopropylethynyl)-6-fluoro-3-methyl-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)imidazolidine-2,4-dione (42) Step 1: (S)-3-((4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-3-methyl-2-oxo-4- (trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)imidazolidine-2,4-dione (42-a) A mixture of intermediate B15 (19 mg, 0.040 mmol), K₂CO₃ (10.92 mg, 0.079 mmol), and imidazolidine-2,4-dione (5.54 mg, 0.055 mmol) in DMF (0.5 mL) was stirred at 45 °C for 16 hours. The reaction mixture was added to water (10 mL) and extracted with EtOAc (2 x 5 mL). The combined organic layers were dried over MgSO₄ and concentrated under vacuum to separate compound 42-a, which was used without further purification. MS (ESI) m / z 545 [M+1].

[0258] Step 2: ( S )-3-((4-(cyclopropylethynyl)-6-fluoro-3-methyl-2-oxo-4-(trifluoromethyl)-1,2,3, 4-Tetrahydroquinazolin-7-yl)methyl)imidazolidine-2,4-dione (42) Will( S 3-((4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-3-methyl-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)imidazolidine-2,4-dione (42-a, 20 mg, 0.037 mmol) was dissolved in ACN (0.75 mL) / water (0.25 mL). CAN (44.3 mg, 0.081 mmol) was added, and the reaction mixture was stirred at 65 °C for 48 hours. The reaction mixture was purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to give compound 42. 1 H NMR (500 MHz, chloroform-) d ) δ 10.00 (s, 1H), 8.55 (s, 1H), 4.85 (d, J = 14.2Hz, 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 / z425 [M+1].

[0259] Example 43 ( S )-7-((3-amino-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-Ketone(43) Step 1: ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-nitro-1 H -pyrazole- 1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-Keto(43-a) K₂CO₃ (36.3 mg, 0.263 mmol) and LiBr (11.40 mg, 0.131 mmol) were added to intermediate B07 (30 mg, 0.088 mmol) and 3-nitro-1 H -Pyrazole (14.85 mg, 0.131 mmol) was in a solution of DMF (0.5 mL). The reaction mixture was stirred at 50 °C for 2 hours. The mixture was then diluted with water (5 mL) and extracted with EtOAc (3 × 10 mL). The organic layers were combined, washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to separate compound 43-a, which was used directly in step 2. MS (ESI) m / z 420 [M+1].

[0260] Step 2: ( S )-7-((3-amino-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoro Ethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-Ketone(43) Add NH4Cl (77 mg, 1.431 mmol) to ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-nitro-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone (43-a, 30 mg, 0.072 mmol) was reacted in a solution of EtOH (1 mL) and water (0.2 mL). Iron powder (40.0 mg, 0.715 mmol) was then added, and the reaction mixture was stirred at 90 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 15 mL). The organic layers were combined, washed with brine (5 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to give compound 43. 1H NMR (400 MHz, MeOH-d4) δ 7.76 (d, J =2.08 Hz, 1H), 7.22 (d, J = 9.90 Hz, 1H), 6.66 (d, J = 6.36 Hz, 1H), 6.13 (d, J =2.20 Hz, 1H), 5.31 (s, 2H), 1.68 (t, J = 18.52 Hz, 3H), 1.39 – 1.37 (m, 1H), 0.89 – 0.86 (m, 2H), 0.74 – 0.72 (m, 2H) ppm. MS(ESI) m / z 390 [M+1].

[0261] The compounds of Examples 44 to 46 illustrated in Table 10 were prepared in a similar manner to that described for Example 43, but using suitable intermediate starting materials as noted in the INT. column.

[0262] Table 10.

[0263] Example 47 ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(2-hydroxyethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(47) KOH (9.82 mg, 0.175 mmol) was added to a solution of intermediate B07 (20 mg, 0.058 mmol) and intermediate C05 (15.85 mg, 0.070 mmol) in DMF (0.2 mL). The reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 15 mL). The organic layers were combined, washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to separate product 47. 1 H NMR (400 MHz, acetonitrile- d 3) 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 = 6.66Hz, 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].

[0264] Example 48 ( S )-6-chloro-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(hydroxymethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(48) Step 1: ( S )-1-((6-chloro-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-2-oxo-1,2,3,4- Tetrahydroquinazolin-7-yl)methyl)-1 H -Pyrazole-3-carboxaldehyde (48-a) 1 H 3-Pyrazole-3-carboxaldehyde (32.1 mg, 0.334 mmol) and K₂CO₃ (77 mg, 0.557 mmol) were added to a solution of intermediate B12 (100 mg, 0.278 mmol) in DMF (1 mL). The reaction mixture was stirred at 40 °C for 16 hours. The reaction mixture was concentrated under vacuum, diluted with NaHCO₃ (20 mL), and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under vacuum to separate compound 48-a, which was used directly in step 2.

[0265] Step 2: ( S )-6-chloro-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(hydroxymethyl)-1 H -pyr (1-(1-yl)methyl)-3,4-dihydroquinazolin-2(1) H )-Ketone(48) NaBH4 (3.25 mg, 0.086 mmol) was added to ( ) at 0℃. S)-1-((6-chloro-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H 48-a (pyrazole-3-carboxaldehyde, 90 mg, 0.215 mmol) was in a solution of MeOH (1 mL). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under vacuum, diluted with NaHCO3 (20 mL), and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to give compound 48. 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].

[0266] The compounds of Examples 49 to 51 illustrated in Table 11 were prepared in a similar manner to that described for Example 48, but using suitable intermediate starting materials as noted in the INT. column.

[0267] Table 11.

[0268] Example 52 ( S )-7-(1 H ,1' H -[3,3'-Bipyrazole]-1-ylmethyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-Ketone(52) K3PO4 (28.1 mg, 0.132 mmol) in water (0.5 mL) was added to the compound of Example 19 (60 mg, 0.132 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1 H -Pyrazole (38.5 mg, 0.199 mmol) and Brettphos Pd G3 (12.00 mg, 0.013 mmol) were in a solution of EtOH (2 mL). The reaction mixture was stirred at 80 °C for 4 hours. The reaction mixture was concentrated under vacuum, diluted with NaHCO3 (20 mL), and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to give compound 52. 1 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].

[0269] Example 53 ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((1'-methyl-1 H ,1' H -[3,3'-Bipyrazole]-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(53) Example 53 was prepared in a similar manner to Example 52, except that it used 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1 H-Pyrazole-substituted 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1 H -Pyrazole. 1 ¹H NMR (400 MHz, acetonitrile-d³) δ 7.69 (s, ¹H), 7.63 (d, ¹H) J = 2.08Hz, 1H), 7.49 (d, J = 1.96 Hz, 1H), 7.26 (d, J = 10.27 Hz, 1H), 6.59 (d, J = 2.08Hz, 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].

[0270] Example 54 ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methoxymethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(54) Add NaH (25.7 mg, 0.642 mmol) to 3-(methoxymethyl)-1 H -Pyrazole (54-a, 30 mg, 0.161 mmol) was added to a solution in DMF (1 mL). The reaction mixture was stirred at 0 °C for 30 min. Intermediate B07 (55.0 mg, 0.161 mmol) was added and the mixture was stirred at 15 °C for 1.5 h. The solution was poured into NH4Cl (5 mL) and extracted with EtOAc (2 x 5 mL). The organic layer was washed with brine (2 x 5 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (water:(MeCN + 10 mM NH4HCO3)) to give compound 54. 1 H NMR (400 MHz, MeOH-d4) δ 7.70 (d, J= 2.26 Hz, 1H), 7.22 (d, J = 10.04 Hz, 1H), 6.50 (d, J = 6.40Hz, 1H), 6.36 (d, J = 2.26 Hz, 1H), 5.37 (s, 2H), 4.43 (s, 2H), 3.35 (s, 3H), 1.67 (t, J = 18.45 Hz, 3H), 1.41 – 1.38 (m, 1H), 0.90 – 0.84 (m, 2H), 0.76 –0.71 (m, 2H) ppm. MS(ESI) m / z 419 [M+1].

[0271] The compounds of Examples 55 to 66 illustrated in Table 12 were prepared in a similar manner to that described for Example 54, but using suitable intermediate starting materials as noted in the INT. column.

[0272] Table 12.

[0273] Example 67 ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-fluoro-3-(hydroxymethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(67) Step 1: ( S )-7-((3-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluoro-1 H -pyrazole-1-yl) methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-Ketone(67-a) NaH (10.50 mg, 0.438 mmol) was added to a solution of intermediate CO6 (67.2 mg, 0.292 mmol) in DMF (2 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min. Intermediate B07 (50 mg, 0.146 mmol) was added, and the mixture was stirred at 20 °C for 1.5 h. The solution was poured into water (10 mL) and extracted with EtOAc (2 x 5 mL). The organic layers were combined, washed with brine (2 x 5 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give product 67-a, which was used without further purification. MS (ESI) m / z537 [M+1].

[0274] Step 2: ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-fluoro-3-(hydroxymethyl)- 1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(67) Will( S )-7-((3-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluoro-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H The mixture of 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 preparative HPLC (water:(MeCN + 0.1% TFA)) to give compound 67. 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), 5.20 (s, 2H), 4.36 (s, 2H), 1.68 (t, J =18.96 Hz, 3H), 1.45 – 1.41 (m, 1H), 0.85 – 0.82 (m, 2H), 0.71 – 0.68 (m, 2H)ppm. MS(ESI) m / z 423 [M+1].

[0275] Example 68 ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(hydroxymethyl)-4-methyl-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(68) Step 1: ( S )-7-((3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-1 H -pyrazole-1- (1,1-difluoroethyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-Keto(68-a) NaH (3.50 mg, 0.088 mmol) was added to a solution of intermediate CO4 (30 mg, 0.133 mmol) in DMF (2 mL). The reaction mixture was stirred at 20 °C for 30 min. Intermediate B07 (30 mg, 0.088 mmol) was added to the reaction mixture and stirred at 20 °C for 1.5 h. The mixture was quenched at 0 °C with saturated NH4Cl aqueous solution (10 mL) and extracted with EtOAc (3 x 15 mL). The organic layer was washed with brine (3 x 9 mL), dried over Na2SO4, filtered, and concentrated under vacuum to separate compound 68-a, which was used without further purification. MS (ESI) m / z 533 [M+1].

[0276] Step 2: ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(hydroxymethyl)-4-methyl) Base-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(68) Add 0.2 mL of 3M HCl / MeOH (0.600 mmol) to ( S )-7-((3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H Compound 68 was obtained by reacting 68-a (36 mg, 0.068 mmol) in a solution of MeOH (1 mL). The reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to give compound 68. 1 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, 2H), 4.49 (s, 2H), 2.05 (s, 3H), 1.66 (t, J = 18.7 Hz, 3H), 1.36 – 1.32 (m, 1H), 0.87 – 0.82 (m, 2H), 0.74 – 0.72 (m, 2H) ppm. MS(ESI) m / z 419 [M+1].

[0277] The compounds of Examples 69 to 71 illustrated in Table 13 were prepared in a similar manner to that described for Example 68, but using suitable intermediate starting materials as noted in the INT. column.

[0278] Table 13.

[0279] Examples 72 and 73 ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-( S or R )-1-hydroxyethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone and ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-( R or S )-1-hydroxyethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-Ketones (72 and 73) Step 1: ( S )-7-((3-acetyl-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-di) (Fluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-Ketone(72 / 73-a) NaH (42.0 mg, 1.050 mmol) was added to 1-(1) at 0 °C. H 3-pyrazol-3-yl)acetone (28.9 mg, 0.263 mmol) was added to a solution in DMF (3 mL). The mixture was stirred at 0 °C for 0.5 h. Then, intermediate B07 (90 mg, 0.263 mmol) was added, and the resulting mixture was stirred at 15 °C for 4 h. The mixture was poured into a saturated aqueous solution of NH4Cl (5 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (SiO2, 66% EtOAc:PE) to give compound 72 / 73-a as a racemic mixture. MS (ESI) m / z 417 [M+1].

[0280] Step 2: ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-( S or R )-1-hydroxyethyl (base)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone and ( S )-4-(cyclopropylethynyl)-4-(1,1- (difluoroethyl)-6-fluoro-7-((3-(( R or S )-1-hydroxyethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2 (1 H )-Ketones (72 and 73) NaBH4 (1.817 mg, 0.048 mmol) was added at 0 °C to a solution of (S)-7-((3-acetyl-1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one (72 / 73-a, 20 mg, 0.048 mmol) in MeOH (1 mL). The mixture was stirred at 15 °C for 1 hour. The mixture was purified by preparative HPLC (water:(MeCN + 0.05% NH3H2O ​​+ 10mM NH4HCO3)) and SFC (Chiralcel OD, 30% iPrOH(0.1% NH3H2O) / CO2, 65 g / min, 150 bar, 35℃) to give compound 72 (faster elution). 1 H NMR (400 MHz, MeOH- d 4) 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 (slower elution): 1 H NMR (400 MHz, MeOH- d 4) δ 7.65 (d, J = 2.32 Hz, 1H), 7.22 (d, J = 10.27Hz, 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 = 6.60Hz, 3H), 1.43 – 1.37 (m, 1H), 0.89 – 0.86 (m, 2H), 0.74 – 0.73 (m, 2H) ppm. MS (ESI) of both. m / z Both are 419 [M+1].

[0281] Example 74 ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((2-methoxy-1 H -imidazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(74) Step 1: ( S )-7-((2-bromo-1 H -imidazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl) )-6-fluoro-3,4-dihydroquinazolin-2(1 H )-Keto(74-a) NaH (40.8 mg, 1.021 mmol) was added to 2-bromo-1 H -Imidazole (75 mg, 0.510 mmol) was added to a solution of THF (1.5 mL). The reaction solution was stirred at 60 °C for 1 hour. Intermediate B07 was added to THF (1 mL) and the reaction mixture was stirred at 60 °C for 6 hours. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 15 mL). The organic layers were combined, washed with brine (35 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (SiO2, 10% MeOH:EtOAc) to give compound 74-a. MS (ESI) m / z 453, 455 [M+1].

[0282] Step 2: ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((2-methoxy-1 H -mi (1-(1-yl)methyl)-3,4-dihydroquinazolin-2(1) H )-Ketone(74) Sodium methoxide (0.1 mL, 0.100 mmol) and CuI (11.76 mg, 0.062 mmol) were added to ( ) under N2. S )-7-((2-bromo-1 H -imidazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H)-ketone (74-a, 140 mg, 0.309 mmol) was in a solution of MeOH (0.5 mL). The reaction mixture was stirred at 120 °C for 7 hours. The mixture was purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to give compound 74. 1 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].

[0283] Example 75 ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methylamino)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(75) The solution of Example 43 (20 mg, 0.051 mmol) and 37% aqueous formaldehyde (8.06 mg, 0.103 mmol) in DMF (1 mL) and AcOH (0.01 mL) was stirred at 15 °C for 1 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 preparative HPLC (water:(MeCN + 0.1% TFA)) to give compound 75. 1 H 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, 1H), 5.16 (br s, 2H), 2.78 (s, 3H), 1.67 (t, J = 18.6 Hz, 3H), 1.39– 1.30 (m, 1H), 0.90 – 0.80 (m, 2H), 0.75 – 0.65 (m, 2H) ppm. MS(ESI) m / z 404[M+1].

[0284] Example 76 ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(dimethylamino)-1 H -pyrazol-1-yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-Ketone(76) Compound 76 was prepared using a similar procedure to that of Example 75, except that 5 equivalents of 37% formaldehyde aqueous solution were used instead of 2 equivalents of 37% formaldehyde aqueous solution, and MeOH was used as the solvent instead of DMF / AcOH. The reaction mixture was stirred at 15°C for 14 hours. 1 ¹H NMR (400 MHz, acetonitrile-d³) δ 7.85 (br s, 1H), 7.53 (s, 1H), 7.25 (d, J = 10.3Hz, 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].

[0285] Example 77 ( S )-4-chloro- N-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -Imidazole-5-carboxamide (77) Step 1: ( S )-4-chloro- N -((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2, 3,4-Tetrahydroquinazolin-7-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -Imidazole-5-formamide (77-a) Intermediate C22 (60 mg, 0.217 mmol) and HATU (82 mg, 0.217 mmol) were added to a vial, followed by DIPEA (114 µL, 0.650 mmol). The mixture was stirred for 10 min, and then intermediate B16 (84 mg, 0.260 mmol) was added to DMF (1084 µL). The solution was stirred at ambient temperature for 16 h. The reaction mixture was added to EtOAc (40 mL), extracted with water (2 x 10 mL) and brine (10 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography, eluting with a gradient of 0 to 100% EtOAc / hexane to separate compound 77-a. MS (ESI) m / z 582 [M+1].

[0286] Step 2: (S)-4-chloro-N-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2, 3,4-Tetrahydroquinazolin-7-yl)methyl)-1H-imidazol-5-carboxamide (77) (S)-4-chloro-N-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-carboxamide (77-a, 97.6 mg, 0.168 mmol) was added to DCM (1524 µL):TFA (152 µL) and maintained at 40 °C for 2 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by preparative HPLC (water:(MeCN + 0.1 % TFA)) to give compound 77. 1 HNMR (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].

[0287] Example 78 ( S )-4-chloro- N -((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -Imidazole-5-carboxamide (78) Compound 78 was prepared using a procedure similar to that described in Example 77, except that intermediate B16 was replaced with intermediate B17. 1 H NMR (500 MHz, DMSO- d 6) 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 Hz, 1H), 4.45 (dd, J = 5.6, 2.8 Hz, 2H), 1.55 – 1.41 (m, 1H), 0.88 (dd, J = 8.3, 3.1 Hz, 2H), 0.81 – 0.65 (m, 2H). MS(ESI) m / z 456 [M+1].

[0288] Example 79 ( S )- N -((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -Imidazole-2-carboxamide (79) 1 HImidazol-2-carboxylic acid (30 mg, 0.268 mmol), EDC (56.4 mg, 0.294 mmol), and HOAt (40.1 mg, 0.294 mmol) were added to a vial, followed by DMF (1.3 mL) and DIPEA (140 µL, 0.803 mmol). The resulting mixture was stirred for 60 min, and then intermediate B16 (85 mg, 0.263 mmol) was added. The mixture was stirred at ambient temperature for 16 h. The reactants were concentrated under vacuum, and the residues were purified by preparative HPLC (water:(MeCN + 0.1 % TFA)). The fractions were added to a saturated aqueous solution of NaHCO3 (15 mL) and extracted with DCM (3 x 15 mL). The organic layers were combined, washed with water (15 mL), and concentrated under vacuum. The residues were dissolved in an ACN:water mixture and lyophilized to isolate compound 79. 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].

[0289] The compounds of Examples 80 to 89 illustrated in Table 14 were prepared in a similar manner to that described for Example 79, but using suitable intermediate starting materials as noted in the INT. column.

[0290] Table 14.

[0291] Examples 90 and 91 ( S )-7-((2 H-Indazol-2-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone and ( S )-7-((1 H -Indazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-Ketones (90 and 91) 1 at 0℃ H -Indazole (50 mg, 0.423 mmol) was dissolved in DMF (394 µL) and NaH (25.2 mg, 0.630 mmol) was added. The mixture was stirred for 30 minutes. BO7 (27 mg, 0.079 mmol) was added at 0 °C and stirred at room temperature for 16 hours. The reaction mixture was adjusted to 0 °C and water was added dropwise. The reaction mixture was stirred for 10 minutes. EtOAc (20 mL) was added, the organic layer was extracted, washed with water (2 x 5 mL), brine (5 mL), and dried over MgSO4. The solution was concentrated under vacuum and purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to give compounds 90 and 91. Rapid elution of isomer (90): 1 HNMR (500 MHz, DMSO- d 6) δ 9.48 (s, 1H), 8.48 (s, 1H), 7.96 (s, 1H), 7.73 (d, J =8.4 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H), 7.27 - 7.21 (m, 1H), 7.15 (d, J = 10.0 Hz,1H), 7.08 - 7.01 (m, 1H), 6.64 (d, J = 6.5 Hz, 1H), 5.67 (d, J = 3.1 Hz, 2H), 1.68 (t, J = 18.8 Hz, 3H), 1.46 - 1.39 (m, 1H), 0.88 - 0.80 (m, 2H), 0.69 (tt, J = 4.8, 2.1 Hz, 2H). Slow elution of isomers (91) 1 H 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. MS (ESI) of both. m / z Both are 425[M+1].

[0292] The compounds of Examples 92 to 98 illustrated in Table 15 were prepared in a similar manner to that described for Example 90, but using suitable intermediate starting materials as noted in the INT. column.

[0293] Table 15.

[0294] Example 99 (S )-7-((3-amino-4-methoxy-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-Ketone(99) Step 1: ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(2,5-dimethyl-1 H -pyr (-1-yl)-4-methoxy-1 H -pyrazol-1-yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-Ketone(99-a) NaH (7.00 mg, 0.175 mmol) was added to a solution of intermediate C15 (24.55 mg, 0.128 mmol) in DMF (2 mL) at 0 °C under N2. The mixture was stirred at 20 °C for 0.5 h. Intermediate B07 (40 mg, 0.117 mmol) was added, and the mixture was stirred at 20 °C for 1 h. The mixture was poured into water (10 mL) and extracted with EtOAc (2 x 8 mL). The organic layers were combined, washed with water (15 mL) and brine (15 mL), dried over Na2SO4, filtered, and concentrated under vacuum to separate compound 99-a, which was used without further purification. MS (ESI) m / z 498 [M+1].

[0295] Step 2: ( S )-7-((3-amino-4-methoxy-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4- (1,1-Difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-Ketone(99) Hydroxylamine hydrochloride (384 mg, 5.53 mmol) and KOH (197 mg, 3.52 mmol) were added to ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(2,5-dimethyl-1 H -pyrrolo-1-yl)-4-methoxy-1 H -pyrazol-1-yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone (99-a, 50 mg, 0.100 mmol) was in a solution of EtOH (6 mL) and water (2 mL). The mixture was stirred at 90 °C for 2 hours. The mixture was poured into water (20 mL) and extracted with EtOAc (2 x 15 mL). The organic phases were combined, washed with brine (2 x 20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to give compound 99. 1 H 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].

[0296] Example 100 ( S )-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -Imidazole-2-carboxamide (100) Step 1: ( S )-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydro Quinazoline-7-yl)methyl)-1 H ethyl imidazole-2-carboxylate (100-a) NaH (34.6 mg, 0.865 mmol) was added to a solution at 0 °C. H Ethyl imidazole-2-carboxylate (50 mg, 0.357 mmol) was added to a solution in DMF (1442 µl) and stirred for 30 min. Subsequently, intermediate B08 (100 mg, 0.288 mmol) was added. The resulting mixture was stirred at 0 °C for 2 h and then warmed to ambient temperature for 16 h. The reaction was quenched dropwise with water. The mixture was added to EtOAc (10 mL) and washed with water (2 x 3 mL) and brine (3 mL). The organic layer was dried over MgSO4 and concentrated under vacuum to isolate compound 100-a, which was used directly in the next reaction. MS (ESI) m / z 451[M+1].

[0297] Step 2: ( S )-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydro Quinazoline-7-yl)methyl)-1 H -Imidazole-2-carboxamide (100) Will( S )-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H Ethyl imidazole-2-carboxylate (100-a, 130 mg, 0.288 mmol) was dissolved in 7N ammonia / MeOH (3 mL, 21.0 mmol) and heated to 50 °C for 16 hours. The solution was concentrated under vacuum. The residue was purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to give compound 100. 1H 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].

[0298] Example 101 ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((3-methyl-1 H -pyrazol-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(101) K2CO3 (63.6 mg, 0.46 mmol) and 3-methyl-1 H 101-Pyrazole (25.2 mg, 0.31 mmol) was added to a solution of intermediate B08 in DMF (2 mL) and stirred at 15 °C for 3 hours. The reaction mixture was added to water (10 mL) and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to give compound 101. 1 H NMR (400 MHz, acetonitrile- d 3) 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].

[0299] Example 102 ( S )-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -Pyrazole-3-carboxaldehyde (102) Compound 102 was prepared using a procedure similar to that described in Example 101, except that intermediate B08 was replaced with intermediate B07. 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 Hz,1H), 5.51 (br s, 2H), 1.68 (br t, J =18.8 Hz, 3H), 1.43 (br s, 1H), 0.84 (br d, J =6.7 Hz, 2H), 0.69 (br s, 2H). MS(ESI) m / z 403 [M+1].

[0300] 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-1 H -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-1 H -Pyrazole-3-carboxamide (104) Step 1: ( S )-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-Tetrahydroquinazolin-7-yl)methyl)-4-fluoro-1 H -Pyrazole-3-carboxylic acid ethyl ester (103-a) and (S)-1-((4-(cyclopropylacetylene) )-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-4-fluoro-1H-pyrazole- Ethyl 5-formate (104-a) LiBr (3.80 mg, 0.044 mmol) and K₂CO₃ (12.10 mg, 0.088 mmol) were added 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). The resulting mixture was stirred at 50 °C for 2 hours, then water (5 mL) was added and the solution was extracted with EtOAc (2 x 5 mL). The organic phases were combined, washed with water (5 mL) and brine (2 x 5 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to separate compounds (10³-a and 10⁴-a), which were used without further purification. MS (ESI) m / z 465 [M+1].

[0301] 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-1 H -Pyrazole-3-carboxyl Amine (104) Will( S )-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-4-fluoro-1 H Ethyl 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 h. The mixture was concentrated under vacuum and purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to give the title compound. 103-a isomers were eluted more quickly. 1 H NMR (400 MHz, DMSO-d6) δ9.41 (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). Slower elution isomers: 10⁴ 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 =10.0Hz, 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). MS (ESI) of both 10³ and 10⁴. m / z Both are 436 [M+1].

[0302] Examples 105 and 106 ( S )-7-((5-amino-1 H -1,2,4-triazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone (105) and ( S )-7-((3-amino-1 H -1,2,4-triazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-Ketone(106) K₂CO₃ (60.5 mg, 0.438 mmol) and LiBr (12.67 mg, 0.146 mmol) were added to intermediate B₀₇ (50 mg, 0.146 mmol) and 1 H-1,2,4-triazol-3-amine (18.40 mg, 0.219 mmol) in a solution of DMF (3 mL). The mixture was stirred at 40 °C for 8 hours. The reactants were added to water (10 mL) and extracted with EtOAc (2 x 10 mL). The organic phases were combined, concentrated under vacuum, and the residue was purified by preparative HPLC (water:(MeCN + 0.1 % TFA)) to give a mixture of isomers. The mixture was purified using SFC (DAICEL CHIRALCEL OZ, 30% MeOH, 100 bar, column temperature 40 °C) to give the title compound. A faster elution peak of 105 was observed. 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). Slower elution peak at 10⁶: 1 H NMR (400MHz, 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). MS (ESI) of both. m / z Both are 391 [M+1].

[0303] Example 107 ( S )-7-((3-amino-1 H-1,2,4-triazol-1-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(107) 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 min. Then, intermediate B08 (200 mg, 0.577 mmol) was added, and the reaction mixture was stirred at 40 °C for 12 h. The mixture was filtered and purified by preparative HPLC (water:(MeCN + 0.1% TFA)), yielding a second elution peak for compound 107. 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].

[0304] The compounds of Examples 108 to 111 illustrated in Table 16 were prepared in a manner similar to that described for Example 107, but using suitable intermediate starting materials as noted in the INT. column.

[0305] Table 16.

[0306] Example 112 ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methoxymethyl)-1 H -pyrazol-1-yl)methyl)-3-methyl-3,4-dihydroquinazolin-2(1 H )-Ketone(112) 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 an oven-dried 2-daramid vial equipped with a stir bar. DMA (1291 µL), followed by 1,1,3,3-tetramethylguanidine (24.30 µL, 0.194 mmol), was added to the vial and the mixture was bubbled with N2 for 5 minutes. The reaction mixture was sealed and irradiated with a blue LED for 24 hours (PennOC M2, 450 nm, 100% intensity, 5200 rpm fan, 1000 rpm stirring). The reaction mixture was filtered and purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to separate compound 112. 1 H 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].

[0307] Examples 113 and 114 ( S )-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -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) LiBr (25.3 mg, 0.292 mmol), K2CO3 (81 mg, 0.584 mmol), and 1... were added at 25℃. H 1,2,4-Triazol-3-carboxamide (49.1 mg, 0.438 mmol) was added to a solution of intermediate B07 (100 mg, 0.292 mmol) in DMF (1 mL). The reaction mixture was stirred at 40 °C for 2 hours. Water (40 mL) was added to the reaction mixture and the mixture was extracted with EtOAc (40 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (water:(MeCN + 0.1 % TFA)) to separate the faster eluting isomer 113. 1 ¹H 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 was separated as the slower-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). MS (ESI) of both. m / z Both are 419 [M+1].

[0308] Example 115 ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-fluoro-3-methoxy-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(115) 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 h. Then B07 (100 mg, 0.292 mmol) was added and the reaction mixture was stirred at 40 °C for 4 h. The mixture was added to water (15 mL) and extracted with EtOAc (3 x 15 mL). The organic layers were combined, washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to isolate compound 115. 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 = 18.8Hz, 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].

[0309] Examples 116 and 117 ( S)-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -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)-1 H -1,2,4-triazole-3-carboxamide (117) Compounds 116 and 117 were prepared using a method similar to that described for the preparation of compounds 113 and 114, but with intermediate B08 used instead of B07. Compound 116 was isolated as the faster eluting isomer: 1 H NMR (400 MHz, DMSO-d6) δ9.68 (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, the slower eluting isomer, was isolated. 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). MS (ESI) of both. m / z Both are 423 [M+1].

[0310] Example 118 ( S)-4-(cyclopropylethynyl)-6-fluoro-7-((5-methyl-2-) H -Tetrazol-2-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(118) K₂CO₃ (71.8 mg, 0.519 mmol) was added to 5-methyl-2- H The mixture was prepared with tetrazolium (29.1 mg, 0.346 mmol), LiBr (30.1 mg, 0.346 mmol), and intermediate B08 (60 mg, 0.173 mmol). The mixture was stirred for 16 hours. The mixture was then filtered and purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to isolate compound 118. 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].

[0311] Example 119 ( S )-7-((2 H -Indazol-3-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(119) Step 1: ( S )-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-7-((2-((2-(trimethylsilane) (2-ethyl)ethoxy)methyl)-2 H -Indazole-3-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(119-a) In a glove box, NiCl2 (DME) (3.17 mg, 0.014 mmol), pyridine formamidin (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 intermediate C21 (47.2 mg, 0.144 mmol) and intermediate B08 (20 mg, 0.058 mmol) in DMA (2 mL). The reaction mixture was removed from the glove box and stirred at 80 °C for 40 min. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to isolate compound 119-a. MS (ESI) m / z 559 [M+1].

[0312] Step 2: ( S )-7-((2 H -indazole-3-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)- 3,4-Dihydroquinazoline-2(1 H )-Ketone(119) Will( S )-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-7-((2-((2-(trimethylsilyl)ethoxy)methyl)-2 H -Indazole-3-yl)methyl)-3,4-dihydroquinazolin-2(1 H A solution of 119-a (30 mg, 0.054 mmol) in 1 M HCl / EtOAc (2 mL) was stirred at 35 °C for 4 hours. The reaction mixture was concentrated under vacuum and the residue was purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to isolate compound 119. 1 H NMR (400 MHz, acetonitrile- d 3) 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].

[0313] Example 120 ( S )-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -Pyrazole-3-sulfonamide (120) DMA (912 µL) was added to intermediate B07 (100 mg, 0.292 mmol), 1 H The mixture of pyrazole-3-sulfonamide (47.2 mg, 0.321 mmol) and K2CO3 (81 mg, 0.584 mmol) was stirred at 80 °C for 30 min. The reaction mixture was cooled, filtered, and purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to isolate compound 120. 1 HNMR (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].

[0314] Example 121 (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((4-(difluoromethyl)-1H-pyrazol-1-yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one (121) Compound 121 was prepared using a similar procedure to that of Example 120, except that 1H-pyrazole-3-sulfonamide was replaced with 4-(difluoromethyl)-1H-pyrazole. 1 ¹H NMR (500 MHz, methanol-d⁴) δ 8.00 (s, ¹H), 7.71 (s, ¹H), 7.23 (d, ¹H) J = 9.9 Hz, 1H), 6.81 (t, J = 56.3 Hz, 1H), 6.58 (d, J = 6.3 Hz, 1H), 5.41(s, 2H), 1.67 (t, J = 18.5 Hz, 3H), 1.39 (ddd, J = 8.3, 4.9, 3.3 Hz, 1H), 0.94 –0.81 (m, 2H), 0.74 (ddd, J = 4.9, 3.6, 2.5 Hz, 2H). MS(ESI) m / z 425 [M+1].

[0315] Example 122 ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-methyl-5-oxo-4,5-dihydro-1) H -1,2,4-triazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(122) 4-methyl-2,4-dihydro-3 H-1,2,4-triazol-3-one (24.86 mg, 0.251 mmol), intermediate B07 (43 mg, 0.125 mmol), NaI (18.81 mg, 0.125 mmol), and K2CO3 (69.4 mg, 0.502 mmol) were added to a vial, followed by DMF (627 µl). The reaction mixture was heated to 50 °C and maintained for 16 hours. The mixture was cooled, filtered, and purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to isolate compound 122. 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 = 6.5Hz, 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].

[0316] Example 123 ( S )-6-chloro-4-(cyclopropylethynyl)-7-((4-methoxy-1 H -pyrazol-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(123) Intermediate B10 (30 mg, 0.083 mmol), 4-methoxy-1 H -Pyrazole (8.1 mg, 0.083 mmol) and K2CO3 (40 mg, 0.289 mmol) were dissolved in DMA (826 µL) and heated to 60 °C for 16 hours. The reaction mixture was cooled, filtered, and purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to separate compound 123. 1 H NMR (500 MHz, chloroform-) d 3) 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].

[0317] 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-methylimidazolidine-2,4-dione (124) and ( R or S )-5-((( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1-methylimidazolidine-2,4-dione (125) Step 1: ( S , E )-5-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3, 4-Tetrahydroquinazolin-7-yl)methylene)-1-methylimidazolidine-2,4-dione (124-a) 1-Methylimidazolidine-2,4-dione (149 mg, 1.303 mmol) was added to a mixture of intermediate B14 (140 mg, 0.434 mmol) and 2-aminoethanol (13.27 mg, 0.217 mmol) in EtOH (1.3 mL) and water (1.3 mL). The mixture was stirred at 120 °C for 48 hours. The solution was filtered, and the precipitate was washed with EtOH (5 mL) to separate compound (124-a). MS (ESI) was then used. m / z 419 [M+1].

[0318] Step 2: ( S or R )-5-(((S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1, 2,3,4-Tetrahydroquinazolin-7-yl)methyl)-1-methylimidazolidine-2,4-dione (124) and ( R or S )-5-(((S)-4-(ring) (propylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1-methyl Imidazolidine-2,4-dione (125) Zn (1643 mg, 25.1 mmol) was added to a solution of (S,E)-5-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methylene)-1-methylimidazolidine-2,4-dione (124-a, 80 mg, 0.198 mmol) in AcOH (3 mL). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was filtered and the solution was concentrated under vacuum. The residue was purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to separate the racemic mixture of products. This substance was analyzed by SFC (Daicel ChiralPak). ® Separation was performed using AS, MeOH 40%, 100 psi, to isolate compounds 124 and 125. The isomer 124 was eluted more quickly. 1 ¹H 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). Slower elution isomer 125: 1 ¹H NMR (400MHz, 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). MS (ESI) of both. m / z Both are 421 [M+1].

[0319] Example 126 ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-((dimethylamino)methyl)-1 H -pyrazol-1-yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-Ketone(126) Dimethylamine hydrochloride (6.08 mg, 0.075 mmol) was added to a mixture of compound 102 (20 mg, 0.050 mmol) in DCM (1 mL), followed by the addition of AcOH (0.1 mL). The resulting mixture was stirred at 15 °C for 0.5 h. Then, sodium triacetoxyborohydride (21.07 mg, 0.099 mmol) was added and the mixture was stirred at 30 °C for 16 h. The reaction mixture was filtered and purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to separate compound 126. 1 ¹H NMR (400MHz, 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].

[0320] Example 127 ( S )-4-(cyclopropylethynyl)-7-((3-methyl-1H-pyrazol-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(127) In a vial, 3-methyl-1 H -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 h. Intermediate B09 (16 mg, 0.049 mmol) in DMA (100 µL) was added and the mixture was stirred at 80 °C for 16 h. The reaction mixture was filtered through a syringe filter and purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to separate compound 127. 1 H NMR (600 MHz, methanol-) d 4) 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].

[0321] Example 128 ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3,4-dimethyl-5-oxo-4,5-dihydro-1 H -1,2,4-triazol-1-yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-Ketone(128) 4,5-dimethyl-2,4-dihydro-3 H -1,2,4-triazol-3-one (28.4 mg, 0.251 mmol), intermediate B07 (43 mg, 0.125 mmol), NaI (18.81 mg, 0.125 mmol), and K2CO3 (69.4 mg, 0.502 mmol) were added to a vial, followed by DMF (627 µl). The reaction mixture was heated to 50 °C and maintained for 16 hours. The mixture was filtered and purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to isolate compound 128.1 H 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].

[0322] Example 129 ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(2-hydroxypropyl-2-yl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(129) Step 1: ( S )-7-((3-acetyl-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-di) (Fluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-Ketone(129-a) NaH (14.00 mg, 0.350 mmol) was added to 1-(1) at 0℃. H 3-pyrazol-3-yl)acetone (9.64 mg, 0.088 mmol) was dissolved in DMF (1 mL). The mixture was stirred at 0 °C for 0.5 h. Intermediate B07 (30 mg, 0.088 mmol) was added and the mixture was stirred at 15 °C for 1.5 h. The solution was poured into saturated NH4Cl aqueous solution (5 mL) and extracted with EtOAc (2 x 5 mL). The organic phases were combined, washed with brine (2 x 5 mL), dried over Na2SO4, filtered, and concentrated under vacuum to separate compound 129-a, which was used without further purification. MS (ESI) m / z 417 [M+1].

[0323] Step 2: ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(2-hydroxypropyl-2- )-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-Ketone(129) 3M MeMgBr / THF (0.018 mL, 0.054 mmol) was added to ( ) at 0℃. S )-7-((3-acetyl-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone (129-a (15 mg, 0.036 mmol)) was dissolved in THF (1 mL). The mixture was stirred at 10 °C for 10 min. The reaction mixture was poured into saturated NH4Cl aqueous solution (10 mL) and extracted with EtOAc (2 x 30 mL). The organic phases were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (water:(MeCN + 0.1% TFA)) to separate compound 129. 1 H NMR (400 MHz, acetonitrile- d 3) 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].

[0324] Assay for HIV-TACK cell killing activity: PBMCs from healthy donors were cultured in a complete medium containing 5 µg / mL phytohemagglutinin (RPMI 1640 with L-glutamine, 10% heat-inactivated fetal bovine serum, and 100 U / mL penicillin-streptomycin) at approximately 2.5 x 10⁻⁶ ppm. 6 Cells / mL were grown for 3 days at 5% CO2, 37°C, and 90% humidity. On day 4, the PHA-stimulated cells were washed and grown at approximately 20 x 10⁻⁶ cells / mL.6 Cells / mL and VSV-G pseudotyped HIV virus stock solution (VSV-G / pNLG1-P2A- Env (20 µg / mL p24) was resuspended together in complete medium containing IL-2 (10 U / mL) and incubated at 37°C, 5% CO2, and 90% humidity for 4 hours. VSV-G / pNLG1-P2A- Env is a VSV-G pseudovirus originating from pNL43, in which... egfp Insert into nef The 5' end of the virus and eGFP expression dissipate the RNA transcripts that are normally spliced. The virus contains Vif, which is truncated by 50 amino acids due to a frameshift caused by the deletion of a single nucleotide, and because... gfp The subsequent stop codon does not express Nef. Due to frameshift, multiple stop codons are generated, therefore HIVEnv is not expressed. Infected cells are then washed three times with complete medium supplemented with 10 U / mL IL-2 and centrifuged at 200 x g for 3 minutes at 22°C. Cells are then transferred to a container with 5 x 10⁻⁶ cells per ... 6 Cells / mL were resuspended in complete culture medium supplemented with 10 U / mL IL-2 and incubated overnight at 37°C, 5% CO2, and 90% humidity. For compound treatment, infected PBMCs were diluted to 4 x 10⁻⁶ cells / mL with RPMI 1640 containing L-glutamine, 50% normal human serum (NHS), 100 U / mL penicillin-streptomycin, and 10 U / mL IL-2. 5 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 <0.5%. The compound was tested using a 10-point 3-fold titration. The plate was analyzed using a Blue Laser 488nm on an Acumen ex3 imager, and the number of GFP-positive objects was collected; GFP loss indicated infected cell death. Titration curves and EC were calculated using four-parameter logistic fitting. 50 Values. The results are shown in Table 17.

[0325] Table 17.

Claims

1. A compound of formula I: (I) Or its pharmaceutically acceptable salt, wherein: 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-, wherein W is surrounded by 0, 1 or 2 R 5 Substituents; Each R 5 Independent of halogen, C 1-4 Alkyl or C 1-4 Fluorinated alkyl groups; R 1 Halogen, C 1-6 Alkyl, (C 3-12 Heterocyclic alkyl (C 0-4 alkyl) or (C 3-12 )cycloalkyl (C 0-4 alkyl); R 2 It is hydrogen, halogen or C 1-10 alkyl; R 3 It is hydrogen, halogen or C 1-10 alkyl; R 4 Selected from: a) A 5-membered heteroaryl group having at least one nitrogen atom, b) A monocyclic, bicyclic, or tricyclic 7- to 14-membered heteroaryl group comprising at least one heteroatom-containing aromatic ring, wherein the 7- to 14-membered heteroaryl group comprises at least one nitrogen atom, or c) Selected from the following ketone-containing ring systems: triazolinone, 2,4-dihydro-3 H -1,2,4-Triazolyl-3-one, dihydropyrrolo[3,4-] b ]pyrrolidone, imidazolidinone, 1,3-dihydro-2H-benzo[d]imidazolidinone, dihydrobenzo[d]imidazolinone, 1,3-dihydroimidazo[4,5- c ]Pyridone group, oxazolo[5,4- c ]pyridin-2-one, 1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one, 1,3-dihydroimidazo[4,5- b ]Pyridin-2-one, isoindolinone, 4,5-dihydropyrrolo[3,4- b ]pyrrolidone, 4,5-dihydropyrrolo[3,4- b ]Pyrrole-6(2 H )keto, benzo[ d Oxazolone, benzo[ d Oxazol-2-keto, 1,4,5,6-tetrahydrocyclopentanol c ]pyrazolone group and 1,5,6,7-tetrahydro-pyrazolo[4,3- c ]Pyridin-4-keto; Where R 4 By 0, 1, 2 or 3 R 4a Substituents; Each R 4a Selected independently from: C 1-6 alkyl, C 1-10 Fluoroalkyl, amino, Cyano, halogen, hydroxyl group (C 1-10 Alkoxy)C 0-10 alkyl, C 1-10 Fluoroalkoxy, -(C 1-10 alkyl)OH, (C 1-6 alkyl) 1-2 amino (C 0-10 alkyl), amino (C 1-10 alkyl), amino carbonyl (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); Where R 4a By 0, 1, 2 or 3 R 4b Substituents; and Each R 4b Independently for C 1-10 Alkoxy, C 1-6 Alkyl, C 1-10 Fluorinated alkyl, amino, hydroxyl, halogen or cyano groups.

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

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

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein W is -C 1-6 Alkyl-, -(C 1-6 alkyl)amino- or -(C 1-6 alkyl)aminocarbonyl, wherein W is surrounded by 0, 1 or 2 R groups. 5 Substituted by a substituent.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein W is -(C 0-6 Alkyl)O-, wherein W is surrounded by 0, 1 or 2 R 5 Substituted by a substituent.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It can be fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl.

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein R 2 It can be hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or neopentyl.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, R 3 It can be hydrogen, fluorine, chlorine, methyl, bromine, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or neopentyl.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from: a) A 5-membered heteroaryl group having at least one nitrogen atom, wherein the 5-membered heteroaryl group having at least one nitrogen atom is selected from: triazolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrroleyl, tetrazolyl, furazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl and 1,2,3,5-oxtriazolyl; b) A monocyclic, bicyclic, or tricyclic 7- to 14-membered heteroaryl group comprising at least one heteroatom-containing aromatic ring, wherein the 7- to 14-membered heteroaryl group comprises at least one nitrogen atom, and the monocyclic, bicyclic, or tricyclic 7- to 14-membered heteroaryl group comprising at least one heteroatom-containing aromatic ring— wherein the 7- to 14-membered heteroaryl group comprises at least one nitrogen atom—is selected from 2 H -pyrazolo[4,3- c ]pyridyl, 1 H -pyrazolo[3,4- c ]pyridyl, 6,7-dihydropyrano[4,3-c]pyrazolyl, 2 H -pyrazolo[3,4- d ]Pyrimidinyl, 2 H -pyrazolo[3,4- d ]Pyrimidinyl, indoleyl, 2 H -pyrazolo[3,4- b ]pyridyl, benzo[ d [1,2,3]-triazolyl, benzo[ d Imidazolyl, indoleazinyl, isoindoleyl, purine, quinazinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthidyl, quinoxalinyl, cyclolinyl, carbazole, phenanthridine, acridineyl, phenanthroxalinyl, phenazinyl, 7H-pyrazino[2,3-c]carbazole, 1,3-benzoxazolyl and 2,1-benzoxazolyl, or c) A ketone-containing ring system, wherein the ketone-containing ring system is selected from 2,4-dihydro-3- H -1,2,4-triazolyl-3-one, imidazolidineone, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 1,3-dihydroimidazol[4,5- c ]Pyridone group, isoindolinone group, 4,5-dihydropyrrolo[3,4- b ]Pyrrole-6(2 H ) Ketone and benzo[ d Oxazol-2-keto, 1,4,5,6-tetrahydrocyclopentanol c ]pyrazolone group, and Furthermore, R 4 By 0, 1, 2 or 3 R 4a Substituted by a substituent.

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein each R 4a Selected independently from: C 1-4 Alkyl, C 1-6 Fluorinated alkyl, amino, cyano, halogen, hydroxyl, (C 1-6 Alkoxy)C 0-6 Alkyl, C 1-6 Fluoroalkoxy, -(C 1-6 alkyl)OH, (C 1-4 alkyl) 1-2 amino (C 0-6 alkyl), amino (C 1-6 alkyl), aminocarbonyl (C 0-6 )alkyl), (C 3-12 )cycloalkyl (C 0-4 Alkyl), (C 5-6 ) heteroaryl (C 0-4 Alkyl), (C 6-14 )Aryl(C 0-6 alkyl), -(C 0-4 alkyl)carbonyl and -(C 0-4 alkyl)-(S(=O)2NH2), where R 4a By 0, 1, 2 or 3 R 4b Substituted by a substituent.

11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein each R 4b Selected independently from C 1-6 Alkoxy, C 1-4 Alkyl, C 1-6 Fluorinated alkyl, amino, hydroxyl, halogen or cyano groups.

12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein each R 5 It is independently fluorine, chlorine, methyl, ethyl, propyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl or fluoromethyl.

13. The compound according to claim 1, wherein the compound is: ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methoxy-1 H -1,2,4-triazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(hydroxymethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-methoxy-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(hydroxymethyl)-1 H -1,2,4-triazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((5-(hydroxymethyl)-1 H -pyrazol-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((3-(hydroxymethyl)-1 H -pyrazol-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((2-oxo-1,2-dihydro-3-) H -imidazo[4,5- b ]pyridin-3-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-7-((2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1 H )-ketone; ( S )-3-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1-methylimidazolidine-2,4-dione; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-(pyridin-4-yl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-methyl-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((2-oxo-2,3-dihydro-1 H -Benz[d]imidazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-3-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)benzo[d]oxazol-2(3 H )-ketone; ( S )-3-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)imidazolidine-2,4-dione; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-fluoro-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((4-chloro-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -Pyrazole-3-carboxynitrile; ( S )-7-((5-chloro-3-(methoxymethyl)-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((3-bromo-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((1 H -1,2,4-triazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((2 H -pyrazolo[4,3-c]pyridin-2-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-7-((6,7-dihydropyrano[4,3-c]pyrazole-1(4 H )-yl)methyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-7-((6,7-dihydropyrano[4,3-c]pyrazole-2(4 H )-yl)methyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((2-oxo-2,3-dihydro-1) H -Benz[d]imidazol-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-7-((1,3-dimethyl-5-oxo-1,5-dihydro-4- H -1,2,4-triazol-4-yl)methyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((3-methyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((3-chloro-5-oxo-1,5-dihydro-4 H -1,2,4-triazol-4-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((3-chloro-5-oxo-1,5-dihydro-4 H -1,2,4-triazol-4-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((3-Cyclopropyl-5-oxo-1,5-dihydro-4- H -1,2,4-triazol-4-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((2-oxo-2,3-dihydro-1) H -imidazo[4,5- c ]pyridin-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((6-oxo-5,6-dihydropyrrolo[3,4-b]pyrrole-1(4 H )-methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((2-oxo-1,2-dihydro-3-) H -imidazo[4,5- c ]pyridin-3-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazoline-2(1 H )-ketone; ( S )-3-((4-(cyclopropylethynyl)-6-fluoro-3-methyl-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)imidazolidine-2,4-dione; ( S )-7-((3-amino-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((3-amino-5-methyl-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((3-amino-4-methyl-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((3-amino-1 H -pyrazol-1-yl)methyl)-4-(cyclopropyldifluoromethyl)-4-(cyclopropylethynyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(2-hydroxyethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-6-chloro-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(hydroxymethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((2-(hydroxymethyl)-1 H -imidazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((5-(hydroxymethyl)-1 H -imidazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-(hydroxymethyl)-1 H -imidazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-(1 H ,1' H -[3,3'-Bipyrazole]-1-ylmethyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((1'-methyl-1 H ,1' H -[3,3'-Bipyrazole]-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methoxymethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((1 H -imidazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methoxy-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-( R or S )-1-methoxyethyl)-1H-pyrazole-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-( S or R )-1-Methoxyethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((3-amino-5-chloro-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-oxo-3,4,5,6-tetrahydrocyclopentan[c]pyrazole-1(2 H )-methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-1-((4-(cyclopropyldifluoromethyl)-4-(cyclopropylethynyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -Imidazole-2-formamide; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(difluoromethoxy)-1 H -pyrazol-1-yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-(methoxymethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methoxymethyl)-1 H -1,2,4-triazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((4-chloro-3-(methoxymethyl)-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-fluoro-3-(hydroxymethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(hydroxymethyl)-4-methyl-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((5-chloro-3-(hydroxymethyl)-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-(2-hydroxyethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((4-chloro-3-(hydroxymethyl)-1H-pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-( S or R )-1-hydroxyethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-( R or S )-1-hydroxyethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((2-methoxy-1 H -imidazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methylamino)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-(dimethylamino)-1 H -pyrazol-1-yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-chloro- N -((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -Imidazole-5-formamide; ( S )-4-chloro- N -((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -Imidazole-5-formamide; ( S )- N -((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -Imidazole-2-formamide; ( S )- N -((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -Imidazole-2-formamide; ( S )- N -((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)- N -Methyl-1 H -Imidazole-2-formamide; ( S )- N -((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1-methyl-1 H -Imidazole-2-formamide; ( S )- N -((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)oxazol-2-carboxamide; ( S )-2-amino- N -((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-4-methylthiazolyl-5-carboxamide; ( S )- N -((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-4 H -1,2,4-triazole-3-carboxamide; ( S )- N -((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-3-methyl-1 H -Pyrrole-2-carboxamide; ( S )- N -((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-4-methyl-1 H -Imidazole-5-formamide; ( S )-4-cyano-N-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -Pyrrole-2-carboxamide; ( S )- N -((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)thiazolyl-2-carboxamide; ( S )-7-((2 H -Indazol-2-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((1 H -Indazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((1 H -Benz[d][1,2,3]triazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methyl-1 H -indazole-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((1 H -Benz[d]imidazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((4-chloro-3-methoxy-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((1-oxoisoindoline-2-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(4-methoxyphenyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((4-oxo-4,5,6,7-tetrahydro-1 H -pyrrolo[3,2-c]pyridin-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; (S )-7-((3-amino-4-methoxy-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -Imidazole-2-formamide; ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((3-methyl-1 H -pyrazol-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -Pyrazole-3-carboxaldehyde; ( S )-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-4-fluoro-1 H -Pyrazole-5-carboxamide; ( S )-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-4-fluoro-1 H -Pyrazole-3-carboxamide; ( S )-7-((5-amino-1 H -1,2,4-triazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((3-amino-1 H -1,2,4-triazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((3-amino-1 H -1,2,4-triazol-1-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((5-oxo-4,5-dihydro-1) H -1,2,4-triazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-3-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1-methylimidazolidine-2,4-dione; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((methyl(1 H -pyrazol-3-yl)amino)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methoxymethyl)-1 H -pyrazol-1-yl)methyl)-3-methyl-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -1,2,4-triazole-3-carboxamide; ( S )-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -1,2,4-triazole-5-carboxamide; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-fluoro-3-methoxy-1) H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -1,2,4-triazole-5-carboxamide; ( S )-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -1,2,4-triazole-3-carboxamide; ( S )-4-(cyclopropylethynyl)-6-fluoro-7-((5-methyl-2-) H -Tetrazole-2-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((2 H -Indazole-3-yl)methyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -Pyrazole-3-sulfonamide; (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((4-(difluoromethyl)-1H-pyrazol-1-yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((4-methyl-5-oxo-4,5-dihydro-1) H -1,2,4-triazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-6-chloro-4-(cyclopropylethynyl)-7-((4-methoxy-1 H -pyrazol-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; 5-((( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1-methylimidazolidine-2,4-dione; ( S )-5-((( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1-methylimidazolidine-2,4-dione; ( R )-5-((( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1-methylimidazolidine-2,4-dione; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3-((dimethylamino)methyl)-1 H -pyrazol-1-yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-7-((3-methyl-1H-pyrazol-1-yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-((3,4-dimethyl-5-oxo-4,5-dihydro-1 H -1,2,4-triazol-1-yl)methyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; and ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(2-hydroxypropyl-2-yl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone, Or its pharmaceutically acceptable salt.

14. The compound according to claim 1, wherein the compound is: ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-methoxy-1 H -1,2,4-triazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-7-((1,3-dimethyl-5-oxo-1,5-dihydro-4- H -1,2,4-triazol-4-yl)methyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((3-amino-1 H -pyrazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-7-((3-(methoxymethyl)-1 H -pyrazol-1-yl)methyl)-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((5-amino-1 H -1,2,4-triazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-7-((3-amino-1 H -1,2,4-triazol-1-yl)methyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1 H )-ketone; ( S )-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -1,2,4-triazole-3-carboxamide; ( S )-1-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -1,2,4-triazole-5-carboxamide; ( S )-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -1,2,4-triazol-5-carboxamide; or ( S )-1-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-1 H -1,2,4-triazole-3-carboxamide; Or its pharmaceutically acceptable salt.

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

16. The pharmaceutical composition of claim 15, further comprising an effective amount of one or more additional nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide reverse transcriptase translocation inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors, HIV maturation inhibitors, post-attachment inhibitors, and latency reversal agents.

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

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

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

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

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

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, said compatible HIV antiviral agents being selected from nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside reverse transcriptase translocation inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors, HIV maturation inhibitors, post-attachment inhibitors, and latency reversal agents.

23. The compound according to any one of claims 1 to 14, used in a therapeutic manner.

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