Dihydroquinazolines useful as cytomegalovirus antiviral agents

Abstract

The present disclosure provides, in part, novel quinazoline compounds, pharmaceutical compositions thereof, and methods for the treatment and prophylaxis of cytomegalovirus infections.

Description

Attorney Docket No. 71180-431439 (ASP-080-WO)DIHYDROQUINAZOLINES USEFUL AS CYTOMEGALOVIRUS ANTIVIRAL AGENTSCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U. S. Provisional Application No. 63 / 720,716, filed November 14, 2024, which is incorporated herein by reference in its entirety.BACKGROUND

[0002] Human cytomegalovirus (HCMV / HHV-5) is an enveloped dsDNA virus that belongs to the P-subfamily of herpes viruses. The estimated global seroprevalence is 83% and it usually causes a self-limited primary infection with mild to asymptomatic disease in healthy individuals. After primary infection, the virus enters a latent state, residing in myeloid progenitor cells in the bone marrow, but can reactivate and cause severe disease when the individual becomes immuno suppressed. HCMV causes significant morbidity and mortality in individuals who are receiving hematopoietic stem cell or solid organ transplants (HSCT / SOT), as well as HIV / AIDS and cancer patients. HCMV can also cause severe congenital defects.

[0003] Currently, there are several approved drugs that are used to treat systemic HCMV infection or used a preemptive or prophylactic treatment in the context of transplantation.Ganciclovir (GCV) or its prodrug valganciclovir (VGCV), cidofovir (CDV), and foscamet (FOS) all target the viral polymerase UL54 and are approved for treatment of active HCMV infection but are associated with myelosuppression and nephrotoxicity. Maribavir (MBV) targets the viral kinase UL97 and has only been FDA approved for treating post-transplant HCMV infections that do not respond to other antiviral treatment. Letermovir (LTV) targets the viral terminase complex (UL56 / UL89 / UL51) that is responsible for cleaving and packaging individual HCMV genomes into capsids. Letermovir has been approved for prophylaxis for HSCT and SOT recipients for up to 200 days but has significant drug-drug interaction (DDI) liabilities, especially with immunosuppressants commonly used during transplantation.

[0004] W02004041790, entitled SUBSTITUTED QUINAZOLINES AS ANTIVIRAL AGENTS, ESPECIALLY AGAINST CYTOMEGALOVIRUSES, relates to substituted quinazolines and to methods for the production thereof, in addition to the use thereof in theAttorney Docket No. 71180-431439 (ASP-080-WO)production of medicaments for the treatment and / or prophylaxis of diseases, especially for use as antiviral agents, especially against cytomegaloviruses.

[0005] W02004072048, entitled 2-(3-PHENYL-2-PIPERAZINYL-3,4- DIHYDROQUIN AZOLINE-4- YL) ACETIC ACIDS AS ANTI-VIRAL AGENTS, ESPECIALLY AGAINST CYTOMEGALO VIRUSES, relates to dihydroquinazolines and methods for the production thereof, the use thereof in the treatment and / or prophylaxis of diseases, in addition to the use thereof in the production of medicaments in the treatment and / or prophylaxis of diseases, especially for use as anti-viral agents, especially against cytomegalo viruses.

[0006] W02004096778, entitled SUBSTITUTED DIHYDROCHINAZOLINES HAVING ANTIVIRAL PROPERTIES, relates to substituted dihydrochinazolines of formula (I), methods for the production thereof, and the use thereof for producing medicaments used for treating and / or preventing diseases, particularly as antiviral agents, especially against cytomegaloviruses.

[0007] W02004099212, entitled HETEROCYCLYL-SUBSTITUTED DIHYDROQUINAZOLINES AND USE THEREOF AS AN ANTIVIRAL AGENT, relates to heterocyclyl-substituted dihydroquinazolines of formula (I), methods for the production and use thereof for the production of medicaments for the treatment and / or prophylaxis of diseases, in particular, for use as anti-viral agents, in particular, against cytomegaloviruses.

[0008] W02005047278, entitled SUBSTITUTED DIHYDROQUINAZOLINES II, relates to substituted dihydroquinazolines and to a method for the production thereof, the use thereof for treating and / or preventing diseases and for producing drugs for treating and / or preventing diseases, in particular for the use of the inventive dihydroquinazolines in the form of antiviral agents, in particular against cytomegaloviruses.

[0009] W02005113552, entitled SUBSTITUTED AZACHINAZOLINES HAVING AN ANTIVIRAL ACTION, relates to substituted azachinazolines and methods for the production thereof. The invention also relates to the use of said azachinazolines for producing medicaments for the treatment and / or prophylaxis of diseases, especially for using as antiviral agents, especially against cytomegaloviruses.

[0010] WO2016109360, entitled DIHYDROQUINAZOLINE INHIBITORS OF VIRAL TERMINASE, relates to new dihydroquinazoline modulators of viral infection, pharmaceutical compositions thereof, and methods of use thereof.Attorney Docket No. 71180-431439 (ASP-080-WO)

[0011] WO2018028556, entitled ANTI-HCMV VIRUS COMPOUND, relates to a class of fused cyclic compounds against the HCMV virus, and use thereof in the preparation of a drugs for treating diseases associated with the HCMV virus. In particular, disclosed is the compound shown in formula (II) and pharmaceutically acceptable salts thereof.

[0012] WO2019154192, entitled CRYSTAL FORM OF 3,4-DIHYDROTHIENO[3,2- D] PYRIMIDINE COMPOUND AND PREPARATION METHOD THEREFOR, relates to a crystal form A of a 3,4-dihydrothieno[3,2-d]pyrimidine compound (1), a preparation method therefor, and an application thereof in the preparation of an anti-human cytomegalovirus (HCMV) drug.

[0013] WO2023236752, entitled HETEROCYCLIC DERIVATIVE, AND PHARMACEUTICAL COMPOSITION AND APPLICATION THEREOF, relates to a heterocyclic derivative having a structure as shown in formula (I), or a stereoisomer and a pharmaceutically acceptable salt thereof. The heterocyclic derivative or the stereoisomer thereof has high HCMV inhibiting activity, has the activity being increased by 8-40 times compared with letermovir, and clinically, can better protect patients suffering from HCMV infection after allogeneic hematopoietic stem cell transplantation, kidney transplantation, and lung transplantation.

[0014] There is still a need for additional compounds for the treatment and prophylaxis of cytomegalovirus infections that have an improved profile with respect to safety, potency, selectivity and / or bioavailability.FIELD OF THE INVENTION

[0015] The novel dihydroquinazoline compounds presented herein target the cytomegalovirus terminase complex and provide a similar or improved antiviral effect against HCMV as existing approved drugs, as well as significantly reducing interactions with hepatic transporters, thus improving DDI liabilities and providing a better overall safety profile.SUMMARY OF THE INVENTION

[0016] In one aspect, the present disclosure provides a compound of Formula I:Attorney Docket No. 71180-431439 (ASP-080-WO)(R2)xoFormula Ior a pharmaceutically acceptable salt thereof, wherein the variables are as described herein.

[0017] In another aspect, the disclosure provides pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0018] In another aspect, the disclosure provides a method of treating or preventing a cytomegalovirus infection in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0019] In another aspect, the disclosure provides a method of treating or preventing a cytomegalovirus infections in a subject in need thereof, comprising: administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.DETAILED DESCRIPTION OF THE INVENTION

[0020] The features and other details of the disclosure will now be more particularly described. Before further description of the present disclosure, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless definedAttorney Docket No. 71180-431439 (ASP-080-WO)otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.I. Definitions

[0021] The terms “halo” or “halogen” as used herein refer to the radicals F, Cl, Br or I.

[0022] The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon radical. Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6 or 1-4 carbon atoms, referred to herein as Ci-6 alkyl and Ci-4 alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-l -butyl, 3-methyl-2-butyl, 2-methyl-l -pentyl. 3-methyl-l -pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-1 -butyl, 2-ethyl-l -butyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl, etc.

[0023] The term “alkoxy” as used herein refers to an alkyl group attached to an oxygen atom (i.e., alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 1-4 carbon atoms, referred to herein as Cn6alkoxy and Ci-4alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy and isopropoxy, etc.

[0024] The term “haloalkyl” as used herein refers to an alkyl group substituted with one or more halo groups. For example, haloCi-ealkyl refers to a straight or branched alkyl group of 1-6 carbon atoms substituted with one or more halogen atoms. Examples include, but are not limited to. -CH2F, -CHC12, -CHF2, -CF3, CF3CH2-, CH3CF2-. CF3CC12- and CF3CF2-.

[0025] The term “cycloalkyl” as used herein refers to a saturated monocyclic hydrocarbon group of, for example, 3-7 carbons, referred to herein as C3-7monocycloalkyl. Exemplary monocycloalkyl groups include, but are not limited to, cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl.

[0026] The term “coinfection” as used herein refers to simultaneous infection of a host by more than one viral pathogen.

[0027] The terms “Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds or pharmaceutical compositions of the disclosure can be administered to a mammal, such as aAttorney Docket No. 71180-431439 (ASP-080-WO)human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, dogs, primates, and the like). The mammal treated in the methods of the disclosure is desirably a mammal in which treatment of HBV infection is desired.

[0028] The term “modulation” includes antagonism (e.g., inhibition), agonism, partial antagonism and / or partial agonism.

[0029] The term “Pharmaceutically acceptable” includes molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologies standards.

[0030] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, fillers, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

[0031] The term “pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable excipients.

[0032] The term "pharmaceutically acceptable salt(s)" as used herein refers to salts of acidic or basic groups that may be present in compounds used in the compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,Attorney Docket No. 71180-431439 (ASP-080-WO)benzenesulfonate, p-toluenesulfonate and pamoate (i.e., l, T-methylene- / > A-(2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that are acidic in nature are capable of forming salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.

[0033] The term “therapeutically effective amount” or “effective amount” as used herein refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g., mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds or pharmaceutical compositions of the disclosure are administered in therapeutically effective amounts to treat a disease.Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and / or prophylactic effect.

[0034] The term “treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating a viral infection that results in the improvement of the disease.

[0035] The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term “stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),”“R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof.Mixtures of enantiomers or diastereomers may be designated “(+)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.

[0036] The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carboncarbon double bond. The symbol =, denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the “Z’ or configuration wherein the terms “Z’ and “E” are used in accordance with IUPACAttorney Docket No. 71180-431439 (ASP-080-WO)standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.

[0037] Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers. Substituents around a carbocyclic or heterocyclic ring may also be referred to as “cis” or “trans”, where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis / trans.”

[0038] Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent.Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective syntheses encompass both enantiomeric and diastereoselective transformations and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaerno. Classics in Stereoselective Synthesis, Wiley- VCH: Weinheim, 2009.Attorney Docket No. 71180-431439 (ASP-080-WO)

[0039] The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form.

[0040] The disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,170,31P,32P,35S,18F, and36C1, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium.

[0041] Certain isotopically-labeled disclosed compounds {e.g., those labeled with3H and14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon-14 {i.e.,14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium {i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0042] The term “prodrug” refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood, or liver). Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, etal., Nature Reviews Drug Discovery 2008, 7, 255).II. Compounds of the Invention

[0043] In one aspect, the present invention provides a compound of Formula I:Attorney Docket No. 71180-431439 (ASP-080-WO)oFormula Iof a pharmaceutically acceptable salt thereof, wherein:R5aR5a(R5)uf ^ <RS>“TbNR1is N A, A[ ~N(R5)VR2is independently selected for each occurrence from the group consisting of halo, CN, Ci-4alkyl, haloCi-4alkyl and Ci-4alkoxy;R3is independently selected for each occurrence from the group consisting of Ci-4alkyl and haloCi-4alkyl;R4is independently selected for each occurrence from the group consisting of CN and halo;R5is independently selected for each occurrence from the group consisting of CN, halo, RaRbN, Ci-4alkyl, haloCi-4alkyl and Ci-4alkoxy;R5ais hydrogen, C1-4alkyl, haloCi-4alkyl or Cs emonocycloalkyl;Raand Rbare independently selected from the group consisting of hydrogen and Ci-4alkyl;x is 0, 1, 2 or 3;y is 0, 1, 2 or 3;Attorney Docket No. 71180-431439 (ASP-080-WO)z is 0, 1, 2 or 3;u is 0, 1 or 2; andv is 0, 1, 2 or 3.III. Methods of Use

[0044] The compounds of the invention can be used for prophylaxis, pre-emptive, and systemic treatment options for the following populations prone to HCMV infection and other related herpes viruses; (1) hematopoietic stem cell or solid organ transplant recipients (2) HIV or AIDS patients (3) pregnant women (4) neonates and infants (5) cancer patients and other individuals undergoing chemotherapy or immunosuppressive treatments (6) HCMV-positive patients with cancers that could be driven by viral oncogenes. The high morbidity and mortality end organ diseases that could be treated in the previously stated populations includes pneumonitis, esophagitis, gastritis, colitis, retinitis, encephalitis, and graft vs. host disease.Additionally, these compounds could be used in combination with other antivirals like ganciclovir, valganciclovir, foscarnet, cidofovir, maribavir, acyclovir, valacyclovir, and other drugs for additive or synergistic antiviral treatments or used in the context of infections that have proven to be resistant to other drugs.

[0045] In one aspect, the invention provides methods for treating or preventing a cytomegalovirus infection in a patient comprising administering to the patient an effective amount of at least one compound o Formula I, or a pharmaceutically acceptable salt thereof.

[0046] In some embodiments, the Compounds of the invention are useful for the treatment of cytomegalovirus infections and / or reduction of the likelihood or severity of symptoms of cytomegalovirus infections. For example, the compound of the invention are useful in treatment after suspected past exposure to cytomegalovirus by such means as blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery or other medical procedures.IV. Combination Therapy

[0047] In another aspect, the present invention provides methods for treating or preventing a cytomegalovirus infection comprising the administration of one or more additional therapeutic agents which are not compounds of the invention.Attorney Docket No. 71180-431439 (ASP-080-WO)

[0048] In some embodiments, the additional therapeutic agent is an antiviral agent.

[0049] In some embodiments, the additional therapeutic agent is an anti-herpes agent.

[0050] Anti-herpes agents useful in the present compositions and methods include, but are not limited to, nucleoside polymerase inhibitors, such as acyclovir, valaciclovir, famciclovir, penciclovir, cidofovir, brincidofovir (CMX-001), valmanciclovir, ganciclovir, valganciclovir, and N-methanocarbathymidine (N-MCT); pyrophosphate polymerase inhibitors, such as foscarnet; CMV terminase inhibitors, such as letermovir; viral kinase inhibitors, such as maribavir; and helicase-primase inhibitors, such as pritelivir (AIC-316), and amenamevir (ASP- 2151).

[0051] In another embodiment, the additional therapeutic agent is an immunomodulatory agent, such as an immunosuppressive agent. Immunosuppressant agents useful in the present compositions and methods include, but are not limited to, cytotoxic agents, such as cyclophosphamide and cyclosporin A; corticosteroids, such as hydrocortisone and dexamethasone, and non-steroidal anti-inflammatory agents (NSAID).

[0052] In another aspect, the present invention provides methods for treating or preventing a cytomegalovirus infection in a patient, the method comprising administering to the patient: (i) at least one compound of the invention, or a pharmaceutically acceptable salt thereof, and (ii) at least one additional therapeutic agent that is other than compound of the invention, wherein the amounts administered are together effective to treat or prevent the cytomegalovirus infection

[0053] When administering a combination therapy of the invention to a patient, therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising therapeutic agents, may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like. The amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts). Thus, for non-limiting illustration purposes, a Compound of the invention and an additional therapeutic agent may be present in fixed amounts (dosage amounts) in a single dosage unit (e.g., a capsule, a tablet and the like).

[0054] In one embodiment, the at least one compound of the invention is administered during a time when the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or vice versa.Attorney Docket No. 71180-431439 (ASP-080-WO)

[0055] In another embodiment, the at least one compound of the invention and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating or preventing a cytomegalovirus infection.

[0056] In another embodiment, the at least one compound of the invention and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating or preventing a cytomegalovirus infection.

[0057] In another embodiment, the at least one compound of the invention and the additional therapeutic agent(s) act synergistically and are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating or preventing a cytomegalovirus infection.

[0058] In another embodiment, the at least one compound of the invention and the additional therapeutic agent(s) are present in the same composition. In one embodiment, this composition is suitable for oral administration. In another embodiment, this composition is suitable for intravenous administration. In another embodiment, this composition is suitable for subcutaneous administration. In still another embodiment, this composition is suitable for parenteral administration.

[0059] The at least one compound of the invention and the additional therapeutic agent(s) can act additively or synergistically. A synergistic combination may allow the use of lower dosages of one or more agents and / or less frequent administration of one or more agents of a combination therapy. A lower dosage or less frequent administration of one or more agents may lower toxicity of therapy without reducing the efficacy of therapy.

[0060] In one embodiment, the administration of at least one compound of the invention and the additional therapeutic agent(s) may inhibit the resistance of a cytomegalovirus infection to these agents.

[0061] The doses and dosage regimen of the other agents used in the combination therapies of the present invention for the treatment or prevention of cytomegalovirus infection can be determined by the attending clinician, taking into consideration the approved doses and dosage regimen in the package insert; the age, sex and general health of the patient; and the type and severity of the viral infection or related disease or disorder. When administered in combination, the compound(s) of the invention, and the other agent(s) can be administeredAttorney Docket No. 71180-431439 (ASP-080-WO)simultaneously (i.e., in the same composition or in separate compositions one right after the other) or sequentially. This particularly useful when the components of the combination are given on different dosing schedules, e.g., one component is administered once daily and another component is administered every six hours, or when the preferred pharmaceutical compositions are different, e.g., one is a tablet, and one is a capsule. A kit comprising the separate dosage forms is therefore advantageous.

[0062] In one embodiment, one or more compounds of the present invention are administered with one or more additional therapeutic agents selected from: an immunomodulator, an anti-herpes agent, a viral replication inhibitor, an antisense agent, a therapeutic vaccine, a virion production inhibitor, a viral entry inhibitor, a viral assembly inhibitor, an antibody therapy (monoclonal or polyclonal), and any agent useful for treating any type of herpesvirus infection.V. Routes of Administration

[0063] Due to their activity, the Compounds of the invention are useful in veterinary and human medicine. As described above, the Compounds of the invention are useful for treating or preventing herpesvirus infection in a patient in need thereof.

[0064] In another aspect, the present invention provides pharmaceutical compositions comprising an effective amount of a Compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0065] In another aspect, the present invention provides pharmaceutical compositions comprising (i) an effective amount of a Compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and (ii) one or more additional therapeutic agents, wherein said additional therapeutic agents are selected from anti-herpes agents and immunomodulators.

[0066] When administered to a patient, the Compounds of the invention can be administered as a component of a composition that comprises a pharmaceutically acceptable carrier or vehicle. The present invention provides pharmaceutical compositions comprising an effective amount of at least one Compound of the invention and a pharmaceutically acceptable carrier. In the pharmaceutical compositions and methods of the present invention, the active ingredients will typically be administered in admixture with suitable carrierAttorney Docket No. 71180-431439 (ASP-080-WO)materials suitably selected with respect to the intended form of administration, i.e., oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices. For example, for oral administration in the form of tablets or capsules, the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms), and the like. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. Powders and tablets may be comprised of from about 0.5 to about 95 percent inventive composition. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.

[0067] Moreover, when desired or needed, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated in the mixture. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Among the lubricants there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include starch, methylcellulose, guar gum, and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate.

[0068] Liquid form preparations include solutions, suspensions and emulsions and may include water or water-propylene glycol solutions for parenteral or intravenous injection.

[0069] Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions, and emulsions.

[0070] For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

[0071] Additionally, the compositions of the present invention may be formulated in sustained release form to provide the rate-controlled release of any one or more of the components or active ingredients to optimize therapeutic effects, i.e., antiviral activity andAttorney Docket No. 71180-431439 (ASP-080-WO)the like. Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.

[0072] In one embodiment, the one or more compounds of the invention are administered orally.

[0073] In another embodiment, the one or more compounds of the invention are administered intravenously.

[0074] In another embodiment, the one or more compounds of the invention are administered sublingually.

[0075] In another embodiment, a pharmaceutical preparation comprising at least one Compound of the invention is in unit dosage form. In such form, the preparation is subdivided into unit doses containing effective amounts of the active components.

[0076] Compositions can be prepared according to conventional mixing, granulating, or coating methods, respectively, and the present compositions can contain, in one embodiment, from about 0.1%, to about 99% of the compound(s) of the invention by weight or volume. In various embodiments, the present compositions can contain, in one embodiment, from about 1%, to about 70% or from about 5%, to about 60% of the compound(s) of the invention by weight or volume.

[0077] The amount and frequency of administration of the compounds of the invention will be regulated according to the judgment of the attending clinician considering such factors as age. condition and size of the patient as well as severity of the symptoms being treated.Generally, a total daily dosage of the at least one compound(s) of the invention alone, or when administered as combination therapy, can range from about 1 to about 2500 mg per day, although variations will necessarily occur depending on the target of therapy, the patient and the route of administration. In one embodiment, the dosage is from about 10 to about 1000 mg / day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 1 to about 500 mg / day, administered in a single dose or in 2-4 divided doses. In still another embodiment, the dosage is from about 1 to about 100 mg / day, administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is from about 1 to about 50 mg / day, administered in a single dose or in 2-4Attorney Docket No. 71180-431439 (ASP-080-WO)divided doses. In another embodiment, the dosage is from about 500 to about 1500 mg / day, administered in a single dose or in 2-4 divided doses. In still another embodiment, the dosage is from about 500 to about 1000 mg / day, administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is from about 100 to about 500 mg / day, administered in a single dose or in 2-4 divided doses.

[0078] The compositions of the invention can further comprise one or more additional therapeutic agents, selected from those listed above herein. Accordingly, in one embodiment, the present invention provides compositions comprising: (i) at least one compound of the invention or a pharmaceutically acceptable salt thereof; (ii) one or more additional therapeutic agents that are not a Compound of the invention; and (iii) a pharmaceutically acceptable carrier, wherein the amounts in the composition are together effective to treat herpesvirus infection.

[0079] In one embodiment, the present invention provides compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0080] In another embodiment, the present invention provides compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and a second therapeutic agent selected from the group consisting of antiherpes agents and immunomodulators.

[0081] In another embodiment, the present invention provides compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and two additional therapeutic agents, each of which are independently selected from the group consisting of anti-herpes agents and immunomodulators.VI. Examples

[0082] The compounds described herein can be prepared in several ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that theAttorney Docket No. 71180-431439 (ASP-080-WO)functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials.

[0083] At least some of the compounds identified as “intermediates” herein are contemplated as compounds of the disclosure.The following LCMS method have been used for the analysis of final compounds:

[0084] Method A: X-Bridge BEH C-18 (3x50 mmx2.5mm); Mobile phase: A; 0.025% formic acid in H2O; B; CH3CN; Injection voloume:2 µL; Flow rate: 1.2 mL / min, column temperature: 50 °C; Gradient program: 2% B to 98% B in 2.2 min, hold till 3 min, at 3.2 min B conc. is 2 % till up to 4 min.

[0085] Method B: X-select CSH 18 (3x50 mmx2.5mm); Mobile phase: A; 0.025% formic acid in H2O; B; CH3CN; Injection voloume:2 µL; Flow rate: 1.2 mL / min, column temperature: 50 °C; Gradient program: 0% B to 98% B in 2 min, hold till 3 min, at 3.2 min B conc. is 0 % till up to 4 min.

[0086] Method C: X-select CSH 18 (3x50 mmx2.5mm); Mobile phase: A; 0.05% formic acid in H2O: CH3CN (95:5); B; 0.05% formic acid in CH3CN; Injection volume: 2 µL; Flow rate: 1.2 mL / min, column temperature: 50 °C, Gradient program: 0% B to 98% B in 2 min, hold till 3 min, at 3.2 min B conc. is 0 % till up to 4 min.

[0087] Method D: X-select CSH C18 (3x50 mmx2.5pm); Mobile phase: A; 2mM in Ammonium Bicarbonate; B; CH3CN; Injection voloume:2 µL; Flow rate:1.2 mL / min, column temperature: 50 °C; Gradient program: 0% B to 98% B in 2 min, hold till 3 min, at 3.2 min B conc. is 0 % till up to 4 min.

[0088] Method E: X-select CSH 18 (3x50 mmx2.5mm); Mobile phase: A; 0.05% formic acid in H2O; B; CH3CN; Injection volume: 2µL; Flow rate: 1.5 mL / min, column temperature: 50 °C; Gradient program: 0% B to 100% B in 1.5 min, hold till 2.2 min, at 2.6 min B conc. is 0 % till up to 3 min.Attorney Docket No. 71180-431439 (ASP-080-WO)Examples 7 and 8Scheme 1Intermediate 2-A F3Cy^O^ O

[0089] 4,4-diethoxy-l,1 -trifluorobut-3-en-2-one: To a stirred solution of 1.1.1-triethoxyethane (5-A) (212.41 g, 1309.33 mmol, 1.0 equivalent) and pyridine (258.93 g, 3273.33 mmol, 2.5 equivalents) in dichloromethane (1.4 L), 2,2,2-trifluoroacetic anhydride (1-A) (550 g, 2618.66 mmol, 2.0 equivalents) was added dropwise at 0°C under a nitrogen atmosphere. The reaction mixture was then stirred at room temperature for 16 hours under nitrogen. After completion, the mixture was poured into a saturated aqueous solution of sodium bicarbonate at 0°C. The resulting mixture was extracted with dichloromethane (400 mL x 3). The combined organic layers were washed with water (500 mL x 1) and dried over anhydrous sodium sulfate. The solution was filtered, and the filtrate was concentrated under reduced pressure to yield 4,4-Attorney Docket No. 71180-431439 (ASP-080-WO)diethoxy- l,l,l-trifluorobut-3-en-2-one (2-A) as a yellow oil (300 g). MS (ESI): calcd. for C8H11F3O3: 212.1; Found: 213.1 [M + 1]+.Intermediate 3-AO NH2

[0090] (E)-4-amino-4-ethoxy-1,1-trifluorobut-3-en-2-one: To a stirred solution of 4,4-diethoxy-l,l,l-trifluorobut-3-en-2-one (2-A) (300 g, 1413.97 mmol, 1.0 equivalent) in acetonitrile (1.5 L), aqueous ammonia (600 mL) was added dropwise at 0°C under a nitrogen atmosphere. The reaction mixture was then stirred at room temperature for 16 hours under nitrogen. After completion, the mixture was concentrated under reduced pressure. The resulting residue was poured into water at room temperature, leading to the precipitation of solids. The precipitated solids were collected by filtration and washed with water (100 mL x 1) to give crude (E)-4-amino-4-ethoxy-l,l,l-trifhiorobut-3-en-2-one (3-A) as a yellow solid (156 g). MS (ESI): calcd. for C6H F3NO2: 183.1: Found: 182.0 [M - 1]’.NMR (300 MHz, CDCl3): δ 5.16 - 5.09 (m, 1H), 4.15 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H) ppm.Intermediate 1-1 /

[0091] 1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-amine: A solution of (E)-4-amino-4-ethoxy-1,1-trifluorobut-3-en-2-one (3-A) (156 g, 851.85 mmol, 1.0 equivalent) in ethanol (960 mL) was treated with triethylamine (129.30 g, 1277.78 mmol, 1.5 equivalents) at room temperature under a nitrogen atmosphere. Methylhydrazine sulfate (6-A) (147.35 g, 1022.22 mmol, 1.2 equivalents) was then added in portions at room temperature. The resulting mixture was stirred at 85 °C for 16 hours under nitrogen. After the reaction, the mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was diluted with saturated aqueous sodium bicarbonate (1 L) and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (500 mL x 1) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residueAttorney Docket No. 71180-431439 (ASP-080-WO)was purified by silica gel column chromatography, using a petroleum ether / ethyl acetate (20%) eluent, to afford l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-amine (1-1) as a yellow oil (34 g, 15.7% over 3 steps). MS (ESI): calcd. for C5H6F3N3: 165.1; Found: 166.1 [M + 1]+.NMR (300 MHz, CDCl3): δ 5.85 (s, 1H), 3.83 – 3.62 (m, 3H), 3.53 (s, 2H) ppm.CS2CO3 Pd2(dba)3, XPhos HCI dioxane EA 100°C, 2 h rt,16 h Step 1 Step 21-BIntermediate 3-BClk / N.Boc

[0092] tert-Butyl (R)-4-(3-chlorophenyl)-3-methylpiperazine-l-carboxylate: A solution of l-bromo-3-chlorobenzene (1-B) (90 g, 470.10 mmol, 1 equiv) and tert-butyl (R)-3-methylpiperazine- 1 -carboxylate (2-B) (94.15 g. 470.10 mmol, 1 equiv) in dioxane (900 mL) was treated with cesium carbonate (CS2CO3) (229.75 g, 705.15 mmol, 1.5 equiv) at room temperature under a nitrogen atmosphere. Pd2(dba)3(8.61 g, 9.402 mmol, 0.02 equiv) and Xantphos (11.21 g, 23.51 mmol, 0.05 equiv) were then added in portions at room temperature. The reaction mixture was stirred at 100 °C for 2 hours. After completion, the mixture was cooled to room temperature and quenched with ice water. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was extracted with ethyl acetate (500 mL x 3). and the combined organic layers were washed with brine (100 mL x 1) and dried over anhydrous sodium sulfate. The solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with a 5:1 mixture of petroleum ether and ethyl acetate, to afford (R)-4-(3-chlorophenyl)-3-methylpiperazine-l-Attorney Docket No. 71180-431439 (ASP-080-WO)carboxylate (3-B) as a yellow oil (43 g, 29.43%). MS (ESI): calcd. for C16H23CIN2O2: 310.1; Found: 311.1 [M + 1]+.Intermediate 1-5HCI

[0093] (R)-l-(3-Chlorophenyl)-2-methylpiperazine hydrochloride: (R)-4-(3-chlorophenyl)-3-methylpiperazine-l -carboxylate (3-B) (43 g, 138.34 mmol, 1 equiv) was dissolved in 2.0 M hydrogen chloride in ethyl acetate (258 mL) and stirred at room temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure. The resulting residue was purified by trituration with a 1:5 mixture of ethyl acetate and petroleum ether to give (R)-l-(3-chlorophenyl)-2-methylpiperazine hydrochloride (1-5) as a yellow solid (31 g, 90.72%). MS (ESI): calcd. for C11H15CIN2: 210.1; Found: 211.1 [M + 1]+. ’H NMR (300 MHz, CD3OD): 5 7.60 - 7.17 (m, 4H), 4.21 (d, J = 11.8 Hz, 1H), 3.86 - 3.41 (m. 6H), 1.18 (dd, J = 6.6, 2.2 Hz, 3H) ppm.Intermediate 1-3CO2Me

[0094] Methyl (E)-3-(2-amino-3-fluorophenyl) acrylate: A stirred solution of 2-bromo-6-fluoroaniline (24 g, 126.31 mmol) in 200 mL of DMF was prepared. Triethylamine (25.56 g, 252.62 mmol) was then added, followed by methyl acrylate (17.57 g, 202.09 mmol). The reaction mixture was purged with nitrogen for 15 minutes. Next, Pd(dppf)Ch (2.8 g, 3.8 mmol) was added under a nitrogen atmosphere, and the reaction was stirred at 90 °C for 16 hours. After completion, as confirmed by TLC, the reaction mixture was quenched with cold water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product wasAttorney Docket No. 71180-431439 (ASP-080-WO)purified using Combi Flash chromatography (0-100% ethyl acetate in heptane) to yield methyl (E)-3-(2-amino-3-fluorophenyl) acrylate (22.3 g, 90.5%) as a pale-yellow oil. TLC: 20% EtOAc in heptane (R 0.5). MS (ESI): calcd for: C10H10FNO2: 195.07; Found: 196.12 [M +1]+. ‘H NMR (400 MHz, CDCh): 57.81 (d, J= 15.79 Hz, 1H), 7.18 (d, J= 7.89 Hz, 1H), 6.96 - 7.06 (m, 1H), 6.61 - 6.82 (m, 1H), 6.38 (d, J - 15.79 Hz, 1H), 3.81 (s, 3H) ppm (two NH2 protons are merged with solvent peak).

[0095] Methyl (E)-3-(3-fluoro-2-isocyanatophenyl) acrylate (1-3): Methyl (E)-3-(2-amino-3-fluorophenyl) acrylate (1 g, 5.12 mmol) was dissolved in 10 mL of isopropyl acetate and stirred. Tri-phosgene (2.11 g, 6.66 mmol) and triethylamine (1.44 mL, 10.2 mmol) were added to the solution at 0 °C. The reaction mixture was gradually warmed to room temperature and stirred for 1 hour. Upon completion, as monitored by TLC, the mixture was washed with ice water and a saturated NaHCO3solution. The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield the crude title compound 1-3 (1 g) as a pale brown oil. which was used directly in the next step without further purification. TLC: 20% EtOAc in heptane (Rf = 0.6).Intermediate 1-2F3C-Y T 'PN'N Ph

[0096] N-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1,1,1-triphenyl-λ5-phosphanimin: To a stirred solution of 1-methyl-5-(trifluoromethyl)-2,3-dihydro-1H-pyrazol-3-amine (1-1) (0.40 g, 2.42 mmol) in acetonitrile (5 mL) at 0 °C under a nitrogen atmosphere, triphenylphosphine (1.60 g, 6.05 mmol), (CCh)2 (2.89 g, 12.11 mmol), and triethylamine (1.70 mL, 12.11 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 16 hours. After the reaction was complete, as monitored by TLC, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash® chromatography using a 20% ethyl acetate in heptane gradient to yield the title compound 1-2Attorney Docket No. 71180-431439 (ASP-080-WO)(0.42 g, 40.76%) as a white solid. TLC: 20% EtOAc in heptane (R / : 0.9). MS (ESI): calcd. for C23H19F3N3P: 425.13; Found: 426.3 [M +1]+.Intermediate 1-4F°\

[0097] Methyl (Z)-3-(3-fluoro-2-((((l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl) imino) methylene) amino) phenyl) acrylate: To a stirred solution of N-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1,1,1-triphenyl-λ5-phosphanimin (1-2) (0.35 g, 0.82 mmol) in dichloromethane (5 mL), methyl (E)-3-(3-fluoro-2-isocyanatophenyl) acrylate (1-3) (0.18 g, 0.82 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. Upon completion of the reaction, as monitored by TLC, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude title compound 1-4 (0.3 g, crude) as a brown semi solid. TLC: 30% EtOAc in heptane (Rf: 0.6). MS (ESI): calcd. for C16H12F4N4O2: 368.09; Found: 369.3 [M+l]+.Intermediate 1-6Cl°\

[0098] Methyl 2-(2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(l-methyl- 5-(trifluoromethyl)-lH-pyrazol-3-yl)-3,4-dihydroquinazolin-4-yl) acetate: To a stirred solution of methyl (Z)-3-(3-fluoro-2-[((l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-Attorney Docket No. 71180-431439 (ASP-080-WO)yl)imino)methylene]amino)phenyl) acrylate (1-4) (0.30 g, 0.81 mmol) in 1,2-dichloroethane (5 mL), (R)-l-(3-chlorophenyl)-2-methylpiperazine (1-5) (0.20 g, 0.97 mmol) and silica gel (0.15 g) were added. The reaction mixture was stirred at 80 °C for 8 hours. After confirming the completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure. The crude product was purified by CombiFlash chromatography using a gradient of 0-100% ethyl acetate in heptane to give the title compound 1-6 (0.14 g, 29.68%) as a white solid. TLC: 30% EtOAc in heptane (Rf: 0.7). MS (ESI): calcd. for C27H27CIF4N6O2: 578.18; Found: 579.22 [M+l]+. ’H NMR (400 MHz, DMSO-rfe): 57.20 (t, 1H), 7.04 (t, 1H), 6.81 – 6.98 (m, 4H), 6.75 (t, 1H), 6.61 (s, 1H), 5.33 - 5.41 (m, 1H), 4.05 - 4.12 (m, 2H), 3.80 - 3.81 (d, 3H), 3.63 - 3.66 (d, 3H), 3.40 - 3.42 (bs, 1H), 3.31 - 3.12 (m, 2H), 2.91 - 2.98 (m, 2H), 2.50 - 2.66 (m, 2H), 0.80 - 1.05 (m, 3H) ppm.Intermediate 1-7ClOH

[0099] 2-(2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl)-3,4-dihydroquinazolin-4-yl) acetic acid: To a stirred solution of methyl 2-[2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(l-methyl-5-(trifhioromethyl)-lH-pyrazol-3-yl)-3,4-dihydroquinazolin-4-yl] acetate (1-6) (0.12 g, 0.20 mmol) in a mixture of tetrahydrofuran and water (3:3 mL) at 0 °C under a nitrogen atmosphere, lithium hydroxide (24.80 mg, 1.03 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. After confirming completion by TLC, the reaction was cooled to 0 °C, quenched with cold water, and extracted with ethyl acetate. The aqueous layer was acidified with IN hydrochloric acid and extracted again with ethyl acetate. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the title compound 1-7 (90 mg, 76.86%) as aAttorney Docket No. 71180-431439 (ASP-080-WO)racemic white solid, consisting of a mixture of four diastereomers. MS (ESI): calcd. for C26H25CIF4N6O2: 564.17; Found: 565.1 [M+l]+.Examples 7 and 8ClOHExample 8

[0100] Examples 7 and 8: 2-[2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(l-methyl-5- (trifluoromethyl)- lH-pyrazol-3-yl)-3,4-dihydroquinazolin-4-yl]acetic acid (1-7) was separated into its enantiomers using chiral preparative supercritical fluid chromatography (SFC) on a CHIRALPAK IC column (20 x 250 mm, 5 pm). The mobile phase consisted of 0.1% formic acid in n-hexane (mobile phase A) and ethanol (mobile phase B), with an elution gradient of A: B (95:5) at a total flow rate of 20 mL / min. Fractions were collected based on retention times and lyophilized to yield Example 7 (peak 1, RT = 5.335 min, 14 mg) and Example 8 (peak 2, RT = 6.718 min, 12 mg), both as white solid.Attorney Docket No. 71180-431439 (ASP-080-WO)Examples 5 and 6Intermediate 2-3°\

[0101] Methyl 2-(8-fluoro-3-(l-methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)-2-oxo-l,2,3,4-tetrahydroquinazolin-4-yl) acetate: A stirred solution of l-methyl-3-(trifluoromethyl)-lH-pyrazole-5-carboxylic acid (2-1) (1.5 g, 7.73 mmol) in toluene (20 mL) was prepared under a nitrogen atmosphere at 0 °C. To this solution, methyl (E)-3-(2-amino-3-fluorophenyl) acrylate (1.5 g, 7.73 mmol), triethylamine (3.25 mL, 23.18 mmol), and diphenyl phosphoryl azide (2.01 mL, 9.27 mmol) were added. The reaction mixture was stirred at 80 °C for 16 hours. Progress was monitored by TLC. Upon completion, the reaction mixture was concentrated under reduced pressure, and the residue was treated with IN HC1. The product was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated again under reduced pressure. The crude material was purified by CombiFlash® chromatography, using a gradient of 0-100% ethyl acetate in heptane, to give the title compound 2-3 as a whiteAttorney Docket No. 71180-431439 (ASP-080-WO)solid (0.48 g, 16.08%). TLC: 30% ethyl acetate in heptane (R 0.5). MS (ESI): calcd. for C16H14F4N4O3: 386.10; Found: 387.3 [M+l]+.Intermediate 2-5

[0102] Methyl 2-(2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(l-methyI-3-(trifluoromethyl)-lH-pyrazol-5-yl)-3,4-dihydroquinazolin-4-yl) acetate: A stirred solution of methyl 2-(8-fluoro-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl) acetate (2-3) (0.45 g, 1.165 mmol) in acetonitrile (5 mL) was prepared. To this, (R)-l-(3-chlorophenyl)-2-methylpiperazine (1-5) (0.27 g, 1.281 mmol) was added, and the mixture was purged with nitrogen gas for 5 minutes. Subsequently, PyBOP (0.92 g, 1.747 mmol) and DBU (0.215 mL, 1.398 mmol) were added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours. Upon completion, as monitored by TLC, the reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash® chromatography, eluting with 0-100% ethyl acetate in heptane, to give the title compound 2-5 as a white solid (0.3 g, 44.48%). TLC: 30% ethyl acetate in heptane (R: 0.6). MS (ESI): calcd. for C27H27CIF4N6O2: 578.18; Found: 579.46 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)Intermediate 2-6

[0103] 2-(2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(l-methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)-3,4-dihydroquinazolin-4-yl) acetic acid: A stirred solution of methyl 2-(2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-1-yl)-8-fluoro-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3,4-dihydroquinazolin-4-yl)acetate (2-5) (0.14 g, 0.24 mmol) in a 1:1 mixture of THF and water (5 mL each) was cooled to 0 °C under a nitrogen atmosphere. Lithium hydroxide (30 mg, 1.24 mmol) was added to the solution, and the mixture was stirred at room temperature for 3 hours. After completion (monitored by TLC), the reaction mixture was cooled back to 0 °C, quenched with cold water, and extracted with ethyl acetate. The aqueous layer was acidified with IN HC1 and extracted again with ethyl acetate. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified using preparative HPLC to give the title compound 2-6 as a white solid (0.12 g, 85.71%). TLC: 80% ethyl acetate in heptane (R 0.4). MS (ESI): calcd. for C26H25CIF4N6O2: 564.17; Found: 565.23 [M+l]+.Examples 5 and 6

[0104] 2-((R)-2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(l-methyl-3- (trifluoromethyl)-lH-pyrazol-5-yl)-3,4-dihydroquinazolin-4-yl)acetic acid (Example 5) and 2-((S)-2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(l-methyl-3- (trifluoromethyl)-lH-pyrazol-5-yl)-3,4-dihydroquinazolin-4-yl)acetic acid (Example 6)Attorney Docket No. 71180-431439 (ASP-080-WO)Example 5

[0105] The compound 2-(2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(l-methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)-3,4-dihydroquinazolin-4-yl)acetic acid (2-6) was separated into two enantiomers by chiral preparative SFC method on a column Cellulose-2 (20*250mm, 5pm). The mobile phase consisted of CO2 (91.0 g / min) (mobile phase A) and 9.0 ml / min (0.1 % Methanolic Ammonia in Methanol) (mobile phase B) with total flow rate (60g-15%, 100 bar). Fractions were collected based on retention times and lyophilized to yield Example 5 (Peak 1, 3.06 min, 60 mg) and Example 6 (Peak 2, 3.86 min, 50 mg) as a white solid.Attorney Docket No. 71180-431439 (ASP-080-WO)Examples 31 and 32Scheme 3Intermediate 3-2 0

[0106] Ethyl 3-(trifluoromethyl)-l-((2-(trimethylsilyl) ethoxy) methyl)-lH-pyrazole-5-carboxylate: A stirred solution of ethyl 3-(trifluoromethyl)-lH-pyrazole-5-carboxylate (3-1) (5 g, 24.02 mmol) in 50 mL of dichloromethane was treated with DIPEA (9.5 g, 72.1 mmol) and 2-(trimethylsilyl) ethoxy methyl chloride (5.1 g, 28.82 mmol) at 0 °C. The reaction mixture was then allowed to warm to room temperature and stirred for 3 hours. Progress was monitored via TLC. Upon completion, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed successively with sodium bicarbonate solutionAttorney Docket No. 71180-431439 (ASP-080-WO)and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to yield a pale-yellow liquid. The crude product was purified by CombiFlash® chromatography (0-100% ethyl acetate in heptane) to give the desired compound 3-2 (4.5 g, 55%) as a pale-yellow liquid. TLC: 30% ethyl acetate in heptane (Ry. 0.4). MS (ESI): calcd. for C13H21F3N2O3Si:338.40; Found: 339.19 [M+l]+.Intermediate 3-3

[0107] 3-(Trifluoromethyl)-l-((2-(trimethylsilyl) ethoxy) methyl)-lH-pyrazole-5-carboxylic acid: A stirred solution of ethyl 5-(trifluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (3-2) (5 g, 14.78 mmol) in 25 mL of tetrahydrofuran and 10 mL of water was treated with lithium hydroxide (1.81 g, 73.88 mmol) and stirred at room temperature for 3 hours. Progress was monitored by TLC. Upon completion, the reaction mixture was concentrated under reduced pressure. The resulting crude product was diluted with water and extracted with ethyl acetate. The aqueous layer was acidified with potassium hydrogen sulfate (KHSCL) and extracted again with ethyl acetate. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford the desired compound 3-3 (4 g, 87.23%) as a pale-yellow solid. TLC: Mobile phase: 60 % ethyl acetate in heptane (R 0.4). MS (ESI): calcd. for CnHi7F3N2O3Si: 310.35; Found: 311.27 [M+l]+.Intermediate 3-4°\

[0108] Methyl 2-(8-fluoro-2-oxo-3-(3-(trifluoromethyl)-l-((2-(trimethylsilyl) ethoxy) methyl)-lH-pyrazol-5-yl)-l,2,3,4-tetrahydroquinazolin-4-yl) acetate: A stirred solution of 3-Attorney Docket No. 71180-431439 (ASP-080-WO)(trifluoromethyl)- l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole-5-carboxylic acid (3-3) (3 g, 9.67 mmol) in 30 mL of 1,4-dioxane was treated with triethylamine (4.92 g, 48.33 mmol) and diphenyl phosphoryl azide (3.26 g, 11.6 mmol), and the mixture was stirred at room temperature for 1 hour. Methyl (E)-3-(2-amino-3-fluorophenyl) acrylate (3.77 g, 19.33 mmol) was then added at 0 °C, and the reaction mixture was stirred at 80 °C for 12 hours. Progress was monitored by TLC. Upon completion, the mixture was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to yield a pale-yellow viscous oil. The crude product was purified using CombiFlash® chromatography (0-100% ethyl acetate in heptane) to give the desired compound 3-4 (1.8 g, 37%) as an off-white solid. TLC: Mobile phase: 30% Ethyl acetate in heptane (Ry: 0.4). MS (ESI): calcd. for C2iH26F4N4O4Si: 502.54. Found: 503.56 [M+l]+.

[0109] Methyl 2-(2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(3-(trifluoromethyl)-l-((2-(trimethylsilyl) ethoxy) methyl)-lH-pyrazol-5-yl)-3,4-dihydro quinazolin-4-yl) acetate: A stirred solution of methyl 2-(8-fluoro-2-oxo-3-(3-(trifluoromethyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-5-yl)-l,2,3,4-tetrahydroquinazolin-4-yl)acetate (3-4) (0.5 g, 0.10 mmol) in 10 mL of acetonitrile was treated with DBU (0.46 g, 2.99 mmol) followed by PyBOP (0.79 g, 1.49 mmol) at 0 °C. The reaction mixture was then stirred at room temperature for 12 hours, with progress monitored by TLC. Upon completion, the mixture was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a pale-yellow viscous oil. The crude product wasAttorney Docket No. 71180-431439 (ASP-080-WO)purified using CombiFlash® chromatography (0-100% ethyl acetate in heptane) to yield the desired compound 3-5 (0.40 g, 0.57 mmol, 57.69%) as an off-white solid. TLC: mobile phase: 30% ethyl acetate in heptane (R 0.4). MS (ESI): calcd. for C32H38F6N6O3Si: 696.77; Found: 697.61 [M+l]+Intermediate 3-6

[0110] Methyl 2-(2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(3-(trifluoromethyl)-lH-pyrazol-5-yl)-3,4-dihydroquinazolin-4-yl) acetate: A stirred solution of methyl 2-[2-[(3R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl]-8-fluoro-3-[5- (trifluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-4H-quinazolin-4-yl]acetate (3-5) (0.4 g, 0.57 mmol) in 5 mL of dichloromethane at 0 °C was treated with trifluoroacetic acid (5 mL) and stirred at room temperature for 4 hours. Progress was monitored by TLC. Upon completion, the reaction mixture was concentrated under reduced pressure to yield a residue, which was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated ammonium bicarbonate solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude material was purified using CombiFlash® chromatography (0-100% ethyl acetate in heptane) to afford the desired compound 3-6 (0.32 g, 98.40%) as an off-white solid. TLC: mobile phase: 40% Ethyl acetate in heptane (R / : 0.3). MS (ESI): calcd. for C26H24F6N6O2: 566.51; Found: 567.65 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)

[0111] 2-(2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(3-(trifluoromethyl)-lH-pyrazol-5-yl)-3,4-dihydroquinazolin-4-yl) acetic acid: A stirred solution of methyl 2-[2-[(3R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl]-8-fluoro-3-[3-(trifluoromethyl)-lH-pyrazol-5-yl]-4H-quinazolin-4-yl] acetate (3-6) (0.32 g. 0.57 mmol) in 5 mL of tetrahydrofuran and 5 mL of water was treated with lithium hydroxide (0.07 g, 2.82 mmol) and stirred at room temperature for 3 hours. Progress was monitored by TLC. Upon completion, the mixture was concentrated under reduced pressure to obtain the crude product. The crude compound was diluted with water and extracted with ethyl acetate. The aqueous layer was acidified with potassium hydrogen sulfate (KHSCL) and extracted again with ethyl acetate. The combined organic layer was concentrated under reduced pressure to yield the desired compound 3-7 (0.3 g, 96.13%) as an off-white solid. TLC: mobile phase: 60 % ethyl acetate in heptane (R 0.4). MS (ESI): calcd. for C25H22F6N6O2: 552.48; Found: 553.17 [M+l]+.Examples 31 and 32Example 31 Example 32Attorney Docket No. 71180-431439 (ASP-080-WO)

[0112] Enantiomers of 2-((R)-2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(3-(trifluoromethyl)-lH-pyrazol-5-yl)-3,4-dihydroquinazolin-4-yl)acetic acid (3-7) were separated using chiral preparative SFC-HPLC. The column used was IG (30 x 250 mm, 5 pm). The mobile phase consisted of A: 0.1% IPA in hexane and B: DCM-IPA (1:1). The eluent ratio was set at A: B (80:20), with a total flow rate of 46 mL / min. The detection was performed at 254 nm. Compound fractions were collected and concentrated under reduced pressure to obtain the following: Example 31 (peak 1, RT = 5.335 min, 45 mg) and example 32 (peak 2, RT = 6.718 min, 50 mg) as white solids.Examples 3 and 4Scheme 4Attorney Docket No. 71180-431439 (ASP-080-WO)Intermediate 4-1

[0113] Methyl (E)-3-(3-fluoro-2-(3-(4-(trifluoromethyl) pyridin-2-yl) ureido) phenyl) acrylate: To a stirred solution of 4-(trifluoromethyl)pyridin-2-amine (1-3) (5 g, 30.84 mmol) in acetonitrile (75.00 mL), methyl (E)-3-(3-fluoro-2-isocyanatophenyl) acrylate (1-3) (5 g. 22.61 mmol) was added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 70 °C for 12 hours, with progress monitored by TLC. Upon completion, the mixture was evaporated under reduced pressure to obtain the crude product. The crude material was washed with diethyl ether and dried under vacuum to give the title compound 4-1 (4.8 g, 41%) as a white solid. TLC: 60% ethyl acetate in heptane, Ry: 0.4.Intermediate 4-2°x

[0114] Methyl 2-(8-fluoro-2-oxo-3-(4-(trifluoromethyl) pyridin-2-yl)-l, 2,3,4-tetrahydroquinazolin-4-yl) acetate: To a stirred solution of compound 4-1 (5.0 g, 13 mmol) in acetone (70 mL), DBU (4.1 g, 26 mmol) was added at room temperature. The reaction mixture was stirred at 70 °C for 12 hours. Upon completion, as monitored by LC-MS, the mixture was evaporated under reduced pressure to obtain the crude product. The crude material was then diluted with water and filtered, yielding the title compound 4-2 (3.1 g, 62%) as a white solid. TLC: Mobile phase: 50% ethyl acetate in heptane, R 0.3. MS (ESI): calcd. for C17H13F4N3O3: 383.30; Found: 384.3 [M +1]+.Attorney Docket No. 71180-431439 (ASP-080-WO)Intermediate 4-3

[0115] Tert-butyl (2R)-4-(8-fluoro-4-(2-methoxy-2-oxoethyl)-3-(4-(trifluoromethyl) pyridin-2-yl)-3, 4-dihydroquinazolin-2-yl)-2-methylpiperazine-l-carboxylate: To a stirred solution of methyl 2-(8-fluoro-2-oxo-3-(4-(trifluoromethyl)pyridin-2-yl)-l, 2,3,4-tetrahydroquinazolin-4-yl) acetate (4-2) (1.60 g, 4.2 mmol) in acetonitrile (10 mL), tert-butyl (R)-2-methylpiperazine-1 -carboxylate (1 g, 5.0 mmol) was added, and the mixture was purged with nitrogen gas for 5 minutes. Under the nitrogen atmosphere, PyBOP (2.7 g, 5.0 mmol) and DBU (0.77 mL, 5.0 mmol) were then added to the resulting solution. The mixture was stirred at room temperature for 12 hours. Upon completion, as monitored by TLC, the reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Na2SO4. filtered, and concentrated under reduced pressure. The crude product was further purified by CombiFlash® chromatography (0-100% ethyl acetate in heptane) to give the title compound 4-3 (0.35 g, 15%) as a white solid. TLC: 30% ethyl acetate in heptane (R 0.6). MS (ESI): calcd. for C27H31F4N5O4: 565.23; Found: 566.4 [M+l]+.Intermediate 4-4

[0116] Methyl 2-(8-fluoro-2-((R)-3-methylpiperazin-l-yl)-3-(4-(trifluoromethyl) pyridin- 2-yl)-3, 4-dihydroquinazolin-4-yl) acetate: To a stirred solution of tert-butyl (2R)-4-(8-fluoro- 4-(2-methoxy-2-oxoethyl)-3-(4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-2-yl)-2-Attorney Docket No. 71180-431439 (ASP-080-WO)methylpiperazine- 1 -carboxylate (4-3) (0.35 g, 0.62 mmol) in 1,4-dioxane (5 mL) at 0 °C under a nitrogen atmosphere, hydrogen chloride solution (4.0 M in dioxane, 2 mL) was added. The resulting mixture was gradually warmed to room temperature and allowed to stir for 6 hours. Upon completion, as monitored by TLC, the mixture was quenched with saturated aq. NaHCCh solution and extracted with DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield the title compound 4-4 (0.22 g, crude) as a white solid. The crude product was used directly in the next step without further purification. TLC: 60% Ethyl acetate in heptane (R<: 0.3). MS (ESI): calcd. for C22H23F4N5O2: 465.18; Found: 466.3 [M+l]+.Intermediate 4-5Cl°\

[0117] Methyl 2-(2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(4-(trifluoromethyl) pyridin-2-yl)-3, 4-dihydroquinazolin-4-yl) acetate: To a stirred solution of l-chloro-3-iodobenzene (70 mg, 0.36 mmol) in toluene (3 mL), methyl 2-(8-fluoro-2-((R)-3-methylpiperazin-l-yl)-3-(4-(trifluoromethyl)pyridin-2-yl)-3.4-dihydroquinazolin-4-yl) acetate (4-4) (0.17 g, 0.365 mmol) was added, followed by CS2CO3 (0.29 g, 0.914 mmol). The mixture was purged with nitrogen gas for 10 minutes. Under the nitrogen atmosphere, Pd2(dba)s (35 mg, 0.04 mmol) and BINAP (47 mg, 0.07 mmol) were added to the resulting solution. The mixture was stirred at 100 °C for 12 hours in a sealed tube. Upon completion, as monitored by TLC, the reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash® chromatography (0-100% ethyl acetate in heptane) to give the title compound 4-5 (65 mg.Attorney Docket No. 71180-431439 (ASP-080-WO)30.86%) as a brown solid. TLC: 40% Ethyl acetate in heptane (R 0.5). MS (ESI): calcd. for C28H26CIF4N5O2: 575.17; Found: 576 [M+l]+.Intermediate 4-6

[0118] 2-(2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(4-(trifluoromethyl) pyridin-2-yl)-3,4-dihydroquinazolin-4-yl) acetic acid: To a stirred solution of methyl 2-(2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(4- (trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl) acetate (4-5) (70 mg, 0.121 mmol) in a mixture of THF and water (3:1 mL) at 0 °C under a nitrogen atmosphere, lithium hydroxide (9 mg, 0.3646 mmol) was added. The resulting mixture was stirred at room temperature for 6 hours. Upon completion, as monitored by TLC, the mixture was cooled to 0 °C, quenched with cold water, and extracted with ethyl acetate. The aqueous layer was treated with IN HC1 and subsequently extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the title compound 4-6 (60 mg, 89%) as an off-white solid. TLC: 80% Ethyl acetate in heptane (R 0.5). MS (ESI): calcd. for C27H24CIF4N5O2: 561.16; Found: 562.21 [M+l]+.Examples 3 and 4

[0119] 2-((S)-2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(4- (trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid (example 3) and 2- ((R)-2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(4- (trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid (example 4)Attorney Docket No. 71180-431439 (ASP-080-WO)OHExample 4

[0120] Enantiomers of 2- (2 - ( (R) -4- (3 -chlorophenyl) -3 -methylpiper azin- 1 -yl) - 8 -fluoro- 3 - (4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid (4-6) were separated using chiral preparative HPLC with the following conditions: a CHIRALCEL OX-H column (20 x 250 mm, 5 pm) was employed, with Mobile Phase A consisting of CO2 at a flow rate of 51.0 g / min and Mobile Phase B containing 0.1% methanolic ammonia in a mixture of ACN and methanol at a flow rate of 9.0 mL / min. The collected fractions were subsequently lyophilized to yield the title compounds: Example 3 (5 mg) and Example 4 (5 mg) as off-white solids.Attorney Docket No. 71180-431439 (ASP-080-WO)Examples 17 and 18Scheme 5Intermediate 5-1CF3

[0121] Methyl (E)-3-(3-fluoro-2-(3-(6-(trifluoromethyl) pyrimidin-4-yl) ureido) phenyl) acrylate: To a stirred solution of 6- (trifluoromethyl) pyrimidin-4- amine (1.6 g, 9.81 mmol) in 10 mL of acetonitrile, add 1.52 g (6.87 mmol) of methyl (E)-3-(3-fluoro-2-isocyanatophenyl) acrylate (1-3). Stir the mixture at 70 °C for 16 hours. Monitor the reaction's progress using TLC. Upon completion, allow the mixture to cool to room temperature, then dilute it with water.Extract the mixture with ethyl acetate. Combine the organic layers, wash with water, and dry over anhydrous Na₂SO₄. Filter the solution and concentrate it under reduced pressure to obtainAttorney Docket No. 71180-431439 (ASP-080-WO)the crude title compound 5-1 (1 g) as a white solid. TLC: 20% ethyl acetate in heptane (R 0.6). MS (ESI): calcd. for C16H12F4N4O3: 384.08; Found: 385.34 [M+l]+.Intermediate 5-2°\

[0122] Methyl 2-(8-fluoro-2-oxo-3-(6-(trifluoromethyl) pyrimidin-4-yl)-l, 2, 3, 4-tetrahydroquinazolin-4-yl) acetate: To a stirred solution of methyl (E)-3-(3-fluoro-2-(3-(6-(trifluoromethyl)pyrimidin-4-yl)ureido)phenyl)acrylate (5-1) (2 g, 5.204 mmol) in 20 mF of acetone, add 1.6 mF (10.41 mmol) of DBU. Stir the mixture at 70 °C for 16 hours, monitoring the reaction's progress by TEC. Once complete, allow the mixture to cool to room temperature, then dilute with water and extract with ethyl acetate. Combine the organic layers, wash with water, and dry over anhydrous Na2SO4. Filter the solution and concentrate under reduced pressure. Purify the crude product using CombiFlash® chromatography with a gradient of 0-100% ethyl acetate in heptane to obtain the title compound 5-2 (1 g, 50%) as a white solid. TEC: 20% ethyl acetate in heptane (R 0.8). MS (ESI): calcd. for C16H12F4N4O3: 384.08; Found: 385.34 [M+l]+.Intermediate 5-3Cl°\

[0123] Methyl 2-(2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(6- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydroquinazolin-4-yl)acetate: To a stirred solution ofAttorney Docket No. 71180-431439 (ASP-080-WO)methyl 2-(8-fluoro-2-oxo-3-(6-(trifluoromethyl)pyrimidin-4-yl)-1,2,3,4-tetrahydroquinazolin-4-yl) acetate (5-2) (1 g, 2.602 mmol) in 10 mL of acetonitrile, add PyBrop (1.83 g, 3.903 mmol) followed by DBU (0.48 mL, 3.123 mmol). Stir the reaction mixture for 5 minutes. Then, add (R)-l-(3-chlorophenyl)-2-methylpiperazine (1-5) (0.6 g, 2.862 mmol) to the resulting solution. Allow the mixture to stir at room temperature for 16 hours, monitoring the reaction's progress by TLC. After completion, dilute the reaction mixture with water and extract with ethyl acetate. Combine the organic layers, wash with water, and dry over anhydrous NazSCL. Filter the solution and concentrate under reduced pressure. Purify the crude product using CombiFlash® chromatography with a gradient of 0-100% ethyl acetate in heptane to yield the title compound 5-3 (0.25 g, 16.65%) as a white solid. TLC: 20% ethyl acetate in heptane (R 0.9). MS (ESI): calcd. for C27H25CIF4N6O2: 576.17; Found: 577.68 [M+l]+.Intermediate 5-4

[0124] 2-(2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(6- (trifluoromethyl) pyrimidin-4-yl)-3,4-dihydroquinazolin-4-yl) acetic acid: To a stirred solution of methyl 2-(2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(6-(trifluoromethyl)pyrimidin-4-yl)-3.4-dihydroquinazolin-4-yl)acetate (5-3) (0.25 g, 0.43 mmol) in a mixture of THF and water (5 mL each) at 0 °C under a nitrogen atmosphere, add LiOH (51 mg, 2.49 mmol). Stir the resulting mixture at room temperature for 12 hours, monitoring the reaction progress by TLC. After completion, cool the mixture to 0 °C, then quench with cold water and extract with ethyl acetate. Treat the aqueous layer with aq. 1 N HO solution and extract again with ethyl acetate. Combine the organic layers, dry over anhydrous Na₂SO₄, filter, and concentrate under reduced pressure to obtain the title compound 5-4 (0.21 g, 86.09%) as a whiteAttorney Docket No. 71180-431439 (ASP-080-WO)solid. TLC: 30% ethyl acetate in heptane (R / : 0.1). MS (ESI): calcd. for C26H23CIF4N6O2:562.15; Found: 563.79 [M+l]+.Examples 17 and 18Example 18

[0125] The enantiomer of 2-(2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(6-(trifluoromethyl)pyrimidin-4-yl)-3.4-dihydroquinazolin-4-yl)acetic acid (5-4) was separated using chiral preparative SFC. The separation was performed on a Chiral Cel-OX-H column (20 x 250 mm, 5 pm). The mobile phase consisted of phase A: CO2 (51.0 g / min) and phase B: 0.1% methanolic ammonia in methanol (9.0 mE / min). The total flow rate was maintained at 60 g / min with a back pressure of 100 bar. Fractions were collected and lyophilized to yield the enantiomers in order of elution. Example 17 was obtained from peak 1 with a retention time (IR) of 2.943 min (5 mg), and Example 18 was obtained from peak 2 with a tR of 3.456 min (10 mg), both as white solids.Attorney Docket No. 71180-431439 (ASP-080-WO)Examples 23 and 246-6 Scheme 6Intermediate 6-2

[0126] 2-chloro-5-(trifluoromethyl) pyridin-3-amine: To a stirred solution of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (6-1) (3.00 g, 13.24 mmol) in 30 mL of ethyl acetate, add tin(II) chloride (6.47 g, 33.10 mmol). Stir the mixture at 80 °C for 2 hours, monitoring the reaction progress by TLC. Upon completion, quench the mixture with ice-cold saturated sodium hydrogen carbonate solution. Filter the mixture through a Celite pad and wash with ethyl acetate. Wash the filtrate with saturated sodium hydrogen carbonate solution, followed by water and saturated aqueous sodium chloride solution. Dry the combined organic layers over anhydrous Na₂SO₄, then filter and concentrate under reduced pressure. Purify the crude product usingAttorney Docket No. 71180-431439 (ASP-080-WO)CombiFlash® chromatography with a gradient of 0-100% ethyl acetate in heptane to obtain the title compound 6-2 (1.5 g, 58%) as a white solid. TLC: 20% ethyl acetate in heptane (Rfi 0.3).Intermediate 6-3COOMe

[0127] Methyl (E)-3-(2-(3-(2-chloro-5-(trifluoromethyl) pyridin-3-yl) ureido)-3-fluorophenyl) acrylate: To a stirred solution of 2-chloro-5-(trifluoromethyl)pyridin-3-amine (6-2) (1.5 g, 7.6 mmol) in 40 mL of acetonitrile at 0 °C under a nitrogen atmosphere, add methyl (E)-3-(3-tluoro-2-isocyanatophenyl) acrylate (1-3) (1.9 g, 8.4 mmol). Stir the mixture at 80 °C for 12 hours, monitoring the reaction progress by TLC. Upon completion, concentrate the mixture under reduced pressure. The resulting solid is triturated with acetonitrile and filtered to yield the title compound 6-3 (2 g, 63%) as a white solid. TLC: 20% ethyl acetate in heptane (R 0.3). MS (ESI): calcd. for C17H12CIF4N3O3: 417.05; Found: 418.27 [M+l]+.Intermediate 6-4°\

[0128] Methyl 2-(3-(2-chloro-5-(trifluoromethyl) pyridin-3-yl)-8-fluoro-2-oxo-l,2,3,4-tetrahydroquinazolin-4-yl) acetate: To a stirred solution of methyl (E)-3-(2-(3-(2-chloro-5-(trifhioromethyl)pyridin-3-yl)ureido)-3-fluorophenyl) acrylate (6-3) (2 g, 4.788 mmol) in 40 mL of THF at 0 °C under a nitrogen atmosphere, add hexamethyldisilane lithium salt (1.0 mol / L in THF, 7.2 mL, 7.18 mmol). Allow the mixture to warm slowly to room temperature and stir for 2 hours. Upon completion, as monitored by TLC, quench the mixture with saturated ammonium chloride solution and extract with ethyl acetate. Dry the combined organic layers over anhydrous Na₂SO₄, filter, and concentrate under reduced pressure. Purify the crude product usingAttorney Docket No. 71180-431439 (ASP-080-WO)CombiFlash® chromatography with 20% ethyl acetate in heptane to obtain the title compound 6-4 (0.8 g, 40%) as a white solid. TLC: 20% ethyl acetate in heptane (R: 0.3). MS (ESI): calcd. for C17H12CIF4N3O3: 417.05; Found: 418.35 [M+l]+.

[0129] Methyl 2-(3-(2-chloro-5-(trifluoromethyl) pyridin-3-yl)-2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3,4-dihydroquinazolin-4-yl) acetate: To a stirred solution of methyl 2-(3-(2-chloro-5-(trifluoromethyl)pyridin-3-yl)-8-fluoro-2-oxo-l,2,3,4-tetrahydroquinazolin-4-yl) acetate (6-4) (0.80 g, 1.91 mmol) in 10 mL of acetonitrile, add PyBrOP (1.35 g, 2.87 mmol), DBU (0.58 mL, 3.83 mmol), and (R)-l-(3,4-difluorophenyl)-2-methylpiperazine (0.48 g, 2.29 mmol). Stir the mixture at room temperature for 16 hours, monitoring the reaction progress by TLC. Upon completion, dilute the mixture with water and extract with ethyl acetate. Dry the combined organic layers over anhydrous Na₂SO₄, filter, and concentrate under reduced pressure. Purify the crude product using Combi Flash® chromatography with a gradient of 0-100% ethyl acetate in heptane to obtain the title compound 6-5 (0.4 g, 34.13%) as a white solid. TLC: 20% Ethyl acetate in heptane (R / : 0.9). MS (ESI): calcd. for C28H24CIF6N5O2: 611.15; Found: 612.91 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)

[0130] 2-(2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(2-methoxy-5-(trifluoromethyl) pyridin-3-yl)-3,4-dihydroquinazolin-4-yl) acetic acid: To a stirred solution of methyl 2-(3-(2-chloro-5-(trifluoromethyl)pyridin-3-yl)-2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3,4-dihydroquinazolin-4-yl) acetate (6-5) (0.15 g, 0.24 mmol) in 3 mL of methanol, add NaOMe (30% in methanol, 0.1 mL, 0.73 mmol). Stir the resulting mixture at 80 °C for 2 hours, monitoring the reaction progress by TLC. After completion, cool the reaction mixture to room temperature, then dilute with water and extract with ethyl acetate. Dry the combined organic layers over anhydrous Na2SCL, filter, and concentrate under reduced pressure to yield the title compound 6-6 (0.1 g, 69%) as a white solid. TLC: 80% Ethyl acetate in heptane (Rf: 0.4). MS (ESI): calcd. for C28H25F6N5O3: 593.19; Found: 594.1 [M+l]+.Examples 23 and 24Example 23 Example 24

[0131] The enantiomers of 2-(2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)-3,4-dihydroquinazolin-4-yl)acetic acid (6-6) were separated by chiral preparative SFC using HPLC. The separation was earned out on a Chiral Cel-Attorney Docket No. 71180-431439 (ASP-080-WO)OX-H column (20 x 250 mm, 5 m). The mobile phase consisted of phase A: CO2 (91.0 g / min) and phase B: 0.1% methanolic ammonia in methanol (9.0 mL / min). The total flow rate was maintained at 60 g / min with a back pressure of 100 bar. Fractions were collected and lyophilized to yield the enantiomers in order of elution. Enantiomer 1 was obtained from peak 1 with a retention time (IR) of 1.895 min, yielding 5 mg (Example 23), while enantiomer 2 was obtained from peak 2 with a tR of 2.234 min, yielding 10 mg (Example 24), both as white solids.Examples 64 and 65POCI3, DIPEA DBUReflux, 12h Dioxane, Reflux Step 1Step 2 4-2Scheme 8Intermediate 8-1 F°\

[0132] Methyl 2-(2-chloro-8-fluoro-3-(4-(trifluoromethyl) pyridin-2-yl)-3,4-dihydroquinazolin-4-yl) acetate: A solution of methyl 2-(8-fluoro-2-oxo-3-(4-(trifluoromethyl)pyridin-2-yl)-l,2,3,4-tetrahydroquinazolin-4-yl) acetate (4-2) (0.50 g, 1.30 mmol) was stirred in POCE (7 mL). To this mixture, DIPEA (0.46 mL, 2.61 mmol) was added,Attorney Docket No. 71180-431439 (ASP-080-WO)and the reaction was heated to 120 °C for 16 hours. The reaction progress was monitored using TLC and LCMS. Upon completion, the mixture was evaporated under reduced pressure, yielding a residue that was co-distilled with ether and toluene to obtain the target compound 8-1 (0.25 g, 22.42%). TLC: 50% of ethyl acetate in heptane (Ry. 0.7). MS (ESI): calcd. for C28H28F4N6O3: 572.56; Found: 573.50 [M+l]+.Intermediate 8-2OMe

[0133] Methyl 2-(8-fluoro-2-((R)-4-(2-methoxypyridin-4-yl)-3-methylpiperazin-l-yl)-3-(4-(trifluoromethyl) pyridin-2-yl)-3,4-dihydroquinazolin-4-yl) acetate: To a stirred solution of methyl 2-(2-chloro-8-fluoro-3-(4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl) acetate (8-1) (0.25 g, 0.62 mmol) in acetonitrile (10 mL), DIPEA (0.82 g, 6.23 mmol) and (2R)-l-(2-methoxy-4-pyridyl)-2-methylpiperazine (0.16 g, 0.75 mmol) were added at room temperature. The resulting solution was stirred at 100 °C for 16 hours. The progress of the reaction was monitored using TLC and LCMS. After completion, the mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude material was purified using CombiFlash® chromatography (0 - 100% ethyl acetate in heptane) to yield the target compound 8-2 (0.15 g, 41.67%) as an off-white solid. TLC: 50% of ethyl acetate in heptane (R / . 0.5). MS (ESI): calcd. for C28H28F4N6O3: 572.56; Found: 573.66 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)Intermediate 8-3OMe

[0134] (8-fluoro-2-((R)-4-(2-methoxypyridin-4-yl)-3-methylpiperazin-l-yl)-3-(4-(trifluoromethyl) pyridin-2-yl)-3,4-dihydroquinazolin-4-yl) acetic acid: A stirred solution of methyl 2-[8-fluoro-2-[(3R)-4-(2-methoxy-4-pyridyl)-3-methyl-piperazin-l-yl]-3-[4-(trifluoromethyl)-2-pyridyl]-4H-quinazolin-4-yl] acetate (8-2) (0.15 g, 0.26 mmol) in tetrahydrofuran (10 mL) and water (5 mL) was treated with lithium hydroxide (0.032 g, 1.31 mmol) at room temperature. The mixture was stirred for 3 hours at room temperature, and the reaction progress was monitored using TLC and LCMS. Upon completion, the mixture was evaporated under reduced pressure, and the resulting residue was acidified with aq. 1 N HC1 solution to a pH of 4. The mixture was then extracted with a 10% MeOH: DCM solution. The separated organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain the target compound 8-3 (70 mg, 47.16%). TLC: 80% of ethyl acetate in heptane (Ry. 0.2). MS (ESI): calcd. for C27H26F4N6O3: 558.54; Found: 559.2 [M+l]+.Examples 64 and 65Example 63 Example 64

[0135] The enantiomers of 2-((R)-8-fluoro-2-((R)-4-(2-methoxypyridin-4-yl)-3-methylpiperazin-l-yl)-3-(4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl) acetic acid 8-3 were successfully separated using chiral preparative SFC HPLC. The separation wasAttorney Docket No. 71180-431439 (ASP-080-WO)conducted on a CHIRALPAK-IC column (30 x 250 mm, 5 pm), employing Mobile Phase A as CO2 at a flow rate of 75.0 g / min and Mobile Phase B as a co-solvent (0.1% MeONH2in a 1:1 mixture of ACN and IPA) at a flow rate of 25.0 mL / min, resulting in a total flow rate of 100 mL / min at a pressure of 100 bar. The diluent used was a mixture of ACN and IPA, with detection performed at a wavelength of 260 nm. Following the separation, the fractions collected were lyophilized, yielding Enantiomer 1, Example 64 (peak 1) with a retention time (RT) of 1.46 min (30 mg) and Enantiomer 2, Example 65 (peak 2) with an RT of 1.45 min (40 mg), both isolated as white solids.Examples 66, 67, 68 and 69 / OH / OH 7 Benzyl Bromide, Et3N Oxalyl chloride, Et3N DMSO HNZAX| ACN,80°C, 12h PCM, -78 °C, RT DAST, DCM, RT Step 3 Boc Step 1 Step 2Boc Boc 9-1CS2CO3, Xphos,Pd2(dba)3Toluene, 90°CStep 510% Pd / C, 100psiMeOH,80°C,3 daysStep 4Scheme 9AAttorney Docket No. 71180-431439 (ASP-080-WO)Scheme 9CAttorney Docket No. 71180-431439 (ASP-080-WO)Intermediate 9-2 / OH

[0136] Tert-butyl (S)-4-benzyl-3-(hydroxymethyl) piperazine-l-carboxylate: To a stirred solution of tert-butyl (S)-3-(hydroxymethyl) piperazine-l-carboxylate 9-1 (20 g, 92.47 mmol) in acetonitrile (250 mL), triethylamine (23.5 g, 231.2 mmol) and benzyl bromide (20.56 g, 120.2 mmol) were added at 0 °C. The reaction mixture was stirred at 80 °C for 12 hours. After confirming completion by TLC, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. Purification of the crude product by CombiFlash® chromatography [0-100% EtOAc in heptane] yielded the title compound 9-2 (18 g, 63.53%) as a brown, viscous semisolid. TLC: 20% ethyl acetate in heptane (R / : 0.5). MS (ESI): calcd. for C17H26N2O3; 306.19; Found: 307.4 [M +1]+.Intermediate 9-3(\ / H

[0137] Tert-butyl (S)-4-benzyl-3-formylpiperazine-l-carboxylate: To a stirred solution of oxalyl chloride (2.54 g, 19.58 mmol) in dichloromethane (20 mL) at -78 °C, a solution of DMSO (3.83 g, 48.96 mmol) in dichloromethane (10 mL) was added dropwise, and the mixture was stirred for 5 minutes. A solution of 9-2 (5 g, 16.32 mmol) in dichloromethane (15 mL) was then added. After stirring for 5 minutes, triethylamine (8.34 g, 81.59 mmol) was added, and the mixture was allowed to warm to ambient temperature. The reaction mixture was diluted with diethyl ether and water, and the layers were separated. The organic layer was washed with water, followed by brine, dried over Na₂SO₄, filtered, and concentrated at 35 °C under reduced pressure to afford the title compound 9-3 (4.0 g, 81%) as a light-yellow liquid. TLC: 20% ethyl acetate in heptane (R 0.5). MS (ESI): calcd. for C17H24N2O3: 304.39; Found: 305.27 [M +1]+.Attorney Docket No. 71180-431439 (ASP-080-WO)Intermediate 9-4CHF2

[0138] Tert-butyl (S)-4-benzyl-3-(difluoro methyl) piperazine-l-carboxylate: To a stirred solution of tert-butyl (S)-4-benzyl-3-formylpiperazine-l-carboxylate 9-3 (4.0 g, 13 mmol) in dichloromethane (40 mL) at 0 °C, diethylamino sulfur trifluoride (6.4 g, 38 mmol) was added under an argon atmosphere. The reaction mixture was stirred at 25 °C for 1 hour. Upon completion, confirmed by TLC, the mixture was cooled to room temperature, quenched with NaHCOs solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by CombiFlash® chromatography (0-100% ethyl acetate in heptane) to yield the title compound 9-4 (3.5 g, 85%) as a yellow liquid. TLC: 20% ethyl acetate in heptane (R 0.5). MS (ESI): calcd. for C17H24F2N2O2: 326.39. Found: 327.22 [M+l]+.Intermediate 9-5CHF2L _ l$LBoc

[0139] Tert-butyl (S)-3-(difluoro methyl) piperazine-l-carboxylate: An autoclave was charged with a solution of tert-butyl 4-benzyl-3-(difluoromethyl) piperazine-l-carboxylate 9-4 (1.8 g, 5.5 mmol) in methanol (20 mL), and the solution was purged with nitrogen for 10 minutes. To this solution, 10% palladium on charcoal (0.9 g, 8.46 mmol) was added at room temperature under an inert atmosphere. The reaction mixture was stirred under hydrogen at 90 psi for 16 hours at room temperature. Upon completion, confirmed by TLC, the mixture was filtered through a pad of Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to yield the title compound 9-5 (1 g, 77%) as an off-white solid. TLC: 50% ethyl acetate in heptane (Ry. 0.9). MS (ESI): calcd. for C10H18F2N2O2: 236.26; Found:237.34 [M +1]+.Attorney Docket No. 71180-431439 (ASP-080-WO)Intermediate 9-6

[0140] Tert-butyl (S)-3-(difluoro methyl)-4-(3,4-difluorophenyl) piperazine-1-carboxylate: To a stirred solution of tert-butyl 3 -(difluoromethyl) piperazine- 1 -carboxylate 9-5 (1 g, 4.23 mmol) in toluene (15 mL) was added 4-bromo-l,2-difluorobenzene (1.23 g, 6.35 mmol), followed by cesium carbonate (2.76 g, 8.47 mmol). The mixture was purged with nitrogen for 10 minutes. To this solution, Pd2(dba)s (0.34 g, 0.42 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.64 mmol, 0.15 equiv.) were added under a nitrogen atmosphere. The reaction was stirred at 80 °C for 10 hours. After completion, confirmed by TLC, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash® chromatography (0-100% ethyl acetate in heptane), yielding the title compound 9-6 (0.78 g, 31.75%) as an off-white solid. TLC: 30% ethyl acetate in heptane (R 0.5). MS (ESI): calcd. for C16H20F4N2O2: 348.34; Found:349.37 [M +1]+.Intermediates 9-7 and 9-9

[0141] The enantiomers of tert-butyl (R)-3-(difluoromethyl)-4-(3,4-difluorophenyl) piperazine-1 -carboxylate 9-6 were separated by chiral preparative SFC HPLC using a Chiral Pak-CELLULOSE-3 column (20 x 250 mm, 5 pm). The mobile phases were: MP(A) - 0.1% ipamine in n-hexane, and MP(B) - ethanol as the co-solvent. The eluent ratio was A: B = 90:10, with a total flow rate of 20 mL / min. The detection wavelength was set at 295 nm, and the diluent used was the mobile phase. Compound fractions were collected and concentrated under reducedAttorney Docket No. 71180-431439 (ASP-080-WO)pressure to yield enantiomer 1,9-7 (peak 1, RT = 2.24 min, 300 mg) and enantiomer 2, 9-9 (peak 2, RT = 2.24 min, 300 mg) as a viscous brown liquid.Intermediate 9-8F

[0142] (R)-2-(difluoro methyl)-l-(3, 4-difluorophenyl) piperazine: To a stirred solution of tert-butyl (3R)-3-(difluoromethyl)-4-(3, 4-difluorophenyl) piperazine- 1 -carboxylate 9-7 (0.30 g, 0.86 mmol) in dichloromethane (5 mL) at 0 °C, hydrochloric acid in dioxane (2 mL, 8 mmol, 4 M) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. Upon completion, as monitored by TLC, the mixture was diluted with water, cooled, and basified with 10% sodium carbonate solution. The product was extracted with dichloromethane, and the organic layer was washed with brine. The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give the title compound 9-8 (0.21 g. 98.22%) as a brown liquid. TLC: Mobile phase: 50% Ethyl acetate in heptane (R 0.2). MS (ESI): calcd. for C11H12F4N2: 248.22; Found: 249.12 [M +1]+.Intermediate 9-10

[0143] (S)-2-(difluoro methyl)- 1 -(3, 4-difluorophenyl) piperazine: To a stirred solution of tert-butyl (3S)-3-(difluoromethyl)-4-(3, 4-difluorophenyl) piperazine- 1 -carboxylate 9-9 (0.30 g, 0.86 mmol) in dichloromethane (5 mL) at 0 °C, hydrochloric acid in dioxane (4 M, 2 mL) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. After completion, confirmed by TLC, the mixture was diluted with water, cooled to room temperature, and basified with 10% sodium carbonate solution. The product was extracted with dichloromethane, and the organic layer was washed with brine. The combined organic layersAttorney Docket No. 71180-431439 (ASP-080-WO)were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to yield the title compound 9-10 (0.21 g, 98.22%) as a brown liquid. TLC: Mobile phase: 50% Ethyl acetate in heptane (R 0.2). MS (ESI): calcd. for C11H12F4N2: 248.22; Found: 249.12 [M +1]+.Intermediate 9-11F

[0144] Methyl 2-(2-((R)-3-(difluoro methyl)-4-(3,4-difluorophenyl) piperazin-l-yl)-8-fluoro-3-(4-(trifluoromethyl) pyridin-2-yl)-3,4-dihydroquinazolin-4-yl) acetate: To a stirred solution of methyl 2-[8-fluoro-2-oxo-3-[4-(trifluoromethyl)-2-pyridyl]-l,4-dihydroquinazolin-4-yljacetate 4-2 (0.3 g, 0.78 mmol) in acetonitrile (5 mL), sodium tert-butoxide (0.19 g, 1.96 mmol) was added, followed by PyBroP (0.44 g, 0.94 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 10 minutes. Then, (2R)-2-(difluoromethyl)-l-(3,4-difluorophenyl) piperazine 9-8 (0.19 g, 0.78 mmol) was added at 0 °C, and the reaction was stirred at room temperature for 4 hours. Upon completion, confirmed by TLC, the mixture was concentrated, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product as a pale-yellow gum. The crude material was purified by CombiFlash® chromatography (0-100% ethyl acetate in heptane), yielding the title compound 9-11 (0.13 g, 27.07%) as an off-white solid. TLC: Mobile phase: 30% Ethyl acetate in heptane (Rf: 0.4). MS (ESI): calcd. for C28H23F8N5O2: 613.51; Found: 614.1 [M +1]+.Attorney Docket No. 71180-431439 (ASP-080-WO)

[0145] 2-(2-((R)-3-(difluoro methyl)-4-(3,4-difluorophenyl) piperazin-l-yl)-8-fluoro-3-(4-(trifluoromethyl) pyridin-2-yl)-3,4-dihydroquinazolin-4-yl) acetic acid: To a stirred solution of methyl 2-[2-[(3R)-4-(3,4-difluorophenyl)-3-(l-fluoroethyl)piperazin-l-yl]-8-fLuoro-3-[4-(trifluoromethyl)-2-pyridyl]-2,4-dihydro-lH-quinazolin-4-yl]acetate hydrofluoride 9-11 (0.13 g, 0.21 mmol) in tetrahydrofuran (5 mL) and water (2 mL), lithium hydroxide (0.20 g, 0.82 mmol) was added at 25 °C. The reaction mixture was stirred for 24 hours at 25 °C. After completion, monitored by TLC, the mixture was evaporated under reduced pressure, diluted with water, and acidified with IN HC1 to pH 4. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with cold brine, dried over anhydrous Na₂SO₄, filtered, and evaporated under reduced pressure to afford the title compound 9-12 (0.11 g, 93.20%) as an off-white solid. MS (ESI): calcd. for C27H21F8N5O2: 599.49; Found: 600.14 [M +1]+.

[0146] Methyl 2-(2-((S)-3-(difluoro methyl)-4-(3,4-difluorophenyl) piperazin- l-yl)-8-fluoro-3-(4-(trifluoromethyl) pyridin-2-yl)-3,4-dihydroquinazolin-4-yl) acetate: To a stirred solution of methyl 2-[8-fluoro-2-oxo-3-[4-(trifluoromethyl)-2-pyridyl]-l,4-dihydroquinazolin-4-Attorney Docket No. 71180-431439 (ASP-080-WO)yl]acetate 4-2 (0.30 g, 0.78 mmol) in acetonitrile (5 mL), sodium tert-butoxide (0.19 g, 1.96 mmol) was added, followed by PyBroP (0.44 g, 0.94 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes. Subsequently, (2S)-2-(difluoromethyl)-l-(3,4-difluorophenyl) piperazine (9-10) (0.19 g, 0.78 mmol) was added at 0 °C, and the reaction was stirred at room temperature for 4 hours. The reaction was monitored by LC-MS and TLC. Upon completion, the mixture was concentrated, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to yield a crude product as a pale-yellow gum. The crude material was purified by CombiFlash® chromatography (0-100% ethyl acetate in heptane), yielding the title compound 9-13 (0.12 g, 24.99%) as an off-white solid. TLC: mobile phase: 30% ethyl acetate in heptane. (R 0.4). MS (ESI): calcd. for C28H23F8N5O2: 613.51; Found: 614.1 [M +1]+.

[0147] 2-(2-((S)-3-(difluoro methyl)-4-(3,4-difluorophenyl) piperazin-1 -yl)-8-fluoro-3-(4-(trifluoromethyl) pyridin-2-yl)-3,4-dihydroquinazolin-4-yl) acetic acid: To a stirred solution of methyl 2-[2-[(3S)-4-(3,4-difluorophenyl)-3-(1-fluoroethyl)piperazin-1-yl]-8-fluoro-3-[4-(trifluoromethyl)-2-pyridyl]-2,4-dihydro-1H-quinazolin-4-yl]acetate hydrofluoride (9-13) (0.12 g, 0.19 mmol) in tetrahydrofuran (5 mL) and water (2 mL), lithium hydroxide (0.02 g, 0.76 mmol) was added at 25 °C. The mixture was stirred for 24 hours at 25 °C. Upon completion, monitored by TLC, the mixture was evaporated under reduced pressure, diluted with water, and acidified with IN HC1 to pH 4. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with cool brine, dried over anhydrous Na₂SO₄, filtered, and evaporated under reduced pressure to yield the title compound 9-14 as an off-white solid. MS (ESI): calcd. for C27H21F8N5O2: 599.49; Found: 600.14 [M +1]+.Attorney Docket No. 71180-431439 (ASP-080-WO)Examples 66 and 67Example 67

[0148] The enantiomers of 2-((R)-2-((R)-3-(difluoromethyl)-4-(3,4-difluorophenyl)piperazin-l-yl)-8-fluoro-3-(4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl) acetic acid 9-12 were successfully separated using chiral preparative SFC HPLC. The separation was conducted with a CHIRALAK ODH column (150 mm x 4.6 mm, 5 pm), utilizing Carbon Dioxide (CO2) as mobile phase A and a solution of 0.1% Methanol Ammonia (MeONH₃) in a mixture of Methanol (MeOH) and Isopropanol (IPA) as mobile phase B. The total flow rate was maintained at 20 mL / min, and a 20% solution of the compound (2 g) was prepared for injection. The eluent composition was set to 80% CO2 (A) and 20% MeONH₃ in MeOH:IPA (B). During the separation process, the retention times of the enantiomers were recorded, with enantiomer 1, Example 66 eluting at 1.616 minutes (Peak 1) and enantiomer 2, Example 67 at 1.621 minutes (Peak 2). The corresponding fractions for each enantiomer were collected and concentrated under reduced pressure using a rotary evaporator to give Example 66 (8 mg) as a white solid and Example 67 (15 mg) as a white solid.Examples 68 and 69OHExample 68Attorney Docket No. 71180-431439 (ASP-080-WO)

[0149] The enantiomers of 2-((R)-2-((S)-3-(difluoromethyl)-4-(3,4-difluorophenyl)piperazin- l-yl)-8-fluoro-3-(4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl) acetic acid 9-14 were effectively separated using chiral preparative SFC HPLC. The separation employed a Chiral Pak-Cellulose-C column (20 mm x 250 mm, 5 pm) with a mobile phase consisting of Carbon Dioxide (CO2) as mobile phase A, flowing at a rate of 91.0 g / min, and a co-solvent (0.1% MeONH₂ in a 1:1 mixture of Methanol (MeOH) and Isopropanol (IP A)) as mobile phase B, flowing at 9.00 mL / min. The total flow rate was set to 60 mL / min at a pressure of 100 bar, with MeOH used as the diluent and detection occurring at 254 nm. During the separation process, the fractions corresponding to the enantiomers were collected based on their retention times, with enantiomer 1, Example 68 eluting at 1.621 minutes (Peak 1) and yielding 9 mg, while enantiomer 2, Example 69 eluted at 1.616 minutes (Peak 2) with a yield of 14 mg. Both enantiomers were obtained as white solids after concentration under reduced pressure.Table 1 shows structures and analytical data for representative Examples of the present invention. These compounds can be prepared according to the synthetic schemes described above and using procedures known to those of ordinary skill in the art.Table 1: Representative Examples of the present inventionExample ¹H NMR and MS1 OMeFb. A.Y nOH(S)-2-(8-fluoro-2-(4-(3-methoxyphenyl) piperazin-l-yl)-3-(4-(trifluoromethyl) pyridin-2-yl)-3,4-dihydroquinazolin-4-yl) acetic acid¹H NMR (400 MHz, DMSO-d₆): 5 12.88 (br s, 1H), 8.53 (d, J = 5.13 Hz, 1H), 7.63 (s, 1 H), 7.36 (d, J= 5.13 Hz, 1 H), 6.99 - 7.14 (m, 3H), 6.89 (td, J = 7.79, 5.07 Hz, 1H). 6.52 (d, J = 7.65 Hz, 1 H), 6.45 (s, 1H), 6.39 (dd, J= 8.00, 2.00 Hz, 1H), 5.95 (br t, J = 7.44 Hz, 1H), 3.70 (s, 3H) 3.50 - 3.60 (m, 2H), 2.90 - 3.20 (m,Attorney Docket No. 71180-431439 (ASP-080-WO)6H), 2.5 - 2.6 (m, 2H) ppm. MS (ESI): calcd. for C27H25F4N5O3: 543.19; Found: 544.2 [M+l]+.OMeOL L Js.nT>NT^OOH(R)-2-(8-fluoro-2-(4-(3-methoxyphenyl) piperazin-l-yl)-3-(4-(trifluoromethyl) pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid¹H NMR (400 MHz, DMSO-d₆): δ 12.57 (br s, 1H), 8.52 (d, J = 5.00 Hz, 1H), 7.66 (br s, 1H), 7.35 (d, J = 4.63 Hz, 1H), 7.11 (t, J = 8.13 Hz, 1H), 6.98 - 7.06 (m, 2H).6.86 - 6.93 (m, 1H), 6.51 (br d, J= 8.50 Hz, 1H), 6.45 (s, 1H), 6.39 (br d, J= 8.00 Hz, 1H), 5.93 (br s, 1H), 3.70 (s, 3H), 3.10 - 2.90 (m, 8H), 2.5 - 2.6 (m, 2H) ppm. MS (ESI): calcd. for C27H25F4N5O3: 543.39; Found: 544.2 [M+l]+ClI. N.. N. JxFsC^^^ T. N TTOH2-((S)-2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(4- (trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid’H NMR (400 MHz, DMSO-J6): 8 12.65 (br s, 1H), 8.50 (br s, 1H), 7.53 (br s, 1H), 7.32 - 7.41 (m, 1H), 7.17 - 7.25 (m, 1H), 7.00 - 7.07 (m, 2H), 6.82 - 6.91 (m, 3H), 6.77 (d, J = 7.75 Hz, 1H), 5.88 (br s, 1 H), 4.24 (br s, 1H), 3.40 - 3.45 (m, 1H), 3.20 - 3.25 (m, 3H), 2.94 (br s, 1H), 2.50 - 2.60 (m, 3H), 1.05 (br s, 3H) ppm. MS (ESI): calcd. for C27H24CIF4N5O2: 561.16: Found: 562.65 [M+1]+Attorney Docket No. 71180-431439 (ASP-080-WO)Clk _N.T Vs]\z>°OH2-((R)-2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(4- (trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid’H NMR (400 MHz, DMSO-76): 8 12.64 (br s, 1H), 8.56 (br s, 1H), 7.71 (br s, 1H), 7.44 (br s, 1H). 7.20 (t, J = 8.13 Hz, 1H), 7.09 (br s, 1H), 7.04 (br d, J = 6.38 Hz, 1H), 6.96 (br s, 1H), 6.86 (br s, 1H), 6.81 (br d, J = 8.38 Hz, 1H), 6.75 (d, 7= 7.63 Hz, 1H), 5.89 (br s, 1H), 4.16 (br s, 1H), 4.00 (br s, 1H), 3.10 - 3.20 (bs, 5H), 2.60 (br s, 2H), 0.99 (br, 3H) ppm. MS (ESI): calcd. for: C27H24CIF4N5O2: 561.16: Found: 562.16 [M+l]+ClL _N'NXOH2-((R)-2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(l- methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)-3,4-dihydroquinazolin-4- yl)acetic acid¹H NMR (400 MHz, DMSO-d6): δ 7.08 - 7.26 (m, 1H). 6.90 - 7.04 (m, 3H), 6.67 - 6.87 (m, 4H), 5.01 (dd, J= 8.13, 6.13 Hz, 1H), 3.91 - 4.15 (m, 2H), 3.51 - 3.67 (m, 1H), 3.38 (s, 3H). 3.33 - 3.35 (m, 1H), 3.04 - 3.24 (m, 2H), 2.70 - 2.92 (m, 2H), 2.40 - 2.49 (m, 1H), 0.90 (d, J = 6.50 Hz, 3H) ppm (The acid proton was missed). MS (ESI): calcd. for C26H25CIF4N6O2: 564.17; Found: 565.2 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)Clk _N. A.XwF3C^ 1 iN'NXOH2-((S)-2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(l- methyl-3-(trifliioromethyl)-lH-pyrazol-5-yl)-3,4-dihydroquinazolin-4- yl)acetic acid¹H NMR (400 MHz, DMSO-d₆): δ 11.67 (s, 1H). 7.09 - 7.30 (m, 2H), 6.94 - 7.06 (m, 2H), 6.80 - 6.89 (m, 3H), 6.74 (dd, J = 7.75, 1.50 Hz, 1H), 5.00 (dd, J= 8.51, 6.00 Hz, 1H), 3.91 - 4.09 (m, 1H), 3.56 - 3.83 (m, 1H), 3.42 - 3.53 (m, 2H), 3.39 (s.3H). 3.05 - 3.19 (m, 1H), 2.86 - 3.02 (m, 2H). 2.68 - 2.80 (m, 1H), 2.48 - 2.50 (m, 1H), 0.33 (d, J = 6.50 Hz, 3H) ppm (The acid proton was missed). MS (ESI): calcd. for C26H25CIF4N6O2: 564.17; Found: 565.2 [M+l]+.Cl6^,F>cXw3N'N / 1OH2-((S)-2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(l- methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl)-3,4-dihydroquinazolin-4- yl)acetic acid’H NMR (400 MHz, DMSO-tfc): 8 12.40 (s, 1H), 7.09 - 7.53 (m, 1H), 6.83 - 7.09 (m, 5H), 6.76 (dd, 7 = 7.88, 1.38 Hz. 1H), 6.64 (s, 1H). 5.19 - 5.35 (m, 1H), 4.03 - 4.22 (m, 2H), 3.82 - 3.93 (m, 1H), 3.79 (s, 3H), 3.33 - 3.52 (m, 1H), 3.11 - 3.26 (m, 2H), 2.88 - 3.04 (m, 2H), 2.53 - 2.60 (m, 1H). 0.80 (d, 7 = 2.75 Hz, 3H) ppm; MS (ESI): calcd. For C26H25CIF4N6O2: 564.17; Found: 565.2 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)Clk _N. -XXx nF3c-f T TN'N / 1OH2-((R)-2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(l- methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl)-3,4-dihydroquinazolin-4- yl)acetic acid¹H NMR (400 MHz, DMSO-d6): δ 12.35 (s, 1H), 7.13 - 7.33 (m, 2H), 6.99 - 7.08 (m, 1H), 6.91 - 6.99 (m, 2H), 6.79 - 6.92 (m, 1H), 6.71 - 6.77 (m, 1H), 6.65 (s, 1H).5.25 - 5.41 (m. 1H). 3.95 - 4.34 (m, 1H), 3.81 (s. 3H). 3.52 - 3.71 (m, 1H), 3.35 - 3.44 (m, 2H), 3.09 - 3.23 (m, 2H), 2.91 - 3.06 (m, 1H), 2.52 - 2.62 (m, 1H), 2.34 - 2.46 (m, 1H), 1.02 (d, J= 6.25 Hz, 3H) ppm. MS (ESI): calcd. for C27H23F6N5O2: 563.18; Found: 565.1 [M+1]+.FF. N. / kv nX NJ Y OH2-((R)-2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(5- (trifluoromethyl)pyridin-3-yl)-3,4-dihydroquinazolin-4-yl)acetic acid¹H NMR (400 MHz, DMSO-d₆): δ 12.80 (br s, 1H), 8.68 (s, 2H), 8.12 (br s, 1H), 7.22 (q, J= 9.62 Hz, 1H), 7.07 (t, J= 9.27 Hz, 1H), 6.87 - 7.00 (m, 3H). 6.63 (br d.7= 9.17 Hz, 1H), 5.41 (dd, J= 9.78, 4.65 Hz, 1H), 3.95 (br s, 1H), 3.30 (br s, 2H), 3.01 - 3.12 (m, 4H), 2.62 - 2.77 (m, 2H), 0.92 (br d, J = 6.36 Hz, 3H) ppm. MS (ESI): calcd. for C26H25ClF4N6O2: 563.18; Found: 564.53 [M+1]+.Attorney Docket No. 71180-431439 (ASP-080-WO)FF T NJ M OH2-((R)-2-((S)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(5- (trifluoromethyl)pyridin-3-yl)-3,4-dihydroquinazolin-4-yl)acetic acid'H NMR (400 MHz, DMSO-6): 8 12.76 (br s, 1H), 8.67 (s, 2H). 8.15 (br s, 1H).7.22 (q, J = 9.70 Hz. 1H), 7.07 (t. J = 9.16 Hz. 1H). 6.86 - 7.00 (m, 3H), 6.63 (br d, 7- 9.41 Hz, 1H), 5.39 (br dd, 7 = 9.41, 4.52 Hz, 1H), 3.95 (br s, 1H), 3.12 (br s, 2H), 2.90 - 3.10 (m, 5H), 2.60 - 2.66 (m, 1H). 0.91 - 0.92 (d, 7 = 6.4 Hz, 3H) ppm. MS (ESI): calcd. for C26H25CIF4N6O2: 563.18; Found: 564.53 LM+1J+.A x,,Y nT J N OH2-((S)-2-((S)-4-(3,4-difluorophenyI)-3-methylpiperazin-l-yl)-8-fluoro-3-(5- (trifluoromethyl)pyridin-3-yl)-3,4-dihydroquinazolin-4-yl)acetic add'H NMR (400 MHz, DMSO-6): 8 8.64 (s, 2H), 8.22 (br s, 1H), 7.23 (q, 7= 9.66 Hz, 1H), 7.02 - 7.10 (m, 1H), 6.96 - 7.01 (m, 1H), 6.88 - 6.96 (m, 2H), 6.64 (br d, 7 = 8.80 Hz, 1H), 5.34 (br s. 1H), 3.96 (br s, 1H), 2.90 - 3.20 (m. 6H), 2.57 - 2.63 (m, 1H), 0.78 - 0.92 (m, 3H) ppm. MS (ESI): calcd. for C26H25ClF4N6O2: 563.18; Found: 564.45 [M+1]+.FF\YY X =L. N. JxY YY X J N OH2-((S)-2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(5- (trifluoromethyl)pyridin-3-yl)-3,4-dihydroquinazolin-4-yl)acetic acidAttorney Docket No. 71180-431439 (ASP-080-WO)¹H NMR (400 MHz, DMSO-d6): δ 12.67 (br s, 1H), 8.00 (br t, J = 7.95 Hz, 1H), 7.46 (br d, J = 7.46 Hz, 2H), 7.26 (br d, 7 = 9.90 Hz, 1H), 7.01 (br d, J = 7.70 Hz, 2H). 6.96 (br s. 1H), 6.88 (br s, 1H), 6.69 (br s. 1H). 4.71 - 4.79 (m, 1H). 4.20 - 4.21 (m, 1H), 3.44 - 3.50 (br s, 2H), 2.92 (br s, 3H), 2.57 - 2.67 (m, 3H), 1.02 (br s, 3H) ppm. MS (ESI): calcd. for C26H25ClF4N6O2: 563.18; Found: 564.45 [M+1]+.FT 1 iF / AF3C^ _N Y uu YOH2-((R)-2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(6- (trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid¹H NMR (400 MHz, CD₃OD): δ 7.99 (br t, J = 7.88 Hz. 1H), 7.61 (br d. J = 8.29 Hz, 1H), 7.46 (d, J = 7.46 Hz, 1H), 6.96 - 7.14 (m, 4H), 6.85 (br s, 1H), 6.70 (br s, 1H), 5.86 - 5.91 (m, 1H), 3.85 (br dd, J= 14.72, 7.67 Hz, 2H), 3.76 (br s, 2H), 2.75 (br dd, 7= 12, 5.39 Hz, 1H), 2.65 (br dd, 7= 15.76, 5.39 Hz, 1H), 2.12 (br s, 3H), 1.04 (br s, 3H), 0.87 - 0.92 (m, 1H) ppm (The acid proton was missed). MS (ESI): calcd. for C27H23F6N5O2: 563.18; Found: 564.84 [M+l]+.kU. A.F. C., N N A YUiU OH2-((R)-2-((S)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(6- (trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid¹H NMR (400 MHz, CD₃OD): δ 7.99 (br t, 7 = 7.88 Hz, 1H), 7.61 (br d, 7 = 8.29 Hz, 1H), 7.46 (d, 7 = 7.46 Hz, 1H), 6.96 - 7.14 (m, 4H), 6.85 (br s, 1H), 6.70 (br s, 1H). 5.86 - 5.91 (m, 1H), 3.85 (br dd. 7= 14.72, 7.67 Hz, 2H), 3.76 (br s, 2H), 2.80 (br dd, 7= 15.76, 9.12 Hz, 1H), 2.65 (br dd, 7= 15.76, 5.39 Hz, 1H), 2.12 (br s, 1H), 1.96 - 2.07 (m, 1H), 1.93 (br d, 7 = 6.63 Hz, 1H), 1.04 (br s, 3H) ppm. MS (ESI): calcd. for C27H23F6N5O2: 563.18; Found: 564.84 [M+1]+.Attorney Docket No. 71180-431439 (ASP-080-WO)Fk AY X iFk _, N.. N. JxY YYF3C N NU X.0OH2-((S)-2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(6- (trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid¹H NMR (400 MHz, DMSO-d6): δ 12.58 (br s, 1H), 8.00 (br t, J = 7.95 Hz, 1H).7.46 (br d, J = 7.46 Hz, 2H), 7.26 (br d, J = 9.90 Hz, 1H), 7.01 (br d, J = 7.70 Hz, 2H), 6.96 (br s, 1H), 6.88 (br s, 1H), 6.69 (br s, 1H), 5.95 (br s, 1H), 4.24 - 4.71 (m.1H). 3.50 (br s. 1H). 2.92 (br s. 3H), 2.57 - 2.61 (m, 4H), 1.02 (br s, 3H) ppm. MS (ESI): calcd. for C27H23F6N5O2: 563.18; Found: 564.88 [M+l]+.Yu FY nF3CX_NX_N^X>!X^U yOH2-((S)-2-((S)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(6- (trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid¹H NMR (400 MHz, DMSO-d₆): δ 8.00 (t, J = 7.95 Hz, 1 H), 7.46 (br d, J = 7.34 Hz, 2 H), 7.21 - 7.28 (m, 1 H), 7.05 (br s, 1 H), 7.01 (br d. 7= 7.46 Hz, 2 H), 6.95 (br s, 1 H), 6.89 (br s, 1 H), 5.92 (br s, 1 H), 4.65 - 4.68 (m, 1H), 3.50 -3.76 (m, 2 H), 2.94 (br s, 2 H), 2.56 - 2.61 (m, 3 H), 2.35 (br s, 1 H), 1.01 (br s, 3 H) ppm (The acid proton was missed). MS (ESI): calcd. for C27H23F6N5O2: 563.18; Found: 564.96 [M+l]+.ClFL _N. AxY V]H T;NX^NOHAttorney Docket No. 71180-431439 (ASP-080-WO)2-((S)-2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(6- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydroquinazolin-4-yl)acetic acid NMR (400 MHz, DMSO-d6): δ 9.03 (br s, 1H), 7.85 (br s, 1 H), 7.22 (t, J= 8.07 Hz, 1H), 7.04 (br s, 2H), 6.88 (br s, 1H), 6.84 (br d, 7= 8.31 Hz, 1H), 6.77 (br s, 1H), 6.21 (br s, 1H), 6.07 (br s, 1H), 4.70 (br d, J = 13.82 Hz, 1H), 4.30 (br s, 1H).3.97 (br s, 1H), 3.48 (br s, 2H), 3.19 (br s, 2H), 2.96 (br s, 2H), 1.04 (br s, 3H) ppm (The acid proton was missed). MS (ESI): calcd. for C26H25CIF4N6O2: 562.15; Found; 563.83 [M+l]+.ClL / LY Y iII IN^N jOH2-((R)-2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(6- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydroquinazolin-4-yl)acetic acid'H NMR (400 MHz, DMSO-6): 5 8.91 (br s, 1 H), 7.86 (bs s 1 H), 7.22 (t, 7=8.13 Hz, 1 H), 7.07 (br d, 7=7.34 Hz, 2 H), 7.03 (br s, 1 H), 6.88 (br d, 7=6.72 Hz, 4 H).6.79 (br s, 1 H), 6.14 (br s, 1 H), 4.66 (br d, 7=13.33 Hz, 1 H), 4.21 (br s, 1 H), 3.41 (br s, 2 H), 3.10 (br s, 2 H), 2.91 (br s, 1 H), 0.96 (br s, 3 H) ppm (The acid proton was missed). MS (ESI): calcd. for C26H25CIF4N6O2: 562.15; Found: 563.79 [M+l]+.ClY X iL jskY nY VF — — F OHF2-((S)-2-((R)-4-(3-chloro-4-fluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3- (5-(trifluoromethyl)pyridazin-3-yl)-3,4-dihydroquinazolin-4-yl)acetic acid 'H NMR (600 MHz, DMSO-d6): δ 9.25 (s, 1H), 7.98 (s, 1H), 7.20 (t, J = 9.1 Hz, 1H), 7.06 – 6.97 (m, 3H), 6.94 – 6.84 (m, 2H), 5.97 (dd, J = 9.0, 5.9 Hz, 1H), 3.77 (d, J = 183.2 Hz, 3H), 3.36 (d, J = 12.7 Hz, 1H), 3.19 (s, 2H), 3.00 (d, J = 11.5 Hz,Attorney Docket No. 71180-431439 (ASP-080-WO)2H), 2.75 (dd, J = 15.6, 9.0 Hz, 1H), 2.64 (dd, 7 = 15.6, 5.9 Hz, 1H), 0.84 (s, 3H) ppm. MS (ESI): calc, for C26H22CIF5N6O2: 580.14; Found 579.0 [M-l]’.ClC —JIFFL JL xT nF— T 1— F O rHF2-((R)-2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(5- (trifluoromethyl)pyridazin-3-yl)-3,4-dihydroquinazolin-4-yl)acetic acid1H NMR (600 MHz, DMSO-d6): δ 12.35 (s, 1H), 9.27 (s, 1H), 8.03 (s, 1H), 7.18 (t, J= 8.1 Hz, 1H), 7.07 - 6.96 (m, 2H), 6.91 (td, J = 7.8, 4.7 Hz, 1H), 6.83 (t, J = 2.2 Hz, 1H), 6.79 (dd, J = 8.3, 2.4 Hz, 1H), 6.73 (dd, J = 7.7, 1.9 Hz, 1H), 5.95 (t, 7= 7.3 Hz, 1H), 4.00 (s, 1H), 3.64 (s, 2H), 3.33 (s, 1H), 3.22 (d, J = 12.4 Hz, 2H), 2.98 (s, 1 H), 2.79 (dd, J = 15.8, 8.4 Hz, 1 H), 2.64 - 2.59 (m, 1 H), 1.06 (d, 7= 6.5 Hz, 3H) ppm. MS (ESI): calcd. for C26H23CIF4N6O2: 562.15; Found 561.0 [M-H]’.ClOvSFL xT VF— 1— F OHF2-((S)-2-((7f)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(5- (trifluoromethyl)pyridazin-3-yl)-3,4-dihydroquinazolin-4-yI)acetic acid1H NMR (600 MHz, DMSO-d6): δ 12.40 (s, 1H), 9.25 (s, 1H), 7.96 (s, 1H), 7.19 (t, 7= 8.1 Hz, 1H), 7.03 (dd, 7= 11.2, 7.8 Hz, 2H), 6.91 (td, 7 = 7.8, 4.8 Hz, 1H), 6.86 (d, 7= 2.2 Hz, 1H), 6.83 (dd, 7= 8.4, 2.4 Hz, 1H), 6.76 (dd, 7= 7.9, 1.9 Hz, 1H). 5.97 (dd, 7= 9.0, 5.9 Hz. 1H). 3.86 (d, 7= 241.6 Hz, 3H). 3.32 (d, 7= 12.1 Hz, 2H), 3.01 (s, 2H), 2.75 (dd, 7= 15.6, 9.0 Hz, 1H), 2.65 (dd, 7= 15.6, 5.9 Hz, 1H), 0.87 (s, 3H) ppm. MS (ESI): calcd. for C26H23CIF4N6O2: 562.15; Found 561.0 [M-H]⁻.Attorney Docket No. 71180-431439 (ASP-080-WO)ClFNAYYN / T>lT VF— 1— F OHF2-((R)-2-((R)-4-(3-chloro-4-fluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3- (5-(trifluoromethyl)pyridazin-3-yl)-3,4-dihydroquinazolin-4-yl)acetic acid 'll NMR (600 MHz, DMSO-d6): 59.27 (s, 1H), 8.04 (s, 1H), 7.19 (t, 7 = 9.1 Hz, 1H). 7.02 (dd, J= 20.9, 8.4 Hz. 2H), 6.96 (dd. J= 6.3, 3.0 Hz, 1H), 6.95 - 6.88 (m, 1H), 6.83 (dt, J= 9.1, 3.5 Hz, 1H), 5.95 (t, 7- 7.4 Hz, 1H), 3.89 (s, 1H), 3.55 (s, 2H), 3.23 (s. 3H), 2.95 (s, 1H), 2.78 (dd, 7= 15.8, 8.5 Hz, 1H), 2.61 - 2.58 (m, 1H), 1.01 (d, 7 = 6.5 Hz, 3H) ppm. MS (ESI): calcd. for C26H22CIF5N6O2: 580.14; Found 579.0 [M-l]’.F L IFk. FL / LY ILu N OLMe^OH2-((R)-2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(2- methoxy-5-(trifluoromethyl)pyridin-3-yl)-3,4-dihydroquinazolin-4-yl)acetic acid1H NMR (400 MHz, CD3OD): δ 8.27 - 8.37 (m, 2H), 6.96 - 7.10 (m, 3H), 6.87 - 6.93 (m, 1H). 6.75 - 6.83 (m, 1H), 6.65 (br d. 7= 10.03 Hz, 1H). 4.97 (br s, 1H).4.60 (br s, 1H), 3.81 - 3.96 (m, 3H), 3.67 (br s, 1H), 3.48 (br s, 2H), 3.23 (br s, 1H), 3.13 (br s, 1H), 3.08 (br s, 1H), 2.73 - 2.99 (m, 1H), 2.48 (br s, 1H), 0.83 - 0.92 (m, 3H) ppm (The acid proton was missed). MS (ESI): calcd. for C28H25F6N5O3: 593.19; Found: 594.1 [M+1]+.Attorney Docket No. 71180-431439 (ASP-080-WO)FF\ J\Y ) iFL.bkY YY T NX OM CeyoOH2-((S)-2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(2- methoxy-5-(trifluoromethyl)pyridin-3-yl)-3,4-dihydroquinazolin-4-yl)acetic acid1H NMR (400 MHz, CD3OD): δ 8.36 (s, 1H), 8.26 (s, 1H), 6.93 - 7.11 (m, 3H).6.87 - 6.92 (m, 1H), 6.74 - 6.83 (m, 1H), 6.64 (br d, J = 9.78 Hz, 1H), 4.87 (br s, 1H), 4.60 (br s, 1H), 3.87 (s, 3H), 3.85 (br s, 1H), 3.53 - 3.63 (m, 2H), 3.48 (br s, 1H). 3.36 - 3.45 (m, 1H), 2.71 - 2.97 (m, 2H), 2.44 (br d, J = 13.57 Hz, 1H), 1.30 (d, J = 6.48 Hz, 3H) ppm (The acid proton was missed). MS (ESI): calcd. for C28H25F6N5O3: 593.19; Found: 594.1 [M+l]+.X xL A.Y nOH2-((S)-2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(4- (trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid1H NMR (400 MHz, CD3OD): δ 8.65 (d, J = 5.13 Hz, 1H), 8.19 (s, 1H), 7.65 (d, J = 5.13 Hz, 1H), 7.28 - 7.37 (m, 2H), 7.20 - 7.25 (m, 1H), 7.09 - 7.18 (m, 1H), 6.84 (br s, 1H), 6.69 (br d, J = 9.26 Hz, 1H), 5.91 (t, J = 7.19 Hz, 1H), 4.71 - 4.82 (m, 1H), 4.12 (br t, J = 7.07 Hz, 2H), 3.20 - 3.28 (m, 2H), 2.98 (d, J = 7.13 Hz, 1H), 2.60 – 2.65 (m, 3H), 1.05 (br s, 3H) ppm (The acid proton was missed). MS (ESI): calcd. for C27H23F6N5O2: 563.18; Found: 564.0 [M+1]+.Attorney Docket No. 71180-431439 (ASP-080-WO)F Y X I L JL x JK.Y YYF? C^^X / N^AA\^NOH2-((R)-2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(4- (trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinoa YYzolin-4-yl)acetic acid1H NMR (400 MHz, CD3OD): δ 12.65 (bs s, 1H), 8.66 (d, J = 5.13 Hz, 1H), 8.18 – 8.23 (m, 1 H), 7.67 (d, J = 5.13 Hz, 1H), 7.30 – 7.38 (m, 2H), 7.21 – 7.26 (m, 1H),7.09-7.18 (m, 1H), 6.85 (br s, 1H), 6.71 (br s, 1H), 5.91 (t, 7 = 7.19 Hz, 1H), 4.71 - 4.82 (m, 1H), 4.12 (br t, J = 7.07 Hz, 2H), 3.20 - 3.28 (m, 2H), 2.98 (d, 7= 7.13 Hz, 1H), 2.60 - 2.65 (m, 3H), 1.05 (br s, 3H) ppm. MS (ESI): calcd. for C27H23F6N5O2: 563.18; Found: 564.0 [M+l]+.YA ClL, N.. N. AY YYYuOH2-((S)-8-chloro-2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-3-(4- (trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid1H NMR (400 MHz, DMSO-d6): δ 12.68 (br s, 1H), 8.52 (br s, 1H), 7.58 (br s, 1H), 7.48 - 7.52 (m, 1H), 7.39 (br s, 1H), 7.36 (br d, 7 = 4.89 Hz, 1H), 7.19 (br d, 7 = 7.46 Hz, 1H), 6.93 (br s, 1H). 6.90 (br s, 1H). 6.69 (br d, 7= 7.46 Hz, 1H), 5.79 - 5.91 (m, 1H), 4.70 - 4.76 (m, 1H), 3.39 - 3.40 (m, 3H), 2.93 (br s, 1H), 2.56 - 2.66 (m, 3H), 2.56 - 2.59 (m, 2H), 1.04 (br s, 3H) ppm. MS (ESI): calcd. For C27H23CIF5N5O2: 579.15; Found: 580.65 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)2-((R)-8-chloro-2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-1-yl)-3-(4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid1H NMR (400 MHz, DMSO-d6): δ 12.61 (br s, 1 H), 8.52 (br s, 1H), 7.69 (s, 1H), 7.40 (br d, J= 4.40 Hz, 1H), 7.21 - 7.34 (m, 2H), 7.15 (d, J= 7.70 Hz, 1H), 6.86 - 6.96 (m. 2H), 6.66 (br d, 7= 8.07 Hz, 1H), 5.82 (d, J= 2 Hz, 1H), 4.05(m,lH), 3.37 - 3.39 (m, 3H), 3.20 (br s, 2H), 2.62 - 2.71 (m, 3H), 1.05 (br s, 3H) ppm. MS (ESI): calcd. for C27H23CIF5N5O2: 579.15; Found: 580.65 [M+l]+.Fk / N-yN. J.Y 1 iOH2-((S)-2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-1-yl)-8-fluoro-3-(6-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydroquinazolin-4-yl)acetic acid1H NMR (400 MHz, CD3OD): δ 8.87 (br d, J = 4.00 Hz, 1H), 7.50 – 7.66 (m, 1H), 7.13 (br d, J = 9.51 Hz, 1H), 7.04 (br d, J = 6.75 Hz, 1H), 6.99 (s, 1H), 6.96 (s, 1H),6.86 (br s, 1H), 6.73 (br s, 1H), 6.24 (br s, 1H), 4.76 (br s, 1H), 4.05 (br s, 1H), 3.79 (br s, 1H), 3.59 (br s, 1H), 3.33(br d, 7= 10.76 Hz, 2H), 3.13 (br s, 1H), 3.08 (br s.1H), 2.72 (br s, 2H), 0.89 (br d, J = 7.25 Hz, 1H), 1.13 (br s, 3H) ppm (The acid proton was missed). MS (ESI): calcd. for C26H22F6N6O2: 564.17; Found: 565.64 [M+1]+.F Y X I L Ji. _N. Y.Y H Y Y Y OH2-((R)-2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-1-yl)-8-fluoro-3-(6-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydroquinazolin-4-yl)acetic acid1H NMR (400 MHz, CD3OD): δ 8.91 (br s, 1H), 7.73 (br s, 1H), 7.28 (br d, J = 8.63 Hz, 1H), 7.12 (q, J = 9.84 Hz, 1H), 6.98 – 7.06 (m, 2H), 6.87 (br s, 1H), 6.71 (br s, 1H). 6.33 (d, 7 = 3.6Hz. 1H), 4.58 (br s, 1H), 3.98 (br s, 1H), 3.70 - 3.92 (m, 1H),Attorney Docket No. 71180-431439 (ASP-080-WO)3.48 (dt, J = 3.35, 1.64 Hz, 1H), 3.38 - 3.44 (m, 1H), 3.33 - 3.34 (m, 1H), 3.03 - 3.17 (m, 1H). 2.78 (br d, J = 10.01 Hz, 1H), 2.60 - 2.72 (m, 1H), 1.99 (br s, 1H).0.98 - 1.22 (m, 3H) ppm (The acid proton was missed). MS (ESI): calcd. for C26H22F6N6O2: 564.17; Found: 565.71 [M+l]+.FF3C~A t TN-NHOH2-((R)-2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-1-yl)-8-fluoro-3-(3-(trifluoromethyl)-1H-pyrazol-5-yl)-3,4-dihydroquinazolin-4-yl)acetic acid1H NMR (400 MHz, DMSO-d6): δ 7.18 – 7.27 (m, 1H), 6.98 - 7.07 (m, 1H), 6.87 - 6.97 (m, 3H), 6.64 (br d, J= 9.38 Hz, 1H), 6.31 (br s, 1H), 5.15 - 5.24 (m, 1H), 3.85 - 4.11 (m, 2H), 3.30 (br s, 4H), 2.98 - 3.15 (m, 2H), 2.87 - 2.97 (m, 1H), 2.17 - 2.28 (m, 1H), 0.92 (d, J = 6.4Hz, 3H) ppm (The acid and pyrazole amine protons were missed). MS (ESI): calcd. for C25H22F6N6O2: 552.177; Found: 553.57 [M+1]+.FFk. N. xkF3C-Z i^Tn;)N-NH k^OOH2-((S)-2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-1-yl)-8-fluoro-3-(3-(trifluoromethyl)-1H-pyrazol-5-yl)-3,4-dihydroquinazolin-4-yl)acetic acid1H NMR (400 MHz, DMSO-d6): δ 13.61 (br s, 1H), 12.68 (br s, 1H), 7.23 (q, J = 9.59 Hz, 1H), 7.08 (br t, J = 9.21 Hz, 1H), 6.90 - 7.03 (m, 3H), 6.67 (br d, J = 8.88 Hz, 1H), 6.56 (s, 1H), 5.18 (br s, 1H). 3.97 (br s, 1H), 3.82 (br d, J= 11.01 Hz, 2H).3.11 - 3.25 (m, 2H), 2.84 - 3.06 (m, 2H), 2.55 - 2.68 (m, 2H), 0.61 (br s, 3H) ppm. MS (ESI): calcd. for C25H22F6N6O2: 552.177; Found: 553.57 [M+1]+.Attorney Docket No. 71180-431439 (ASP-080-WO)F X I iFT | iX5*OH02-((S)-2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-1-yl)-8-fluoro-3-(2-(trifluoromethyl)pyridin-4-yl)-3,4-dihydroquinazolin-4-yl)acetic acid1H NMR (400 MHz, DMSO-d6): δ 12.57 - 13.03 (m, 1H), 8.51 (br s, 1H), 7.70 (br s, 1H), 7.25 (q, J = 9.67 Hz, 1H), 7.07 (br d, J = 7.13 Hz, 2H), 6.92 (br s, 2H), 6.67 (br s, 1H), 6.54 (br s, 1H), 5.69 (br s, 1H), 4.20 (br s, 1H), 3.45 (br s, 3H), 3.02 (br s, 2H), 2.85 (bs s, 1H), 2.55 - 2.60 (m, 2H), 1.23 - 1.03 (br s, 3H) ppm. MS (ESI): calcd. for C27H23F6N5O2: 563.18; Found: 564.1 [M+1]+.FF\ ^^\X I FT T 1OH2-((R)-2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(2- (trifluoromethyl)pyridin-4-yl)-3,4-dihydroquinazolin-4-yl)acetic acid’H NMR (400 MHz, DMSO-6): 5 12.73 (br s, 1H), 8.60 (br s, 1H), 7.79 (br s, 1H), 7.24 (q, J = 9.59 Hz, 1H), 7.18 (br s, 1H), 7.03 - 7.15 (m. 2H), 7.00 (br s, 1H), 6.94 (br s, 1H), 6.66 (br d, J = 8.25 Hz, 1H), 5.62 (br d, J = 5.75 Hz, 1H), 4.65 (br s, 1H), 4.09 (br s, 1H), 3.33 (m, 4H), 2.62 - 2.73 (m, 3H), 2.58 (br s, 2H), 2.32 - 2.34 (m.1H), 0.90 (br s, 3H) ppm. MS (ESI): calcd. for C27H23F6N5O2: 563.18; Found: 564.1 [M+l]+.Cl0. / .XNx^°OHAttorney Docket No. 71180-431439 (ASP-080-WO)2-((S)-2-((R)-4-(3-chlorophenyl)-3-ethylpiperazin-1-yl)-8-fluoro-3-(4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid1H NMR (400 MHz, DMSO-d6): δ 12.72 (br s, 1H), 8.50 (br s, 1H), 7.50 (br s, 1H), 7.36 (br s, 1H), 7.19 (t, J= 8.13 Hz, 1H), 7.02 (br d, J= 7.38 Hz, 2H), 6.80 - 6.88 (m, 3H), 6.72 (d, J= 7.45 Hz, 1H), 5.89 (br s, 1H), 3.96 (br s, 1H), 3.60 (bs s, 1H).3.15 (bs s, 2H), 2.95 (br s, 1H), 2.50 - 2.60 (br s, 4H), 1.66 (br s, 1H), 1.34 (br s, 1H), 1.01 (br s, 3H) ppm. MS (ESI): calcd. for C28H26CIF4N5O2: 575.17; Found: 576.62 [M+l]+.2-((R)-2-((R)-4-(3-chlorophenyl)-3-ethylpiperazin-1-yl)-8-fluoro-3-(4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid’H NMR (400 MHz, DMSO-6): 5 12.69 (br s, 1H), 8.50 (br s, 1H), 7.51 (br s, 1H), 7.36 (br s, 1H). 7.19 (t, J= 8.13 Hz, 1H), 7.02 (br d, 7= 7.38 Hz, 2H), 6.81 - 6.87 (m, 3H), 6.73 (dd, J = 7.69, 1.31 Hz, 1H), 5.88 (br s, 1H), 3.96 (br s, 1H), 3.45 (br s, 1H), 3.17 (br s, 2H), 2.95 (br s, 1H), 2.60 (br s, 2H), 2.52 - 2.53 (m, 2H), 1.66 (br s, 1H), 1.33 (br s, 1H), 0.88 - 1.29 (m, 3H) ppm. MS (ESI): calcd. for C28H26CIF4N5O2: 575.17; Found: 576.62 [M+l]+.UL1L x x Us.2-((S)-8-fluoro-2-((R)-4-(3-methoxyphenyl)-3-methylpiperazin-1-yl)-3-(4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid1H NMR (400 MHz, DMSO-d6): δ 12.76 (br s, 1H), 8.57 (br s, 1H), 7.71 (br s, 1H), 7.47 (br s, 1H), 7.15 (br s, 1H), 7.10 (br d, J = 7.25 Hz, 1H), 7.03 (br s, 2H), 6.44 (br s, 3H), 5.92 (br s, 1H), 4.50 (bs s, 1H), 3.90 (s, 3H), 3.20 – 3.45 (m, 4H), 2.60 –Attorney Docket No. 71180-431439 (ASP-080-WO)2.89 (m, 4H), 1.02 (br s, 3H) ppm. MS (ESI): calcd. for C28H27F4N5O3: 557.21; Found: 558.46 [M+l]+.OMeOH2-((R)-8-fluoro-2-((R)-4-(3-methoxyphenyl)-3-methylpiperazin-1-yl)-3-(4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid1H NMR (400 MHz, DMSO-d6): δ 12.80 (br s, 1H), 8.57 (br s, 1H), 7.71 (br s, 1H), 7.47 (br s, 1H), 7.15 (br s, 1H), 7.10 (br d, J = 7.25 Hz, 1H), 7.03 (br s, 2H), 6.44 (br s, 3H), 5.94 (br s, 1H), 4.48 (bs s, 1H), 3.90 (bs, 3H), 3.20 – 3.45 (m, 5H), 2.60 – 2.89 (m, 3H), 1.08 (d, J = 7.2Hz, 3H) ppm. MS (ESI): calcd. for C28H27F4N5O3: 557.21; Found: 558.90 [M+1]+.OMeUL1Cl_=~^^°OH2-((S)-8-chloro-2-((R)-4-(3-methoxyphenyl)-3-methylpiperazin-1-yl)-3-(4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid’H NMR (400 MHz, DMSO-6): 5 12.39 (br s, 1H), 8.53 (br s, 1H), 7.60 (br s, 1H), 7.40 (br s, 1H), 7.31 (br d, 7= 6.13 Hz, 1H), 7.19 (br d, 7 = 7.25 Hz, 1H), 7.12 (br s, 1H), 6.91 (br s, 1H), 6.50 (br s, 1H), 6.42 (br s, 2H), 5.88 (br s, 1H), 4.51 (br s, 1H), 3.71 (bs s, 3H), 3.32 - 3.45 (m, 3H), 3.21 - 3.31 (m, 2H), 2.90 (bs s, 1H), 2.50 - 2.65 (m, 2H). 1.02 (br s. 3H) ppm. MS (ESI): calcd. for C28H27CIF3N5O3: 573.18 Found: 574.46 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)OMeAA o,L J\K JxY nL^OOH2-((R)-8-chloro-2-((R)-4-(3-methoxyphenyl)-3-methylpiperazin-l-yl)-3-(4- (trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acidJH NMR (400 MHz, DMSO-6: 5 12.62 (br s. 1H), 8.51 (br s, 1H), 7.72 (br s, 1H).7.39 (br d, J = 4.63 Hz, 1H), 7.29 (br d, J = 7.88 Hz, 1H), 7.14 (br d, J = 7.25 Hz, 1H), 7.10 (t, 7= 8.13 Hz, 1H), 6.87 (br s, 1H), 6.46 (br d, 7= 8.50 Hz, 1H), 6.32 - 6.40 (m, 2H). 5.83 (br s. 1H), 4.51 (br s, 1H), 3.70 (s. 3H), 3.20 (br s, 4H), 2.90 (bs s, 2H), 2.60 - 2.71 (m, 2H), 0.94 A. (br s, 3H) ppm. MS (ESI): calcd. for C28H27CIF3N5O3: 573.18; Found: 574.46 [M+l]+.AY'A A FL / Nx / N. Js.\ YznOH2-((S)-2-((2S,5R)-4-(3,4-difluorophenyl)-2,5-dimethylpiperazin-l-yl)-8-fluoro- 3-(4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acidJH NMR (400 MHz, DMSO-6: 5 12.62 (br s. 1H), 8.69 (br s, 1H), 7.67 (br s, 1H).7.42 (br s, 1H), 7.35 - 7.40 (m, 1H), 7.22 (q, 7 = 9.55 Hz, 2H), 7.05 (br d, 7 = 8.38 Hz, 1H), 6.99 (br d, 7= 7.00 Hz, 1H), 6.92 (br s, 1H), 6.88 (br s, 1H), 5.85 (br d.7=5.13 Hz, 1H), 4.73 (br s, 1H), 3.98 - 4.15 (m, 1H). 3.45 - 3.48 (d, 7= 10.4 1H), 3.37 (bs s, 1H), 3.11 (bs s, 2H), 2.59 - 2.75 (m, 2H), 1.05 (brs, 3H), 0.85 (bs s, 3H) ppm. MS (ESI): calcd. for C28H25F6N5O2: 577.19; Found: 578.20 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)2-((R)-2-((2S,5R)-4-(3,4-difluorophenyl)-2,5-diinethylpiperazin-l-yl)-8-fluoro- 3-(4-(trifluoromethyl)pyridine-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid NMR (400 MHz. DMSO-cfc): 5 12.61 (br s. 1H). 8.69 (br s, 1H), 7.67 (br s, 1H), 7.41 (br s, 1H), 7.32 - 7.38 (m, 1H), 7.01 - 7.22 (m, 2H), 7.05 (br d, J = 8.38 Hz, 1H), 6.99 (br d, J = 7.00 Hz, 1H), 6.92 (br s, 1 H), 6.88 (br s, 1H). 5.85 (br d, J = 5.13 Hz, 1H), 4.20 (br s, 1H), 3.60 - 3.89 (m, 1H), 3.45 - 3.48 (m, 1H), 3.37 (bs s, 1H), 3.11 (bs s, 2H), 2.59 - 2.75 (m, 2H), 1.07 - 1.33 (m, 3H), 0.95 (d, J = 6 Hz, 3H) ppm. MS (ESI): calcd. for C28H25F6N5O2: 577.19; Found: 578.21 [M+l]+.FF\ J\' Sc6T YF— — F OHF2-((S)-2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(5- (trifluoromethyl)pyridazin-3-yl)-3,4-dihydroquinazolin-4-yl)acetic acid'H NMR (500 MHz, DMSO-d6): 5 12.69 (s, 1H), 9.32 (s, 1H), 8.04 (s, 1H), 7.23 (q, 7= 9.7 Hz, 1H), 7.10 - 6.97 (m, 2H), 6.91 (s, 2H), 6.65 (d, J = 9.1 Hz, 1H), 5.96 (s, 1H), 4.39 (d. J = 235.2 Hz, 2H), 3.27 - 2.98 (m, 4H), 2.89 (s, 1H), 2.66 (s, 2H), 0.70 (d, 7= 315.7 Hz, 3H) ppm. MS (ESI): calcd. for C26H22F6N6O2: 564.17; Found 565.2 [M+l]+.F1 1 1F— Y 1— F Y OHF2-((R)-2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(5- (trifluoromethyl)pyridazin-3-yl)-3,4-dihydroquinazolin-4-yl)acetic acid'H NMR (500 MHz, DMSO-d6): 5 12.65 (s, 1H), 9.34 (s, 1H), 8.15 (s, 1H), 7.22 (q, 7 = 9.7 Hz, 1H), 7.06 (t, 7 = 9.5 Hz, 1H), 7.00 (d, 7 = 7.5 Hz, 1H), 6.89 (d, 7 = 13.8 Hz, 2H), 6.62 (d, 7 = 9.2 Hz, 1H), 5.92 (s, 1H), 4.74 - 3.80 (m, 2H), 3.15 (s,Attorney Docket No. 71180-431439 (ASP-080-WO)2H), 2.76 (dd, J = 16.0, 8.7 Hz, 1H), 2.52 (s, 4H), 0.97 (d, J= 53.3 Hz, 3H) ppm. MS (ESI): calcd. for C26H22F6N6O2: 564.17; Found 565.0 [M+l]+.FLl * FF3Cn■k^N 1^.0OMe OH2-(2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(6- methoxy-4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acidJH NMR (400 MHz, DMSO-6): 5 12.58 (br s, 1H), 7.25 (q, J= 9.46 Hz, 1H), 6.97 - 7.11 (m, 3H), 6.92 (br s, 2H), 6.78 (br s, 1H). 6.66 (br d, J = 8.13 Hz, 1H), 5.87 (br s, 1 H), 4.72 (br s, 1 H), 3.89 (br s, 4H), 3.46 (bs s, 2H), 2.56 - 2.65 (m, 2H), 0.96 (br s, 3H) ppm (Methoxy protons merged with solvent). MS (ESI): calcd. for C28H25F6N5O3: 593.19Found: 594.15 [M+l]+.Fci T n=\^oOH2-((S)-3-(4-chloropyridin-2-yl)-2-((R)-4-(3,4-difluorophenyl)-3- methylpiperazin-l-yl)-8-fluoro-3,4-dihydroquinazolin-4-yl)acetic acidJH NMR (400 MHz, DMSO-dfe): 8 12.61 (br s, 1H), 8.22 (br d, J = 5.25 Hz, 1H), 7.18 - 7.33 (m, 2H), 7.15 (br d, 7= 4.63 Hz, 1H), 6.87 - 7.07 (m, 4H), 6.67 (brd, J = 8.88 Hz, 1H). 5.82 (br s. 1H), 4.13 (br s, 1H), 3.71 - 3.80 (m, 2H), 3.27 - 3.29 (m.2H), 2.89 (bs s, 2H), 2.52 - 2.61 (m, 2H), 0.98 (br s, 3H) ppm. MS (ESI): calcd. for C26H23CIF3N5O2: 529.15; Found: 530.13 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)F X X iFX^N\<s>0OH2-((R)-3-(4-chloropyridin-2-yl)-2-((R)-4-(3,4-difluorophenyl)-3- methylpiperazin-l-yl)-8-fluoro-3,4-dihydroquinazolin-4-yl)acetic acidJH NMR (400 MHz. DMSO-6): 5 12.61 (br s, 1H), 8.22 (br d. 7= 5.25 Hz, 1H).7.18 - 7.33 (m, 2H), 7.15 (br d, 7= 4.63 Hz, 1H), 6.87 - 7.07 (m, 4H), 6.67 (br d, 7 = 8.88 Hz, 1H). 5.82 (br s, 1H), 4.13 (br s, 1H), 3.71 - 3.80 (m, 2H), 3.27 - 3.29 (m.2H). 2.89 (bs s. 2H). 2.52 - 2.61 (m, 2H), 0.98 (br s. 3H) ppm. MS (ESI): calcd. for C26H23CIF3N5O2: 529.15; Found: 530.13 [M+l]+.OMeA s,L. N.v X iT T ■FOH2-((S)-6,8-difluoro-2-((R)-4-(3-methoxyphenyl)-3-methylpiperazin-l-yl)-3-(4- (trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid’H NMR (400 MHz, CD3OD): 88.38 (br d, J = 5.13 Hz, 1H), 7.47 (br s, 1H), 7.19 (br s, 1H), 6.70 - 6.77 (m, 2H), 6.47 (br d, J = 8.19 Hz, 1H), 6.36 - 6.43 (m, 2H), 5.77 (bs s, 1H). 4.82 (s, 1H), 4.77 (s, 1H), 4.50 (s, 1H), 3.59 (bs, 1H), 3.60 - 3.70 (m, 3H), 3.54 (s, 1H), 3.03 (s, 2H), 2.54 - 2.65 (m, 2H), 0.80 (br t, J = 6.97 Hz, 3H) ppm. MS (ESI): calcd. for C28H26F5N5O3, 575.20; Found: 576.65 [M+l]+.OMeFT XX XNOHAttorney Docket No. 71180-431439 (ASP-080-WO)2-((R)-6,8-difluoro-2-((R)-4-(3-methoxyphenyl)-3-methylpiperazin-l-yl)-3-(4- (trifluoromethyl) pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid NMR (400 MHz. CD3OD): 88.52 (br s, 1H). 7.70 (br s. 1H). 7.30 (br s, 1H), 7.15 (br s, 1H), 6.90 - 6.91 (m, 2H), 6.53 (br d, J - 8.19 Hz, 1H), 6.36 - 6.43 (m, 2H), 5.86 (bs s, 1H), 4.82 (s, 1H). 4.77 (s, 1H), 4.60 (s, 1H), 3.59 (bs, 1H), 3.60 - 3.70 (m, 3H), 3.54 (s, 3H), 2.80 - 2.85 (m, 1H), 2.60 - 2.65 (m, 1H), 1.06 (d, J = 6.97 Hz, 3H) ppm (The acid proton was missed). MS (ESI): calcd. for C28H26F5N5O3:575.20; Found: 576.69 [M+l]+.OMeAA k -N. x,kT V]Z\^OOH2-((S)-3-(4-cyanopyridin-2-yl)-8-fluoro-2-((R)-4-(3-methoxyphenyl)-3- methylpiperazin-l-yl)-3,4-dihydroquinazolin-4-yI)acetic acidJH NMR (400 MHz, DMSO-6: 5 12.62 (br s, 1H). 8.48 (br d. J = 4.50 Hz. 1H).7.60 (br s, 1H), 7.42 (br d, J = 4.00 Hz, 1H), 7.12 (t, 7= 8.19 Hz, 1H), 6.95 - 7.06 (m, 2H), 6.88 (br s. 1H), 6.49 (br d, 7 = 8.25 Hz. 1H), 6.33 - 6.44 (m, 2H), 5.96 (br s, 1H), 4.20 (br s, 1H). 3.88 (s, 1H), 3.71 (s, 3H), 3.25-3.31 (m, 3H), 2.95 (br s, 2H), 2.60 (br d, J = 6.63 Hz, 2H), 1.03 (br s, 3H) ppm. MS (ESI): calcd. for C28H27FN6O3: 514.21; Found: 515.23 [M+l]+.OMeOH2-((R)-3-(4-cyanopyridin-2-yl)-8-fluoro-2-((R)-4-(3-methoxyphenyl)-3- methylpiperazin-l-yl)-3,4-dihydroquinazolin-4-yl)acetic acidJH NMR (400 MHz, DMSO-6): 8 12.61 (br s, 1H), 8.50 (br d, J = 4.75 Hz, 1H), 7.75 (br s. 1H), 7.45 (br s, 1H), 7.02 - 7.18 (m, 2H). 6.99 (brd. 7= 6.75 Hz. 1H),Attorney Docket No. 71180-431439 (ASP-080-WO)6.91 (br s, 1H), 6.47 (br d, J = 8.00 Hz, 1H), 6.32 - 6.35 (m, 2H), 5.85 - 5.92 (m, 1H), 4.60 (br s, 1H), 4.10 - 4.15 (m, 2H), 3.71 (s, 3H), 3.25-3.31 (m, 1H), 2.95 (br s, 3H), 2.60 (br d, 7= 6.63 Hz, 2H), 0.97 (br s, 3H) ppm. MS (ESI): calcd. for C28H27FN6O3: 514.21; Found: 515.20 [M+l]+.OMeAA.L. N. X.YYC=U\^OOH2-((S)-8-fluoro-2-((R)-4-(3-methoxyphenyl)-3-methylpiperazin-l-yl)-3-(4- methylpyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acidJH NMR (400 MHz, DMSO-6: 5 12.62 (br s, 1H), 8.48 (br d, J = 4.50 Hz, 1H), 7.60 (br s, 1H), 7.42 (br d, J = 4.00 Hz, 1H), 7.12 (t, J = 8.19 Hz, 1H), 6.95 - 7.06 (m, 2H), 6.88 (br s. 1H), 6.49 (br d. J= 8.25 Hz. 1H), 6.33 - 6.44 (m, 2H), 5.96 (br s, 1H), 4.20 (br s, H), 3.88 (s, 1H), 3.71 (s, 3H), 3.25-3.31 (m, 3H), 2.95 (br s, 2 H), 2.60 (br d, 7= 6.63 Hz, 2H), 2.32 (s, 3H), 1.03 (br s, 3H) ppm. MS (ESI): calcd. for C28H30FN5O3: 503.23; Found: 504.25 [M+l]+.OMeO COOH2-((R)-8-fluoro-2-((R)-4-(3-methoxyphenyl)-3-methylpiperazin-l-yl)-3-(4- methylpyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid1H NMR (400 MHz, DMSO-6): 5 12.59 (br s, 1H), 8.50 (br d, 7 = 4.75 Hz, 1H), 7.73 (br s, 1 H), 7.47 (br s, 1H). 7.02 - 7.13 (m, 2H), 6.99 (br d, 7= 6.75 Hz, 1H), 6.91 (br s, 1H), 6.46 (br d, 7 = 8.00 Hz, 1H), 6.32 - 6.41 (m, 2H), 5.85 - 5.92 (m, 1H), 4.20 (br s, 1 H). 3.88 (s, 1H), 3.71 (s, 3 H), 3.25-3.31 (m, 3H), 2.95 (br s, 2H), 2.60 (br d, 7 = 6.63 Hz, 2H), 1.03 (br s, 3H) ppm (3 protons merged in solvent peak). MS (ESI): calcd. for C28H30FN5O3: 503.23; Found: 504.20 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)OMeY ViBk ^. NOH2-((S)-3-(4-bromopyridin-2-yl)-8-fluoro-2-((R)-4-(3-methoxyphenyl)-3- methylpiperazin-l-yl)-3,4-dihydroquinazolin-4-yl) acetic add’H NMR (400 MHz, DMSO-d6): 58.19 (br s, 1H), 7.37 (br s, 1H), 7.14 (br s, 2H), 7.08 (br d, J = 6.75 Hz, 2H), 7.00 (br s, 1H), 6.43 - 6.52 (m, 3H), 5.83 (br s, 1H).4.10 (br s, 2H), 3.70 (s, 3H), 3.50 - 3.52 (m, 4H), 3.17 (s, 2H), 3.00 (br s, 2H), 0.85 (br s, 3H) ppm (The acid proton was missed). MS (ESI): calcd. for 00.C27H27BrFN5O3: 567.13; Found: 568.11 [M+l]+.^z / _OMe Z O —1°L _Nk -XY nC-0OH2-((R)-3-(4-bromopyridin-2-yl)-8-fluoro-2-((R)-4-(3-methoxyphenyl)-3- methyIpiperazin-l-yl)-3,4-dihydroquinazoIin-4-yl)acetic acid1H NMR (400 MHz, DMSO-d6): 5 12.32 (br s, 1H), 8.22 (br d, 7= 5.50 Hz. 2H), 7.69 (br s, 1H), 7.42 (br d, J = 3.63 Hz, 1H), 7.00 - 7.23 (m, 4H), 6.47 (br d, J = 7.63 Hz, 1H), 6.31 - 6.42 (m, 2H), 5.82 (br s, 1H), 4.55 (br s, H), 4.01 (br s, 2H), 3.70 (m, 3H), 3.56-3.58 (m, 2H), 3.20 - 3.25 (m. 4H), 0.97 (br s, 3H) ppm. MS (ESI): calcd. for C27H27BrFN5O3: 567.13; Found: 568.11 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)2-((R)-8-chloro-2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-3-(l- (2,2,2-trifluoroethyl)-lH-pyrazol-4-yl)-3,4-dihydroquinazolin-4-yl) acetic acid NMR (400 MHz. DMSO-6: 5 12.11 (br s, 1H). 7.49 - 7.81 (m, 2H), 7.25 (q. J = 9.76 Hz, 2H), 7.11 (br s, 1H), 6.89-6.97 (m, 2H), 6.66 (br d, J= 9.13 Hz, 1H), 5.07 (br s. 3H), 4.12 (br s, 1H), 3.97 (br s, 1H), 3.38-3.39 (m, 1H), 3.30-3.32 (m, 3H), 3.17 (s, 1H), 3.12 (br s, 1H), 2.86 (br s, 1H), 0.91 (br d, 7= 4.88 Hz, 3H) ppm. MS (ESI): calcd. for C26H24CIF5N6O2: 582.16; Found: 583.1 [M+l]+.ClY-NF3C'~N J ■OH2-((S)-8-chloro-2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-3-(l- (2,2,2-trifluoroethyl)-lH-pyrazol-4-yl)-3,4-dihydroquinazolin-4-yl) acetic acid ¹H NMR (400 MHz, DMSO-d₆): 5 12.60 (br s, 1H), 7.73 (br s,1H), 7.50 (br s, 1H), 7.20 - 2.29 (m, 2H), 7.08 - 7.10 (m, 1H), 6.89 - 6.97 (m, 2H), 6.66 (br d, J = 9.13 Hz, 1H). 5.03 - 4.90 (m, 3H), 4.12 (br s, 1H), 3.96 (br s. 1H), 3.31 - 3.33 (m, 3H), 3.17 (s, 1H), 3.12 (br s, 1H), 2.45 - 2.50 (m, 2H), 0.69 (br d, 7 = 4.88 Hz, 3H) ppm. MS (ESI): calcd. for C26H24CIF5N6O2: 582.16; Found: 583.1 [M+l]+.ClCI Y YYOH2-((S)-8-chloro-2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yI)-3-(4- (trifluoromethyl) pyridin-2-yl)-3,4-dihydroquinazolin-4-yl) acetic acidY NMR (400 MHz, DMSO-6): 5 12.62 (br s, 1H), 8.49 (br s, 1H), 7.57 (br s, 1H), 7.37 (br s, 1H), 7.28 (br d, 7= 6.75 Hz, 1H), 7.21 (t, 7= 8.13 Hz, 1H), 7.16 (br d, 7 = 7.50 Hz, 1H), 6.83-6.91 (m, 3H), 6.77 (d, 7 = 7.50 Hz, 1H), 5.85 (s, 1H), 4.30 (s, 1H), 3.30 (br s, 1H), 2.90 (br s, 2H), 2.60 (br s, 1H), 2.50 (br s, 2H), 2.42 -Attorney Docket No. 71180-431439 (ASP-080-WO)2.45 (m, 2H), 0.85 (d, J = 6.00 Hz, 3H) ppm. MS (ESI): calcd. for C27H24CI2F3N5O2: 577.13; Found: 578.1 [M+l]+.ClClL. N. / kFjCyy vNy TVnOH2-((R)-8-chloro-2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-3-(4- (trifluoromethyl) pyridin-2-yl)-3,4-dihydroquinazolin-4-yl) acetic acid’H NMR (400 MHz, DMSO-d6): 5 12.62 (br s, 1H), 8.52 (br s, 1H), 7.70 (br s, 1H). 7.40 (br d, J = 4 Hz, 1H), 7.30 (br d, J =7.50 Hz, 1H), 7.27-7.29 (m, 1H). 7.10-7.26 (m, 2H), 6.85-6.89 (m, 1H), 6.82 (br d, 7= 8.88 Hz, 1H), 6.75 (dd, J= 7.82, 1.44 Hz, 1H). 5.85 (s, 1H), 4.35 (s, 1H), 3.31 (br s, 1H), 2.93 (br s, 3H), 2.65 (br s, 1H). 2.52 (br s. 2H), 2.42 - 2.45 (m, 2H). 0.97 (br s. 3H) ppm. MS (ESI): calcd. for C27H24CI2F3N5O2: 577.13; Found: 578.13 [M+l]+.OMeF3C- / Y ■N'N -\^O / 1OH2-((S)-8-fluoro-2-((R)-4-(3-methoxyphenyl)-3-methylpiperazin-l-yl)-3-(l- methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl)-3,4-dihydroquinazolin-4-yl) acetic acidJH NMR (400 MHz, DMSO-6): 8 12.5 (br s, 1H), 7.11 (t, J= 8.19 Hz, 1H), 7.03 (t, J = 9.44 Hz, 1H), 6.96 (d,.7 = 7.41 Hz, 1H), 6.86 - 6.93 (m, 1H), 6.63 (s, 1H), 6.49 (dd, J = 8.19Hz 1H), 6.33 - 6.41 (m, 2H), 5.29 (brt, 7 = 7.50 Hz, 1H), 4.02 (br s, 1H), 3.92 (s, 3H), 3.77 (s, 3H), 3.23 - 3.45 (m, 4H). 2.92 - 3.05 (m, 2H), 2.52 - 2.59 (m, 2H), 0.79 (br s, 3H) ppm. MS (ESI): calcd. for C27H28F4N6O3: 560.22; Found: 561.13 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)OMek Y.F3C~f T YN'N / rOH2-((R)-8-fluoro-2-((R)-4-(3-methoxyphenyl)-3-methylpiperazin-l-yl)-3-(l- methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl)-3,4-dihydroquinazolin-4-yl) acetic acid'H NMR (400 MHz, DMSO-6): 8 12.56 (br s, 1 H), 7.10 (br t, J= 8 Hz, 2H), 6.91 - 6.98 (m, 2H), 6.48 (br s 1H), 6.39 (br s 1H), 6.34 - 6.35 (m, 2H), 5.38 (br s, 1H).4.01 (br s, 1H), 3.83 (br s, 3H), 3.71 (s. 3H), 3.10 - 3.13 (m, 3H), 2.99 - 3.01 (m, 3H), 2.55 (br s, 2H), 0.958 (d, J - 4 Hz, 3H) ppm. MS (ESI): calcd. for C27H28F4N6O3: 560.22; Found: 561.11 [M+l]+.ClFII 1 iFOH2-((S)-2-((R)-4-(3-chloro-4-fluorophenyl)-3-methylpiperazin-l-yl)-6,8- difluoro-3-(4-(trifluoromethyl) pyridin-2-yl)-3,4-dihydroquinazolin-4-yl) acetic acidJH NMR (400 MHz, DMSO-6: 8 12.75 (br s, 1H). 8.51 (br s. 1H), 7.57 (br s, 1H), 7.41 (br d, J = 5.13 Hz, 1H), 7.25 (t, J = 9.13 Hz, 1H), 7.10 (br t, J = 9.71 Hz, 1H), 6.98 - 7.01 (dd,. / = 6.32, 2.81 Hz, 1H), 6.86 - 6.89 (br d, J= 8.63 Hz, 1H), 5.86 (br s, 1H). 4.63 (br s. 1H), 4.02 (br s, 1H), 2.67 (br s, 2H), 2.62 (br s. 2H). 2.63 (br s, 1H), 2.51 - 2.50 (m, 3H), 1.03 (br s, 3H) ppm. MS (ESI): calcd. for C27H22CIF6N5O2: 597.14; Found: 598.14 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)ClF. N.. XF3G\r / ^N. / A^#?kF^x^NOH2-((R)-2-((R)-4-(3-chloro-4-fluorophenyl)-3-methylpiperazin-l-yl)-6,8- difluoro-3-(4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid¹H NMR (400 MHz, DMSO-d₆): δ 12.64 (br s, 1H), 8.53 (br s, 1H), 7.68 (s, 1H),7.41 (br d, 7= 5.13 Hz, 1H), 7.23 (t, 7= 9.13 Hz, 1H), 7.10 (br t, 7= 9.71 Hz, 1 H), 7.00 (dd, 7 = 6.32, 2.81 Hz, 1H), 6.96 (brd, 7= 8.63 Hz, 1 H), 6.85 (m, 1H) 5.86 (br s, 1H). 4.57 (br s. 1H), 3.89 (br s, 2 H), 3.18 (br s, 4 H) 2.56 - 2.64 (m. 2 H), 0.94 (br s, 3 H) ppm. MS (ESI): calcd. for C27H22CIF6N5O2: 597.14; Found: 598.14 [M+l]+.OMeNA xFL, N.. N. AxY V]F3C / N X / XJAOH2-((S)-8-fluoro-2-((R)-4-(2-methoxypyridin-4-yl)-3-methylpiperazin-l-yl)-3- (4-(trifluoromethyl) pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acidJH NMR (400 MHz, DMSO-6): δ 12.67 (br s, 1H), 8.49 (br s, 1H), 7.80 (d, J = 6.13 Hz, 1H), 7.55 (br s, 1H), 7.36 (br s, 1H), 7.02 (br d, J = 7.75 Hz, 2H) 6.88 (br s, 1 H), 6.51 (br d, J = 4.88 Hz, 1H), 6.03 - 6.09 (m, 1H) 5.85 (br s, 1 H), 4.33 (br s, 2H), 3.75 (s, 3H), 3.52 (br s, 2 H), 3.18 - 3.25 (m, 2H), 2.96 (m, 1H) 2.60 (br s, 2H), 1.04 (d, J=6.00 Hz, 3H) ppm. MS (ESI): calcd. for C27H26F4N6O3: 558.20; Found: 559.2 [M+1]+.Attorney Docket No. 71180-431439 (ASP-080-WO)OMeF3C. ^. N. JL<^\^N\< S>°OH2-((R)-8-fluoro-2-((R)-4-(2-methoxypyridin-4-yl)-3-methylpiperazin-l-yl)-3- (4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic add’H NMR (400 MHz, DMSO-6): 88.46 (br s, 1H), 7.84 (br s, 1H), 7.79 (d, 7=6.13 Hz, 1H), 7.35 (br d, J = 4.38 Hz, 1H), 6.98 (br d, J = 7.00 Hz, 2H), 6.83 (br s, 1H).6.47 (br d, J =5.00 Hz, 1H), 6.02 (br s, 1H), 5.76 (br s, 1H), 4.62 (br s, 2 H), 4.00 (br s, 1H), 3.75 (s, 3H), 3.55 - 3.60 (m, 1H), 3.32 (m, 2H), 2.59 (br dd. 7= 15.63, 9.01 Hz, 2H), 2.42 (br dd. 7= 15.51, 5.25 Hz, 1H), 1.04 (d. 7=6.00 Hz, 3 H) ppm (1H merged with solvent peak). MS (ESI): calcd. for C27H26F4N6O3: 558.20; Found: 559.2 [M+l]+.F CHF2. N. JxZ\^OOH2-((S)-2-((R*)-3-(difluoromethyl)-4-(3,4-difluorophenyl)piperazin-l-yl)-8- fluoro-3-(4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic add¹H NMR (400 MHz, DMSO-d₆): δ 8.43 (br s, 1H), 7.79 (br s, 1H), 7.33 (br s, 1H), 7.22 (q, J = 9.59 Hz, 1H), 6.98 - 7.05 (m, 3H), 6.87 (br s, 1H), 6.72 (br d, J = 9.01 Hz, 1 H), 6.24 (m 1H), 5.70 (br s, 1H), 4.98 (br s, 1H), 3.55 (m, 2H), 3.20 (m, 4H), 2.90 (m, 1H), 2.42 - 2.48 (m, 1 H) ppm (1H merged with solvent peak). MS (ESI): calcd. for C27H21F₈N₅O₂: 599.16; Found: 600.1 [M+1]+.Attorney Docket No. 71180-431439 (ASP-080-WO)FF'T |I CHF2FF3C'V-^X'N^. N L ^OOH2-((R)-2-((R*)-3-(difluoromethyl)-4-(3,4-difluorophenyl)piperazin-l-yl)-8- fluoro-3-(4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid¹H NMR (400 MHz, DMSO-d₆): δ 8.50 (br s, 1H), 7.82 (br s, 1H), 7.39 (br d, J = 4.75 Hz, 1H), 7.24 (q, J= 9.63 Hz, 1H), 6.93 - 7.07 (m, 3H), 6.88 (br s, 1H), 6.70 (br d, J = 9.26 Hz, 1H), 6.24 (br d, J = 4.75 Hz, 1H), 5.78 (br s, 1H), 4.44 (br s, 2H), 3.50 (br s, 2H), 3.18 (br s, 2H), 2.89 (m, 1H), 2.60 (br d, J = 1.75 Hz, 1H), 2.35 - 2.47 (m, 1H) ppm (1H merged with solvent peak). MS (ESI): calcd. For C27H21F8N5O2: 599.16; Found: 600.1 [M+1]+.FFv\? HF2FF3C^xx^ _N^ JL^OH2-((R)-2-((S*)-3-(difluoromethyl)-4-(3,4-difluorophenyl)piperazin-l-yl)-8- fluoro-3-(4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid¹H NMR (400 MHz, DMSO-d₆): δ 8.43 (br s, 1H), 7.83 - 7.85 (br s, 1H), 7.33 (br s, 1H), 7.23 (q, J = 9.76 Hz, 1H), 6.96 - 7.05 (m, 3H), 6.88 (br s, 1H), 6.72 (br d, J = 10.01 Hz, 1H), 5.67 (br s, 2H), 4.96 (br s, 1H), 4.39 (br s, 1H), 3.46 (m, 3 H), 3.19 (m, 2H), 2.61 (br s, 1H), 2.38 (br s, 1H) ppm (1H merged with solvent peak). MS (ESI): calcd. for C27H21F8N5O2: 599.16; Found: 600.1 [M+1]+.Attorney Docket No. 71180-431439 (ASP-080-WO)FF" V |1 QHF2FL _ NyNykF3c^x<^NN '\yOOH2-((S)-2-((S*)-3-(difluoromethyl)-4-(3,4-difluorophenyl)piperazin-l-yl)-8- fluoro-3-(4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid¹H NMR (400 MHz, DMSO-d₆): δ 12.78 (br s, 1H), 8.49 (br s, 1H), 7.86 (br s, 1H), 7.38 (br d, J = 4.88 Hz, 1H), 7.24 (q, J = 9.51 Hz, 1H), 6.93 - 7.05 (m, 3H), 6.88 (br s, 1H), 6.70 (br d, J = 9.01 Hz, 1H), 6.25 (br d, J = 5.25 Hz, 1H), 5.75 (br s, 1H), 4.44 (br s, 2H) 3.47 (br s, 2H), 3.25 (br s, 2H), 2.99 (br s, 1H) 2.68 - 2.79 (m, 1H), 2.38 - 2.40 (m, 1H) ppm. MS (ESI): calcd. for C27H21F₈N₅O2: 599.16; Found: 600.1 [M+1]+.ClAA,FSC^XA^ NY T ■FOH2-((S)-2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-6,8-difluoro-3-(4- (trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acidJH NMR (400 MHz, DMSO-6): 58.52 (d, J = 4.88 Hz, 1H), 7.45 (s, 1H), 7.32 (d, 7=5.13 Hz, 1H), 7.21 (t, J= 8.07 Hz, 1H), 6.95 - 7.00 (m. 1H), 6.92 (br d, 7= 8.63 Hz, 1H) 6.83 - 6.89 (m, 2H), 6.77 (br d, 7= 7.88 Hz, 1H), 5.89 (br t, 7= 7.38 Hz, 1H), 4.05 (br s, 2H) 3.71 (br s, 1H) 3.32 - 3.37 (m, 2H), 3.06 (br d, 7= 9.01 Hz, 2H), 2.64 - 2.68 (m, 2H), 0.92 (d. 7= 6.12 Hz, 3H) ppm (1H merged with solvent peak). MS (ESI): calcd. For C27H21F8N5O2: 599.16; Found: 600.1 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)ClOH2-((R)-2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-6,8-difluoro-3-(4- (trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid’H NMR (400 MHz, DMSO-6): 5 12.66 (br s, 1 H), 8.54 (br s, 1 H), 7.70 (br s, 1 H), 7.43 (br d, J= 3.88 Hz, 1H), 7.16 - 7.26 (m, 2H), 7.07 - 7.15 (m, 1H). 6.97 (br s, 1H), 6.85 (br s, 1H), 6.81 (br d, J = 8.50 Hz, 1H), 6.75 (br d, J = 7.63 Hz, 1H), 5.88 (m, 1H), 3.99 (br s, 2H), 3.68 (br s, 1H), 3.21 - 3.37 (m, 3H), 2.50 - 2.75 (m, 2 H), 1.09 (d. J = 6.40 Hz. 3H) ppm. MS (ESI): calcd. for C27H23CIF5N5O2:579.15; Found: 580.61 [M+l]+.ClT X;FOH2-((S)-2-((R)-4-(3-chloro-4-fluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3- (4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid’H NMR (400 MHz, DMSO-6: 58.51 (d, J = 5.39 Hz, 1H), 7.48 (s, 1H), 7.31 (br d, 7= 4.98 Hz, 1H), 7.21 (br t, 7= 9.12 Hz, 1H), 6.95 -7.06 (m, 3H), 6.82 - 6.95 (m, 2H), 5.86 - 5.90 (m, 1H), 3.93 (br s, 2H), 3.64 - 3.67 (m, 1H). 3.37 - 3.39 (m, 1H), 3.19 - 3.22 (m, 2H), 3.04 (br s, 1H), 2.75 (br d, 7= 9.12 Hz, 1H), 2.49 - 2.65 (m, 1H), 0.88 (br s, 3H) ppm (1H merged with solvent peak). MS (ESI): calcd. for C27H23CIF5N5O2: 579.15; Found: 580.61 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)ClT 1?OH2-((R)-2-((R)-4-(3-ddoro-4-fluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3- (4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic add’H NMR (400 MHz, DMSO-d6): 58.52 (br d, J = 4.98 Hz, 1H), 7.64 (br s, 1 H), 7.32 (br d, J = 4.98 Hz, 1H), 7.19 (br t. J = 9.12 Hz. 1H), 6.97 - 6.99 (m, 3H), 6.80 - 6.94 (m, 2H), 5.87 (br d, J = 7.46 Hz, 1, 3.91 (br s, 2H), 3.20 - 3.26 (m, 4 H), 2.62 - 2.66 (m, 2H), 2.38 - 2.43 (m, 1H), 1.04 (br d, 7=6.63 Hz, 3H) ppm (1H merged with solvent peak). MS (ESI): calcd. for C27H23CIF5N5O2: 579.15; Found: 580.62 [M+l]+.ClF3c-<^r TN'\OH2-((R)-2-((R)-4-(3-chloro-4-fluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3- (l-methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)-3,4-dihydroquinazolin-4- yl)acetic add¹H NMR (400 MHz, DMSO-d₆): δ 12.70 (br s, 1H), 7.23 (t, J= 9.07 Hz, 1H), 7.09 - 7.13 (m, 1H), 7.00 - 7.11 (m, 1H), 6.95 - 7.09 (m, 3H), 6.84 - 6.90 (m, 1H), 6.83 (s, 1H), 4.95 (t, J= 6.01 Hz, 1H), 3.87 (brd, 1H), 3.69 (m, 1H), 3.53 (brd, J = 12.51 Hz, 1H), 3.49 (s, 3H), 2.87 - 2.93 (m, 2H), 2.73 (m, 1H), 2.42 - 2.47 (m, 1H), 0.89 (d, J= 6.38 Hz, 3H) ppm (1H merged with solvent peak). MS (ESI): calcd. for C26H24ClF5N6O2: 582.16; Found: 583.1 [M+1]+.Attorney Docket No. 71180-431439 (ASP-080-WO)ClFX-NxzNx / L / JCUF3C-< N •N'NXOH2-((S)-2-((R)-4-(3-chloro-4-fluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3- (l-methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)-3,4-dihydroquinazolin-4- yl)acetic acid¹H NMR (400 MHz, DMSO-d₆): δ 12.73 (br s, 1H), 7.21 (t, J= 9.21 Hz, 1H), 7.10 - 7.15 (m, 1H), 6.86 - 7.05 (m, 3H), 6.85 (br s, 2H), 4.93 - 4.96 (t, J = 6.13 Hz, 1H), 3.82 (br d, J = 13.20 Hz, 2H), 3.84 (br d, J = 12.40 Hz, 1H), 3.42 (s, 3H), 3.22 (m, 2H), 3.07 - 3.10 (m, 1H), 2.93 (m, 2H), 2.64 - 2.73 (m, 1H), 0.50 (d, J = 6.38 Hz, 3H) ppm. MS (ESI): calcd. for C26H24ClF5N6O2: 582.16; Found: 583.2 [M+1]+.ClF / JOuF3C-YT IN'N / 1OH2-((R)-2-((R)-4-(3-chloro-4-fluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3- (l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl)-3,4-dihydroquinazolin-4- yl)acetic acid¹H NMR (400 MHz, DMSO-d₆): δ 12.60 (br s, 1H), 7.25 (br t, J= 9.07 Hz, 5 H),6.87 (dt, J = 9.01, 3.31 Hz, 2H), 5.44 (br s, 1H), 4.00 (br s, 1H), 3.85 (s, 3H), 3.42 - 3.46 (m, 2H), 3.23 - 3.32 (m, 2H), 3.02 (br s, 2H), 2.73 (br s, 1H) 2.50 (br s, 1H), 0.98 (br d, 7= 6.38 Hz, 3H) ppm. MS (ESI): calcd. for C26H24CIF5N6O2: 582.16; Found: 583.0 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)ClFk^N^N^ Jx__^YNOOF3C-< T •N'N X^O / rOH2-((S)-2-((R)-4-(3-chloro-4-fluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3- (l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl)-3,4-dihydroquinazolin-4- yl)acetic acid¹H NMR (400 MHz, DMSO-d₆): δ 7.24 (t, J = 9.07 Hz, 1H), 6.99 - 7.07 (m, 2 H), 6.96 (d, J = 6.92 Hz, 1H), 6.89 (br d, J = 7.00 Hz, 2H), 6.66 (s, 1H), 5.28 (br s, 1 H), 4.00 (m, 2H), 3.75 - 3.78 (m, 4H), 3.24 - 3.28 (m, 4H), 3.04 - 3.06 (m, 1H), 2.89 - 2.94 (m, 1H), 0.76 (br s, 3H) ppm (1H merged with solvent peak). MS (ESI): calcd. for C26H24ClF5N6O2: 582.16; Found: 583.0 [M+1]+.FF\ J\ Fx. _FN, N NJJF— I pF O 1H0F2-((RS)-2-((R*)-3-(difluoromethyl)-4-(3,4-difluorophenyl)piperazin-l-yl)-8- fluoro-3-(5-(trifluoromethyl)pyridazin-3-yl)-3,4-dihydroquinazolin-4-yl)acetic acid'll NMR (600 MHz, DMSO-d6): 8 12.34 (s, 1H), 9.29 (s. 1H), 8.07 (s, 1H), 7.19 (q. J = 9.7 Hz, 1H), 7.08 - 6.98 (m. 2H). 6.93 (td, J = 7.9, 4.8 Hz, 2H), 6.69 (d. J = 8.8 Hz, 1H), 6.21 (td,. / = 55.3, 5.1 Hz, 1H), 5.92 (t, J= 7.2 Hz, 1H), 4.27 (s, 1H), 4.11 (s, 1H), 3.35 (d, J= 44.6 Hz. 4H), 3.20 - 3.12 (m, 1H), 2.76 (dd, J = 15.9, 8.3 Hz, 1H), 2.55 (dd, J = 15.9, 6.2 Hz, 1H) ppm. MS (ESI): calcd. for C26H20F₈N₆O2: 600.15; Found: 601.2 [M+1]+.Attorney Docket No. 71180-431439 (ASP-080-WO)FF-x / FT X iF>< Xl JuXJ X^0F - F OHF2-((RS)-2-((S*)-3-(difluoromethyl)-4-(3,4-difluorophenyl)piperazin-l-yl)-8- fluoro-3-(5-(trifluoromethyl)pyridazin-3-yl)-3,4-dihydroquinazolin-4-yl)acetic acidJH NMR (600 MHz, DMSO-d6): 5 12.41 (s, 1H), 9.26 (s, 1H), 8.02 (s. 1H), 7.18 (q, J= 9.7 Hz, 1H), 7.03 (dd, J= 18.6, 8.4 Hz, 2H), 6.95 (dtd, J= 20.8, 8.0, 5.2 Hz, 2H), 6.72 (dd, J = 8.7, 4.3 Hz, 1H), 6.01 (s, 1H), 5.91 - 5.86 (m, 1H), 4.27 (s, 2H). 3.72 (s, 1H), 3.44 (d, J = 12.8 Hz. 1H), 3.37 (d, J= 13.7 Hz, 1H), 3.24 (t, J = 11.4 Hz, 1H), 3.00 - 2.92 (m, 1H), 2.76 (dd, J = 15.7, 8.9 Hz, 1H), 2.64 (dd, J = 15.7, 5.8 Hz, 1H) ppm. MS (ESI): calcd. for C26H20F8N6O2: 600.15; Found: 601.2 [M+1]+.FF\ / FXX T FN, NJXUT YF— — F OHF2-((RS)-2-((S*)-3-(difluoromethyl)-4-(3,4-difluorophenyl)piperazin-l-yl)-8- fluoro-3-(5-(trifluoromethyl)pyridazin-3-yl)-3,4-dihydroquinazoIin-4-yl)acetic acid'H NMR (600 MHz, DMSO-d6): 8 12.61 (s, 1H), 9.36 (s, 1H), 8.16 (s, 1H), 7.22 (q, J = 9.6 Hz, 1H), 7.07 (t, J= 9.4 Hz, 1H), 7.00 (d, J= 7.5 Hz, 1H), 6.96 (ddd, J = 14.4, 7.0. 3.1 Hz, 2H). 6.68 (d, J= 9.2 Hz. 1H). 6.27 (t. J= 53.3 Hz, 1H). 5.92 (s, 1H), 4.27 (d, J = 192.9 Hz, 2H), 3.51 (s, 2H), 3.24 - 3.14 (m, 1H), 2.78 (d, J = 50.8 Hz, 2H). 2.56 - 2.50 (m, 2H) ppm. MS (ESI): calcd. for C26H20F8N6O2: 600.15; Found: 601.2 [M+1]+.Attorney Docket No. 71180-431439 (ASP-080-WO)F X I T F L Jk,hk / LF— T — F Y OH°F2-((RS)-2-((R*)-3-(difluoromethyl)-4-(3,4-difluorophenyl)piperazin-l-yl)-8- fluoro-3-(5-(trifluoromethyl)pyridazin-3-yl)-3,4-dihydroquinazolin-4-yl)acetic acid’H NMR (600 MHz, DMSO-d6): 5 12.41 (s, 1H), 9.26 (s, 1H), 8.01 (s, 1H), 7.18 (q, J= 9.6 Hz, 1H), 7.03 (dd, J = 18.4, 8.1 Hz, 2H), 6.95 (dtd, J = 23.9, 7.4, 4.4 Hz, 2H), 6.76 - 6.67 (m. 1H), 6.09 (s, 1H), 5.90 (t, J = 7.5 Hz, 1H), 4.27 (s. 2H), 3.72 (s, 1 H), 3.44 (d, J = 12.7 Hz, 1 H), 3.37 (d, J = 13.7 Hz, 1 H), 3.24 (t, J = 11.2 Hz, 1H), 2.97 (dd, J = 7.6, 4.6 Hz, 1H), 2.76 (dd, J = 15.7, 8.9 Hz, 1H), 2.64 (dd, J = 15.7, 5.7 Hz, 1H) ppm. MS (ESI): calcd. for C26H20F₈N₆O2: 600.15; Found: 601.2 [M+1]+.ClXvFY XOH2-((R)-2-((2S,3S)-4-(3-chlorophenyl)-2,3-dimethylpiperazin-l-yl)-8-fluoro-3- (4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid'H NMR (400 MHz, DMSO-6): 5 12.67 (br s, 1H), 8.49 (br s, 1H), 7.39-7.34 (m, 2H). 7.20 (t, 7 = 4.1 Hz. 1H). 7.07 (m. 2H), 6.94 (m, 2H), 6.86 (d. J= 4.1 Hz, 1H), 5.95 (br s, 1H), 5.13 (br s, 1H), 4.08 (s, 1H), 3.37 (m, 3H), 3.29 (br s, 1 H), 2.92 (br d, J = 4.12 Hz, 2H), 2.66 - 2.68 (m, 1H), 1.39 (br s, 3H), 0.33 (br s, 3 H) ppm. MS (ESI): calcd. for C28H26CIF4N5O2: 575.17; Found: 576.20 [M+1]+.Attorney Docket No. 71180-431439 (ASP-080-WO)ClL _N. _N. / LY n'\^OOH2-((S)-2-((2S,3S)-4-(3-chlorophenyl)-2,3-dimethylpiperazin-l-yl)-8-fluoro-3- (4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic add’H NMR (400 MHz, DMSO-6): 5 12.66 (br s, 1H), 8.49 (br s, 1H), 7.35 (m, 2H), 7.18 - 7.22 (m, 1H), 7.07 (m, 2H), 6.95 (br s, 1H). 6.87 (br s. 1H) 6.83 (br d, 7=8.50 Hz, 1H), 5.95 (br s, 1H), 5.14 (br s, 1H), 4.09 (br s, 1H), 3.49 (br s, 1 H) 3.37 - 3.39 (m, 1H), 2.92 (br d, 7=7.50 Hz, 1H), 2.63 - 2.66 (m, 1H), 2.59 (br d, 7=10.51 Hz, 1H), 2.52 - 2.53 (m, 2H), 1.39 (br s, 3H), 0.33 (br s, 3H) ppm. MS (ESI): calcd. for C28H26CIF4N5O2: 575.17; Found: 576.14 [M+l]+ClFiCYpcON'Nx2-((S)-2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-3-(l-cydopropyl-3- (trifluoromethyl)-lH-pyrazol-5-yl)-8-fluoro-3,4-dihydroquinazolin-4-yl)acetic addJH NMR (400 MHz, DMSO-6): 5 12.58 (br s, 1H). 7.24 - 7.19 (m, 1H), 7.09 - 7.03 (m, 1H), 6.96 (d, 7 = 7.2 Hz, 1H), 6.92 - 6.84 (m, 3H), 6.79 - 6.75 (m, 1H), 6.70 - 6.65 (m, 1H), 5.30 - 5.26 (m, 1H), 4.10 - 4.01 (m, 1H), 3.79 - 3.72 (m, 1H), 3.62 - 3.57 (m, 1H), 3.21 (d, 7= 12.0 Hz, 2H). 2.95 - 2.91 (m, 2H), 2.55 - 2.51 (m, 2H), 1.11 - 0.98 (m, 4H), 0.83 - 0.78 (m, 3H) ppm (1H merged with solvent peak). MS (ESI): calcd. for C28H27CIF4N6O2: 590.18; Found: 591.1 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)Cliu,k. N,. N. / LXx nF:C- / Y TN'N< y°v7OH2-((R)-2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-3-(l-cyclopropyl-3- (trifluoromethyl)-lH-pyrazol-5-yl)-8-fluoro-3,4-dihydroquinazolin-4-yl)acetic acid'H NMR (400 MHz, DMSO-6): 8 12.55 (br s, 1H), 7.24 - 7.19 (m, 1H), 7.09 - 6.89 (m, 3H), 6.88 - 6.87 (m, 1H), 6.84 - 6.82 (m, 1H), 6.73 - 6.72 (m. 2H), 5.39 - 5.33 (m, 1H). 4.05 - 4.02 (m, 2H), 3.69 - 3.62 (m. 2H), 3.43 - 3.33 (m, 2H). 3.16 - 3.14 (m, 2H), 3.01 - 2.95 (m, 1H), 2.60 - 2.57 (m, 1H), 1.10 - 0.99 (m, 7H) ppm. MS (ESI): calcd. for C28H27CIF4N6O2: 590.18; Found: 591.1 [M+l]+.OMeCLfFF3CXTC3N'NXOH2-((R)-8-fluoro-2-((R)-4-(3-methoxyphenyl)-3-methyIpiperazin-l-yl)-3-(l- methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)-3,4-dihydroquinazolin-4- yl)acetic acid1H NMR (400 MHz, DMSO-6): δ 12.71 (br s, 1H), 7.13 - 7.01 (m. 2H), 6.99 - 6.94 (m, 2H), 6.78 (s. 1H), 6.43 (d, J= 8.4 Hz, 1H). 6.42 - 6.35 (m, 2H), 5.00 (dd. J = 8.0, 6.4 Hz, 1H), 4.00 - 3.87 (m, 2H), 3.69 (s, 3H), 3.55 (d, J = 12.4 Hz, 2H), 3.38 (s, 3H), 3.27 - 3.23 (m, 1H), 3.15 (d, J = 12.4 Hz, 2H), 2.82 - 2.70 (m, 2H), 0.87 (d.7= 6.4 Hz, 3H) ppm. MS (ESI): calcd. for C27H28F4N6O3: 560.22; Found: 561.71 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)OMeL -N. -N.XTJOF3C-< N:N'NXOH2-((S)-8-fluoro-2-((R)-4-(3-methoxyphenyl)-3-methylpiperazin-l-yl)-3-(l- methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)-3,4-dihydroquinazolin-4-yl) acetic acid1H NMR (400 MHz, DMSO-6): 8 12.72 (br s, 1H), 7.14 - 7.03 (m. 2H), 7.02 - 6.97 (m, 2H), 6.84 (s, 1H), 6.47 - 6.45 (m, 1H), 6.44 - 6.41 (m, 1H), 6.40 - 6.37 (m, 1H), 5.00 (dd, J = 8.8, 6.8 Hz, 1H), 3.98 - 3.91 (m, 2H), 3.62 (s, 3H), 3.61 (d, J= 12.8 Hz, 2H), 3.39 (s, 3H), 3.13 - 3.07 (m, 1H), 3.04 - 3.02 (m, 1H), 3.02 - 2.97 (m, 1H).2.85 - 2.70 (m, 1H), 2.50 - 2.49 (m, 1H), 0.32 (d,. / = 6.4 Hz, 3H) ppm. MS (ESI): calcd. for C27H28F4N6O3: 560.22; Found: 561.79 [M+l]+.ClF3C-f T JN-N k^OOH2-((R)-2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-3-(l-cyclopropyl-5- (trifluoromethyl)-lH-pyrazol-3-yl)-8-fluoro-3,4-dihydroquinazolin-4-yl)acetic acid'H NMR (400 MHz, DMSO-6: 8 12.65 (s, 1H), 7.21 - 7.17 (m, 1H), 7.12 - 7.09 (m, 1H), 7.01 - 6.93 (m. 2H), 6.86 - 6.80 (m, 3H). 6.79 - 6.73 (m, 1H), 5.04 (d. J = 7.6 Hz, 1H), 4.09 - 4.05 (m, 1H), 4.02 - 3.89 (m, 1H), 3.54 - 3.51 (m, 1H), 3.39 - 3.35 (m, 1H), 3.20 - 3.12 (m, 2H), 3.09 - 3.02 (m, 1H), 2.99 - 2.92 (m, 1H), 2.84 - 2.78 (m, 1H), 1.33 - 1.23 (m, 1H), 0.93 (d, J = 6.4 Hz, 3H), 0.86 - 0.82 (m, 2H), 0.44 - 0.35 (m, 2H) ppm. MS (ESI): calcd. for C28H27CIF4N6O2: 590.18; Found: 591.15 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)Cl6^,k. N.XcOF3C-f T =N-N -yO<f OH2-((S)-2-((R)-4-(3-chlorophenyl)-3-methylpiperazin-l-yl)-3-(l-cyclopropyl-5- (trifluoromethyl)-lH-pyrazol-3-yl)-8-fluoro-3,4-dihydroquinazolin-4-yl)acetic acidNMR (400 MHz, DMSO-6: 5 12.65 (s, 1H), 7.21 - 7.12 (m. 2H), 7.10 - 7.00 (m, 1H), 7.97 - 6.95 (m, 1H), 6.89 - 6.87 (m, 2H), 6.84 - 6.82 (m, 1H), 6.75 - 6.72 (m, 1H), 5.02 (dd, 7= 8.4, 6.0 Hz, 1H). 4.09 - 4.05 (m, 1H), 3.93 (d, 7 = 12.8 Hz.1H). 3.63 (d, J= 12.0 Hz, 1H), 3.32 (d. J= 11.6 Hz, 1H). 3.10 - 3.06 (m, 2H), 3.01 - 2.98 (m, 1H), 2.91 - 2.87 (m, 1H), 2.79 - 2.73 (m, 1H), 1.23 - 1.20 (m, 1H), 0.90 - 0.83 (m, 2H), 0.37 - 0.30 (m, 5H) ppm. MS (ESI): calcd. for C28H27CIF4N6O2: 590.18; Found: 591.15 [M+l]+.ClF L A.F3C NII 4 sN^N y^OOH2-((S)-2-((R)-4-(3-chloro-4-fluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3- (6-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydroquinazolin-4-yl)acetic acidJH NMR (400 MHz. DMSO-6: 5 12.80 (s, 1H), 8.94 (s. 1H), 7.75 - 7.62 (m, 1H) 7.27 (d, 7= 9.2 Hz, 1H), 7.11 - 6.87 (m, 5H), 6.29 - 6.21 (m, 1H), 4.65 (d, J= 12.4 Hz, 1H), 4.29 - 4.22 (m, 1H), 3.95 - 3.71 (m. 1H), 3.69 - 3.53 (m, 1H), 3.49 - 3.39 (m, 1H), 3.27 - 3.20 (m, 1H), 3.00 - 2.90 (m, 2H), 2.63 - 2.61 (m, 1H), 1.01 - 0.70 (m, 3H) ppm. MS (ESI): calcd. for C26H22CIF5N6O2: 580.14; Found: 581.0[M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)Cl2-((R)-2-((R)-4-(3-chloro-4-fluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3- (6-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydroquinazolin-4-yl)acetic acid NMR (400 MHz, DMSO-6: 5 12.80 (s, 1H), 9.01 - 8.95 (m. 1H), 7.79 (d, J = 28.8 Hz, 1H) 7.25 (d, J= 9.2 Hz, 1H), 7.11 - 7.01 (m, 3H), 6.98 - 6.81 (m, 2H), 6.24 - 6.12 (m, 1H), 4.68 (d. J = 10.4 Hz, 1H), 4.19 - 4.07 (m, 1H), 3.95 - 3.89 (m, 1H). 3.49 - 3.39 (m, 2H), 3.25 - 3.12 (m. 3H), 2.92 - 2.85 (m, 1H). 1.14 - 0.90 (m, 3H)) ppm; MS (ESI): calcd. for C26H22CIF5N6O2: 580.14; Found: 581.1 [M+l]+.2-((R)-2-((2R,3R)-4-(3-chlorophenyl)-2,3-dimethylpiperazin-l-yl)-8-fluoro-3- (4-(trifluoromethyl) pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic acid ’H NMR (400 MHz, DMSO-6: 58.46 (br s, 1H), 7.95 (br s, 1H), 7.32(br s, 1H), 7.19 (t, 7=8 Hz, 1H), 7.05 (br s, 2H), 6.86 (s, 1H), 6.82 (d, 7 = 8 Hz, 1H), 6.73 (d, 7= 7.2 Hz, 1H), 5.89 (br s, 1H), 5.13 (br s, 1H), 4.01 - 4.07 (m, 2H), 3.23 - 3.30 (m, 3H), 2.90 - 2.92 (m, 3H), 1.38 (d, 7 = 4 Hz, 3H), 1.07 (d, 7 = 4 Hz, 3H) ppm (The acid proton was missed). MS (ESI): calcd. for C28H26CIF4N5O2: 575.17; Found: 576.62 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)2-((S)-2-((2R,3R)-4-(3-chlorophenyl)-2,3-dimethylpiperazin-l-yl)-8-fluoro-3- (4-(trifluoromethyl) pyridin-2-yl)-3,4-dihydroquinazolin-4-yl)acetic add NMR (400 MHz. DMSO-6: 58.49 (d, J= 6.8 Hz 1H). 7.76 (br s. 1H), 7.37 (br s, 1H), 7.19 (t, J= 8 Hz, 1H), 6.90 - 7.05 (m 2H), 6.86 (s, 1H), 6.82 (d, J= 8 Hz, 1H), 6.73 (d, J = 7.2 Hz, 1H). 5.82 (br s, 1H), 4.63 (br s, 1H), 3.99 - 4.04 (m, 2H), 3.23 - 3.30 (m, 3H), 2.90 - 2.92 (m, 3H), 1.39 (d, 7 = 4 Hz, 3H), 1.38 (d, J = 4 Hz, 3H), 1.14(d, 7= 4 Hz,3H) ppm (The acid proton was missed). MS (ESI): calcd. for C28H26CIF4N5O2: 575.17: Found: 576.62 [M+l]+.OMeClL xkF3y TC^x^xNTI T N OM Ce^OOH2-((S)-8-chloro-3-(2-methoxy-5-(trifluoromethyI) pyridin-3-yl)-2-((R)-4-(3- methoxyphenyl)-3-methylpiperazin- 1 -yl)-3,4-dihydroquinazolin-4-yl) acetic acid’H NMR (400 MHz, DMSO-6): 58.48 (br s, 1H), 7.48 (br s, 1H), 7.10 - 7.15 (m, 3H). 6.48 (br s, 2H), 6.30 (br s, 2H), 5.05 (br s, 1H), 3.80 - 3.95 (m, 4H), 3.74 (s.3H), 3.23 - 3.30 (m, 3H), 2,90 - 2.92 (m, 3H), 2.60 - 2.66 (m, 2H), 0.98 (br s, 3H) ppm (The acid proton was missed). MS (ESI): calcd. for C29H29CIF3N5O4: 603.19; Found: 604.1 [M+l]+.OMeTji iClL _ N _ N^x-kF3C^x^xNTTX T CoN OMe yOH2-((R)-8-chloro-3-(2-methoxy-5-(trifluoromethyl) pyridin-3-yl)-2-((R)-4-(3- methoxyphenyl)-3-methyIpiperazin-l-yl)-3,4-dihydroquinazoIin-4-yl) acetic acidAttorney Docket No. 71180-431439 (ASP-080-WO)XH NMR (400 MHz, DMSO-6: 88.75 (br s, 1H), 7.65 (br s, 1H), 7.09 - 7.15 (m, 3H), 6.49 (br s, 2H), 6.31 (br s, 2H), 3.94 (br s, 1H), 3.76 (br s. 1H), 3.77 (s, 3H), 3.74 (s, 3H), 3.23 - 3.30 (m. 3H), 2.90 - 2.92 (m, 3H), 2.60 - 2.66 (m, 2H), 0.91 (br s, 3H) ppm (Th acid proton was missed). MS (ESI): calcd. for C29H29CIF3N5O4: 603.19; Found: 604.62 [M+l]+.FXcuF3c-f T TN'N / 1OH2-((R)-2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(l- methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl)-3,4-dihydroquinazolin-4-yl) acetic acidNMR (400 MHz, DMSO-6): δ 12.63 (br s, 1H), 7.23 (q, J= 8 Hz, 1H), 7.03 - 7.10 (m, 2H), 6.88 - 6.90 (m, 2H), 6.67 (br s, 1H), 6.65 (br s, 1H), 5.35 (br s, 1H), 3.99 (br s, 1H), 3.82 (s, 3H), 3.51 - 3.55 (m, 3H), 3.11 - 3.15 (m, 3H), 2.97 - 2.98 (m, 1H), 2.50 - 2.52 (m. 1H), 0.98 (br s, 3H) ppm. MS (ESI): calcd. for C26H24F6N6O2: 566.19; Found: 567.1 [M+l]+.FT 1 iFk. N.F3C- Xf TTJ- ■N'N O / 1OH2-((S)-2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-8-fluoro-3-(l- methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl)-3,4-dihydroquinazolin-4-yl) acetic acid'H NMR (400 MHz, DMSO-6): δ 12.63 (br s, 1H), 7.30 (q, J = 8 Hz, 1H), 7.13 - 7.15 (m, 2 H), 6.90 - 6.95 (m, 2H), 6.80 (br s, 1H), 6.65 (br s, 1H). 5.34 (br s, 1H), 3.96 (br s,lH), 3.82 (s,3 H), 3.50 - 3.55 (m, 3 H), 3.10 - 3.11 (m, 3H), 2.92 - 2.95Attorney Docket No. 71180-431439 (ASP-080-WO)(m, 1H), 2.60 - 2.62 (m. 1H), 0.75 (br s, 3H) ppm. MS (ESI): calcd. for C26H24F6N6O2: 566.19; Found: 567.18 [M+l]+.OMeL. N.. XF3Cy^N^AFN^N L^OOH2-((R)-6,8-difluoro-2-((R)-4-(3-methoxyphenyl)-3-methylpiperazin-l-yl)-3-(6- (trifluoromethyl) pyrimidin-4-yl)-3,4-dihydroquinazolin-4-yl)acetic acid 'H NMR (400 MHz, DMSO-6): 8 10.76 (br s, 1H), 9.20 (d, J = 4 Hz, 1H), 8.32 (d, 7= 8 Hz, 1H), 7.30 (t, 7= 4 Hz, 1H), 7.20 (t, 7 = 4 Hz, 1H), 7.07 - 7.11 (m, 1H), 6.34 - 6.43 (m, 3H), 4.20 (br s, 1H), 4.01 (br s, 1H), 3.70 (s, 3H), 3.50 - 3.52 (m, 2H), 3.10 - 3.15 (m, 1H), 2.90 - 3.05 (m, 4H), 2.60 - 2.62 (m. 1H), 0.81 (d, 7 = 4 Hz, 3H) ppm. MS (ESI): calcd. for C27H25F5N6O3: 576.19; Found: 577.18 [M+l]+.OMeL. KL. N.Y YYN^N \^OOH2-((S)-6,8-difluoro-2-((R)-4-(3-methoxyphenyl)-3-methylpiperazin-l-yl)-3-(6- (trifluoromethyl) pyrimidin-4-yI)-3,4-dihydroquinazolin-4-yl)acetic acidJH NMR (400 MHz, DMSO-6: 8 10.78 (br s, 1H). 9.21 (d, 7 = 4 Hz, 1H), 8.33 (d, 7 = 8 Hz 1 H), 7.32 (t, 7 = 4 Hz 1 H), 7.20 (t, 7 = 4Hz 1 H), 7.08 - 7.11 (m, 1 H), 6.35 - 6.43 (m, 3H), 4.22 (br s, 1H), 4.10 (br s, 1H), 3.72 (s, 3H), 3.52 - 3.55 (m, 2H). 3.11 - 3.15 (m, 1H), 2.92 - 3.05 (m. 4H), 2.61 - 2.65 (m. 1H). 0.88 (d, 7 = 4 Hz, 3H) ppm. MS (ESI): calcd. for C27H25F5N6O3: 576.19; Found: 577.14 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)OMek _N. A.Y YYF2HC. / ^. NOH2-((S)-3-(4-(difluoromethyl) pyridin-2-yl)-8-fluoro-2-((R)-4-(3- methoxyphenyl)-3-methylpiperazin-l-yl)-3,4-dihydroquinazolin-4-yl) acetic acidJH NMR (400 MHz, DMSO-6: 5 12.50 (br s, 1H). 8.49 (d, J = 4 Hz. 1H), 7.50 (br s, 1H), 7.29 (br s, 2H), 7.10 - 7.20 (br s, 3H), 7.02 - 7.06 (m, 2H), 6.49 (br s, 2H), 5.92 (br s, 1H), 3,77 (s, 3H), 3.20 -3.30 (br s, 7H), 2.80 (br s, 2H), 0.88 (d, J = 8 Hz, 3H) ppm. MS (ESI): calcd. for C28H28F3N5O3: 539.21; Found: 540.16 [M+l]+.OMe& Y FF2HC^ / ^. N SYXYY> OOH2-((R)-3-(4-(difluoromethyl) pyridin-2-yl)-8-fluoro-2-((R)-4-(3- methoxyphenyl)-3-methyIpiperazin-l-yl)-3,4-dihydroquinazoIin-4-yl) acetic acidJH NMR (400 MHz. DMSO-6: 5 12.50 (br s, 1H). 8.57 (d, J = 4 Hz. 1H). 7.77 (br s, 1H), 7.46 (br s, 1H), 7.20 - 7.30 (br s, 3H), 7.02 - 7.06 (m, 2H), 6.46 (br s, 1H). 6.39 (br s, 2H), 5.92 (br s, 1H), 3,78 (s, 3H), 3.20 - 3.35 (br s, 7H), 2.82 (br s, 2H), 0.92 (d, J = 8 Hz, 3H) ppm. MS (ESI): calcd. for C28H28F3N5O3: 539.21; Found: 540.19 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)OMetty,,FaC^f T ■FN-N / 1OH2-((S)-6,8-difluoro-2-((R)-4-(3-methoxyphenyl)-3-methylpiperazin-l-yl)-3-(l- methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl)-3,4-dihydroquinazolin-4-yl) acetic acid’H NMR (400 MHz, DMSO-6): 5 12.58 (br s, 1H), 7.01 - 7.10 (m, 2H), 6.82 - 6.84 (m, 1H). 6.64 (br s, 1H), 6.47 - 6.49 (br s. 1H). 6.34 - 6.40 (m, 2H), 5.30 (t, J = 8 Hz, 1H), 4.01 (br s,lH), 3.79 (s, 3H), 3.70 (s, 3H), 3.20 - 3.23 (m, 3H), 2,90 - 3.01 (m, 3H), 2.50 - 2.52 (m. 2H), 0.76 (d, J = 4 Hz, 3H) ppm (The acid proton was missed). MS (ESI): calcd. for C27H27F5N6O3: 578.21; Found: 579.1 fM+l]+.OMeL _N _ N. A.FaC^fT JN'N k ^OF / TOH2-((R)-6,8-difluoro-2-((R)-4-(3-methoxyphenyl)-3-methylpiperazin-l-yl)-3-(l- methyI-5-(trifluoromethyl)-lH-pyrazol-3-yl)-3,4-dihydroquinazolin-4-yl) acetic acidJH NMR (400 MHz. DMSO-6: 5 12.53 (br s, 1H). 7.04 - 7.10 (m, 2H), 6.82 - 6.84 (m, 1H), 6.62 (br s, 1H), 6.44 - 6.46 (br s, 1H), 6.31 - 6.40 (m, 2H), 5.33 (t, J = 8 Hz, 1H), 3.96 (br s,lH), 3.79 (s, 3H). 3.68 (s, 3H), 3.45 (br s, 1H). 3.25 - 3.35 (m, 2H), 3.10 - 3.15 (m, 2H), 2.90 (br s, 1H), 2.50 - 2.55 (m, 2H), 0.95 (d, J= 4 Hz, 3H) ppm. MS (ESI): calcd. for C27H27F5N6O3: 578.21; Found: 579.60 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)FF^ kTJ1F Y YY N OMe^OH2-((S)-2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-6,8-difluoro-3-(2- methoxy-5-(trifluoromethyl) pyridin-3-yl)-3,4-dihydroquinazolin-4-yl) acetic acid'H NMR (400 MHz, DMSO-6): 8 12.80 (br s, 1H), 8.42 br s, 1H), 8.15 (t, J = 6 Hz, 1H), 7.13 - 7.24 (m, 2H), 6.48 - 6.98 (m. 2H), 6.61 - 6.68 (m, 1H), 5.03 (br s, 1H), 3.89 (br s,lH), 3.85 (s, 3H), 3.30 (br s, 2H), 3.10 (br s, 2H), 2.90 - 3.05 (m, 2H), 2.60 - 2.65 (m, 2H), 0.85 (br s, 3H) ppm. MS (ESI): calcd. for C28H24F7N5O3: 611.18; Found: 612.12 [M+l]+.FFxYY 1?FsC^^ NU toN OMe ^OH2-((R)-2-((R)-4-(3,4-difluorophenyl)-3-methylpiperazin-l-yl)-6,8-difluoro-3- (2-methoxy-5-(trifluoromethyl) pyridin-3-yl)-3,4-dihydroquinazolin-4-yl) acetic acid’H NMR (400 MHz, DMSO-d6): 8 12.70 (br s, 1H), 8.43 br s, 1H), 8.20 (t, J= 6 Hz, 1H), 7.16 - 7.24 (m, 1H), 7.05 - 7.16 (m, 1H). 6.70 - 6.88 (m, 2H), 6.58 (d, J = 9.2 Hz, 1H), 4.97 (t, 7= 6.8 Hz, 1H), 3.89 (br s,lH), 3.81 (s, 3 H), 3.31 (br s, 2H), 3.15 (br s, 2H), 2.99 - 3.10 (m, 2H), 2.60 - 2.65 (m, 2H), 0.82 (d, J = 6.4 Hz, 3H) ppm. MS (ESI): calcd. for C28H24F7N5O3: 611.18; Found: 612.12 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)OMe6 A,L _NXJxT nI lN OM Me ^OH2-((S)-8-fluoro-3-(2-methoxy-5-(trifluoromethyl) pyridin-3-yl)-2-((R)-4-(3- methoxyphenyl)-3-methylpiperazin- 1 -yl)-3,4-dihydroquinazolin-4-yl) acetic acid’H NMR (400 MHz, DMSO-6): 5 12.80 (br s, 1H), 8.43 (br s, 1H), 7.05 - 7.15 (m, 2H), 6.90 - 6.99 (m, 2H), 6.44 (d, J= 8 Hz, 2H), 6.36 (br s, 1H), 6.33 (br s, 1H), 5.05 (br s, 1H), 3.86 (br s, 4H), 3.68 (s, 3 H), 3.31 (br s, 2H), 3.20 (br s, 2H), 2.99 - 3.10 (m, 2H), 2.60 - 2.70 (m, 2H), 0.98 (br s, 3H) ppm. MS (ESI): calcd. for C29H29F4N5O4: 587.22; Found: 588.16 [M+l]+.OMeFF3. C^^,nH L N OMe 'pOH2-((R)-8-fluoro-3-(2-methoxy-5-(trifluoromethyl) pyridin-3-yl)-2-((R)-4-(3- methoxyphenyl)-3-methylpiperazin- 1 -yl)-3,4-dihydroquinazolin-4-yl) acetic acid¹H NMR (400 MHz, DMSO-d₆): 5 12.50 (br s, 1H), 8.44 (br s, 1H), 7.05 - 7.13 (m, 2H), 6.91 - 6.99 (m, 2H), 6.45 (d, J = 8 Hz, 2H), 6.36 (br s, 1H), 6.33 (br s, 1H).4.99 (br s, 1H). 3.86 (br s. 4H), 3.68 (s, 3H). 3.31 (br s. 2H). 3.20 (br s, 2H), 2.99 - 3.10 (m, 2H), 2.50 - 2.60 (m, 2H), 0.84 (br s, 3H) ppm. MS (ESI): calcd. for C29H29F4N5O4: 587.22; Found: 588.16 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)OMeYFN'l\OH2-((R)-6,8-difluoro-2-((R)-4-(3-methoxyphenyl)-3-methylpiperazin- 1 -y 1 )- 3-( 1 - methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)-3,4-dihydroquinazolin-4-yl) acetic acid1H NMR (400 MHz, DMSO-d6): δ 12.17 (br s, 1H), 7.18 - 7.19 (m, 1H), 7.07 - 7.14 (m, 1H). 6.84 - 6.92 (m, 1H), 6.78 (br s, 1H). 6.42 (d, J = 8 Hz. 1H). 6.33 - 6.35 (m, 2H), 5.02 (q,. / = 4 Hz, 1H), 3.96 (br s, 1H), 3.69 (br s, 3H), 3.56 - 3.60 (s, 1H), 3.38 (br s, 3H), 3.10 - 3.30 (m, 3H), 2.80 - 2.90 (m, 2H). 2.55 (br s, 2H), 0.86 (d, J = 4 Hz, 3H) ppm. MS (ESI): calcd. for C27H27F5N6O3: 578.21; Found: 579.1 [M+l]+.OMeF3C-Z^r iFN'NXOH2-((S)-6,8-difluoro-2-((R)-4-(3-methoxyphenyl)-3-methylpiperazin-l-yl)-3-(l- methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)-3,4-dihydroquinazolin-4-yl) acetic acidJH NMR (400 MHz, DMSO-6): 8 12.75 (br s, 1H), 7.17 - 7.20 (m, 1H), 7.14 - 7.15 (m, 1H), 6.91 - 6.93 (m, 1H), 6.90 (br s, 1H), 6.44 (d,.7= 8 Hz, 1H), 6.3 (br s, 1H), 6.32 (d, J= 8 Hz 1H), 5.03 (q, J = 4 Hz, 1H), 3.97 (br s, 1H), 3.70 (br s, 3H), 3.60 - 3.62 (s, 1H). 3.31 (br s. 3H), 3.10 - 3.12 (m, 1H). 2.90 - 2.98 (m, 1H), 2.80 - 2.85 (m, 1H), 2.60 - 2.65 (m, 2H), 2.55 (br s, 2 H), 0.32 (d, J = 4 Hz, 3H) ppm. MS (ESI): calcd. for C27H27F5N6O3: 578.21; Found: 579.1 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)OMeiu,.U LoN CMeVOH2-((R)-6,8-difluoro-3-(2-methoxy-5-(trifluoromethyl) pyridin-3-yl)-2-((R)-4- (3-methoxyphenyl)-3-methylpiperazin-l-yl)-3,4-dihydroquinazolin-4-yl) acetic acidJH NMR (400 MHz, DMSO-6: 58.44 (br s, 1H), 8.04 (br s, 1H), 7.06 - 7.10 (m, 2H), 6.84 (d, J = 8 Hz, 1H), 6.42 (d, J = 8 Hz, 1H), 6.36 (d, 7=8 Hz, 2H), 5.05 (br s, 1H), 3.88 (br s, 3H). 3.79 (br s, 1H), 3.71 (br s, 3H), 3.47 - 3.50 (m, 2H), 2.81 - 3.89 (m, 4H), 2.50 - 2.60 (m, 2H), 0.99 (d, 7 = 4 Hz, 3H) ppm (The acid proton was missed). MS (ESI): calcd. for C29H28F5N5O4: 605.21; Found: 606.1 [M+l]+.OMe& A FT X CoN OMe yOH2-((S)-6,8-difluoro-3-(2-methoxy-5-(trifluoromethyl) pyridin-3-yl)-2-((R)-4-(3- methoxyphenyl)-3-methylpiperazin- 1 -yl)-3,4-dihydroquinazolin-4-yl) acetic acid'H NMR (400 MHz, DMSO-6): 58.41 (br s, 1H), 7.06 - 7.10 (m, 2H), 6.84 (d, 7 = 8 Hz, 1H), 6.45 (d. 7 = 8 Hz, 1H), 6.33 (d. 7 = 8 Hz, 2H). 5.05 (br s. 1H), 3.88 (br s, 3H), 3.79 (br s, 1H), 3.71 (br s, 3H), 3.47 - 3.50 (m, 2H), 2.81 - 3.89 (m, 4H), 2.50 - 2.60 (m, 2H), 0.99 (d, 7 = 4 Hz, 3H) ppm (The acid proton was missed). MS (ESI): calcd. for C29H28F5N5O4: 605.21; Found: 606.1 [M+1J+.Attorney Docket No. 71180-431439 (ASP-080-WO)ClF^Ux,F3C^TNY^^N-N / IOH2-((S)-2-((R)-4-(3-chloro-4-fluorophenyl)-3-methylpiperazin-l-yl)-6,8- difluoro-3-(l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl)-3,4- dihydroquinazolin-4-yl) acetic acid1H NMR (400 MHz, DMSO-d6): δ 12.74 - 12.60 (br s, 1H), 7.26 - 7.21 (t, J = 9.1 Hz, 1H), 7.09 -7.01 (m, 2H), 6.93 - 6.86 (m, 2H), 6.66 (s, 1H), 5.30 - 5.26 (br t, J = 7.4 Hz, 1H), 4.16 - 4.10 (m, 2H), 3.98 - 3.73 (m, 5H), 3.25 - 3.22 (m, 3H), 3.05 - 3.00 (m, 1H). 2.93 - 2.89 (m, 1H). 0.76 - 0.72 (br d, J= 2.6 Hz, 3H) ppm. MS (ESI): calcd. for C26H23ClF6N6O2: 600.15; Found: 601.1 [M+l]+.ClFxx^k,T X ‘N-N / 1OH2-((R)-2-((R)-4-(3-chloro-4-fluorophenyl)-3-methylpiperazin-l-yl)-6,8- difluoro-3-(l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl)-3,4- dihydroquinazolin-4-yl) acetic acid1H NMR (400 MHz, DMSO-d6): δ 12.69 - 12.58 (br s. 1H), 7.25 - 7.21 (t, J = 9.1 Hz, 1H), 7.09 - 7.07 (m, 1H), 7.04 - 7.00 (dd, J = 2.9, 6.3 Hz, 1H), 6.91 - 6.84 (m, 2H), 6.66 (s, 1H), 5.36 - 5.32 (dd, J= 6.3, 8.3 Hz, 1H), 4.07 - 3.95 (m, 2H), 3.81 (s, 3H). 3.59 - 3.55 (br dd, J = 3.4, 8.4 Hz, 1H), 3.20 - 3.10 (m, 2H), 2.97 - 2.94 (m, 1H), 2.57 - 2.50 (m, 2H), 2.44 - 2.42 (m, 1H), 0.96 - 0.95 (d, J = 6.5 Hz, 3H) ppm. MS (ESI): calcd. for C26H23ClF6N6O2: 600.15; Found: 601.1 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)ClFx^kT 1 iFk _N. X.X NX OM CeAoOH2-((S)-2-((R)-4-(3-chloro-4-fluorophenyl)-3-methylpiperazin-l-yl)-6,8- difluoro-3-(2-methoxy-5-(trifluoromethyl) pyridin-3-yl)-3,4- dihydroquinazolin-4-yl) acetic acid1H NMR (400 MHz, DMSO-d6): δ 12.73 - 12.64 (br s, 1H), 8.41 (s, 1H), 8.16 - 8.10 (br m, 1H), 7.22 - 7.13 (m, 2H), 6.99 - 6.97 (br d, J = 3.4 Hz, 1H), 6.85 - 6.81 (m, 2H). 5.04 - 5.00 (m, 1H), 3.89 - 3.74 (m, 5H), 3.53 - 3.42 (br d, J = 4.3 Hz, 1H), 3.16 - 3.13 (m, 1H), 2.96 - 2.91 (m, 1H), 2.82 - 2.77 (m, 2H), 2.60 - 2.56 (m, 2H), 2.24 (br s, 3H) ppm. MS (ESI): calcd. for C28H24CIF6N5O3: 627.15; Found: 628.1 [M+l]+.ciXA FL _F3C^^NCLC-FI L / ON OMe^OH2-((R)-2-((R)-4-(3-chloro-4-fluorophenyl)-3-methylpiperazin-l-yl)-6,8- difluoro-3-(2-methoxy-5-(trifluoromethyl) pyridin-3-yl)-3,4- dihydroquinazolin-4-yl)acetic acid1H NMR (400 MHz, DMSO-d6): δ 12.67 - 12.61 (m, 1H), 8.46 (br s, 1H), 8.09 - 8.02 (m, 1H), 7.22 - 7.18 (t, J= 9.1 Hz, 1H). 7.13 - 7.11 (m, 1H), 6.98 - 6.94 (dd, J = 2.9, 6.2 Hz, 1H), 6.82 - 6.79 (m, 2H), 5.03 - 4.99 (br d, J = 2.3 Hz, 1H), 3.88 - 3.83 (m, 5H), 3.53 - 3.48 (m, 1H), 3.18 - 3.16 (br d, J= 8.3 Hz, 1H), 3.08 - 3.02 (m, 2H). 2.87 - 2.82 (m, 1H), 2.59 - 2.55 (br d, J = 8.5 Hz, 2H), 0.82 - 0.80 (br d. J = 6.0 Hz, 3H) ppm. MS (ESI): calcd. for C28H24CIF6N5O3: 627.15; Found: 628.1 [M+l]+.Attorney Docket No. 71180-431439 (ASP-080-WO)VII. Biological DataCell culture

[0150] MRC-5 fibroblast cells were cultured in Eagle’s Minimum Essential Medium (MEM) supplemented with 1.5 g / L sodium bicarbonate, non-essential amino acids, 292 mg / L L-glutamine, 110 mg / L sodium pyruvate, 10% fetal bovine serum and 100 units / mL penicillin and streptomycin. The cells are incubated at 37°C and 5% CO2 and passaged 2-3 times per week to maintain sub-confluent densities.AssayAD- 169 HCMV antiviral assay

[0151] MRC-5 cells were seeded into transparent 96-well plates at a density of 5.0 x 103cells per well and allowed to attach overnight. Following attachment, the media was replaced with 50 uL of infection medium (MEM supplemented with 2% fetal bovine serum and 100 units / mL penicillin and streptomycin). A Tecan D300e digital dispenser was then used to add compounds to the culture using an 8-point 4-fold serial dilution format. The DMSO concentration was normalized to 0.5% for all treatments. Following compound addition, 50 uL of infection medium containing a 1:200 dilution of a HCMV stock (1.6 x 107TCID50 / mL) was added to the cells for a final dilution of 1:400 and incubated at 37°C for 7 days. After the incubation, 10 uL of WST-1 was added to each well and incubated for 4 hours at 37°C. The absorbance was then measured at a wavelength of 450 nm using a Tecan Infinite M1000 Pro plate reader and the cytopathic effect (CPE) was then quantified relative to the full inhibition achieved with 0.5 uM of Letermovir.Table 2 provides assay data for exemplified compounds of the invention grouped in the following ranges: A indicates EC50 < 50 nM; B indicates 50 < EC50 < 500 nM; and C indicates 500 < EC50 < 1 pM.Table 2. Assay data for exemplified compounds of the invention.Example CMV EC501 A2 BAttorney Docket No. 71180-431439 (ASP-080-WO)A B C A A B C B C A B C A B A B A C A C B A A B A B A B CAAttorney Docket No. 71180-431439 (ASP-080-WO)A C A C A B A C A B A C B A C A C A C A C A B C C A C A BAAttorney Docket No. 71180-431439 (ASP-080-WO)B A B A B C B A B A B B A C A C A C C B A A B B A B A A CCAttorney Docket No. 71180-431439 (ASP-080-WO)93 B94 A95 B96 C97 A98 C99 C100 A101 B102 A103 A104 A105 A106 A107 A108 C109 A110 A111 A112 A113 B114 A115 AEQUIVALENTS

[0152] While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.Attorney Docket No. 71180-431439 (ASP-080-WO)

[0153] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

Claims

Attorney Docket No. 71180-431439 (ASP-080-WO)CLAIMS:

1. A compound of Formula I:OFormula Iof a pharmaceutically acceptable salt thereof, wherein:N;R2is independently selected for each occurrence from the group consisting of halo, CN, Ci-4alkyl, haloCi-4alkyl and Ci-4alkoxy;R3is independently selected for each occurrence from the group consisting of Ci-4alkyl and haloCi-4alkyl;R4is independently selected for each occurrence from the group consisting of CN and halo;R5is independently selected for each occurrence from the group consisting of CN, halo, RaRbN, Ci-4alkyl, haloCi-4alkyl and C lkoxy;R5ais hydrogen, Ci-4alkyl, haloCi-4alkyl or Csemonocycloalkyl;Attorney Docket No. 71180-431439 (ASP-080-WO)Raand Rbare independently selected from the group consisting of hydrogen and Ci-4alkyl;x is 0, 1, 2 or 3;y is 0, 1, 2 or 3;z is 0. 1, 2 or 3;u is 0, 1 or 2; andv is 0, 1, 2 or 3.

2. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

3. The pharmaceutical composition of claim 2, further comprising one or more additional therapeutic agents, wherein said additional therapeutic agents are selected from the group consisting or anti-herpes agents and immunomodulators.

4. A method for the treatment or prophylaxis of a cytomegalovirus infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

5. A method for the treatment or prophylaxis of a cytomegalovirus infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a pharmaceutical composition of claim 2.

6. The compound of claim 1 for use as a medicament.

7. The compound of claim 1 for the use in therapy.

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