Pyridopyrimidinone derivatives as AHR antagonists

Abstract

The present disclosure relates to compounds of formula (Ia) and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the same, methods of preparing the same, intermediate compounds useful for preparing the same, and methods for treating or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signaling. These compounds may also be useful in treating cancer when administered in combination with at least one additional therapy.

Description

[0001] This application claims priority to U.S. Patent Application No. 62 / 939,377 filed November 22, 2019, U.S. Patent Application No. 63 / 050,416 filed July 10, 2020, and U.S. Patent Application No. 63 / 091,192 filed October 13, 2020, which are hereby incorporated by reference in their entirety.

[0002] Disclosed herein are novel 3,6,8-trisubstituted pyrido[3,4-d]pyrimidin-4(3H)-one compounds of formula (la) and pharmaceutically acceptable salts thereof, methods of preparing said compounds and salts, intermediate compounds useful for preparing said compounds and salts, pharmaceutical compositions comprising said compounds and salts, and methods of using said compounds and salts for the treatment or prophylaxis of diseases, in particular of cancer or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signaling. Also disclosed herein are compositions comprising at least one such compound and / or pharmaceutically acceptable salt thereof and at least one additional therapy and methods of treating cancer comprising administering at least one such compound and / or pharmaceutically acceptable salt thereof and at least one additional therapy. (la)

[0003] The Aryl Hydrocarbon Receptor (AHR) is a ligand-activated transcription factor, belonging to the basic helix-loop-helix / Per-Amt-Sim (bHLH / PAS) family that is located in the cytosol. Upon ligand binding, the AHR translocates to the nucleus where it heterodimerises with ARNT (AHR Nuclear Translocator) upon which it interacts with DREs (Dioxin Response Elements) of AHR-responsive genes to regulate their transcription. The AHR is best known for binding to environmental toxins and inducing the metabolic machinery, such as cytochrome P 450 enzymes (eg. CYP1A1, CYP1A2 and CYP1B1), required fortheir elimination (Reyes et al., Science, 1992, 256(5060):1 193-5). Activation of AHR by xenobiotics has demonstrated its role in numerous cellular processes such as embryogenesis, tumorigenesis and inflammation.

[0004] AHR is expressed in many cells of the immune system, including dendritic cells (DCs), macrophages, T cells and NK cells, and plays an important role in immunoregulation (Nguyen et al., Front. Immunol., 2014, 5:551). The classic exogenous AHR ligands TCDD and 3-methylcholanthrene, for example, are known to induce profound immunosuppression, promote carcinogenesis and induce tumour growth (Gramatzki et al., Oncogene, 2009, 28(28):2593- 605; Bui et al., Oncogene, 2009, 28(41):3642-51; Esser et al., Trends Immunol., 2009, 30:447- 454). In the context of immunosuppression, AHR activation promotes regulatory T cell generation, inhibits Thl and Th 17 differentiation, directly and indirectly, and decreases the activation and maturation of DCs (Wang et al., Clin. Exp. Immunol., 2014, 177(2):521-30; Mezrich et al., J. Immunol., 2010, 185(6):3190-8; Wei et al., Lab. Invest., 2014, 94(5):528-35; Nguyen et al., PNAS, 2010, 107(46):19961-6). AHR activation modulates the innate immune response and constitutive AHR expression has been shown to negatively regulate the type-1 interferon response to viral infection (Yamada et al., Nat. Immunol., 2016, 17(6):687-94). Additionally, mice with a constitutively active AHR spontaneously develop tumours (Andersson et al., PNAS, 2002, 99(15):9990-5).

[0005] In addition to xenobiotics, the AHR can also bind metabolic products of tryptophan degradation. Tryptophan metabolites, such as kynurenine and kynurenic acid, are endogenous AHR ligands that activate the AHR under physiological conditions (DiNatale et al., Toxicol. Sci., 2010, 115(l):89-97; Mezrich et al., J. Immunol., 2010, 185(6):3190-8; Opitz et al., Nature, 2011, 478(7368):197-203). Other endogenous ligands are known to bind the AHR, although their physiological roles are currently unknown (Nguyen & Bradfield, Chern. Res. Toxicol., 2008, 21(1):102-116).

[0006] The immunosuppressive properties of kynurenine and tryptophan degradation are well described and are implicated in cancer-associated immunosuppression. The enzymes indoleamine-2,3-dioxygenases 1 and 2 (IDO1 / IDO2) as well as tryptophan-2,3-dioxygenase 2 (TDO2) are responsible for catalysing the first and rate-limiting step of tryptophan metabolism. IDOl / 2-mediated degradation of tryptophan in tumours and tumour-draining lymph nodes reduces anti-tumour immune responses and inhibition of IDO can suppress tumour formation in animal models (Uyttenhove et al., Nat. Med, 2003, 9(10):1269-74 ; Liu et al., Blood, 2005, 115(17): 3520-30; Muller et al., Nat. Med, 11(3):312-9; Metz, Cancer Res., 2007, 67(15):7082-7).

[0007] TDO2 is also strongly expressed in cancer and can lead to the production of Immunosuppressive kynurenine. In glioma, activation of the AHR by kynurenine, downstream of TDO-mediated tryptophan degradation, enhances tumour growth as a consequence of inhibiting anti-tumour immune responses as well as directly promoting tumour cell survival and motility (Opitz et al., Nature, 2011, 478(7368):197-203). AHR ligands generated by tumour cells therefore act in both an autocrine and paracrine fashion on tumour cells and lymphocytes, respectively, to promote tumour growth.

[0008] Additional therapies may be useful in the treatment of cancer in combination with AhR. Immune checkpoint inhibitors (ICIs) have been used in cancer treatment to enhance the immune response of the host. Non-limiting examples of ICI targets include programmed death 1 (PD-1), ligand for PD-1 (PD-L1) and Cytotoxic T lymphocyte antigen 4 (CTLA-4).

[0009] PD-1 is highly expressed by activated T cells, B cells, dendritic cells (DC), and natural killer cells (NK), whereas PD-L1 can be expressed on several types of tumor cells.

[0010] ICIs are currently approved by the Food and Drug Administration to treat melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck squamous cell carcinoma, Hodgkin's lymphoma, urothelial carcinoma, small cell lung cancer, esophageal squamous cell carcinoma, cervical cancer, primary mediastinal large B-cell lymphoma, MSI-H / dMMR colorectal cancer, hepatocellular carcinoma, Merkel cell carcinoma, triplenegative breast cancer, and cutaneous squamous cell carcinoma.

[0011] The present disclosure is drawn to novel 3,6,8-trisubstituted pyrido[3,4-d]pyrimidin-4(3H)-one of formula (I) or formula (la) and / or pharmaceutically acceptable salts thereof. Compounds of the present disclosure have surprisingly been found to effectively inhibit AHR and may therefore be used for treatment or prophylaxis of cancer and / or other conditions where exogenous and endogenous AHR ligands induce dysregulated immune responses, uncontrolled cell growth, proliferation and / or survival of tumor cells, immunosuppression in the context of cancer, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses or diseases that are accompanied by uncontrolled cell growth, proliferation and / or survival of tumor cells, immunosuppression in the context of cancer inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell 2020386967   30 Jul 2026 growth, proliferation and / or survival of tumor cells, immunosuppression in the context of cancer, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by AHR, such as, for example, liquid and solid tumors, and / or metastases thereof, e.g. head and neck tumors including brain tumors and brain metastases, tumors of the thorax including non-small cell and small cell lung tumors, gastrointestinal tumors including colon, colorectal and pancreatic tumors, liver tumors, endocrine tumors, mammary and other gynecological tumors, urological tumors including renal, bladder and prostate tumors, skin tumors, and sarcomas, and / or metastases thereof.

[0012] The present disclosure also relates to pharmaceutical compositions comprising at least one entity chosen from compounds of formula (I) or formula (Ia) and pharmaceutically acceptable salts thereof. The present disclosure also relates to methods of treatment comprising administering at least one compound, pharmaceutically acceptable salt thereof, and / or pharmaceutical composition of the present disclosure. In some embodiments, the disclosure provides a method of treating a disease or condition mediated by AHR signaling. In some embodiments, the disclosure provides a method of treating a disease or condition associated with aberrant AHR signaling. In some embodiments, the disclosure provides a method of inhibiting cancer cell proliferation mediated by AHR signaling. [0012A]      In some embodiments, the disclosure provides use of a compound or pharmaceutically acceptable salt thereof according to the disclosure in the manufacture of a medicament for the treatment of a disease or condition mediated by AhR signaling. In some embodiments the disclosure provides use of a compound or pharmaceutically acceptable salt thereof according to the disclosure in the manufacture of a medicament for the treatment of cancer mediated by AhR signaling, wherein the treatment comprises administration of a therapeutically effective amount of i) a compound or pharmaceutically acceptable salt thereof of the disclosure, and ii) a therapeutically effective amount of at least one additional therapy wherein the at least one additional therapy is chosen from checkpoint inhibitors. • BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG. 1 shows the dosing regimen for the in vivo syngeneic model study using CT26 Balb / C mice. FIG. 2 shows the tumor growth curves of the vehicle versus single agent PD-L1 antibody or PD-L1 antibody with Compound No. 7 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy. 2020386967   26 May 2026

[0015] FIG. 3 shows tumor weight upon termination of study of the vehicle versus single agent PD-L1 antibody or PD-L1 antibody with Compound No. 7 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy.

[0016] FIG. 4 shows the tumor growth curves of the vehicle versus single agent PD-L1 antibody or PD-L1 antibody with Compound No. 30 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy.

[0017] FIG. 5 shows tumor weight upon termination of study of the vehicle versus single agent PD-L1 antibody or PD-L1 antibody with Compound No. 30 in a syngeneic colon cancer mouse model resistant to anti-PD-Ll therapy.

[0018] FIG. 6 shows the tumor growth curves of the vehicle versus single agent PD-L1 antibody or PD-L1 antibody with Compound No. 30 in a syngeneic colon cancer mouse model resistant to anti-PD-Ll therapy.

[0019] FIG. 7 shows tumor weight upon termination of study of the vehicle versus single agent PD-L1 antibody or PD-L1 antibody with Compound No. 30 in a syngeneic colon cancer mouse model resistant to anti-PD-Ll therapy.

[0020] FIG. 8 shows the tumor growth curves of the vehicle versus single agent PD-L1 antibody or PD-L1 antibody with Compound No. 9 in a syngeneic colon cancer mouse model resistant to anti-PD-Ll therapy.

[0021] FIG. 9 shows tumor weight upon termination of study of the vehicle versus single agent PD-L1 antibody or PD-L1 antibody with Compound No. 9 in a syngeneic colon cancer mouse model resistant to anti-PD-Ll therapy.

[0022] FIG. 10 shows the tumor growth curves of the vehicle versus single agent PD-L1 antibody or PD-L1 antibody with Compound No. 9 in a syngeneic colon cancer mouse model resistant to anti-PD-Ll therapy.

[0023] FIG. 11 shows tumor weight upon termination of study of the vehicle versus single agent PD-L1 antibody or PD-L1 antibody with Compound No. 9 in a syngeneic colon cancer mouse model resistant to anti-PD-Ll therapy.

[0024] FIG. 12 shows the tumor growth curves of the vehicle versus single agent PD-L1 antibody or PD-L1 antibody with Compound No. 46 in a syngeneic colon cancer mouse model resistant to anti-PD-Ll therapy.

[0025] FIG. 13 shows tumor weight upon termination of study of the vehicle versus single agent PD-L1 antibody or PD-L1 antibody with Compound No. 46 in a syngeneic colon cancer mouse model resistant to anti-PD-Ll therapy.

[0026] FIG. 14 shows a plot of the mean plasma concentration over time for Compound No. 46 after 1 mg / kg IV and 10 mg / kg PO in CD1 mice.

[0027] FIG. 15 shows a plot of the mean plasma concentration over time for Compound No. 46 after 1 mg / kg IV and 3 mg / kg PO in SD rats.

[0028] FIG. 16 shows a plot of the mean plasma concentration over time for Compound No. 9 after 1 mg / kg IV and 10 mg / kg PO in CD1 mice.

[0029] FIG. 17 shows a plot of the mean plasma concentration over time for Compound No. 9 after 1 mg / kg IV and 3 mg / kg PO in SD rats.

[0030] As used herein, the term “pharmaceutically acceptable salt” refers to a salt that is pharmaceutically acceptable as defined herein and that has the desired pharmacological activity of the parent compound. Non-limiting examples of pharmaceutically acceptable salts include those derived from inorganic acids, non-limiting examples of which include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and those derived from organic acids, non-limiting examples of which include acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, stearic acid, malic acid, maleic acid, malonic acid, salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, and lactic acid.

[0031] Additional non-limiting examples of pharmaceutically acceptable salts include those formed when an acidic proton in a parent compound is replaced by a metal ion, nonlimiting examples of which include an alkali metal ion and an alkaline earth metal ion, and those formed when an acidic proton present in a parent compound is replaced by a ammonium ion, a primary ammonium ion, a secondary ammonium ion, a tertiary ammonium ion, or a quaternary ammonium ion. Non-limiting examples of alkali metals and alkaline earth metals include sodium, potassium, lithium, calcium, aluminum, magnesium, copper, zinc, iron, and manganese. Additional non-limiting examples of pharmaceutically acceptable salts include those comprising one or more counterions and zwitterions.

[0032] Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. The same rule applies for any other ranges described herein, even if the values within the range are not specifically called out in this disclosure.

[0033] As used herein, the terms "checkpoint inhibitor" and “checkpoint inhibitor therapy” are used interchangeably to refer to any therapeutic agent, including any small molecule chemical compound, antibody, nucleic acid molecule, or polypeptide, or any fragments thereof, that inhibits one or more inhibitory pathways, thereby allowing more extensive immune activity. In some embodiments, a checkpoint inhibitor therapy comprises administering at least one checkpoint inhibitor to a patient in need of such treatment.

[0034] The term “compound,” as used herein unless otherwise indicated, refers to a collection of molecules having an identical chemical structure as a collection of stereoisomers (for example, a collection of racemates, a collection of cis / trans stereoisomers, or a collection of (E) and (Z) stereoisomers). Therefore, geometric and conformational mixtures of the present compounds and salts are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.

[0035] “Stereoisomer” as used herein refers to enantiomers and diastereomers.

[0036] The term “tautomer,” as used herein, refers to one of two or more isomers of a compound that exist together in equilibrium, and are readily interchanged by migration of an atom or group within the molecule.

[0037] Unless indicated otherwise, nomenclature used to describe chemical groups or moieties as used herein follow the convention where, reading the name from left to right, the point of attachment to the rest of the molecule is at the right-hand side of the name. For example, the group “(C1-3 alkoxy)Ci-3 alkyl," is attached to the rest of the molecule at the alkyl end. Further examples include methoxyethyl, where the point of attachment is at the ethyl end, and methylamino, where the point of attachment is at the amine end.

[0038] Unless indicated otherwise, where a chemical group is described by its chemical formula or structure having a terminal bond moiety indicated by it will be understood that the represents the point of attachment. In some embodiments, a wavy line (i.e., ) depicts the point of attachment.

[0039] As used herein, an “acyl” or “alkanoyl” is a functional group with formula RCO- where R is bound to the carbon atom of the carbonyl functional group by a single bond and the denotes the point of attachment to the rest of the molecule. Non-limiting examples of acyls include formyl (HC(O)-, also called methanoyl), acetyl (CH3C(O)-, also called ethanoyl), and benzoyl (PhC(O)-).

[0040] The term “alkyl” or “aliphatic” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated and that has a single point of attachment to the rest of the molecule. Unless otherwise specified, an alkyl group is a hydrocarbon chain of 1 to 20 alkyl carbon atoms. In some embodiments, an alkyl group contains one to twelve carbon atoms (Ci-C12). In some embodiments, an alkyl group contains one to eight carbon atoms (Ci-Cs). In some embodiments, an alkyl group contains one to six carbon atoms (Ci-Ce). In some embodiments, an alkyl group contains one to four carbon atoms (C1-C4). In some embodiments, a cyclic alkyl group contains three to six carbon atoms (Cs-Ce). Nonlimiting examples of substituted and unsubstituted linear, branched, and cyclic alkyl groups include methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxymethyl, chloromethyl, fluoromethyl, trifluoromethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, trifluoroethyl, and trifluoropropyl.

[0041] “Alkoxy,” as used herein, refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen (“alkoxy”) atom.

[0042] “Halo” and “halogen,” as used herein, are interchangeable and refer to halogen atoms such as fluoro (F), chloro (Cl), bromo (Br), and iodo (I).

[0043] “Haloalkyl” refers to an alkyl group substituted with one or more halo atoms (F, Cl, Br, I). For example, “fluoromethyl” refers to a methyl group substituted with one or more fluoro atoms (e.g., monofluoromethyl, difluoromethyl, or trifluoromethyl).

[0044] “Haloalkoxy” refers to an alkoxy group substituted with one or more halo atoms (F, Cl, Br, I). For example, “fluoromethoxy” refers to a methoxy group substituted with one or more fluoro atoms (e.g., monofluoromethoxy, difluoromethoxy, or trifluoromethoxy).

[0045] “Hydroxyalkyl” refers to an alkyl group substituted with one or more hydroxy groups (-OH).

[0046] The terms “cycloalkyl” and “cycloalkyl group” as used interchangeably herein refer to a cyclic saturated monovalent hydrocarbon radical of three to twelve carbon atoms that has a single point of attachment to the rest of the molecule. Cycloalkyl groups may be unsubstituted or substituted. In some embodiments, a cycloalkyl group comprises three to eight carbon atoms (Cs-Cs). In some embodiments, a cycloalkyl group comprises three to six carbon atoms (Cs-Ce). Non-limiting examples of substituted and unsubstituted cycloalkyls include cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0047] The terms “alkylene” and “alkylene group” as used interchangeably herein refer to a saturated divalent (i.e., having two points of attachment to the rest of the molecule) hydrocarbon radical comprising one to twelve carbon atoms (C1-C12). Alkylene groups may be linear, branched, or cyclic. Alkylene groups may be unsubstituted or substituted. In some embodiments, an alkylene group comprises one to eight carbon atoms (Ci-Cs). In some embodiments, an alkylene group comprises one to six carbon atoms (Ci-Ce). In some embodiments, an alkylene group comprises one to four carbon atoms (C1-C4). Nonlimiting examples of alkylene groups include methylene and ethylene.

[0048] The terms “alkenyl” and “alkenyl group” as used interchangeably herein refer to a monovalent (i.e., having a single point of attachment to the rest of the molecule) hydrocarbon radical comprising two to eight carbon atoms (C2-Cs) with at least one site of unsaturation (i.e., an sp2 carbon-carbon double bond). Alkenyl groups may be linear, branched, or cyclic. Alkenyl groups may be unsubstituted or substituted. In some embodiments, an alkenyl group contains two to six carbon atoms (C2-C6). In some embodiments, an alkenyl group contains two to four carbon atoms (C2-C4). Alkenyl groups may have E or Z orientations. Non-limiting examples of alkenyl groups include ethenyl (also called vinyl), 1-propenyl, iso-propenyl, and 2-chloroethenyl.

[0049] The terms “alkenylene” and “alkenylene group” as used interchangeably herein refer to a divalent (i.e., having two points of attachment to the rest of the molecule) hydrocarbon radical of two to eight carbon atoms (C2-Cs) with at least one site of unsaturation (e.g., an sp2 carbon-carbon double bond). Alkenylene groups may be linear, branched, or cyclic. Alkenylene groups may be unsubstituted or substituted. In some embodiments, an alkylene group contains two to six carbon atoms (C2-C6). In some embodiments, an alkylene group contains two to four carbon atoms (C2-C4). Alkylene groups may have E or Z orientations. A non-limiting example of an alkenyl group is ethenylene (also called vinylene).

[0050] The terms “alkynyl” and “alkynyl group” as used interchangeably herein refer to a monovalent (i.e., having a single point of attachment to the rest of the molecule) hydrocarbon radical of two to eight carbon atoms (C2-Cs) with at least one site of unsaturation (i.e., an sp carbon-carbon triple bond). Alkynyl groups may be linear or branched. Alkynyl groups may be unsubstituted or substituted. In some embodiments, an alkynyl group contains two to six carbon atoms (C2-C6). In some embodiments, an alkynyl group contains two to four carbon atoms (C2-C4). A non-limiting example of an alkynyl group is ethynyl.

[0051] The terms “alkynylene” and “alkynylene group” as used interchangeably herein refer to a divalent (i.e., having two points of attachment to the rest of the molecule) hydrocarbon radical of two to eight carbon atoms (C2-Cs) with at least one site of unsaturation (i.e., an sp carbon-carbon triple bond). Alkynylene groups may be linear or branched. Alkynylene groups may be unsubstituted or substituted. In some embodiments, an alkynylene group contains two to six carbon atoms (C2-C6). In some embodiments, an alkynylene group contains two to four carbon atoms (C2-C4). A non-limiting example of an alkynylene group is ethynylene.

[0052] As used herein, “aromatic groups” or “aromatic rings” refer to chemical groups that contain conjugated, planar ring systems with delocalized pi electron orbitals comprised of [4n+2] p orbital electrons, wherein n is an integer ranging from 0 to 6. Nonlimiting examples of aromatic groups include aryl and heteroaryl groups.

[0053] The terms “aryl” and “aryl group” as used interchangeably herein refer to a monovalent (i.e., having a single point of attachment to the rest of the molecule) aromatic hydrocarbon radical of 6-20 carbon atoms (C6-C20). Aryl groups can be unsubstituted or substituted. Non-limiting examples of unsubstituted and substituted aryl groups include phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 3,4-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-phenoxyphenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-dimethylaminophenyl, 3-dimethylaminophenyl, 4-dimethylaminophenyl, 3-methylsulfonylphenyl, 4- methylsulfonylphenyl, 3-aminophenyl, 3-methylaminophenyl, 3-(2-hydroxyethoxy)phenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 1-naphthyl and 2-naphthyl.

[0054] The term “heteroalkyl” as used herein refers to an alkyl group wherein at least one of the carbon atoms in the chain is replaced by a heteroatom, such as nitrogen, oxygen, phosphorous, and sulfur. A heteroalkyl group may be unsubstituted or substituted.

[0055] The terms “heterocycloalkyl,” “heterocycle,” “heterocyclyl,” and “heterocyclic group” as used interchangeably herein refer to a saturated or partially unsaturated ring system of 3 to 20 atoms, wherein at least one of the ring atoms is a heteroatom, such as nitrogen, oxygen, phosphorous, and sulfur. A heterocycloalkyl group may be unsubstituted or substituted. In some embodiments, a heterocycloalkyl group comprises 3 to 10 atoms. In some embodiments, a heterocycloalkyl group contains 3 to 7 atoms. In some embodiments, a heterocycloalkyl group is monocyclic. In some embodiments, a heterocycloalkyl group is bicyclic. In some embodiments, a heterocycloalkyl group comprises fused rings. Non-limiting examples of unsubstituted and substituted heterocycloalkyl groups include pyrrolidinyl, N-methylpyrrolidinyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 3-hydroxypyrrolidinyl, 3-methoxypyrrolidinyl, and benzodioxolyl.

[0056] The terms “heteroaryl” and “heteroaryl group” as used interchangeably herein refer to an aromatic ring system of 3 to 20 atoms, wherein at least one of the ring atoms is a heteroatom, such as nitrogen, oxygen, phosphorous, and sulfur. A heteroaryl group may be unsubstituted or substituted. In some embodiments, a heteroaryl group contains 5 to 20 atoms. In some embodiments, a heteroaryl group contains 5 to 9 atoms. In some embodiments, a heteroaryl group contains 5 atoms. In some embodiments, a heteroaryl group contains 6 atoms. In some embodiments, a heteroaryl group contains 7 atoms. In some embodiments, a heteroaryl group is monocyclic. In some embodiments, a heteroaryl group is bicyclic. In some embodiments, a heteroaryl group contains fused rings. Nonlimiting examples of heteroaryl groups include pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, 2-thienyl, 3-thienyl, isoxazolyl, thiazolyl, oxadiazolyl, 3-methyl-l,2,4-oxadiazolyl, 3-phenyl-l,2,4-oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and lH-pyrrolo[2,3-b]pyridinyl. Non-limiting examples of heteroaryl groups include:

[0057] The phrase “optionally substituted” as used herein means may or may not be “substituted.” The term “substituted” as used herein refers to the replacement of one or more hydrogen atoms on a group (such as on an alkyl group, alkylene group, alkenyl group, alkenylene group, alkynyl group, alkynylene group, aryl group, heterocycloalkyl group, or heteroaryl group) by one or more substituents. Non-limiting examples of substituents that replace a single hydrogen atom include halogen, hydroxyl, and amino. Non-limiting examples of substituents that replace two hydrogen atoms include oxo and methene. Non-limiting examples of substituents that replace three hydrogen atoms include nitrile.

[0058] Additional non-limiting examples of substituents include: Ci-Ce linear, branched, and cyclic alkyl groups, non-limiting examples of which include methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl sec-butyl, iso-butyl, tertbutyl, cyclobutyl, cyclopentyl, and cyclohexyl; C2-C8 linear, branched, and cyclic alkenyl groups, non-limiting examples of which include ethenyl (also called vinyl), 1-propenyl, and iso-propenyl; C2-C8 linear and branched alkynyl groups, non-limiting examples of which include ethynyl; substituted and unsubstituted aryl groups, non-limiting examples of which include phenyl, 2-fluorophenyl, 3-methylphenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 3,4-difluorophenyl, 3-hydroxyphenyl, 4-cyanophenyl, 2-dimethylaminophenyl, 3-methylsulfonylphenyl, 4-trifluoromethylphenyl, 3-isopropylphenyl, 1-naphthyl, and 2-naphthyl; substituted and unsubstituted heterocyclic groups, non-limiting examples of which include pyrrolidinyl, N-methylpyrrolidinyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 3-hydroxypyrrolidinyl, and 3-methoxypyrrolidinyl; substituted and unsubstituted heteroaryl groups, non-limiting examples of which include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, furyl, 2-thienyl, 3-thienyl, isoxazolyl, thiazolyl, oxadiazolyl, 3-methyl-l,2,4-oxadiazolyl, 3-phenyl-l,2,4-oxadiazolyl, indolyl, benzothiazolyl, and lH-pyrrolo[2,3-b]pyridinyl; -(CRaRb)zORc, non-limiting examples of which include -OH, -OCH3, -OCH2OH, and -OCH2CH3; -(CRaRb)zN(Rc)(Rd), non-limiting examples of which include -NH2, -NHCH3, -N(CH3)2, -CH2NH2, -CH2NHCH3, a halogen atom, non-limiting examples of which include a fluorine atom (-F) and a chlorine atom (-C1); -(CRaRb)zCN; -(CRaRb)zNO2; -CHxXy, wherein X is a halogen atom and x + y sum to 3, non-limiting examples of which include -CH2F, -CHF2, and -CF3; -(CRaRb)zC(O)Rc, non-limiting examples of which include -COCH3, -COCH2CH3, and -CH2COCH3; -(CRaRb)zC(O)ORc, non-limiting examples include CO2H, -CO2CH3, -CO2CH2CH3, and -CH2CO2CH3, -(CRaRb)zC(O)N(Rc)(Rd), non-limiting examples of which include -CONH2, -CONHCH3, -CON(CH3)2, -CH2CONH2, -CH2CONHCH3, -CH2CON(C H3)2; -(CRaRb)zSO2Rc; non-limiting examples of which include -SO2H, -SO2CH3, -CH2SO2H, -CH2SO2CH3, -SO2C6H5, and -CH2SO2C6H5; and -(CRaRb)zSO3Rc; non-limiting examples of which include -SO3H, -SO3CH3, -CH2SO3H, -CH2SO3CH3, -SO3C6H5, and -CH2SO3C6H5; wherein each of Ra and Rb is independently chosen from hydrogen and substituted or unsubstituted Ci-Ce linear, branched, or cyclic alkyl, each of Rc and Rd is independently chosen from hydrogen, substituted or unsubstituted Ci-Ce linear, branched, or cyclic alkyl, and aryl, or wherein Rc and Rd together form a ring system comprising 3 to 7 atoms, and z is chosen from 0, 1, 2, 3, and 4.

[0059] As used herein, the term “pharmaceutical composition” refers to a preparation that is in such form as to permit the biological activity of the active ingredient to be effective, and that contains no additional components that are unacceptably toxic to a subject to which the composition would be administered. In some embodiments, such compositions may be sterile.

[0060] The term “pharmaceutically acceptable,” as used herein in “pharmaceutically acceptable salt” and “pharmaceutically acceptable excipient,” refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio.

[0061] The phrase “pharmaceutically acceptable excipient” is employed herein to refer to a pharmaceutically acceptable material chosen from a solvent, dispersion media, diluent, dispersion, suspension aid, surface active agent, isotonic agent, thickening or emulsifying agent, preservative, polymer, peptide, protein, cell, hyaluronidase, and mixtures thereof. In some embodiments, the solvent is an aqueous solvent.

[0062] “Treatment,” “treat,” and “treating” refer to reversing, alleviating (e.g., alleviating one or more symptoms), and / or delaying the progression of a medical condition or disorder described herein.

[0063] The terms “disease” and “disorder” are used interchangeably herein and refer to any alteration in state of the body or of some of the organs, interrupting or disturbing the performance of the functions and / or causing symptoms such as discomfort, dysfunction, distress, or even death to the person afflicted or those in contact with a person. A disease or disorder can also relate to a distemper, ailing, ailment, malady, sickness, illness, complaint, indisposition, or affection.

[0064] “Subject,” as used herein, means an animal subject, such as a mammalian subject, and particularly human beings.

[0065] As used herein, the term “administering” refers to the placement of a compound, pharmaceutically accecptable salt thereof, and / or a pharmaceutical composition comprising into a mammalian tissue or a subject by a method or route that results in at least partial localization of the compound, salt, and / or composition at a desired site or tissue location.

[0066] The term “therapeutically effective amount” as used herein refers to an amount of a compound or salt that produces a desired effect for which it is administered (e.g., improvement in symptoms of a disease or condition mediated by AhR signaling, lessening the severity of such a disease or condition or a symptom thereof, and / or reducing progression any one of the foregoing). The exact amount of an effective dose will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0067] One of ordinary skill in the art would recognize that, when an amount of a compound is disclosed, the relevant amount of a pharmaceutically acceptable salt form of the compound is an amount equivalent to the amount of the free base of the compound. The amounts of the compounds and pharmaceutically acceptable salts disclosed herein are based upon the free base form of the relevant compound. For example, “10 mg of at least one entity chosen from compounds of Formulas I or la and pharmaceutically acceptable salts thereof’ refers to 10 mg of a compound of Formulas I or la or an amount of a pharmaceutically acceptable salt of the compound of Formulas I or la equivalent to 10 mg of the relevant compound of Formulas I or la.

[0068] The “effectiveness” of a compound or composition of the disclosure can be assessed by any method known to one of ordinary skill in the art, including those described in the examples of this disclosure. Effectiveness can be established in vitro (biochemical and / or biological in cultured cells) and / or in vivo. Effectiveness in vitro may be used to extrapolate or predict some degree of effectiveness in vivo, in an animal or in a human subject. A reference or standard or comparison may be used. The term “effective” at inhibiting a receptor (such as AhR), and / or signaling mediated by the enzyme in the context of this disclosure and claims means reducing / activating the activity of the receptor and / or the activation and propagation of the signaling pathway in terms of activation of a downstream molecule or known biological effect by a detectable or measurable amount relative to the baseline activity. This can be assessed in vitro or in vivo and, in some cases, extrapolated to what an activity or benefit in vivo might be by one of ordinary skill in the art. In some embodiments, the reduction or activation is measured in terms of percentage reduction or activation, relative to the activity in the absence of exposure to the compound of the disclosure, including, for example, at least 5%, at least 10%, 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or about 100%. The activity might also fall within a range, e.g., 5-10%, 10-20%, and any other range interval between 1% and 100%. An amount is “effective” in vivo if it produces any benefit to the subject to whom the compound or salt is administered.

[0069] Disclosed herein are compounds of Formula (I): R2 O (I) and pharmaceutically acceptable salts thereof, wherein: each of R1 and R2 is independently chosen from optionally substituted alkyls, optionally substituted esters, optionally substituted heteroalkyls, optionally substituted acyls, optionally substituted amides, optionally substituted aryls, optionally substituted heteroaryls, optionally substituted cycloalkyls, optionally substituted amines and optionally substituted heterocycloalkyls; and R3 is chosen from hydrogen, optionally substituted alkyls, optionally substituted acyls, optionally substituted amides, optionally substituted aryls, optionally substituted cycloalkyls, optionally substituted esters, optionally substituted heteroalkyls, optionally substituted heteroaryls, optionally substituted heterocycloalkyls, optionally substituted amines, cyano, halos, hydroxy, and -C(O)H.

[0070] In some embodiments R2 is a dialkyl amine. In some embodiments R2 is a diethyl amine.

[0071] Also disclosed herein are compounds of Formula la: (la) and pharmaceutically acceptable salts thereof, wherein: ring A is chosen from optionally substituted aryls, optionally substituted heteroaryls, optionally substituted cycloalkyls, and optionally substituted heterocy cl oalky 1 s; ring B is chosen from optionally substituted aryls, optionally substituted heteroaryls, optionally substituted cycloalkyls, and optionally substituted heterocycloalkyls; and R is chosen from hydrogen, optionally substituted alkyls, optionally substituted acyls, optionally substituted amides, optionally substituted aryls, optionally substituted cycloalkyls, optionally substituted esters, optionally substituted heteroalkyls, optionally substituted heteroaryls, optionally substituted heterocycloalkyls, amino, cyano, halos, hydroxy, and -C(O)H.

[0072] In some embodiments, ring A is chosen from 6-10 membered aryls, 5-10 membered heteroaryls, 3-10 membered cycloalkyls, and 3-10 membered heterocycloalkyls, wherein each 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl is independently optionally substituted with 1 to 5 instances of RA.

[0073] In some embodiments, ring B is chosen from 6-10 membered aryls, 5-10 membered heteroaryls, 3-10 membered cycloalkyls, and 3-10 membered heterocycloalkyls, wherein each 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl is independently optionally substituted with 1 to 5 instances of RB.

[0074] In some embodiments, R is chosen from hydrogen, Ci-Cio alkyls, 6-10 membered aryls, -C(O)R’, -C(O)NR’R’, 3-10 membered cycloalkyls, -C(O)OR’, Ci-Cio heteroalkyls, 5-10 membered heteroaryls, 3-10 membered heterocycloalkyls, amino, cyano, halos, hydroxy, and -C(O)H, wherein each Ci-Cio alkyl, 6-10 membered aryl, 3-10 membered cycloalkyl, Ci-Cio heteroalkyl, 5-10 membered heteroaryl, and 3-10 membered heterocycloalkyl is independently optionally substituted with 1 to 5 instances of Rc.

[0075] In some embodiments, each R’ is independently chosen from hydrogen, Ci-Cio alkyls, Ci-Cio haloalkyls, Ci-Cio hydroxy alkyls, and Ci-Cio heteroalkyls.

[0076] In some embodiments, each RAis independently chosen from halos, hydroxy, Ci-Cio alkyls, Ci-Cio haloalkyls, Ci-Cio alkoxys, Ci-Cio haloalkoxys, Ci-Cio hydroxy alkyls, and NR’ ’R”.

[0077] In some embodiments, each RB is independently chosen from halos, hydroxy, Ci-Cio alkyls, Ci-Cio haloalkyls, Ci-Cio alkoxys, Ci-Cio haloalkoxys, Ci-Cio hydroxy alkyls, and NR’ ’R”.

[0078] In some embodiments, each Rc is independently chosen from halos, hydroxy, cyano, Ci-Cio alkyls, Ci-Cio alkoxys, Ci-Cio haloalkyls, 3-10 membered cycloalkyls, 3-10 membered heterocycloalkyls, 6-10 membered aryls, and 5-10 membered heteroaryls.

[0079] In some embodiments, each R” is independently chosen from hydrogen, Ci-Cio alkyls, Ci-Cio haloalkyls, Ci-Cio hydroxy alkyls, and Ci-Cio heteroalkyls.

[0080] In some embodiments, ring A is chosen from 6-10 membered aryls, 5-8 membered heteroaryls, 3-10 membered cycloalkyls, and 3-10 membered heterocycloalkyls, wherein each 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl is independently optionally substituted with 1 to 5 instances of RA; ring B is chosen from 6-10 membered aryls, 5-10 membered heteroaryls, 3-10 membered cycloalkyls, and 3-10 membered heterocycloalkyls, wherein each 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl is independently optionally substituted with 1 to 5 instances ofRB; R is chosen from hydrogen, Ci-Cio alkyls, 6-10 membered aryls, -C(O)R’, -C(O)NR’R’, 3-10 membered cycloalkyls, -C(O)OR’, C1-C10 heteroalkyls, 5-10 membered heteroaryls, 3-10 membered heterocycloalkyls, amino, cyano, halos, hydroxy, and -C(O)H, wherein each Ci-Cio alkyl, 6-10 membered aryl, 3-10 membered cycloalkyl, C1-C10 heteroalkyl, 5-10 membered heteroaryl, and 3-10 membered heterocycloalkyl is independently optionally substituted with 1 to 5 instances of Rc; each R’ is independently chosen from hydrogen, Ci-Cio alkyls, Ci-Cio haloalkyls, Ci-Cio hydroxyalkyls, and Ci-Cio heteroalkyls; each RAis independently chosen from halos, hydroxy, Ci-Cio alkyls, Ci-Cio haloalkyls, Ci-Cio alkoxys, Ci-Cio haloalkoxys, Ci-Cio hydroxy alkyls, and NR”R”; each Rb is independently chosen from halos, hydroxy, Ci-Cio alkyls, Ci-Cio haloalkyls, Ci-Cio alkoxys, Ci-Cio haloalkoxys, Ci-Cio hydroxy alkyls, and NR”R”; each Rc is independently chosen from halos, hydroxy, cyano, Ci-Cio alkyls, Ci-Cio alkoxys, Ci-Cio haloalkyls, 3-10 membered cycloalkyls, 3-10 membered heterocycloalkyls, 6-10 membered aryls, and 5-10 membered heteroaryls; and each R” is independently chosen from hydrogen, Ci-Cio alkyls, Ci-Cio haloalkyls, Ci-Cio hydroxyalkyls, and Ci-Cio heteroalkyls.

[0081] In some embodiments, ring A is chosen from 3-10 membered cycloalkyl optionally substituted with 1 to 5 instances of RA. In some embodiments, ring A is chosen from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl optionally substituted with 1 to 5 instances of RA. In some embodiments, ring A is chosen from 6-8 membered aryls optionally substituted with 1 to 5 instances of RA. In some embodiments, ring A is phenyl optionally substituted with 1 to 3 instances of RA. In some embodiments, ring A is chosen from 5-8 membered heteroaryls optionally substituted with 1 to 5 instances of RA.

[0082] In some embodiments, ring A is chosen from pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazoyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl, wherein each ofpyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazoyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl is independently optionally substituted with 1 to 3 instances of RA.

[0083] In some embodiments, ring A is pyridinyl optionally substituted with 1 to 3 instances of RA. In some embodiments, ring A is chosen from 5-8 membered heterocycloalkyls optionally substituted with 1 to 5 instances of RA. In some embodiments, ring A is chosen from pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydropyranyl, and tetrahydrofuranyl, wherein each of pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydropyranyl, and tetrahydrofuranyl is independently optionally substituted with 1 to 3 instances of RA. In some embodiments, ring A is piperidinyl or morpholino optionally substituted with 1 to 3 instances of RA.

[0084] In some embodiments, each RA is independently chosen from halos, Ci-Cio alkyls, Ci-Cio haloalkyls, Ci-Cio alkoxys, Ci-Cio haloalkoxys, andNR”R”. In some embodiments, each Rb is independently chosen from halos, Ci-Cio alkyls, and Ci-Cio haloalkyls. In some embodiments, each Rc is independently chosen from halos, hydroxy, cyano, Ci-Cio alkyls, Ci-Cio alkoxys, 3-8 membered cycloalkyls, 3-8 membered heterocycloalkyls, and 6-8 membered aryls. In some embodiments, each R” is independently chosen from hydrogen and Ci-Cio alkyls.

[0085] In some embodiments, each RA is independently chosen from halos, Ci-Cio alkyls, Ci-Cio haloalkyls, Ci-Cio alkoxys, Ci-Cio haloalkoxys, andNR”R”; each Rb is independently chosen from halos, Ci-Cio alkyls, and Ci-Cio haloalkyls; each Rc is independently chosen from halos, hydroxy, cyano, Ci-Cio alkyls, Ci-Cio alkoxys, 3-8 membered cycloalkyls, 3-8 membered heterocycloalkyls, and 6-8 membered aryls; and each R” is independently chosen from hydrogen and Ci-Cio alkyls.

[0086] In some embodiments, ring B is chosen from 6-8 membered aryls optionally substituted with 1 to 5 instances of RB. In some embodiments, ring B is phenyl optionally substituted with 1 to 3 instances of RB. In some embodiments, ring B is chosen from 5-8 membered heteroaryls optionally substituted with 1 to 5 instances of RB. In some embodiments, ring B is chosen from pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazoyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyridinonyl, and pyrimidinyl, wherein each ofpyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazoyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl is independently optionally substituted with 1 to 3 instances of RB. In some embodiments, ring B is chosen from pyrazolyl, isothiazoyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl, wherein each of pyrazolyl, isothiazoyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl is independently optionally substituted with 1 to 3 instances of RB.

[0090] In some embodiments, ring B is chosen from

[0093] In some embodiments, R is chosen from methyl, 2020386967   30 Jul 2026 OH CF3 , , OH OH , OH

[0094] OH OH OH OH CF3 ,                                , OH OH OH OH , OH CN , , OH OH , , , OH OH HO OMe , In some embodiments, R is chosen from methyl, OH OH , and . [0094A] OH and , In some embodiments, disclosed herein are compounds of Formula (Ia): (Ia) , or a pharmaceutically acceptable salt thereof, wherein: ring A is chosen from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazoyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydropyranyl, and tetrahydrofuranyl, wherein each cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazoyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, 2020386967   30 Jul 2026 pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydropyranyl, and tetrahydrofuranyl is independently optionally substituted with 1 to 5 instances of RA; ring B is chosen from phenyl, benzodioxolyl, pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazoyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyridinonyl, and pyrimidinyl, wherein each phenyl, benzodioxolyl, pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazoyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyridinonyl, and pyrimidinyl is independently optionally substituted with 1 to 5 instances of RB; (rn-^ (xn^_  q / x or ring B is '----'      ,              ,   '----, or \---- /      ; R is chosen from hydrogen, C1-C10 alkyls, 6-10 membered aryls, 3-10 membered cycloalkyls, 5-10 membered heteroaryls, and 3-10 membered heterocycloalkyls, wherein each C1-C10 alkyl, 6-10 membered aryl, 3-10 membered cycloalkyl, 5-10 membered heteroaryl, and 3-10 membered heterocycloalkyl is independently optionally substituted with 1 to 5 instances of RC; each RA is independently chosen from halos, C1-C10 alkyls, C1-C10 haloalkyls, and C1-C10 haloalkoxys; each RB is independently chosen from halos, C1-C10 alkyls, and C1-C10 haloalkyls; each RC is independently chosen from halos, hydroxy, and C1-C10 alkoxys.

[0095] Also disclosed herein are compounds of Formula Ib: (Ib) and pharmaceutically acceptable salts thereof, wherein: ring A is chosen from optionally substituted heteroaryls and optionally substituted heterocycloalkyls; ring B is chosen from optionally substituted heteroaryls and optionally substituted heterocycloalkyls; and R is chosen from hydrogen, optionally substituted alkyls, optionally substituted acyls, optionally substituted amides, optionally substituted aryls, optionally substituted cycloalkyls, optionally substituted esters, optionally substituted heteroalkyls, optionally substituted heteroaryls, optionally substituted heterocycloalkyls, amino, cyano, halos, hydroxy, and -C(O)H.

[0096] In some embodiments, the present disclosure is drawn to one or more compounds recited in Table 1. Table 1 Compound No. Structure and name 1 F'O OH f3co^^ 8-(5 -fluoropyridin-3 -yl)-3 - [(2 S)-1 -hydroxypropan-2-yl]-6-[4- (trifluoromethoxy)phenyl]-3H,4H-pyrido[3,4-d]pyrimidin-4-one 3 m oh JU I 8-(2H-1,3 -benzodi oxol-4-yl)-6-(4-chlorophenyl)-3 -[(2S)-1 -hydroxypropan-2-yl]-3H,4H-pyrido[3,4-d]pyrimidin-4-one Compound No. Structure and name 2 o f| NH NXs / Nx oh N X JU 0 cr 5-[6-(4-chlorophenyl)-3- [(2 S)-1 -hydroxypropan-2-yl]-4-oxo-3H,4H- pyrido[3,4-d]pyrimidin-8-yl]-l,2-dihydropyridin-2-one 4 N Q NX^Nx OH A J I f3c n 3-[(2S)-l-hydroxypropan-2-yl]-8-(pyridin-4-yl)-6-[6-(trifluoromethyl)pyridin-3 -yl]-3H,4H-pyrido[3,4-d]pyrimidin-4-one Compound No. Structure and name Compound No. Structure and name p N. o 5 oh XX s 8-(5-fluoropyri din-3 -y 1)-3 -[(2S)-l-hydroxypropan-2-yl]-6-[4-(trifluoromethyl)phenyl]-3H,4H-pyrido[3,4-d]pyrimidin-4-one 6 oh h j       Y ] 0     1 3-[(2S)-l-hydroxypropan-2-yl]-6,8-bis(pyridin-4-yl)-3H,4H-pyrido[3,4-d]pyrimidin-4-one F^^ Y ] Fx^x^ u 7 OH JU 0 cr 6-(4-chlorophenyl)-8-(3-fluorophenyl)-3 - [(2 S)-1 -hydroxypropan-2-yl]-3H,4H-pyrido[3,4-d]pyrimidin-4-one 8 oh N J XX I 3' f3c"^n 8-(3 -fluorophenyl)-3 - [(2 S)-1 -hydroxypropan-2-yl]-6-[6-(trifluoromethyl)pyridin-3 -yl]-3H,4H-pyrido[3,4-d]pyrimidin-4-one 9 Q OH n ^xx Jl J o CF3 N 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 10 Q N          OH N V 0 6,8-di(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hy droxy propy l)py ri do [3,4-d]pyrimidin-4(3H)-one Q Q 11 N          OH ciY^Y 0   = (S)-6-chl oro-3 -(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 12 oh XJ I 1 cf3 n (S)-3 -(1 -hy droxypropan-2-yl)-8-(pyri din-3 -yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one Compound No. Structure and name Compound No. Structure and name 13 \-N Z A N          OH N '^cf3 Cl^   0 6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3 -trifluoro-2-hy droxy propy l)py ri do [3,4-d]pyrimidin-4(3H)-one 14 Q N          OH N '^cf3 FsCoY^    0 8-(pyri din-3 -y 1)-3 -(3,3,3-trifluoro-2-hydroxypropyl)-6-(4- (trifluoromethoxy)phenyl)pyr ido[3,4-d]pyrimidin-4(3H)-one 15 \-N A A N          OH Cl-M    0 6-(4-chlorophenyl)-8-(l-methyl-lH-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hy droxy propy l)py ri do [3,4-d]pyrimidin-4(3H)-one 16 Q oh XX o F3C^^ 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3 -yl)-6-(4-(trifluoromethyl)phenyl)pyrid o[3,4-d]pyrimidin-4(3H)-one 17 Q oh XX 0 = (S)-3 -(1 -hy droxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one 18 Q oh XX I Cl 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 19 \ N-N Z OH N Y     n Y   0 / 3-(2-hydroxy-2-methylpropyl)-6,8-bis(l-methyl-lH-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 20 Q oh CX o = N (S)-3 -(1 -hy droxypropan-2-yl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin- 4(3H)-one Compound No. Structure and name Compound No. Structure and name 21 \-N Z A OH JU 0 cr 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1 -methyl -1 H-py razol -4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 22 Q nA^N-^ oh AT 0 i cf3o^^ (S)-3 -(1 -hy droxypropan-2-yl)-8-(pyri din-3 -yl)-6-(4-(tri fluoromethoxy )phenyl)pyr ido[3,4-d]pyrimidin-4(3H)- one 23 Q NA^N-^ oh A^T O F3C'^ / (S)-3 -(1 -hy droxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrid o[3,4-d]pyrimidin-4(3H)-one 24 Q nA^N-^ oh jCT o cr (S)-6-(4-chlorophenyl)-3-(l-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 25 \-N A A OH ^AAA^^ jCT o cf3o^^ (S)-3 -(1 -hy droxypropan-2-yl)- 8-(l-methyl-lH-pyrazol-4-yl)-6-(4- (tri fluoromethoxy )phenyl)pyri dof3,4-d]pyrimidin-4(3H)-one 26 \-N A A oh (S)-3-(l-hydroxypropan-2-yl)-8-(1 -methyl- lH-pyrazol-4-yl)-6-phenylpyrido[3,4-d]pyrimidin-4(3H)-one 27 \-N A A oh / ^AJAA^"1 AT J (S)-6-(4-chlorophenyl)-3-(l-hydroxypropan-2-yl)-8-(l-methyl-lH-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 28 Q ATT o 3-methyl-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyri do[3,4-d]pyrimidin-4(3H)-one Compound No. Structure and name Compound No. Structure and name 29 Q h            °h o A rac-6-(4-chlorophenyl)-3-((trans)-4-hy droxytetrahy drofuran-3 -yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 30 \-N ci-A1     o ; (S)-6-(4-chlorophenyl)-3 -(3 -hydroxy-3 -methylbutan-2-yl)-8-(1 -methyl- lH-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 31 \-N jyA-A (R)-6-(4-chlorophenyl)-3 -(3 -hydroxy-3 -methylbutan-2-yl)-8-(1 -methyl -1 H-py razol -4-yl)pyrido[3,4-d]pyrimidin- 4(3H)-one 32 Q OH CIJU o w rac-6-(4-chlorophenyl)-3 -((cis)-4-hy droxytetrahy drofuran-3 -yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 33 Q N ''['OH cr (R)-6-(4-chlorophenyl)-3 -(3 -hydroxy-3 -methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 34 Q o £ (S)-3 -(3 -hydroxy-3 -methylbutan-2-yl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 35 f^f CA Il                    |T      |     Un o F (S)-6,8-bis(3,5-difluorophenyl)-3 -(1 -hy droxy-3 -methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 36 Q ci4U    0 = (S)-6-(4-chlorophenyl)-3 -(3 -hydroxy-3 -methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one Compound No. Structure and name Compound No. Structure and name 37 (S)-8-(3,5-difluorophenyl)-3-(1 -hydroxy-3 -methylbutan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one 38 6-(4-chlorophenyl)-8-(3-fluorophenyl)-3 -(2-hy droxy-2-methylpropyl)pyrido[3,4-d]pyrimidin-4(3H)-one 39 or .X cr— (R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3 -(3 -hy droxy-3 -methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 40 F itN*| N___ [|                          OBn ° £ (S)-3 -(1 -(benzyloxy )propan-2-yl)-8-(3-fluorophenyl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one 41 F 7 H        CF3 6-(4-chlorophenyl)-8-(3-fluorophenyl)-3 -(3,3,3-trifluoro-2- hy droxy propy l)py ri do [3,4-d]pyrimidin-4(3H)-one, enantiomer 1 42 ?F3 CI--V     o 6-(4-chlorophenyl)-8-(3-fluorophenyl)-3 -(3,3,3- trifluoro-2- hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one, enantiomer 2 43 Q NXsxN^, N V Y ■ OH 0   = (S)-3 -(1 -hy droxypropan-2-yl)-6-morpholino-8-(pyridin-3 -yl)pyrido[3,4-d]pyrimidin- 4(3H)-one 44 O 1 FaCO^^ (S)-3-(l-hydroxypropan-2-yl)-8-( IH-imidazol-1 -yl)-6-(4-(trifluoromethoxy)phenyl)pyri do[3,4-d]pyrimidin-4(3H)-one Compound No. Structure and name Compound No. Structure and name 45 Q N p         n T 0Me AkA    ° (S)-3 -(1 -methoxypropan-2-yl)-8-(pyri din-3 -yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one 46 N^i |l J f3c^n    0  1 (S)-3-(l-hydroxypropan-2-yl)-8-(pyri din-3 -yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 47 f3c^n    0  1 (S)-8-(3 -fluorophenyl)-3 -(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 48 o = (S)-8-(3 -fluorophenyl)-3 -(1-hydroxypropan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one 49 1 a o = f3co^x (S)-8-(3 -fluorophenyl)-3 -(1-hydroxypropan-2-yl)-6-(4- (trifluoromethoxy)phenyl)pyri do[3,4-d]pyrimidin-4(3H)-one 50 Q xL N          OH 14 11 CF3O N (5)-3-(1 -hy droxypropan-2-yl)-8-(pyri din-3 -yl)-6-(6-(trifluoromethoxy)pyridin-3 -yl)pyrido[3,4-J]pyrimidin-4(377)-one 51 N-NH / / A n-Xy-n^ OH Xj s CF3^ N (5)-3 -(2-hy droxy-2-methylpropyl)-8-(lZ / -pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 52 Q oh IJ 11' MeOOC N methyl (5)-5-(3-(1-hydroxypropan-2-yl)-4-oxo-8- (pyridin-3-yl)-3,4- dihydropyrido[3,4-J]pyrimidin-6-yl)picolinate Compound No. Structure and name Compound No. Structure and name 53 Q X ^N. N^A   OH (5)-3 -(1 -hy droxypropan-2-yl)-6-(isothiazol-4-yl)-8-(pyridin-3-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 54 N-S / / A OH N xAC JU I cf / V 3 -(2-hy droxy-2-methylpropyl)-8-(isothiazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 55 N-S A A N          OH ALXA A-J o = err (5)-3 -(1 -hy droxypropan-2-yl)-8-( isothiazol-4-yl)-6-(6-(trifluoromethyl)pyri din-3-yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 56 N-S oh / \JUUn___J N ' T   Ya o = (5)-3-(1 -hy droxypropan-2-yl)-6,8-di(isothiazol-4-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 57 Q N'^A CF3 n              N       H AsJ o CF^^ (5)-8-(pyri din-3 -y 1)-3 -(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyri din-3-yl)pyrido[3,4-J]pyrimidin- 4(3Z / )-one 58 N-S / / A oh / AA / N___j JU s i Cl (5)-6-(4-chlorophenyl)-3 -(1-hydroxypropan-2-yl)-8-(i sothi azol -4-y l)py ri do [3,4-J]pyrimidin-4(3J7)-one 59 Q oh U 5 N 3 -(2-hy droxy-2-methylpropyl)- 6,8-di(pyridin-3-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 60 n-nZ / / X A N         OH AA aA o 3 -(2-hy droxy-2-methylpropyl)-8-(1 -methyl- l / f-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one Compound No. Structure and name Compound No. Structure and name 61 N-l / A A oh XT I 6-(4-chloro-2-methylphenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1 -methyl- 17 / -pyrazol-4-yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 62 HN-N A A jfYAr Yoh Y       o 1 F3C N (5)-3-(1 -hy droxypropan-2-yl)-8-(17 / -pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 63 Me F,cV ° (5)-3 -(1 -hy droxypropan-2-yl)-8-(2-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 64 jO Il                H : OH 0 Me F3C N (5)-3-(1 -hy droxypropan-2-yl)-8-(4-methylpyri din-3 -yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 65 Q \\ J         II = N-\    0 (S)-3 -(1 -hy droxypropan-2-yl)-6-(4-methylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 66 Q rrT ovsyAn^oh N-J       O = (S)-6-(2-cyclopropylthiazol-5-y 1)-3 - (1 -hy droxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 67 Q IT ° = (S)-3 -(1 -hy droxypropan-2-yl)-6-(2-isopropylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 68 N—NZ 0 £ (S)-3-(l-hydroxypropan-2-yl)-8-(1 -methyl- lH-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one Compound No. Structure and name Compound No. Structure and name 69 cf3 o l!^AArN'^oH UL        o = F3C N (S)-3 -(1 -hy droxypropan-2-yl)-6,8-bis(6-(trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 70 Q OH zyUUU CIJU o Q 6-(4-chlorophenyl)-3-((3 S,4S)-4-hy droxytetrahy drofuran-3 -yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one. 71 Q OH CIX^ o 6-(4-chlorophenyl)-3-((3R,4R)-4-hy droxytetrahy drofuran-3 -yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 72 Q ^0H 3-(2-hydroxyethyl)-8-(pyridin-3-yl)-6-(4- (trifluoromethoxy)phenyl)pyri do[3,4-d]pyrimidin-4(3H)-one 73 0 (V 0     1 cr (5)-6-(4-chlorophenyl)-3 -(1-hydroxypropan-2-yl)-8-(l-methyl-6-oxo-1,6-dihy dropyridin-3 -yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 74 Q It*1 Y       o 1 (5)-6-(6-cyclopropylpyridin-3-y 1)-3 - (1 -hy droxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 75 Q 0     1 F3C n (5)-3 -(1 -hy droxypropan-2-yl)-6-(4-methyl-6-(trifluoromethyl)pyri din-3-yl)-8-(pyridin-3-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 76 \ N—N <           o 1 N (5)-3-(1 -hy droxypropan-2-yl)- 8-(1 -methyl- lZ7-pyrazol-4-yl)-6-(pyridin-3-yl)pyrido[3,4- J]pyrimidin-4(3J7)-one Compound No. Structure and name Compound No. Structure and name 77 Q A Q-MyN .^0H o 1 (5)-6-(cyclohex-1 -en-1 -y 1)-3 -(l-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 78 Fxo <           0   1 N (5)-6,8-bis(5-fluoropyridin-3 -y 1)-3 - (1 -hy droxypropan-2-yl)pyrido[3,4-J]pyrimidin-4(377)-one 79 Q N'Y'S OH ° 0 3-((37?,45)-4- hy droxytetrahy drofuran-3 -yl)-8-(pyridin-3-yl)-6-(6- (trifluoromethyl)pyridin-3-yl)pyrido[3,4-J]pyrimidin-4(377)-one 80 Q Acf3 0 3 -(2-hy droxy-2-methylpropyl)-8-(pyri din-3 -yl)-6-(2-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 81 Q ° 6-(6-cyclopropylpyridin-3-yl)-3 -(2-hy droxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-<7]pyrimidin-4(377)-one 82 N-NZ / 7 A UL       o Vz N 6-(6-cyclopropylpyri din-3 -yl)-3 -(2-hy droxy-2-methylpropyl)-8-(1 -methyl- lZ / -pyrazol-4-yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 83 N-NZ / / A nA-Y JL         o = V / N (S)-6-(6-cy clopropylpyridin-3 -y 1)-3 -(1 -hy droxypropan-2-yl)-8-(1 -methyl-177-pyrazol-4-yl)pyrido[3,4-J]pyrimidin-4(377)-one 84 Q N <v^N^0„ s       o = (5)-3-(1 -hy droxypropan-2-yl)-8-(pyridin-3-yl)-6-(thiazol-5-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one Compound No. Structure and name Compound No. Structure and name 85 Q n 0   = f3c (5)-3 -(1 -hy droxypropan-2-yl)-8-(pyridin-3-yl)-6-(2- (trifluoromethyl)thiazol-5-yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 86 Q pA .V J o £ f3c^n (5)-3-(1 -hy droxypropan-2-yl)-8-(pyri din-3 -yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 87 Q s       o f3c 3 -(2-hy droxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 88 \-N N           OH ju I Q f3c n                u 3-((35,45)-4-hy droxytetrahy drofuran-3 -yl)-8-(1 -methyl- lZ / -pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 89 Q T"°h Vs      o 1 (5)-3 -(1 -hy droxypropan-2-yl)-6-(2-methylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 90 u i a Cl^ o X (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3 -(1 -hydroxy-3 -methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 91 f3cU 0 ’ (S)-3 -(1 -hy droxypropan-2-yl)-8-(1 -methyl-1,2,5,6-tetrahy dropyri din-3 -yl)-6-(6-(trifluoromethyl)pyri din-3- 92 \-N Czl 6-(4-chlorophenyl)-3-((35,45)-4-hy droxytetrahy drofuran-3 -yl)- 8 -(1 -methyl-1 H-pyrazol-4- Compound No. Structure and name Compound No. Structure and name yl)pyrido[3,4-d]pyrimidin-4(3H)-one yl)pyrido[3,4-X]pyrimidin-4(370-one 93 Q N^^oh Ji J      0 = H3C n (5)-3-(1 -hydroxypropan-2-yl)-6-(2-methylpyrimidin-5-yl)-8- (pyridin-3 -yl)pyrido [3,4-ri]pyrimidin-4(377)-one 94 F3C N—N Z rYX v f3c^n^     0 3 -(2-hydroxy-2-methylpropyl)-8-(1 -(trifluoromethyl)- 1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3,4-ri| py ri m idi n-4(377)-one 95 N-l / X \ n              N      H Ji J      o - F3C N (5)-3-(1 -hydroxypropan-2-yl)-8- (1 -methyl-1 H-pyrazol-4-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-ri]pyrimidin-4(370- one 96 Q N          OH Ji J o CF< N 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3 -yl)-6-(2-(trifluoromethyl)pyrimidin-5 -yl)pyrido[3,4-ri]pyrimidin-4(370- one 97 Q oh XX I 3 HOOC N (5)-5-(3-(1 -hydroxypropan-2- yl)-4-oxo-8-(pyridin-3-yl)- 3,4-dihydropyrido [3,4- 98 Q N          OH J J I (5)-3-(1 -hydroxypropan-2- yl)-6-(6-methylpyridin-3-yl)- Compound No. Structure and name Compound No. Structure and name < / ]pyrimidin-6-yl)picolinic acid 8 -(pyridin-3 -yl)pyrido [3,4-< / ]pyrimidin-4(327)-one 99 \-N A A N          OH nAUynA< AL       o CF3 N 3-(2-hydroxy-2-methylpropyl)-8-( 1 -methyl- 1 / / -pyrazol-4-yl )-6-(2-(trifluoromethyl)pyrimidin-5 -yl)pyrido [3,4-r / | py ri m idin-4(3 / / )-onc 100 q N jA (5)-3-(1 -hy droxypropan-2-yl)-6-(piperidin-1-yl)-8-(pyridin-3 -yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 101 N-S / / \ A xNk N          OH N xOOAxxX N ^xA Xj I cFr^ 3 -(2-hy droxy-2-methylpropyl)-8-( isothiazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 102 N-S / / 4 n V   oh _N. JL xA .N. J JJ । (5)-3 -(1 -hy droxypropan-2-yl)-8-( isothiazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-J]pyrimidin-4(37 / )-one 103 n-nZ UI-3 3 -(2-hy droxy-2-methylpropyl)-8-(1 -methyl- lJ7-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-J]pyrimidin-4(3 / / )-one 104 Q N       <1   CF3 II                        ।           I / N^JO^xN^ h               n         cin o (5)-8-(pyri din-3 -y 1)-3 -(3,3,3-trifluoro-2-hydroxypropyl)-6- 105 Q xO xNx N V   OH JU o Compound No. Structure and name Compound No. Structure and name (5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one (3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3 -yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 106 Q nX^ BA XX F3C N 3-(1,1-dioxidotetrahydrothiophen-3 -yl)-8-(pyri din-3 -yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 107 o XXX XX f3c n (R)-3-(l,l-dioxidotetrahydrothiophen-3 -yl)-8-(pyri din-3 -yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-d]pyrimidin- 4(3H)-one 108 \ N-N FaC'^'N^       ° (R)-3 -(2-hy droxypropyl)-8-( 1 -methyl-lH-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin- 4(3H)-one 1090 \-n Z A = FsC^N^      ° (5)-3-(2-hydroxypropyl)-8-(l-methyl- l / / -pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 110 Me, N-N f^^n^    0 (7?)-8-(l -methyl- l / / -pyrazol-4-yl)-3-(3,3,3 -trifluoro-2-hydroxypropyl)-6-(6- (trifluoromethyl)pyridin-3-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 111 Me, N-N N            CF3 II                        1 I / ¾. XX     .N. A, ii                n          oh o F3C N (5)-8-(l-methyl-l / / -pyrazol-4-yl)-3 -(3,3,3 -trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one Compound No. Structure and name Compound No. Structure and name 112 Q N           Me iii^ir oh A     o f3c n (7?)-3-(2-hydroxypropyl)-8-(pyri din-3 -yl)-6-(6-(trifluoromethyl)pyri din-3-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 113 Q A _N. N           Me pAPyN^0H (7?)-8-(l-methyl-lZ / -pyrazol-4-yl)-3 - (3,3,3 -trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 114 \ N-N n           0H / / ¾ f3c^n^          ° 3-((3 S,4R)-4-hydroxytetrahydrofuran-3 -y 1)-8 -(l-methyl-lH-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-d]pyrimidin- 4(3H)-one 115 \ N-N H           0H f3cx^n^      0    ° 3-((3R,4S)-4- hy droxytetrahy drofuran-3 -yl)-8-(1 -methyl- lH-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 116 \-N 6-(4-chlorophenyl)-3-((3S,4R)-4- hy droxytetrahy drofuran-3 -yl)-8-(1 -methyl -1 H-py razol -4-yl)pyrido[3,4-d]pyrimidin- 4(3H)-one 117 Q 3-((3 S,4R)-4- hy droxytetrahy drofuran-3 -yl)-8-(pyri din-3 -yl)-6-(6- (trifluoromethyl)pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one 118 p FZ' z >=o \= /  2= / 2= / o co 119 Q F,C^   ° Compound No. Structure and name Compound No. Structure and name 3,8-di(pyridin-3-yl)-6-(6-(trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3J7)-one 8-(pyri din-3 -yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3J7)-one 120 Q J. N NCF3 (S)-6-(6-cyclopropylpyridin-3-yl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hy droxy propy l)py ri do [3,4-d]pyrimidin-4(3H)-one 121 Q A N           cf3 II                        1           - (7?)-6-(6-cy clopropylpyridin-3 -yl)-8-(pyri din-3 -y 1)-3 -(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 122 Q N N'Y'     ?F3 n Ar'5*!!'' N O (7?)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 123 Q x-L N           CF3 o CFsO^^ (7?)-8-(pyridin-3-yl)-3-(3,3,3- trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyri do[3,4-^?]pyrimidin-4(3 H)-one 124 Q N.'Y^ V cf3cA^    0 (5)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4- (trifluoromethoxy)phenyl)pyrid o[3,4-d]pyrimidin-4(3 / 7)-one 125 Q xL n V y oh .Av 6-(4-chlorophenyl)-3 -((35,4R)-4-hy droxytetrahy drofuran-3 -yl)-8-(pyridin-3-yl)pyrido[3,4-J]pyrimidin-4(3 / / )-°ne 126 Q A n A   0H Ur 3 127 Q nXy% o ___ (l Ap          if** ; OMe cf3^ n methyl (5)-2-(4-oxo-8-(pyri din-3 -yl)-6-(6- Compound No. Structure and name Compound No. Structure and name 3-((35,45)-4-hy droxytetrahy drofuran-3 -yl)-8-(pyri din-3 -yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-J]pyrimidin-4(3J7)-one (trifluoromethyl)pyridin-3 -yl)pyrido[3,4-J]pyrimidin-3 (4J7)-yl)propanoate 128 Q tiS °h dJy O 6-(4-chlorophenyl)-3-(4-hydroxy-1 -methylpyrrolidin-3 -yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 129 Q N          OH n*. ii t         n m / cf^   0 Lo 3-((35,45)-4-hy droxytetrahy drofuran-3 -yl)-8-(pyri din-3 -yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-J]pyrimidin- 4(3J7)-one 130 N-l / A \ oh CF3^   0 3-((35,45)-4-hy droxytetrahy drofuran-3 -yl)-8-(1 -methyl- l / f-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-J]pyrimidin- 4(3Z / )-one 131 / N-N 5 X oh CI^   0 6-(4-chl orophenyl)-3-((35,45)-4-hy droxytetrahy drofuran-3 -y 1)-8-(1 -methyl- IH-pyrazol -4-yl)pyrido[3,4-J]pyrimidin- 4(3J7)-one 132 Q "V"! 0   '— / CF:r 3-cyclopentyl-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 133 Q N          >f if n JU  o U cf3^^ 3-phenyl-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one Compound No. Structure and name Compound No. Structure and name 134 Q ’ll 1 N§l 0H C|JM 0 '-NH 6-(4-chlorophenyl)-3-(3R, 4R)-4-hydroxypyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 135 / N—N X H 1         QFs (5)-6-(6-cyclopropylpyridin-3-yl)-8-(l-methyl-1 / 7-pyrazol-4 -yl)-3 - (3,3,3 -trifluoro-2-hy droxy propy l)py ri do [3,4-d]pyrimidin-4(3J7)-one 136 N-l / A A N V -=11   cf3 1                            1             I Y     ° (5)-6-(6-cy clopropylpyridin-3 -y 1)-8-( 1 -methyl- U / -pyrazol-4-yl)-3 - (3,3,3 -trifluoro-2-hydroxypropyl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 137 \-N 0 0 Id 3-((3S,4R)-4- hy droxytetrahy drofuran-3 -yl)- 8-(l-methyl-lH-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 138 \ N—N oh F]CJLn 0 To> 3-((35,45)-4-hy droxytetrahy drofuran-3 -yl)-8-(1 -methyl- l / Z-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 139 Q II              OH 3-((35,45)-4- hy droxytetrahy drofuran-3 -y 1)-8 -(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 140 Q OH F          0 L / 1-3(^ 3-((35,45)-4- hy droxytetrahy drofuran-3 -yl)-8-(pyri din-3 -yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one Compound No. Structure and name Compound No. Structure and name 141 \ N—N f3c^n    0 (7?)-3-(2-hydroxypropyl)-8-(l-methyl-l / / -pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3J7)-one 142 \ N-N = f3c^n    0 (5)-3-(2-hydroxypropyl)-8-(l-methyl-l / / -pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3Z / )-one 143 Q n            n        on o (5)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 144 Q fr*1 1 CF3^k^     ° (7?)-3-(2-hydroxypropyl)-8-(pyri din-3 -yl)-6-(5 -(trifluoromethyl)pyridin-2-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 145 Q xk N          OH UI-3 3-((35,45)-4-hydroxytetrahydrofuran-3 -y 1)-8 -(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 146 Mex N-N Z A xk N      <1   CF3 II                       I           - f3c^n    0 (5)-3-(2-hydroxypropyl)-8-(pyri din-3 -yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 147 Mex N-N xk .N. N            CF3 fcA^n 0 hsC (5)-8-( 1 -methyl- l / / -pyrazol-4-y 1) - 3 -(3,3,3 -trifluoro-2-hydroxypropyl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 148 Q xk xN^ N          OH CF               ^--0 3-((3R,4R)-4-hy droxytetrahy drofuran-3 -yl)-8-(pyri din-3 -yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-J]pyrimidin- 4(3Z / )-one Compound No. Structure and name Compound No. Structure and name 149 \-N oh r 3-((37?,47?)-4-hydroxytetrahydrofuran-3 -yl)-8-(1 -methyl- l / 7-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-J]pyrimidin- 4(3Z / )-one 150 / N-N y X t^oh o = (S)-3-(l-hydroxypropan-2-yl)-8- (l-methyl-lH-pyrazol-4-yl)-6-(5-(trifluoromethyl) pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 151 \-N A A fjC-Cn 0 3-((35,45)-4-hydroxytetrahydrofuran-3 -y 1)-8 -(1 -methyl-l / 7-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 152 Q N           OH aAj o To> 6-(4-chl orophenyl)-3-((35,45)-4-hy droxytetrahy drofuran-3 -yl)-8-(pyridin-3-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 153 \ N-N Z A N           OH C|JM ° 6-(4-Chlorophenyl)-3 -((35,45)-4-hy droxytetrahy drofuran-3 -y 1)-8-(1 -methyl- l / f-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3J7)-one 154 Q N V <1 CF3 Il jT           n           on xAA    o (5)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 155 Q n<xVyny“>h aA o ' F3c^^ (5)-2-(4-oxo-8-(pyri din-3 -yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-J]pyrimidin- 3(4Z / )-yl)propanoic acid 156 Q o n              N n jU o h f3ct (5)-N-methyl-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3 - Compound No. Structure and name Compound No. Structure and name yl)pyrido[3,4-d]pyrimidin-3 (4 / / )-yl)propanamide 157 Q N^r"N^ 0 N N N JfxJ      O = 1 FC^ (S)-N,N-dimethyl-2-(4-oxo-8-(pyri din-3 -yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3 (4H)-yl)propenamide 158 Q oH°^ JU o H (S)-N-((3R,4S)-4-hy droxytetrahy drofuran-3 -yl)-2-(4-oxo-8-(pyri din-3 -yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanamide 159 N-NH X". p r3^ 3-(2-hydroxy-2-methylpropyl)-8-(lH-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido|'3,4-d]pyrimidin-4(3H)-one 160 if N^|^[f N f3c^A    0 3-(2-hydroxy-2-methylpropyl)-8-(lH-imidazol-1 -y 1)-6-(5 -(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin- 4(3H)-one 161 / rN o F3C^^ 3 -(2-hy droxy-2-methylpropyl)-8-( IH-imidazol- 1 -yl)-6-(6-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one Compound No. Structure and name Compound No. Structure and name 162 .N. XL      .N. < Y n : 0H o = f3c^ / (S)-3 -(1 -hy droxypropan-2-yl)-8-(lH-imidazol-l-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 163 0 n              N      H FaC^ (S)-3-(l-hydroxypropan-2-yl)-8-( IH-imidazol-1 -yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one 164 < ,N N n              N      h o = (5)-3-(1 -hy droxypropan-2-yl)-8-(1 / / -1,2,4-triazol-1 -yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 165 o. N n              N      h CF^ (5)-3-(1 -hy droxypropan-2-yl)-8-(1 / / -pyrazol-1 -yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 166 N CI-V    o ; (5)-6-(4-chlorophenyl)-3 -(1-hydroxypropan-2-yl)-8-(l / / -pyrazol-1 -yl)pyrido[3,4-d]pyrimidin-4(3J7)-one 167 On N ifnOOyN^oH CF,^    O £ (5)-3-(1 -hy droxypropan-2-yl)-8-(17 / -pyrazol-l-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 168 \-N x~, V-s      o = F3c S )-3 - (1 -hy droxypropan-2-yl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol- 169 Q OH S            N CF=-« J    I £ > N-J       0 3-((35,47?)-4-hy droxytetrahy drofuran-3 -yl)-8-(pyri din-3 -yl)-6-(2-(trifluoromethyl)thi azol-5- Compound No. Structure and name Compound No. Structure and name 5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 170 \-N Z \\ oh J    J 3-(2-hydroxy-2-methylpropyl)-8-(l-methyl-17 / -pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 171 \-N N / X % OH f3c-« y  x o N-J     0  X 3-((35,47?)-4- hy droxytetrahy drofuran-3 -yl)-8-(1 -methyl- 17 / -pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 172 \-N QH F3C~< J     X  L / hr        0   ^-0 3-((3R, 45)-4-hy droxytetrahy drofuran-3 -yl)-8-(1 -methyl- 177-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 173 Q qH f3cXj    j X / N-^       °   ^-O 3-((3R, 45)-4-hy droxytetrahy drofuran-3 -yl)-8-(pyri din-3 -yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 174 u 'AA- X       o 1 f3c n (S)-8-(diethylamino)-3-(l-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyri din-3 -yl)pyrido|’3,4-d]pyrimidin-4(3H)-one Compound No. Structure and name Compound No. Structure and name 175 0 .A Y      o 1 f3c n (5)-3 -(1 -hy droxypropan-2-yl)-8-(piperidin-1 -y 1)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 176 A”"1 J / YAY'"'0" X       o 1 f3c^n^ (5)-3-(1 -hy droxypropan-2-yl)-8-(pyrrolidin-1 -yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 177 NAy yyMyy^ o 1 or— (5)-6-(4-chlorophenyl)-3 -(1-hydroxypropan-2-yl)-8-(piperidin-l-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 178 0 N xk          O 1 F3C N (5)-3-(1 -hy droxypropan-2-yl)-8-morpholino-6-(6- (trifluoromethyl)pyridin-3 -yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 179 fA V f3c^n^     0 3-(2-hydroxy-2-methylpropyl)-8-(piperidin-1 -yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 180 Ay rA"NY'°H Y       0   1 F3C N (S)-3-(l-hydroxypropan-2-yl)-8-(pyri din-2-yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one 181 Q NXyN^ N Y" Ah (5)-6-cyclohexyl-3-(l-hydroxypropan-2-yl)-8- 182 Q /         y oh YA 0 (5)-3-(1 -hy droxypropan-2-yl)- 6-(pyridin-2-yl)-8-(pyri din-3- Compound No. Structure and name Compound No. Structure and name (pyridin-3-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 183 Q V o 1 (5)-3-(1 -hy droxypropan-2-yl)-6-(2-methylthiazol-4-yl)-8-(pyridin-3-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 184 Q rCY   t ^0H n-nx     o  = (5)-3-(1 -hy droxypropan-2-yl)-6-(1 -methyl-1 / 7-1,2,3 -triazol-5-yl)-8-(pyridin-3- yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 185 enantiome r 1 and 185 enantiome r 2 O     Q qF3          N AfS CF3 (^AArN^0H JI             o                                   o (7?)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-J]pyrimidin-4(3J7)-one and (5)-6-(4-chlorophenyl)-8-(pyri din-3 -y 1)-3 -(3,3,3 -trifluoro-2-hydroxypropyl)pyrido[3,4-J]pyrimidin-4(3Z / )-one 186 Q n 0   = (S)-3 -(1 -hy droxypropan-2-yl)-6-(5-methylpyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 187 Q n 0 ~ (S)-3-(l-hydroxypropan-2-yl)-6-(5-methylpyrimidin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one Compound No. Structure and name Compound No. Structure and name 188 F3C^   O (S)-8-(cyclohex-1 -en-1 -y 1)-3 -(1 -hy droxypropan-2-yl)-6-(5 -(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin- 4(3H)-one 189 f3c-x^^      °  ’ (S)-8-cyclohexyl-3-(l-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 190 Q o       o = (S)-3 -(1 -hy droxypropan-2-yl)- N,N-dimethyl-4-oxo-8- (pyridin-3-yl)-3,4- dihydropyrido[3,4-d]pyrimidine-6-carboxamide 191 HN-N -nA f3c^n    0 a (S)-3-(l-hydroxypropan-2-yl)-8-(lH-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin- 4(3H)-one 192 N^i nJ N Y^OH 0   = (S)-3 -(1 -hydroxypropan-2-yl)-6-(2-methoxyethyl)-8-(pyridin-3-yl)pyrido [3,4-d] pyrimidin-4(3H)-one 193 A f3c^n    0 £ (S)-3-(l-hydroxypropan-2-yl)-8-(2-methoxyethyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido [3,4-d]pyrimidin-4(3H)-one

[0097] In some embodiments, the present c isclosure is c rawn to one or more compounds chosen from the compounds below and pharmaceutically acceptable salts thereof: (i) (S)-8-(5-fluoropyridin-3-yl)-3-(l-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (ii) (S)-6-(4-chlorophenyl)-3-(l-hydroxypropan-2-yl)-8-(6-oxo-l,6-dihydropyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (iii)(S)-8-(benzo[d] [ 1,3 ]dioxol-4-yl)-6-(4-chlorophenyl)-3 -(1 -hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (iv)(S)-3-(l-hydroxypropan-2-yl)-8-(pyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (v) (S)-8-(5-fluoropyridin-3-yl)-3-(l-hydroxypropan-2-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (vi)(S)-3-(l-hydroxypropan-2-yl)-6,8-di(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (vii)      (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(l-hydroxypropan-2- yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (viii)      (S)-8-(3-fluorophenyl)-3-(l-hydroxypropan-2-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (ix)3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (x) 6,8-di(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xi)(S)-6-chloro-3-(l-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xii)       (S)-3-(l-hydroxypropan-2-yl)-8-(pyri din-3-yl)-6-(6- (trifluoromethyl)pyri din-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xiii)       6-(4-chlorophenyl)-8-(pyri din-3 -yl) - 3 -(3,3,3 -trifluoro-2- hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xiv)      8-(pyri din-3 -yl)-3 - (3,3,3 -trifluoro-2-hy droxypropyl)-6-(4- (trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xv)       6-(4-chlorophenyl)-8-(l-methyl-lH-pyrazol-4-yl)-3-(3,3,3-trifluoro-2- hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xvi)      3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(4- (trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xvii)     (S)-3-(l-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4- d]pyrimidin-4(3H)-one; (xviii)     6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3 - yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xix)      3-(2-hy droxy-2-methylpropyl)-6,8-bis(l -methyl-IH-pyrazol -4- yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xx)      (S)-3-(l-hydroxypropan-2-yl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin- 4(3H)-one; (xxi)      6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(l-methyl-lH- pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxii)     (S)-3 -(1 -hydroxypropan-2-yl)-8-(pyri din-3 -yl)-6-(4- (trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxiii)     (S)-3 -(1 -hydroxypropan-2-yl)-8-(pyri din-3 -yl)-6-(4- (trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxiv)    (S)-6-(4-chlorophenyl)-3-(l-hydroxypropan-2-yl)-8-(pyridin-3- yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxv)     (S)-3-(l-hydroxypropan-2-yl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(4- (trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxvi)    (S)-3-(l-hydroxypropan-2-yl)-8-(l-methyl-lH-pyrazol-4-yl)-6- phenylpyrido[3,4-d]pyrimidin-4(3H)-one; (xxvii) (S)-6-(4-chlorophenyl)-3-(l-hydroxypropan-2-yl)-8-(l-methyl-lH-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxviii) 3-methyl-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxix) Rac-6-(4-chlorophenyl)-3-(( / raws)-4-hydroxytetrahydrofuran-3-yl)-8-(pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxx)     (S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(l-methyl-lH- pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxi)    (R)-6-(4-chl orophenyl)-3-(3-hy droxy-3-methylbutan-2-yl)-8-(l -methyl- 1H- pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxii)    rac-6-(4-chlorophenyl)-3-((czs)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin- 3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxiii)   (R)-6-(4-chlorophenyl)-3-(3 -hydroxy-3 -methylbutan-2-yl)-8-(pyridin-3 - yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxiv)   (S)-3-(3-hydroxy-3-methylbutan-2-yl)-6,8-di(pyridin-3-yl)pyrido[3,4- d]pyrimidin-4(3H)-one; (xxxv)    (S)-6,8-bi s(3,5 -difluorophenyl)-3 -(1 -hydroxy-3 -methylbutan-2- yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxvi)   (S)-6-(4-chlorophenyl)-3 -(3 -hydroxy-3 -methylbutan-2-yl)-8-(pyridin-3 - yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxvii) (S)-8-(3,5-difluorophenyl)-3-(l-hydroxy-3-methylbutan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxviii) 6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(2-hydroxy-2-methylpropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxix)   (R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2- yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xl)(S)-3-(l-(benzyloxy)propan-2-yl)-8-(3-fluorophenyl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xli)       (R)-6-(4-chlorophenyl)-8-(3 -fluorophenyl)-3 -(3,3,3 -trifluoro-2 - hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlii)      (S)-6-(4-chlorophenyl)-8-(3 -fluorophenyl)-3 -(3,3,3 -trifluoro-2- hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xliii)     (S)-3-(l-hydroxypropan-2-yl)-6-morpholino-8-(pyridin-3-yl)pyrido[3,4- d]pyrimidin-4(3H)-one; (xliv)     (S)-3-(l-hydroxypropan-2-yl)-8-(lH-imidazol-l-yl)-6-(4- (trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlv)      (S)-3-(l-methoxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4- d]pyrimidin-4(3H)-one; (xlvi)     (S)-3-(l-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlvii)     (S)-8-(3-fluorophenyl)-3-(l-hydroxypropan-2-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlviii)    (S)-8-(3-fluorophenyl)-3-(l-hydroxypropan-2-yl)-6-(p-tolyl)pyrido[3,4- d]pyrimidin-4(3H)-one; (xlix)     (S)-8-(3-fluorophenyl)-3-(l-hydroxypropan-2-yl)-6-(4- (trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (1) (S)-3 -(1 -hydroxypropan-2-yl)-8-(pyridin-3 -yl)-6-(6-(trifluoromethoxy)pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (li) (S)-3-(2-hydroxy-2-methylpropyl)-8-(lH-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lii)methyl (S)-5-(3-(l-hydroxypropan-2-yl)-4-oxo-8-(pyridin-3-yl)-3,4- dihydropyrido[3,4-d]pyrimidin-6-yl)picolinate (liii)      (S)-3-(l-hydroxypropan-2-yl)-6-(isothiazol-4-yl)-8-(pyridin-3- yl)pyrido[3,4-d]pyrimidin-4(3H)-one (liv)       3-(2-hydroxy-2-methylpropyl)-8-(isothiazol-4-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lv)(S)-3-(l-hydroxypropan-2-yl)-8-( isothiazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ivi)       (S)-3-(l-hydroxypropan-2-yl)-6,8-di(isothiazol-4-yl)pyrido[3,4- d]pyrimidin-4(3H)-one (Ivii)      (S)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Iviii)     (S)-6-(4-chlorophenyl)-3-(l-hydroxypropan-2-yl)-8-(isothiazol-4- yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lix)      3-(2-hydroxy-2-methylpropyl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin- 4(3H)-one (lx)3-(2-hydroxy-2-methylpropyl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixi)      6-(4-chloro-2-methylphenyl)-3-(2-hydroxy-2-methylpropyl)-8-(l-methyl- lH-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixii)      (S)-3-(l-hydroxypropan-2-yl)-8-(lH-pyrazol-4-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixiii)     (S)-3-(l-hydroxypropan-2-yl)-8-(2-methylpyridin-3-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixiv)     (S)-3-(l-hydroxypropan-2-yl)-8-(4-methylpyridin-3-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixv)      (S)-3-(l-hydroxypropan-2-yl)-6-(4-methylthiazol-5-yl)-8-(pyridin-3- yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixvi)     (S)-6-(2-cyclopropylthiazol-5-yl)-3-(l-hydroxypropan-2-yl)-8-(pyridin-3- yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixvii)     (S)-3-(l-hydroxypropan-2-yl)-6-(2-isopropylthiazol-5-yl)-8-(pyridin-3- yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixviii)    (S)-3-(l-hydroxypropan-2-yl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixix)     (S)-3-(l-hydroxypropan-2-yl)-6,8-bis(6-(trifluoromethyl)pyridin-3- yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixx)      6-(4-chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin- 3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one. (Ixxi)     6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin- 3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxii)     3-(2-hydroxyethyl)-8-(pyridin-3-yl)-6-(4- (trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxiii)    (S)-6-(4-chlorophenyl)-3-(l-hydroxypropan-2-yl)-8-(l-methyl-6-oxo-l,6- dihydropyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxiv)    (S)-6-(6-cy clopropylpyridin-3-yl)-3 -(1 -hydroxypropan-2-yl)-8-(pyridin-3 - yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxv)     (S)-3 -(1 -hydroxypropan-2-yl)-6-(4-methyl-6-(trifluoromethyl)pyridin-3 - yl)-8-(pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxvi)    (S)-3-(l-hydroxypropan-2-yl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(pyridin-3- yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxvii)   (S)-6-(cyclohex-l-en-l-yl)-3 -(1 -hydroxypropan-2-yl)-8-(pyridin-3 - yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxviii) (S)-6,8-bis(5-fluoropyridin-3-yl)-3-(l-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxix) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxx)    3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxxi)    6-(6-cy clopropylpyridin-3 -yl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3 - yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxxii)   6-(6-cy cl opropylpyri din-3 -yl)-3-(2-hy droxy-2-m ethylpropyl)-8-( 1-methyl- lH-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxxiii) (S)-6-(6-cyclopropylpyridin-3-yl)-3-(l-hydroxypropan-2-yl)-8-(l-methyl-lH-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxxiv) (S)-3-(l-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxxv)   (S)-3 -(1 -hydroxypropan-2-yl)-8-(pyri din-3 -yl)-6-(2- (trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxxvi)   (S)-3 -(1 -hydroxypropan-2-yl)-8-(pyri din-3 -yl)-6-(2- (trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxxvii) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxxviii) 3-((3 S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxxix) (S)-3-(l-hydroxypropan-2-yl)-6-(2-methylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xc) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xci)      (S)-3-(l-hydroxypropan-2-yl)-6-(piperidin-l-yl)-8-(pyridin-3- yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcii)     3-(2-hydroxy-2-methylpropyl)-8-( isothiazol-4-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xciii)     (S)-3-(l-hydroxypropan-2-yl)-8-( isothiazol-4-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xciv)     3-(2-hydroxy-2-methylpropyl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcv)      (S)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcvi)     (3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcvii)    3-(l,l-dioxidotetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcviii)   (R)-3-(l,l-dioxidotetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcix) (R)-3-(2-hydroxypropyl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (c) (S)-3-(2-hydroxypropyl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (ci)(R)-8-(l-methyl-lH-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cii)       (S)-8-(l-methyl-lH-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6- (6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (ciii)      (R)-3-(2-hydroxypropyl)-8-(pyridin-3 -yl)-6-(6-(trifluoromethyl)pyridin-3 - yl)pyrido[3,4-d]pyrimidin-4(3H)-one (civ)      (R)-8-( 1 -methyl-1 H-pyrazol-4-yl)-3 -(3,3,3 -trifluoro-2-hy droxypropyl)-6- (5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cv)      3-((3 S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(l-methyl-lH-pyrazol-4-yl)- 6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cvi)      3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(l-methyl-lH-pyrazol-4-yl)- 6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cvii)     6-(4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(l- methyl-lH-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cviii)     3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cix)      (S)-6-(6-cy cl opropylpyri din-3 -yl)-8-(pyri din-3 -y 1)-3 -(3,3,3 -trifluoro-2- hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (ex)       (R)-6-(6-cyclopropylpyridin-3-yl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2- hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxi)      (R)-8-(pyri din-3 -yl)-3 -(3,3,3-trifluoro-2-hydroxypropyl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxii)      (R)-8-(pyri din-3 -yl)-3 -(3,3,3 -trifluoro-2-hy droxypropyl)-6-(4- (trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxiii)     (S)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4- (trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxiv)     6-(4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin- 3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxv)      3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxvi)     methyl (S)-2-(4-oxo-8-(pyridin-3 -yl)-6-(6-(trifluoromethyl)pyridin-3 - yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoate (cxvii)    6-(4-chlorophenyl)-3-(4-hydroxy-l-methylpyrrolidin-3-yl)-8-(pyri din-3- yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxviii)   6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidin-3-yl)-8-(pyridin-3 - yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxix)     (R)-6-(6-cy cl opropylpyri din-3-yl)-8-(l -methyl-lH-pyrazol-4-yl)-3-(3,3,3- trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxx)     (S)-6-(6-cyclopropylpyridin-3-yl)-8-(l-methyl-lH-pyrazol-4-yl)-3-(3,3,3- trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxi)     3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(l-methyl-lH-pyrazol-4-yl)- 6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxii)    3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(l-methyl-lH-pyrazol-4-yl)- 6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxiii)   3-((3 S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxiv)    3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxv)    (R)-3-(2-hydroxypropyl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxvi)   (S)-3-(2-hydroxypropyl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxvii)   (S)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2- yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxviii)  (R)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyri din-2- yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxix)    3-((3 S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxx)    (S)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3 - yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxi) (S)-8-(l-methyl-lH-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxii) (S)-3-(l-hydroxypropan-2-yl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxiii) 3-((3 S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxiv) 6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxv) 6-(4-Chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(l-methyl-lH-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxvi)   (R)-8-(pyri din-3 -yl)-3 -(3,3,3 -trifluoro-2-hy droxypropyl)-6-(5 - (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxvii) (S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoic acid (cxxxviii) (S)-N-methyl-2-(4-oxo-8-(pyridin-3 -yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanamide (cxxxix) (S)-N,N-dimethyl-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propenamide (cxl) 3-(2-hydroxy-2-methylpropyl)-8-(lH-pyrazol-4-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxli)     3-(2-hydroxy-2-methylpropyl)-8-(lH-imidazol-l-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlii)    3-(2-hydroxy-2-methylpropyl)-8-(lH-imidazol-l-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxliii)    (S)-3-(l-hydroxypropan-2-yl)-8-(lH-imidazol-l-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxliv)    (S)-3-(l-hydroxypropan-2-yl)-8-(lH-imidazol-l-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlv)     ( S)-3 -(1 -hydroxypropan-2-yl)-8-(lH-1,2,4-triazol-1 -yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlvi)    (S)-3-(l-hydroxypropan-2-yl)-8-(lH-pyrazol-l-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlvii) (S)-3-(l-hydroxypropan-2-yl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(2- (trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlviii) (S)-8-(diethylamino)-3-(l-hydroxypropan-2-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlix) (S)-3-(l-hydroxypropan-2-yl)-8-(piperidin-l-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cl)(S)-3-(l-hydroxypropan-2-yl)-8-(pyrrolidin-l-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cli)       (S)-6-(4-chlorophenyl)-3-(l-hydroxypropan-2-yl)-8-(piperidin-l- yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clii)      (S)-3-(l-hydroxypropan-2-yl)-8-(pyridin-2-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cliii)     (S)-6-cyclohexyl-3-(l-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4- d]pyrimidin-4(3H)-one (cliv)     (S)-3-(l-hydroxypropan-2-yl)-6-(pyri din-2-yl)-8-(pyri din-3-yl)pyrido[3,4- d]pyrimidin-4(3H)-one (civ)      (S)-3 -(1 -hydroxypropan-2-yl)-6-(2-methylthiazol-4-yl)-8-(pyridin-3 - yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clvi)     (S)-3-(l-hydroxypropan-2-yl)-6-(l-methyl-lH-l,2,3-triazol-5-yl)-8- (pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clvii)     (R)-6-(4-chlorophenyl)-8-(pyri din-3 -y 1)-3 -(3,3,3 -trifluoro-2- hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (clviii)    (S)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2- hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (clix)     (S)-3-(l-hydroxypropan-2-yl)-8-(l-methyl-l,2,5,6-tetrahydropyridin-3-yl)- 6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clx)      6-(4-chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(l- methyl-lH-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxi)     (5)-3-(l-hydroxypropan-2-yl)-6-(2-methylpyrimidin-5-yl)-8-(pyridin-3- yl)pyrido[3,4-d]pyrimidin-4(3 J7)-one (clxii)     3-(2-hydroxy-2-methylpropyl)-8-(l-(trifluoromethyl)-lJH-pyrazol-4-yl)-6- (6-(trifluoromethyl)pyri din-3 -yl)pyrido[3,4-J]pyrimidin-4(3J7)-one (clxiii)    f'5)-3-(l-hydroxypropan-2-yl)-8-(l-methyl-lJH-pyrazol-4-yl)-6-(2- (trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one (clxiv)    3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2- (trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one (clxv)     (5)-5-(3-(l-hydroxypropan-2-yl)-4-oxo-8-(pyridin-3-yl)-3,4- dihydropyrido[3,4-J]pyrimidin-6-yl)picolinic acid (clxvi)    f5)-3-(l-hydroxypropan-2-yl)-6-(6-methylpyridin-3-yl)-8-(pyridin-3- yl)pyrido[3,4-d]pyrimidin-4(3 J7)-one (clxvii)   3-(2-hydroxy-2-methylpropyl)-8-(l-methyl-l / / -pyrazol-4-yl)-6-(2- (trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one (clxviii) 3,8-di(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3J7)-one (clxix) 8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3J7)-one (clxx)     3-((37?,47?)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one (clxxi)    3-((37?,47?)-4-hydroxytetrahydrofuran-3-yl)-8-(l-methyl-1 / Z-pyrazol-4-yl)- 6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one (clxxii) 6-(4-chlorophenyl)-3-((37?,47?)-4-hydroxytetrahydrofuran-3-yl)-8-(l-methyl-lH-pyrazol-4-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one (clxxiii)   3-cy clopentyl-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3 - yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxiv) 3-phenyl-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxv) 3-((37?,47?)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one (clxxvi)   3-((37?,47?)-4-hydroxytetrahydrofuran-3-yl)-8-(l-methyl-1 / Z-pyrazol-4-yl)- 6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one (clxxvii) (S)-3-(l-hydroxypropan-2-yl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxviii) (S)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimi din-3 (4H)-yl)propanamide (clxxix) 3-(2-hydroxy-2-methylpropyl)-8-(lH-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxx) (5)-6-(4-chlorophenyl)-3-(l-hydroxypropan-2-yl)-8-(l / / -pyrazol-l-yl)pyrido[3,4-d]pyrimidin-4(3 H)-one (clxxxi) (5)-3-(l-hydroxypropan-2-yl)-8-(l / / -pyrazol-l-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one (clxxxii) 3-((35,45)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(2- (trifluoromethyl)thiazol-5-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one (clxxxiii) 3-(2-hydroxy-2-methylpropyl)-8-(l-methyl-l / / -pyrazol-4-yl)-6-(2- (trifluoromethyl)thiazol-5-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one (clxxxiv) 3-((35,45)-4-hydroxytetrahydrofuran-3-y 1)-8-(1 -methyl- l / / -pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one (clxxxv)  3-((35,45)-4-hydroxytetrahydrofuran-3-yl)-8-(l -methyl- l / / -pyrazol-4-yl)- 6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one (clxxxvi) 3-((35,45)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(2- (trifluoromethyl)thiazol-5-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one (clxxxvii) (5)-3-(1 -hydroxypropan-2-yl)-8-morpholino-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one (clxxxviii) 3-(2-hydroxy-2-methylpropyl)-8-(piperidin-l-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one (clxxxix) (S)-3-(l-hydroxypropan-2-yl)-6-(5-methylpyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxc)     (S)-3-(l-hydroxypropan-2-yl)-6-(5-methylpyrimidin-2-yl)-8-(pyridin-3- yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxci)     (S)-8-(cyclohex-l-en-l-yl)-3-(l-hydroxypropan-2-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxcii) (S)-8-cyclohexyl-3-(l-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxciii) (S)-3-(l-hydroxypropan-2-yl)-N,N-dimethyl-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidine-6-carboxamide (cxciv) (S)-3-(l-hydroxypropan-2-yl)-8-(lH-pyrazol-4-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxcv) (S)-3-(l-hydroxypropan-2-yl)-6-(2-methoxyethyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxcvi) (S)-3-(l-hydroxypropan-2-yl)-8-(2-methoxyethyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one.

[0098] The compounds of formula I or formula la and pharmaceutically acceptable salts thereof can be incorporated into pharmaceutical compositions. In some embodiments, the disclosure is drawn to a pharmaceutical composition comprising at least one entity chosen from compounds of formula I or formula la and pharmaceutically acceptable salts thereof. In some embodiments, the disclosure is drawn to a pharmaceutical composition consisting essentially of at least one entity chosen from compounds of formula I or formula la and pharmaceutically acceptable salts thereof.

[0099] In some embodiments, the at least one entity chosen from compounds of formula I or formula la and pharmaceutically acceptable salts thereof can be administered in combination with at least one additional therapy. In some embodiments, the at least one additional therapy is chosen from immune checkpoint inhibitors (ICIs).

[00100] In some embodiments, the at least one additional therapy is chosen from anti-CTLA-4 compounds, anti-PD-1 compounds, and anti-PDL-1 compounds. In some embodiments, the at least one additional therapy is chosen from Pembrolizumab (Keytruda); Nivolumab (Opdivo); Ipilimumab (Yervoy); Avelumab (Bavencio); Atezolizumab (Tecentriq); Durvalumab (Imfinzi); Cemiplimab (LBTAYO); Sintilimab (Tyvyt); Toripalimab (Tuoyi); Camrelizumab (AiRuiKa); Spartalizumab; and Tislelizumab. In some embodiments, the at least one additional therapy is chosen from anti-LAG-3 (lymphocyte activation gene-3) compounds; anti-TIM-3 (T-cell immunoglobulin and mucin-domaincontaining-3) compounds; anti-TIGIT (T-cell immunoglobulin and ITIM domain) compounds; anti-VISTA (V-domain Ig suppressor of T-cell activation) compounds; or a combination thereof. Non-limiting examples of anti-LAG-3 compounds include IMP321 (Eftilagimod alpha), Relatlimab (BMS-986016), LAG525, MK-4280, REGN3767, TSR-033, BI754111, Sym022, FS118, and MGD013. Non-limiting examples of anti-TIM-3 compounds include TSR-022, MBG453, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, RO7121661. Non-limiting examples of anti-TIGIT compounds include MK-7684, Etigilimab (OMP-313), Tiragolumab (MTIG7192A, RG-6058), BMS- 986207, AB-154, and ASP-8374. Non-limiting examples of anti-VISTA compounds include JNJ-61610588 and CA-170.

[00101] In some embodiments, the pharmaceutical composition comprises at least one entity chosen from compounds of formula I or formula la and pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients are well-known to persons having ordinary skill in the art and are described in, as a non-limiting example, Remington: The Science and Practice of Pharmacy, 22nd Edition, Lippincott Williams & Wilkins, Philadelphia, Pa. (2013) and any other editions, which are hereby incorporated by reference. In some embodiments, the pharmaceutical composition further comprises at least one at least one additional therapy.

[00102] Compounds of the disclosure, pharmaceutically acceptable salts thereof, and / or pharmaceutical compositions comprising said at least one entity chosen from compounds of formula I or formula la and pharmaceutically acceptable salts thereof, and optionally further comprising at least one at least one additional therapy, can be used in therapeutic treatments.

[00103] The compounds, pharmaceutically acceptable salts, additional therapies, and / or pharmaceutical compositions can be administered in unit forms of administration to mammalian subjects, including human beings. Suitable non-limiting examples of unit forms of administration include orally administered forms and forms administered via a parenteral / systemic route, non-limiting examples of which including inhalation, subcutaneous administration, intramuscular administration, intravenous administration, intradermal administration, and intravitreal administration.

[00104] In some embodiments, pharmaceutical compositions suitable for oral administration can be in the form of tablets, pills, powders, hard gelatine capsules, soft gelatine capsules, and / or granules. In some embodiments of such pharmaceutical compositions, a compound of the disclosure and / or a pharmaceutically acceptable salt of a compound of the disclosure is (or are) mixed with one or more inert diluents, non-limiting examples of which including starch, cellulose, sucrose, lactose, and silica. In some embodiments, such pharmaceutical compositions may further comprise one or more substances other than diluents, such as (as non-limiting examples), lubricants, coloring agents, coatings, or varnishes. In some embodiments, such pharmaceutical compositions may further comprise at least one at least one additional therapy.

[00105] In some embodiments, pharmaceutical compositions for parenteral administration can be in the form of aqueous solutions, non-aqueous solutions, suspensions, emulsions, drops, or any combination(s) thereof. In some embodiments, such pharmaceutical compositions may comprise one or more of water, pharmaceutically acceptable glycol(s), pharmaceutically acceptable oil(s), pharmaceutically acceptable organic esters, or other pharmaceutically acceptable solvents. In some embodiments, such pharmaceutical compositions may further comprise at least one at least one additional therapy.

[00106] In some embodiments, disclosed herein is a method of inhibiting AhR comprising administering to a subject in need thereof at least one entity chosen from compounds of formula I or formula la and pharmaceutically acceptable salts thereof. In some embodiments, disclosed herein is a method of reducing the activity of AhR comprising administering to a subject in need thereof at least one entity chosen from compounds of formula I or formula la and pharmaceutically acceptable salts thereof. In some embodiments, such pharmaceutical compositions may further comprise at least one at least one additional therapy.

[00107] In some embodiments, disclosed herein is a method of treating a cancer comprising administering to a subject in need thereof at least one entity chosen from compounds of formula I or formula la and pharmaceutically acceptable salts thereof. In some embodiments, the cancers are chosen from liquid tumors and solid tumors. In some embodiments, the cancer is chosen from breast cancers, respiratory tract cancers, brain cancers, cancers of reproductive organs, digestive tract cancers, urinary tract cancers, eye cancers, liver cancers, skin cancers, head and neck cancers, thyroid cancers, parathyroid cancers, and metastases of any of the foregoing. In some embodiments, the cancers are chosen from breast cancers, pancreatic cancers, prostate cancers, and colon cancers. In some embodiments, the cancers are chosen from lymphomas, sarcomas, and leukemias.

[00108] In some embodiments, disclosed herein is a method of treating cancer comprising administering to a subject in need thereof at least one entity chosen from compounds of formula I or formula la and pharmaceutically acceptable salts thereof and at least one additional therapy. In some embodiments, the cancer is chosen from non-small cell lung cancer (NSCLC); small cell lung cancer; head and neck squamous cell carcinoma; renal cell carcinoma; gastric adenocarcinoma; nasopharyngeal neoplasms; urothelial carcinoma; colorectal cancer; pleural mesothelioma; triple-negative breast cancer (TNBC); esophageal neoplasms; multiple myeloma; gastric and gastroesophageal junction cancer; melanoma; Hodgkin lymphoma; hepatocellular carcinoma; lung cancer; head and neck cancer; non-Hodgkin lymphoma; metastatic clear cell renal carcinoma; squamous cell lung carcinoma; mesothelioma; gastric cancer; gastroesophageal junction cancer; metastatic melanoma; metastatic non-cutaneous melanoma; urothelial cancer; diffuse large B-cell lymphoma; renal cell cancer; ovarian cancer, fallopian tube cancer; peritoneal neoplasms; extensive stage small cell lung cancer; bladder cancer; transitional cell carcinoma; prostatic neoplasms; recurrent or metastatic PD-L1 positive or negative squamous cell carcinoma of the head and neck (SCCHN); recurrent squamous cell lung cancer; advanced solid malignancies; SCCHN; hypo pharyngeal squamous cell carcinoma; laryngeal squamous cell carcinoma; unresectable or metastatic melanoma; biliary tract neoplasms; esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, glioblastoma, metastatic cancer, prostatic cancer, solid organ cancer; stomach cancer; colon cancer; and liver cancer.

[00109] In some embodiments, disclosed herein is a method of treating ocular disorders comprising administering to a subject in need thereof at least one entity chosen from compounds of formula I or formula la and pharmaceutically acceptable salts thereof and optionally at least one additional therapy.

[00110] With regard to the methods disclosed herein, the mode (or modes) of administration, dose (or doses), and pharmaceutical form (or forms) can be determined according to criteria generally considered during the establishment of a treatment of a patient, such as, by way of non-limiting examples, the potency of the compound(s) and / or pharmaceutically acceptable salts of the compound(s), the at least one additional therapy (if present), the age of the patient, the body weight of the patient, the severity of the patient’s condition (or conditions), the patient’s tolerance to the treatment, and secondary effects observed in treatment. Determination of doses effective to provide therapeutic benefit for specific modes and frequency of administration is within the capabilities of those skilled in the art.

[00111] In some embodiments, a compound of formula I or formula la and / or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount ranging from 5 pg to 2,000 mg. In some embodiments, a compound of the disclosure and / or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount ranging from 5 pg to 1,000 mg. In some embodiments, a compound of the disclosure and / or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount ranging from 5 pg to 500 mg. In some embodiments, a compound of the disclosure and / or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount ranging from 5 pg to 250 mg. In some embodiments, a compound of the disclosure and / or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount ranging from 5 pg to 100 mg. In some embodiments, a compound of the disclosure and / or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount ranging from 5 pg to 50 mg.

[00112] In some embodiments, a compound of the disclosure and / or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount ranging from 1 mg to 5,000 mg. In some embodiments, a compound of the disclosure and / or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount ranging from 1 mg to 3,000 mg. In some embodiments, a compound of the disclosure and / or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount ranging from 1 mg to 2,000 mg. In some embodiments, a compound of the disclosure and / or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount ranging from 1 mg to 1,000 mg. In some embodiments, a compound of the disclosure and / or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount ranging from 1 mg to 500 mg. In some embodiments, a compound of the disclosure and / or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount ranging from 1 mg to 250 mg. In some embodiments, a compound of the disclosure and / or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount ranging from 1 mg to 100 mg. In some embodiments, a compound of the disclosure and / or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount ranging from 1 mg to 50 mg.

[00113] In some embodiments, a compound of the disclosure and / or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 1,000 mg, 1,100 mg, 1,200 mg, 1,300 mg, 1,400 mg, 1,500 mg, 1,600 mg, 1,700 mg, 1,800 mg, 1,900 mg, 2,000 mg, 2,100 mg, 2,200 mg, 2,300 mg, 2,400 mg, 2,500 mg, 2,600 mg, 2,700 mg, 2,800 mg, 2,900 mg, 3,000 mg, 3,100 mg, 3,200 mg, 3,300 mg, 3,400 mg, 3,500 mg, 3,600 mg, 3,700 mg, 3,800 mg, 3,900 mg, 4,000 mg, 4,100 mg, 4,200 mg, 4,300 mg, 4,400 mg, 4,500 mg, 4,600 mg, 4,700 mg, 4,800 mg, 4,900 mg, or 5,000 mg.

[00114] Effective amounts and dosages can be estimated initially from in vitro assays. For example, an initial dosage for use in animals can be formulated to achieve a circulating blood or serum concentration of active compound that is at or above an ICso of the particular compound as measured in an in vitro assay. Calculating dosages to achieve such circulating blood or serum concentrations taking into account the bioavailability of the particular compound is well within the capabilities of skilled artisans. For guidance, the reader is referred to Fingl & Woodbury, “General Principles,” in Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, latest edition, Pergamagon Press, and the references cited therein, which methods are incorporated herein by reference in their entirety. Initial dosages can also be estimated from in vivo data, such as animal models. Animal models useful for testing the efficacy of compounds to treat or prevent the various diseases described in this disclosure are well-known in the art.

[00115] In some embodiments, the administered dose ranges from 0.0001 or 0.001 or 0.01 mg / kg / day to 100 mg / kg / day, but can be higher or lower, depending upon, among other factors, the activity of the compound, its bioavailability, the mode of administration and various factors discussed above. Doses and intervals can be adjusted individually to provide plasma levels of the compound(s) which are sufficient to maintain therapeutic or prophylactic effect. For example, the compounds can be administered once per week, several times per week (e.g., every other day), once per day or multiple times per day, depending upon, among other things, the mode of administration, the specific indication being treated and the judgment of the prescribing physician. In cases of local administration or selective uptake, such as local topical administration, the effective local concentration of active compound(s) may not be related to plasma concentration. Skilled artisans will be able to optimize effective local dosages without undue experimentation.

[00116] Non-limiting embodiments of the present disclosure include: 1.     A compound of Formula I: R2 O (I) and pharmaceutically acceptable salts thereof, wherein: each of R1 and R2 is independently chosen from optionally substituted alkyls, optionally substituted esters, optionally substituted heteroalkyls, optionally substituted acyls, optionally substituted amides, optionally substituted aryls, optionally substituted heteroaryls, optionally substituted cycloalkyls, optionally substituted amines and optionally substituted heterocycloalkyls; and R3 is chosen from hydrogen, optionally substituted alkyls, optionally substituted acyls, optionally substituted amides, optionally substituted aryls, optionally substituted cycloalkyls, optionally substituted esters, optionally substituted heteroalkyls, optionally substituted heteroaryls, optionally substituted heterocycloalkyls, optionally substituted amines, cyano, halos, hydroxy, and -C(O)H. 2. A compound of Formula la (la) or a pharmaceutically acceptable salt thereof, wherein: ring A is chosen from optionally substituted aryls, optionally substituted heteroaryls, optionally substituted cycloalkyls, and optionally substituted heterocy cl oalky 1 s; ring B is chosen from optionally substituted aryls, optionally substituted heteroaryls, optionally substituted cycloalkyls, and optionally substituted heterocycloalkyls; and R is chosen from hydrogen, optionally substituted alkyls, optionally substituted acyls, optionally substituted amides, optionally substituted aryls, optionally substituted cycloalkyls, optionally substituted esters, optionally substituted heteroalkyls, optionally substituted heteroaryls, optionally substituted heterocycloalkyls, amino, cyano, halos, hydroxy, and -C(O)H. 3. The compound of embodiment 2, or a pharmaceutically acceptable salt thereof, wherein: ring A is chosen from optionally substituted 6-10 membered aryls, optionally substituted 5-10 membered heteroaryls, optionally substituted 3-10 membered cycloalkyls, and optionally substituted 3-10 membered heterocycloalkyls; ring B is chosen from optionally substituted 6-10 membered aryls, optionally substituted 5-10 membered heteroaryls, optionally substituted 3-10 membered cycloalkyls, and optionally substituted 3-10 membered heterocycloalkyls; R is chosen from hydrogen, optionally substituted Ci-Cio alkyls, optionally substituted 6-10 membered aryls, -C(O)R’, -C(O)NR’R’, optionally substituted 3-10 membered cycloalkyls, -C(O)OR’, optionally substituted Ci-Cio heteroalkyls, optionally substituted 5-10 membered heteroaryls, optionally substituted 3-10 membered heterocycloalkyls, amino, cyano, halos, hydroxy, and -C(O)H; and each R’ is independently chosen from hydrogen, optionally substituted Ci-Cio alkyls, and optionally substituted Ci-Cio heteroalkyls. 4. The compound of embodiment 2 or 3, or a pharmaceutically acceptable salt thereof, wherein: ring A is chosen from 6-10 membered aryls, 5-10 membered heteroaryls, 3-10 membered cycloalkyls, and 3-10 membered heterocycloalkyls, wherein each 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl is independently optionally substituted with 1 to 5 instances ofRA; ring B is chosen from 6-10 membered aryls, 5-10 membered heteroaryls, 3-10 membered cycloalkyls, and 3-10 membered heterocycloalkyls, wherein each 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl is independently optionally substituted with 1 to 5 instances ofRB; R is chosen from hydrogen, Ci-Cio alkyls, 6-10 membered aryls, -C(O)R’, -C(O)NR’R’, 3-10 membered cycloalkyls, -C(O)OR’, Ci-Cio heteroalkyls, 5-10 membered heteroaryls, 3-10 membered heterocycloalkyls, amino, cyano, halos, hydroxy, and -C(O)H, wherein each Ci-Cio alkyl, 6-10 membered aryl, 3-10 membered cycloalkyl, Ci-Cio heteroalkyl, 5-10 membered heteroaryl, and 3-10 membered heterocycloalkyl is independently optionally substituted with 1 to 5 instances of Rc; each R’ is independently chosen from hydrogen, Ci-Cio alkyls, Ci-Cio haloalkyls, Ci-Cio hydroxyalkyls, and Ci-Cio heteroalkyls; each Ra is independently chosen from halos, hydroxy, Ci-Cio alkyls, Ci-Cio haloalkyls, Ci-Cio alkoxys, Ci-Cio haloalkoxys, Ci-Cio hydroxy alkyls, and NR”R”; each Rb is independently chosen from halos, hydroxy, Ci-Cio alkyls, Ci-Cio haloalkyls, Ci-Cio alkoxys, Ci-Cio haloalkoxys, Ci-Cio hydroxy alkyls, and NR”R”; each Rc is independently chosen from halos, hydroxy, cyano, Ci-Cio alkyls, Ci-Cio alkoxys, Ci-Cio haloalkyls, 3-10 membered cycloalkyls, 3-10 membered heterocycloalkyls, 6-10 membered aryls, and 5-10 membered heteroaryls; and each R” is independently chosen from hydrogen, Ci-Cio alkyls, Ci-Cio haloalkyls, Ci-Cio hydroxyalkyls, and Ci-Cio heteroalkyls. 5. The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein ring A is chosen from 3-10 membered cycloalkyl optionally substituted with 1 to 5 instances of RA. 6. The compound of embodiment 4 or 5, or a pharmaceutically acceptable salt thereof, wherein ring A is chosen from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl optionally substituted with 1 to 5 instances of RA 7. The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein ring A is chosen from 6-8 membered aryls optionally substituted with 1 to 5 instances of RA. 8. The compound of embodiment 4 or 7, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl optionally substituted with 1 to 3 instances of RA. 9. The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein ring A is chosen from 5-8 membered heteroaryls optionally substituted with 1 to 5 instances of RA. 10. The compound of embodiment 4 or 9, or a pharmaceutically acceptable salt thereof, wherein ring A is chosen from pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazoyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl, wherein each of pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazoyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl is independently optionally substituted with 1 to 3 instances of RA. 11. The compound of any one of embodiments 4, 9, or 10, or a pharmaceutically acceptable salt thereof, wherein ring A is pyridinyl optionally substituted with 1 to 3 instances of RA. 12. The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein ring A is chosen from 5-8 membered heterocycloalkyls optionally substituted with 1 to 5 instances of RA. 13. The compound of embodiment 4 or 12, or a pharmaceutically acceptable salt thereof, wherein ring A is chosen from pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydropyranyl, and tetrahydrofuranyl, wherein each of pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydropyranyl, and tetrahydrofuranyl is independently optionally substituted with 1 to 3 instances of RA. 14. The compound of any one of embodiments 4, 12, or 13, or a pharmaceutically acceptable salt thereof, wherein ring A is piperidinyl or morpholino optionally substituted with 1 to 3 instances of RA. 15. The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein ring B is chosen from 6-8 membered aryls optionally substituted with 1 to 5 instances of RB. 16. The compound of embodiment 4 or 15, or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl optionally substituted with 1 to 3 instances of RB. 17. The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein ring B is chosen from benzodioxolyl and 5-8 membered heteroaryls optionally substituted with 1 to 5 instances of RB. 18. The compound of embodiment 4 or 17, or a pharmaceutically acceptable salt thereof, wherein ring B is chosen from benzodioxolyl, pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazoyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyridinonyl, and pyrimidinyl, wherein each of benzodioxolyl, pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazoyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl is independently optionally substituted with 1 to 3 instances of RB. 19. The compound of any one of embodiments 4, 17, or 18, or a pharmaceutically acceptable salt thereof, wherein ring B is chosen from pyrazolyl, isothiazoyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl, wherein each of pyrazolyl, isothiazoyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl is independently optionally substituted with 1 to 3 instances of RB. 20. The compound of any one of embodiments 4 to 19, or a pharmaceutically acceptable salt thereof, wherein: each Ra is independently chosen from halos, Ci-Cio alkyls, Ci-Cio haloalkyls, Ci-Cio alkoxys, Ci-Cio haloalkoxys, and NR”R”; each Rb is independently chosen from halos, Ci-Cio alkyls, and Ci-Cio haloalkyls; each Rc is independently chosen from halos, hydroxy, cyano, Ci-Cio alkyls, Ci-Cio alkoxys, 3-8 membered cycloalkyls, 3-8 membered heterocycloalkyls, and 6-8 membered aryls; and each R” is independently chosen from hydrogen and Ci-Cio alkyls. 21. The compound of any one of embodiments 2 to 4, and 7 to 20, or a 23. The compound of any one of embodiments 2 to 4, and 7 to 20, or a 24. The compound of any one of embodiments 2 to 4, and 7 to 20, or a pharmaceutically acceptable salt thereof, wherein ring B is chosen from         , 25. The compound of any one of embodiments 2 to 14 and 20, or a pharmaceutically 26. The compound of any one of embodiments 2 to 4, and 7 to 20, or a pharmaceutically acceptable salt thereof, wherein ring B is chosen from 27. The compound of any one of embodiments 2 to 26, or a pharmaceutically acceptable salt thereof, wherein R is chosen from methyl, 28. The compound of any one of embodiments 2 to 27, or a pharmaceutically 29. At least one entity chosen from the compounds below and pharmaceutically acceptable salts thereof: (i) (S)-8-(5-fluoropyridin-3-yl)-3-(l-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (ii) (S)-6-(4-chlorophenyl)-3-(l-hydroxypropan-2-yl)-8-(6-oxo-l,6-dihydropyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (iii)(S)-8-(benzo[d] [ 1,3 ]dioxol-4-yl)-6-(4-chlorophenyl)-3 -(1 -hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (iv)(S)-3-(l-hydroxypropan-2-yl)-8-(pyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (v) (S)-8-(5-fluoropyridin-3-yl)-3-(l-hydroxypropan-2-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (vi)(S)-3-(l-hydroxypropan-2-yl)-6,8-di(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (vii) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(l-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (viii) (S)-8-(3-fluorophenyl)-3-(l-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (ix)3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (x) 6,8-di(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xi)(S)-6-chloro-3-(l-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xii) (S)-3-(l-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xiii) 6-(4-chlorophenyl)-8-(pyri din-3 -yl)-3 -(3,3,3 -trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xiv) 8-(pyridin-3 -yl)-3 -(3,3,3 -trifluoro-2-hy droxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xv) 6-(4-chlorophenyl)-8-(l-methyl-lH-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xvi) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xvii) (S)-3-(l-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xviii) 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xix) 3-(2-hydroxy-2-methylpropyl)-6,8-bis(l-methyl-IH-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xx) (S)-3-(l-hydroxypropan-2-yl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxi) 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(l-methyl-lH-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxii) (S)-3-(1 -hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4- (trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxiii) (S)-3 -(1 -hydroxypropan-2-yl)-8-(pyri din-3 -yl)-6-(4- (trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxiv) (S)-6-(4-chlorophenyl)-3-(l-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxv) (S)-3-(l-hydroxypropan-2-yl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxvi) (S)-3-(l-hydroxypropan-2-yl)-8-(l-methyl-lH-pyrazol-4-yl)-6-phenylpyrido[3,4-d]pyrimidin-4(3H)-one; (xxvii)       (S)-6-(4-chlorophenyl)-3-(l-hydroxypropan-2-yl)-8-(l-methyl-lH- pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxviii)      3-methyl-8-(pyridin-3-yl)-6-(4- (trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxix) Rac-6-(4-chlorophenyl)-3-(( / raws)-4-hydroxytetrahydrofuran-3-yl)-8-(pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxx) (S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(l-methyl-lH-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxi) (R)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(l -methyl- 1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxii)       rac-6-(4-chlorophenyl)-3-((czs)-4-hydroxytetrahydrofuran-3-yl)-8- (pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxiii)      (R)-6-(4-chlorophenyl)-3-(3 -hydroxy-3 -methylbutan-2-yl)-8- (pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxiv)      (S)-3 -(3 -hydroxy-3 -methylbutan-2-yl)-6,8-di(pyridin-3 - yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxv)(S)-6,8-bi s(3,5 -difluorophenyl)-3 -(1 -hydroxy-3 -methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxvi)      (S)-6-(4-chlorophenyl)-3-(3 -hydroxy-3 -methylbutan-2-yl)-8- (pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxvii)      (S)-8-(3,5-difluorophenyl)-3-(l-hydroxy-3-methylbutan-2-yl)-6-(p- tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxviii)     6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(2-hydroxy-2- methylpropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxix)      (R)-6-(4-chlorophenyl)-8-(3 -fluorophenyl)-3 -(3 -hydroxy-3 - methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xl)(S)-3-(l-(benzyloxy)propan-2-yl)-8-(3-fluorophenyl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xli) (R)-6-(4-chlorophenyl)-8-(3 -fluorophenyl)-3 -(3,3,3 -trifluoro-2 -hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlii) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3 -trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xliii) (S)-3-(l-hydroxypropan-2-yl)-6-morpholino-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xliv) (S)-3-(l-hydroxypropan-2-yl)-8-(lH-imidazol-l-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlv) (S)-3-(l-methoxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlvi) (S)-3-(l-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlvii) (S)-8-(3-fluorophenyl)-3-(l-hydroxypropan-2-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlviii) (S)-8-(3-fluorophenyl)-3-(l-hydroxypropan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlix) (S)-8-(3-fluorophenyl)-3-(l-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (1) (S)-3-(l-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(6- (trifluoromethoxy)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (li) (S)-3-(2-hydroxy-2-methylpropyl)-8-(lH-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lii)methyl (S)-5-(3-(l-hydroxypropan-2-yl)-4-oxo-8-(pyridin-3-yl)-3,4- dihydropyrido[3,4-d]pyrimidin-6-yl)picolinate (liii) (S)-3-(l-hydroxypropan-2-yl)-6-(isothiazol-4-yl)-8-(pyridin-3- yl)pyrido[3,4-d]pyrimidin-4(3H)-one (liv) 3-(2-hydroxy-2-methylpropyl)-8-(isothiazol-4-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lv)(S)-3-(l-hydroxypropan-2-yl)-8-( isothiazol-4-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ivi) (S)-3-(l-hydroxypropan-2-yl)-6,8-di(isothiazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ivii) (S)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Iviii) (S)-6-(4-chlorophenyl)-3-(l-hydroxypropan-2-yl)-8-(isothiazol-4- yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lix) 3-(2-hydroxy-2-methylpropyl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lx)3-(2-hydroxy-2-methylpropyl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixi) 6-(4-chloro-2-methylphenyl)-3-(2-hydroxy-2-methylpropyl)-8-(l-methyl- lH-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixii) (S)-3-(l-hydroxypropan-2-yl)-8-(lH-pyrazol-4-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixiii) (S)-3-(l-hydroxypropan-2-yl)-8-(2-methylpyridin-3-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixiv) (S)-3-(l-hydroxypropan-2-yl)-8-(4-methylpyridin-3-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixv) (S)-3-(l-hydroxypropan-2-yl)-6-(4-methylthiazol-5-yl)-8-(pyridin-3- yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixvi) (S)-6-(2-cyclopropylthiazol-5-yl)-3-(l-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixvii) (S)-3-(l-hydroxypropan-2-yl)-6-(2-isopropylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixviii) (S)-3-(l-hydroxypropan-2-yl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixix) (S)-3-(l-hydroxypropan-2-yl)-6,8-bis(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixx) 6-(4-chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one. (Ixxi) 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxii) 3-(2-hydroxyethyl)-8-(pyridin-3-yl)-6-(4- (trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxiii)       (S)-6-(4-chlorophenyl)-3-(l-hydroxypropan-2-yl)-8-(l-methyl-6- oxo- 1,6-dihydropyri din-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxiv)       (S)-6-(6-cy cl opropylpyri din-3-yl)-3-(1-hy droxypropan-2-yl)-8- (pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxv) (S)-3 -(1 -hydroxypropan-2-yl)-6-(4-methyl-6-(trifluoromethyl)pyridin-3 -yl)-8-(pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxvi)       (S)-3-(l-hydroxypropan-2-yl)-8-(l-methyl-lH-pyrazol-4-yl)-6- (pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxvii)      (S)-6-(cyclohex-l-en-l-yl)-3 -(1 -hydroxypropan-2-yl)-8-(pyridin-3 - yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxviii)      (S)-6,8-bis(5-fluoropyridin-3-yl)-3-(l-hydroxypropan-2- yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxix)       3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6- (trifluoromethyl)pyri din-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxx) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2- (trifluoromethyl)pyri din-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxxi) 6-(6-cyclopropylpyridin-3-yl)-3-(2-hydroxy-2-methylpropyl)-8- (pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxxii)      6-(6-cy cl opropylpyri din-3 -yl)-3-(2-hy droxy-2-methylpropyl)-8-( 1- methyl-lH-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxxiii)      (S)-6-(6-cyclopropylpyridin-3-yl)-3-(l-hydroxypropan-2-yl)-8-(l- methyl-lH-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxxiv)      (S)-3-(l-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(thiazol-5- yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxxv)      (S)-3 -(1 -hydroxypropan-2-yl)-8-(pyri din-3 -yl)-6-(2- (trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxxvi)      (S)-3 -(1 -hydroxypropan-2-yl)-8-(pyri din-3 -yl)-6-(2- (trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxxvii)     3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2- (trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxxviii)    3-((3 S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(l -methyl-lH- pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Ixxxix) (S)-3-(l-hydroxypropan-2-yl)-6-(2-methylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xc) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xci) (S)-3-(l-hydroxypropan-2-yl)-6-(piperidin-l-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcii) 3-(2-hydroxy-2-methylpropyl)-8-( isothiazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xciii) (S)-3-(l-hydroxypropan-2-yl)-8-( isothiazol-4-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xciv) 3-(2-hydroxy-2-methylpropyl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcv) (S)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcvi) (3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcvii)3-(l,l-dioxidotetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcviii) (R)-3-(l,l-dioxidotetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcix) (R)-3-(2-hydroxypropyl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (c) (S)-3-(2-hydroxypropyl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (ci)(R)-8-(l-methyl-lH-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cii) (S)-8-(l-methyl-lH-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (ciii) (R)-3-(2-hydroxypropyl)-8-(pyridin-3 -yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (civ) (R)-8-( 1 -methyl-1 H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cv) 3-((3 S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cvi) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cvii) 6-(4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(l-methyl-lH-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cviii) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cix) (S)-6-(6-cyclopropylpyridin-3-yl)-8-(pyridin-3-y 1)-3-(3,3,3 -trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (ex) (R)-6-(6-cyclopropylpyridin-3-yl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxi) (R)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxii) (R)-8-(pyridin-3 -yl)-3 -(3,3,3 -trifluoro-2-hydroxypropyl)-6-(4- (trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxiii) (S)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxiv) 6-(4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxv) 3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxvi) methyl (S)-2-(4-oxo-8-(pyridin-3 -yl)-6-(6-(trifluoromethyl)pyridin-3 - yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoate (cxvii)6-(4-chlorophenyl)-3-(4-hydroxy-l-methylpyrrolidin-3-yl)-8-(pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxviii) 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidin-3-yl)-8- (pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxix) (R)-6-(6-cyclopropylpyridin-3-yl)-8-(l-methyl-lH-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxx) (S)-6-(6-cyclopropylpyridin-3-yl)-8-(l-methyl-lH-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxi) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxii)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxiii)      3-((3 S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxiv)       3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxv)(R)-3-(2-hydroxypropyl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxvi) (S)-3-(2-hydroxypropyl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxvii)      (S)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxviii)     (R)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxix) 3-((3 S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxx)(S)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxi) (S)-8-(l-methyl-lH-pyrazol-4-yl)-3-(3,3,3-trifluoro-2- hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxii)      (S)-3-(l-hydroxypropan-2-yl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxiii)     3-((3 S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(l -methyl-lH- pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxiv)     6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8- (pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxv)      6-(4-Chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8- (1-methyl-lH-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxvi)      (R)-8-(pyri din-3 -yl)-3 -(3,3,3 -trifluoro-2-hy droxypropyl)-6-(5 - (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxvii)     (S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3- yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoic acid (cxxxviii)    (S)-N-methyl-2-(4-oxo-8-(pyridin-3-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimi din-3 (4H)-yl)propanamide (cxxxix)     (S)-N,N-dimethyl-2-(4-oxo-8-(pyridin-3-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimi din-3 (4H)-yl)propenamide (cxl) 3-(2-hydroxy-2-methylpropyl)-8-(lH-pyrazol-4-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxli) 3-(2-hydroxy-2-methylpropyl)-8-(lH-imidazol-l-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlii) 3-(2-hydroxy-2-methylpropyl)-8-(lH-imidazol-l-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxliii) (S)-3-(l-hydroxypropan-2-yl)-8-(lH-imidazol-l-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxliv)(S)-3-(l-hydroxypropan-2-yl)-8-(lH-imidazol-l-yl)-6-(6-(trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlv) (S)-3-(1 -hydroxypropan-2-yl)-8-(lH-1,2,4-triazol-1 -yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlvi)(S)-3-(l-hydroxypropan-2-yl)-8-(lH-pyrazol-l-yl)-6-(6-(trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlvii)      (S)-3-(l-hydroxypropan-2-yl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(2- (trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlviii)      (S)-8-(diethylamino)-3-(l-hydroxypropan-2-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlix)(S)-3-(l-hydroxypropan-2-yl)-8-(piperidin-l-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cl)(S)-3-(l-hydroxypropan-2-yl)-8-(pyrrolidin-l-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cli) (S)-6-(4-chlorophenyl)-3-(l-hydroxypropan-2-yl)-8-(piperidin-l-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clii) (S)-3-(l-hydroxypropan-2-yl)-8-(pyridin-2-yl)-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cliii) (S)-6-cyclohexyl-3-(l-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cliv) (S)-3-(l-hydroxypropan-2-yl)-6-(pyri din-2-yl)-8-(pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (civ) (S)-3 -(1 -hydroxypropan-2-yl)-6-(2-methylthiazol-4-yl)-8-(pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clvi) (S)-3-(l-hydroxypropan-2-yl)-6-(l-methyl-lH-l,2,3-triazol-5-yl)-8- (pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clvii) (R)-6-(4-chlorophenyl)-8-(pyridin-3-y 1)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (clviii) (S)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (clix) (S)-3-(l-hydroxypropan-2-yl)-8-(l-methyl-l,2,5,6-tetrahydropyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (clx) 6-(4-chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(l-methyl-lH-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (clxi) (5)-3-(l-hydroxypropan-2-yl)-6-(2-methylpyrimidin-5-yl)-8-(pyridin-3-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one; (clxii) 3-(2-hydroxy-2-methylpropyl)-8-(l-(trifluoromethyl)-lJH-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one; (clxiii) f5)-3-(l-hydroxypropan-2-yl)-8-(l-methyl-l / / -pyrazol-4-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one; (clxiv)3-(2-hydroxy-2-methylpropyl)-8-(pyri din-3 -yl)-6-(2- (trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one; (clxv) (5)-5-(3-(l-hydroxypropan-2-yl)-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-J]pyrimidin-6-yl)picolinic acid; (clxvi)f5)-3-(l-hydroxypropan-2-yl)-6-(6-methylpyridin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one; (clxvii)      3-(2-hydroxy-2-methylpropyl)-8-(l-methyl-l / / -pyrazol-4-yl)-6-(2- (trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one; (clxviii)      3,8-di(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4- d]pyrimidin-4(3J7)-one; (clxix)8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3J7)-one; (clxx) 3-((37?,47?)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyri din-3-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one; (clxxi)3-((37?,47?)-4-hydroxytetrahydrofuran-3-yl)-8-(l-methyl-1 / Z-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one; (clxxii)      6-(4-chlorophenyl)-3-((37?,47?)-4-hydroxytetrahydrofuran-3-yl)-8- (1 -methyl-lH-pyrazol-4-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one; (clxxiii)      3-cy clopentyl-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3- yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (clxxiv)      3-phenyl-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3- yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (clxxv)       3-((37?,47?)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one; (clxxvi) 3-((35,45)-4-hydroxytetrahydrofuran-3-yl)-8-(l-methyl-l / / -pyrazol-4-yl)-6-(5-(trifluoromethyl)pyri din-2-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one; (clxxvii)     (S)-3-(l-hydroxypropan-2-yl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (clxxviii)    (S)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-2-(4-oxo-8- (pyridin-3-yl)-6-(6-(trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanamide (clxxix)      3-(2-hydroxy-2-methylpropyl)-8-(lH-pyrazol-4-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (clxxx)      (5)-6-(4-chlorophenyl)-3-(l-hydroxypropan-2-yl)-8-(l / / -pyrazol-l- yl)pyrido[3,4-J]pyrimidin-4(3J7)-one; (clxxxi)      (5)-3-(l-hydroxypropan-2-yl)-8-(l / / -pyrazol-l-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one; (clxxxii)     3-((35,45)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(2- (trifluoromethyl)thiazol-5-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one; (clxxxiii)     3-(2-hydroxy-2-methylpropyl)-8-(l-methyl-l / / -pyrazol-4-yl)-6-(2- (trifluoromethyl)thiazol-5-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one; (clxxxiv)    3-((35,45)-4-hydroxytetrahydrofuran-3-y 1)-8-(1 -methyl- \H- pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one; (clxxxv) 3-((35,45)-4-hydroxytetrahydrofuran-3-y 1)-8-(1 -methyl- \H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one; (clxxxvi)     3-((35,45)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(2- (trifluoromethyl)thiazol-5-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one; (clxxxvii)    (5)-3-(l-hydroxypropan-2-yl)-8-morpholino-6-(6- (trifluoromethyl)pyri din-3-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one; (clxxxviii) 3-(2-hydroxy-2-methylpropyl)-8-(piperidin-l-yl)-6-(6-(trifluoromethyl)pyri din-3-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one; (clxxxix) (S)-3-(l-hydroxypropan-2-yl)-6-(5-methylpyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (cxc) (S)-3-(l-hydroxypropan-2-yl)-6-(5-methylpyrimidin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (cxci) (S)-8-(cyclohex-l-en-l-yl)-3-(l-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (cxcii)(S)-8-cyclohexyl-3-(l-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (cxciii)      (S)-3-(l-hydroxypropan-2-yl)-N,N-dimethyl-4-oxo-8-(pyridin-3 - yl)-3,4-dihydropyrido[3,4-d]pyrimidine-6-carboxamide; (cxciv)      (S)-3-(l-hydroxypropan-2-yl)-8-(lH-pyrazol-4-yl)-6-(5- (trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (cxcv)(S)-3-(l-hydroxypropan-2-yl)-6-(2-methoxyethyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; and (cxcvi) (S)-3-(l-hydroxypropan-2-yl)-8-(2-methoxyethyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one. (cxcvii) 30. A pharmaceutical composition comprising at least one entity chosen from the compounds of any one of embodiment 1 to 29 and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient. 31. A method of treating a disease or condition mediated by AhR signaling in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one entity chosen from the compounds of any one of embodiments 1 to 29 and pharmaceutically acceptable salts thereof, or at least one pharmaceutical composition of embodiment 30. 32. A method of treating a disease or condition associated with aberrant AhR signaling in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one entity chosen from the compounds of any one of embodiments 1 to 29 and pharmaceutically acceptable salts thereof, or at least one pharmaceutical composition of embodiment 30. 33.    The method of embodiment 31 or 32, wherein the disease is chosen from cancers. 34.    The method of embodiment 31 or 32, wherein the disease is chosen from liquid tumors and solid tumors. 35. The method of any one of embodiments 31 to 34, wherein the disease is chosen from breast cancers, respiratory tract cancers, brain cancers, cancers of reproductive organs, digestive tract cancers, urinary tract cancers, eye cancers, liver cancers, skin cancers, head and neck cancers, thyroid cancers, parathyroid cancers, and metastases of any of the foregoing. 36. The method of any one of embodiments 31 to 35, wherein the disease is chosen from breast cancers, pancreatic cancers, prostate cancers, and colon cancers. 37. The method of any one of embodiments 31 to 34, wherein the disease is chosen from lymphomas, sarcomas, melanomas, glioblastomas, and leukemias. 38. A method of inhibiting cancer cell proliferation mediated by AhR signaling in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one entity chosen from the compounds of any one of embodiments 1 to 29 and pharmaceutically acceptable salts thereof, or at least one pharmaceutical composition of embodiment 30. 39. A method of inhibiting tumor cell invasion or metastasis mediated by AhR signaling in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one entity chosen from the compounds of any one of embodiments 1 to 29 and pharmaceutically acceptable salts thereof, or at least one pharmaceutical composition of embodiment 30. 40. A method of treating cancer in a subject in need thereof comprising administering to said subject a therapeutically effective amount of i) at least one entity chosen from the compounds of any one of embodiments 1 to 29 and pharmaceutically acceptable salts thereof or at least one pharmaceutical composition of embodiment 30, and ii) a therapeutically effective amount of at least one additional therapy. 41. The method of embodiment 40, wherein the at least one additional therapy comprises at least two, at least three, at least four, or at least five additional therapies. 42. The method of embodiment 40, wherein administration of the at least one entity chosen from the compounds of any one of embodiments 1 to 29 and pharmaceutically acceptable salts thereof or at least one pharmaceutical composition of embodiment 30, is initiated before administration of the at least one additional therapy. 43. The method of embodiment 40, wherein the at least one entity chosen from the compounds of any one of embodiments 1 to 29 and pharmaceutically acceptable salts thereof or at least one pharmaceutical composition of embodiment 30, is administered after administration of the at least one additional therapy. 44. The method of embodiment 40, wherein the at least one entity chosen from the compounds of any one of embodiments 1 to 29 and pharmaceutically acceptable salts thereof or at least one pharmaceutical composition of embodiment 30, is administered concurrently with administration of the at least one additional therapy. 45. The method of any one of embodiments 40 to 44, wherein the at least one additional therapy is chosen from checkpoint inhibitors. 46. The method of embodiment 45, wherein the subject is intolerant, non-responsive, and / or poorly responsive to the at least one additional therapy when administered alone. 47. The method of embodiment 46, wherein the at least one additional therapy is chosen from checkpoint inhibitors that target CTLA-4, PD-1, PD-L1, LAG-3, TIM-3, TIGIT and / or VISTA. 48. The method of embodiment 46, wherein the at least one additional therapy is chosen from checkpoint inhibitors that target CTLA-4, PD-1, and / or PD-L1. 49. The method of embodiment 46, wherein the at least one additional therapy is chosen from cytotoxic T-lymphocyte-associated antigen 4 pathway inhibitors. 50. The method of embodiment 49, wherein the cytotoxic T-lymphocyte-associated antigen 4 pathway inhibitors are chosen from anti-CTLA-4 antibodies. 51.    The method of embodiment 50, wherein the anti-CTLA-4 antibody is ipilimumab. 52.    The method of embodiment 46, wherein the at least one additional therapy is chosen from programmed death-1 pathway inhibitors. 53. The method of embodiment 52, wherein the programmed death-1 pathway inhibitors are chosen from anti-PD-1 antibodies. 54.    The method of embodiment 52, wherein the anti-PD-1 antibody is nivolumab. 55.    The method of embodiment 52, wherein the anti-PD-1 antibody is pembrolizumab. 56.    The method of embodiment 52, wherein the anti-PD-1 antibody is cemiplimab 57.    The method of embodiment 52, wherein the anti-PD-1 antibody is camrelizumab. 58.    The method of embodiment 52, wherein the anti-PD-1 antibody is sintilimab. 59.    The method of embodiment 52, wherein the anti-PD-1 antibody is spartalizumab. 60.    The method of embodiment 52, wherein the anti-PD-1 antibody is tislelizumab. 61.    The method of embodiment 52, wherein the anti-PD-1 antibody is BCD-100. 62.    The method of embodiment 52, wherein the anti-PD-1 antibody is JS001. 63.    The method of embodiment 52, wherein the programmed death-1 pathway inhibitors are chosen from anti-PD-Ll antibodies. 64.    The method of embodiment 63, wherein the anti-PD-Ll antibody is atezolizumab. 65.    The method of embodiment 63, wherein the anti-PD-Ll antibody is avelumab. 66.    The method of embodiment 63, wherein the anti-PD-Ll antibody is durvalumab. 67.    The method of embodiment 63, wherein the anti-PD-Ll antibody is KN035. 68. The method of embodiment 46, wherein the at least one additional therapy is chosen from lymphocyte activation gene-3 (LAG-3) inhibitors. 69. The method of embodiment 68, wherein the LAG-3 inhibitors are chosen from anti-LAG-3 antibodies. 70. The method of embodiment 46, wherein the at least one additional therapy is chosen from T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) inhibitors. 71. The method of embodiment 70, wherein the TIM-3 inhibitors are chosen from antiTIM-3 antibodies. 72. The method of embodiment 46, wherein the at least one additional therapy is chosen from T-cell immunoglobulin and ITIM domain (TIGIT) inhibitors. 73. The method of embodiment 72, wherein the TIGIT inhibitors are chosen from TIGIT antibodies. 74. The method of embodiment 46, wherein the at least one additional therapy is chosen from V-domain Ig suppressor of T-cell activation (VISTA) inhibitors. 75. The method of embodiment 74, wherein the VISTA inhibitors are chosen from anti-VISTA antibodies. 76. The method of any one of embodiments 40 to 75, wherein the cancer is chosen from non-small cell lung cancer (NSCLC); small cell lung cancer; head and neck squamous cell carcinoma; renal cell carcinoma; gastric adenocarcinoma; nasopharyngeal neoplasms; urothelial carcinoma; colorectal cancer; pleural mesothelioma; triple-negative breast cancer (TNBC); esophageal neoplasms; multiple myeloma; gastric and gastroesophageal junction cancer; melanoma; Hodgkin lymphoma; hepatocellular carcinoma; lung cancer; head and neck cancer; non-Hodgkin lymphoma; metastatic clear cell renal carcinoma; squamous cell lung carcinoma; mesothelioma; gastric cancer; gastroesophageal junction cancer; metastatic melanoma; metastatic non-cutaneous melanoma; urothelial cancer; diffuse large B-cell lymphoma; renal cell cancer; ovarian cancer, fallopian tube cancer; peritoneal neoplasms; extensive stage small cell lung cancer; bladder cancer; transitional cell carcinoma; prostatic neoplasms; recurrent or metastatic PD-L1 positive or negative squamous cell carcinoma of the head and neck (SCCHN); recurrent squamous cell lung cancer; advanced solid malignancies; SCCHN; hypo pharyngeal squamous cell carcinoma; laryngeal squamous cell carcinoma; unresectable or metastatic melanoma; biliary tract neoplasms; esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, glioblastoma, metastatic cancer, prostatic cancer, solid organ cancer; stomach cancer; colon cancer; and liver cancer. EXAMPLES

[00117] The following non-limiting examples and data illustrate various aspects and features relating to the compounds and / or methods of the present disclosure, including the preparation of various compounds, as are available through the synthetic methodologies described herein. In comparison with the prior art, in some embodiments, the present compounds and / or methods provide results and data which are surprising, unexpected and contrary thereto. While the utility of this disclosure is illustrated through the use of several compounds and moieties / groups which can be used therewith, it will be understood by those skilled in the art that comparable results are obtainable with various other compounds, moieties and / or groups, as are commensurate with the scope of this disclosure. Example 1. Synthesis of Pyridopyrimidinone Compounds

[00118] The compounds encompassed within the present disclosure can be prepared by the procedure outlined in Scheme I and described in the Examples herein below. Preparation of tert-butyl N-[(lS)-2-benzyloxy-l-methyl-ethyl]carbamate: BocHN. OH BocHN OBn

[00119] To a solution of tert-butyl N-[(lS)-2-hydroxy-l-methyl-ethyl]carbamate (8, 10 g, 57 mmol, 1 eq) in THF (300 mL) was added NaH (2.51 g, 62.78 mmol, 60% purity, 1.1 eq) at 0 °C and the mixture was stirred at 0 °C for 30 min. The BnBr (11.71 g, 68.48 mmol, 8.13 mL, 1.2 eq) and tetrabutylammonium iodide (210.80 mg, 570.69 umol, 0.01 eq) was added to the mixture at 0 °C and then the mixture was stirred at 25 °C for 3 hr. The reaction mixture was quenched by addition MeOH (50 mL) at 0°C, and then filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=l / O to 0 / 1) to get the title compound (12 g, 45.22 mmol, 79% yield) 1H NMR (400 MHz, CDC13), 5 ppm 1.20 (d, J=6.8 Hz, 3H), 1.45 (s, 9H), 3.35-3.48 (m, 2H), 3.80-3.94 (m, 1H), 4.48 (q, J=12.0, 17.6 Hz, 2H), 4.67-4.80 (m, 1H), 7.27-7.38 (m, 5H). Preparation of (2S)-l-benzyloxypropan-2-amine trijluoroacetic acid: BocHN OBn H2N OBn

[00120] To a solution of tert-butyl N-[(lS)-2-benzyloxy-l-methyl-ethyl]carbamate (9, 12 g, 45.22 mmol, 1 eq) in DCM (100 mL) was added dropwise TFA (30.80 g, 270.12 mmol, 20 mL, 5.97 eq). The mixture was stirred at 25 °C for 3 hr. The reaction mixture was concentrated under reduced pressure to get the title compound (10, 10 g, 35.81 mmol, 79.18% yield, TFA) which was used directly. Preparation of (S)-8-(5-fluoropyridin-3-yl)-3-(l-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (1) Step 1. Preparation of (S)-3-amino-2,6-dichloro-N-(l-hydroxypropan-2-yl)isonicotinamide (Intermediate Al):

[00121] A mixture of 3-amino-2,6-dichloroisonicotinic acid (2.0 g, 9.66 mmol) and (S)-2-aminopropan-l-ol (Reactant 1, 0.80 g, 10.63 mmol) were dissolved in DMF (32.2 mL) and the reaction mixture was cooled to 0 °C. Diisopropylethylamine (3.37 mL, 19.3 mmol) and HATU (4.41 g, 11.59 mmol) were added and the reaction was stirred at 0 °C for 1 hour. The reaction was quenched with water and partitioned between ethyl acetate and water. The organic phase was separated, washed with saturated aqueous ammonium chloride and then with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography with ethyl acetate / hexane to afford the title compound (1.82 g, 6.89 mmol, 71% yield). XH NMR (CH3OH-d4, 400 MHz) 8 1.21 (3H, d, J = 6.8 Hz), 3.58-3.56 (2H, m), 4.17-4.12 (1H, m), 7.49 (1H, s); MS (m / z): 265.1 [M+H]+.

[00122] Table 2 lists intermediates that were made via a procedure similar to that described in Step 1 above. Table 2 Intermediate ID Structure and name *H-NMR MS (m / z) [M+HJ+; Purity (%) A2 Cl OH 0 3-amino-2,6-dichloro-N-(2-hydroxy-2-methylpropyl)isonicotinamide (CH3OH-t / 4, 400 MHz): 5 1.22 (6H, s), 3.36 (2H, t, 7= 6.1 Hz), 7.51 (1H, s), 7.67 (2H, s). 278.1; NA A3 Cl N^rNH2 OH II                  H        I Cl           N      cf3 0 3 -amino-2,6-dichloro-N-(3,3,3 -trifluoro-2-hydroxypropyl)-isonicotinamide N / A 318.0; NA A4 Cl n^NH2 II 1 H ci^^y 0 3 -amino-2,6-dichloro-N-(3,3,3 -trifluoro-2-hydroxypropyl)-isonicotinamide N / A 220.0; NA WO 2021 / 102288                                                 PCT / US2020 / 061548 A5 Cl mX / NH2 Hl H ?H 0   ^o' 3-amino-2,6-dichloro-N-(4-hydroxytetrahydrofuran-3-yl)isonicotinamide, trans racemic mixture (DMSO-t / e, 400 MHz): 5 0.97 (3H, s), 1.27 (3H, s), 1.48 (3H, d, J= 7.2 Hz), 3.95 (3H, s), 4.97 (1H, m), 5.07 (1H, s), 7.57 (2H, d, J= 8.4 Hz), 8.31-8.28 (3H, m), 8.48 (1H, s), 8.56 (1H, s), 8.82 (1H, s). 424.1; 99 A6 Cl n-VNH2 , II 1 H / cr v y v oh 0   = (S)-3-amino-2,6-dichloro-N-(3-hydroxy-3-methylbutan-2-yl)isonicotinamide (CHCh-7, 400 MHz): 5 1.25 (3H, d, J = 6.7 Hz), 1.30 (6H, s), 1.78 (1H, s), 4.08 (1H, dd, J= 15.4, 7.7 Hz), 5.93 (2H, br s), 6.50 (1H, br s), 7.17 (1H, s). 292.0; >90 A7 Cl (R)-3 -amino-2,6-di chi oro-N-(3 -hydroxy-3 -methylbutan-2-yl)isonicotinamide (CHCh-7, 400 MHz): 5 1.25 (3H, d, J = 6.6 Hz), 1.29 (6H, s), 4.14-4.05 (1H, m), 5.93 (2H, br s), 6.55 (1H, br s), 7.18 (1H, s), 7.26 (1H, s). 292.0; >90 A8 Cl mX / NH2 II 1 H ?H o L- / 3-amino-2,6-dichloro-N-(4-hydroxytetrahydrofuran-3-yl)isonicotinamide, cis racemic mixture (DMSO-t / e, 400 MHz): 53.88 (2H, m), 4.23 (1H, m), 4.32 (1H, m), 5.28 (1H, d, J= 4.4 Hz), 6.53 (2H, s), 7.66 (1H, s), 8.51 (1H, d, 7= 7.4 Hz). 292.0; >90 WO 2021 / 102288                                                 PCT / US2020 / 061548 A9 Cl (R)-3 -amino-2,6-di chi oro-N-(3 -hydroxy-3 -methylbutan-2-yl)isonicotinamide (CHCh-t / , 400 MHz): 5 1.25 (3H, d, J = 6.6 Hz), 1.29 (6H, s), 4.14-4.05 (1H, m), 5.93 (2H, br s), 6.55 (1H, br s), 7.18 (1H, s), 7.26 (1H, s). 292.0; >90 A10 Cl n\-NH2 C<          OH 0 (S)-3-amino-2,6-dichloro-N-(l-hydroxy-3-methylbutan-2-yl)isonicotinamide (CH3OHK, 400 MHz): 5 0.94 (6H, dd, J= 14.4, 6.8 Hz), 1.92-1.87 (1H, m), 3.66 (2H, d, J= 4.7 Hz), 3.80 (2H, br s), 7.37 (1H, s), 7.62 (1H, br s). 292.0; >90 All Cl nAtNH2 1              H / ¼.    / K cr    y Y OBn o = 3-amino-N-[(l S)-2-benzyloxy-l-methyl-ethyl]-2,6-dichloro-pyridine-4-carboxamide N / A 354.0; NA All Cl N^YNH2 CF3 II             H i cr y ^s / oh 0 (K3-amino-2,6-dichloro-7V-(3,3,3-trifluoro-2-hydroxypropyl)isonicotinamide (CH3OHK, 300 MHz): 5h 3.44 (1H, dd, J = 14.1, 8.7 Hz), 3.74 (1H, dd, J = 13.8, 4.0 Hz), 4.23 (1H, s), 7.48 (1H, s). 317.9; NA WO 2021 / 102288                                                 PCT / US2020 / 061548 A13 Cl n^YNH2 1        1 H N,, cr y । 0H 0 (S)-3-amino-2,6-dichloro- / V-(1-hydroxy-3-methylbutan-2-yl)isonicotinamide NA 292.0; 90.0 A14 Cl ANH2 I             H cr            OTBS 0 3-amino- / V-(2-((fert-butyldimethylsilyl) oxy)ethyl)-2,6-dichloroisonicotinamide NA 364.1; NA A15 Cl xk / NH2 n h ?H 0 k0 / NA 293.10; NA NA = Not available WO 2021 / 102288                                                 PCT / US2020 / 061548 Preparation of 3-amino-2,6-dichloro-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)isonicotinamide (A16).

[00123] Propylphosphonic anhydride (T3P, 64.6 g, 101 mmol, 60.3 mL, 50% purity, 1.05 eq) was added in one portion to a solution of 3-amino-2,6-dichloroisonicotinic acid (Reagent 1, 20 g, 96.6 mmol, 1 eq), (3S,4R)-4-aminotetrahydrofuran-3-ol (10.5 g, 101 mmol, 1.05 eq) and triethylamine (29.3 g, 290 mmol, 40.3 mL, 3 eq) in EtOAc (150 mL). The resulting solution was stirred at 25°C for 1 h. The reaction was poured into water (100 mL). The organic phase was collected and the aqueous phase was extracted by EtOAc (30 mL x 2). The combined organic phase was washed with brine (100 mL) and concentrated under vacuum to afford the title compound 3-amino-2,6-dichloro-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)isonicotinamide (A16, 25 g, 85.6 mmol, 88.6% yield) as off-white solid. The crude product was used for the next step without purification. ’H-NMR (400 MHz, CD3OD): 6h ppm 7.49 (s, 1H), 4.28-4.34 (m, 2H), 4.104.17 (m, 1H), 4.02 (dd, J = 10.0 Hz, J = 4.4 Hz, 1H), 3.73-3.78 (m, 1H), 3.65-3.70 (m, 1H); MS(m / z): 290.0 [M+H]+. Step 2. Preparation of (S)-6,8-dichloro-3-(1 -hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate Bl): A1                                               B1

[00124] To (S)-3-amino-2,6-dichloro-N-(l-hydroxypropan-2-yl)isonicotinamide (Al, 2.54 g, 9.66 mmol) in a flask was added tri ethyl orthoformate (20 mL). Concentrated hydrochloric acid (0.8 mL, 9.7 mmol) was added dropwise slowly at room temperature and the resulting mixture was stirred for 2 hours. The mixture was concentrated and the solid was collected by vacuum filtration, washed with water and dried under high vacuum to afford the title compound (Bl, 1.82 g, 6.64 mmol, 69% yield). 1HNMR (CH3OH-d4, 400 MHz) 6 1.51 (3H, d, J = 7.1 Hz), 3.80 (1H, dd, J = 11.9, 4.2 Hz), 3.92 (1H, dd, J = 11.9, 6.9 Hz), 4.93-4.88 (1H, m), 8.05 (1H, s), 8.45 (1H, s); MS (m / z):274.0[M+H]+. Preparation of 3-[(lS)-2-benzyloxy-l-methyl-ethyl]-6,8-dichloro-pyrido[3,4-d]pyrimidin-4-one (Intermediate Bll) O =                                           O = A11                                              B11

[00125] Formic acid (18.94 g, 411.41 mmol, 15.52 mL, 1.5 eq) was added dropwise into acetyl acetate (28 g, 274.27 mmol, 25.69 mL, 1 eq) at 0 °C and stirred at 60 °C for 2 hr under N2 atmosphere. The solution was obtained as a colorless liquid (41mL, 6.65 M) and used into the next step without further purification. To a solution of 3-amino-N-[(lS)-2-benzyloxy-l-methyl-ethyl]-2,6- dichloro- pyridine-4-carboxamide (All, 4.5 g, 12.70 mmol, 1 eq) in THF (50 mL) was added formyl acetate solution (6.65 M, 41 mL, 21.47 eq,) at 25 °C and stirred at 60 °C for 30 min. Then the mixture was stirred at 100 °C for 9.5 hr. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with EtOAc (50 mL) and washed with sat. NaHCOs (200 mL), water (50 mL) and brine (50 mL) sequentially, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=l / O to 1 / 1) to get the title compound (Bll, 2.4 g, 6.59 mmol, 51.88% yield). XHNMR (400 MHz, CDCh) 6 ppm 1.56 (d, J=7.2 Hz, 3H), 3.65-3.79 (m, 2H), 4.50 (q, J=12.4, 18.8 Hz, 2H), 5.08-5.20 (m, 1H), 7.20-7.31 (m, 5H), 8.02 (s, 1H), 8.41 (s, 1H); MS: M+H+, 364.0.

[00126] Table3lists intermediates that were made via a procedure similar to that described for the synthesis of Intermediate Bl above. Table 3 Intermediate ID Structure and name ‘H-NMR MS (m / z) [M+HJ+; Purity (%) B2 Cl 0H o 6,8-dichloro-3-(2-hydroxy-2- methylpropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (CHCh-t / , 400 MHz): 5 1.31 (6H, s), 1.90 (1H, s), 4.08 (2H, s), 8.06 (1H, s), 8.36 (1H, s). 288.0; NA B3 Cl oh cK Y ^ cf3 0 6,8-dichloro-3-(3,3,3-trifluoro-2- hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (CHsOH-tA, 400 MHz): 5 3.97 (1H, dd, J = 13.7, 9.7 Hz), 4.36 (1H, t, J= 8.0 Hz), 4.56 (1H, dd, J= 13.7, 2.9 Hz), 8.08 (1H, s), 8.38 (1H, s). 328.0; NA B4 Cl 0 (CHCW, 400 MHz): 5 3.64 (3H, s), 8.07 (1H, s), 8.18 (1H, s). 230.0; >90 WO 2021 / 102288                                                 PCT / US2020 / 061548 6,8-dichloro-3-methylpyrido[3,4-d]pyrimidin-4(3H)-one B5 Cl o 6,8-dichloro-3-(4-hydroxytetrahydrofuran-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, trans racemic mixture NA 302.0; >90 B6 Cl ci o 5 (S)-6,8-dichloro-3-(3-hydroxy-3-methylbutan- 2-yl)pyrido|'3,4-d]pyrimidin-4(3H)-one (CHsOH-tA, 400 MHz): 5 1.05 (3H, s), 1.35 (3H, s), 1.53 (3H, d, J= 7.2 Hz), 5.03 (1H, br s), 8.05 (1H, s), 8.62 (1H, s). 302.0; >90 B7 Cl Cl       N Y^0H (R)-6,8-dichloro-3-(3-hydroxy-3-methylbutan-2-yl)pyrido|'3,4-d]pyrimidin-4(3H)-one (CHCW, 400 MHz): 5 1.15 (3H, s), 1.41 (3H, s), 1,55 (3H, d, J= 12 Hz), 5.03 (1H, br s), 8.06 (1H, s), 8.59 (1H, s). 302.0; >90 B8 Cl °h ciAA^yt o '-V NA 302.0; >90 WO 2021 / 102288                                                 PCT / US2020 / 061548 6,8-di chi oro-3 -(4-hydroxytetrahydrofuran-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one, cis racemic mixture B9 Cl c|xli^ (R)-6,8-di chi oro-3-(3-hy droxy-3-methylbutan-2-yl)pyridoi3,4-d]pyrimidin-4(3H)-one (CHCh-t / , 400 MHz): 5 1.15 (3H, s), 1.41 (3H, s), 1,55 (3H, d, J= 7.2 Hz), 5.03 (1H, br s), 8.06 (1H, s), 8.59 (1H, s). 302.0; >90 BIO Cl 0 (S)-6,8-dichloro-3-(l-hydroxy-3-methylbutan- 2-yl)pyridoi3,4-d]pyrimidin-4(3H)-one (CHCW, 400 MHz): 5 0.84 (3H, d, J= 6.7 Hz), 1.16 (3H, d, J= 6.5 Hz), 2.45-2.36 (1H, m), 2.67 (1H, br s), 3.91 (1H, dd, J= 11.8, 2.8 Hz), 4.14 (1H, dd, J= 11.9, 5.5 Hz), 4.50 (1H, br s), 8.03 (1H, s), 8.40 (1H, s). 302.0; >90 Bll Cl N            CF3 II                       1 I cr v y ^s?oh 0 (5)-6,8-di chi oro-3 -(3,3,3 -trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3Z / )-one XHNMR (CHCW, 300 MHz): 5h 3.96 (1H, dd, J = 13.7, 9.6 Hz), 4.36 (1H, t, J = 7.6 Hz), 4.56 (1H, dd, J = 13.4, 3.0 Hz), 5.48 (1H, s), 8.07 (1H, s), 8.37 (1H, s). 327.8; NA WO 2021 / 102288                                                 PCT / US2020 / 061548 B12* Cl Cl N 0 6,8-dichloro-3-(2-hydroxyethyl)pyrido[3,4-d]pyrimidin-4(3 / 7)-one NA 260.0; 90.0 B13 °'"P° / z \ u (DMSO-t / e, 400 MHz): 5 3.60 (1H, dd, J = 9.6, 3.2 Hz), 4.06-4.03 (1H, m), 4.18-4.09 (2H, m), 4.52 (1H, s), 4.90 (1H, s), 5.70 (1H, d, J= 4.3 Hz), 8.07 (1H, s), 8.40 (1H, s). 302.0; NA B14 Cl °h O (DMSO-t / e, 400 MHz): 5h 3.76 (2H, d, J = 9.8 Hz), 3.98-3.88 (3H, m), 4.15 (2H, dd, J= 10.0, 5.7 Hz), 4.47-4.44 (2H, m), 5.32 (2H, q, J= 6.6 Hz), 8.06 (1H, s), 8.37 (1H, s). 302.0; NA NA = Not available; * The TBS group is cleaved during the cyclization conditions. WO 2021 / 102288                                                 PCT / US2020 / 061548 Preparation of (S)-6,8-dichloro-3-(l-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (BIO). B10

[00127] 4-Methylbenzenesulfonic acid (141.46 mg, 821.46 mmol) was added to a mixture of (S)-3-amino-2,6-dichloro-N-(l-hydroxy-3-methylbutan-2-yl)isonicotinamide (1.2 g, 4.11 mmol) in trimethyl orthoformate (10 mL) and was degassed and purged with nitrogen for 3 times. The mixture was stirred at 120°C for 8 hours under nitrogen atmosphere. TLC indicated the starting reactant was remained and two new spots formed. The solvent is evaporated and the residue is taken up in ethyl acetate (20 mL), washed three times with brine (10mL), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by prep-HPLC to afford the title compound (S)-6,8-dichioro-3-(l-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (600 mg, 1.99 mmol, 48% yield). ’H-NMR (400 MHz, DMSO-de): 6h ppm 8.60 (s, 1H) , 8.05 (s, 1H), 5.02 (d, J=3.2 Hz, 1H), 4.19-4.56 (m, 1H), 3.85-3.97 (m, 1 H), 3.74 (q, J=11.8 Hz, J=3.4 Hz, 1H), 2.23-2.38 (m, 1H), 1.04 (d, J=6.6 Hz, 3H), 0.75 (d, J=6.6 Hz, 3H); MS(m / z): 302.0 [M+H]+; 90% purity. Step 3. Preparation of (S)-6-chloro-8-(5-jluoropyridin-3-yl)-3-(l—2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate Cl): OH i O =                                               O = B1                                                  C1

[00128] A mixture of (S)-6,8-dichloro-3-(l-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Bl, 0.10 g, 0.37 mmol), (5-fluoropyridin-3-yl)boronic acid (Reactant 2, 0.057 g, 0.401 mmol), sodium carbonate (0.16 g, 1.46 mmol) and tetrakis(triphenylphosphine)palladium (0.042 g, 0.036 mmol) in a sealed tube was purged with argon. Toluene (3.0 mL) and ethanol (1.5 mL) were added and the resulting mixture was stirred at 75 °C for 15 hours. The mixture was cooled to room temperature, filtered through Celite and the Celite pad was washed with ethyl acetate and filtrate was concentrated to dryness. Purification of the residue by silica gel chromatography with methanol / dichloromethane afforded the title compound (Cl, 0.078 g, 0.19 mmol, 53% yield). 1HNMR (DMSO-d6, 300 MHz): 5 1.41 (3H, d, J = 7.0 Hz), 3.69-3.62 (1H, m), 3.82-3.74 (1H, m), 4.89-4.83 (1H, m), 5.06 (1H, t, J = 5.6 Hz), 8.12 (1H, s), 8.38 (1H, ddd, J = 10.2, 2.8, 1.7 Hz), 8.60 (1H, s), 8.73 (1H, d, J = 2.8 Hz), 9.14 (1H, s). ; MS (m / z): 335.1[M+H]+.

[00129] Table 4 lists intermediates that were made via a procedure similar to that described in Step 3 above. Table 4 Intermediate name Structure and name 1H-NMR chemical shifts MS (m / z) [M+H]+; Purity (%) C2 0 || NH ^°H 0 1 S)-6-chl oro-3-(1 -hydroxypropan-2 -yl)-8-(6-oxo- l,6-dihydropyridin-3-yl)pyrido[3,4-d]pyrimidin- 4(3H)-one (DMSO-t / e, 400 MHz): 5 1.41 (3H, d, 7= 7.0 Hz), 3.68-3.62 (1H, m), 3.81-3.75 (1H, m), 4.87-4.82 (1H, m), 5.06 (1H, t, J= 5.7 Hz), 6.48 (1H, d, J= 9.7 Hz), 7.87 (1H, s), 8.32 (1H, dd, 7= 9.7, 2.7 Hz), 8.57 (1H, s), 8.78 (1H, s), 12.08 (1H, s). 333.0; NA C3 m o । (S)-8-(benzo[d][l,3]dioxol-4-yl)-6-chloro-3-(l-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (DMSO-76, 400 MHz): 5 1.39 (3H, d, 7= 7.1 Hz), 3.67-3.61 (1H, m), 3.77-3.72 (1H, m), 4.85-4.80 (1H, m), 5.05 (1H, t,7 = 5.7 Hz), 6.03 (2H, s), 6.99-6.93 (1H, m), 7.07 (2H, t, 7= 8.1 Hz), 8.06 (1H, s), 8.47 (1H, s). 360.0; NA WO 2021 / 102288                                                 PCT / US2020 / 061548 C4 N. ci        N V"^0H (S)-6-chl oro-3-(1-hy droxypropan-2-yl)-8-(pyridin-4-yl)pyrido|'3,4-d]pyrimidin-4(3H)-one (DMSO-t / e, 400 MHz): 5 1.41 (3H, d, 7= 7.0 Hz), 3.68-3.62 (1H, m), 3.80-3.74 (1H, m), 4.87-4.82 (1H, m), 5.06 (1H, t, J= 5.7 Hz), 8.04 (2H, dd, J= 4.8, 1.5 Hz), 8.13 (1H, s), 8.57 (1H, s), 8.76-8.74 (2H, m). 316.9; NA C5 ci        N V'^0H (S)-6-chloro-8-(3-fluorophenyl)-3-(l-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (CH3OH-74, 400 MHz): 5 1.52 (3H, d, 7= 7.1 Hz), 3.82 (1H, dd, 7= 11.9, 4.3 Hz), 3.93 (1H, dd,7 = 11.9, 7.0 Hz), 4.96-4.91 (1H, m), 7.22 (1H, dd, 7 = 10.1, 7.8 Hz), 7.52-7.47 (1H, m), 7.98-7.92 (2H, m), 8.07 (1H, s), 8.40 (1H, s). 334.1; NA C6 o N          OH o 6-chloro-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido|’3,4-d]pyrimidin-4(3H)-one (CH3OH-74, 400 MHz): 5 1.25 (6H, s), 4.10 (2H, s), 7.59 (1H, t, 7= 6.5 Hz), 8.13 (1H, s), 8.34 (1H, s), 8.62 (2H, d, 7= 7.3 Hz), 9.32 (1H, s). 331.1; NA WO 2021 / 102288                                                 PCT / US2020 / 061548 C7 Q oh cr    y     cf3 o 6-chloro-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (CHCW + 10% CH3OH-d4, 400 MHz): 5 3.75 (1H, dd, J= 13.7, 9.6 Hz), 4.29 (1H, s), 4.60 (1H, dd, J= 13.7,2.9 Hz), 7.44 (1H, dd, 7 = 8.0, 4.9 Hz), 8.08 (1H, s), 8.14 (1H, s), 8.44 (1H, d, 7= 8.0 Hz), 8.59 (1H, d, J= 4.9 Hz), 9.27 (1H, s). 371.0; NA C8 \-N Z A oh cf3 0 6-chloro-8-(l-methyl-lH-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (CHCh-7+10% CH3OH-d4, 400 MHz): 5 3.72 (1H, dd, J= 13.7, 9.5 Hz), 3.91 (3H, s), 4.28 (1H, t, J= 7.9 Hz), 4.57 (1H, dd, J= 13.7, 3.0 Hz), 7.78 (1H, s), 8.11 (1H, s), 8.40 (1H, s), 8.48 (1H, s). 374.1; NA WO 2021 / 102288                                                 PCT / US2020 / 061548 C9 \-N OH 0 6-chl oro-3-(2-hydroxy-2-m ethylpropyl)-8-( 1-methyl-lH-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (CH3OH-A 400 MHz): 5 1.24 (6H, s), 3.98 (3H, s), 4.09 (2H, s), 7.83 (1H, s), 8.36 (1H, s), 8.43 (1H, s), 8.73 (1H, s). 334.1; NA CIO \-N A A N     A OH 0   = (S)-6-chl oro-3-(1 -hy droxypropan-2-yl)-8-( 1-methyl-lH-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (CH3OH-A 400 MHz): 5H 1.53-1.50 (3H, m), 3.82 (1H, dd, J= 11.9, 4.3 Hz), 3.88 (3H, s), 3.94-3.91 (1H, m), 4.96-4.91 (1H, m), 7.71 (1H, s), 7.79 (1H, s), 8.43 (1H, s), 8.69 (1H, s). 320.1; NA Cll o A z / =\ a / —4. / / / —\ o4 / z Z^ / Not available 273.0; >90 WO 2021 / 102288                                                 PCT / US2020 / 061548 6-chl oro-3-methyl-8-(pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one C12 Q °h -A o 6-chloro-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, trans racemic mixture (DMSO-t / e, 400 MHz): 5 3.59 (1H, dd, 7=9.6, 3.3 Hz), 4.03 (1H, dd, J= 10.1, 4.0 Hz), 4.18-4.09 (2H, m), 4.53 (1H, s), 4.93 (1H, s), 5.68 (1H, d,7 = 4.4 Hz), 7.56 (1H, dd, J= 8.0, 4.9 Hz), 8.08 (1H, s), 8.35 (1H, d, 7= 0.6 Hz), 8.40 (1H, dt, 7=8.0, 2.0 Hz), 8.68 (1H, dd, 7=4.8, 1.7 Hz), 9.20 (1H, d,7 = 2.2 Hz). 345.0; >90 C13 \-N Cl N o -(S)-6-chl oro-3 -(3 -hydroxy-3 -methylbutan-2-yl)-8-(l-methyl-lH-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (CHCh-7, 400 MHz): 5 1.04 (3H, s), 1.31 (3H, s), 1.48 (3H, d, 7= 7.2 Hz), 3.33 (1H, s), 3.90 (3H, s), 4.96 (1H, br s), 7.80 (1H, s), 8.41 (1H, s), 8.47 (1H, s), 8.50 (1H, s). 348.1; >90 WO 2021 / 102288                                                 PCT / US2020 / 061548 C14 \-N N ci            N 0   * (R)-6-chl oro-3 -(3 -hydroxy-3 -methylbutan-2-yl)-8-(l-methyl-lH-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one NA 348.1; >90 C15 Q °h O 6-chl oro-3 -(4-hy droxytetrahy drofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, cis racemic (DMSO-t / e, 400 MHz): 5 3.75 (1H, dd, 7= 9.7, 2.3 Hz), 3.98 (2H, m), 4.15 (1H, dd, 7=9.8, 5.9 Hz), 4.48 (1H, m), 5.33 (1H, q, 7= 6.7 Hz), 5.44 (1H, d, 7= 4.3 Hz), 7.56 (1H, dd, 7= 8.0, 4.8 Hz), 8.08 (1H, s), 8.34 (1H, s), 8.42 (1H, dt,7= 8.0, 2.0 Hz), 8.68 (1H, dd, 7=4.8, 1.7 Hz), 9.21 (1H, s). 345.0 >90 C16 Q cr   y y on o * NA 345.1; >90 WO 2021 / 102288                                                 PCT / US2020 / 061548 (R)-6-chl oro-3 -(3 -hydroxy-3 -methylbutan-2-yl)-8-(pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one C17 Q n \ / Cl            N O = (S)-6-chl oro-3 -(3 -hydroxy-3 -methylbutan-2-yl)-8-(pyri din-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (CHCh-7, 400 MHz): 5 1.06 (3H, s), 1.32 (3H, s), 1.47 (3H, d, 7=7.2 Hz), 4.99 (1H, br s), 5.25 (1H, s), 7.43 (1H, dd, 7=8.0, 4.9 Hz), 8.08 (1H, s), 8.44 (1H, d,7= 8.1 Hz), 8.49-8.48 (1H, m), 8.57 (1H, dd, 7=4.9, 1.7 Hz), 9.27 (1H, d, 7= 2.2 Hz). 345.1; >90 C18 tor nX^ cr v y V 0H ° (S)-6-chloro-8-(3,5-difluorophenyl)-3 -(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one NA 380.0; >90 WO 2021 / 102288                                                 PCT / US2020 / 061548 C19 0 6-chloro-8-(3-fluorophenyl)-3-(2-hydroxy-2-methylpropyl)pyridof3,4-d]pyrimidin-4(3H)-one (400 MHz, DMSO-d6) 5 ppm 1.14 (s, 6H), 4.01 (s, 2H), 4.86 (s, 1H), 7.37 (t, d=6.8Hz, 1H), 7.55-7.61 (m, 1H), 7.90-7.95 (m, 2H), 8.07 (s, 1H), 8.38 (s, 1H) NA C20 i if V Cl            N        H (R)-6-chloro-8-(3 -fluorophenyl)-3 -(3 -hydroxy-3 -methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (400 MHz, DMSO-d6) 5 ppm 0.97 (s, 3H), 1.25 (s, 3H), 1.46 (d, J=7.2 Hz, 3H), 4.92 (d, J=7.2 Hz, 1H), 5.04 (s, 1H), 7.37 (t, J=7.6 Hz, 1H), 7.54-7.60 (m, 1H), 7.95 (d, J=7.6 Hz, 2H), 8.06 (s, 1H), 8.54 (s, 1H) NA C21 F CK Y : °Bn 0   = 3-[(lS)-2-benzyloxy-l-methyl-ethyl]-6-chloro-8-(3-fluorophenyl)pyrido|'3,4-d]pyrimidin-4-one (400 MHz, CDCh) 5 ppm 1.45-1.58 (m, 3H), 3.65-3.76 (m, 2H), 4.48 (q, J=12.0, 20.0 Hz, 2H), 5.05-5.17 (m, 1H), 7.13-7.28 (m, 6H), 7.40-7.50 (m, 1H), 7.86-7.95 (m, 2H), 8.06 (s, 1H), 8.28 (s, 1H) 424.0; NA WO 2021 / 102288                                                 PCT / US2020 / 061548 C22 i if       ?F3 Y   oh 0 6-chloro-8-(3 -fluorophenyl)-3 -(3,3,3 -trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one NA 388.0; 90 C23 N-NH A oh 0 6-chl oro-3 -(2-hydroxy-2-methylpropyl)-8-(\H-pyrazol-4-yl)pyrido|'3,4-d]pyrimidin-4(3J7)-one (DMSO-t / e, 400 MHz): 5h 1.03 (6H, s), 3.99 (2H, s), 4.87 (1H, s), 7.77 (1H, s), 8.38 (2H, d, J = 11.2 Hz), 8.75 (1H, s), 13.27 (1H, s). 320.0; NA C24 N-S A A N          OH 0 6-chloro-3-(2-hydroxy-2-methylpropyl)-8-(isothiazol-4-yl)pyrido[3,4-d]pyrimidin-4(3Z / )-one (DMSO-t / e, 300 MHz): 5h 1.15 (6H, s), 4.03 (2H, s), 4.89 (1H, s), 8.01 (1H, s), 8.45 (1H, s), 9.40 (1H, s), 10.06 (1H, s). 336.9; NA WO 2021 / 102288                                                 PCT / US2020 / 061548 C25 N-S A n V   oh clVyM 0   = (5)-6-chl oro-3-(l-hydroxypropan-2-yl)-8- ( isothiazol-4-yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one (CHsOHV, 400 MHz): 5h 1.54 (3H, d, J = 7.1 Hz), 3.83 (1H, dd, J = 11.9, 4.3 Hz), 3.94 (1H, dd, J= 11.9, 7.0 Hz), 4.98-4.93 (1H, m), 8.03 (1H, s), 8.50 (1H, s), 9.49 (1H, s), 10.09 (1H, s). 322.9 NA C26 Q N V    CF3 0 (5)-6-chloro-8-(pyri din-3 -yl)-3-(3,3,3 -trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3J7)-one (CHsOHV, 300 MHz): 5h 4.04-3.94 (1H, m), 4.41 (1H, brs), 4.64-4.57 (1H, m), 7.60 (1H, brs), 8.17-8.16 (1H, m), 8.35-8.35 (1H, m), 8.68-8.62 (2H, m), 9.35-9.32 (1H, m). 370.9 NA C27 HN-N A A ci         N V''^0H o । (5)-6-chloro-3-(l-hydroxypropan-2-yl)-8-(lZ / -pyrazol-4-yl)pyrido[3,4V]pyrimidin-4(3J7)-one (DMSOV, 400 MHz): 5h 1.40 (4H, d, 7= 7.0 Hz), 3.65-3.62 (1H, m), 3.78-3.73 (1H, m), 4.85-4.80 (1H, m), 5.06 (1H, t, J= 5.7 Hz), 7.76 (1H, s), 8.38 (1H, s), 8.55 (1H, s), 8.74 (1H, s), 13.28 (1H, s). 306.0; >90 WO 2021 / 102288                                                 PCT / US2020 / 061548 C28 o 0 Me (S)-6-chl oro-3-(1-hydroxypropan-2-yl)-8-(2-methylpyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one NA 331.9; NA C29 Xj cr Y y oh O Me (S)-6-chl oro-3-(1 -hy droxypropan-2-yl)-8-(4-methylpyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one NA 331.0; NA C30 Q Cl            N 0 6-chloro-3-(2-hydroxyethyl)-8-(pyridin-3 -yl)pyrido|'3,4-d]pyrimidin-4(3H)-one NA 303.0; 95 WO 2021 / 102288                                                 PCT / US2020 / 061548 C31 0 (V 0 1 (5)-6-chloro-3-(l-hydroxypropan-2-yl)-8-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)pyrido[3,4-7]pyrimidin-4(3J7)-one (DMSO-t / e, 400 MHz): 5 1.41 (3H, d, 7= 7.0 Hz), 3.57-3.55 (3H, m), 3.68-3.64 (1H, m), 3.79-3.74 (1H, m), 4.87-4.82 (1H, m), 5.06 (1H, t,7=5.6 Hz), 6.53 (1H, d, 7=9.6 Hz), 7.89 (1H, s), 8.30 (1H, dd, 7= 9.6, 2.6 Hz), 8.57-8.56 (1H, s), 8.93 (1H, d, 7= 2.6 Hz). 347.1; NA C32 Q OH 0 6-chl oro-3 -((3R, 45)-4-hy droxytetrahy drofuran-3 -yl)-8-(pyri din-3-yl)pyrido[3,4-7]pyrimidin-4(3J7)-one (DMSO-t / 6, 400 MHz): 5 3.61 (1H, dd, 7=9.6, 3.3 Hz), 4.04 (1H, dd, 7 = 10.1, 3.9 Hz), 4.19-4.10 (2H, m), 4.56-4.53 (1H, m), 4.95-4.92 (1H, m), 5.71 (1H, d, 7= 4.4 Hz), 7.58 (1H, dd,7 = 8.0, 4.8 Hz), 8.09 (1H, s), 8.36 (1H, s), 8.41 (1H, d,7= 8.0 Hz), 8.69 (1H, d,7= 4.7 Hz), 9.21 (1H, s). 345.1; NA WO 2021 / 102288                                                 PCT / US2020 / 061548 C33 \-N O k / 6-chl oro-3-((3 5,45)-4-hydroxytetrahydrofuran-3-yl)-8-(l -methyl-l / / -pyrazol-4-yl)pyrido[3,4-t / ]pyrimidin-4(3Z7)-one (DMSO-t / e, 400 MHz): 5 3.79 (1H, t, 7= 9.3 Hz), 4.00-3.90 (5H, m), 4.18 (1H, dd, 7=9.9, 5.4 Hz), 4.52-4.48 (1H, m), 5.37 (1H, q, 7= 6.4 Hz), 5.48 (1H, d, 7=4.3 Hz), 7.79 (1H, s), 8.34 (2H, d,7= 2.4 Hz), 8.78 (1H, s). 348.0; NA C34 Jk ^N,, c< v Y •< oh 0 (S)-6-chloro-8-(3- fluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (400 MHz, DMSO-d6) 5 ppm 8.56 (s, 1H), 8.06 (s, 1H), 7.88-7.99 (m, 2H), 7.50-7.63 (m, 1H), 7.26-7.44 (m, 1 H), 5.01 (t, J=5.3 Hz, 1H), 4.29-4.57 (m, 1H), 3.84-3.98 (m, 1H), 3.32-3.78 (m, 1H), 2.18-2.38 (m, 1H), 0.99-1.10 (m, 3H), 0.76 (d, J=6.6 Hz, 3H). 362.1; 90.0 WO 2021 / 102288                                                 PCT / US2020 / 061548 C35 Cl       N N^oh 0 (S)-6-chloro-3-(1 -hydroxypropan-2-yl)-8-(1 -methyl-1,2,5,6-tetrahydropyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3 / - / )-one NA 335.1; NA C36 f3c n-n cr Y oh o 6-chl oro-3-(2-hydroxy-2-m ethylpropyl)-8-( 1- (trifluoromethyl)-l.H-pyrazol-4-yl)pyrido[3,4- J]pyrimidin-4(3J7)-one 1H NMR (DMSO-t / e, 400 MHz): 5 1.16-1.14 (6H, m), 4.02 (2H, s), 4.91 (1H, s), 7.97 (1H, s), 8.46 (1H, s), 8.74 (1H, s), 9.33 (1H, s). 387.9 NA = Not available WO 2021 / 102288                                                 PCT / US2020 / 061548 Step 4. Preparation of (S)-8-(5-jluoropyridin-3-yl)-3-(l-hydroxypropan-2-yl)-6-(4-(trijluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (1):

[00130] A mixture of (S)-6-chloro-8-(5-fluoropyridin-3-yl)-3-(l-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Cl, 0.023 g, 0.069 mmol), (4-(trifluoromethoxy)phenyl)boronic acid (Reactant 3, 0.016 g, 0.076 mmol), sodium carbonate (0.029 g, 0.275 mmol) and tetrakis(triphenylphosphine)palladium (0.008 g, 0.007 mmol) in a sealed tube was purged with argon. Toluene (1.0 mL) and ethanol (0.5 mL) were added and the resulting mixture was stirred at 75 °C for 15 hours. The mixture was cooled to room temperature, filtered through Celite and the Celite pad was washed with ethyl acetate and filtrate was evaporated. Purification of the residue by silica gel chromatography with methanol / dichloromethane afforded the title compound (0.022 g, 0.047 mmol, 68% yield). ’H NMR (DMSO-de, 400 MHz): 8 1.44 (3H, d, J = 7.0 Hz), 3.72-3.66 (1H, m), 3.84-3.78 (1H, m), 4.91 (1H, s), 5.08 (1H, t, J = 5.6 Hz), 7.53 (2H, d, J = 8.4 Hz), 8.43 (2H, d, J = 8.6 Hz), 8.53 (1H, ddd, J = 10.3, 2.9, 1.7 Hz), 8.60 (2H, d, J = 3.7 Hz), 8.73 (1H, d, J = 2.8 Hz), 9.29 (1H, s); MS (m / z): 461.1 [M+H]+; >99% purity.

[00131] Table5lists compounds made via procedures similar to that described for 1, replacing reactants 1, 2, and 3 with the indicated groups. Table 5 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 2 HO— h2n / 0 ^NH J) 0~ Cl B(OH)2 o (| NH oh N . ,. J JU IJ (S)-6-(4-chlorophenyl)-3 -(1-hydroxypropan-2-yl)-8-(6-oxo-l,6-dihydropyridin-3-yl)pyrido[3,4- d]pyrimidin-4(3H)-one (DMSO4, 400 MHz): 5h 1.43 (3H, d, 7=7.0 Hz), 3.70-3.65 (1H, m), 3.83-3.77 (1H, m), 4.91-4.86 (1H, m), 5.08 (1H, t, J= 5.6 Hz), 6.51 (1H, d, J= 9.7 Hz), 7.60 (2H, d, J= 8.4 Hz), 8.28 (2H, d, J= 8.4 Hz), 8.38 (1H, s), 8.53 (1H, dd, J= 9.7, 2.6 Hz), 8.56 (1H, s), 12.02 (1H, s). 409.1; 96 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 3 HO— H2r / <0^ . EL HO OH Cl B(OH)2 w n V   oh / UUUn JU o (S)-8-(benzo[d] [ 1,3 ]dioxol-4-yl)-6-(4-chlorophenyl)-3 -(1 -hy droxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (DMSO4, 400 MHz): 5h 1.42 (3H, d,7=7.0 Hz), 3.69-3.64 (1H, m), 3.82-3.76 (1H, m), 4.88 (1H, s), 5.08 (1H, t, 7 = 5.6 Hz), 6.03 (2H, s), 6.98 (lH,t,7= 7.8 Hz), 7.06 (1H, d,7 = 7.6 Hz), 7.17 (1H, d,7 = 7.8 Hz), 7.58 (2H, d,7= 8.4 Hz), 8.25 (2H, d,7= 8.4 Hz), 8.48 (1H, s), 8.52 (1H, s). 435.0; >99 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 4 HO—% H2l / 9 „BS HO OH cf3 B(OH)2 n oh N j IJ I 7 F3C N (S)-3-(l-hydroxypropan-2-yl)-8- (pyridin-4-yl)-6-(6- (trifluoromethyl)pyridin-3 - yl)pyrido[3,4-d]pyrimidin-4(3H)-one (DMSO4, 400 MHz): 5h 1.45 (3H, d, 7=7.0 Hz), 3.72-3.66 (1H, m), 3.84-3.78 (1H, m), 4.94-4.89 (1H, m), 5.09 (1H, t, J= 5.6 Hz), 8.07 (1H, d, J= 8.3 Hz), 8.20 (2H, d, J= 5.4 Hz), 8.63 (1H, s), 8.81-8.77 (3H, m), 8.93 (1H, d, J= 8.4 Hz), 9.64 (1H, s). 427.9; >99 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 5 HO—< h2i / B(OH)2 cf3 B(OH)2 Fp OH N \ XX I (S)-8-(5-fluoropyri din-3 -y 1)-3 -(1- hydroxypropan-2-yl)-6-(4- (trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (DMSO4, 400 MHz): 5h 1.44 (3H, d,7=7.0 Hz), 3.70 (1H, t, J= 5.6 Hz), 3.80 (1H, s), 4.92 (1H, s), 5.09 (1H, s), 7.91 (2H, d, J= 8.2 Hz), 8.53 (3H, d, J= 8.5 Hz), 8.63 (1H, s), 8.67 (1H, s), 8.74 (1H, d, J= 2.8 Hz), 9.30 (1H, s). 445.1; >99 6 HO—< H2N^ 9 HO OH Q B(OH)2 Z=\ )= z   / =\ 4        z \\ / / \ / / O=( __z—' / O i (DMSO4, 400 MHz): 5h 1.44 (3H, d,7=7.0 Hz), 3.72- 3.66 (1H, m), 3.84- 3.78 (1H, m), 4.93- 360.0; >95 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) (S)-3 -(1 -hy droxypropan-2-yl)-6,8-di(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 4.88 (1H, m), 5.09 (1H, t, 7 = 5.6 Hz), 8.19 (2H, dd,7 = 4.7, 1.6 Hz), 8.26 (2H, d, J= 5.4 Hz), 8.62 (1H, s), 8.78-8.73 (5H, m). 7 HO—< H^ ■p B(OH)2 Cl B(OH)2 oh N JU IJ or (S)-6-(4-chlorophenyl)-8-(3- fluorophenyl)-3 -(1 -hy droxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (CHCh-t / , 400 MHz): 5 1.60 (3H, d, 7= 7.2 Hz), 3.99 (2H, d, J= 4.8 Hz), 5.10-5.06 (1H, m), 7.20 (1H, td, J= 8.4, 2.7 Hz), 7.51-7.46 (3H, m), 7.93-7.89 (1H, m), 7.96 (1H, d, J= 7.8 Hz), 410.1; 98 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 8.18-8.14 (2H, m), 8.34 (1H, s), 8.51 (1H, s). 8 HO—< h2n^ u B(OH)2 cf3 B(OH)2 Fn oh XT J 3' F3C N (S)-8-(3 -fluorophenyl)-3 -(1- hydroxypropan-2-yl)-6-(6- (trifluoromethyl)pyridin-3 - yl)pyrido[3,4-d]pyrimidin-4(3H)-one (CHsOH-tA, 400 MHz): 5 1.56 (3H, d, 7=7.1 Hz), 3.85 (1H, dd, J= 11.9, 4.3 Hz), 3.96 (1H, dd, J= 11.9, 6.9 Hz), 5.02-4.97 (1H, m), 7.24-7.20 (1H, m), 7.53-7.48 (1H, m), 7.95 (1H, d, J= 8.3 Hz), 8.01 (1H, d, J= 10.7 Hz), 8.06 (1H, d, J= 7.9 Hz), 8.45 (1H, s), 8.66 (1H, s), 444.9; 99 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 8.81 (1H, d, J= 8.3 Hz), 9.50 (1H, s). 9 HO- H2N 9 B(OH)2 cf3 9 B(OH)2 Q OH jC J o cf3-^n^ 3-(2-hydroxy-2-methylpropyl)-8- (pyridin-3-yl)-6-(6- (trifluoromethyl)pyridin-3 - yl)pyrido[3,4-d]pyrimidin-4(3H)-one (CH3OH-t / 4, 400 MHz): 5 1.27 (6H, s), 4.14 (2H, s), 7.61 (1H, dd, J= 8.0, 4.9 Hz), 7.97 (1H, d, J= 8.3 Hz), 8.40 (1H, s), 8.64 (1H, d, J= 4.9 Hz), 8.73-8.70 (2H, m), 8.84 (1H, d, J= 8.4 Hz), 9.41 (1H, s), 9.54 (1H, s). 442.2; 99 10 cf3 ho—r h2n Qn B(OH)2 q B(OH)2 Q N          OH (rV^r^^ V (CH3OH-t / 4, 400 MHz): 5 3.98 (1H, dd, J= 13.7, 9.7 Hz), 4.45 (1H, d, J= 8.3 Hz), 4.61 414.1; 97 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 6,8-di(pyridin-3 -y 1)-3 -(3,3,3 -trifluoro-2-hydroxypropyl)pyrido[3,4- d]pyrimidin-4(3H)-one (1H, dd, J= 13.7, 2.8 Hz), 7.57 (2H, t, J= 6.4 Hz), 8.35 (1H, s), 8.61-8.58 (4H, m), 8.67 (1H, d, J= 8.1 Hz), 9.34 (2H, d, J= 12.3 Hz). 11 HO— h2i / 9 B(OH)2 — Q n V   oh 0   = (S)-6-chl oro-3 -(1 -hy droxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4- d]pyrimidin-4(3H)-one (CHsOH-tA, 400 MHz): 5 1.52 (3H, d, 7=7.1 Hz), 3.82 (1H, dd, J= 11.9, 4.3 Hz), 3.93 (1H, dd, J= 11.9, 7.0 Hz), 4.96-4.91 (1H, m), 7.58-7.55 (1H, m), 8.08 (1H, s), 8.41 (1H, s), 8.61- 317.1; 96 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 8.59 (2H, m), 9.31 (1H, s). 12 HO— h2n / 9 B(OH)2 cf3 B(OH)2 Q n'La oh JU S i CF3^ N (S)-3-(l-hydroxypropan-2-yl)-8- (pyridin-3-yl)-6-(6- (trifluoromethyl)pyridin-3 - yl)pyrido[3,4-d]pyrimidin-4(3H)-one (CHsOH-tA, 400 MHz): 5h 1.56 (3H, d, 7=7.1 Hz), 3.86 (1H, dd, J= 11.9, 4.3 Hz), 3.97 (1H, dd, J= 11.9, 7.0 Hz), 5.03-4.98 (1H, m), 7.62 (1H, dd, J= 8.0, 4.9 Hz), 7.98 (1H, d, J= 8.2 Hz), 8.49 (1H, s), 8.65 (1H, d, J= 4.9 Hz), 8.76-8.72 (2H, m), 8.86 (1H, d, J= 8.3 Hz), 428.1; 99 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 9.43 (1H, s), 9.55 (1H, s). 13 cf3 HO— H2N 9 B(OH)2 Cl 9 B(OH)2 Q N          OH N ^^cf3 ci^   0 6-(4-chlorophenyl)-8-(pyridin-3-yl)-3 -(3,3,3 -trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (CHsOH-tA, 400 MHz): 5h3.98 (1H, dd, J= 13.7, 9.6 Hz), 4.45-4.40 (1H, m), 4.62 (1H, dd, J= 13.8, 3.0 Hz), 7.53 (2H, d, J= 8.4 Hz), 7.60 (1H, dd, J= 8.0, 4.9 Hz), 8.23 (2H, d, J= 8.4 Hz), 8.33 (1H, s), 8.58 (1H, s), 8.63-8.62 (1H, m), 8.70 (1H, dt, J= 8.0, 1.9 Hz), 9.38 (1H, s). 447.1; 96 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 14 cf3 HO- h2n 9 B(OH)2 ocf3 B(OH)2 Q OH N "^3 F3CO^^    ° 8-(pyri din-3 -y 1)-3 -(3,3,3 -trifluoro-2- hydroxypropyl)-6-(4- (trifluoromethoxy)phenyl)pyrido[3,4- d]pyrimidin-4(3H)-one (CH3OH-t / 4, 400 MHz): 5h3.99(1H, dd, J= 13.7, 9.7 Hz), 4.44 (1H, s), 4.63-4.59 (1H, m), 7.44 (2H, d, J= 8.4 Hz), 7.60 (1H, dd, J= 8.0, 4.9 Hz), 8.35 (3H, d, 7=9.1 Hz), 8.63-8.60 (2H, m), 8.71 (1H, d, J= 8.1 Hz), 9.39 (1H, s). 497.1; 97 15 cf3 HO—C h2n \-N V B(OH)2 Cl 0 B(OH)2 \-N A A n y 9 OH iTY^nN CIAJ o       6_(4_ chlorophenyl)-8-(l-methyl-lH-pyrazol-4-yl)-3 -(3,3,3 -trifluoro-2- (DMSO-t / 6, 400 MHz): 5h3.95 (3H, s), 4.05 (1H, dd, J= 14.0, 9.7 Hz), 4.43 (2H, d, J= 13.1 Hz), 6.77 (1H, d, 450.1; 97 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one J= 6.5 Hz), 7.57 (2H, d, J= 8.4 Hz), 8.30-8.27 (3H, m), 8.47 (2H, s), 8.78 (1H, s). 16 HO— h2n 9 B(OH)2 cf3 B(OH)2 Q OH ° f3c^^            3-(2- hydroxy-2-methylpropyl)-8-(pyridin- 3-yl)-6-(4- (trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (CHsOH-tA, 400 MHz): 5h 1.27 (6H, s), 4.14 (2H, s), 7.61 (1H, t, J= 6.4 Hz), 7.84 (2H, d, J= 8.2 Hz), 8.38 (1H, s), 8.43 (2H, d, J= 8.2 Hz), 8.64 (1H, s), 8.68 (1H, s), 8.73 (1H, d, J= 8.1 Hz), 9.41 (1H, s). 441.2; 99 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 17 HO—< h2i / 9 B(OH)2 B^OH)2 Q IMOH kJ 5 °         (S)-3-(l- hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one (CHsOH-tA, 400 MHz): 5h 1.55 (3H, d, 7=7.1 Hz), 2.42 (3H, s), 3.85 (1H, dd, J= 11.8, 4.3 Hz), 3.97 (1H, dd, J= 11.9, 7.0 Hz), 5.02-4.97 (1H, m), 7.36-7.34 (2H, m), 7.61-7.58 (1H, m), 8.12 (2H, d, J= 7.9 Hz), 8.40 (1H, s), 8.53 (1H, s), 8.62-8.61 (1H, m), 8.71 (1H, dt, J= 8.0, 1.9 Hz), 9.40 (1H, s) . 373.2; 99 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 18 HO- H2N 9 B(OH)2 Cl ¢3 B(OH)2 Q oh XJ o 6-(4- chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (CH3OH-t / 4, 400 MHz): 5h 1.27 (6H, s), 4.13 (2H, s), 7.54-7.51 (2H, m), 7.62-7.59 (1H, m), 8.24 (2H, d, J= 8.4 Hz), 8.35 (1H, s), 8.59 (1H, s), 8.64-8.62 (1H, m), 8.71 (1H, dt, J= 8.0, 1.9 Hz), 9.40 (1H, s). 407.1; 99 19 HO- h2n \-N V B(OH)2 \-N Y B(OH)2 \-N Z A oh n T Y 0 / 3 -(2-hy droxy-2-methylpropyl)-6,8-bis(l -methyl-IH-pyrazol -4-yl)pyrido|'3,4-d]pyrimidin-4(3H)-one (CH3OH-t / 4, 400 MHz): 5h 1.25 (6H, s), 3.98 (6H, d, J=5.5 Hz), 4.10 (2H, s), 8.02 (1H, s), 8.11 (1H, s), 8.29 (2H, d, J= 380.2; 95 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 3.2 Hz), 8.51 (1H, s), 8.75 (1H, s). 20 HO— h2n / / 9 B(OH)2 9 B(OH)2 q oh ^UUUn^1 C J o = N (S)-3 -(1 -hy droxypropan-2-yl)-6,8-di(pyridin-3-yl)pyrido[3,4- d]pyrimidin-4(3H)-one (CHCh-7, 400 MHz): 5h 1.60 (3H, d, 7=7.1 Hz), 4.11-4.01 (2H, m), 5.10 (1H, d, J= 7.7 Hz), 7.35 (2H, d, J= 7.0 Hz), 8.29 (1H, s), 8.36 (1H, d, J= 8.0 Hz), 8.48 (2H, s), 8.57 (2H, s), 9.22 (1H, s), 9.33 (1H, s). 360.1; 96 21 HO- h2n \-N B(OH)2 Cl 9 B(OH)2 \-N / A OH UXU JU 0 cr (CHsOH-tA, 400 MHz): 5h 1.26 (6H, s), 3.99 (3H, s), 4.10 (2H, s), 7.51 (2H, d,7=8.4 410.2; 98 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-( 1 -methyl- 1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin- 4(3H)-one Hz), 8.19 (2H, d, J= 8.4 Hz), 8.30 (1H, s), 8.35 (1H, s), 8.52 (1H, s), 8.76 (1H, s). 22 HO— h2i / B(OH)2 ocf3 B(OH)2 Q OH 5 1 (S)-3-(l-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (CHsOH-tA, 400 MHz): 5h 1.55 (3H, d, 7=7.1 Hz), 3.85 (1H, dd, J= 11.9, 4.3 Hz), 3.96 (1H, dd, J= 11.9, 6.9 Hz), 5.01-4.96 (1H, m), 7.42 (2H, d, J= 8.4 Hz), 7.59 (1H, dd, J= 8.0, 4.9 Hz), 8.31 (2H, d, J= 8.6 Hz), 8.42 (1H, s), 8.56 (1H, s), 443.2; 99 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 8.62 (1H, d, 7= 4.9 Hz), 8.71-8.69 (1H, m), 9.39 (1H, s). 23 HO— H2r / 9 B(OH)2 cf3 9 B(OH)2 Q oh jCj o (S)-3-(l-hydroxypropan-2-yl)-8- (pyridin-3-yl)-6-(4- (trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (CHsOH-tA, 400 MHz): 5h 1.56 (3H, d, 7=7.1 Hz), 3.87 (1H, t,7= 4.4 Hz), 3.96 (1H, t,7 = 6.8 Hz), 4.97-5.04 (1H, m), 7.61 (1H, dd, 7= 8.0, 4.9 Hz), 7.83 (2H, d,7= 8.2 Hz), 8.46-8.42 (3H, m), 8.63 (1H, s), 8.67 (1H, s), 8.73 (1H, d, 7= 8.0 Hz), 9.42 (1H, s). 427.2; 98 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 24 HO—-; Hjl / 9 B(OH)2 Cl B(OH)2 Q OH JU I 1 (S)-6-(4-chlorophenyl)-3 -(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (CH3OHU4, 400 MHz): 5h 1.55 (3H, dU=71 Hz), 3.85 (1H, dd,J = 11.9, 4.3 Hz), 3.96 (1H, dd, J = 11.9, 7.0 Hz), 5.00 (1H, d, J = 7.7 Hz), 7.52 (2H, d, J= 8.4 Hz), 7.60 (1H, t,J = 6.4 Hz), 8.21 (2H, d, J= 8.3 Hz), 8.42 (1H, s), 8.55 (1H, s), 8.62 (1H, s), 8.71 (1H, d, J = 8.1 Hz), 9.40 (1H, s). 393.1; 98 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 25 HO— h2n / \-N B(OH)2 ocf3 B(OH)2 \-N A oh 0 cf3°                       (S)-3-(l- hydroxypropan-2-yl)-8-( 1 -methyl- 1H-pyrazol-4-yl)-6-(4- (trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (CH3OH-74, 400 MHz): 5h 1.56 (3H, d, 7=7.1 Hz), 3.85 (1H, dd, J= 12.0, 4.3 Hz), 3.99-3.94 (4H, m), 5.02-4.97 (1H, m), 7.42 (2H, d, J= 8.3 Hz), 8.33-8.30 (3H, m), 8.46 (1H, s), 8.55 (1H, s), 8.78 (1H, s). 446.2; 97 26 HO—<. h2i / \-N Y B(OH)2 Q B(OH)2 \ N-N A A oh O = (S)-3 -(1 -hy droxypropan-2-yl)-8-( 1 -methyl-lH-pyrazol-4-yl)-6- (CH3OH-74, 400 MHz): 5h 1.56 (3H, d, 7=7.1 Hz), 3.85 (1H, dd, 7 = 11.9, 4.3 Hz), 3.99-3.94 (4H, 396.1; 99 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) phenylpyrido[3,4-d]pyrimidin-4(3H)-one m), 4.99 (1H, d, J= 7.9 Hz), 7.45 (1H, d, J= 7.2 Hz), 7.52 (2H, t, J= 7.5 Hz), 8.20 (2H, d, J= 7.7 Hz), 8.31 (1H, s), 8.44 (1H, s), 8.55 (1H, s), 8.77 (1H, s). 27 HO— h2n / \-N B(OH)2 Cl 0 B(OH)2 \-N A A OH JU o 1 (S)-6-(4-chlorophenyl)-3 -(1- hydroxypropan-2-yl)-8-( 1 -methyl- 1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin- 4(3H)-one (CHCW, 400 MHz): 5h 1.60 (3H, d, 7=7.2 Hz), 4.01-3.99 (5H, m), 5.09-5.04 (1H, m), 7.46-7.44 (2H, m), 8.10 (2H, d, J= 8.4 Hz), 8.26 (2H, d, J= 362.2; 99 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 4.2 Hz), 8.51 (2H, s). 28 h2nZ nJ B(OH)2 CM T ll. o—v   7—co \= / Q F aMa JcUU I F 0 ^^ 3-methyl-8-(pyridin-3-yl)-6-(4- (trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (DMSO4, 400 MHz): 5 3.55 (3H, s), 7.59-7.50 (3H, m), 8.38 (2H, d, J= 8.5 Hz), 8.52-8.50 (3H, m), 8.67 (1H, d, 7= 4.8 Hz), 9.31 (1H, s). 399.1; 98 29 OH h2Nk7 Trans, racemic mixture H J B(OH)2 Cl B(OH)2 Q ^Xf”^ oh CIXJ o w 6-(4-chlorophenyl)-3-(4- hydroxytetrahydrofuran-3 -y 1)-8 -(pyri din-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one, trans racemic mixture (DMSO4, 400 MHz): 5 3.61 (1H, dd, 7=9.6, 3.3 Hz), 4.05 (1H, dd, 7 = 10.1, 4.0 Hz), 4.20-4.11 (2H, m), 4.56 (1H, s), 4.98 (1H, s), 5.71 (1H, bs), 7.59 (2H, d, 421.1; 99 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) J= 8.3 Hz), 7.75 (2H, m), 8.30 (2H, d, J= 8.3 Hz), 8.35 (1H, s), 8.54 (1H, s), 8.59 (1H, m). 30 H0Y" h2n \-N Y B(OH)2 Cl B(OH)2 \-N ci-V    o (S)-6-(4-chlorophenyl)-3 -(3 -hy droxy-3 -methylbutan-2-yl)-8-(l -methyl- 1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin- 4(3H)-one (DMSO4, 400 MHz): 5 0.97 (3H, s), 1.27 (3H, s), 1.48 (3H, d, 7=7.2 Hz), 3.95 (3H, s), 4.97 (1H, m), 5.07 (1H, s), 7.57 (2H, d, J= 8.4 Hz), 8.31-8.28 (3H, m), 8.48 (1H, s), 8.56 (1H, s), 8.82 (1H, s). 424.1; 99 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 31 HOY_ h2n \-N Y B(OH)2 Cl B(OH)2 \-N cr (R)-6-(4-chlorophenyl)-3 -(3 -hy droxy-3 -methylbutan-2-yl)-8-(l -methyl- 1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin- 4(3H)-one (DMSO4, 400 MHz): 5 0.97 (3H, s), 1.27 (3H, s), 1.48 (3H, d, 7= 7.2 Hz), 3.95 (3H, s), 4.96 (1H, m), 5.07 (1H, s), 7.56 (2H, d, J= 8.3 Hz), 8.29 (2H, d, J= 3.6 Hz), 8.31 (1H, s), 8.48 (1H, s), 8.55 (1H, s), 8.82 (1H, s). 424.1; 98 32 OH h2n^7 Cis, racemic mixture nJ B(OH)2 Cl ¢= B(OH)2 Q N           OH CIJU o Y 6-(4-chlorophenyl)-3 -(4-hydroxytetrahydrofuran-3 -y 1)-8 - (pyri din-3 -yl)pyrido[3,4-d]pyrimidin- 4(3H)-one, cis racemate (DMSO4, 400 MHz): 5 3.77 (1H, dd, 7=9.8,2.3 Hz), 4.02-3.92 (2H, m), 4.18 (1H, dd, 7 = 9.8, 5.9 Hz), 4.50 (1H, s), 421.1; 99 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 5.38 (1H, q, 7= 6.7 Hz), 5.47 (1H, s), 7.59 (3H, d, J= 8.3 Hz), 8.31 (2H, d, J= 8.4 Hz), 8.34 (1H, s), 8.55-8.54 (1H, m), 8.58 (1H, s), 8.70 (1H, s), 9.35 (1H, s). 33 h2n 9 B(OH)2 Cl B(OH)2 Q N T°H Cl^   0 ‘ (R)-6-(4-chlorophenyl)-3 -(3 -hy droxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (CH3OH-74, 400 MHz): 5 1.11 (3H, s), 1.39 (3H, s), 1.59 (4H, d, 7= 7.2 Hz), 5.13 (1H, s), 7.54-7.52 (2H, m), 8.15 (1H, dd, J= 8.2, 5.6 Hz), 8.24 (2H, d, J= 8.3 Hz), 8.65 (2H, d, J= 421.1; 99 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 5.5 Hz), 8.89 (1H, d, J= 5.5 Hz), 9.50 (1H, d, J= 8.2 Hz), 9.87 (1H, s). 34 HO—r— Y.«m h2n 9 B(OH)2 9 B(OH)2 Q ■pA P o = (S)-3 -(3 -hydroxy-3 -methylbutan-2-yl)-6,8-di(pyridin-3-yl)pyrido[3,4- d]pyrimidin-4(3H)-one (CHCW, 400 MHz): 5 1.22 (3H, s), 1.44 (3H, s), 1.60 (3H, d, 7=7.2 Hz), 5.17-5.07 (1H, m), 7.46 (2H, dt, J= 8.0, 4.9 Hz), 8.56-8.50 (2H, m), 8.59-8.56 (2H, m), 8.71 (2H, ddd, J= 4.8, 1.7 Hz), 9.46 (2H, dd, J= 18.7, 2.2 Hz). 388.1; 99 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 35 H°^..... / h2n ' B(OH)2 B(OH)2 vj AA    0 F (S)-6,8-bi s(3,5 -difluorophenyl)-3 -(1-hy droxy-3 -methylbutan-2- yl)pyrido[3,4-d]pyrimidin-4(3H)-one (CHCW, 400 MHz): 5 0.88 (3H, d, J= 6.6 Hz), 1.19 (3H, d, J= 6.5 Hz), 2.27 (1H, br s), 2.49-2.43 (1H, m), 3.99 (1H, d, J= 11.9 Hz), 4.17 (1H, dd, J= 11.9, 5.9 Hz), 4.53 (1H, s), 6.96-6.87 (2H, m), 7.72 (2H, d, J= 7.6 Hz), 7.86 (2H, d, J= 8.0 Hz), 8.32 (1H, s), 8.47 (1H, s). 458.1; 99 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 36 HO—4— \...... h2n H d B(OH)2 Cl B(OH)2 Q CI-V    0 E (S)-6-(4-chlorophenyl)-3 -(3 -hy droxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (DMSO4, 400 MHz): 5 0.98 (3H, s), 1.26 (3H, s), 1.47 (3H, d, 7=7.2 Hz), 4.97 (1H, m), 5.03 (1H, s), 7.59 (3H, d, J= 8.5 Hz), 8.30 (2H, d, J= 8.3 Hz), 8.53 (3H, m), 8.67 (1H, d, J= 4.8 Hz), 9.33 (1H, s). 421.1; 99 37 H0^..... / h2n ' B(OH)2 B(OH)2 n >""^OH (S)-8-(3,5 -difluorophenyl)-3 -(1-hydroxy-3-methylbutan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one (CHCW, 400 MHz): 5 0.87 (3H, d, J= 6.7 Hz), 1.16 (3H, d, J= 6.5 Hz), 2.42 (4H, m), 2.81 (1H, s), 3.95 (1H, d, J= 12.1 Hz), 436.1; 99 WO 2021 / 102288                                                 PCT / US2020 / 061548 LA 00 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 4.14-4.11 (1H, m), 4.47 (1H, s), 6.91 (1H, tt, J= 8.8, 2.4 Hz), 7.29 (2H, d, J= 7.9 Hz), 7.87-7.83 (2H, m), 8.04 (2H, d, 7=7.9 Hz), 8.23 (1H, s), 8.40 (1H, s). 38 h2nJ?H f HO OH OH / vBsoh f aXj& 6-(4-chlorophenyl)-8-(3-fluorophenyl)-3 -(2-hy droxy-2-methylpropyl)pyrido[3,4-d]pyrimidin- 4(3H)-one (400 MHz, DMSO-d6): 5 ppm 1.16 (s, 6H), 4.04 (s, 2H), 4.88 (s, 1H), 7.33-7.39 (m, 1H), 7.56-7.63 (m, 3H), 8.01-8.09 (m, 2H), 8.31 (d, J=9.2 Hz, 2H), 8.38 (s, 424.0; 97 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 1H), 8.55 (s, 1H) 39 TFA   \ h2n^ ^OH or ho'b"oh OH or m y Oi^nN Y^OH Cl^    ° ‘ (R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3 -(3 -hydroxy-3 -methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (400 MHz, DMSO-d6): 5 ppm 0.99 (s, 3H), 1.27 (s, 3H), 1.48 (d, J=7.2 Hz, 3H), 4.90-5.02 (m, 1H), 5.04 (s, 1H), 7.35 (t, J=12.0Hz, 1H), 7.54-7.63 (m, 3H), 8.06 (t, J=8.0 Hz, 2H), 8.28 (d, J=8.0 Hz, 2H), 8.53 (d, J=12.0Hz, 2H) 464.0; 97 40 TFA H2N^ ^OBn or ho'b"oh OH B"°H F T if p^Ao^OoBn 0 5 (400 MHz, DMSO-d6) 5 ppm 1.47 (d, J=6.8Hz, 3H), 2.39(s, 3H), 3.72- 480.2; 97 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 3-[(lS)-2-benzyloxy-l-methyl-ethyl]-8-(3 -fluorophenyl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4-one 3.76(m, 1H), 3.87-3.92(m, 1H), 4.49 (q, J=12.4, 21.6 Hz, 2H), 5.10-5.12 (m, 1H), 7.20-7.26 (m, 5H), 7.33-7.37 (m, 3H), 7.55-7.62(m, 1H), 8.02-8.07(m, 2H), 8.15(d, J=8.0 Hz, 2H), 8.44 (s, 1H), 8.57(s, 1H) 41** OH CF3— h2n ho"B"oh OH i? H          CF3 0 6-(4-chlorophenyl)-8-(3-fluorophenyl)-3 -[3,3,3 -trifluoro-2-hydroxy-propyl]pyrido[3,4-d]pyrimidin-4-one Enantiomer-1 (400 MHz, DMSO-d6) 5 ppm 4.07 (q, J=9.6, 14.0 Hz, 1H), 4.45 (d, J=12.0Hz, 2H), 6.78 (d, J=6.4 Hz, 1H), 7.34- 464.0; 97 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 7.41 (m, 1H), 7.56-7.64 (m, 3H), 7.96-8.06 (m, 2H), 8.31 (d, J=8.8Hz, 2H), 8.49 (s, 1H), 8.54 (s, 1H). 42** OH CF3— h2n F or ho'B"oh OH i H           -Fa As, . N. A, Il              if        OH o cr 6-(4-chlorophenyl)-8-(3-fluorophenyl)-3 - [(3,3,3 -trifluoro-2-hydroxy-propyl]pyrido[3,4-d]pyrimidin-4-one Enantiomer-2 (400 MHz, DMSO-tA) 5 ppm 4.07 (q, J=9.6, 14.0 Hz, 1H), 4.45 (d, J=12.0Hz, 2H), 6.78 (d, J=6.4 Hz, 1H), 7.34-7.41 (m, 1H), 7.56-7.64 (m, 3H), 7.96-8.06 (m, 2H), 8.31 (d, J=8.8Hz, 2H), 8.49 (s, 464.0; 97 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 1H), 8.54 (s, ml__________________________ HO' 50 h2n B(OH)2 ocf3 B(OH)2 (S)-3 -(1-hy droxypropan-2-yl)-8-(pyridin-3-yl)-6-(6- (trifluoromethoxy)pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3J7)-one (CHsOH-tA, 400 MHz): \ 5h1.56(3H, | d, J = 7.1      | Hz), 3.85     | (1H, dd, J = | 11.9,4.3      \ Hz), 3.97     | (1H, dd, J = | 11.9,7.0      | Hz), 5.01     | (1H, td, J = | 7.2, 4.5 Hz), \ 7.31 (lH,d, J = 8.6 Hz), | 7.61 (1H, dd, | J = 8.0, 5.0   \ Hz), 8.46     \ (1H, s), 8.65- | 8.63 (2H,     | m), 8.72      | (1H, dd, J = | 8.1,1.7 Hz), \ (1H, dd, | J = 8.6, 2.5   | Hz), 9.16 J WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________,(Step„,4)„„„„, Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) RIH, d,J= \ ^2.4 Hz), 9.42 k”1- $).       | \             N-NH KCH3OH-t / 4, ROO MHz): | \ \ \ Mh1.27(6H, \ h), 4.15 (2H, i                     >                  J CF3         S              N            OH \       /        \ N-NH         1 h), 7.97 (ih, \ HO-(-     * # j      fi N         f J J M, J = 8.2 51                                         \ ||    \       \ cf3^n^ Hz), 8.45   H311;98% H2N         \ B(OH)2                 \ (5)-3-(2-hydroxy-2-methylpropyl)-8- klH, s), 8.53 \ \                  \               \ B(OH)2 \ (U7-pyrazol-4-yl)-6-(6- K1H, s), 8.88- \                \                \ (trifluoromethyl)pyridin-3- M-81 (3¾ \ \                  \               \               \ yl)pyrido[3,4-d]pyrimidin-4(3J7)-one ^m), 9.55      \ K1H, s).       ; HO— 52 H2N COOMe B(OH)2 B(OH)2 MeOOC methyl (5)-5-(3-(1 -hydroxypropan-2-yl)-4-oxo-8 -(pyri din-3 -y 1) - 3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)picolinate kCH3OH-^4,  |            | MOO MHz):   |            | |5h1.56(3H, |             | [d, J = 7.1      \                 \ |Hz), 3.86      |                | |(1H, dd,J=  | 418.1; 99% | hl 9,4.2      I               I |Hz), 3.99-     |                | |3.94(1H, |m), 4.02       |                | |(3H, s), 5,03- || WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________,(Step„,4)„„„„, Compound Structure / Name ‘H-NMR ------ m), 7.63-7.60 (1H, m), 8.31 (1H, d, J = 8.2 Hz), 8.49 (1H, s), 8.65-8.64 (1H, m), 8.75-8.72 (2H, m), 8.82 (1H, dd, J = 8.2, 2.1 Hz), 9.43 (1H, s), 9.53 (1H, d, J = 2.1 Hz). MS (m / z); Purity (%) 53 HO— GN B(OH)2 S-N Y B(OH)2 Q N          OH (5)-3-(1 -hy droxypropan-2-yl)-6- (isothiazol-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3J7)-one (CHsOH-tA, 400 MHz): 5h 1.55 (3H, d, J = 7.1 Hz), 3.85 (1H, dd, J = 11.8, 4.3 Hz), 3.96 (1H, dd, J = 11.9, 7.0 Hz), 5.01- 366.1; 99% WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 4.97 (1H, m), 7.60 (1H, dd, J = 7.9, 4.9 Hz), 8.43 (1H, s), 8.54 (1H, s), 8.63 (1H, d, J = 4.8 Hz), 8.71 (1H, d, J = 8.1 Hz), 9.26 (1H, s), 9.40 (1H, s), 9.59 (1H, s). KCHsOH-tA, | 1                   I N-S | 1   /   i V  X 54 i   >    i  X   0 \ H2N |               | 7 \ 1   B(°H)2 MOO MHz): \            \ \                                         |5h1.30(6H, |              | \         y                     k, J = 1.4 1                          oh                   ^Hz), 4.19- I                I \                                   p,17(2H, CFa^N^     °                            T   । 4479; 98% । \                                       YH, dd, J= ;             ; 3-(2-hydroxy-2-methylpropyl)-8-          1 6 Hz) | (isothiazol-4-yl)-6-(6-                  ^50 (1H, d,’ |              | \ (trifluoromethyl)pyridin-3-           b =1 4 Hz)’                         B \ yl)pyrido[3,4-d]pyrimidin-4(3J7)-one 71 (1H d |                                         |j=1.3Hz),’ |              |         o J________________________________________________1.8:92-8:.87     1                1           B Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) (1H, m), 9.59-9.58 (1H, m), 9.66 (1H, s), 10.20 (1H, d. J= 1.3 Hz). HO 55 N-S h2n O’ cf3 B(OH)2 (5)-3 -(1 -hydroxypropan-2-yl)-8- ( isothiazol-4-yl)-6-(6- (trifluoromethyl)pyridin-3 - yl)pyrido[3,4-d]pyrimidin-4(3J7)-one (CHsOH-tA, 300 MHz): 5h 1.62-1.57 (3H, m), 3.92-3.86 (1H, m), 4.03-3.96 (1H, m), 5.08-5.02 (1H, m), 8.02-7.99 (1H, m), 8.59-8.59 (1H, m), 8.70-8.70 (1H, m), 8.92-8.88 (1H, m), 9.59-9.58 (1H, m), 9.68-9.68 433.9; 98% WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________,(Step„,4)„„„„, Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) (1H, m), 10.21-10.20 (1H, m). HO— 56a N-S N-S H2N O O O 0 (5)-3-(1 -hy droxypropan-2-yl)-6,8-di(isothiazol-4-yl)pyrido[3,4-d]pyrimidin-4(3J7)-one (CH3OIW4, 300 MHz): | 5h 1.57 (3H, d, J = 7.1      \ Hz), 3.86     | (1H, dd, J = | 11.9,4.3      | Hz), 3.97     | (1H, dd, J = \ 11.8,6.9      | )371.9,98% m), 8.45      \ (1H, s), 8.50- 8.49 (1H,     | m), 9.27      | (1H, s), 9.60 | (1H, s), 9.63 \ (1H, s),        | 10.14 (1H, s). WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________,(Step„,4)„„„„ Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 57 OH CF3—4s; H2N B(OH)2 cf3 B(OH)2 (5)-8-(pyri din-3 -y 1)-3 -(3,3,3 -trifluoro-2-hydroxypropyl)-6-(6- (trifluoromethyl)pyridin-3 - yl)pyrido[3,4-t / ]pyrimidin-4(3 / / )-one (CH3OH-t / 4, 400 MHz): 5h 4.08-3.99 (1H, m), 4.49-4.44 (1H, m), 4.69-4.63 (1H, m), 7.67-7.63 (1H, m), 8.04-8.00 (1H, m), 8.44-8.42 (1H, m), 8.69-8.66 (1H, m), 8.77-8.72 (1H, m), 8.82-8.80 (1H, m), 8.91-8.87 (1H, m), 9.45-9.43 (1H, m), 9.60-9.58 (1H, m). 481.9; 99% WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________,(Step„,4)„„„„, Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) HO— 58 N-S h2n O’ Cl B(OH)2 N-S ci (5)-6-(4-chlorophenyl)-3-(l-hydroxypropan-2-yl)-8-(isothiazol-4-yl)pyrido[3,4-t / ]pyrimidin-4(3J7)-one (CH3OIW4, 400 MHz): | 5h 1.57 (3H, I d, J = 7.1      | Hz), 3.86     \ (1H, dd, J = | 11.9,4.3      | Hz), 3.97     | (1H, dd, J = | 11.9,6.9      \ Hz), 5.02-    | 4.97 (1H,    | 398.9; 99% m), 7.52      | (2H, d, J =    | 8.3 Hz), 8.21 \ (2H, d, J =    \ 8.2 Hz), 8.47 | (2H, d, J =    | 14.6 Hz), | 9.59 (lH,s), | 10.11 (1H,    | s). WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________,(Step„,4)„„„„, Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 59b HO H2N B(OH)2 B(OH)2 60 HO h2n B(OH)2 cf3 N B(OH)2 3 -(2-hy droxy-2-methylpropyl)-6,8-di(pyridin-3-yl)pyrido[3,4- d]pyrimidin-4(3J7)-one (CH3OH-t / 4, 400 MHz): 5h 1.27 (6H, s), 4.11 (2H, s), 7.58 (2H, t, J = 6.3 Hz), 8.35 (1H, s), 8.61 (4H, d, J = 8.1 Hz), 8.69 (1H, d, J = 8.1 Hz), 9.34 (1H, s), 9.38 (1H, s). 374.0; 99% cf3 3 -(2-hy droxy-2-methylpropyl)-8-( 1 -methyl-U7-pyrazol-4-yl)-6-(6- (trifluoromethyl)pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3J7)-one (CH3OH-t / 4, 400 MHz): 5h 1.27 (6H, s), 4.00 (3H, s),4.12(2H, s), 7.95 (1H, d, J = 8.3 Hz), 8.41 (1H, s), 8.45 (1H, s), 8.54 (1H, s), 8.81 8.79 (2H, m), 9.50 444.9; 99% WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________,(Step„,4)„„„„, Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) (1H, s). 61 HO h2n B(OH)2 Cl B(OH)2 ci 6-(4-chloro-2-methylphenyl)-3-(2-hydroxy-2-methylpropyl)-8-(l-methyl-l / / -pyrazol-4-yl)pyrido[3,4- J]pyrimidin-4(3J7)-one (CHsOH-tA, \ 400 MHz): | 5h1.26(6H, | s), 2.45 (3H, | s), 3.97 (3H, \ s),4.12(2H, \ s), 7.31 (1H, | d, J = 8.3     | 423.9; Hz), 7.36     | 99 (1H, s), 7.50 | (1H, d, J =    \ 8.2 Hz), 7.94 | (1H, s), 8.40 | (1H, s), 8.44 | (1H, s), 8.72 | (1H, s).        | 62 HO— HN H2N cf3 HN-N ‘OH B(OH)2 (5)-3-(1 -hy droxypropan-2-yl)-8-( 1H-pyrazol-4-yl)-6-(6- (DMS04, 400 MHz):   \ 5h1.44(3H, | d, 7=7.0    | Hz), 3.70-    | 417.1; >98 3.65 (1H,     | m), 3.82- 3.77 (1H,     | m), 4.89     ] WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________ Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) (trifluoromethyl)pyridin-3 - (1H, d, J= yl)pyrido[3,4-J]pyrimidin-4(3J7)-one ^7.7 Hz), 5.09 R1H, t, J = h.6Hz), 8.02 R1H, d, J= 18.3 Hz), 8.49 R1H, s), 8.59 Rih, s), 8.60 Rih, s), 8.86 Rih, s), 8.93 Rih, d, j= ^8.3 Hz), 9.64 Rih, s), ^13.22 (1H, 63 h^n^oh Me Me B(OH)2 f5c n B(OH)2 (5)-3-(l-hydroxypropan-2-yl)-8-(2-methylpyri din-3 -yl)-6-(6- (trifluoromethyl)pyridin-3 - yl)pyrido[3,4-t / ]pyrimidin-4(3 / / )-one (300 MHz, \ DMSO-de): | 5h 9.58 (1 H, \ d. . / 1.8).       | 8.90-8.84 | (2 H, m),     \ 8.76 (1H,           ’ dd. . / 5.5.      996 1.7),8.52(1 \ II. s), 8.23 (1 | II. d. . / 6.7). | 8.05 (1H, d, | . / 8.3).7.69   | WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________ Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 64 h2n<^qh Me Me B(OH)2        F3° N B(OH)2 (5)-3-(l-hydroxypropan-2-yl)-8-(4-methylpyri din-3 -yl)-6-(6- (trifluoromethyl)pyridin-3 - yl)pyrido[3,4-t / ]pyrimidin-4(3Z / )-one (1 H, dd, J 8.2. 5.2), 4.95 4.85 (I H, m), 3.79 (1 H, dd. J 11.6, 7.3). 3.68 (1 H, dd, J 11.4, 4.6), 2.51 (3 H, s), 1.43 (3 H, d, 77:0), '(IOOMhT’'’ DMSCUi: du 9.57(1 H, s), 8.86 (1 H, d.. / 7.7). 8.80 (1 H, s), 8.58 (1 H, s), 8.54 (I H, d, . / 4.9). 8.50 (I H, s), 8.04 442.9 98.3 8.3), 7.42 (1 H, d. . / 4.9). 5.07(1 II. t. . / 5.3). 4.90 (I II. dd, J WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 12.0, 6.6). 3.84-3.74 (1 H, m), 3.72-3.63 (1 H, m), 2.24 (3 H, s), 1.42 (3 H, d, Q / 7.0). '(DMSO-^........ 400 MHz): 5h 1.42 (3H, d, 7=7.0 Hz), 3.32 (2H, s), 3.67-3.64 (1H, m), 3.81- 3.77 (1H, m), 4.89- 380.0; L if 4.84 (1H, >99 S             ___x ° £ ^OH m), 5.08 (1H, s), 7.57 (1H, dd, J= 7.9, 4.8 Hz), 8.22 (1H, s), 8.47 (1H, d, J= 8.0 Hz), 8.55 (1H, s), 8.67 (1H, d, WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound Structure / Name 1H-NMR J Purity (%) ................................. 9.07 (lH,s), | 9.26(1¾ s).| (DMSO-76, |.................................... 400 MHz): | 5h 1.04-1.01 | (2H, m), 1.18-1.13     \ (2H, m),      | 1.41 (3H,d, | 7= 7.0 Hz), | 2.45-2.40     | o (1H, m),      \ 3.68-3.63     \ I z 2=o r (1H, m),      \ 406.1; 3.81-3.75     | 98 (1H, m),      | 4.89-4.84 (1H, m),      | 5.06 (1H, t, J | = 5.6 Hz), | 7.56 (1H, dd, | 7=7.9,4.8 \ Hz), 8.48-    \ 8.43 (4H,     | m), 8.66-     \ 8.65 (1H,     \ WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound Reactant 1 Reactant 2 Reactant 3 Compound Structure / Name 1H-NMR J Purity (%) m)?925"""""""[     .................... (IH- s)._________________j___________________________________ (DMSO4, 400 MHz): | 5h 1.35 (3H, | s), 1.37 (3H, | s), 1.42(3H, \ d, 7=7.0    \ Hz), 3.69-    | 3.63 (IH,     | m), 3.81-     | 3.75 (IH,     | Q m), 4.89- 4.84 (IH, | 1 °=\ ,z 'z—J T m), 5.05     ^408.1; (IH, t, 7 =    | 99 5.6 Hz), 7.56 (IH, dd,7 = 7.9, 4.8 Hz), | 8.46 (IH, d, | 7=8.1 Hz), | 8.50 (2H, d, | J= 4.9 Hz), 8.55 (IH, s), \ 8.67-8.66     | (IH, m),      | 9.25 (IH, d, | J= 2.1 Hz). | WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________(StepJL 68 HO NH2 HO' 'OH CF- B(OH)2 F- F Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) N—X # A .X I if *1 (DMSoXe, 300 MHz): 5h 1.47 (3H, d, 7=7.0 Hz), 3.74-3.68 (1H, m), 3.87-3.78 (1H, m), 3.98 (3H, s), 4.96-4.85 (1H, m), 5.18- 431.1; 5.08 (1H, 98 . X         o = N F m), 8.03 (1H, d, J= 8.3 Hz), 8.50 (1H, s), 8.55 (1H, s), 8.61 (1H, s), 8.85 (1H, s), 8.94 (1H, d, J= 8.4 Hz), 9.66 (1H, s). WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________,(Step„,4)„„„„, Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) ^DMSO-76, \ ^300 MHz): | ^5h1.46(3H, | |d,7=7.0    | |Hz), 3.85-    \ CF3 p.67(2H, l                      Y|l ^m), 4.96-     \ I cf3       cf3              ‘V k9° (1H’ 1 ^m), 5.10      \ 69a      \ iU U 1 jyAr- ^IH’ b       \ 49g p 99 p.6 Hz), 8.10        ’ \     \          \    1             FjC^N^ |(2H, dd,7= | B(OH)2      B(OH)2     (S)-3-(l-hydroxypropan-2-yl)-6,8- U6.8, 8.3      | \ bis(6-(trifluoromethyl)pyridin-3-      ^Hz), 8.64 \ yl)pyrido[3,4-d]pyrimidin-4(3H)-one K1H, s), 8.83  \ '                                         km, s), 8.96- \ (8.85 (2H,     | ^m), 9.55      \ |(1H, s),9.66 | KdMSO-76, | ^400 MHz): | ^5h3.77(1H, | |d,7=9.8    | 421.1; Hz), 4.02-    \ 99o / o ^3.92 (2H, |m), 4.20-     | ^4.16 (1H,     | Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________ Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) (pyri din-3-yl)pyrido[3,4-d]pyrimidin- ^m), 4.50 4(3H)-one. Enantiomer 1 OH H2N 71c 3R, 4R Cl B(OH)2 B(OH)2 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxytetrahydrofuran-3 -y 1)-8-(pyri din-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one Enantiomer 2 ^(1H, s), 5.38 (111. q, J 6.7 Hz), 5.47 (1H, d. J 3.8 Hz), 7.58 (311. t, J 8.5 Hz), 8.30 (211. d, J 8.4 Hz), 8.34 (111. s), 8.54 (211. m), 8.68 (1H, d, . / 4.8 Hz). j9:33 (1H, s): (CHsOH-^ 400 MHz): du 3.95 (1H, d, J 10.2 Hz). 4.04-4.00 (1H, m). 4.10 (Hl. t.. / 8.7 Hz), 4.22 (1H, dd, J 10.2, 5.1 Hz). 4.67 (111. m). 421.1; 99 WO 2021 / 102288                                                 PCT / US2020 / 061548 00 o Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________ Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 5.58 (1H, q, . / 6.2 Hz). 7.50 (2H, d. J 8.4 Hz), 72 h2n^otbs ocf3 'OH B(0H)2 F 3-(2-hydroxyethyl)-8-(pyridin-3-yl)- 6-(4- B(OH)2 = 6.4 Hz), 8.19 (2H, d, . / 8.4 Hz), 8.39 (1H, s), 8.56 (1H, s), 8.61 (1H, d, . / 4.8 Hz). 8.69 (1H, d, . / 8.0 Hz), ^9.38 (1H, s). (DMSO-tA, 400 MHz): On 3.71-3.70 (2H, m), 4.10(211. t, J 5.1 Hz), 4.99(111. t, J |= 4.7 Hz), 7.52 (2H, d, 429.1; 99 (trifluoromethoxy)phenyl)pyrido[3,4- \j= 8.4 Hz), d]pyrimidin-4(3H)-one 7.58 (1H, dd. . / 8.0,4.9 Hz). 8.41 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________ Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) k2H, d,J= \ ^8.6 Hz), 8.43 | klH, s), 8.55- | 18.52 (2H, | |m), 8.68      \ |(1H, d,J= | ^4.8 Hz), 9.32 \ |(HL s)..................| kDMSO^ MOO MHz): | Mh 1.43 (3H, | |d, J= 7.0 | |Hz), 3.59 \ K3H, s), 3.70J 73 \ HO— Cl 1 d 1       Q1' 1 0 1 p.65 (1H,    \ h), 3.82-     I |3.77(1H,     1 423.1; 95 \ H2b / ; I _°\ E- 1 T \ ho'b'oh \ (5)-6-(4-chlorophenyl)-3-(l- \ hydroxypropan-2-yl)-8-(l-methyl-6- \ oxo-1,6-dihydropyridin-3- \ yl)pyrido[3,4-d]pyrimidin-4(3J7)-one p.87(lH, |m), 5.08      | klH,t,J= | h $ Hz), 6.56 | km,d,j= M-5 Hz), |7.60-7.57 1(2H, m), h.31-8.29 WO 2021 / 102288                                                 PCT / US2020 / 061548 00 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________£> Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) HO— 74 H2N HO^^OH HO' (5)-6-(6-cy cl opropylpyri din-3-yl)-3-(l-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one 8.40 (1H, s), 8.47 (1H, dd, | . / 9.6.2.6  | Hz), 8.57     | (111. s), 9.01 \ (111. d.. /       | ^2.6 Hz). J__________ ^MSO^ \............................. 400 MHz): | On 1.03-1.01 | (411. m),       | 1.44(311. d. | . / 7.0 11z). \ 2.20 (1H, s), | 3.71-3.67     | (HI- m),      | 3.82-3.77     | (111. m),       400.0; 99 4.90 (1H, d, | . / 7.9 11z). | 5.08 (1H, t, J | = 5.6 Hz), | 7.46 (1H, d, . / 8.2 Hz). \ 7.58 (1H, dd, | . / 8.0.4.8 | Hz). 8.48     | (111. dd, J= | WO 2021 / 102288                                                 PCT / US2020 / 061548 00 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________ Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) HO 75 h2n HO' CF3 (5)-3-(1 -hy droxypropan-2-yl)-6-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-8-(pyridin-3-yl)pyrido[3,4- J]pyrimidin-4(3J7)-one 8.2, 2.4 Hz), 8.55 (3H, t. J = 5.3 Hz). 8.69 (1H, dd, . / 4.8. 1.7 Hz). 9.26 (1H, d. J 2.3 Hz), 9.35 (1H, d, J 2.2 Hz).______________ ^DMSO^T 400 MHz): du 1.44 (3H, d.. / 7.0 Hz), 2.59 (311. s), 3.71-3.67 (1H, m). 3.85-3.79 (1H, m). 4.93-4.87 (1H, m). 5.08 (HI. 1.. / 5.6 Hz), 7.57 (1H, dd, J 7.9. 4.8 Hz), 7.98 (1H, s), 8.33 (1H, 4, 441.9; 99 WO 2021 / 102288                                                 PCT / US2020 / 061548 00 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________(StepJL,,,,,, Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 8.50-8.47 (1H, m), 8.63 (1H, s). 8.68 (1H, dd. . / 4.8. 1.7 Hz). 8.94 (III. s), 9.29 (HL d. J 2.1 Hz). HO 76 h2n OH ZBX HO OH ZBS HO OH (5)-3-(1 -hy droxypropan-2-yl)-8-( 1 -methyl-lZ / -pyrazol-4-yl)-6-(pyridin-3-yl)pyrido[3,4-t / ]pyrimidin-4(3J7)-one (DMS04, \ 400 MHz): 5h 1.45 (3H, \ d,J=7.0    | Hz), 3.71-    | 3.66 (1H,     | m), 3.85-     | 3.79 (1H,     | m)’ 3 97      \ 363 0' 99 (3H, s), 4.92-         ’ 4.87 (1H,     | m), 5.10 (1H, t,J =    | 5.6 Hz), 7.56 \ (1H, dd, J= | 8.0,4.8 Hz), | 8.37 (1H, s), | 8.53 (1H, s), WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________,(Step„,4)„„„„, Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 8.57 ( H I. s). 8.67-8.63 (2H, m), 8.83 (1H, s), 9.46 (1H, s). 00 LA 77 HO— h2n / Q XBX HO OH HO OH Q o (5)-6-(cy clohex-1 -en-1 -y 1) - 3 -(1 -hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one (CHCh-T 300 MHz): 5 1.58 (3H, d, 7=7.0 Hz), 1.76-1.70 (2H, m), 1.89-1.81 (2H, m), 2.37-2.31 (2H, m), 2.63-2.59 (2H, m), 3.98 (2H, d, J= 4.8 Hz), 5.08-5.00 (1H, m), 7.09-7.06 (1H, m), 7.40 (1H, dd, J= 8.0, 4.8 Hz), 8.07 (1H, s), 8.22 (1H, s), 8.47 363.0; 95 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________ Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) (1H, dt, J= 8.0. 2.0 Hz), 8.64 (1H, d, . / 4.9 Hz), 9.37(111. s). 78a HO H2N HO OH HO OH (5)-6,8-bis(5-fluoropyridin-3-yl)-3-(l hydroxypropan-2-yl)pyrido[3,4-t / ]pyrimidin-4(3Z / )-one (DMSO4, 300 MHz): 5h 1.46-1.42 (3H, m), 3.74-3.68 (1H, m), 3.82-3.77 (1H, m), 4.93-4.91 (1H, m), 5.11-5.07 (1H, m), 8.61-8.55 (1H, m), 8.66-8.61 (2H, m), 8.70-8.69 (1H, m), 8.74-8.73 (2H, m), 9.33-9.32 395.9; 98 WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________ Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 79 OH h2n^X HO OH cf3 N HO OH 3-((37?,45)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6- (trifluoromethyl)pyridin-3 -yl)pyrido[3,4-t / ]pyrimidin-4(3 / / )-one (1H, m), 9.38 (1H, d, | 7= 1.8 Hz).| Kdmso^ 400 MHz): | du 3.64 (III. | dd, 7=9.6, \ 3.3 Hz), 4.08 \ (1H, dd, 7= | 10.1,4.0      | Hz). 4.23-    | 4.14 (2H,     | m), 4.60      \ (1H, dd, 7= | 5.3. 2.9 Hz). | 5.01-4.98     | 466.1; 98 (UI- m),      | 5.71(111. d, 7 4.4 Hz). | 7.60(111. dd, | 7 8.0.4.8 | Hz). 8.07     | (1H, d,7= 8.4 Hz), 8.43 \ (HI. s), 8.58 | (HL dt,7= | 8.0. 1.9 Hz), | 8.71 (1H, dd, | WO 2021 / 102288                                                 PCT / US2020 / 061548 00 00 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________ Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 80 HO H2N cf3 .Bx HO OH HO OH 'OH 3-(2-hydroxy-2-methylpropyl)-8- (pyridin-3-yl)-6-(2- (trifluoromethyl)pyridin-3 - yl)pyrido[3,4-7]pyrimidin-4(3J7)-one ^7=4.8,1.7 Hz). 8.79     | (III. s), 8.95 | (111. dd. 7 8.3.2.1Hz). \ 9.37(111. d. | 7 2.2 Hz). | ^9.65 (!H, sj.I XDMSO^,........p'—— 300 MHz): | du 1.16 (611. | s). 4.05 (2H, | s). 4.88 (1H, \ s). 7.57 (1H, \ dd.. / 7.9.   | 4.8 Hz). 7.88 | (1H, dd, 7= | 7.9, 4.7 Hz), \ 8.32-8.27 p ’ (211. m),       | 8.49-8.45     | (2H, m),      | 8.68(111. d, 7 4.7 Hz). \ 8.87(111. d, | 7 4.7 Hz). | 9.28(111. s). | WO 2021 / 102288                                                 PCT / US2020 / 061548 00 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________ Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 81 HO H2N HO OH 'OH 6-(6-cy cl opropylpyri din-3 -yl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-t / ]pyrimidin-4(3Z / )-one (DMSO-de, 300 MHz): | du 1.03-1.00 | (411. m),       | 1.16 (6H,s), | 2.20 (1H, s), \ 4.04 (2H, s), \ 4.87 (1H, s), | 7.45 (1H, d, | . / 8.2 Hz). | 7.58 (1H, dd, | J= 8.0, 4.8 Hz), 8.38             ’ (111. s), 8.48 | (111. d.. /       | 8.5 Hz), 8.56-8.54 (2H, m),      | 8.69(111. d. | . / 4.8 Hz), | 9.26 (1H, s), | 9.34 (1H, s). \ WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________ Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) (DMS04, 300 MHz): 5h 1.01 (4H 82 HO H2N HO 83 h2n HO OH zB. O O 6-(6-cy cl opropylpyri din-3 -yl)-3 -(2-hydroxy-2-methylpropyl)-8-(l-methyl-l / / -pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3J7)-one 'OH Hz), 1.15 (611. s), 2.20 | (HI- m),      | 3.96 (3H, s), | 4 03 (2H, s),   417 q. 99 4.89 (1H, s),          ’ 7.44 (1H, d, | . / 8.2 Hz). | 8.29 (1H, s), | 8.40 (1H, s), | 8.49-8.46 (2H, m),      \ 8.83 (1H, s), | 9.28 (111, s). | 300 MHz): | du 1.02(411. HO OH (S)-6-(6-cy cl opropylpyri din-3 -y 1)-3 -(l-hydroxypropan-2-yl)-8-(l-methyl- OH 1’I 403-2; 99 (3H, d, J =   \ 7.0 Hz), 2.21 | (1H, t, J =    | 6.9 Hz),      \ 3.71-3.66     \ WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________£> Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) l / / -pyrazol-4-yl)pyrido[3,4- J]pyrimidin-4(3J7)-one (1H, m), 3.82 (111. d. . / 10.3 Hz), 3.97 (3H, s). 4.90 (1H, d. . / 8.1 Hz), 5.09(111. t, J 5.7 Hz). 7.45 (1H, d, J 8.3 Hz), 8.29 (1H, s), 8.53-8.46 (3H, m), 8.82 (1H, s). 9.28 (111. s). 84 HO— H2N OH HO OH (5)-3 -(1-hy droxypropan-2-yl)-8-(pyridin-3-yl)-6-(thiazol-5 - yl)pyrido[3,4-J]pyrimidin-4(3J7)-one (DMSO4, 300 MHz): | 5h1.44(3H, | d, 7=7.0    | Hz), 3.75 (2H,d,J=   \ 365.9; 99 33.2 Hz), | 4.90 (1H, s), | 5.08 (1H, s), | 7.60 (1H, s), | 8.60-8.48     \ WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________,(Step„,4)„„„„, Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) (3H, m), 8.70 (1H, s), 8.85 (1H, s), 9.21 (1H, s), 9.29 (1H, s). HO— 85 H2N ,cf3 HO OH 'OH (DMSO4, 300 MHz): | 5h1.44(3H, | d, 7=7.0    | Hz), 3.75     \ (2H, d, 7 =   | 32.7 Hz),     | 4.91 (1H, br  | s), 5.08 (1H, | s), 7.59 (1H, \ s), 8.50 (1H, (5)-3 -(1 -hy droxypropan-2-yl)-8- (pyridin-3-yl)-6-(2- (trifluoromethyl)thiazol-5-yl)pyrido[3,4-J]pyrimidin-4(3J7)-one Hz), 8.60 (1H, s), 8.71 (1H, s), 8.79 (1H, s),9.10 (1H, s), 9.30 (1H, s). WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________.(Step„,4)„„„„, Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) (DMS04, 400 MHz): 5h 1.46 (3H HO' 86 h2n cf3 87 HO h2i HO OH HO OH HO OH ,CF3 ■OH f3c (5)-3 -(1 -hy droxypropan-2-yl)-8- (pyridin-3-yl)-6-(2- (trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3J7)-one Hz), 3.76 (211. d.. /       | 45.5 Hz),     | 5.01(211. d. | J~ Hz), \ 429 p 99 :7.62 (1H, t, J ’ = 6.3 Hz), | 8.71-8.62     | (311. m),       | 8.89 (1H, s), | 9.42 (1H, s), 9.91 (2H, s). \ OH 3-(2-hydroxy-2-methylpropyl)-8-(pyri din-3-yl)-6-(2- (DMSO4, 400 MHz): | 5h1.16(6H, | s), 4.05 (2H, | s), 4.88 (1H, \ s), 7.60 (1H, dd, 7=8.0, | 4.8 Hz), 8.42 | (1H, s), 8.50 | WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) 9 HO OH Reactant 3 _________(StepJL £F3 N=\ ^O O^ Compound Structure / Name (trifluoromethyl)thiazol-5-yl)pyrido[3,4-7]pyrimidin-4(3J7)-one ‘H-NMR (1H, d, J= 4.8 Hz), 8.81 (1H, s), 9.10 (1H, s), 9.29 (1H, s). MS (m / z); Purity (%) 88 oh h2n,, \-N cf3 ¢- \-N (DMSO4, 400 MHz): 5h3.80(1H, dd, 7=9.7, 2.2 Hz), 3.96-3.93 (4H, m), 4.02 (1H, dd, 7=9.9, 7.5 Hz), 4.22 459.1; 98 ^C) HO OH T HO OH f3cAY    0   0 3-((35,45)-4-hydroxytetrahydrofuran-3 -yl)-8-(l -methyl-l / / -pyrazol-4-yl)-6- (6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-7]pyrimidin-4(3J7)-one (1H, dd, 7 = 9.9, 5.5 Hz), 4.54-4.51 (1H, m), 5.43 (1H, q, 7= 6.5 Hz), 5.51 (1H, d, 7= 4.4 Hz), 8.03 (1H, d, 7= 8.3 Hz), WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________,(Step„,4)„„„„, Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 8.41 (1H, s), 8.52 (1H, s), 8.55 (1H, s), 8.89 (1H, s), 8.95 (1H, dd. HO— 89 H2N ,CH3 HO OH (5)-3-(1 -hy droxypropan-2-yl)-6-(2-methylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-7]pyrimidin-4(3J7)-one Hz), 9.66     \ (IH.s)..................|........................... (DMSO^ 400 MHz): | 5h 1.43 (3H, | d,7=7.0    | Hz), 2.71     \ (3H, s), 3.69-1 3.64 (1H,     | m), 3.80      | (1H, dt, 7= | 379.9; 95 Hz), 4.91-    \ 4.86 (1H,     | m), 5.07      | (1H, t, 7 =    | 5.7 Hz), 7.58 \ (1H, dd, 7= 8.0,4.8 Hz), | 8.55-8.47     | (4H, m),      | 8.69 (1H, d, | WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________.(Step„,4)„„„„, Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) ^=4.8 Hz), 9.28 (III. s). 90d H,N„ r oh HO OH Cl 3, HO OH (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3 -(1 -hydroxy-3 -methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (400 MHz, \ DMSO-d6): | 5h ppm 8.40- \ 8.61 (m,      \ 2H), 8.19-    | 8.35 (m,      | 2H), 7.97-    | 8.14 (m, 2H), 7.53-    | 7.67 (m,      | 3H), 7.33-    | 7.38 (m,      | 438.2; 1H), 5.02 (s,   99 9 1H), 4.18-    \ 4.70 (m,      | 1H), 3.88-    | 4.00 (m,      | 1H), 3.79 (d, | J=11.8,3.5   \ Hz, 1H),      | 2.20-2.42     | (m, 1H),      | 107 (d,       | J=6.6 Hz,    \ WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________ Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) 3H), 0.79 (d, J=6.7 Hz, 3H);_______ 400 MHz): 5h 1.54 (3H HO' 91 h2n Hz), 2.51 (3H, s), 2.57 (2H, s), 2.73 (2H, t, J= 5.8 Hz), 3.72 (2H, s), 3.84 (1H, OH B(OH)2 (S)-3 -(1 -hy droxypropan-2-yl)-8-( 1 -methyl-l,2,5,6-tetrahydropyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 4.0 Hz), \ 446.2; 95% 3.96 (1H,    | dd, J= 11.9, 6.9 Hz), | 4.97(2H, br | s), 7.34 (1H, | s), 7.96 (1H, | Hz), 8.43 (1H, s), 8.58 (1H, s), 8.77 (1H, d, J= 8.3 Hz), WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) ,948 (DMSO-i 400 MHz): 5 3.79(1H, N—N N / z OH Cl 6-(4-chlorophenyl)-3-((35,45)-4-hydroxytetrahydrofuran-3 -y 1)-8 -(1 -methyl- lZ / -pyrazol-4- yl)pyrido[3,4-J]pyrimidin-4(3Z / )-one Hz), 4.02-   \ 3.92 (5H, m), 4.20     \ (1H, dd, 7 = | 9.9, 5.6 Hz), | ^2 Sim S ’ 424 1’ 99 5.41 (1H, q, \ 7= 6.5 Hz), \ 5.50 (lH,d, | J= 4.2 Hz), | 7.59 (2H,d, | J= 8.3 Hz), | 8.35-8.30 (4H, m),     | 8.50 (1H, s), | 8.84 (1H, s). ] WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________(StepJL 93 HO— h2n hoxB"oh ho.d.oh D CH3 Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) Q n       N ^oh (DMS^ 400 MHz): 5 1.44 (3H, d, 7=7.0 Hz), 2.72 (3H, s), 3.71-3.65 (1H, m), 3.84-3.78 (1H, m), 4.93-4.88 xk         0 - H3C N (5)-3 -(1 -hy droxypropan-2-yl)-6-(2-methylpyrimidin-5-yl)-8-(pyridin-3-yl)pyrido[3,4- J]pyrimidin-4(3J7)-one (1H, m), 5.09 (1H, t, J= 5.7 Hz), 7.60 (1H, d, J= 6.8 Hz), 8.58-8.55 (2H, m), 8.70-8.69 (2H, m), 9.36 (1H, s), 375.1; 99 j9.53(2H, s). \ WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________(§tepJl_ 94 HO f3cx 200 95 h2n HO" OH ho.d.oh D CH3 HO— h2n N-N ho"b"oh ho.d.oh D CF3 Compound Structure / Name f3c N-N 3-(2-hydroxy-2-methylpropyl)-8-(1 -(trifluoromethyl)- 17 / -py razol -4-yl)-6-(6-(trifluoromethyl)pyridin-3 - yl)pyrido[3,4-d]pyrimidin-4(3Z / )-one (5)-3-(l-hydroxypropan-2-yl)-8- (1 -methyl- 177-pyrazol-4-yl)-6-(2-(trifluoromethyl)pyrimidin-5- 1H-NMR \ (DMS04, \ 400 MHz): \ 5 1.16 (6H, \ s), 4.06 I (2H, s), | 4.94 (1H, | s), 8.04 (1H, d, J= \ 8.3 Hz), \ 8.52 (1H, \ s), 8.68 | (1H, s), \ 9.03 (2H, \ s), 9.48 I (1H, s), | 9.75 (1H, M_______________________ (DMSO4, | 400 MHz): \ 5 1.46 (3H, \ d, J=7.0 \ Hz), 3.71-\ 3.66 (1H, | m), 3.85- \ 3.79 (1H, \ m), 3.97 | (3H, s), \ 4.93-4.88 MS (m / z); Purity (%) | 499.1; 96.6 | | 432.1; 95.7 | WO 2021 / 102288                                                 PCT / US2020 / 061548 201 Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) yl)pyrido[3,4-d]pyrimidin-4(3Z / )- (1H, mj, one 5.12 (1H, t, J= 5.6 Hz), 8.60 (1H, s), 8.62 (2H, s), 8.90 (1H, s), 9.92 (2H, s). 3-(2-hydroxy-2-methylpropyl)-8-(pyri din-3 -yl)-6-(2- (trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3Z / )-one \ 9.77 (211. s). (CH3OH-a4, \ \ 400 MHz): | \ 5h 1.27 (6H, | \ s),4.16(2H, \ \ s), 7.63 (1H, | |dd,J = 8.0, |              ; \ 5 0 Hz), 8.43 (1H, s),          ’       \ \ 8.65 (1H, s), | 8.74 (1H, d,  |                | | J = 8.0 Hz),  |                | \ 8.84 (1H, s), |                 | \ 9.43 (1H, s), |                 | WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 _________(§tepJl_ 202 97 HO— h2n B(OH)2 COOMe B(OH)2 Compound Structure / Name ‘H-NMR MS (m / z); Purity (%) (CH3OH-t / 4, 400 MHz): | 5h 1.59-1.57 | (3H, m),     | 3.89-3.85    \ (1H, m),     | 3.98 (1H,    | dd, J = 11.8, | 6.8 Hz), Q 5.07-5.00    \ (1H, m), oh 8.34-8.30 IJ I 1' HOOC N (1H, m), 8.51-8.48 404.1; 95% (5)-5-(3-(l-hydroxypropan-2-yl)- (1H, m),     \ 4-oxo-8-(pyridin-3-yl)-3,4- 8.60 (1H, s), dihydropyrido[3,4-d]pyrimidin-6- 8.99-8.96 yl)picolinic acid (2H, m),     \ 9.17-9.12    | (1H, m),     | 9.66-9.63    \ (1H, m),     | 9.74-9.71    | (1H, m),     | 10.01 (1H,   | d, J = 2.6 Hz). WO 2021 / 102288                                                 PCT / US2020 / 061548 203 Compound Structure / Name Q N--L^Nx oh N x "'xl X j s i (S)-3 -(1 -hy droxypropan-2-yl)-6-(6-methylpyridin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3J7)-one ‘H-NMR 400 MHz): 5h 1.55 (3H, d, J = 7.1 Hz), 2.62 (3H, s), 3.85 (1H, dd, J = 11.9, 4.2 Hz), 3.97 (1H, dd, J = 11.9, 7.0 Hz), 5.00 (1H, s), 7.47 (1H, d, J = 8.3 Hz), 7.60 (1H, s), 8.45 (1H, s), 8.61-8.52 (3H, m), 8.70 (1H, s), 9.24 (1H, s), 9.40 (1H, s). MS (m / z); Purity (%) 374.1; 99% \-N ZA X ^N. N         OH X^x         O CF3^ n (CHsOH-tA, 400 MHz): 5h 1.26 (6H, s), 3.98 (3H, s), 4.09 (2H, s), 8.39 (1H, 446.1; 99% WO 2021 / 102288                                                 PCT / US2020 / 061548 204 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name *H-NMR MS (m / z); Purity (%) 3-(2-hydroxy-2-methylpropyl)-8-(1 -methyl- l / / -pyrazol-4-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3 / / )- one s), 8.44 (1H, s), 8.49 (1H, s), 8.75 (1H, s), 9.66 (2H, s). ** Compounds 41 and 42 were obtained via SFC purification of the racemic mixture (column: DAICEL CHIRALPAK AD (250mm*30mm,10um); mobile phase: [0.1%NH3H2O EtTOH]; B%: 40%-40%,7min). a) The compound was synthesized from Intermediate B2 in one step coupling with 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isothi azole b) The compound was synthesized from Intermediate Bl in one step coupling with (6-(trifluoromethyl)pyridin-3-yl)boronic acid. c) Compounds 70 and 71 were obtained via SFC purification of the racemic mixture 29. d) The reaction was performed using THF / water 2 / 1 as solvent and K2CO3 as base. WO 2021 / 102288                                                 PCT / US2020 / 061548 Preparation of 3-((S)-l-hydroxypropan-2-yl)-8-(l-methylpiperidin-3-yl)-6-(6- (trifluoromethyl)pyridin-3-yl)pyrido [3,4-d] pyrimidin-4(3H)-one

[00132] To a solution of (5)-3-(l-hydroxypropan-2-yl)-8-(l-methyl-l,2,5,6-tetrahydropyri din-3-yl)-6-(6-(trifluoromethyl)pyri din-3-yl)pyrido[3,4-d]pyrimidin-4(3J7)-one (60 mg, 0.135 mmol) in EtOH (1 mL) under N2, PtO2 (15 mg, 0.088 mmol) was added. The flask was degassed and subjected to H2 gas in balloon. After overnight, the reaction mixture was filtered through Celite®, washed well with methanol, concentrated and purified by reverse phase chromatography eluting with 0.1% formic acid in H2O and acetonitrile, to give desired product as diastereomeric mixture (4 mg, 7%). 1H NMR (CH3OJW4, 400 MHz): 6h 1.29 (1H, s), 1.54 (4H, d, J= 7.1 Hz), 1.94 (2H, s), 2.13 (1H, s), 2.50 (3H, s), 3.13 (2H, s), 3.85 (1H, s), 3.95 (2H, s), 4.28 (1H, s), 4.62 (2H, s), 4.99 (2H, m), 7.96 (1H, d, J= 8.2 Hz), 8.47 (1H, s), 8.60 (1H, s), 8.80 (1H, d, J= 8.2 Hz), 9.51 (1H, s). MS (m / z): 448.2 [M+H]+; >90% purity. Preparation of (S)-3-(l-hydroxypropan-2-yl)-6-morpholino-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (43)

[00133] (S)-6-chloro-3-(l-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (11, 0.060 g, 0.19 mmol), potassium carbonate (0.011 g, 0.76 mmol) in a sealed tube was added dimethylformamide (2.0 ml) followed by morpholine (0.038 g, 0.38 mmol). The resulting mixture was stirred at 120 °C. After 24 hours another portion of morpholine (38.1 mg, 0.38 mmol) was added and stirring was continued for another 24 hours at 120 °C. The reaction mixture was allowed to cool to room temperature and was then partitioned between water and ethyl acetate. Organic layer was separated, dried over sodium sulphate and concentrated. Purification of the residue by silica gel chromatography with methanol / dichloromethane afforded the title compound (0.026 g, 0.071 mmol, 37% yield). ’H NMR (DMSO-de, 400 MHz): 8 1.38 (3H, d, J = 7.04 Hz), 3.58-3.65 (5H, m), 3.76 (5H, t, J = 4.80 Hz), 4.82-4.87 (1H, m), 7.30 (1H, s); 5.03 (1H, s), 7.52 (1H, dd, J = 7.96; 4.81 Hz), 8.23 (1H, s), 8.46 (1H, dt, J = 7.97; 1.97 Hz), 8.63 (1H, dd, J = 4.79; 1.75 Hz), 9.26 (1H, d, J = 2.11 Hz); MS (m / z): 368.2 [M+H]+; 93.6% purity.

[00134] Compounds listed in Table 6 below were made according to methods similar to 43 immediately above: 207 Table 6 Compound No Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name ‘H-NMR MS (m / z) [M+H]+; Purity (%) 100 HO— H2N / 9 HO OH 0 H Q N >""^OH o । (5)-3-(1 -hy droxypropan-2-yl)-6-(piperidin-1 -yl)-8-(pyridin-3-yl)pyrido[3,4-7]pyrimidin- 4(3 / / )-one (DMSO-t / e, 300 MHz): 5h 1.37 (3H, dd, 7=6.8, 3.1 Hz), 1.67-1.59 (6H, m), 3.74-3.62 (6H, m), 4.85-4.82 (1H, m), 5.04-5.00 (1H, m), 7.25 (1H, s), 7.53-7.49 (1H, m), 8.17 (1H, s), 8.43 (1H, dt, J= 8.0, 1.9 Hz), 8.62 (1H, dd, 7=4.8, 1.6 Hz), 9.24 (1H, d, 7=2.1 Hz). 366.0; 99 WO 2021 / 102288                                                 PCT / US2020 / 061548 Preparation of (S)-3-(l-hydroxypropan-2-yl)-8-(lH-imidazol-l-yl)-6-(4- (trifluoromethoxy)-phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (44): Step 1. Preparation of (S)-6-chloro-3-(l-hydroxypropan-2-yl)-8-(lH-imidazol-l- yl)pyrido[3,4-d]pyrimidin-4(3H) -one (C23): B1                                         C23

[00135] To a resealable Schlenk tube, a screw-cap test tube, were added Cui (4mg, 0.02mmol), imidazole (25mg, 0.37mmol), cesium carbonate (250mg, 0.77 mmol), and a stir bar. The tube was degassed before addition of (S)-6,8-dichloro-3-(l-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lOOmg, 0.37mmol), 1,10-Phenanthroline (7 mg, 0.04mmol) and anhydrous dioxane (2 mL) under a stream of argon. The reaction tube was degassed and back-filled with argon before stirring at 90 °C for 24 h. The reaction mixture was allowed to cool to room temperature. The solution was diluted with ethyl acetate (2-3 mL), filtered through a plug of Celite, and eluted with additional ethyl acetate (10-20 mL). The filtrate was washed with water, brine, dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel column chromatography (CH2C12 / MeOH) to provide the title compound (C23, 20mg, 0.06mmol, 18% yield). TH NMR (CHCh-ds with 10% CH3OH-d4, 400 MHz): 6H 1.46 (3H, dd, J = 16.4, 7.1 Hz), 3.81 (2H, s), 4.94 (1H, s), 5.24 (1H, s), 7.94 (1H, s), 8.31 (1H, s); MS (m / z): 306.1 [M+H]+. Imidazole protons were not observed possibly due to complexation with copper. Step 2. Preparation of (S)-3-(l-hydroxypropan-2-yl)-8-(lH-imidazol-l-yl)-6-(4-(trijluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (44):

[00136] (S)-6-chloro-3-(l-hydroxypropan-2-yl)-8-(lH-imidazol-l-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (C23, 30mg, O.lmmol) and (4-(Trifluoromethoxy)phenyl)boronic acid (30mg, 0.15mmol) was dissolved in 1 mL toluene-EtOH (2:1), and sodium carbonate (42mg, 0.4mmol) was added. The suspension was degassed and refilled with argon (3 cycles). Tetrakis(triphenylphosphine)palladium (12 mg, O.Olmmol) was added and the suspension was degassed and refilled with argon (3 cycles). The reaction mixture was stirred at 85 °C under argon overnight. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate. The solution was washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (CH2C12 / MeOH) followed by a C18 column to provide a TFA salt of (S)-3-(l-hydroxypropan-2-yl)-8-(lH-imidazol-l-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, which was washed with sat. Na2CO3 to provide the free base of the title compound 44 (11 mg, 0.026mmol, 26% yield). XH NMR (CH3OH-d4, 400 MHz): 8 1.56 (3H, d, J = 7.1 Hz), 3.86 (1H, dd, J = 11.9, 4.3 Hz), 3.97 (1H, dd, J = 11.9, 6.9 Hz), 5.02-4.97 (1H, m), 7.16 (1H, s), 7.42 (2H, d, J = 8.4 Hz), 8.28 (2H, d, J = 8.7 Hz), 8.36 (1H, s), 8.50 (2H, s), 9.14 (1H, s); MS (m / z): 432.2[M+H]+; purity 98%. Preparation of (S)-3-(l-methoxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one (45)

[00137] (S)-3-(l-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one (17, 20 mg, 0.05mmol) was dissolved in anhydrous THF and the resulting solution was cooled with an ice-water bath. t-BuOK (6mg, 0.05mmol) was then added, followed by CH3I (8mg, 0.05mmol). The reaction mixture was stirred for Ih at 0 °C. The reaction was quenched by addition of methanol and diluted with EtOAc. This solution washed with water, brine, dried over Na2SO4, concentrated and purified by HPLC, providing a TFA salt of (S)-3-(1 -methoxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one, which was washed with aqueous sat. Na2CO3 to provide a free base of the title compound 45. (2 mg, 0.005mmol, 10% yield). ’H NMR (CH3OH-d4, 400 MHz): 8 1.55 (3H, d, J = 7.1 Hz), 2.41 (3H, s), 3.36 (3H, s), 3.68 (IH, dd, J = 10.5, 4.2 Hz), 3.85 (IH, dd, J = 10.4, 7.2 Hz), 5.14 (IH, d, J = 7.3 Hz), 7.33 (2H, d, J = 7.9 Hz), 7.59 (IH, dd, J = 8.0, 4.9 Hz), 8.09 (2H, d, J = 8.0 Hz), 8.39 (IH, s), 8.50 (IH, s), 8.61 (IH, s), 8.70 (IH, d, J = 8.0 Hz), 9.39 (IH, s); MS (m / z): 387.1 [M+H]+; purity 97%. Preparation of (S)-3-(l-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (46)

[00138] (S)-6-chloro-3-(l-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (11, 50mg, 0.15mmol) was dissolved in toluene. The solution was degassed before addition of Pd(dppf)Cb"CH2C12 (13mg, 0.016mmol), LiCl (26mg, 4eq), Cui (6mg, 0.032mmol) and 2-(tributylstannyl)-5-(trifluoromethyl)pyridine (83mg, 0.19mmol). The solution was degassed again and stirred at 80 °C overnight. LCMS monitoring of the reaction mixture showed incomplete conversion to the expected product, thus 30mg of Cui was added and the reaction was allowed to proceed for an additional 6 hours at 80 °C. The reaction mixture was allowed to cool to room temperature and it was diluted with EtOAc. This solution was washed with water, brine and dried over Na2SO4. Solvents were removed under reduced pressure and the residue was purified by a silica gel column chromatography (CH2C12 / MeOH) followed by a C18 column chromatography to provide a TFA salt of (S)-3-(l-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, which was washed with aqueous sat. Na2CO3 to provide the free base of the title compound (8 mg, 0.019 mmol, 12% yield) ’H NMR (CH3OH-d4, 400 MHz): 8 1.56 (3H, d, J = 7.1 Hz), 3.85 (1H, dd, J = 11.9, 4.3 Hz), 3.96 (1H, dd, J = 11.9, 6.9 Hz), 5.01-4.96 (1H, m), 7.60 (1H, dd, J = 8.0, 4.9 Hz), 8.24 (1H, d, J = 8.5 Hz), 8.46 (1H, s), 8.63 (1H, d, J = 4.9 Hz), 8.74-8.70 (2H, m), 8.99 (1H, s), 9.13 (1H, s), 9.41 (1H, s); MS (m / z):428.1 [M+H]+; purity 99%. Preparation of (S)-8-(3-fluorophenyl)-3-(l-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (47): 2020386967   26 May 2026

[0017] (S)-6-chloro-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin- 4(3H)-one (C1, 50mg, 0.15mmol) was dissolved in toluene and degassed before addition of Pd(dppf)Cb'CH2Cl2 (24mg, 0.18mg), LiCl (26mg, 0.6mmol), CuI (29mg, 0.15mmol) and 2-(tributylstannyl)-5-(trifluoromethyl)pyridine (79 mg, 0.18mmol) . The solution was degassed again and stirred at 80°C overnight. The reaction mixture was diluted with EtOAc, washed with water, brine and dried over Na2SO4. Solvents were removed under vacuum and the residue was purified by silica gel column chromatography (CH2Cl2 / MeOH) followed by a C18 column to provide a TFA salt of (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, which was washed with sat. Na2CO3 to provide the free base of the title compound (19 mg, 0.04mmol, 25% yield). 1H NMR (CH3OH-d4, 400 MHz): SH 1.56 (3H, d, J = 7.1 Hz), 3.85 (1H, dd, J = 11.9, 4.3 Hz), 3.96 (1H, dd, J = 11.9, 6.9 Hz), 5.01-4.96 (1H, m), 7.60 (1H, dd, J = 8.0, 4.9 Hz), 8.24 (1H, d, J = 8.5 Hz), 8.46 (1H, s), 8.63 (1H, d, J = 4.9 Hz), 8.74-8.70 (2H, m), 8.99 (1H, s), 9.13 (1H, s), 9.41 (1H, s).; MS (m / z):445.1 [M+H]+; purity 99%.

[0018] Compounds prepared in a similar manner to 47 are listed in Table 7, below: Table? 213 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Strncture / Name lH-NMR MS (m / z) [M+H]+; Purity (%) 101 ho—y-h2n N-S ¥ O O cf3 SnBu3 N-S oh 3-(2-hydroxy-2-methylpropyl)-8-( isothiazol-4-yJ}-6-(5-(trifluoromethyl)pyridin-2-yl) pyr ido [ 3,4-r / ]py rim idin-4(3 / / )-one (CHjOH^, 300 MHz): Su 1.29 (6H, s), 4.12 (2H,s), 8.24 (IH.d, J = 8.3 Hz), 8.43 (IH.s), 8.70 (1H, d, J = 8.2 Hz), 8,99 (2H,d, J = 8.5 Hz), 9.58 (1H, s), 10.12 (1H, s). 447.9; 99 102 HO—% h2n N-S ¥ J? cf3 V SnBu3 N-S n\N^ oh (5)-3-( 1 -hydroxypropan-2-yl)-8-( isothiazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-t / ]pyrimidin-4(3 / 7)-one (CHsOH-^ 300 MHz): Su 1.60 (3H,d, J = 7.1 Hz), 3,91 (IH,d, J = 4.3 Hz), 3.98 (IH,d, J = 6.8 Hz), 5.03 (IH.s), 8.30 (IH.s), 8.57 (IH.s), 8.79 (1H, d, J = 8.3 Hz), 9.02 (IH.s), 433.9; 99 214 Compound No. Reactant 1 (Step 1) Reactant 2 (Step 3) Reactant 3 (Step 4) Compound Structure / Name *H-NMR MS (m / z) Purity (%) 9.10 (IH. s). 9.65 (IH.s), 10. IS (IH, s). 103 HO—4- H2N N-N B(OH)2 cf3 J SnBu3 / N-N N AU- N. X JU o cf3x^ 3-(2-hydroxy-2-methylpropyl )-8-( 1 -methyl-1 H-py razoI-4-y 1 )-0-( 5 -(tri fluoromethyl )py rid i n-2-yl)pyrido[3,4-( / ]pyrimidin-4(3W)-one (CHjOH-A, 300 MHz): 8h 1.29 (6H,s), 4.02 (3H. s), 4J3(2H,s), 8.25 (1H. d. J = 8.5 Hz), 8.41 (1H, s), 8.55 (IH.s). 8.75 (1H. d. J = 8.4 Hz). 8.80 (IH.s), 8.92 (lH,s), 8.98 (IH.s). 444.9; 99 104 OH h2n Q B(OH)2 co 3 r—Z CD LL / /   \\ C o-# y— w Q* N          CF, JL       o cf3-^ (S)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-( tri fluoromelhyl )pyridin-2-yl)pvridor3,4-Jlpvrimidin- (CH}OH-< / 4. 400 MHz): 6h 4.01 (IH.t, J = 11.7 Hz), 4.47 (1H. brs), 4.65 (1H. d. J = 13.9 Hz). 7.64 (IH.t, J = 6.5 Hz). 8.29 (1H. d. J 481.9; 97 215 Compound No. Reactant 1 (Step I) Reactant 2 (Step 3) Reactant 3 {Step 4) Compound Structure / Naine 4(3 / / )-one 105 h2n SnBu3 (3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)O{5 (trifluoromethyl )pyridin-2-yl)pyrido [3,4-rf]py rim idin-4(3 / / )-one 'H-NMR = 8.5 Hz), S.4I (I H.s), 8.67(IH.d, J = 4.9 Hz), 8.77 {2H,t, J = 7.8 Hz), 9.04 (I H.s), 9.22 (I H.s), 9.43 (I H.s). 400 MHz): 8h 1.29 (OH. s), 4.13 (2H.s), 4.61 (I H.s), 7.58 (I H.s), 8.26( I H.d, J = 8.5 Hz), 8.39 (I H.s), 8.69 (3H,m), 9.00 (I H.s), 9.12 (I H.s), 9.38 (I H.s). MS (m / z) Purify (%) 441.9; 99 Preparation of 8-(3-fluorophenyl)-3-[(lS)-2-hydroxy-l-methyl-ethyl]-6- (p-tolyl)pyrido[3,4-d]pyrimidin-4-one (48) 40                                                          48

[00141] A mixture of 3-[(lS)-2-benzyloxy-l-methyl-ethyl]-8-(3-fluorophenyl)-6- (p-tolyl)pyrido[3,4-d]pyrimidin-4-one (40, 160 mg, 333.65 umol, 1 eq) and Pd / C (80 mg, 333.65 umol, 10% purity, 1.00 eq) in MeOH (25 mL) and EtOAc (25 mL) was degassed and purged with Hz (15 psi) for 3 times, and then the mixture was stirred at 80 °C for 15 hr under H2 atmosphere. LCMS showed desired compound was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate=l:l) to get the title compound (47 mg, 120.69 umol, 36.17% yield) ’H NMR (400 MHz, DMSO-de) 6 ppm 1.43 (d, J=6.8 Hz, 3H), 2.39 (s, 3H), 3.62-3.71 (m, 1H), 3.76-3.84 (m, 1H), 4.84-4.96 (m, 1H), 5.07 (t, J=5.6 Hz, 1H), 7.33-7.37 (m, 3H), 7.59 (q, J=7.6, 14.0 Hz, 1H), 8.03-8.09 (m, 2H), 8.16 (d, J=8.4 Hz, 2H), 8.46 (s, 1H), 8.53 (s, 1H); MS: M+H+, 390.1; 98% purity. Preparation of 8-(3-fluorophenyl)-3-[(lS)-2-hydroxy-l-methyl-ethyl]-6-[4-(trifluoromethoxy)phenyl]pyrido[3,4-d]pyrimidin-4-one (49) Step 1. Preparation of 3-[(lS)-2-benzyloxy-l-methyl-ethyl]-8-(3-fluorophenyl)-6-[4-(trifluoromethoxy)phenyl]pyrido[3,4-d]pyrimidin-4-one (Precursor 1)

[00142] To a solution of 3-[(lS)-2-benzyloxy-l-methyl-ethyl]-6-chloro-8-(3-fluorophenyl)pyrido[3,4-d] pyrimidin-4-one (C21, 460 mg, 1.09 mmol, 1 eq) and [4-(trifluoromethoxy)phenyl]boronic acid (268.18 mg, 1.30 mmol, 1.2 eq) in toluene (8 mL) and EtOH (4 mL) was added Na2CO3 (460.10 mg, 4.34 mmol, 4 eq) and Pd(PPh3)4 (125.41 mg, 108.52 umol, 0.1 eq). The mixture was taken up into a microwave tube. The sealed tube was heated at 100 °C for 1 h under microwave. LCMS showed desired compound was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=l / O to 0 / 1) to get the title compound (400 mg, 727.92 umol, 67.07% yield). MS: M+H+, 550.1. Step 2. Preparation of 8-(3-jluorophenyl)-3-[(lS)-2-hydroxy-l-methyl-ethyl]-6-[4- (trifluoromethoxy)phenyl]pyrido[3,4-d]pyrimidin-4-one (49) Precursor 1

[00143] To a solution of 3-[(lS)-2-benzyloxy-l-methyl-ethyl]-8-(3-fluorophenyl) -6-[4-(trifluoromethoxy) phenyl]pyrido[3,4-d]pyrimidin-4-one (Precursor 1, 290 mg, 527.74 umol, 1 eq) in EtOAc (20 mL) and MeOH (20 mL) was added Pd(OH)2 / C (130 mg, 527.74 umol, 10% purity, 1.00 eq). The mixture was stirred at 25 °C for 6 hr under Ek (15 psi). LCMS showed desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate = 1:1) to get the title compound 49 (22 mg, 47.41 umol, 8.98% yield), ’HNMR (400 MHz, CDCk) 6 ppm 1.61 (d, J=7.1 Hz, 3H), 1.94-2.05 (m, 1H), 3.95-4.04 (m, 2H), 5.04-5.15 (m, 1H), 7.17-7.25 (m, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.46-7.54 (m, 1H), 7.94-8.07 (m, 2H), 8.26 (d, J=8.4 Hz, 2H), 8.32 (s, 1H), 8.53 (s, 1H). MS: M+H+, 460.1; 99% purity.

[00144] The compounds encompassed within the present disclosure can be prepared by the procedure outlined in Scheme II and described in the Examples herein below: i. LiOH ii. RNH2, HATU Reactant 6 Step 3 Ar-B(OH)2 Reactant 4 Step 1 Ar'—B(OH)2 Reactant 5 Step 2 Triethyl orthoformate Ar O Scheme II Preparation of 3-(1,l-dioxidotetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3 / T)-one (106) Step 1. Preparation of methyl 3-amino-6-chloro-[2,3'-bipyridine]-4-carboxylate (Precursor 2):

[00145] Precursor 2 was prepared according to the procedure reported for Step 3 for the synthesis of 1. 'HNMR (CHCW, 400 MHz): 6h 3.95 (3H, s), 5.91 (2H, s), 7.44 (1H, dd, J= 7.9, 4.9 Hz), 7.74 (1H, s), 7.97 (1H, d, J= 7.9 Hz), 8.69 (1H, dd, J= 4.9, 1.7 Hz), 8.91 (1H, s); MS (m / z): 264.0 [M+H]+.

[00146] Table8lists intermediates that were made via a procedure similar to that described in Step 1 above. 219 Table 8 Intermediate ID Intermediate Structure and Name ‘H-NMR MS (m / z) [M+H]+; Purity (%) DI \-N Z A cr    y 0 Methyl 3-amino-6-chloro-2-(l -methyl- 1H-pyrazol-4-yl)i sonicotinate NA 267.0; >95 WO 2021 / 102288                                                 PCT / US2020 / 061548 Step 2. Preparation of methyl 3'-amino-6"-(trijluoromethyl)-[3,2':6',3"-terpyridine]-4'-carboxylate (Precursor 3): Precursor 2                                             Precursor 3

[00147] Precursor 3 was prepared according to the procedure reported for Step 3 for the synthesis of 1. XHNMR (CHCW, 400 MHz): 8 h 4.01 (3H, s), 6.20 (2H, s), 7.49 (1H, t, J = 6.4 Hz), 7.73 (1H, d, J= 8.2 Hz), 8.06 (1H, d, J= 7.9 Hz), 8.25 (1H, s), 8.46 (1H, d, J= 8.3 Hz), 8.74 (1H, d, J= 4.9 Hz), 9.00 (1H, s), 9.27 (1H, s); MS (m / z): 375.0[M+H]+.

[00148] Table 9 lists intermediates that were made via a procedure similar to that described in the above. 221 Table 9 Intermediate ID Intermediate Structure and Name '11 NMR MS (m / z) [M+H]+; Purity (%) El \-N n\nh2 f3cAn^     0 Methyl 5-amino-6-(l-methyl-l / / -pyrazol-4-yl)-6'-(trifluoromethyl)-[2,3'-bipyridine]-4-carboxylate (CHCh-tZ, 300 MHz): 5h4.01 (3H, s), 4.05 (3H, s), 7.74 (1H, d, J= 8.2 Hz), 7.96 (1H, s), 8.04 (1H, s), 8.13 (1H, s), 8.46 (1H, d, J= 8.3 Hz), 9.31 (1H, s) 378.1; >95 E2 Q o CF3O^^ methyl 3 -amino-6-(4-(trifluoromethoxy)phenyl)-[2,3'-bipyridine]-4-carboxylate (CHsOH-tA, 400 MHz): 5h 3.98 (3H, s), 7.32 (2H, d, J = 8.4 Hz), 7.62 (1H, s), 8.05 (2H, d, J = 8.5 Hz), 8.22-8.21 (2H, m), 8.63 (1H, d, J = 5.0 Hz), 8.89 (1H, s). 389.9; NA WO 2021 / 102288                                                 PCT / US2020 / 061548 222 Intermediate ID Intermediate Structure and Name '11 NMR MS (m / z) [M+H]+; Purity (%) E3 Q JU 0 cr methyl 3-amino-6-(4-chlorophenyl)-[2,3'-bipyridine]-4-carboxylate (CHCh-7, 400 MHz): 5h 3.99 (3H, s), 6.02 (2H, s), 7.40 (2H, d, J = 8.4 Hz), 7.47 (1H, t, J = 6.3 Hz), 7.93 (2H, d, J = 8.4 Hz), 8.07 (1H, d, J = 7.9 Hz), 8.15 (1H, s), 8.71 (1H, d, J = 4.8 Hz), 9.01 (1H, s). 340.1; NA E4 Q JU I V / N methyl 3'-amino-6"-cyclopropyl-[3,2':6',3"- terpyridine]-4'-carboxylate (DMSO-t / e, 400 MHz): 5 0.95 (4H, t, J= 7 A Hz), 2.15-2.09 (1H, m), 3.91 (3H, s), 6.67 (2H, s), 7.33 (1H, d, J= 8.2 Hz), 7.55 (1H, dd, 7=7.9, 4.9 Hz), 8.17-8.11 (3H, m), 8.67 (1H, d, J= 4.7 Hz), 8.89 (1H, s), 8.96 (1H, d, J= 2.2 Hz). 347.0 NA WO 2021 / 102288                                                 PCT / US2020 / 061548 223 Intermediate ID Intermediate Structure and Name '11 NMR MS (m / z) [M+H]+; Purity (%) E5 N-l / / / X JU I V / N methyl 5-amino-6'-cyclopropyl-6-(l-methyl-\H- pyrazol-4-yl)-[2,3'-bipyridine]-4-carboxylate (DM SOU, 400 MHz): 5 0.97 (4H, d, J= 8.6 Hz), 2.16-2.10 (1H, m), 3.90 (3H, s), 3.93 (3H, s), 6.58 (2H, s), 7.34 (1H, d, J= 8.2 Hz), 8.01 (2H, m), 8.19 (1H, dd, J= 8.2, 2.3 Hz), 8.33 (1H, s), 9.02 (1H, s). 350.0; NA E6 \-N NJyNH2 „xri~ methyl 3-amino-6-(4-chlorophenyl)-2-(1-methyl-1 / 7-pyrazol-4-yl)isonicotinate (DM SOU, 300 MHz): 5h 3.91 (3H, s), 3.94 (3H, s), 6.60 (2H, s), 7.48 (2H, d, J= 8.4 Hz), 8.02 (3H, m), 8.06 (1H, s), 8.33 (1H, s). 342.9; NA WO 2021 / 102288                                                 PCT / US2020 / 061548 Step 3. Preparation of 3'-amino-N-(l,l-dioxidotetrahydrothiophen-3-yl)-6"~ (trifluoromethyl)-[3,2’:6’,3"-terpyridine]-4'-carboxamide (Precursor 4)

[00149] A solution of methyl 3'-amino-6"-(trifluoromethyl)-[3,2':6',3"-terpyridine]-4'-carboxylate (Precursor 3, 3.5 g, 8.32 mmol) in THF: water (42 mL:14 mL) was cooled to 0°C; LiOH (1.05 g, 24.96 mmol) was added. The reaction was stirred at 0°C for 1 hour and stirred at room temperature overnight. The reaction mixture was acidified with Amberlite IR120 to pH 4, followed by addition of ethyl acetate and MeOH. The solution was filtered to remove the resin and the solvent was evaporated to afford 3'-amino-6"-(trifluoromethyl)-[3,2':6',3"-terpyridine]-4'-carboxylic acid (3.0 g, 7.91 mmol, 95% yield, >95% purity). MS (m / z): 361.1[M+H]+. The acid intermediate was directly subjected to the next step.

[00150] A mixture of 3'-amino-6"-(trifluoromethyl)-[3,2':6',3"-terpyridine]-4'-carboxylic acid (0.6 g, 1.67 mmol) and 3-aminotetrahydrothiophene 1,1-dioxide.HCl (0.314 g, 1.83 mmol) were dissolved in DMF (8.0 mL) and the reaction mixture was cooled to 0°C. Diisopropylethylamine (0.87 mL, 4.5 mmol) and HATU (0.633 g, 1.67 mmol) were added. The reaction was stirred at 0°C for 1 hour and stirred at room temperature overnight. The reaction was quenched with water and partitioned between ethyl acetate and water. The organic phase was separated, washed with saturated aqueous ammonium chloride and then with saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to afford the title compound 3'-amino-A-(l,l-dioxidotetrahydrothiophen-3-yl)-6"-(trifluoromethyl)-[3,2':6',3"-terpyridine]-4'-carboxamide (Precursor 4, 0.58 g, 66% yield, >90% purity). MS (m / z): 478.1[M+H]+. The crude product was subjected to the next step without purification.

[00151] Table 10 lists intermediates that were made via a procedure similar to that described in the above step. 225 Table 10 Intermediate Name Structure and Name *H-NMR MS (m / z) [M+H]+; Purity (%) Fl For 107 Q A J S LAo f3c n (R)-3'-amino-N-(l,l-dioxidotetrahydrothiophen-3-yl)-6"-(trifluoromethyl)-[3,2':6',3"-terpyridine]-4'-carboxamide NA 478.1; >90 F2 For 108 \-N A II I H [i               n         0H F3C N (7?)-5-amino-A-(2-hydroxypropyl)-6-(l-methyl-l / 7-pyrazol-4-yl)-6'-(trifluoromethyl)-[2,3'-bipyridine]-4-carb oxamide NA 421.1; >90 WO 2021 / 102288                                                 PCT / US2020 / 061548 226 Intermediate Name Structure and Name *H-NMR MS (m / z) [M+H]+; Purity (%) F3 For 109 \-N A A = J T H = ii7     n     oh F3C N (5)-5-amino-A-(2-hydroxypropyl)-6-(l-methyl-l / 7-pyrazol-4-yl)-6'-(trifluoromethyl)-[2,3'-bipyridine]-4-carb oxamide NA 421.1; >90 F4 Q An CF3qA^    ° (R)-3 -amino-A-(3,3,3 -trifluoro-2-hy droxypropyl)-6-(4- (trifluoromethoxy)phenyl)-[2,3'-bipyridine]-4-carb oxamide (CH3OJW4, 300 MHz): 5h 3.51 (1H, dd, J = 13.9, 8.4 Hz), 3.82 (1H, dd, J = 13.8, 4.0 Hz), 4.29 (1H, d, J = 7.8 Hz), 7.35 (2H, d, J = 8.4 Hz), 7.62 (1H, dd, J = 8.0, 4.9 Hz), 8.00 (1H, s), 8.11 (2H, d, J = 8.7 Hz), 8.25 (1H, d, J = 8.0 Hz), 8.64 (1H, s), 8.92 (1H, s). 486.9; NA WO 2021 / 102288                                                 PCT / US2020 / 061548 227 Intermediate Name Structure and Name ‘H-NMR MS (m / z) [M+H]+; Purity (%) F5 Q ^OH cf3o^^ (5)-3 -amino-N-(3,3,3 -trifluoro-2-hy droxypropyl)-6-(4- (trifluoromethoxy)phenyl)-[2,3'-bipyridine]-4-carb oxamide (CH3OIW4, 300 MHz): 5h 3.51 (1H, dd, J = 13.9, 8.4 Hz), 3.82 (1H, dd, J = 13.8, 4.0 Hz), 4.29 (1H, br s), 7.35 (2H, d, J = 8.4 Hz), 7.61 (1H, dd, J = 7.9, 4.9 Hz), 8.00 (1H, s), 8.11 (2H, d, J = 8.7 Hz), 8.26-8.23 (1H, m), 8.63 (1H, d, J = 5.0 Hz), 8.92 (1H, s). 486.9; NA F6 Q Anhh o cf3^^ (7?)-3'-amino-N-(3,3,3-trifluoro-2-hydroxypropyl)-6"- (trifluoromethyl)-[3,2':6',3"-terpyridine]-4'-carboxamide (CH3OH-t / 4, 300 MHz): 5h 3.56-3.47 (1H, m), 3.89-3.80 (1H, m), 4.34-4.26 (1H, m), 7.66-7.59 (1H, m), 7.93-7.87 (1H, m), 8.19-8.16 (1H, m), 8.29-8.22 (1H, m), 8.73-8.63 (2H, m), 9.00-8.87 (1H, m), 9.39-9.34 (1H, m). 471.9; NA WO 2021 / 102288                                                 PCT / US2020 / 061548 228 Intermediate Name Structure and Name *H-NMR MS (m / z) [M+H]+; Purity (%) F7 Q II 1 H ,xCOOMe N NT        n 1 0 CF^ methyl (3'-amino-6"-(trifluoromethyl)-[3,2':6',3"- terpyridine]-4'-carbonyl)-Z-alaninate (CH3OIW4, 400 MHz): 5h 1.55 (3H, d, J = 7.4 Hz), 3.78 (3H, s), 4.66 (1H, d, J = 7.4 Hz), 7.60 (1H, dd, J = 7.8, 4.9 Hz), 7.87 (1H, d, J = 8.3 Hz), 8.19 (1H, s), 8.25-8.23 (1H, m), 8.64 (2H, d, J = 7.6 Hz), 8.91 (1H, s), 9.35 (1H, s). 445.9; NA F9 Q oh 0 0 3'-amino-A-((3£,45)-4-hydroxytetrahydrofuran-3-yl)-6"-(trifluoromethyl)-[3,2':6',3"-terpyridine]-4'-carboxamide NA 446.1; NA WO 2021 / 102288                                                 PCT / US2020 / 061548 229 Intermediate Name Structure and Name *H-NMR MS (m / z) [M+H]+; Purity (%) F10 Q ?! T H °H C|JM 0 Y 3-amino-6-(4-chlorophenyl)-N-((3S,47?)-4-hydroxytetrahydrofuran-3-yl)-[2,3'-bipyridine]-4-carb oxamide (DMSO4 400 MHz): 5h 3.57-3.54 (1H, m), 3.71-3.69 (1H, m), 3.96-3.92 (1H, m), 4.04 (1H, dd, J = 9.1, 5.7 Hz), 4.25 (2H, s), 5.34 (1H, s), 6.42 (2H, s), 7.56-7.49 (3H, m), 8.12-8.03 (4H, m), 8.65 (1H, d, J = 4.7 Hz), 8.88 (2H, s). 411.1; NA Fil Q N^YNHh Me <      Y ^(R) OH f3c n (R)-3'-amino-N-(2-hydroxypropyl)-6"-(trifluoromethyl)-[3,2':6',3"-terpyridine]-4'-carboxamide LVL-05-110 (300 MHz, DMSO) 9.40 (1 H, s), 8.95 - 8.85 (2 H, m), 8.66 (1 H, d, J3.6), 8.63 (1 H, d, J 8.8), 8.29 (1 H, s), 8.12 (1 H, d, J 7.9), 7.98 (1 H, d, J 8.3), 7.55 (1 H, dd, J 7.7, 4.9), 6.71 (2 H, s), 4.86 (1 H, d, J4.7), 3.84 (1 H, hept, J6.7), 3.32 - 3.17 (2 H, m), 1.11 (3 H, d, J6.2). 418.1; NA WO 2021 / 102288                                                 PCT / US2020 / 061548 230 Intermediate Name Structure and Name ‘H-NMR MS (m / z) [M+H]+; Purity (%) F12 Q fly H ?H O ^NBoc tert-butyl (3R,4R)-3-(3-amino-6-(4-chlorophenyl)-[2,3'-bipyridine]-4-carboxamido)-4-hydroxypyrrolidine-l-carb oxy late NA 510.2; 95 F13 \-N As ° U° 5-amino-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-6-(1 -methyl-lH-pyrazol-4-yl)-6'-(trifluoromethyl)-[2,3'-bipyridine]-4-carboxamide NA 449.1; 90 WO 2021 / 102288                                                 PCT / US2020 / 061548 231 Intermediate Name Structure and Name ‘H-NMR MS (m / z) [M+H]+; Purity (%) F14 \-N fscAn^     0 5-amino-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-6-(1-methyl-lH-pyrazol-4-yl)-6'-(trifluoromethyl)-[2,3'-bipyridine]-4-carboxamide NA 449.0; 95 F15 Q Hl H 9H C|JU 0 3-amino-6-(4-chlorophenyl)-N-((3S,4R)-4-hydroxy-l-methylpyrrolidin-3-yl)-[2,3'-bipyridine]-4-carboxamide NA 424.1; NA WO 2021 / 102288                                                 PCT / US2020 / 061548 232 Intermediate Name Structure and Name ‘H-NMR MS (m / z) [M+H]+; Purity (%) F16 o nX^h, II             H i —^0H v / /   0 (5)-3'-amino-6"-cyclopropyl-A-(3,3,3-trifluoro-2-hydroxypropyl)-[3,2':6',3"-terpyridine]-4'-carboxamide NA 444.0; NA F17 o nX^ cf3 II             H - ° (7?)-3'-amino-6"-cyclopropyl-A-(3,3,3-trifluoro-2-hydroxypropyl)-[3,2':6',3"-terpyridine]-4'-carboxamide NA 444.0; NA WO 2021 / 102288                                                 PCT / US2020 / 061548 233 Intermediate Name Structure and Name *H-NMR MS (m / z) [M+H]+; Purity (%) F18 N-NZ / / X Il T H 9F= JL        o s—<  N (5)-5-amino-6'-cyclopropyl-6-(l-methyl-l / / -pyrazol-4-yl)-A-(3,3,3 -trifluoro-2-hy droxypropyl)- [2,3 bipyridine]-4-carboxamide NA 447.0; NA F19 N-NZ / / \ Ay CF3 II             H - Aoh AL       o V / N (7?)-5-amino-6'-cyclopropyl-6-(l-methyl-l / / -pyrazol-4-yl)-A-(3,3,3 -trifluoro-2-hy droxypropyl)- [2,3 bipyridine]-4-carboxamide NA 447.0; NA WO 2021 / 102288                                                 PCT / US2020 / 061548 Intermediate Name Structure and Name ‘H-NMR MS (m / z) [M+H]+; Purity (%) F20 Mex N—N * CF II             H - N <      y    OH f3c n (R)-5-amino-6-(l -methyl-lH-pyrazol-4-yl)-N-(3,3,3-trifluoro-2-hydroxypropyl)-6'-(trifluoromethyl)-[2,3'-bipyridine]-4-carboxamide LVL-05-084 (300 MHz, DMSO) 9.44 (1 H, s), 9.08 (1 H, t, J 6.1), 8.66 (1 H, d, J7.1), 8.34 (1 H, s), 8.15 (1 H, s), 8.05 (1 H, s), 7.99 (1 H, d, J 8.2), 6.67 - 6.59 (2 H, m), 4.23 (1 H, s), 3.94 (3 H, s), 3.75 - 3.63 (1 H, m), 3.29 (1 H, s). 475.1; NA F21 N-l / X CF3 II             H » rYy ^fsj'oH o f3c n (S)-5-amino-6-(l -methyl-lH-pyrazol-4-yl)-N-(3,3,3-trifluoro-2-hydroxypropyl)-6'-(trifluoromethyl)-[2,3'-bipyridine]-4-carboxamide NA 475.1; NA WO 2021 / 102288                                                 PCT / US2020 / 061548 235 Intermediate Name Structure and Name ‘H-NMR MS (m / z) [M+H]+; Purity (%) F22 Q oh 17¾¾ F3C N 3'-amino-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-6"- (trifluoromethyl)-[3,2':6',3"-terpyridine]-4'-carboxamide NA 446.10; NA F23 \-N oh l-(3-amino-6-(4-chlorophenyl)-2-(l -methyl-IH-pyrazol-4-yl)pyridin-4-yl)-2-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)ethan-l-one NA 414.1; NA F24 A— CM IZ I \ z 2=0 Z—a \— / / / A__# A \= / z=Z o LL? ’H NMR (DMSO-t / e, 400 MHz): 5h 3.72-3.65 (2H, m), 3.94 (2H, t, J= 8.2 Hz), 4.28 (1H, s), 4.46 (1H, s), 5.34 (1H, d, J= 4.0 Hz), 6.66 (2H, s), 7.55 (1H, d, J= 6.3 Hz), 7.97 (1H, d, J= 8.3 Hz), 8.11 (1H, d, J= 446.1; NA WO 2021 / 102288                                                 PCT / US2020 / 061548 236 Intermediate Name Structure and Name ‘H-NMR MS (m / z) [M+H]+; Purity (%) 3'-amino-N-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-6"-(trifluoromethyl)-[3,2':6',3"-terpyridine]-4'-carboxamide 7.8 Hz), 8.30 (1H, s), 8.61 (3H, t, J= 13.4 Hz), 8.89 (1H, s), 9.40 (1H, s). F25 N-NZ ?h f3c'xX^      °    0 5-amino-N-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-6-(1-methyl-lH-pyrazol-4-yl)-6'-(trifluoromethyl)-[2,3'-bipyridine] -4-carboxamide ’H NMR (DMSO-t / e, 400 MHz): 5h 3.72-3.65 (2H, m), 3.95-3.93 (5H, m), 4.27 (1H, s), 4.45 (1H, d, J= 8.2 Hz), 5.32 (1H, d, J= 4.2 Hz), 6.55 (2H, s), 7.97 (1H, d, J= 8.3 Hz), 8.04 (1H, s), 8.16 (1H, s), 8.32 (1H, s), 8.52 (1H, d, J= 7.7 Hz), 8.66 (1H, d, J= 8.3 Hz), 9.45 (1H, s). 449.1; NA F26 N-NZ OH FT X X / 3-amino-6-(4-chlorophenyl)-N-((3R,4R)-4- hydroxytetrahydrofuran-3 -yl)-2-( 1 -methyl- lH-pyrazol-4-yl)isonicotinamide ’H NMR (DMSO-t / e, 400 MHz): 5h 3.72-3.64 (2H, m), 3.95-3.91 (5H, m), 4.26 (1H, d, J= 5.0 Hz), 4.43 (1H, t, J= 7 A Hz), 5.30 (1H, d, J= 4.1 Hz), 6.30 (2H, s), 7.49 (2H, d, J = 8.3 Hz), 7.98 (2H, d, J= 13.2 Hz), 8.11 (2H, d, J= 8.3 Hz), 8.27 (1H, s), 8.52 (1H, d, 7= 7.6 Hz). 414.1; NA WO 2021 / 102288                                                 PCT / US2020 / 061548 237 Intermediate Name Structure and Name ‘H-NMR MS (m / z) [M+H]+; Purity (%) F27 Q xL / NH2 h f3c^   0 3 '-amino-N-cyclopentyl-6"-(trifluoromethyl)-[3,2': 6', 3 terpyridine] -4'-carboxamide ’H NMR (DMSO-t / e, 400 MHz): 5h 1.61-1.53 (4H, m), 1.76-1.68 (2H, m), 1.98-1.88 (2H, m), 4.27-4.22 (1H, m), 6.66 (2H, t, J= 2.3 Hz), 7.55-7.52 (1H, m), 7.96 (1H, dd, J= 8.1, 1.6 Hz), 8.11 (1H, dd,7=7.5, 2.3 Hz), 8.17 (1H, s), 8.65-8.60 (3H, m), 8.89 (1H, t, J= 2.2 Hz), 9.39 (1H, s). 428.1; NA F28 Q / L .NH2 J        H 0 3'-amino-N-phenyl-6"-(trifluoromethyl)-[3,2':6',3"-terpy ri dine] -4' -carb oxami de ’H NMR (DMSO-t / e, 400 MHz): 5h 6.53 (2H, s), 7.17 (1H, d, 7= 7.6 Hz), 7.40 (2H, t, 7= 7.6 Hz), 7.56 (1H, s), 7.74 (2H, d, 7= 7.9 Hz), 7.97 (1H, d, 7= 8.3 Hz), 8.14 (1H, d, 7= 7.7 Hz), 8.37 (1H, s), 8.67 (2H, s), 8.92 (1H, s), 9.43 (1H, s), 10.54 (1H, s). 436.1; NA WO 2021 / 102288                                                 PCT / US2020 / 061548 238 Intermediate Name Structure and Name *H-NMR MS (m / z) [M+H]+; Purity (%) F29 Q H 1 H JU 6 U 3 '-amino-N-(pyridin-3 -yl)-6"-(trifluoromethyl)- [3,2': 6', 3 terpyridine] -4'-carboxamide 3'-amino-N-(pyridin-3-yl)-6"-(trifluoromethyl)-[3,2':6',3"-terpyridine]-4'-carboxamide NA 437.1; NA WO 2021 / 102288                                                 PCT / US2020 / 061548 Preparation of 3'-amino-6"-(trifluoromethyl)-[3,2':6',3"-terpyridine]-4'-carboxamide (F30)

[00152] To methyl 3'-amino-6"-(trifluoromethyl)-[3,2':6',3"-terpyridine]-4'-carboxylate (300 mg, 0.801 mmol) in vial was added a 7M solution of ammonia in MeOH, sealed and heated at 65 °C overnight. The solvent was evaporated and compound F30 was obtained as a white solid and was used without further purification (270 mg, 89%). MS (m / z): 488.0 [M+H]+; 95% purity Step 4 - Preparation of 3-(1, l-dioxidotetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6- (trijluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (106). o o

[00153] Triethyl orthoformate (10 mL) was added to 3'-amino-7V-(l,l-dioxidotetrahydrothiophen-3-yl)-6"-(trifluoromethyl)-[3,2':6',3"-terpyridine]-4'-carboxamide (Precursor 4, 0.3 g, 0.618 mmol) in a sealed tube. Acetic acid (1 mL, 10% v / v) was added at room temperature and the resulting mixture was heated at 95°C overnight. The mixture was concentrated, followed by addition of sat. NaHCOs and the solid was collected by vacuum filtration, washed with water and dried. The residue was purified by normal phase chromatography to afford the title compound 3-(1,1-dioxidotetrahydrothiophen-3 -yl)-8-(pyridin-3 -yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3J7)-one (106, 0.13 g, 43% yield). ’H NMR (DMSO-de, 300 MHz): 8 h 2.70-2.67 (2H, m), 3.37-3.30 (1H, m), 3.70-3.57 (2H, m), 5.42 (1H, t, J= 8.3 Hz), 7.62 (1H, dd, J= 7.9, 4.8 Hz), 8.07 (1H, d, J= 8.3 Hz), 8.58 (1H, d, J= 8.1 Hz), 8.64 (1H, s), 8.72 (1H, d, J= 4.7 Hz), 8.80 (1H, s), 8.96 (1H, d, J= 8.4 Hz), 9.37 (1H, s), 9.66 (1H, s); MS (m / z): 488.0 [M+H]+; >98% purity. Preparation of (l?)-3-(l,l-dioxidotetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6- (trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3 / T)-one (107).

[00154] Dioxane (7 mL) and triethyl orthoformate (1.2 mL, 7.02 mmol) were added to intermediate (7?)-3'-amino-7V-( 1,1-dioxidotetrahydrothiophen-3-yl)-6"-(trifluoromethyl)-[3,2':6',3"-terpyridine]-4'-carboxamide (Fl, 0.67 g, 1.4 mmol) in a flask. / ?-Toluene sulfonic acid (0.267 mg, 1.4 mmol) was added at room temperature and the resulting mixture was stirred overnight. The mixture was concentrated, followed by addition of sat. NaHCCh and the formed solid was collected by vacuum filtration, washed with water and dried. The residue was purified by silica gel column chromatography to afford the title compound (R)-3-(l,l-dioxidotetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3J7)-one (98 1.82 g, 69% yield). 'HNMR (DMSO-tA, 400 MHz): 6h 3.25-3.18 (2H, m), 3.90-3.87 (1H, m), 4.25-4.12 (3H, m), 5.96 (1H, t, J= 8.5 Hz), 8.16 (1H, d, J= 6.7 Hz), 8.62 (1H, d, J= 8.3 Hz), 9.11 (1H, d, J= 8.0 Hz), 9.18 (1H, s), 9.27 (1H, s), 9.35 (1H, s), 9.50 (1H, s), 9.90 (1H, s), 10.20 (1H, s); MS (m / z): 488.1 [M+H]+; 99% purity

[00155] Table 11 lists compounds made via procedures similar to that described for 98, replacing reactant 4, 5 and 6 with the indicated groups. 241 Table 11 Compound No. Reactant 4 (step 1) Reactant 5 (step 2) Reactant 6 (step 3) Compound Structure / Name ‘H-NMR MS (m / z) [M+H]+; Purity (%) 110 Mex N-N Y B(OH)2 / ^,B(OH)2 1J f3c n cf3 h2n. A Me, N-N JI N fl 4        QF3 f3cYn^     0 (7?)-8-( 1 -methyl- 177-pyrazol-4-yl)-3-(3,3,3 -trifluoro-2- hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3Z / )-one (300 MHz, DMSO): 5h 9.65 (1 H, s), 8.93 (1 H, d, J 7.9), 8.84(1 H, s), 8.57-8.47 (3 H, m), 8.03 (1 H, d, J8.1), 6.81 (1 H, bs), 4.46 (2 H, d, J 11.3), 4.09(1 H, dd, J 13.2, 9.9), 3.97 (3 H, s). 485.0; 98 111 Mex N-N Y B(OH)2 / ^.B(OH)2 JJ F3c n cf3 Me, n-n z N            CF3 Y     o f3c n (5)-8-( 1 -methyl- 177-pyrazol -4-yl)- 3-(3,3,3 -trifluoro-2-hydroxypropyl)-6-(6- (400 MHz, DMSO): 5h 9.65 (1 H, d, J2.0), 8.93 (1 H, dd, J8.1, 1.9), 8.84 (1 H, s), 8.52 (3 H, dd, J 9.6, 8.9), 8.03 (1 H, d, J 8.3), 6.81 (1 H, d, J6.6), 4.48 - 4.40 (2 H, m), 4.09 (1 H, dd, J 14.2, 9.9), 3.97 (3 H, s). 485.1; 97.8 WO 2021 / 102288                                                 PCT / US2020 / 061548 242 Compound No. Reactant 4 (step 1) Reactant 5 (step 2) Reactant 6 (step 3) Compound Structure / Name ‘H-NMR MS (m / z) [M+H]+; Purity (%) (trifluoromethyl)pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3Z / )-one 112 Q B(OH)2 XJ f3c^ n Me H2N^oh Q / L .N. N           Me FaC^N^     ° (7?)-3-(2-hydroxypropyl)-8-(pyri din-3 -yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3Z / )-one (400 MHz, DMSO): 5h 9.63 (1 H, s), 9.36 (1 H, s), 8.93 (1 H, d, J 8.1), 8.75 (1 H, s), 8.70 (1 H, d, J3.9), 8.59- 8.55 (1 H, m), 8.46 (1 H, s), 8.05 (1 H, d, J8.3), 7.60(1 H, dd, J7.8, 4.8), 5.06 (1 H, d, J 5.0),4.16(1 H, dd, J 13.2, 3.2), 4.06-3.96 (1 H, m), 3.77(1 H, dd, J 13.3, 8.6). 428.1 99.2 113 9 B(OH)2 x<5^.B(OH)2 xj f5c n Me H2N. 2      OH Q X |\L N           Me FaC^N^     ° (7?)-8-( 1 -methyl- 177-pyrazol-4-yl)- 3-(3,3,3 -trifluoro-2- hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2- (400 MHz, DMSO): 5h 9.64(1 H, d, J 1.2), 9.36 (1 H, d, J 1.6), 8.94(1 H, dd, J 8.2, 1.5), 8.76 (1 H, s), 8.71 (1 H, dd, J4.8, 1.4), 8.57 (1 H, dt, J7.9, 1.8), 8.47 (1 H, s), 8.06 (1 H, d, J 8.2), 7.60(1 H, dd, J7.9, 4.8), 5.06 (1 H, d, J 5.0),4.16(1 H, dd, J 428.1 99.9 WO 2021 / 102288                                                 PCT / US2020 / 061548 243 Compound No. Reactant 4 (step 1) Reactant 5 (step 2) Reactant 6 (step 3) Compound Structure / Name ‘H-NMR MS (m / z) [M+H]+; Purity (%) yl)pyrido[3,4- 7]pyrimidin-4(3J7)-one 13.2, 3.2), 4.06-3.96 (1 H, m), 3.78 (1 H, dd, J 13.2, 8.6). 114 cf3 B(OH)2 \-N Y B(OH)2 OH H2N„. U '"O 3S, 4R \-N N          OH X / VcS f3c^n^          ° 3-((3S,4R)-4- hydroxytetrahydrofuran-3 -y 1)-8 -(1 -methyl-1 H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (DMSO-t / e, 300 MHz): 5h 3.67-3.62 (1H, m), 3.98 (3H, s), 4.18-4.14 (1H, m), 4.23-4.18 (1H, m), 4.59 (1H, bs), 5.01 (lH,bs), 5.72 (1H, d, J= 4.3 Hz), 8.04 (1H, d,7 = 8.3 Hz), 8.42 (1H, s), 8.53 (2H, d, 7= 7.8 Hz), 8.87 (1H, d, 7= 0.9 Hz), 8.97-8.93 (1H, m), 9.67 (1H, s). 459.1; 98% 115 cf3 B(OH)2 \-N B(OH)2 OH ^oz 3R, 4S \ N-N A A FjC^bT      °    0 3-((3R,4S)-4- hydroxytetrahydrofuran-3 -y 1)-8 - (DMSO-76, 300 MHz): 5h3.65 (1H, dd, 7=9.7, 3.3 Hz), 3.98 (3H, s), 4.19-4.13 (1H, m), 4.25-4.19 (1H, m), 4.58 (1H, m), 5.03-4.98 (1H, m), 5.72 (1H, d, 7=4.3 Hz), 8.04 (1H, d, 7= 8.3 Hz), 8.42 (1H, s), 8.54 (2H, d, 459.1; 98% WO 2021 / 102288                                                 PCT / US2020 / 061548 244 Compound No. Reactant 4 (step 1) Reactant 5 (step 2) Reactant 6 (step 3) Compound Structure / Name ‘H-NMR MS (m / z) [M+H]+; Purity (%) (1 -methyl-1 H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one 7= 7.6 Hz), 8.87 (1H, s), 8.97-8.93 (1H, m), 9.67 (1H, s). 116 \-N Y hoxB"oh Cl ho"b'oh moH CT \-N 0H YAY c<             o 1H NMR (DMS04 400 MHz): 5h 3.62 (1H, dd, J = 9.6, 3.2 Hz), 3.95 (3H, s), 4.21-4.09 (3H, m), 4.99-4.97 (1H, m), 5.69 (1H, d,7=4.3 Hz), 7.57 (2H, d, 7= 8.4 Hz), 8.31-8.28 (3H, m), 8.35 (1H, s), 8.48 (1H, s), 8.79 (1H, s). 424.1;98 117 o B(OH)2 cf3 B(OH)2 h2n H qY Q N          OH F1 (DMSO-76, 300 MHz): 5h3.64(1H, dd, 7=9.6, 3.2 Hz), 4.09 (1H, dd,7 = 10.1, 4.1 Hz), 4.25-4.15 (2H, m), 4.60 (1H, s), 5.01 (1H, s), 5.72 (1H, d, 7=4.3 Hz), 7.60 (2H, dd, 7= 8.6, 5.1 Hz), 8.06 (1H, d,7= 8.3 Hz), 8.43 456.1;>99 WO 2021 / 102288                                                 PCT / US2020 / 061548 245 Compound No. Reactant 4 (step 1) Reactant 5 (step 2) Reactant 6 (step 3) Compound Structure / Name ‘H-NMR MS (m / z) [M+H]+; Purity (%) (1H, s), 8.58 (1H, d,J= 8.0 Hz), 8.76-8.69 (2H, m), 8.94 (1H, d, J= 8.4 Hz), 9.37 (1H, s), 9.64 (1H, s). 118 Q B(OH)2 cf3 B(OH)2 nh2 Q n tU JU 0 U 3,8-di(pyri din-3 -yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3 H)-one (DM SOU, 400 MHz): 5h 7.69-7.60 (2H, m), 8.07 (2H, t, J = 9.1 Hz), 8.59 (1H, d, J = 8.0 Hz), 8.66 (1H, s), 8.73 (2H, dd, J = 10.5, 4.7 Hz), 8.82 (2H, s), 8.96 (1H, d, J= 8.3 Hz), 9.38 (1H, s), 9.66 (1H, s). 447.1; >99% 119 Q B(OH)2 cf3 B(OH)2 nh3 Q N tU n-UVh FS<U^    ° 8-(pyri din-3 -yl)-6-(6-(trifluoromethyl)pyri din-3- (DM SOU, 400 MHz): 5h 7.57 (1H, t, J = 6.3 Hz), 8.04 (1H, d, J = 8.3 Hz), 8.33 (1H, s), 8.54 (1H, d, J = 8.0 Hz), 8.71-8.66 (2H, m), 8.92 (1H, d, J = 8.3 Hz), 9.33 (1H, s), 9.62 (1H, s), 12.86 (1H, s). 370.1; >99% WO 2021 / 102288                                                 PCT / US2020 / 061548 246 Compound No. Reactant 4 (step 1) Reactant 5 (step 2) Reactant 6 (step 3) Compound Structure / Name ‘H-NMR MS (m / z) [M+H]+; Purity (%) yl)pyrido[3,4-d]pyrimidin-4(3 H)-one WO 2021 / 102288                                                 PCT / US2020 / 061548 Preparation of (5)-6-(6-cydopropylpyridin-3-yl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-J|pyrimidin-4(3 / r)-one as a white solid (120)

[00156] Triethylorthoformate (1.69 ml, 10.2 mmol) and / ?-toluenesulfonic acid (117 mg, 0.679 mmol) were added to a solution of (5)-3'-amino-6''-cyclopropyl-7V-(3,3,3-trifluoro-2-hydroxypropyl)-[3,2':6',3"-terpyridine]-4'-carboxamide (301 mg, 0.679 mmol) in dioxane (3.4 ml). After Ih DMF (0.5 ml) was added and the reaction mixture was heated to 40°C and stirred for 48 h. The reaction mixture was quenched with sodium bicarbonate (pH >11). Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, concentrated and purified by silica gel column chromatography to afford the title compound (5)-6-(6-cyclopropylpyridin-3-yl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-J]pyrimidin-4(3J7)-one as a white solid (120, 115 mg, 37%). ’H NMR (DMSO-de, 400 MHz): 8 1.02 (4H, d, J= 8.2 Hz), 2.23-2.17 (IH, m), 4.08 (IH, dd, J= 14.1, 9.9 Hz), 4.45 (2H, d, J= 12.5 Hz), 6.78 (IH, d, J= 6.4 Hz), 7.47 (IH, d, J= 8.2 Hz), 7.59 (IH, dd, J= 7.9, 4.8 Hz), 8.49-8.47 (2H, m), 8.54 (2H, d, J= 11.8 Hz), 8.70 (IH, d, J= 4.8 Hz), 9.26 (IH, s), 9.32 (IH, s); MS (m / z): 454.2 [M+H]+; >99% purity.

[00157] Table 12 lists compounds made via procedures similar to that described for 120, replacing reactant 4, 5 and 6 with the indicated groups. 248 Table 12 Compound No. Reactant 4 (step 1) Reactant 5 (step 2) Reactant 6 (step 3) Compound Structure / Name ‘H-NMR MS (m / z) [M+H]+; Purity (%) 121 9 HO OH ZBS ^0  0^ cf3 Q N        <>1    CF3 II                            1              - 0 (R)-6-(6-cy clopropylpyridin-3 -yl)-8-(pyri din-3 -y 1)-3 -(3,3,3-trifluoro-2- hydroxypropyl)pyrido[3,4- J]pyrimidin-4(3J7)-one (DMSO4 400 MHz): 5 1.02 (4H, d, J= 8.1 Hz), 2.23-2.18 (1H, m), 4.11-4.05 (1H, m), 4.46-4.41 (2H, m), 6.79-6.77 (1H, m), 7.47 (1H, d, J= 8.3 Hz), 7.60 (1H, dd, J= 7.9, 4.8 Hz), 8.51-8.48 (2H, m), 8.56-8.52 (2H, m), 8.70 (1H, dd, 7=4.8, 1.6 Hz), 9.27 (1H, d, J = 2.2 Hz), 9.33 (1H, d, 7= 2.2 Hz). 454.1; 99 WO 2021 / 102288                                                 PCT / US2020 / 061548 Preparation of (l?)-3-(2-hydroxypropyl)-8-(l-methyl-lH-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-J|pyrimidin-4(3Z / )-one (108) \-N

[00158] 108 was prepared according to the procedure reported for Step 2 for the synthesis of 1 (synthesis of Intermediate Bl). ’H NMR (DMSO-tfe, 400 MHz): 6h 1.17 (3H, d, J= 6.2 Hz), 3.76 (1H, dd, J= 13.3, 8.6 Hz), 3.97 (3H, s), 4.16 (1H, dd, J= 13.3, 3.2 Hz), 5.08 (1H, d, J= 5.0 Hz), 8.03 (1H, d, J= 8.3 Hz), 8.46 (1H, s), 8.49 (1H, s), 8.53 (1H, s), 8.86 (1H, s), 8.93 (1H, d, J= 8.3 Hz), 9.65 (1H, s); MS (m / z): 431.1 [M+H]+; >99% purity.

[00159] Table 13 lists compounds made via procedures similar to that described for 108, replacing reactant 4, 5, and 6 with the indicated groups. 250 Table 13 Compound No. Reactant 4 (step 1) Reactant 5 (step 2) Reactant 6 (step 3) Compound Structure / Name ‘H-NMR MS (m / z) [M+H]+; Purity (%) 109 \-N Y B(OH)2 cf3 A B(OH)2 nh2 OH \-N (5)-3-(2-hydroxypropyl)-8-(l-methyl- l / / -pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3 H)-one (DMSO4, 400 MHz): 5h 1.15 (3H, d, J = 6.2 Hz), 3.75 (1H, dd, J= 13.3, 8.6 Hz), 3.96 (3H, s), 4.15 (1H, dd, J= 13.2, 3.2 Hz), 5.06 (1H, d, J = 5.0 Hz), 8.02 (1H, d, J = 8.3 Hz), 8.45 (1H, s), 8.49 (1H, s), 8.52 (1H, s), 8.85 (1H, s), 8.92 (1H, d, J 431.1; >98 WO 2021 / 102288                                                 PCT / US2020 / 061548 251 Compound No. Reactant 4 (step 1) Reactant 5 (step 2) Reactant 6 (step 3) Compound Structure / Name 'H-NMR MS (m / z) [M+H]+; Purity (%) = 8.3 Hz), 9.64 (1H, s). 122 Q B(OH)2 CM I ^- / / O—e  y— tn OH F3C""^ h2n Q ?F3 n^^°h (7?)-8-(pyri din-3 -y 1)-3 -(3,3,3- trifluoro-2-hydroxypropyl)-6-(6- (trifluoromethyl)pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3 H)-one (CHsOH-tA, 400 MHz): 5h 4.07-3.99 (1H, m), 4.48 (1H, br s), 4.65 (1H, d, J = 13.9 Hz), 7.64 (1H, t, J = 6.5 Hz), 8.00 (1H, d, J = 8.3 Hz), 8.42 (1H, s), 8.67 (2H, s), 8.74 (1H, d, J = 8.2 Hz), 8.78 (1H, s), 8.88 (1H, d, J = 8.4 Hz), 9.43 (1H, s), 9.57 (1H, s). 481.9; 99% WO 2021 / 102288                                                 PCT / US2020 / 061548 252 Compound No. Reactant 4 (step 1) Reactant 5 (step 2) Reactant 6 (step 3) Compound Structure / Name ‘H-NMR MS (m / z) [M+H]+; Purity (%) 123 Q B(OH)2 ocf3 0 B(OH)2 OH F3C""^ h2n Q N           CF3 II                          ।             - r^^YN^OH cf3o"^^     ° (7?)-8-(pyri din-3 -y 1)-3 -(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[ 3,4-d]pyrimidin-4(3J7)-one (CHsOH-tTi, 300 MHz): 5h 4.00 (1H, dd, J = 13.7, 9.6 Hz), 4.46 (1H, t, J = 8.3 Hz), 4.63 (1H, dd, J = 13.8, 3.0 Hz), 7.46 (2H, d, J = 8.4 Hz), 7.62 (1H, dd, J = 8.1,4.9 Hz), 8.36 (3H, dd, J = 7.0, 1.9 Hz), 8.66-8.62 (2H, m), 8.72 (1H, dt, J = 8.0, 2.0 Hz), 9.40 (1H, s). 496.9; 99% WO 2021 / 102288                                                 PCT / US2020 / 061548 253 Compound No. Reactant 4 (step 1) Reactant 5 (step 2) Reactant 6 (step 3) Compound Structure / Name ‘H-NMR MS (m / z) [M+H]+; Purity (%) 124 Q ocf3 6 OH f3c*< Q J. N 'll 1" *1 N ^^0 H cf3o'x^^      0 (CHsOH-p 400 MHz): 5h 3.94 (1H, dd, J = 13.8, 9.7 Hz), 4.40 (1H, s), 4.57 (1H, dd, J = 13.8, 2.9 Hz), 7.39 (2H, d, J = 8.4 Hz), 7.55 (1H, dd, 496.9; B(OH)2 V B(OH)2 > h2n (5)-8-(pyri din-3 -y 1)-3 -(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[ 3,4-d]pyrimidin-4(3J7)-one J = 8.0, 4.9 Hz), 8.30 (3H, d, J = 8.4 Hz), 8.56 (1H, s), 8.58 (1H, d, J = 4.8 Hz), 8.66 (1H, d, J = 8.1 Hz), 9.34 (1H, s). 99% WO 2021 / 102288                                                 PCT / US2020 / 061548 254 Compound No. Reactant 4 (step 1) Reactant 5 (step 2) Reactant 6 (step 3) Compound Structure / Name ‘H-NMR MS (m / z) [M+H]+; Purity (%) 125 Q B(OH)2 Cl B(OH)2 OH h2na / o N          OH 6-(4-chlorophenyl)-3-((35,47?)-4-hydroxytetrahydrofuran-3 -y 1)-8 -(pyridin-3-yl)pyrido[3,4- d]pyrimidin-4(3J7)-one (CHsOH-tA, 400 MHz): 5h 3.77 (1H, dd, J= 10.0, 3.1 Hz), 4.23 (1H, d, J = 3.3 Hz), 4.29 (2H, dd, J = 10.6, 5.9 Hz), 4.61 (1H, s), 5.07 (1H, s), 7.53 (2H, d, J = 8.4 Hz), 7.60 (1H, t, J = 6.4 Hz), 8.23 (2H, d, J = 8.4 Hz), 8.32 (1H, s), 8.58 (1H, s), 8.63 (1H, s), 8.70 (1H, d, J = 8.0 Hz), 9.39 (1H, s). 421.1; 99% WO 2021 / 102288                                                 PCT / US2020 / 061548 255 Compound No. Reactant 4 (step 1) Reactant 5 (step 2) Reactant 6 (step 3) Compound Structure / Name ‘H-NMR MS (m / z) [M+H]+; Purity (%) 126 Q B(OH)2 cf3 0“ B(OH)2 OH H2N,,   ? Q N          OH ^3 3-((35,45)-4- hydroxytetrahydrofuran-3 -y 1)-8 - (pyri din-3 -yl)-6-(6- (trifluoromethyl)pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3 H)-one (DMSO4, 400 MHz): 5h 3.78 (1H, d, J = 9.8 Hz), 4.03-3.93 (2H, m), 4.20 (1H, dd, J = 9.7, 5.9 Hz), 4.52 (1H, s), 5.42-5.37 (1H, m), 5.49 (1H, d, J = 4.4 Hz), 7.59 (1H, dd, J = 7.9, 4.8 Hz), 8.06 (1H, d, J = 8.3 Hz), 8.40 (1H, s), 8.59 (1H, d, J = 7.9 Hz), 8.70 (1H, dd, J = 4.7, 1.7 Hz), 8.77 (1H, s), 8.94 (1H, d, J = 456.1; 99% WO 2021 / 102288                                                 PCT / US2020 / 061548 256 Compound No. Reactant 4 (step 1) Reactant 5 (step 2) Reactant 6 (step 3) Compound Structure / Name ‘H-NMR MS (m / z) [M+H]+; Purity (%) 8.3 Hz), 9.37 (1H, d, J = 2.1 Hz), 9.64 (1H, s). 127 Q B(OH)2 cf3 § B(OH)2 OMe ...... h2n Q o N V^oMe CFj N methyl (5)-2-(4-oxo-8-(pyridin-3 -yl)-6-(6-(trifluoromethyl)pyridin- 3-yl)pyrido[3,4-d]pyrimidin- 3 (4J7)-yl)propanoate (CHsOH-tA, 400 MHz): 5h 1.81 (3H, d, J = 7.2 Hz), 3.78 (3H, s), 5.40 (1H, d, J = 7.4 Hz), 7.63 (1H, s), 7.98 (1H, d, J = 8.3 Hz), 8.49 (1H, s), 8.65 (1H, s), 8.75 (2H, s), 8.86 (1H, d, J = 8.3 Hz), 9.43 (1H, s), 9.56 (1H, s). 455.9; 95% WO 2021 / 102288                                                 PCT / US2020 / 061548 257 Compound No. Reactant 4 (step 1) Reactant 5 (step 2) Reactant 6 (step 3) Compound Structure / Name ‘H-NMR MS (m / z) [M+H]+; Purity (%) 128 Q B(OH)2 Cl B(OH)2 OH H2N_J \ cis racemic Q °h o Un 6-(4-chlorophenyl)-3-(4-hydroxy-l-methylpyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4- d]pyrimidin-4(3H)-one (CHCW, 300 MHz): 5h 1.86 (6H, bs), 3.07 (3H, s), 4.78 (1H, m), 7.49 (3H, m), 7.62-7.56 (1H, m), 8.14 (3H, m), 8.49 (1H, s), 8.73-8.69 (2H, m), 9.54 (1H, s). 434.1; 99% 129XX 9 B(OH)2 cf3 B(OH)2 OH h2n* / Q OH 'i । i            n         > CF3^   0 3-((37?,47?)-4- hydroxytetrahydrofuran-3 -y 1)-8 -(pyri din-3 -yl)-6-(6- (trifluoromethyl)pyri din-3- (dmso-j6, 400 MHz): 5h 3.78 (1H, d, J = 9.8 Hz), 4.03-3.93 (2H, m),4.20(lH, t, J = 7.7 Hz), 4.51 (1H, s), 5.38 (1H, t, J = 6.8 Hz), 5.49 (1H, d, J = 4.3 Hz), 7.59( 1H, 456.1; 99% WO 2021 / 102288                                                 PCT / US2020 / 061548 Compound No. Reactant 4 (step 1) Reactant 5 (step 2) Reactant 6 (step 3) Compound Structure / Name ‘H-NMR MS (m / z) [M+H]+; Purity (%) yl)pyrido[3,4-J]pyrimidin-4(3 H)-one t, J = 6.3 Hz), 8.05 (1H, d, J = 8.3 Hz), 8.40 (1H, s), 8.58 (1H, d, J = 8.0 Hz), 8.70 (1H, d, J = 4.7 Hz), 8.77 (1H, s), 8.94 (1H, d, J = 8.3 Hz), 9.36 (1H, s), 9.64 (1H, s). 130 \-N B(OH)2 cf3 ¢: B(OH)2 OH h2n.J / N—N X OH CF,^   0 L° 3-((37?,47?)-4- hydroxytetrahydrofuran-3 -y 1)-8 -(1 -methyl- l / / -pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3 -yl)pyrido[3,4-J]pyrimidin-4(3 H)-one (DMSO-J6, 400 MHz): SH 3.79 (1H, d, J = 9.8 Hz), 4.02-3.95 (5H, m),4.20(lH, t, J = 7.2 Hz), 4.52 (...

Claims

1. A compound of Formula Ia(Ia), or a pharmaceutically acceptable salt thereof, wherein:ring A is chosen from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazoyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydropyranyl, and tetrahydrofuranyl, wherein each cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazoyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydropyranyl, and tetrahydrofuranyl is independently optionally substituted with 1 to 5 instances of RA;ring B is chosen from phenyl, benzodioxolyl, pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazoyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyridinonyl, and pyrimidinyl, wherein each is independently optionally substituted with 1 to 5 instances of RB; /       CN-^- /  XN-^-   O N-^-or ring B is '----'      ,             ,  '----, or \---- /      ;R is chosen from hydrogen, C1-C10 alkyls, 6-10 membered aryls, 3-10 membered cycloalkyls, 5-10 membered heteroaryls, and 3-10 membered heterocycloalkyls, wherein each C1-C10 alkyl, 6-10 membered aryl, 3-10 membered cycloalkyl, 5-10 membered2020386967   30 Jul 2026heteroaryl, and 3-10 membered heterocycloalkyl is independently optionally substituted with 1 to 5 instances of RC;each RA is independently chosen from halos, C1-C10 alkyls, C1-C10 haloalkyls, and C1-C10 haloalkoxys;each RB is independently chosen from halos, C1-C10 alkyls, and C1-C10 haloalkyls; each RC is independently chosen from halos, hydroxy, and C1-C10 alkoxys.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ringA is phenyl optionally substituted with 1 to 3 instances of RA.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ringA is chosen from pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazoyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl,wherein each of pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazoyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl is independently optionally substituted with 1 to 3 instances of RA.

4. The compound of claim 1 or 3, or a pharmaceutically acceptable salt thereof, whereinring A is pyridinyl optionally substituted with 1 to 3 instances of RA.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ringA is chosen from pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydropyranyl, and tetrahydrofuranyl,wherein each of pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydropyranyl, and tetrahydrofuranyl is independently optionally substituted with 1 to 3 instances of RA.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable saltthereof, wherein ring B is phenyl optionally substituted with 1 to 3 instances of RB.

7. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable saltthereof, wherein ring B is chosen from benzodioxolyl, pyrrolyl, furanyl, furazanyl,2020386967   30 Jul 2026thiophenyl, imidazolyl, isothiazoyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyridinonyl, and pyrimidinyl,wherein each of benzodioxolyl, pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazoyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl is independently optionally substituted with 1 to 3 instances of RB.

8. The compound of any one of claims 1 to 5 or 7, or a pharmaceutically acceptable saltthereof, wherein ring B is chosen from pyrazolyl, isothiazoyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl,wherein each of pyrazolyl, isothiazoyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl is independently optionally substituted with 1 to 3 instances of RB.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt,,N =,,,,,2020386967   30 Jul 2026o o o- c> "t> o->- Q" ,   ,,,   ,   ,“O o cy C> , ,,,,,-O, O, ?>. O. O, O. and10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable saltthereof, wherein ring B is chosen from2020386967   30 Jul 2026and11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable saltOHo ,thereof, wherein R is chosen from methyl,OHOHOH,OHOH,,,,,OHF3C OH,MeO,,,OH.OHOHOH,OHCF 3 ,                                 ,OH ,,,OHOMe2020386967   30 Jul 202612. A compound or pharmaceutically acceptable salt thereof, wherein the compound is selected from:(i) (S)-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;(ii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(6-oxo-1,6-dihydropyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;(iii)(S)-8-(benzo[d][1,3]dioxol-4-yl)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;(iv)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;(v) (S)-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;(vi)(S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;(vii)  (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;(viii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;(ix)3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;(x) 6,8-di(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xi)(S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xii)  (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xiii) 6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xiv) 8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xv)  6-(4-chlorophenyl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;2020386967   30 Jul 2026(xvi) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xvii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xviii) 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xix) 3-(2-hydroxy-2-methylpropyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xx) (S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xxi) 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xxii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xxiii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xxiv) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xxv) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xxvi) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-phenylpyrido[3,4-d]pyrimidin-4(3H)-one;(xxvii)       (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xxviii)      3-methyl-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xxix) Rac-6-(4-chlorophenyl)-3-((trans)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xxx) (S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xxxi) (R)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xxxii)       rac-6-(4-chlorophenyl)-3-((cis)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;2020386967   30 Jul 2026(xxxiii)      (R)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xxxiv)       (S)-3-(3-hydroxy-3-methylbutan-2-yl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xxxv)(S)-6,8-bis(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xxxvi)      (S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xxxvii)      (S)-8-(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xxxviii)     6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(2-hydroxy-2-methylpropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xxxix)       (R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xl)(S)-3-(1-(benzyloxy)propan-2-yl)-8-(3-fluorophenyl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xli)  (R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xlii) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xliii) (S)-3-(1-hydroxypropan-2-yl)-6-morpholino-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xliv) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xlv) (S)-3-(1-methoxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xlvi) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xlvii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xlviii)       (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one;(xlix) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;2020386967   30 Jul 2026(l) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethoxy)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(li) (S)-3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lii)methyl (S)-5-(3-(1-hydroxypropan-2-yl)-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)picolinate(liii)  (S)-3-(1-hydroxypropan-2-yl)-6-(isothiazol-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(liv)  3-(2-hydroxy-2-methylpropyl)-8-(isothiazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lv)(S)-3-(1-hydroxypropan-2-yl)-8-( isothiazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lvi)  (S)-3-(1-hydroxypropan-2-yl)-6,8-di(isothiazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lvii) (S)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lviii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lix)  3-(2-hydroxy-2-methylpropyl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lx)3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lxi)  6-(4-chloro-2-methylphenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lxii) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lxiii) (S)-3-(1-hydroxypropan-2-yl)-8-(2-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lxiv) (S)-3-(1-hydroxypropan-2-yl)-8-(4-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lxv) (S)-3-(1-hydroxypropan-2-yl)-6-(4-methylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lxvi) (S)-6-(2-cyclopropylthiazol-5-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one2020386967   30 Jul 2026(lxvii) (S)-3-(1-hydroxypropan-2-yl)-6-(2-isopropylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lxviii)       (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lxix) (S)-3-(1-hydroxypropan-2-yl)-6,8-bis(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lxx) 6-(4-chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one.(lxxi) 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lxxii) 3-(2-hydroxyethyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one(lxxiii)       (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lxxiv)       (S)-6-(6-cyclopropylpyridin-3-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lxxv) (S)-3-(1-hydroxypropan-2-yl)-6-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lxxvi)       (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lxxvii)      (S)-6-(cyclohex-1-en-1-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lxxviii)      (S)-6,8-bis(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lxxix)       3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lxxx) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lxxxi)       6-(6-cyclopropylpyridin-3-yl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lxxxii)      6-(6-cyclopropylpyridin-3-yl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lxxxiii)      (S)-6-(6-cyclopropylpyridin-3-yl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one2020386967   30 Jul 2026(lxxxiv)      (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lxxxv)       (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lxxxvi)      (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lxxxvii)     3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lxxxviii)    3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(lxxxix)      (S)-3-(1-hydroxypropan-2-yl)-6-(2-methylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(xc)  (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(xci) (S)-3-(1-hydroxypropan-2-yl)-6-(piperidin-1-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(xcii) 3-(2-hydroxy-2-methylpropyl)-8-( isothiazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(xciii) (S)-3-(1-hydroxypropan-2-yl)-8-( isothiazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(xciv) 3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(xcv) (S)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(xcvi) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(xcvii)3-(1,1-dioxidotetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(xcviii)       (R)-3-(1,1-dioxidotetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(xcix) (R)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(c) (S)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one2020386967   30 Jul 2026(ci) (R)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cii)  (S)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(ciii) (R)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(civ) (R)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cv)  3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cvi) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cvii) 6-(4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cviii) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cix) (S)-6-(6-cyclopropylpyridin-3-yl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one(cx) (R)-6-(6-cyclopropylpyridin-3-yl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxi) (R)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxii) (R)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxiii) (S)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxiv) 6-(4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxv) 3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxvi) methyl (S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoate(cxvii)6-(4-chlorophenyl)-3-(4-hydroxy-1-methylpyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one2020386967   30 Jul 2026(cxviii)       6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxix) (R)-6-(6-cyclopropylpyridin-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxx) (S)-6-(6-cyclopropylpyridin-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxxi) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxxii)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxxiii)       3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxxiv)       3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxxv)(R)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxxvi)       (S)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxxvii)      (S)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxxviii)     (R)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxxix)       3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxxx)(S)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxxxi)       (S)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxxxii)      (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxxxiii)     3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxxxiv)     6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one2020386967   30 Jul 2026(cxxxv)      6-(4-Chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxxxvi)     (R)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxxxvii)     (S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoic acid(cxxxviii)    (S)-N-methyl-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanamide(cxxxix)     (S)-N,N-dimethyl-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanamide(cxl) 3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxli) 3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxlii) 3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxliii)       (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxliv)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxlv) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-1,2,4-triazol-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxlvi)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxlvii)       (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxlviii)      (S)-8-(diethylamino)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxlix)(S)-3-(1-hydroxypropan-2-yl)-8-(piperidin-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cl) (S)-3-(1-hydroxypropan-2-yl)-8-(pyrrolidin-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cli)  (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(piperidin-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one2020386967   30 Jul 2026(clii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cliii) (S)-6-cyclohexyl-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cliv) (S)-3-(1-hydroxypropan-2-yl)-6-(pyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clv) (S)-3-(1-hydroxypropan-2-yl)-6-(2-methylthiazol-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clvi) (S)-3-(1-hydroxypropan-2-yl)-6-(1-methyl-1H-1,2,3-triazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clvii) (R)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;(clviii)       (S)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;(clix) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clx) 6-(4-chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clxi) (S)-3-(1-hydroxypropan-2-yl)-6-(2-methylpyrimidin-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clxii) 3-(2-hydroxy-2-methylpropyl)-8-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clxiii)       (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clxiv)3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clxv) (S)-5-(3-(1-hydroxypropan-2-yl)-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)picolinic acid(clxvi) (S)-3-(1-hydroxypropan-2-yl)-6-(6-methylpyridin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clxvii)       3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clxviii)      3,8-di(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one2020386967   30 Jul 2026(clxix)8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clxx) 3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clxxi)3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clxxii)       6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clxxiii)      3-cyclopentyl-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clxxiv)      3-phenyl-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clxxv)       3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clxxvi)      3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clxxvii)     (S)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanamide(clxxviii)     3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clxxix)      (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clxxx)       (S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clxxxi)      3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clxxxii)     3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clxxxiii)     3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clxxxiv)    3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one2020386967   30 Jul 2026(clxxxv)     3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clxxxvi)    (S)-3-(1-hydroxypropan-2-yl)-8-morpholino-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clxxxvii)    3-(2-hydroxy-2-methylpropyl)-8-(piperidin-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clxxxviii)   (S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(clxxxix)     (S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyrimidin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxc) (S)-8-(cyclohex-1-en-1-yl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxci) (S)-8-cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxcii)(S)-3-(1-hydroxypropan-2-yl)-N,N-dimethyl-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidine-6-carboxamide(cxciii)       (S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one(cxciv)      (S)-3-(1-hydroxypropan-2-yl)-6-(2-methoxyethyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one or(cxcv) (S)-3-(1-hydroxypropan-2-yl)-8-(2-methoxyethyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one.

13. A compound selected from:(3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6-trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one),2020386967   30 Jul 2026(6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one);(3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one);(3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one);(3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one); or(6-(4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one), or a pharmaceutically acceptable salt thereof.2020386967   30 Jul 202614. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 13, and at least one pharmaceutically acceptable excipient.

15. A method of treating a disease or condition mediated by AhR signaling in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 13 or a pharmaceutical composition of claim 14.

16. The method of claim 15, wherein the disease is chosen from cancers.

17. The method of claim 15 or 16, wherein the disease is chosen from breast cancers,respiratory tract cancers, brain cancers, cancers of reproductive organs, digestive tract cancers, urinary tract cancers, eye cancers, liver cancers, skin cancers, head and neck cancers, thyroid cancers, parathyroid cancers, and metastases of any of the foregoing.

18. A method of treating cancer mediated by AhR signaling in a subject in need thereof comprising administering to said subject a therapeutically effective amount of i) a compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 13 or a pharmaceutical composition of claim 14, and ii) a therapeutically effective amount of at least one additional therapy wherein the at least one additional therapy is chosen from checkpoint inhibitors.

19. The method of claim 18, wherein the subject is intolerant, non-responsive, and / or poorly responsive to the at least one additional therapy when administered alone.

20. The method of claim 19, wherein the at least one additional therapy is chosen from checkpoint inhibitors that target CTLA-4, PD-1, PD-L1, LAG-3, TIM-3, TIGIT and / or VISTA.

21. The method of claim 20, wherein the at least one additional therapy is chosen from anti-PD-1 antibodies or anti-PD-L1 antibodies selected from nivolumab, pembrolizumab, cemiplimab, camrelizumab, sintilimab, spartalizumab, tislelizumab, BCD-100, JS001, atezolizumab, avelumab, durvalumab, and KN035.2020386967   30 Jul 202622. The method of any one of claims 18 to 21, wherein the cancer is chosen from nonsmall cell lung cancer (NSCLC); small cell lung cancer; head and neck squamous cell carcinoma; renal cell carcinoma; gastric adenocarcinoma; nasopharyngeal neoplasms; urothelial carcinoma; colorectal cancer; pleural mesothelioma; triple-negative breast cancer (TNBC); esophageal neoplasms; multiple myeloma; gastric and gastroesophageal junction cancer; melanoma; Hodgkin lymphoma; hepatocellular carcinoma; lung cancer; head and neck cancer; non-Hodgkin lymphoma; metastatic clear cell renal carcinoma; squamous cell lung carcinoma; mesothelioma; gastric cancer; gastroesophageal junction cancer; metastatic melanoma; metastatic non-cutaneous melanoma; urothelial cancer; diffuse large B-cell lymphoma; renal cell cancer; ovarian cancer, fallopian tube cancer; peritoneal neoplasms; extensive stage small cell lung cancer; bladder cancer; transitional cell carcinoma; prostatic neoplasms; recurrent or metastatic PD-L1 positive or negative squamous cell carcinoma of the head and neck (SCCHN); recurrent squamous cell lung cancer; advanced solid malignancies; SCCHN; hypo pharyngeal squamous cell carcinoma; laryngeal squamous cell carcinoma; unresectable or metastatic melanoma; biliary tract neoplasms; esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, glioblastoma, metastatic cancer, prostatic cancer, solid organ cancer; stomach cancer; colon cancer; and liver cancer.

23. Use of a compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease or condition mediated by AhR signaling.

24. Use of a compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer mediated by AhR signaling, wherein the treatment comprises administration of a therapeutically effective amount of i) a compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 14, and ii) a therapeutically effective amount of at least one additional therapy wherein the at least one additional therapy is chosen from checkpoint inhibitors.

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