Pyridopyrimidinone derivatives as AHR antagonists

Abstract

The present disclosure relates to compounds of formula (Ia) and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising them, methods for preparing them, intermediate compounds for preparing them, and methods for treating or preventing diseases, particularly cancers or conditions with dysregulated immune responses or other disorders associated with abnormal AHR signaling. These compounds may also be used to treat 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 on November 22, 2019, U.S. Patent Application No. 63 / 050,416 filed on July 10, 2020, and U.S. Patent Application No. 63 / 091,192 filed on 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 (Ia) and pharmaceutically acceptable salts thereof, methods for preparing the compounds and salts, intermediate compounds for preparing the compounds and salts, pharmaceutical compositions comprising the compounds and salts, and methods for using the compounds and salts to treat or prevent diseases, particularly cancers or conditions with dysregulated immune responses or other disorders associated with abnormal AHR signaling. Also disclosed herein are compositions comprising at least one such compound and / or its pharmaceutically acceptable salt and at least one additional therapy and methods for treating cancer, which methods include administering at least one such compound and / or its pharmaceutically acceptable salt and at least one additional therapy.

[0003]

[0004] The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that belongs to the basic helix-loop-helix / Per-Arnt-Sim (bHLH / PAS) family located in the cytosol. Upon ligand binding, the AHR translocates to the nucleus where it heterodimerizes with the ARNT (AHR nuclear translocator) where it interacts with the DREs (dioxin response elements) of AHR-responsive genes to regulate their transcription. The AHR is best known for binding to environmental toxins and inducing metabolic machinery required for their elimination, such as cytochrome P450 enzymes (e.g., CYP1A1, CYP1A2, and CYP1B1) (Reyes et al., Science, 1992, 256(5060): 1 193-5). Activation of the AHR by xenobiotics has demonstrated its role in many cellular processes such as embryogenesis, tumorigenesis, and inflammation.

[0005] 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 immune regulation (Nguyen et al., Front. Immunol., 2014, 5:551). For example, the classical exogenous AHR ligands TCDD and 3-methylcholanthrene are known to induce profound immunosuppression, promote carcinogenesis, and induce tumor 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 the generation of regulatory T cells, directly and indirectly inhibits Th1 and Th17 differentiation, and reduces the activation and maturation of DCs (Wang et al., Clin. Exp. Immunol., 2014, 177(2):521-30; Mezrieh 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 regulates 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. [Natural Immunology], 2016, 17(6): 687-94). In addition, mice with constitutively active AHR spontaneously develop tumors (Andersson et al., PNAS [Proceedings of the National Academy of Sciences of the United States of America], 2002, 99(15): 9990-5).

[0006] In addition to xenobiotics, AHR can also bind metabolites of tryptophan degradation. Tryptophan metabolites, such as kynurenine and kynurenic acid, are endogenous AHR ligands that activate AHR under physiological conditions (DiNatale et al., Toxicol. Sci., 2010, 115(1):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 AHR, although their physiological roles are currently unknown (Nguyen & Bradfield, Chem. Res, Toxicol., 2008, 21(1):102-116).

[0007] The immunosuppressive properties of kynurenine and tryptophan degradation have been well described and have been implicated in cancer-associated immunosuppression. The enzymes indoleamine-2,3-dioxygenase 1 and 2 (IDO1 / IDO2) and tryptophan-2,3-dioxygenase 2 (TDO2) are responsible for catalyzing the first, rate-limiting step in tryptophan metabolism. IDO1 / 2-mediated degradation of tryptophan in tumors and tumor-draining lymph nodes reduces antitumor immune responses, and inhibition of IDO can inhibit tumor 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).

[0008] TDO2 is also strongly expressed in cancer and can lead to the production of immunosuppressive kynurenine. In gliomas, activation of AHR by kynurenine, downstream of TDO-mediated tryptophan degradation, enhances tumor growth by suppressing antitumor immune responses and directly promoting tumor cell survival and motility (Opita et al., Nature, 2011, 478(7368): 197-203). Thus, AHR ligands produced by tumor cells act on tumor cells and lymphocytes in an autocrine and paracrine manner, respectively, to promote tumor growth.

[0009] Add-on therapy in combination with AhR may be useful for treating cancer. Immune checkpoint inhibitors (ICIs) have been used in cancer treatment to enhance the host's immune response. Non-limiting examples of ICI targets include programmed death 1 (PD-1), PD-1 ligand (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4).

[0010] PD-1 is highly expressed by activated T cells, B cells, dendritic cells (DCs), and natural killer (NK) cells, whereas PD-L1 can be expressed on several types of tumor cells.

[0011] ICIs are currently approved by the U.S. Food and Drug Administration for the treatment of melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck squamous cell carcinoma, Hodgkin lymphoma, urothelial carcinoma, small cell lung cancer, esophageal squamous cell tumor, cervical cancer, primary mediastinal large B-cell lymphoma, MSI-H / dMMR colorectal cancer, hepatocellular carcinoma, Merkel cell carcinoma, triple-negative breast cancer, and cutaneous squamous cell carcinoma.

[0012] The present disclosure relates to novel 3,6,8-trisubstituted pyrido[3,4-d]pyrimidine-4(3H)-ones of formula (I) or formula (Ia) and / or pharmaceutically acceptable salts thereof. It has been surprisingly found that the compounds of the present disclosure effectively inhibit AHR and are therefore useful for treating or preventing cancer and / or other conditions in which exogenous and endogenous AHR ligands induce: a dysregulated immune response, uncontrolled cell growth, proliferation and / or survival of tumor cells, immunosuppression in the context of cancer, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response or disease accompanied by: uncontrolled cell growth, proliferation and / or survival of tumor cells, immunosuppression in the context of cancer, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response, particularly wherein Uncontrolled cell growth, proliferation and / or survival of tumor cells in the context of cancer, immunosuppression in the context of cancer, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses are mediated by AHR, such as, for example, liquid and solid tumors and / or their metastases, such as head and neck tumors (including brain tumors and brain metastases), thoracic tumors (including non-small cell and small cell lung tumors), gastrointestinal tumors (including colon, colorectal and pancreatic tumors), liver tumors, endocrine tumors, breast and other gynecological tumors, urological tumors (including kidney, bladder and prostate tumors), skin tumors and sarcomas, and their metastases.

[0013] The present disclosure also relates to pharmaceutical compositions comprising at least one entity selected from a compound of formula (I) or formula (Ia) and a pharmaceutically acceptable salt thereof. The present disclosure also relates to methods of treatment comprising administering at least one compound of the present disclosure, a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition. In some embodiments, the present disclosure provides a method for treating a disease or condition mediated by AHR signaling. In some embodiments, the present disclosure provides a method for treating a disease or condition associated with abnormal AHR signaling. In some embodiments, the present disclosure provides a method for inhibiting cancer cell proliferation mediated by AHR signaling. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 Dosing regimens for in vivo syngeneic model studies using CT26 Balb / C mice are shown.

[0015] Figure 2 Shown are tumor growth curves for 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] Figure 3 Shown are tumor weights at study termination for vehicle versus single agent PD-L1 antibody or PD-L1 antibody plus Compound No. 7 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy.

[0017] Figure 4 Shown are tumor growth curves for vehicle versus single agent PD-L1 antibody or PD-L1 antibody plus Compound No. 30 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy.

[0018] Figure 5 Shown are tumor weights at study termination for vehicle versus single agent PD-L1 antibody or PD-L1 antibody plus Compound No. 30 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy.

[0019] Figure 6 Shown are tumor growth curves of vehicle versus single agent PD-L1 antibody or PD-L1 antibody plus Compound No. 30 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy.

[0020] Figure 7 Shown are tumor weights at study termination for vehicle versus single agent PD-L1 antibody or PD-L1 antibody plus Compound No. 30 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy.

[0021] Figure 8Shown are tumor growth curves for vehicle versus single-agent PD-L1 antibody or PD-L1 antibody plus Compound No. 9 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy.

[0022] Fig. 9 Shown are tumor weights at study termination for vehicle versus single agent PD-L1 antibody or PD-L1 antibody plus Compound No. 9 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy.

[0023] Fig.10 Shown are tumor growth curves of vehicle versus single-agent PD-L1 antibody or PD-L1 antibody plus Compound 9 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy.

[0024] Fig.11 Shown are tumor weights at study termination for vehicle versus single agent PD-L1 antibody or PD-L1 antibody plus Compound No. 9 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy.

[0025] Fig.12 Shown are tumor growth curves of vehicle versus single-agent PD-L1 antibody or PD-L1 antibody plus Compound No. 46 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy.

[0026] Fig.13 Shown are tumor weights at study termination for vehicle versus single agent PD-L1 antibody or PD-L1 antibody plus Compound No. 46 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy.

[0027] Fig.14 Shown is a graph of mean plasma concentrations of Compound No. 46 over time following 1 mg / kg IV and 10 mg / kg PO dosing in CD1 mice.

[0028] Fig.15 Shown is a graph of mean plasma concentrations of Compound No. 46 over time following 1 mg / kg IV and 3 mg / kg PO administration in SD rats.

[0029] Fig.16 Shown is a graph of mean plasma concentrations of Compound No. 9 over time following 1 mg / kg IV and 10 mg / kg PO dosing in CD1 mice.

[0030] Fig.17 Shown is a graph of mean plasma concentrations of Compound No. 9 over time following 1 mg / kg IV and 3 mg / kg PO administration in SD rats.

[0031] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is pharmaceutically acceptable as defined herein and 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.

[0032] Additional non-limiting examples of pharmaceutically acceptable salts include those formed when an acidic proton in the parent compound is replaced by a metal ion, non-limiting examples of metal ions include alkali metal ions and alkaline earth metal ions, and those formed when an acidic proton present in the parent compound is replaced by an 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 containing one or more counterions and zwitterions.

[0033] The ranges provided herein are understood to be shorthand for all values ​​within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or subrange 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 rules apply to any other ranges described herein even if no values ​​within the range are specifically indicated in the disclosure.

[0034] As used herein, the terms "checkpoint inhibitor" and "checkpoint inhibitor therapy" are used interchangeably and refer to any therapeutic agent that inhibits one or more inhibitory pathways to allow for broader immune activity, including any small molecule compound, antibody, nucleic acid molecule or polypeptide or any fragment thereof. In some embodiments, checkpoint inhibitor therapy comprises administering at least one checkpoint inhibitor to a patient in need of such treatment.

[0035] Unless otherwise indicated, the term "compound" as used herein refers to a collection of molecules having the same chemical structure as a collection of stereoisomers (e.g., 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 compounds and salts of the present invention are within the scope of the present disclosure. Unless otherwise indicated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0036] As used herein, "stereoisomers" refers to both enantiomers and diastereomers.

[0037] As used herein, the term "tautomer" refers to one of two or more isomers of a compound that exist together in equilibrium and are readily interchangeable by migration of atoms or groups within the molecule.

[0038] Unless otherwise indicated, the nomenclature used to describe chemical groups or moieties as used herein follows the convention in which the name is read from left to right with the point of attachment to the rest of the molecule being to the right of the name. For example, the group "(C 1-3 Alkoxy)C 1-3 An "alkyl" group is attached to the remainder of the molecule at the alkyl terminus. Further examples include methoxyethyl, where the point of attachment is at the ethyl terminus, and methylamino, where the point of attachment is at the amine terminus.

[0039] Unless otherwise indicated, when a chemical group is described by its chemical formula or by a structure having a terminal bonding moiety indicated by a "-", it should be understood that the "-" represents the point of attachment. In some embodiments, the wavy line (i.e., ) depicts the attachment point.

[0040] As used herein, "acyl" or "alkanoyl" is a functional group having the formula RCO-, wherein R is bonded to the carbon atom of the carbonyl functional group by a single bond, and "-" indicates the point of attachment to the rest of the molecule. Non-limiting examples of acyl groups include methyl ether (HC(O)-, also known as methanoyl), ethyl ether (CH3C(O)-, also known as ethanoyl), and benzoyl (PhC(O)-).

[0041] As used herein, the term "alkyl" or "aliphatic" refers to a straight (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated and has a single point of attachment to the rest of the molecule. Unless otherwise specified, an alkyl group is a hydrocarbon chain having 1 to 20 alkyl carbon atoms. In some embodiments, an alkyl group contains one to twelve carbon atoms (C1-C 12). In some embodiments, the alkyl group comprises one to eight carbon atoms (C1-C8). In some embodiments, the alkyl group comprises one to six carbon atoms (C1-C8). In some embodiments, the alkyl group comprises one to four carbon atoms (C1-C4). In some implementations, the cyclic alkyl group comprises three to six carbon atoms (C3-C6). Non-limiting examples of substituted and unsubstituted straight chain, branched and cyclic alkyl groups include methyl, ethyl, n-propyl, isopropyl, 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.

[0042] As used herein, "alkoxy" refers to an alkyl group as previously defined attached to the backbone carbon chain through an oxygen ("alkoxy") atom.

[0043] As used herein, "halo" and "halogen" are interchangeable and refer to halogen atoms such as fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0044] "Haloalkyl" refers to an alkyl group substituted by one or more halogen atoms (F, Cl, Br, I). For example, "fluoromethyl" refers to a methyl group substituted by one or more fluorine atoms (e.g., monofluoromethyl, difluoromethyl, or trifluoromethyl).

[0045] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms (F, Cl, Br, I). For example, "fluoromethoxy" refers to a methoxy group substituted with one or more fluorine atoms (e.g., monofluoromethoxy, difluoromethoxy, or trifluoromethoxy).

[0046] "Hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy (-OH) groups.

[0047] The terms "cycloalkyl" and "cycloalkyl group" as used interchangeably herein refer to a cyclic saturated monovalent hydrocarbon radical having three to twelve carbon atoms, which has a single attachment point to the rest of the molecule. The cycloalkyl group can be unsubstituted or substituted. In certain embodiments, the cycloalkyl group comprises three to eight carbon atoms (C3-C8). In certain embodiments, the cycloalkyl group comprises three to six carbon atoms (C3-C6). Non-limiting examples of substituted and unsubstituted cycloalkyl include cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0048] The terms "alkylene" and "alkylene group" as used interchangeably herein refer to a group containing from one to twelve carbon atoms (C1-C 12 ) is a saturated divalent (i.e., having two points of attachment to the rest of the molecule) hydrocarbon group. An alkylene group can be linear, branched, or cyclic. An alkylene group can be unsubstituted or substituted. In some embodiments, an alkylene group comprises one to eight carbon atoms (C1-C8). In some embodiments, an alkylene group comprises one to six carbon atoms (C1-C6). In some embodiments, an alkylene group comprises one to four carbon atoms (C1-C4). Non-limiting examples of alkylene groups include methylene and ethylene.

[0049] The terms "alkenyl" and "alkenyl group" as used interchangeably herein refer to a single (i.e., having a single attachment point to the rest of the molecule) hydrocarbon group comprising two to eight carbon atoms (C2-C8) and having at least one unsaturated site (i.e., sp2 carbon-carbon double bond). An alkenyl group can be straight, branched or cyclic. An alkenyl group can be unsubstituted or substituted. In certain embodiments, an alkenyl group comprises two to six carbon atoms (C2-C6). In certain embodiments, an alkenyl group comprises two to four carbon atoms (C2-C4). An alkenyl group can have an E or Z orientation. Non-limiting examples of alkenyl groups include vinyl (also referred to as vinyl (vinyl)), 1-propenyl, isopropenyl and 2-chlorovinyl.

[0050] The terms "alkenylene" and "alkenylene group" as used interchangeably herein refer to a divalent (i.e., having two attachment points to the rest of the molecule) hydrocarbon group with two to eight carbon atoms (C2-C8) having at least one unsaturated site (e.g., sp2 carbon-carbon double bond). An alkenylene group can be linear, branched or cyclic. An alkenylene group can be unsubstituted or substituted. In certain embodiments, an alkylene group comprises two to six carbon atoms (C2-C6). In certain embodiments, an alkylene group comprises two to four carbon atoms (C2-C4). An alkylene group can have an E or Z orientation. A non-limiting example of an alkenyl group is vinylene (also referred to as vinylene).

[0051] 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 group with two to eight carbon atoms (C2-C8) having at least one unsaturated site (i.e., sp carbon-carbon triple bond). Alkynyl groups can be straight or branched. Alkynyl groups can be unsubstituted or substituted. In certain embodiments, alkynyl groups comprise two to six carbon atoms (C2-C6). In certain embodiments, alkynyl groups comprise two to four carbon atoms (C2-C4). The non-limiting example of an alkynyl group is ethynyl.

[0052] The terms "alkynylene" and "alkynylene group" as used interchangeably herein refer to a divalent (i.e., having two attachment points to the rest of the molecule) hydrocarbon group with two to eight carbon atoms (C2-C8) having at least one unsaturated site (i.e., sp carbon-carbon triple bond). The alkynylene group can be straight or branched. The alkynylene group can be unsubstituted or substituted. In certain embodiments, the alkynylene group comprises two to six carbon atoms (C2-C6). In certain embodiments, the alkynylene group comprises two to four carbon atoms (C2-C4). A non-limiting example of an alkynylene group is ethynylene.

[0053] As used herein, "aromatic group" or "aromatic ring" refers to a chemical group containing a conjugated planar ring system with a delocalized π electron orbital consisting of [4n+2]p orbital electrons, where n is an integer ranging from 0 to 6. Non-limiting examples of aryl groups include aryl and heteroaryl.

[0054] As used herein interchangeably, the terms "aryl" and "aryl group" refer to a group consisting of 6 to 20 carbon atoms (C6-C 20 ) monovalent (i.e., having a single point of attachment to the rest of the molecule) aromatic hydrocarbon radical. 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. phenyl, 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.

[0055] As used herein, the term "heteroalkyl" refers to an alkyl group in which at least one carbon atom in the chain is replaced by a heteroatom such as nitrogen, oxygen, phosphorus and sulfur. The heteroalkyl group can be unsubstituted or substituted.

[0056] The terms "heterocycloalkyl", "heterocycle", "heterocyclyl" and "heterocyclic group" as used interchangeably herein refer to a saturated or partially unsaturated ring system having 3 to 20 atoms, wherein at least one of the ring atoms is a heteroatom, such as nitrogen, oxygen, phosphorus and sulfur. The heterocycloalkyl group may be unsubstituted or substituted. In some embodiments, the heterocycloalkyl group comprises 3 to 10 atoms. In some embodiments, the heterocycloalkyl group contains 3 to 7 atoms. In some embodiments, the heterocycloalkyl group is monocyclic. In some embodiments, the heterocycloalkyl group is bicyclic. In some embodiments, the heterocycloalkyl group comprises a condensed ring. Non-limiting examples of unsubstituted and substituted heterocycloalkyl groups include pyrrolidinyl, N-methylpyrrolidinyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 3-hydroxypyrrolidinyl, 3-methoxypyrrolidinyl and benzodioxolyl.

[0057] The terms "heteroaryl" and "heteroaryl group" as used interchangeably herein refer to an aromatic ring system having 3 to 20 atoms, wherein at least one of these ring atoms is a heteroatom, such as nitrogen, oxygen, phosphorus and sulfur. The heteroaryl group can be unsubstituted or substituted. In some embodiments, the heteroaryl group contains 5 to 20 atoms. In some embodiments, the heteroaryl group contains 5 to 9 atoms. In some embodiments, the heteroaryl group contains 5 atoms. In some embodiments, the heteroaryl group contains 6 atoms. In some embodiments, the heteroaryl group contains 7 atoms. In some embodiments, the heteroaryl group is monocyclic. In some embodiments, the heteroaryl group is bicyclic. In some embodiments, the heteroaryl group contains condensed rings. Non-limiting examples of heteroaryl groups include pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, 2-thienyl, 3-thienyl, isoxazolyl, thiazolyl, oxadiazolyl, 3-methyl-1,2,4-oxadiazolyl, 3-phenyl-1,2,4-oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, tetrahydroisoquinolyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furanpyridinyl, and 1H-pyrrolo[2,3-b]pyridinyl. Non-limiting examples of heteroaryl groups include:

[0058]

[0059] As used herein, the phrase "optionally substituted" refers to may or may not be "substituted". As used herein, the term "substituted" refers to one or more hydrogen atoms on a group (such as an alkyl group, an alkylene group, an alkenyl group, an alkenylene group, an alkynyl group, an alkynylene group, an aryl group, a heterocycloalkyl group, or a heteroaryl group) are replaced by one or more substituents. Non-limiting examples of substituents replacing a single hydrogen atom include halogen, hydroxyl, and amino. Non-limiting examples of substituents replacing two hydrogen atoms include oxo and methylene. Non-limiting examples of substituents replacing three hydrogen atoms include nitrile.

[0060] Additional non-limiting examples of substituents include:

[0061] C1-C6 straight chain, branched and cyclic alkyl groups, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl and cyclohexyl;

[0062] C2-C8 straight chain, branched, and cyclic alkenyl groups, non-limiting examples of which include ethenyl (also known as vinyl), 1-propenyl, and isopropenyl;

[0063] C2-C8 straight chain and branched alkynyl groups, non-limiting examples of which include ethynyl;

[0064] 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;

[0065] Substituted and unsubstituted heterocyclyl groups, non-limiting examples of which include pyrrolidinyl, N-methylpyrrolidinyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 3-hydroxypyrrolidinyl, and 3-methoxypyrrolidinyl;

[0066] Substituted and unsubstituted heteroaryl groups, non-limiting examples of which include pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, furanyl, 2-thienyl, 3-thienyl, isoxazolyl, thiazolyl, oxadiazolyl, 3-methyl-12,4-oxadiazolyl, 3-phenyl-1,2,4-oxadiazolyl, indolyl, benzothiazolyl, and 1H-pyrrolo[2,3-b]pyridinyl;

[0067] -(CR a R b ) z OR c , non-limiting examples of which include -OH, -OCH3, -OCH2OH, and -OCH2CH3;

[0068] -(CR a R b ) z N(R c )(R d ), non-limiting examples of which include -NH2, -NHCH3, -N(CH3)2, -CH2NH2, -CH2NHCH3,

[0069] A halogen atom, non-limiting examples of which include a fluorine atom (-F) and a chlorine atom (-Cl);

[0070] -(CR a R b ) z CN;

[0071] -(CR a R b ) z NO2;

[0072] -CH x X y , wherein X is a halogen atom and the sum of x+y is 3, non-limiting examples of which include -CH2F, -CHF2 and -CF3;

[0073] -(CR a R b ) z C(O)R c , non-limiting examples of which include -COCH3, -COCH2CH3, and -CH2COCH3;

[0074] -(CR a R b ) z C(O)OR c , non-limiting examples include CO2H, -CO2CH3, -CO2CH2CH3, and -CH2CO2CH3,

[0075] -(CR a R b ) z C(O)N(R c )(R d ), non-limiting examples of which include -CONH2, -CONHCH3, -CON(CH3)2, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2;

[0076] -(CR a R b ) z S02R c; Non-limiting examples of which include -SO2H, -SO2CH3, -CH2SO2H, -CH2SO2CH3, -SO2C6H5, and -CH2SO2C6H5; and

[0077] -(CR a R b ) z 3R c ; Non-limiting examples thereof include -SO3H, -SO3CH3, -CH2SO3H, -CH2SO3CH3, -SO3C6H5, and -CH2SO3C6H5;

[0078] Where R a and R b Each of R is independently selected from hydrogen and substituted or unsubstituted C1-C6 straight chain, branched or cyclic alkyl, c and R d Each of the R is independently selected from hydrogen, substituted or unsubstituted C1-C6 straight chain, branched or cyclic alkyl and aryl, or wherein R c and R d Together they form a ring system containing 3 to 7 atoms, and z is selected from 0, 1, 2, 3 and 4.

[0079] As used herein, the term "pharmaceutical composition" refers to a preparation that is in a form that permits the biological activity of the active ingredient to be effective and that does not contain additional components that are unacceptably toxic to the subject to which the composition will be administered. In some embodiments, such compositions may be sterile.

[0080] The term "pharmaceutically acceptable" as used herein in "pharmaceutically acceptable salts" and "pharmaceutically acceptable excipients" refers to components that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without excessive toxicity, irritation, allergic response, etc., and are commensurate with a reasonable benefit / risk ratio.

[0081] The phrase "pharmaceutically acceptable excipient" employed herein refers to a pharmaceutically acceptable material selected from solvents, dispersion media, diluents, dispersants, suspension aids, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, polymers, peptides, proteins, cells, hyaluronidase, and mixtures thereof. In some embodiments, the solvent is an aqueous solvent.

[0082] "Treating," "treating," "treating," and "treating" refers to reversing, alleviating (eg, reducing one or more symptoms) and / or slowing the progression of a medical condition or disorder described herein.

[0083] The terms "disease" and "disorder" are used interchangeably herein and refer to any change in the state of the body or certain organs that interrupts or interferes with the performance of functions and / or causes symptoms such as discomfort, dysfunction, pain, or even death to the afflicted person or those with whom the person comes in contact. A disease or disorder may also be associated with a distemper, sickness, ailment, ailment, illness, disease, complaint, discomfort, or emotion.

[0084] As used herein, "subject" means an animal subject, such as a mammalian subject, and particularly a human.

[0085] As used herein, the term "administering" refers to placing the compound, salt and / or composition into a mammalian tissue or subject by a method or route that localizes the compound, pharmaceutically acceptable salt thereof and / or pharmaceutical composition comprising the same at least partially to a desired site or tissue location.

[0086] As used herein, the term "therapeutically effective amount" refers to the amount of a compound or salt that produces the desired effect for which it is administered (e.g., ameliorating the symptoms of a disease or condition mediated by AhR signaling, lessening the severity of such a disease or condition or its symptoms, and / or reducing the progression of any of the foregoing). The exact amount of an effective dose will depend on the purpose of the treatment and will be able to be determined by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0087] One of ordinary skill in the art will 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 compounds and pharmaceutically acceptable salts disclosed herein are based on the free base form of the relevant compound. For example, "10 mg of at least one entity selected from a compound of Formula I or Ia and a pharmaceutically acceptable salt thereof" refers to 10 mg of a compound of Formula I or Ia or an amount of a pharmaceutically acceptable salt equivalent to 10 mg of the relevant compound of Formula I or Ia.

[0088] The "effectiveness" of the compounds or compositions of the present disclosure can be evaluated by any method known to those of ordinary skill in the art, including those described in the examples of the present disclosure. Effectiveness can be established in vitro (biochemistry and / or biology in cultured cells) and / or in vivo. In vitro effectiveness can be used to infer or predict a certain degree of effectiveness in an animal or human subject. A reference or standard or comparison can be used. In the context of the present disclosure and claims, the term "effective" inhibition of receptors (such as AhR) and / or enzyme-mediated signal transduction refers to reducing / activating the activity of receptors and / or reducing / activating the activation and propagation of signal transduction pathways in terms of activation of downstream molecules or known biological effects in a detectable or measurable amount relative to baseline activity. This can be evaluated in vitro or in vivo, and in some cases, a person of ordinary skill in the art can infer what the activity or benefit in vivo is. In some embodiments, the reduction or activation is measured by a percentage of reduction or activation relative to the activity without exposure to the compounds of the present 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 may also fall within the range of, for example, 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.

[0089] Disclosed herein are compounds of formula (I):

[0090]

[0091] and pharmaceutically acceptable salts thereof,

[0092] in:

[0093] R 1 and R 2 each of which is independently selected from optionally substituted alkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted amine, and optionally substituted heterocycloalkyl; and

[0094] R 3 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amine, cyano, halo, hydroxy, and -C(O)H.

[0095] In some embodiments, R 2 In some embodiments, R2 It is diethylamine.

[0096] Also disclosed herein are compounds of Formula Ia:

[0097]

[0098] and pharmaceutically acceptable salts thereof,

[0099] in:

[0100] Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl;

[0101] Ring B is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl; and

[0102] R is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H.

[0103] In some embodiments, Ring A is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl, wherein each 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl is independently optionally substituted by 1 to 5 R A Instances of .

[0104] In some embodiments, Ring B is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl, wherein each 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl is independently optionally substituted by 1 to 5 R B Instances of .

[0105] In some embodiments, R is selected from hydrogen, C1-C 10 alkyl, 6-10 membered aryl, -C(O)R', -C(O)NR'R', 3-10 membered cycloalkyl, -C(O)OR', C1-C 10 heteroalkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, amino, cyano, halo, hydroxyl and -C(O)H, wherein each C1-C 10 Alkyl, 6-10 membered aryl, 3-10 membered cycloalkyl, C1-C 10 Heteroalkyl, 5-10 membered heteroaryl and 3-10 membered heterocycloalkyl are independently optionally substituted by 1 to 5 R C Instances of .

[0106] In some embodiments, each R' is independently selected from hydrogen, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Hydroxyalkyl and C1-C 10 Heteroalkyl.

[0107] In some embodiments, each R A Independently selected from halo, hydroxy, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy, C1-C 10 Hydroxyalkyl and NR"R".

[0108] In some embodiments, each R B Independently selected from halo, hydroxy, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy, C1-C 10 Hydroxyalkyl and NR"R".

[0109] In some embodiments, each R C independently selected from halo, hydroxy, cyano, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 haloalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl and 5-10 membered heteroaryl.

[0110] In some embodiments, each R" is independently selected from hydrogen, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Hydroxyalkyl and C1-C 10 Heteroalkyl.

[0111] In some embodiments, Ring A is selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl, wherein each 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl is independently optionally substituted by 1 to 5 R A Instances of ;

[0112] Ring B is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl, wherein each 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl is independently optionally substituted by 1 to 5 R B Instances of ;

[0113] R is selected from hydrogen, C1-C 10 alkyl, 6-10 membered aryl, -C(O)R', -C(O)NR'R', 3-10 membered cycloalkyl, -C(O)OR', C1-C10 heteroalkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, amino, cyano, halo, hydroxyl and -C(O)H, wherein each C1-C 10 Alkyl, 6-10 membered aryl, 3-10 membered cycloalkyl, C1-C 10 Heteroalkyl, 5-10 membered heteroaryl and 3-10 membered heterocycloalkyl are independently optionally substituted by 1 to 5 R C Instances of ;

[0114] Each R' is independently selected from hydrogen, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Hydroxyalkyl and C1-C 10 heteroalkyl;

[0115] Each R A Independently selected from halo, hydroxy, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy, C1-C 10 Hydroxyalkyl and NR"R";

[0116] Each R B Independently selected from halo, hydroxy, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy, C1-C 10 Hydroxyalkyl and NR"R";

[0117] Each R C independently selected from halo, hydroxy, cyano, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 haloalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and

[0118] Each R" is independently selected from hydrogen, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 100 Hydroxyalkyl and C1-C 10 Heteroalkyl.

[0119] In some embodiments, Ring A is selected from optionally substituted with 1 to 5 R A In some embodiments, ring A is selected from the group consisting of 1 to 5 R A In some embodiments, ring A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl substituted with 1 to 5 R A In some embodiments, ring A is optionally substituted with 1 to 3 R A In some embodiments, ring A is selected from phenyl optionally substituted with 1 to 5 R A Examples of substituted 5-8 membered heteroaryl.

[0120] In some embodiments, Ring A is selected from pyrrolyl, furanyl, furazanyl, thienyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, wherein each of pyrrolyl, furanyl, furazanyl, thienyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl is independently optionally substituted with 1 to 3 R A Instances of .

[0121] In some embodiments, Ring A is optionally substituted with 1 to 3 R A In some embodiments, ring A is selected from the group consisting of 1 to 5 R A In some embodiments, ring A is selected from pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, aminoheterocycloalkyl, yl, tetrahydropyranyl and tetrahydrofuranyl, among which pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, aza Each of tetrahydropyranyl, tetrahydrofuranyl and tetrahydropyranyl is independently optionally substituted by 1 to 3 R A In some embodiments, Ring A is optionally substituted with 1 to 3 R A Examples of are substituted piperidinyl or morpholinyl.

[0122] In some embodiments, each R A Independently selected from halo, C1-C 10 Alkyl, C1-C 10Halogenated alkyl, C1-C 10 Alkoxy, C1-C 10 Haloalkoxy and NR"R". In some embodiments,

[0123] Each R B Independently selected from halo, C1-C 10 Alkyl and C1-C 10 In some embodiments, each R C independently selected from halo, hydroxy, cyano, C1-C 10 Alkyl, C1-C 10 In some embodiments, each R" is independently selected from hydrogen and C1-C 10 alkyl.

[0124] In some embodiments, each R A Independently selected from halo, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy, C1-C 10 Haloalkoxy and NR"R";

[0125] Each R B Independently selected from halo, C1-C 10 Alkyl and C1-C 10 Haloalkyl;

[0126] Each R C independently selected from halo, hydroxy, cyano, C1-C 10 Alkyl, C1-C 10 Alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, and 6-8 membered aryl; and

[0127] Each R" is independently selected from hydrogen and C1-C 10 alkyl.

[0128] In some embodiments, Ring B is selected from optionally substituted with 1 to 5 R B In some embodiments, ring B is optionally substituted with 1 to 3 R B In some embodiments, ring B is selected from phenyl optionally substituted with 1 to 5 R BIn some embodiments, ring B is selected from pyrrolyl, furanyl, furazanyl, thienyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyridonyl and pyrimidinyl, wherein each of pyrrolyl, furanyl, furazanyl, thienyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl is independently optionally substituted with 1 to 3 R B In some embodiments, ring B is selected from pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl and thienyl, wherein each of pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl and thienyl is independently optionally substituted with 1 to 3 R B Instances of .

[0129] In some embodiments, Ring A is selected from

[0130] In some embodiments, Ring A is selected from

[0131] In some embodiments, Ring A is selected from

[0132] In some embodiments, Ring B is selected from

[0133] In some embodiments, Ring B is selected from

[0134] In some embodiments, Ring B is selected from

[0135] In some embodiments, R is selected from methyl,

[0136] In some embodiments, R is selected from methyl,

[0137] Also disclosed herein are compounds of Formula Ib:

[0138]

[0139] and pharmaceutically acceptable salts thereof,

[0140] in:

[0141] Ring A is selected from optionally substituted heteroaryl and optionally substituted heterocycloalkyl;

[0142] Ring B is selected from optionally substituted heteroaryl and optionally substituted heterocycloalkyl; and

[0143] R is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H.

[0144] In some embodiments, the disclosure relates to one or more compounds listed in Table 1.

[0145] Table 1

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173] In some embodiments, the present disclosure relates to one or more compounds selected from the following compounds and pharmaceutically acceptable salts thereof:

[0174] (i) (S)-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0175] (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;

[0176] (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;

[0177] (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;

[0178] (v) (S)-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0179] (vi) (S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0180] (vii) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0181] (viii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0182] (ix) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0183] (x) 6,8-di(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0184] (xi) (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0185] (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;

[0186] (xiii) 6-(4-fluorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0187] (xiv) 8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0188] (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;

[0189] (xvi) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0190] (xvii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0191] (xviii) 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0192] (xix) 3-(2-hydroxy-2-methylpropyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0193] (xx) (S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0194] (xxi) 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0195] (xxii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0196] (xxiii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0197] (xxiv) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0198] (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;

[0199] (xxvi) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-phenylpyrido[3,4-d]pyrimidin-4(3H)-one;

[0200] (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;

[0201] (xxviii) 3-methyl-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0202] (xxix) rac-6-(4-chlorophenyl)-3-((trans)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0203] (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;

[0204] (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;

[0205] (xxxii) rac-6-(4-chlorophenyl)-3-((cis)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0206] (xxxiii) (R)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0207] (xxxiv) (S)-3-(3-hydroxy-3-methylbutan-2-yl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0208] (xxxv) (S)-6,8-bis(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0209] (xxxvi) (S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0210] (xxxvii) (S)-8-(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0211] (xxxviii) 6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(2-hydroxy-2-methylpropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0212] (xxxix) (R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0213] (xl) (S)-3-(1-(benzyloxy)propan-2-yl)-8-(3-fluorophenyl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0214] (xli) (R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0215] (xlii) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0216] (xliii) (S)-3-(1-hydroxypropan-2-yl)-6-morpholinyl-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0217] (xliv)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0218] (xlv)(S)-3-(1-methoxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0219] (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:

[0220] (xlvii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0221] (xlviii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0222] (xlix) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0223] (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

[0224] (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

[0225] (lii) (S)-5-(3-(1-hydroxypropan-2-yl)-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)picolinic acid methyl ester

[0226] (liii) (S)-3-(1-hydroxypropan-2-yl)-6-(isothiazol-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0227] (liv) 3-(2-hydroxy-2-methylpropyl)-8-(isothiazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0228] (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

[0229] (lvi) (S)-3-(1-hydroxypropan-2-yl)-6,8-di(isothiazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0230] (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

[0231] (lviii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0232] (lix) 3-(2-hydroxy-2-methylpropyl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0233] (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

[0234] (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

[0235] (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

[0236] (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

[0237] (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

[0238] (lxv) (S)-3-(1-hydroxypropan-2-yl)-6-(4-methylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0239] (lxvi) (S)-6-(2-cyclopropylthiazol-5-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0240] (lxvii) (S)-3-(1-hydroxypropan-2-yl)-6-(2-isopropylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0241] (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

[0242] (lxix) (S)-3-(1-hydroxypropan-2-yl)-6,8-bis(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0243] (lxx) 6-(4-chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one.

[0244] (lxxi) 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0245] (lxxii) 3-(2-hydroxyethyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0246] (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

[0247] (lxxiv) (S)-6-(6-cyclopropylpyridin-3-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0248] (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

[0249] (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

[0250] (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

[0251] (lxxviii) (S)-6,8-bis(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0252] (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

[0253] (lxxx) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0254] (lxxxi) 6-(6-cyclopropylpyridin-3-yl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0255] (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

[0256] (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)-one

[0257] (lxxxiv) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0258] (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

[0259] (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

[0260] (lxxxvii) 3-(2-Hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0261] (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

[0262] (lxxxix) (S)-3-(1-hydroxypropan-2-yl)-6-(2-methylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0263] (xc) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0264] (xci)(S)-3-(1-hydroxypropan-2-yl)-6-(piperidin-1-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0265] (xcii) 3-(2-hydroxy-2-methylpropyl)-8-(isothiazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0266] (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

[0267] (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

[0268] (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

[0269] (xcvi) (3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0270] (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

[0271] (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

[0272] (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

[0273] (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)-one

[0274] (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

[0275] (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

[0276] (ciii) (R)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0277] (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

[0278] (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

[0279] (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

[0280] (cvii) 6-(4-fluorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0281] (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

[0282] (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

[0283] (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

[0284] (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

[0285] (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

[0286] (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

[0287] (cxiv) 6-(4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0288] (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

[0289] (oxvi)(S)-methyl 2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoate

[0290] (cxvii) 6-(4-chlorophenyl)-3-(4-hydroxy-1-methylpyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0291] (cxviii) 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0292] (cxix) (R)-6-(6-cyclopropylpyridin-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-3-yl)-3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0293] (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

[0294] (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

[0295] (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

[0296] (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

[0297] (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

[0298] (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

[0299] (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

[0300] (cxxvii) (S)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3)-one

[0301] (cxxviii) (R)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0302] (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

[0303] (cxxx)(S)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0304] (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

[0305] (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

[0306] (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

[0307] (cxxxiv) 6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0308] (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

[0309] (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

[0310] (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

[0311] (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

[0312] (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)acrylamide

[0313] (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

[0314] (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

[0315] (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

[0316] (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

[0317] (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

[0318] (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

[0319] (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

[0320] (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

[0321] (cxlviii) (S)-8-(Diethylamino)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0322] (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

[0323] (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

[0324] (cli)(S)-6-(4-fluorophenyl)-3-(1-hydroxypropan-2-yl)-8-(piperidin-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0325] (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

[0326] (cliii) (S)-6-cyclohexyl-3-(1-hydroxypropan-2-yl)-8-pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0327] (cliv)(S)-3-(1-hydroxypropan-2-yl)-6-(pyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0328] (clv)(S)-3-(1-hydroxypropan-2-yl)-6-(2-methylthiazol-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0329] (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

[0330] (clvii) (R)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0331] (clviii) (S)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0332] (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

[0333] (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

[0334] (clxi) (S)-3-(1-hydroxypropan-2-yl)-6-(2-methylpyrimidin-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0335] (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

[0336] (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

[0337] (clxiv) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0338] (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

[0339] (clxvi) (S)-3-(1-hydroxypropan-2-yl)-6-(6-methylpyridin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0340] (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

[0341] (clxviii) 3,8-di(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0342] (clxix) 8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0343] (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

[0344] (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

[0345] (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

[0346] (clxxiii) 3-cyclopentyl-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[2,4-d]pyrimidin-4(3H)-one

[0347] (clxxiv) 3-phenyl-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0348] (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

[0349] (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

[0350] (clxxvii) (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

[0351] (clxxviii) (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

[0352] (clxxix) 3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0353] (clxxx)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0354] (clxxxi) (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

[0355] (clxxxii) 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

[0356] (clxxxiii) 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

[0357] (clxxxiv) 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

[0358] (clxxxv) 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)-one

[0359] (clxxxvi) 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

[0360] (clxxxvii) (S)-3-(1-hydroxypropan-2-yl)-8-morpholinyl-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0361] (clxxxviii) 3-(2-Hydroxy-2-methylpropyl)-8-(piperidin-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0362] (clxxxix) (S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0363] (cxc)(S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyrimidin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0364] (cxci)(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

[0365] (cxcii) (S)-8-cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0366] (cxciii) (S)-3-(1-hydroxypropan-2-yl)-N,N-dimethyl-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidine-6-carboxamide

[0367] (cxciv)(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

[0368] (cxcv)(S)-3-(1-hydroxypropan-2-yl)-6-(2-methoxyethyl)-8(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0369] (cxcvi) (S)-3-(1-Hydroxypropan-2-yl)-8-(2-methoxyethyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one.

[0370] The compounds of Formula I or Formula Ia and pharmaceutically acceptable salts thereof can be incorporated into pharmaceutical compositions. In some embodiments, the disclosure relates to pharmaceutical compositions comprising at least one entity selected from the compounds of Formula I or Formula Ia and pharmaceutically acceptable salts thereof. In some embodiments, the disclosure relates to a pharmaceutical composition consisting essentially of at least one entity selected from the compounds of Formula I or Formula Ia and pharmaceutically acceptable salts thereof.

[0371] In some embodiments, the at least one entity selected from a compound of Formula I or Formula Ia and a pharmaceutically acceptable salt thereof may be administered in combination with at least one additional therapy. In some embodiments, the at least one additional therapy is selected from an immune checkpoint inhibitor (ICI).

[0372] In some embodiments, the at least one additional therapy is selected from anti-CTLA-4 compounds, anti-PD-1 compounds and anti-PDL-1 compounds. In some embodiments, the at least one additional therapy is selected from Pembrolizumab (Keytruda); Nivolumab (Opdivo); Ipilimumab (Yervoy); Avelumab (Bavencio); Atezolizumab (Tecentriq); Durvalumab (Imfinzi); Cemiplimab (LBTAYO); Sintilimab (Tyvyt); Toripalimab (Tuoyi); Camrclizumab (AiRuiKa); Spartalizumab; and Tislelizumab. In some embodiments, the at least one additional therapy is selected from anti-LAG-3 (lymphocyte activation gene-3) compounds; anti-TIM-3 (T cell immunoglobulin and mucin domain-3) compounds; anti-TIGIT (T cell immunoglobulin and ITIM domain) compounds; anti-VISTA (V domain lg inhibitor of T cell activation) compounds; or combinations 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.

[0373] In some embodiments, the pharmaceutical composition comprises at least one entity selected from a compound of Formula I or Formula Ia and a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients are well known to those of ordinary skill in the art and are described, by way of non-limiting example, in 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 additional therapy.

[0374] The compounds of the present disclosure, their pharmaceutically acceptable salts and / or pharmaceutical compositions comprising at least one compound selected from Formula I or Formula Ia and their pharmaceutically acceptable salts, and optionally further comprising at least one additional therapy, can be used for therapeutic treatment.

[0375] These compounds, pharmaceutically acceptable salts, additional therapies and / or pharmaceutical compositions can be administered to mammalian subjects, including humans, in a unit administration form. Suitable non-limiting examples of unit administration forms include oral administration forms and forms of administration via parenteral / systemic routes, non-limiting examples of which include inhalation, subcutaneous administration, intramuscular administration, intravenous administration, intradermal administration, and intravitreal administration.

[0376] In some embodiments, the pharmaceutical composition suitable for oral administration can be in the form of tablets, pills, powders, hard gelatin capsules, soft gelatin capsules and / or granules. In some embodiments of such pharmaceutical compositions, the compound of the present disclosure and / or the pharmaceutically acceptable salt of the compound of the present disclosure are mixed with one or more inert diluents, and the non-limiting examples of inert diluents include starch, cellulose, sucrose, lactose and silicon dioxide. In some embodiments, such pharmaceutical compositions may further include one or more materials except diluents, such as (as non-limiting examples) lubricants, colorants, coatings or varnishes. In some embodiments, such pharmaceutical compositions may further include at least one at least one additional therapy.

[0377] In some embodiments, the pharmaceutical composition for parenteral administration can be in the form of an aqueous solution, a non-aqueous solution, a suspension, an emulsion, drops, or any combination thereof. In some embodiments, such pharmaceutical compositions may include one or more of water, a pharmaceutically acceptable glycol, a pharmaceutically acceptable oil, a pharmaceutically acceptable organic ester, or other pharmaceutically acceptable solvents. In some embodiments, such pharmaceutical compositions may further include at least one additional therapy.

[0378] In some embodiments, disclosed herein is a method of inhibiting AhR, comprising administering to a subject in need thereof at least one entity selected from a compound of Formula I or Formula Ia and a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is a method of reducing AhR activity, comprising administering to a subject in need thereof at least one entity selected from a compound of Formula I or Formula Ia and a pharmaceutically acceptable salt thereof. In some embodiments, such pharmaceutical compositions may further comprise at least one additional therapy.

[0379] In some embodiments, disclosed herein is a method for treating cancer, the method comprising administering to a subject in need thereof at least one entity selected from a compound of Formula I or Formula Ia and a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is selected from liquid tumors and solid tumors. In some embodiments, the cancer is selected from breast cancer, respiratory tract cancer, brain cancer, reproductive organ cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and metastasis of any of the foregoing diseases. In some embodiments, the cancer is selected from breast cancer, pancreatic cancer, prostate cancer, and colon cancer. In some embodiments, the cancer is selected from lymphoma, sarcoma, and leukemia.

[0380] In some embodiments, disclosed herein is a method of treating cancer, the method comprising administering to a subject in need thereof at least one entity selected from a compound of Formula I or Formula Ia and a pharmaceutically acceptable salt thereof and at least one additional therapy. In some embodiments, the cancer is selected from non-small cell lung cancer (NSCLC); small cell lung cancer; head and neck squamous cell carcinoma; renal cell carcinoma; gastric adenocarcinoma; nasopharyngeal tumors; urothelial carcinoma; colorectal cancer; pleural mesothelioma; triple negative breast cancer (TNBC); esophageal tumors; multiple myeloma; gastric cancer 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 cancer; mesothelioma; gastric cancer; gastroesophageal junction cancer; metastatic melanoma; metastatic non-cutaneous melanoma; urothelial carcinoma ; diffuse large B-cell lymphoma; renal cell carcinoma; ovarian cancer, fallopian tube cancer; peritoneal tumors; extensive-stage small cell lung cancer; bladder cancer; transitional cell carcinoma; prostate tumors; 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; hypopharyngeal squamous cell carcinoma; laryngeal squamous cell carcinoma; unresectable or metastatic melanoma; biliary tract tumors; esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, glioblastoma, metastatic carcinoma, prostate cancer, solid organ cancer; gastric cancer; colon cancer; and liver cancer.

[0381] In some embodiments, disclosed herein is a method of treating an ocular disorder comprising administering to a subject in need thereof at least one entity selected from a compound of Formula I or Formula Ia and pharmaceutically acceptable salts thereof, and optionally at least one additional therapy.

[0382] With respect to the methods disclosed herein, a mode of administration (or modes of administration), a dosage (or dosages), and a pharmaceutical form (or forms) can be determined according to criteria generally considered during the establishment of a patient's treatment, such as, by way of non-limiting example, the potency of the compound and / or a pharmaceutically acceptable salt of the compound, at least one additional therapy (if present), the patient's age, the patient's weight, the severity of the patient's condition (or conditions), the patient's tolerance to treatment, and the secondary effects observed in the treatment. It is within the capabilities of the skilled artisan to determine the dosage effective to provide a therapeutic benefit for a particular mode and frequency of administration.

[0383] In some embodiments, the compound of Formula I or Formula Ia and / or its pharmaceutically acceptable salt is present in the pharmaceutical composition in an amount ranging from 5 μg to 2,000 mg. In some embodiments, the compound of the present disclosure and / or its pharmaceutically acceptable salt is present in the pharmaceutical composition in an amount ranging from 5 μg to 1,000 mg. In some embodiments, the compound of the present disclosure and / or its pharmaceutically acceptable salt is present in the pharmaceutical composition in an amount ranging from 5 μg to 500 mg. In some embodiments, the compound of the present disclosure and / or its pharmaceutically acceptable salt is present in the pharmaceutical composition in an amount ranging from 5 μg to 250 mg. In some embodiments, the compound of the present disclosure and / or its pharmaceutically acceptable salt is present in the pharmaceutical composition in an amount ranging from 5 μg to 100 mg. In some embodiments, the compound of the present disclosure and / or its pharmaceutically acceptable salt is present in the pharmaceutical composition in an amount ranging from 5 μg to 50 mg.

[0384] In some embodiments, the compounds of the present disclosure and / or their pharmaceutically acceptable salts are present in pharmaceutical compositions in an amount ranging from 1 mg to 5,000 mg. In some embodiments, the compounds of the present disclosure and / or their pharmaceutically acceptable salts are present in pharmaceutical compositions in an amount ranging from 1 mg to 3,000 mg. In some embodiments, the compounds of the present disclosure and / or their pharmaceutically acceptable salts are present in pharmaceutical compositions in an amount ranging from 1 mg to 2,000 mg. In some embodiments, the compounds of benzene and / or their pharmaceutically acceptable salts are present in pharmaceutical compositions in an amount ranging from 1 mg to 1,000 mg. In some embodiments, the compounds of the present disclosure and / or their pharmaceutically acceptable salts are present in pharmaceutical compositions in an amount ranging from 1 mg to 500 mg. In some embodiments, the compounds of the present disclosure and / or their pharmaceutically acceptable salts are present in pharmaceutical compositions in an amount ranging from 1 mg to 250 mg. In some embodiments, the compounds of the present disclosure and / or their pharmaceutically acceptable salts are present in pharmaceutical compositions in an amount ranging from 1 mg to 100 mg. In some embodiments, the compounds of the present disclosure and / or pharmaceutically acceptable salts thereof are present in the pharmaceutical composition in an amount ranging from 1 mg to 50 mg.

[0385] In some embodiments, the compounds of the present disclosure and / or pharmaceutically acceptable salts thereof are administered 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. mg, 1,700mg, 1,800mg, 1,900mg, 2,000mg, 2,100mg, 2,200mg, 2,300mg, 2,400mg, 2,50 0mg, 2,600mg, 2,700mg, 2,800mg, 2,900mg, 3,000mg, 3,100mg, 3,200mg, 3,300mg, 3,40 00 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 is present in the pharmaceutical composition.

[0386] Effective amounts and dosages can be estimated initially from in vitro assays. For example, an initial dose for use in animals can be formulated to achieve an IC value equal to or greater than that of a particular compound as measured in an in vitro assay. 50 The circulating blood or serum concentration of the active compound. Taking into account the bioavailability of the particular compound, it is well within the capabilities of the skilled person to calculate the dosage to achieve such a circulating blood or serum concentration. For guidance, the reader is referred to Fingl & Woodbury, "General Principles", Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pages 1-46, latest edition, Pergamagon Press, and references cited therein, which are incorporated herein by reference in their entirety. The initial dose can also be estimated from in vivo data, such as animal models. Animal models for testing the efficacy of compounds in treating or preventing the various diseases described in the present disclosure are well known in the art.

[0387] In some embodiments, the dosage range applied is 0.0001 or 0.001 or 0.01 mg / kg / day to 100 mg / kg / day, but may be higher or lower, depending on, among other factors, the activity of the compound, its bioavailability, mode of administration, and the various factors discussed above. The dose and interval may be adjusted individually to provide a plasma level of the compound sufficient to maintain a therapeutic or preventive effect. For example, the compound may be administered once a week, several times a week (e.g., every other day), once a day, or multiple times a day, depending, among other factors, on the mode of administration, the specific indication being treated, and the judgment of the prescribing physician. In the case of local administration or selective uptake (e.g., topical administration), the effective local concentration of this or these active compounds may not be related to the plasma concentration. Without excessive experimentation, the technician can optimize the effective local dose.

[0388] Non-limiting examples of the present disclosure include:

[0389] 1. A compound of formula I:

[0390]

[0391] and pharmaceutically acceptable salts thereof,

[0392] in:

[0393] R 1 and R 2 each of which is independently selected from optionally substituted alkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted amine, and optionally substituted heterocycloalkyl; and

[0394] R 3 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amine, cyano, halo, hydroxy, and -C(O)H.

[0395] 2. A compound of formula Ia

[0396]

[0397] or a pharmaceutically acceptable salt thereof,

[0398] in:

[0399] Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl;

[0400] Ring B is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl; and

[0401] R is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, amino, cyano, halo, hydroxy and -C(O)H.

[0402] 3. The compound of embodiment 2, or a pharmaceutically acceptable salt thereof, wherein:

[0403] Ring A is selected from optionally substituted 6-10 membered aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered cycloalkyl and optionally substituted 3-10 membered heterocycloalkyl;

[0404] Ring B is selected from optionally substituted 6-10 membered aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered cycloalkyl and optionally substituted 3-10 membered heterocycloalkyl;

[0405] R is selected from hydrogen, optionally substituted C1-C 10 alkyl, optionally substituted 6-10 membered aryl, -C(O)R', -C(O)NR'R', optionally substituted 3-10 membered cycloalkyl, -C(O)OR', optionally substituted C1-C 10 heteroalkyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H; and

[0406] Each R' is independently selected from hydrogen, optionally substituted C1-C 10 Alkyl and optionally substituted C1-C 10 Heteroalkyl.

[0407] 4. The compound of embodiment 2 or 3, or a pharmaceutically acceptable salt thereof, wherein:

[0408] Ring A is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl, wherein each 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl is independently optionally substituted by 1 to 5 R A Instances of ;

[0409] Ring B is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl, wherein each 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl is independently optionally substituted by 1 to 5 RB Instances of ;

[0410] R is selected from hydrogen, C1-C 10 alkyl, 6-10 membered aryl, -C(O)R', -C(O)NR'R', 3-10 membered cycloalkyl, -C(O)OR', C1-C 10 heteroalkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, amino, cyano, halo, hydroxyl and -C(O)H, wherein each C1-C 10 Alkyl, 6-10 membered aryl, 3-10 membered cycloalkyl, C1-C 10 Heteroalkyl, 5-10 membered heteroaryl and 3-10 membered heterocycloalkyl are independently optionally substituted by 1 to 5 R C Instances of ;

[0411] Each R' is independently selected from hydrogen, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Hydroxyalkyl and C1-C 10 heteroalkyl;

[0412] Each R A Independently selected from halo, hydroxy, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy, C1-C 10 Hydroxyalkyl and NR"R";

[0413] Each R B Independently selected from halo, hydroxy, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy, C1-C 10 Hydroxyalkyl and NR"R";

[0414] Each R C independently selected from halo, hydroxy, cyano, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 haloalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and

[0415] Each R" is independently selected from hydrogen, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Hydroxyalkyl and C1-C10 Heteroalkyl.

[0416] 5. The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from the group consisting of A Examples of substituted 3-10 membered cycloalkyl.

[0417] 6. The compound of embodiment 4 or 5, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from the group consisting of A Examples of substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0418] 7. The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from the group consisting of A Examples of substituted 6-8 membered aryl groups are:

[0419] 8. The compound as described in Example 4 or 7, or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted with 1 to 3 R A Examples of substituted phenyl groups.

[0420] 9. The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from the group consisting of A Examples of substituted 5-8 membered heteroaryl.

[0421] 10. The compound of embodiment 4 or 9, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from pyrrolyl, furanyl, furazanyl, thienyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl,

[0422] wherein each of pyrrolyl, furanyl, furazanyl, thienyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl is independently optionally substituted by 1 to 3 R A Instances of .

[0423] 11. The compound as described in any one of Embodiments 4, 9 or 10, or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted with 1 to 3 R A Examples of substituted pyridinyl.

[0424] 12. The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from the group consisting of A Examples of substituted 5-8 membered heterocycloalkyl.

[0425] 13. The compound of embodiment 4 or 12, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, aza yl, tetrahydropyranyl and tetrahydrofuranyl,

[0426] Among them, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, aza Each of tetrahydropyranyl, tetrahydrofuranyl and tetrahydropyranyl is independently optionally substituted by 1 to 3 R A Instances of .

[0427] 14. The compound of any one of embodiments 4, 12 or 13, or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted with 1 to 3 R A Examples of are substituted piperidinyl or morpholinyl.

[0428] 15. The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of B Examples of substituted 6-8 membered aryl groups are:

[0429] 16. The compound of embodiment 4 or 15, or a pharmaceutically acceptable salt thereof, wherein ring B is optionally substituted with 1 to 3 R B Examples of substituted phenyl groups.

[0430] 17. The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of B Examples of are substituted benzodioxolyl and 5-8 membered heteroaryl.

[0431] 18. The compound of embodiment 4 or 17, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from benzodioxolyl, pyrrolyl, furanyl, furazanyl, thienyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyridonyl and pyrimidinyl,

[0432] wherein each of benzodioxolyl, pyrrolyl, furanyl, furazanyl, thienyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl is independently optionally substituted by 1 to 3 R B Instances of .

[0433] 19. The compound of any one of embodiments 4, 17 or 18, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl and thienyl,

[0434] wherein each of pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl and thienyl is independently optionally substituted by 1 to 3 R B Instances of .

[0435] 20. The compound of any one of embodiments 4 to 19, or a pharmaceutically acceptable salt thereof, wherein:

[0436] Each R A Independently selected from halo, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy, C1-C 10 Haloalkoxy and NR"R";

[0437] Each R B Independently selected from halo, C1-C 10 Alkyl and C1-C 10 Haloalkyl;

[0438] Each R C independently selected from halo, hydroxy, cyano, C1-C 10 Alkyl, C1-C 10 Alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, and 6-8 membered aryl; and

[0439] Each R" is independently selected from hydrogen and C1-C 10 alkyl.

[0440] 21. A compound as described in any one of embodiments 2 to 4 and 7 to 20, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from

[0441] 22. A compound as described in any one of embodiments 2 to 6 and 15 to 20, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from

[0442] 23. A compound as described in any one of embodiments 2 to 4 and 7 to 20, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from

[0443] 24. A compound as described in any one of embodiments 2 to 4 and 7 to 20, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from

[0444] 25. The compound of any one of embodiments 2 to 14 and 20, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from

[0445] 26. A compound as described in any one of embodiments 2 to 4 and 7 to 20, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from

[0446] 27. A compound as described in any one of embodiments 2 to 26, or a pharmaceutically acceptable salt thereof, wherein R is selected from methyl,

[0447] 28. A compound as described in any one of embodiments 2 to 27, or a pharmaceutically acceptable salt thereof, wherein R is selected from methyl,

[0448] 29. At least one entity selected from the following compounds and pharmaceutically acceptable salts thereof:

[0449] (i) (S)-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0450] (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;

[0451] (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;

[0452] (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;

[0453] (v) (S)-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0454] (vi) (S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0455] (vii) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0456] (viii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0457] (ix) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0458] (x) 6,8-di(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0459] (xi) (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0460] (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;

[0461] (xiii) 6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0462] (xiv) 8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0463] (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;

[0464] (xvi) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0465] (xvii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0466] (xviii) 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0467] (xix) 3-(2-hydroxy-2-methylpropyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0468] (xx) (S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0469] (xxi) 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0470] (xxii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0471] (xxiii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0472] (xxiv) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0473] (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;

[0474] (xxvi) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-phenylpyrido[3,4-d]pyrimidin-4(3H)-one;

[0475] (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;

[0476] (xxviii) 3-methyl-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0477] (xxix) rac-6-(4-chlorophenyl)-3-((trans)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0478] (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;

[0479] (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;

[0480] (xxxii) rac-6-(4-chlorophenyl)-3-((cis)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0481] (xxxiii) (R)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0482] (xxxiv) (S)-3-(3-hydroxy-3-methylbutan-2-yl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0483] (xxxv) (S)-6,8-bis(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0484] (xxxvi) (S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0485] (xxxvii) (S)-8-(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0486] (xxxviii) 6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(2-hydroxy-2-methylpropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0487] (xxxix) (R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0488] (xl) (S)-3-(1-(benzyloxy)propan-2-yl)-8-(3-fluorophenyl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0489] (xli) (R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0490] (xlii) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0491] (xliii) (S)-3-(1-hydroxypropan-2-yl)-6-morpholinyl-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0492] (xliv)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0493] (xlv)(S)-3-(1-methoxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0494] (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;

[0495] (xlvii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0496] (xlviii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0497] (xlix)(8)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0498] (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

[0499] (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

[0500] (lii) (S)-5-(3-(1-hydroxypropan-2-yl)-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)picolinic acid methyl ester

[0501] (liii) (S)-3-(1-hydroxypropan-2-yl)-6-(isothiazol-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0502] (liv) 3-(2-hydroxy-2-methylpropyl)-8-(isothiazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0503] (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

[0504] (lvi) (S)-3-(1-hydroxypropan-2-yl)-6,8-di(isothiazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0505] (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

[0506] (lviii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0507] (lix) 3-(2-hydroxy-2-methylpropyl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0508] (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

[0509] (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

[0510] (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

[0511] (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

[0512] (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

[0513] (lxv) (S)-3-(1-hydroxypropan-2-yl)-6-(4-methylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0514] (lxvi) (S)-6-(2-cyclopropylthiazol-5-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0515] (lxvii) (S)-3-(1-hydroxypropan-2-yl)-6-(2-isopropylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0516] (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

[0517] (lxix) (S)-3-(1-hydroxypropan-2-yl)-6,8-bis(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0518] (lxx) 6-(4-chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one.

[0519] (lxxi) 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0520] (lxxii) 3-(2-hydroxyethyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0521] (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

[0522] (lxxiv) (S)-6-(6-cyclopropylpyridin-3-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0523] (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

[0524] (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

[0525] (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

[0526] (lxxviii) (S)-6,8-bis(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0527] (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

[0528] (lxxx) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0529] (lxxxi) 6-(6-cyclopropylpyridin-3-yl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0530] (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

[0531] (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)-one

[0532] (lxxxiv) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0533] (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

[0534] (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

[0535] (lxxxvii) 3-(2-Hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0536] (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

[0537] (lxxxix) (S)-3-(1-hydroxypropan-2-yl)-6-(2-methylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0538] (xc) (S)-6-(4-chlorophenyl)-8-(3-chlorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0539] (xci)(S)-3-(1-hydroxypropan-2-yl)-6-(piperidin-1-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0540] (xcii) 3-(2-hydroxy-2-methylpropyl)-8-(isothiazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0541] (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

[0542] (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

[0543] (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

[0544] (xcvi) (3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0545] (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

[0546] (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

[0547] (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

[0548] (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)-one

[0549] (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

[0550] (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

[0551] (ciii) (R)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0552] (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

[0553] (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

[0554] (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

[0555] (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

[0556] (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

[0557] (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

[0558] (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

[0559] (cxi) (R)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trichloromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0560] (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

[0561] (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

[0562] (cxiv) 6-(4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0563] (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

[0564] (cxvi) (S)-methyl 2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoate

[0565] (cxvii) 6-(4-chlorophenyl)-3-(4-hydroxy-1-methylpyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0566] (cxviii) 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0567] (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

[0568] (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

[0569] (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

[0570] (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

[0571] (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

[0572] (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

[0573] (cxxv) (R)-3-(2-Hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trichloromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0574] (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

[0575] (cxxvii) (S)-3-(2-Hydroxypropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0576] (cxxviii) (R)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0577] (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

[0578] (cxxx)(S)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0579] (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

[0580] (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

[0581] (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

[0582] (cxxxiv) 6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0583] (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

[0584] (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

[0585] (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

[0586] (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

[0587] (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)acrylamide

[0588] (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

[0589] (cxli) 3-(2-hydroxy-2-methylpropyl)-2-(1H-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0590] (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

[0591] (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

[0592] (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

[0593] (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

[0594] (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

[0595] (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

[0596] (cxlviii) (S)-8-(Diethylamino)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0597] (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

[0598] (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

[0599] (cli)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(piperidin-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0600] (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

[0601] (cliii)(S)-6-cyclohexyl-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0602] (cliv)(S)-3-(1-hydroxypropan-2-yl)-6-(pyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0603] (clv)(S)-3-(1-hydroxypropan-2-yl)-6-(2-methylthiazol-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0604] (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

[0605] (clvii) (R)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0606] (clviii) (S)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0607] (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;

[0608] (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;

[0609] (clxi) (S)-3-(1-hydroxypropan-2-yl)-6-(2-methylpyrimidin-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0610] (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;

[0611] (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;

[0612] (clxiv) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0613] (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;

[0614] (clxvi) (S)-3-(1-hydroxypropan-2-yl)-6-(6-methylpyridin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0615] (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;

[0616] (clxviii) 3,8-di(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0617] (clxix) 8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0618] (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;

[0619] (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;

[0620] (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;

[0621] (clxxiii) 3-cyclopentyl-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0622] (clxxiv) 3-phenyl-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0623] (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;

[0624] (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;

[0625] (clxxvii) (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;

[0626] (clxxviii) (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

[0627] (clxxix) 3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0628] (clxxx) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0629] (clxxxi) (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;

[0630] (clxxxii) 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;

[0631] (clxxxiii) 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;

[0632] (clxxxiv) 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;

[0633] (clxxxv) 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)-one;

[0634] (clxxxvi) 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;

[0635] (clxxxvii) (S)-3-(1-hydroxypropan-2-yl)-8-morpholinyl-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0636] (clxxxviii) 3-(2-hydroxy-2-methylpropyl)-8-(piperidin-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0637] (clxxxix) (S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0638] (cxc)(S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyrimidin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0639] (cxci)(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;

[0640] (cxcii) (S)-8-cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido [13,4-d]pyrimidin-4(3H)-one;

[0641] (cxciii) (S)-3-(1-hydroxypropan-2-yl)-N,N-dimethyl-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidine-6-carboxamide;

[0642] (cxciv) (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;

[0643] (cxcv)(S)-3-(1-hydroxypropan-2-yl)-6-(2-methoxyethyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; and

[0644] (cxcvi) (S)-3-(1-Hydroxypropan-2-yl)-8-(2-methoxyethyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one.

[0645] (cxcvii)

[0646] 30. A pharmaceutical composition comprising at least one entity selected from the compound of any one of embodiments 1 to 29 and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

[0647] 31. A method of treating a disease or condition mediated by AhR signaling in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one entity selected 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.

[0648] 32. A method of treating a disease or condition associated with abnormal AhR signaling in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one entity selected 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.

[0649] 33. The method of embodiment 31 or 32, wherein the disease is selected from cancer.

[0650] 34. The method of embodiment 31 or 32, wherein the disease is selected from liquid tumors and solid tumors.

[0651] 35. The method of any one of embodiments 31 to 34, wherein the disease is selected from breast cancer, respiratory tract cancer, brain cancer, reproductive organ cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and metastasis of any of the foregoing diseases.

[0652] 36. The method of any one of embodiments 31 to 35, wherein the disease is selected from breast cancer, pancreatic cancer, prostate cancer, and colon cancer.

[0653] 37. The method of any one of embodiments 31 to 34, wherein the disease is selected from lymphoma, sarcoma, melanoma, glioblastoma, and leukemia.

[0654] 38. A method of inhibiting cancer cell proliferation mediated by AhR signaling in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one entity selected 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.

[0655] 39. A method of inhibiting tumor cell invasion or metastasis mediated by AhR signaling in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one entity selected 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.

[0656] 40. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of i) at least one entity selected 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.

[0657] 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.

[0658] 42. The method of embodiment 40, wherein the administration of at least one entity selected from the compound of any one of embodiments 1 to 29 and pharmaceutically acceptable salts thereof or at least one pharmaceutical composition of embodiment 30 is initiated prior to the administration of the at least one additional therapy.

[0659] 43. The method of embodiment 40, wherein the at least one entity selected from the compound 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 the administration of the at least one additional therapy.

[0660] 44. The method of embodiment 40, wherein the at least one entity selected from the compound of any one of embodiments 1 to 29 and pharmaceutically acceptable salts thereof or at least one pharmaceutical composition of embodiment 30 is administered simultaneously with the administration of the at least one additional therapy.

[0661] 45. The method of any one of embodiments 40 to 44, wherein the at least one additional therapy is selected from a checkpoint inhibitor.

[0662] 46. ​​The method of embodiment 45, wherein the subject is intolerant, unresponsive and / or poorly responsive to the at least one additional therapy when administered alone.

[0663] 47. The method of embodiment 46, wherein the at least one additional therapy is selected from checkpoint inhibitors targeting CTLA-4, PD-1, PD-L1, LAG-3, TIM-3, TIGIT and / or VISTA.

[0664] 48. The method of embodiment 46, wherein the at least one additional therapy is selected from checkpoint inhibitors targeting CTLA-4, PD-1 and / or PD-L1.

[0665] 49. The method of embodiment 46, wherein the at least one additional therapy is selected from a cytotoxic T-lymphocyte-associated antigen 4 pathway inhibitor.

[0666] 50. The method of embodiment 49, wherein the cytotoxic T-lymphocyte-associated antigen 4 pathway inhibitor is selected from anti-CTLA-4 antibodies.

[0667] 51. The method of embodiment 50, wherein the anti-CTLA-4 antibody is ipilimumab.

[0668] 52. The method of embodiment 46, wherein the at least one additional therapy is selected from a programmed death-1 pathway inhibitor.

[0669] 53. The method of embodiment 52, wherein the programmed death-1 pathway inhibitor is selected from an anti-PD-1 antibody.

[0670] 54. The method of embodiment 52, wherein the anti-PD-1 antibody is nivolumab.

[0671] 55. The method of embodiment 52, wherein the anti-PD-1 antibody is pembrolizumab.

[0672] 56. The method of embodiment 52, wherein the anti-PD-1 antibody is cemiplimab

[0673] 57. The method of embodiment 52, wherein the anti-PD-1 antibody is camrelizumab.

[0674] 58. The method of embodiment 52, wherein the anti-PD-1 antibody is sintilimab.

[0675] 59. The method of embodiment 52, wherein the anti-PD-1 antibody is spartalizumab.

[0676] 60. The method of embodiment 52, wherein the anti-PD-1 antibody is tislelizumab.

[0677] 61. The method of embodiment 52, wherein the anti-PD-1 antibody is BCD-100.

[0678] 62. The method of embodiment 52, wherein the anti-PD-1 antibody is JS001.

[0679] 63. The method of embodiment 52, wherein the programmed death-1 pathway inhibitor is selected from an anti-PD-L1 antibody.

[0680] 64. The method of embodiment 63, wherein the anti-PD-L1 antibody is atezolizumab.

[0681] 65. The method of embodiment 63, wherein the anti-PD-L1 antibody is avelumab.

[0682] 66. The method of embodiment 63, wherein the anti-PD-L1 antibody is durvalumab.

[0683] 67. The method of embodiment 63, wherein the anti-PD-L1 antibody is KN035.

[0684] 68. The method of embodiment 46, wherein the at least one additional therapy is selected from lymphocyte activation gene-3 (LAG-3) inhibitors.

[0685] 69. The method of embodiment 68, wherein the LAG-3 inhibitor is selected from an anti-LAG-3 antibody.

[0686] 70. The method of embodiment 46, wherein the at least one additional therapy is selected from T cell immunoglobulin and a mucin domain-containing-3 (TIM-3) inhibitor.

[0687] 71. The method of embodiment 70, wherein the TIM-3 inhibitor is selected from an anti-TIM-3 antibody.

[0688] 72. The method of embodiment 46, wherein the at least one additional therapy is selected from T cell immunoglobulin and ITIM domain (TIGIT) inhibitors.

[0689] 73. The method of embodiment 72, wherein the TIGIT inhibitor is selected from a TIGIT antibody.

[0690] 74. The method of embodiment 46, wherein the at least one additional therapy is selected from V-domain Ig inhibitor of T-cell activation (VISTA) inhibitors.

[0691] 75. The method of embodiment 74, wherein the VISTA inhibitor is selected from an anti-VISTA antibody.

[0692] 76. The method of any one of embodiments 40 to 75, wherein the cancer is selected from non-small cell lung cancer (NSCLC); small cell lung cancer; squamous cell carcinoma of the head and neck; renal cell carcinoma; gastric adenocarcinoma; nasopharyngeal tumors; urothelial carcinoma; colorectal cancer; pleural mesothelioma; triple negative breast cancer (TNBC); esophageal tumors; multiple myeloma; gastric cancer and gastroesophageal junction cancer; melanoma; Hodgkin's lymphoma; hepatocellular carcinoma; lung cancer; head and neck cancer; non-Hodgkin's lymphoma; metastatic clear cell renal carcinoma; squamous cell lung cancer; mesothelioma; gastric cancer; gastroesophageal junction cancer; metastatic melanoma; metastatic non-cutaneous melanoma Pigmented tumors; urothelial carcinoma; diffuse large B-cell lymphoma; renal cell carcinoma; ovarian cancer, fallopian tube cancer; peritoneal tumors; extensive-stage small cell lung cancer; bladder cancer; transitional cell carcinoma; prostate tumors; 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; hypopharyngeal squamous cell carcinoma; laryngeal squamous cell carcinoma; unresectable or metastatic melanoma; biliary tract tumors; esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, glioblastoma, metastatic carcinoma, prostate cancer, solid organ cancer; gastric cancer; colon cancer; and liver cancer.

[0693] Examples

[0694] The following non-limiting examples and data show various aspects and features related to the compounds and / or methods of the present disclosure, including the preparation of various compounds, such as those obtainable by the synthetic methods described herein. Compared to the prior art, in some embodiments, the compounds and / or methods of the present invention provide surprising, unexpected and contrary results and data. Although the practicality of the present disclosure is demonstrated by using several compounds and parts / groups that can be used therewith, it will be understood by those skilled in the art that various other compounds, parts and / or groups commensurate with the scope of the present disclosure can obtain comparable results.

[0695] Example 1. Synthesis of pyridopyrimidone compounds

[0696] Compounds encompassed within the present disclosure can be prepared by the procedures outlined in Scheme 1 and described in the Examples below.

[0697]

[0698] Scheme I

[0699] Preparation of tert-butyl N-[(1S)-2-benzyloxy-1-methyl-ethyl]carbamate:

[0700]

[0701] To a solution of tert-butyl N-[(1S)-2-hydroxy-1-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. 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) were added to the mixture at 0°C, and the mixture was stirred at 25°C for 3 hours. The reaction mixture was quenched by adding MeOH (50 mL) at 0°C, 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 = 1 / 0 to 0 / 1) to give the title compound (12 g, 45.22 mmol, 79% yield) 1H NMR (400 MHz, CDCl3), δ 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).

[0702] Preparation of (2S)-1-benzyloxypropan-2-amine trifluoroacetic acid:

[0703]

[0704] To a solution of tert-butyl N-[(1S)-2-benzyloxy-1-methyl-ethyl]carbamate (9, 12 g, 45.22 mmol, 1 eq) in DCM (100 mL) was added TFA (30.80 g, 270.12 mmol, 20 mL, 5.97 eq) dropwise. The mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give the title compound (10, 10 g, 35.81 mmol, 79.18% yield, TFA) which was used directly.

[0705] Preparation of (S)-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (1)

[0706] Step 1. Preparation of (S)-3-amino-2,6-dichloro-N-(1-hydroxypropan-2-yl)isonicotinamide (Intermediate A1):

[0707]

[0708] A mixture of 3-amino-2,6-dichloroisonicotinic acid (2.0 g, 9.66 mmol) and (S)-2-aminopropan-1-ol (reactant 1, 0.80 g, 10.63 mmol) was 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 solution, then with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography with ethyl acetate / hexane to give the title compound (1.82 g, 6.89 mmol, 71% yield). 1 H NMR (CH3OH-d4, 400MHz) δ1.21 (3H, d, J=6.8Hz), 3.58-3.56 (2H, m), 4.17-4.12 (1H, m), 7.49 (1H, s); MS (m / z): 265.1[M+H] + .

[0709] Table 2 lists intermediates prepared via procedures similar to those described in Step 1 above.

[0710]

[0711]

[0712]

[0713]

[0714] Preparation of 3-amino-2,6-dichloro-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)isonicotinamide (A16).

[0715]

[0716] 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 with EtOAc (30 mL x 2). The combined organic phases were washed with brine (100 mL) and concentrated in vacuo 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 an off-white solid. The crude product was used in the next step without purification. 1 H-NMR (400MHz, CD3OD): δ H ppm7.49 (s, 1H), 4.28-4.34 (m, 2H), 4.10-4.17 (m, 1H), 4.02 (dd, J=10.0Hz , J=4.4Hz, 1H), 3.73-3.78 (m, 1H), 3.65-3.70 (m, 1H); MS (m / z): 290.0[M+H] + .

[0717] Step 2. Preparation of (S)-6,8-dichloro-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate B1):

[0718]

[0719] To (S)-3-amino-2,6-dichloro-N-(1-hydroxypropyl-2-yl)isonicotinamide (A1, 2.54 g, 9.66 mmol) in a flask was added triethyl orthoformate (20 mL). Concentrated hydrochloric acid (0.8 mL, 9.7 mmol) was slowly added dropwise 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 give the title compound (B1, 1.82 g, 6.64 mmol, 69% yield). 1H NMR (CH3OH-d4, 400MHz) δ1.51 (3H, d, J=7.1Hz), 3.80 (1H, dd, J=11.9, 4.2Hz), 3.92 (1H, d d, J=11.9, 6.9Hz), 4.93-4.88 (1H, m), 8.05 (1H, s), 8.45 (1H, s); MS (m / z): 274.0 [M+H]+.

[0720] Preparation of 3-[(1S)-2-benzyloxy-1-methyl-ethyl]-6,8-dichloro-pyrido[3,4-d]pyrimidin-4-one (Intermediate B11)

[0721]

[0722] At 0 ° C, formic acid (18.94g, 411.41mmol, 15.52mL, 1.5 equivalents) was added dropwise to acetoacetate (28g, 274.27mmol, 25.69mL, 1 equivalent) and stirred at 60 ° C for 2 hours under N2 atmosphere. The solution was obtained as a colorless liquid (41mL, 6.65M) and was used in the next step without further purification. To a solution of 3-amino-N-[(1S)-2-benzyloxy-1-methyl-ethyl]-2,6-dichloro-pyridine-4-carboxamide (A11, 4.5g, 12.70mmol, 1 equivalent) in THF (50mL) was added acetic acid formoyl ester solution (6.65M, 41mL, 21.47 equivalents) and stirred at 60 ° C for 30min. The mixture was then stirred at 100 ° C for 9.5 hours. LCMS showed that the 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 saturated NaHCO (200 mL), water (50 mL) and brine (50 mL) successively, dried over Na SO, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give the title compound (B11, 2.4 g, 6.59 mmol, 51.88% yield). 1H NMR (400MHz, CDCl3) δppm 1.56 (d, J=7.2Hz, 3H), 3.65-3.79 (m, 2H), 4.50 (q, J=12.4, 18.8Hz, 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.

[0723] Table 3 lists intermediates prepared via procedures similar to those described above for the synthesis of intermediate Bl.

[0724]

[0725]

[0726]

[0727]

[0728] Preparation of (S)-6,8-dichloro-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (B10).

[0729]

[0730] 4-Methylbenzenesulfonic acid (141.46 mg, 821.46 mmol) was added to a mixture of (S)-3-amino-2,6-dichloro-N-(1-hydroxy-3-methylbutyl-2-yl)isonicotinamide (1.2 g, 4.11 mmol) in trimethyl orthoformate (10 mL) and degassed and purged 3 times with nitrogen. The mixture was stirred at 120 ° C for 8 hours under a nitrogen atmosphere. TLC showed that the starting reactants remained and two new spots were formed. The solvent was evaporated and the residue was absorbed in ethyl acetate (20 mL), washed three times with brine (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by preparative HPLC to give the title compound (S)-6,8-dichloro-3-(1-hydroxy-3-methylbutyl-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (600 mg, 1.99 mmol, 48% yield). 1 H-NMR (400MHz, DMSO-d6): δ Hppm 8.60 (s, 1H), 8.05 (s, 1H), 5.02 (d, 1=3.2Hz, 1H), 4.19-4.56 (m, 1H), 3.85-3.97 (m, 1H), 3.74 (q, J=11.8 Hz, J=3.4Hz, 1H), 2.23-2.38 (m, 1H), 1.04 (d, J=6.6Hz, 3H), 0.75 (d, J=6.6Hz, 3H); MS (m / z): 302.0[M+H] + ; 90% purity.

[0731] Step 3. Preparation of (S)-6-chloro-8-(5-fluoropyridin-3-yl)-3-(1-fluoro-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate C1):

[0732]

[0733] A mixture of (S)-6,8-dichloro-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (B1, 0.10 g, 0.37 mmol), (5-fluoropyridin-3-yl)boric 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) was purged with argon in a sealed tube. 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 diatomaceous earth and the diatomaceous earth pad was washed with ethyl acetate and the filtrate was concentrated to dryness. The residue was purified by silica gel chromatography with methanol / dichloromethane to give the title compound (C1, 0.078 g, 0.19 mmol, 53% yield). 1H NMR (DMSO-d6, 300MHz): δ1.41 (3H, d, J = 7.0Hz), 3.69-3.62 (1H, m), 3.82-3.74 (1H, m), 4.89-4.83 (1H, m), 5.06 (1 H, t, J=5.6Hz), 8.12 (1H, s), 8.38 (1H, ddd, J=10.2, 2.8, 1.7Hz), 8.60 (1H, s), 8.73 (1H, d, J=2.8Hz), 9.14 (1H, s). ; MS(m / z): 335.1[M+H]+.

[0734] Table 4 lists intermediates prepared via procedures similar to those described in Step 3 above.

[0735]

[0736]

[0737]

[0738]

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747] Step 4. Preparation of (S)-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (1):

[0748]

[0749] A mixture of (S)-6-chloro-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (C1, 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) was purged with argon in a sealed tube. 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 the filtrate was evaporated. The residue was purified by silica gel chromatography with methanol / dichloromethane to give the title compound (0.022 g, 0.047 mmol, 68% yield). 1H NMR (DMSO-d6, 400MHz): δ1.44 (3H, d, J = 7.0Hz), 3.72-3.66 (1H, m), 3.84-3.78 (1H, m), 4.91 (1H, s), 5.08 (1H, t, J = 5.6Hz), 7.53 (2H, d, J = 8.4Hz), 8. 43 (2H, d, J = 8.6Hz), 8.53 (1H, ddd, J = 10.3, 2.9, 1.7Hz), 8.60 (2H, d, J = 3. 7Hz), 8.73 (1H, d, J=2.8Hz), 9.29 (1H, s); MS (m / z): 461.1[M+H]+; >99% purity.

[0750] Table 5 lists compounds prepared via a procedure similar to that described for 1 by replacing reactants 1, 2, and 3 with the indicated groups.

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758]

[0759]

[0760]

[0761]

[0762]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

[0788]

[0789]

[0790]

[0791]

[0792]

[0793]

[0794]

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822] Preparation of 3-((S)-1-hydroxypropan-2-yl)-8-(1-methylpiperidin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0823]

[0824] To a solution of (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 (60 mg, 0.135 mmol) in EtOH (1 mL) under N2 was added PtO2 (15 mg, 0.088 mmol). The flask was degassed and subjected to H2 gas in a balloon. After overnight, the reaction mixture was filtered through Filtered, washed thoroughly with methanol, concentrated and purified by reverse phase chromatography eluting with H2O and 0.1% formic acid in acetonitrile to give the desired product as a mixture of diastereomers (4 mg, 7%). 1 H NMR (CH3OH-d4, 400MHz): δ H 1.29 (1H, s), 1.54 (4H, d, J = 7.1Hz), 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 = 8.2Hz), 8.47 (1H, s), 8.60 (1H, s), 8.80 (1H, d, J = 8.2Hz), 9.51 (1H, s). MS(m / z):448.2[M+H] + ;>90% purity.

[0825] Preparation of (S)-3-(1-hydroxypropan-2-yl)-6-morpholinyl-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (43)

[0826]

[0827] To (S)-6-chloro-3-(1-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) was added dimethylformamide (2.0 ml) followed by morpholine (0.038 g, 0.38 mmol) in a sealed tube. 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 at 120°C for another 24 hours. The reaction mixture was cooled to room temperature and then partitioned between water and ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography using methanol / dichloromethane to give the title compound (0.026 g, 0.071 mmol, 37% yield). 1 H NMR (DMSO-d6, 400MHz): δ1.38 (3H, d, J = 7.04Hz), 3.58-3.65 (5H, m), 3.76 (5 H, t, J=4.80Hz), 4.82-4.87 (1H, m), 7.30 (1H, s); 5.03 (1H, s), 7.52 (1H, dd, J=7.96; 4.81Hz), 8.23 ​​(1H, s), 8.46 (1H, dt, J=7.97; 1.97Hz), 8.63 (1H, dd, J=4.79; 1.75Hz), 9.26 (1H, d, J=2.11Hz); MS (m / z): 368.2 [M+H]+; 93.6% purity.

[0828] The compounds listed in Table 6 below were prepared according to a method similar to that described in 43 above:

[0829]

[0830] Preparation of (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(4-(trifluoromethoxy)-phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (44):

[0831] Step 1. Preparation of (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (C23):

[0832]

[0833] Into a resealable Schlenk tube (screw cap test tube) was added CuI (4 mg, 0.02 mmol), imidazole (25 mg, 0.37 mmol), cesium carbonate (250 mg, 0.77 mmol) and a stirring bar. The tube was degassed, and then (S)-6,8-dichloro-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (100 mg, 0.37 mmol), 1,10-phenanthroline (7 mg, 0.04 mmol) and anhydrous dioxane (2 mL) were added under a stream of argon. The reaction tube was degassed and backfilled with argon, and then stirred 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 diatomaceous earth plug, 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 (CH2Cl2 / MeOH) to give the title compound (C23, 20 mg, 0.06 mmol, 18% yield). 1 H NMR (CHCl3-d3 with 10% CH3OH-d4, 400 MHz): δH 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.

[0834] Step 2. Preparation of (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (44):

[0835]

[0836] (S)-6-Chloro-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (C23, 30 mg, 0.1 mmol) and (4-(trifluoromethoxy)phenyl)boronic acid (30 mg, 0.15 mmol) were dissolved in 1 mL of toluene-EtOH (2:1), and sodium carbonate (42 mg, 0.4 mmol) was added. The suspension was degassed and refilled with argon (3 cycles). Tetrakis(triphenylphosphine)palladium (12 mg, 0.01 mmol) 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 cooled 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 (CH2Cl2 / MeOH) followed by C18 column to give the TFA salt of (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, which was washed with saturated Na2CO3 to give the free base of the title compound 44 (11 mg, 0.026 mmol, 26% yield). 1 H NMR (CH3OH-d4, 400MHz): δ1.56 (3H, d, J=7.1Hz), 3.86 (1H, dd, J=11.9, 4.3Hz), 3.97 (1H, dd, J=11.9, 6.9Hz), 5.02-4.97 (1H , m), 7.16 (1H, s), 7.42 (2H, d, J = 8.4Hz), 8.28 (2H, d, J = 8.7Hz), 8.36 (1H, s), 8.50 (2H, s), 9.14 (1H, s); MS (m / z): 432.2[M+H] + ; Purity 98%.

[0837] Preparation of (S)-3-(1-methoxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one (45)

[0838]

[0839] (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one (17, 20 mg, 0.05 mmol) was dissolved in anhydrous THF and the resulting solution was cooled with an ice-water bath. t-BuOK (6 mg, 0.05 mmol) was then added followed by CH3I (8 mg, 0.05 mmol). The reaction mixture was stirred at 0°C for 1 hour. The reaction was quenched by the addition of methanol and diluted with EtOAc. The solution was washed with water, brine, dried over Na2SO4, concentrated and purified by HPLC to give the 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 saturated Na2CO3 aqueous solution to give the free base 45 of the title compound. (2 mg, 0.005 mmol, 10% yield). 1 H NMR (CH3OH-d4, 400MHz): δ1.55 (3H, d, J = 7.1Hz), 2.41 (3H, s), 3.36 (3H, s), 3.68 (1H , dd, J=10.5, 4.2Hz), 3.85 (1H, dd, J=10.4, 7.2Hz), 5.14 (1H, d, J=7.3Hz), 7.33 (2H, d , J=7.9Hz), 7.59 (1H, dd, J=8.0, 4.9Hz), 8.09 (2H, d, J=8.0Hz), 8.39 (1H, s), 8.50 (1H , s), 8.61 (1H, s), 8.70 (1H, d, J=8.0Hz), 9.39 (1H, s); MS (m / z): 387.1[M+H]+; purity 97%.

[0840] Preparation of (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (46)

[0841]

[0842] (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (11, 50 mg, 0.15 mmol) was dissolved in toluene. The solution was degassed and then Pd(dppf)Cl2.CH2Cl2 (13 mg, 0.016 mmol), LiCl (26 mg, 4 eq), CuI (6 mg, 0.032 mmol) and 2-(tributyltinyl)-5-(trifluoromethyl)pyridine (83 mg, 0.19 mmol) were added. The solution was degassed again and stirred at 80°C overnight. LCMS monitoring of the reaction mixture showed incomplete conversion to the desired product, so 30 mg of CuI was added and the reaction was allowed to proceed at 80°C for another 6 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc. The solution was washed with water, brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (CH2Cl2 / MeOH) followed by C18 column chromatography to give the TFA salt of (S)-3-(1-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 saturated aqueous Na2CO3 to give the free base of the title compound (8 mg, 0.019 mmol, 12% yield) 1 H NMR (CH3OH-d4, 400MHz): δ1.56 (3H, d, J=7.1Hz), 3.85 (1H, dd, J=11.9, 4.3Hz), 3.96 (1H, dd, J=11.9, 6.9Hz), 5.01-4.96 (1H, m), 7.60 (1H, dd, J=8.0, 4.9 Hz), 8.24 (1H, d, J = 8.5Hz), 8.46 (1H, s), 8.63 (1H, d, J = 4.9Hz), 8.74-8.70 (2 H, m), 8.99 (1H, s), 9.13 (1H, 8), 9.41 (1H, s); MS (m / z): 428.1 [M+H]+; purity 99%.

[0843] Preparation of (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (47):

[0844]

[0845] (S)-6-Chloro-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (C1, 50 mg, 0.15 mmol) was dissolved in toluene and degassed, then Pd(dppf)Cl2.CH2Cl2 (24 mg, 0.18 mg), LiCl (26 mg, 0.6 mmol), CuI (29 mg, 0.15 mmol) and 2-(tributyltinyl)-5-(trifluoromethyl)pyridine (79 mg, 0.18 mmol) were added. 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. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (CH2Cl2 / MeOH) followed by C18 column to give the 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 saturated Na2CO3 to give the free base of the title compound (19 mg, 0.04 mmol, 25% yield). 1 H NMR (CH3OH-d4, 400MHz): δH 1.56 (3H, d, J = 7.1Hz), 3.85 (1H, dd, J = 11.9, 4.3Hz), 3.96 (1H, dd, J = 11.9, 6.9Hz), 5.01-4.96 (1H, m), 7.60 (1H, dd, J = 8.0, 4.9Hz), 8.24 (1H , d, J=8.5Hz), 8.46 (1H, s), 8.63 (1H, d, J=4.9Hz), 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%.

[0846] Compounds prepared in a manner similar to 47 are listed in Table 7 below:

[0847]

[0848]

[0849]

[0850] Preparation of 8-(3-fluorophenyl)-3-[(1S)-2-hydroxy-1-methyl-ethyl]-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4-one (48)

[0851]

[0852] A mixture of 3-[(1S)-2-benzyloxy-1-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 H2 (15 psi) 3 times, and then the mixture was stirred at 80 ° C under H2 atmosphere for 15 hours. LCMS showed that the 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 preparative TLC (SiO2, petroleum ether / ethyl acetate=1:1) to give the title compound (47 mg, 120.69 umol, 36.17% yield) 1 H NMR (400MHz, DMSO-d6) δppm 1.43 (d, J=6.8Hz, 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=5.6Hz, 1H), 7.33-7.37 ( m, 3H), 7.59 (q, J=7.6, 14.0Hz, 1H), 8.03-8.09 (m, 2H), 8.16 (d, J=8.4Hz, 2H), 8.46 (s, 1H), 8.53 (s, 1H); MS: M+H+, 390.1; 98% purity.

[0853] Preparation of 8-(3-fluorophenyl)-3-[(1S)-2-hydroxy-1-methyl-ethyl]-6-[4-(trifluoromethoxy)phenyl]pyrido[3,4-d]pyrimidin-4-one (49)

[0854] Step 1. Preparation of 3-[(1S)-2-benzyloxy-1-methyl-ethyl]-8-(3-fluorophenyl)-6-[4-(trifluoromethoxy)phenyl]pyrido[3,4-d]pyrimidin-4-one (precursor 1)

[0855]

[0856] To a solution of 3-[(1S)-2-benzyloxy-1-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 NaCO (460.10 mg, 4.34 mmol, 4 eq) and Pd(PPh) (125.41 mg, 108.52 umol, 0.1 eq). The mixture was absorbed into a microwave tube. The sealed tube was heated at 100 °C for 1 h under microwave. LCMS showed that the 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 = 1 / 0 to 0 / 1) to give the title compound (400 mg, 727.92 umol, 67.07% yield). MS: M+H+, 550.1.

[0857] Step 2. Preparation of 8-(3-fluorophenyl)-3-[(1S)-2-hydroxy-1-methyl-ethyl]-6-[4-(trifluoromethoxy)phenyl]pyrido[3,4-d]pyrimidin-4-one (49)

[0858]

[0859] To a solution of 3-[(1S)-2-benzyloxy-1-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 under H2 (15 psi) for 6 hours. LCMS showed that the expected 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 preparative TLC (SiO2, petroleum ether / ethyl acetate = 1:1) to give the title compound 49 (22 mg, 47.41 umol, 8.98% yield), 1H NMR (400 MHz, CDCl3) δ 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.

[0860] Compounds encompassed within the present disclosure can be prepared by the procedures outlined in Scheme II and described in the Examples below:

[0861]

[0862] Solution II

[0863] Preparation of 3-(1,1-dioxidotetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (106)

[0864] Step 1. Preparation of 3-amino-6-chloro-[2,3′-bipyridine]-4-carboxylic acid methyl ester (precursor 2):

[0865]

[0866] Precursor 2 was prepared according to the procedure reported for step 3 of synthesis 1. 1 H NMR (CHCl3-d, 400 MHz): δ H 3.95 (3H, s), 5.91 (2H, s), 7.44 (1H, dd, J=7.9, 4.9Hz), 7.74 (1H, s), 7.97 (1H , d, J=7.9Hz), 8.69 (1H, dd, J=4.9, 1.7Hz), 8.91 (1H, s); MS (m / z): 264.0[M+H] + .

[0867] Table 8 lists intermediates prepared via procedures similar to those described in Step 1 above.

[0868]

[0869] Step 2. Preparation of 3′-amino-6″-(trifluoromethyl)-[3,2′:6′,3″-terpyridine]-4′-carboxylic acid methyl ester (precursor 3):

[0870]

[0871] Precursor 3 was prepared according to the procedure reported for step 3 of synthesis 1. 1 H NMR (CHCl3-d, 400 MHz): δ H 4.01 (3H, s), 6.20 (2H, s), 7.49 (1H, t, J = 6.4Hz), 7.73 (1H, d, J = 8.2Hz), 8.06 (1H, d, J = 7.9Hz), 8.25 ( 1H, s), 8.46 (1H, d, J = 8.3Hz), 8.74 (1H, d, J = 4.9Hz), 9.00 (1H, s), 9.27 (1H, s); MS (m / z): 375.0 [M+H] + .

[0872] Table 9 lists intermediates prepared via procedures similar to those described above.

[0873]

[0874]

[0875]

[0876] Step 3. Preparation of 3′-amino-N-(1,1-dioxytetrahydrothiophen-3-yl)-6″-(trifluoromethyl)-[3,2′:6′,3″-terpyridine]-4′-carboxamide (precursor 4)

[0877]

[0878] 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 at room temperature overnight. The reaction mixture was acidified to pH 4 with Amberlite IR120, followed by the addition of ethyl acetate and MeOH. The solution was filtered to remove the resin and the solvent was evaporated to give 3′-hydrogen-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 carried to the next step.

[0879] 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 hydrochloride (0.314 g, 1.83 mmol) was 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 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 solution and then with saturated aqueous sodium bicarbonate solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to give the title compound 3′-amino-N-(1,1-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 carried on to the next step without purification.

[0880] Table 10 lists intermediates prepared via procedures similar to those described in the above steps.

[0881]

[0882]

[0883]

[0884]

[0885]

[0886]

[0887]

[0888]

[0889]

[0890]

[0891]

[0892]

[0893]

[0894] Preparation of 3′-amino-6″-(trifluoromethyl)-[3,2′:6′,3″-terpyridine]-4′-carboxamide (F30)

[0895]

[0896] To 3'-amino-6"-(trifluoromethyl)-[3,2':6'3"-terpyridine]-4'-carboxylic acid methyl ester (300 mg, 0.801 mmol) in a 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 used without further purification (270 mg, 89%). MS (m / z): 488.0 [M+H] + ; 95% purity

[0897] Step 4 - Preparation of 3-(1,1-dioxidotetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (106).

[0898]

[0899] Triethyl orthoformate (10 mL) was added to 3′-amino-N-(1,1-dioxidotetrahydrothiophene-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 saturated NaHCO3, and the solid was collected by vacuum filtration, washed with water and dried. The residue was purified by normal phase chromatography to give the title compound 3-(1,1-dioxidotetrahydrothiophene-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (106, 0.13 g, 43% yield). 1 H NMR (DMSO-d6, 300 MHz): δ H2.70-2.67 (2H, m), 3.37-3.30 (1H, m), 3.70-3.57 (2H, m), 5.42 (1H, t, J = 8.3Hz), 7.62 (1H, dd, J = 7.9, 4.8Hz), 8.07 (1H, d, J = 8.3Hz), 8.58 (1H, d, J = 8.1Hz), 8.64 (1H, s), 8.72 (1H, d, J = 4.7Hz), 8.80 (1H, s), 8.96 (1H, d, J = 8.4Hz), 9.37 (1H, s), 9.66 (1H, s); MS (m / z): 488.0 [M+H] + ;>98% purity.

[0900] Preparation of (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 (107).

[0901]

[0902] Dioxane (7 mL) and triethyl orthoformate (1.2 mL, 7.02 mmol) were added to the intermediate (R)-3′-amino-N-(1,1-dioxidotetrahydrothiophen-3-yl)-6″-(trifluoromethyl)-[3,2′:6′,3″-terpyridine]-4′-carboxamide (F1, 0.67 g, 1.4 mmol) in a flask. p-Toluenesulfonic 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 the addition of saturated NaHCO3, and the resulting solid was collected by vacuum filtration, washed with water and dried. The residue was purified by silica gel column chromatography to give the title compound (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 (98, 1.82 g, 69% yield). 1 H NMR (DMSO-d6, 400 MHz): δ H3.25-3.18(2H,m), 3.90-3.87(1H,m), 4.25-4.12(3H,m), 5.96(1H,t,H=8.5Hz), 8.16(1H,d,J=6.7Hz), 8.62(1H,d,J=8.3Hz) , 9.11 (1H, d, J = 8.0Hz), 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

[0903] Table 11 lists compounds prepared via a procedure similar to that described for 98 by replacing reactants 4, 5, and 6 with the indicated groups.

[0904]

[0905]

[0906]

[0907]

[0908]

[0909] Preparation of (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 as a white solid (120)

[0910]

[0911] Triethyl orthoformate (1.69 ml, 10.2 mmol) and p-toluenesulfonic acid (117 mg, 0.679 mmol) were added to a solution of (S)-3′-amino-6″-cyclopropyl-N-(3,3,3-trifluoro-2-hydroxypropyl)-[3,2′:6′,3″-terpyridine]-4′-carboxamide (301 mg, 0.679 mmol) in dioxane (3.4 ml). After 1 h, 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 give the title compound (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 as a white solid (120, 115 mg, 37%). 1 H NMR (DMSO-d6, 400MHz): δ1.02 (4H, d, J = 8.2Hz), 2.23-2.17 (1H, m), 4.08 (1H, dd, J=14.1, 9.9Hz), 4.45 (2H, d, J=12.5Hz), 6.78 (1H, d, J=6.4Hz), 7.47 (1H, d , J=8.2Hz), 7.59 (1H, dd, J=7.9, 4.8Hz), 8.49-8.47 (2H, m), 8.54 (2H, d, J=11 .8Hz), 8.70 (1H, d, J=4.8Hz), 9.26 (1H, s), 9.32 (1H, s); MS (m / z): 454.2[M+H] + ;>99% purity.

[0912] Table 12 lists compounds prepared via a procedure similar to that described for 120 by replacing reactants 4, 5, and 6 with the indicated groups.

[0913]

[0914] Preparation of (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 (108)

[0915]

[0916] 108 was prepared according to the procedure reported for step 2 of the synthesis of 1 (synthesis of intermediate B1). 1 H NMR (DMSO-d6, 400 MHz): δ H1.17 (3H, d, J = 6.2Hz), 3.76 (1H, dd, J = 13.3, 8.6Hz), 3.97 (3H, s), 4.16 (1H, dd, J = 13.3, 3.2Hz), 5.08 (1H, d, J = 5.0Hz), 8.03 (1 H, d, J = 8.3Hz), 8.46 (1H, s), 8.49 (1H, s), 8.53 (1H, s), 8.86 (1H, s), 8.93 (1H, d, J = 8.3Hz), 9.65 (1H, s); MS (m / z): 431.1 [M+H] + ;>99% purity.

[0917] Table 13 lists compounds prepared via a procedure similar to that described for 108 by replacing reactants 4, 5, and 6 with the indicated groups.

[0918]

[0919]

[0920]

[0921]

[0922]

[0923]

[0924]

[0925]

[0926]

[0927]

[0928] K-0004422 Preparation of 6-(4-chlorophenyl)-3-((3R, 4R)-4-hydroxypyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (134)

[0929] Step 1. Preparation of tert-butyl (3R, 4R)-3-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)-4-hydroxypyrrolidine-1-carboxylate (precursor 5)

[0930]

[0931] The above steps were performed according to the procedure reported for 108 to give a mixture of tert-butyl (3R,4R)-3-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)-4-hydroxypyrrolidine-1-carboxylate (precursor 5) and 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (134)

[0932] Step 2. 6-(4-Chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (134).

[0933]

[0934] A mixture of precursors 5 and 134 (218 mg, 0.43 mmol) was dissolved in 3.0 mL 4M HCl in dioxane and stirred at room temperature for 1 hour. Ether (2.0 ml) was added and the solid was centrifuged, decanted, triturated with ether and dried. The solid was purified by reverse phase column chromatography to give the title compound 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (134, 120 mg, 0.29, 67% yield) as a white solid. 1 H NMR (DMSO-d6, 400 MHz): δ H 2.70 (1H, dd, J = 11.5, 4.7Hz), 3.00 (1H, dd, J = 11.8, 5.3Hz), 3.23 (1H, dd, J=11.6, 6.1Hz), 3.27 (1H, s), 3.34-3.31 (1H, m), 4.43-4.41 (1H, m), 4.83- 4.80 (1H, m), 5.31 (1H, d, J = 4.6Hz), 7.60-7.55 (3H, m), 8.31 (2H, d, J = 8.4H z), 8.54-8.51 (3H, m), 8.68 (1H, dd, J=4.8, 1.7Hz), 9.32 (1H, d, J=2.1Hz). MS (m / z): 420.1 [M+H] + ; 99% purity.

[0935] Preparation of (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 (135):

[0936]

[0937] Triethyl orthoformate (1.74 ml, 10.5 mmol) and 12.1 N HCl (115 μl, 1.39 mmol) were added to a solution of (R)-5-amino-6′-cyclopropyl-6-(1-methyl-1H-pyrazol-4-yl)-N-(3,3,3-trifluoro-2-hydroxypropyl)-[2,3′-bipyridine]-4-carboxamide (F19, 311 mg, 0.697 mmol) in dioxane (3.5 ml). DMF (0.5 ml) was added after 1 h, and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with sodium bicarbonate (pH>11). Water was added and extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, concentrated and purified by silica gel column chromatography to give the title compound (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 (135, 152 mg, 48%). 1 H NMR (DMSO-d6, 400MHz): δ1.03-1.00 (4H, m), 2.23-2.18 (1H, m), 3.98 (3H, s), 4.10-4.03 (1H, m), 4.49-4.40 (2H, m), 6.79 (1H, t, J=6. 1Hz), 7.46 (1H, dd, J=8.1, 4.9Hz), 8.31-8.30 (1H, m), 8.50-8.47 (3H, m), 8.84-8.82 (1H, m), 9.29-9.28 (1H, m); MS (m / z): 457.1[M+H] + ;>99% purity.

[0938] Table 14 lists compounds prepared via a procedure similar to that described for 139 by replacing reactants 4, 5, and 6 with the indicated groups.

[0939]

[0940] Compounds encompassed within the present disclosure can be prepared by the procedures outlined in Scheme III and described in the Examples below.

[0941]

[0942] Scheme III

[0943] Preparation of 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 (137).

[0944] Step 1. Preparation of 3-amino-6-chloro-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)isonicotinamide (Intermediate G1).

[0945]

[0946] Intermediate G1 was prepared according to step 3 for the synthesis of 114. MS (m / z): 338.0 [M+H] + .

[0947] Table 15 shows the intermediates prepared according to the procedures shown above.

[0948]

[0949]

[0950]

[0951]

[0952]

[0953]

[0954] Step 2. Preparation of 6-chloro-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate H1)

[0955]

[0956] Intermediate H1 was synthesized according to the last step used for the synthesis of 98. 1 H-NMR (DMSO-d6, 400MHz): δ H3.62-3.55 (1H, m), 3.92 (3H, s), 4.11-4.06 (2H, m), 4.16 (1H, dd, J=10.0, 5.6Hz), 4.52 (1H, s), 4.92 (1H, s ), 5.71 (1H, d, J = 4.1Hz), 7.79-7.76 (1H, m), 8.32 (1H, s), 8.33 (1H, s), 8.73 (1H, s); MS (m / z): 348.0 [M+H] + ;>90% purity.

[0957] The intermediates in Table 16 were synthesized according to the above steps.

[0958]

[0959]

[0960]

[0961]

[0962]

[0963]

[0964] Step 3. Method A: Preparation of 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 (137):

[0965]

[0966] 6-Chloro-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (H1, 200 mg, 0.575 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[3-(2-aminoethyl)phenyl)]palladium(II) [Xphos Pd G1] (22.24 mg, 0.029 mmol) and 5-trifluoromethyl-2-pyridineboronic acid MIDA ester (260 mg, 0.863 mmol) were added to a flame-dried 10 mL pressure vial equipped with a stir bar under air. The vial was backfilled with argon, then 1-methyl-2-pyrrolidone (NMP) (4 mL) was added, followed by diethanolamine (0.055 ml, 0.575 mmol), K PO (610 mg, 2.87 mmol) and Cu (OAc) (52.2 mg, 0.288 mmol) and the vial was sealed with a lid. The reaction mixture was heated to 100 ° C and stirred for 18 hours. The vial was then cooled. 8 mL of 2N HCl was added to the reaction mixture and the resulting solution was stirred for 10 min, then 1N NaOH (12 mL) was added and the resulting solution was stirred for 20 min. The formed precipitate was filtered, collected and dried. The precipitate was purified by silica gel column chromatography to give the title compound 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 (137, 151 mg, 57% yield). 1 H-NMR (DMSO-d6, 400MHz): δ H 3.64 (1H, d, J = 9.3Hz), 3.98 (4H, s), 4.15 (3H, s), 4.20 (1H, d, J = 8.1Hz), 4.57 (2H, s), 5.01 (2H, s), 5. 75 (2H, s), 8.39 (3H, d, J=11.3Hz), 8.55 (1H, s), 8.87-8.81 (4H, m), 9.14 (1H, s); MS (m / z): 459.1[M+H] + :>99% purity.

[0967] Table 18 lists compounds prepared via a procedure similar to that described for 137 by replacing reactants 6 and 7 with the indicated groups.

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975] Scheme IV

[0976] Table 19 lists the compounds synthesized according to the procedure used in the last step of the synthesis of 137

[0977]

[0978] Compounds encompassed within the present disclosure can be prepared by the procedures outlined in Scheme V and described in the Examples below.

[0979]

[0980] Scheme V

[0981] Preparation of 6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 18 (152):

[0982]

[0983] 152 was synthesized according to step 4 used for the synthesis of 1. 1 H NMR (DMSO-d6, 400MHz): δ3.63 (1H, dd, J=9.6, 3.3Hz), 4.07 (1H, dd, J=10.0, 4.0Hz), 4.22-4.13 (2H, m), 4.58 (1H, s), 5.00 (1H, s), 5.70 (1H , d, J=4.4Hz), 7.60 (3H, m), 8.32 (2H, d, J=8.4Hz), 8.37 (1H, s), 8.54 (1H, s), 8.56 (1H, s), 8.70 (1H, s), 9.34 (1H, s); MS (m / z): 421, 1[M+H] + ;>98% purity.

[0984] Table 20 lists compounds prepared via procedures similar to those described for 152 by replacing reactants 6, 7, and 8 with the indicated groups.

[0985]

[0986] Preparation of (S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoic acid (155)

[0987]

[0988] (S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidine-3(4H)-yl)methyl propanoate (127,70mg, 0.15mmol) was dissolved in 0.5THF and 0.5mL 1M LiOH was added dropwise. The reaction mixture was kept stirring at room temperature. After completion, the solution was acidified with Amberlite-1R120[H], filtered, concentrated and the residue was purified by reverse phase chromatography to obtain the title compound (S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidine-3(4H)-yl)propionic acid (155,32mg, 0.073mmol, 47% yield). 1 H-NMR (CH3OH-d4, 400MHz); δ H 1.76 (3H, d, J = 7.5Hz), 5.42 (1H, d, J = 7.5Hz), 7.62 (1H, dd, J = 8.0, 5.0Hz), 7.98 (1H, d, J = 8.3Hz), 8.4 6 (1H, s), 8.64 (1H, d, J = 4.8Hz), 8.77-8.75 (2H, m), 8.86 (1H, d, J = 8.3Hz), 9, 43 (1H, s), 9.56 (1H, s). MS(m / z): 442.1[M+H]. Purity: 99%.

[0989] Preparation of (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 (156)

[0990]

[0991] (S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoic acid (155, 150 mg, 0.34 mmol) and methylamine hydrochloride (35 mg, 0.51 mmol) were dissolved in 1.1 mL of anhydrous NMP. N,N-diisopropylethylamine (0.18 mL, 1.02 mmol) was added. The solution was cooled in an ice-water bath and HATU (155 mg, 0.408 mmol) was added. The reaction mixture was allowed to warm to room temperature and kept stirring at room temperature. Upon completion, the reaction was quenched with water and diluted with EtOAc. The organic phase was washed with saturated NaHCO, brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by normal phase chromatography to give the title compound (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 (156, 94 mg, 0.21 mmol, 61% yield). 1 H-NMR (CH3OH-d4, 400MHz): δ H 1.78 (3H, d, J = 7.3Hz), 2.79 (3H, s), 5.48 (1H, d, J = 7.3Hz), 7.62 (1H, dd, J = 7.9, 5.0Hz), 7.97 (1H, d, J = 8.3H z), 8.52 (1H, s), 8.65 (1H, d, J = 4.8Hz), 8.74-8.73 (2H, m), 8.85 (1H, d, J = 8.4Hz), 9.43 (1H, s), 9.55 (1H, s). MS(m / z): 455.1[M+H]. Purity: 99%.

[0992] Preparation of (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)acrylamide (157)

[0993]

[0994] 157 was synthesized according to the procedure reported for 156 . 1 H-NMR (DMSO-d6, 400MHz): δ H1.66 (3H, d, J = 7.3Hz), 2.87 (3H, s), 3.19 (3H, s), 5.88 (1H, d, J = 7.5Hz), 7.59 (1H, dd, J = 7.9, 4.7Hz), 8.06 (1H, d, J = 8.3 Hz), 8.59-8.57 (1H, m), 8.64 (1H, s), 8.70-8.69 (1H, m), 8.74 (1H, s), 8.92 (1H, d, J = 8.4Hz), 9.37 (1H, s), 9.62 (1H, s). MS(m / z): 469.1[M+H]. Purity: 99%.

[0995] Preparation of (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)acrylamide (158)

[0996]

[0997] 158 was synthesized according to the procedure reported for 138. 1 H-NMR (DMSO-d6, 400MHz): δ1.68 (3H, d, J=7.3Hz), 3.53 (2H, dd, J=17.9, 9.2Hz), 3.83 (1H, dd, J =9.3, 4.4Hz), 3.91 (1H, t, J = 7.3Hz), 3.99 (1H, t, J = 5.6Hz), 4.06 (1H, s), 5.29 (1H, d, J = 3.9Hz), 5.46-5.40 (1H, m), 7.61 (1H, dd, J = 7.9, 4.9Hz), 8.07 (1H, d, J = 8.3Hz), 8.58 (2H, t, J = 7.8Hz), 8. 64 (1H, s), 8.72 (1H, d, J = 4.8Hz), 8.76 (1H, s), 8.95 (1H, d, J = 8.4Hz), 9.38 (1H, s), 9.65 (1H, s). MS(m / z): 527.1[M+H]. Purity: >99%

[0998] Preparation of 3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (159)

[0999] Step 1. Preparation of 6-chloro-3-(2-hydroxy-2-methylpropyl)-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (precursor 6)

[1000]

[1001] 6-chloro-3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (C23, 140mg, 0.44mmol) is suspended in anhydrous THF (4.4mL) and the mixture is cooled by an ice-water bath. NaH (60% dispersion in oil, 26mg, 1.10mmol) is added and the mixture is stirred for 10min, and then SEMCl (0.19mL, 1.10mmol) is added. After completion, the reaction is quenched with saturated NH4Cl aqueous solution (25mL) and water (10mL). The aqueous layer is separated and extracted with DCM. The combined organic layer is washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal phase chromatography to give the title compound 6-chloro-3-(2-hydroxy-2-methylpropyl)-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (6, 170 mg, 0.38 mmol, 86% yield). 1 H-NMR (CHCl3-d, 400MHz): δ H -0.02 (9H, s), 0.94 (2H, t, J = 8.2Hz), 1.21 (1H, d, J = 6.1Hz), 1.33 (6H, s), 3.63 (2H, t, J = 8.3Hz), 4.10(2H,s), 5.50(2H,s), 7.92(1H,s), 8.26(1H,s), 8.54(1H,s), 8.79(1H,s). MS(m / z):450.2[M+H] + .

[1002] Step 2. Preparation of 3-(2-hydroxy-2-methylpropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (precursor 7)

[1003]

[1004] Precursor 7 was prepared according to the procedure reported above. 1 H-NMR (CHCl3-d, 400MHz): δH -0.001 (9H, s), 0.96 (2H, t, J = 8.3Hz), 1.35-1.32 (6H, m), 2.12 (1H, s), 3.67 (2H, t, J = 8.3Hz), 4.15 (2H, s), 5.55 (2 H, s), 8.10-8.08 (1H, m), 8.32 (1H, s), 8.62 (1H, s), 8.70 (1H, d, J = 8.3Hz), 8.89 (1H, s), 8.97 (1H, s), 9.09 (1H, s). MS(m / z):561.2[M+H] + .

[1005] Step 3. Preparation of 3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (159)

[1006]

[1007] 3-(2-Hydroxy-2-methylpropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Precursor 7, 90 mg, 0.16 mmol) was dissolved in 1.6 mL of anhydrous DCM and the solution was cooled with an ice-water bath. Trifluoroacetic acid (0.61 mL, 8.0 mmol) was added. The reaction mixture was kept stirring at 0°C for 30 min and warmed to room temperature. Upon completion, the volatiles were removed under reduced pressure. The residue was taken up in EtOAc, washed with saturated NaHCO, brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by normal phase chromatography and subsequently recrystallized from MeOH to give the title compound 3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (159, 35 mg, 51% yield). 1 H-NMR (CH3OH-d4, 400MHz): δ H 1.27(6H,s), 4.13(2H,s), 8.27-8.25(1H,m), 8.43(1H,s), 8.67(1H,s), 8.81-8.79(1H,m), 8.90(1H,s), 8.99-8.97(2H,m). MS(m / z):431.1[M+H] + . Purity: 98%.

[1008] Preparation of 3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (160)

[1009] Step 1. Preparation of 6-chloro-3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (precursor 8)

[1010]

[1011] CuI (53 mg, 0.28 mmol), 4,7-dimethoxy-1,10-phenanthroline (134 mg, 0.56 mmol), imidazole (95 mg, 1.4 mmol), 6,8-dichloro-3-(2-hydroxy-2-methylpropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (B2, 400 mg, 1.4 mmol), polyethylene glycol (233 mg, 0.07 mmol), CsCO (908 mg, 2.8 mmol) and a magnetic stirring bar were loaded into a dried screw cap test tube. Anhydrous NMP (7 mL) was then added and the reaction vessel was equipped with a rubber septum. The vessel was evacuated and refilled with argon for 3 cycles. The reaction mixture was heated at 108 ° C for 2-3 hours. After completion, the reaction mixture was cooled to room temperature, diluted with dichloromethane, filtered through a diatomaceous earth plug, and eluted with additional dichloromethane. The filtrate was washed with saturated NaHCO3, brine, dried over anhydrous sodium sulfate, concentrated and the resulting residue was purified by normal phase chromatography to give the title compound 6-chloro-3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (precursor 8, 200 mg, 45% yield). 1 H-NMR (CH3OH-d4, 300MHz): δ H 1.24-1.21 (6H, m), 3.65 (1H, s), 4.13 (1H, s), 7.18 (1H, s), 8.08 (1H, s), 8.26 (1H, s), 8.44 (1H, s), 9.11 (1H, s). MS(m / z):319.9[M+H] + .

[1012] Step 2. Preparation of 3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (160)

[1013]

[1014] Compound 160 was prepared according to the procedure reported for 121. 1 H-NMR (CH3OH-d4, 400MHz): δ H 1.27 (6H, s), 4.08 (2H, s), 7.11 (1H, s), 8.14 (1H, d, J = 8.1Hz), 8.27 (1H, s) , 8, 37 (1H, s), 8.44 (1H, d, J = 8.3Hz), 8.87 (2H, d, J = 16.9Hz). 9.06 (1H, s). MS(m / z): 430.9[M+H]. Purity: 99%.

[1015] Preparation of 3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (161)

[1016]

[1017] 161 was synthesized according to step 4 used for the synthesis of 1. 1 H-NMR (CH3OH-d4, 300MHz): δ H 1.30 (6H, s), 4.16 (2H, s), 7.20 (1H, s), 7.98 (1H, d, J = 8.3Hz), 8, 40 (1H, s), 8.48 (1H, s), 8.68 (1H, s), 8.82 (1H, d, J = 8.3Hz), 9.18 (1H, s), 9.51 (1H, s). MS(m / z): 430.9[M+H]. Purity: 98%.

[1018] Preparation of (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 (162).

[1019] Step 1. Preparation of (S)-3-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6,8-dichloropyrido[3,4-d]pyrimidin-4(3H)-one (Precursor 9).

[1020]

[1021] Imidazole (99mg, 1.5mmol) is added to a solution of (S)-6,8-dichloro-3-(1-hydroxypropane-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (B1, 200mg, 0.73mmol) in anhydrous DMF. The solution is cooled with an ice-water bath and TBDMSCl (132mg, 0.88mmol) is added. The reaction mixture is warmed to room temperature and kept stirring for 2 hours. After completion, the reaction is quenched with methanol. The reaction mixture is diluted with EtOAc and washed with saturated NaHCO3 and water successively. The organic phase is dried over anhydrous sodium sulfate and concentrated to give the title compound (S)-3-(1-((tert-butyldimethylsilyl)oxy)propane-2-yl)-6,8-dichloropyrido[3,4-d]pyrimidine-4(3H)-one (precursor 9, 280mg, 99% yield). 1 H-NMR (DMSO-d6, 400MHz): δ H -0.07 (6H, d, J = 10.7Hz), 0.73 (9H, s), 1.41 (3H, d, J = 7.0Hz), 3.93-3.81 (2H, m), 4.87 (1H, s), 8.05 (1H, s), 8.61 (1H, s). MS(m / z):387.9[M+H] + .

[1022] Step 2. Preparation of (S)-3-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6-chloro-8-(1H-imidazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (P1).

[1023]

[1024] Intermediate P1 was synthesized according to the procedure reported for step 1 of the synthesis of 160. MS (m / z): 420.0 [M+H].

[1025] Table 21 shows the intermediates synthesized according to the above steps.

[1026]

[1027] Step 3. Preparation of (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Q1).

[1028]

[1029] (S)-3-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6-chloro-8-(1H-imidazole-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (intermediate P1, 460 mg, 1.1 mmol) was dissolved in anhydrous THF (11 mL) and cooled with an ice-water bath. Tetrabutylammonium fluoride (1.0 M THF solution, 1.3 mL, 1.3 mmol) was added dropwise and the solution was stirred for 10 min. After completion, the reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The organic phase was collected, washed with water, brine, dried over anhydrous sodium sulfate and concentrated. The residue was taken up in MeOH and the precipitate was collected and dried to give the title compound which was used in the next step without further purification (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate Q1, 340 mg, 1.1 mmol, quantum yield). 1 H-NMR (DMSO-d6, 300MHz): δ H 1.45-1.39 (3H, m), 3.84-3.62 (2H, m), 4.93-4.78 (1H, 1m), 5.06-5.11 (1H, m), 7.17-7. 14(1H,m), 8.03-8.00(1H,m).8.12-8.09(1H,m), 8.66-8.62(1H,m), 8.85-8.83(1H,m). MS(m / z):305.9[M+H] + .

[1030] Table 22 lists the intermediates synthesized according to the above steps.

[1031]

[1032] Step 4. Preparation of (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 (162).

[1033]

[1034] 162 was prepared according to the procedure reported for 137. 1 H-NMR (CH3OH-d4, 400MHz): δ H1.57 (3H, d, J = 7.1Hz), 3.87 (1H, dd, J = 11.9, 4.3Hz), 3.97 (1H, dd, J = 11.9, 6.9Hz), 5.01 (1H, td, J = 7.1, 4.4Hz), 7.19 (1H, s), 8.28 (1H, dd, J=8.3, 2.2Hz), 8.43 (1H, s), 8.57 (1H, s), 8.70 (1H, d, J=8.4Hz), 9.03 (1H, s), 9.15 (1H, s), 9.19 (1H, s). MS(m / z): 416.9[M+H]. Purity: 98%.

[1035] Preparation of (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 (163)

[1036]

[1037] (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(1H-imidazole-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate Q1, 85 mg, 0.28 mmol) and 2-trifluoromethyl-pyridine-5-boronic acid (80 mg, 0.42 mmol) were dissolved in 2 mL toluene-EtOH (2: 1) and sodium carbonate (118 mg, 1.1 mmol) was added. The suspension was degassed and refilled with argon (3 cycles). Tetrakis(triphenylphosphine)palladium (32 mg, 0.028 mmol) was added and the suspension was degassed and refilled with argon (3 cycles). The reaction mixture was heated to 85 °C under argon and kept stirring overnight. After completion, the reaction mixture was cooled, diluted in EtOAc, washed with water and brine. The organic phase was dried over anhydrous sodium sulfate. The solution was concentrated and purified by normal phase column chromatography, followed by crystallization in MeOH to give the title compound (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 (163, 52 mg, 45% yield). 1 H-NMR (CH3OH-d4, 300MHz): δ H0.08 (3H, d, J = 7.1Hz), 2.47-2.38 (2H, m), 3.53 (1H, s), 5.69 (1H, s), 6.48 (1H, d, J = 8.3Hz) , 6.91 (1H, s), 7.08 (1H, s), 7.20 (1H, s), 7.34 (1H, d, J = 8.4Hz), 7.70 (1H, s), 8.03 (1H, s). MS (m / z): 416.9 [M+H], purity: 99%.

[1038] Table 23 lists compounds synthesized according to the synthetic procedure reported for 163, substituting the reactants in step 2.

[1039]

[1040]

[1041] Preparation of (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 (168).

[1042]

[1043] (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (C10, 100 mg, 0.313 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)thiazole (96.0 mg, 0.344 mmol) were dissolved in dioxane. Pd(OAc)2 (7.02 mg, 0.031 mmol), triphenylphosphine (16.4 mg, 0.063 mmol) and K3PO4 (266 mg, 1.25 mmol) were added to the solution. The suspension was degassed and refilled with argon (3 cycles). The reaction mixture was heated to 90°C and stirred for 16 hours. The reaction mixture was extracted with ethyl acetate and washed with water and brine. The combined organic layers were dried over anhydrous magnesium sulfate, concentrated and purified by silica gel column chromatography to give (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 (168, 28 mg, 20% yield). 1H NMR (DMSO-d6, 400MHz): δ1.45 (3H, d, J = 7.0Hz), 3.71-3.66 (1H, m), 3.82-3.77 (1H, m), 3.97 (3H, s), 4.9 2-4.87 (1H, m), 5.10 (1H, t, J = 5.4Hz), 8.45 (1H, s), 8.51 (1H, s), 8.58 (1H, s), 8.77 (1H, s), 9.03 (1H, s). MS(m / z):437.1[M+H] + ; 98% purity.

[1044] Table 24 lists compounds synthesized according to Synthetic Scheme V, where the steps were performed according to the procedure reported for 168.

[1045]

[1046]

[1047]

[1048] Compounds encompassed within the present disclosure can be prepared by the procedures outlined in Scheme V and described in the Examples below.

[1049]

[1050] Scheme V

[1051] Preparation of (S)-8-(diethylamino)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (174)

[1052] Step 1. Preparation of (S)-6-chloro-8-(diethylamino)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate S1)

[1053]

[1054] Dimethylformamide (2.0 ml) was added to (S)-6,8-dichloro-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (B1, 0.200 g, 0.73 mmol) and potassium carbonate (0.403 g, 2.92 mmol) in a sealed tube. Diethylamine (0.0586 g, 0.803 mmol) was added and the reaction mixture was stirred at 120 °C for 2 hours. The reaction mixture was cooled to room temperature, water was added and the mixture was partitioned with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound (S)-6-chloro-8-(diethylamino)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (intermediate S1, 0.062 g, 27% yield). 1 H-NMR (DMSO-d6, 400MHz): δ H 1.21 (6H, t, J=6.9Hz), 1.37 (3H, d, J=7.1Hz), 3.64-3.60 (1H, m), 3.83-3.75 (5H, m), 4. 82-4.76 (1H, m), 5.04 (1H, t, J=5.5Hz), 7.03 (1H, s), 8.32 (1H, s); MS (m / z): 311.1[M+H] + .

[1055] Table 25 lists the intermediates synthesized according to the above steps.

[1056] Table 25

[1057]

[1058] Step 2. Preparation of (S)-8-(diethylamino)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (174)

[1059]

[1060] The above steps for preparing 174 were performed according to the procedure reported for the last step 1.

[1061] Table 26 lists compounds synthesized according to the synthetic procedure reported for 174 by replacing the reactants in Step 1 and Step 2.

[1062]

[1063]

[1064]

[1065] Preparation of (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (180)

[1066] Step 1. Preparation of (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (precursor 10)

[1067]

[1068] (S)-6,8-dichloro-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate B1, 200 mg, 0.73 mmol) was dissolved in toluene and degassed, then PdCl2 (2.62 mg, 0.015 mmol), CsF (0.222 g, 1.46 mmol), CuI (0.056 g, 0.292 mmol), tri-tert-butylphosphine (0.292 μl, 0.292 mmol, 1.0 M in THF) and 2-(tributyltinyl)pyridine (0.348 mg, 0.803 mmol) were added. The solution was degassed again and stirred at 50° C. overnight. The reaction mixture was diluted with EtOAc, washed with water, brine, and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (CH2Cl2 / MeOH) to give (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Precursor 10, 55.6 mg, 24% yield). 1 H-NMR (CHCl3-d, 400MHz): δ H 1.34 (3H, m), 3.92 (2H, t, J = 4.4Hz), 5.07-5.00 (1H, m), 7.41 (1H, dd, J = 73, 1.9Hz), 7.89-7.82 (1H, m), 8.03-7.98 (1H, m), 8.19-8.19 (1H, m), 8.34 (1H, t, J=1.6Hz), 8.90-8.83 (1H, m); MS (m / z): 316.9[M+H] + .

[1069] Step 2. Preparation of (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (180)

[1070]

[1071] The above steps for preparing 180 were carried out according to the procedure reported for the last step of 1. 1 H-NMR (DMSO-d6, 300MHz): δ H 1.44-1.40(3H,m), 3.79-3.64(2H,m), 4.91(1H,s), 5.09-5.04(1H,m), 7.55-7.50(1H,m), 7.92-7.89(1H,m), 7.99-7.95(1H,m), 8.07-8 .02 (1H, m), 8.51 (1H, t, J = 0.9Hz), 8.77-8.74 (1H, m), 8.81 (1H, t, J = 0.8Hz), 8.89-8.85 (1H, m), 9.60-9.58 (1H, m); MS (m / z): 427.9 [M+H] + ; 99% purity.

[1072] Preparation of (S)6-cyclohexyl-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (181)

[1073]

[1074] (S) 6-(cyclohex-1-ene-1-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (77, 76.2 mg, 0.210 mmol) and PtO2 (4.77 mg, 0.021 mmol) were dissolved in EtOH (3 ml). The suspension was degassed and refilled with argon and purged with hydrogen. The reaction mixture was stirred at room temperature for 3 days under a hydrogen atmosphere. The reaction mixture was filtered through celite and the filtrate was concentrated and purified by silica gel column chromatography to give (S)-6-cyclohexyl-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (181, 46.0 mg, 60% yield). 1H-NMR (CHCl3-d, 300MHz): δ1.81-1.29 (9H, m), 1.93-1.87 (2H, m), 2.06 (2H, d, J = 12.5Hz), 2.95-2.85 (1H, m), 3.98 (2H, d, J = 4.6Hz), 5.06- 4.97 (1H, m), 7.38 (1H, dd, J = 7.8, 4.7Hz), 7.91 (1H, s), 8.22 (1H, s), 8.41 (1H, d, J = 8.0Hz), 8.61 (1H, s), 9.34 (1H, s); MS (m / z): 365.0 [M+H] + ; 99% purity.

[1075] Preparation of (S)-3-(1-hydroxypropan-2-yl)-6-(pyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (182)

[1076]

[1077] The above steps were performed according to the procedure reported for step 1 of the synthesis of 180 to give (S)-3-(1-hydroxypropan-2-yl)-6-(pyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (182). 1 H-NMR (DMSO-d6, 300MHz): δ H 1.43 (3H, d, J = 7.0Hz), 3.84-3.64 (2H, m), 4.91 (1H, m), 5.07 (1H, t, J = 5.6Hz), 7.50 (1H, ddd, J = 7.4, 4.8, 1.2Hz), 7.59 (1H, dd, J = 7.9, 4.8Hz), 8 ... + ; 99% purity.

[1078] Table 27 lists the compounds synthesized according to the synthetic procedure reported for 180.

[1079]

[1080] Preparation of (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 (184)

[1081]

[1082] The above steps were carried out according to the procedure reported for 47 to give (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 (184, 40 mg, 18%). 1 H-NMR (DMSO-d6, 300MHz): δ1.44 (3H, d, J=7.0Hz), 3.84-3.66 (2H, m), 4.42 (3H, s), 4.90 (1H, td, J=7.1, 4.9Hz), 5.09-5.06 (1H, m) ), 7.59 (1H, dd, J=8.0, 4.8Hz), 8.54-8.50 (2H, m), 8.56 (1H, s), 8.60 (1H, s), 8.70 (1H, dd, J=4.8, 1.6Hz), 9.31 (1H, d, J=2.1Hz). MS(m / z):364.0[M+H] + ; 98% purity.

[1083] Preparation of (R)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (185 enantiomer 1) and (S)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (185 enantiomer 2)

[1084]

[1085] Racemic 6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(H)-one (rac-185, 20 mg, 0.045 mmol) was purified by SFC to give the title compound. (R)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (6.9 mg, 35% yield). 1 H-NMR (CH3OH-d4, 400MHz): δ H3.98 (1H, dd, J = 13.7, 9.6Hz), 4.45-4.41 (1H, m), 4.62 (1H, dd, J = 13.8, 3.0Hz), 7.53 (2H, d, J = 8.4Hz), 7.60 (1H, dd, J = 7.9, 4.9Hz), 8.23 ​​(2H, d, J=8.4Hz), 8.33 (1H, s), 8.58 (1H, s), 8.64-8.62 (1H, m), 8.70 (1H, d, J=8.0Hz), 9.38 (1H, t, J=2.6Hz). MS(m / z): 446.9[M+H]. Purity: 99%. (S)-6-(4-Chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trichloro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (6.4 mg, 32% yield). 1 H-NMR (CH3OH-d4, 400MHz): δ H 3.99 (1H, dd, J = 13.7, 9.7Hz), 4.46-4.41 (1H, m), 4.62 (1H, dd, J = 13.6, 2.8Hz), 7.54 (2H, d, J = 8.4Hz), 7.61 (1H, dd, J = 8. 0, 4.9Hz), 8.24 (2H, d, J = 8.4Hz), 8.33 (1H, s), 8.60 (1H, s), 8.64-8.62 (1H, m), 8.72-8.70 (1H, m), 9.39 (1H, d, J = 2.5Hz). MS(m / z): 446.9[M+H]. Purity: 99%.

[1086] Preparation of (S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (186)

[1087]

[1088] (S) -6- chloro-3- (1- hydroxypropyl -2- bases) -8- (pyridin-3-yl) pyrido [3, 4-d] pyrimidin-4 (3H) -one (100mg, 1 equivalent) and 5- methyl -2- (tributyltin base) pyridine (145mg, 0.131mL, 1.2 equivalents) are dissolved in toluene (3mL). The suspension is degassed and refilled with argon (3 cycles). Tetrakis (triphenylphosphine) palladium (73mg, 0.2 equivalents) is added and the suspension is degassed and refilled with argon again (3 cycles). The reaction mixture is heated to 100 ° C under argon and monitored by LC-MS. After 24 hours of reaction, KF and water / MeOH are added and stirred overnight. The reaction mixture is filtered through diatomaceous earth and the filtrate is concentrated and purified by Combi-Fash using DCM / MeOH from 0% to 10% MeOH in 25min. The obtained product (100 mg, 84% yield) was further purified by reverse phase chromatography to give (S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (186) as a white solid. 1 H NMR (DMSO-d6, 400 MHz): δ H 1.42 (3H, d, J = 7.0Hz), 2.38 (3H, s), 3.67-3.64 (1H, m), 3.77 (1H, t, J = 7.5Hz), 4.90 (1H, d, J = 7.9Hz), 5.07 (1H, t, J = 5.6Hz), 7.58 (1H, dd, J = 7. 9, 4.9Hz), 7.81 (1H, d, J = 8.1Hz), 8.44 (1H, d, J = 8.1Hz), 8.55 (2H, t, J = 3.9Hz), 8.59 (1H, s), 8.68 (1H, d, J = 4.7Hz), 8.97 (1H, s), 9.34 (1H, s). MS(m / z): 374.1[M+H]. Purity:>99%.

[1089] Table 28 lists the compounds synthesized according to the synthetic procedure reported for 186.

[1090]

[1091] Preparation of (S)-8-cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (189)

[1092]

[1093] Step 1. Preparation of (S)-6-chloro-8-(cyclohex-1-en-1-yl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[1094]

[1095] (S)-6,8-dichloro-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate B1, 200 mg, 0.73 mmol) and cyclohex-1-ene-1-ylboronic acid (101 mg, 0.80 mmol) were dissolved in toluene-EtOH (3:1, 7 mL), and sodium carbonate (309 mg, 2.9 mmol) was added. The suspension was degassed and refilled with argon (3 cycles). Tetrakis(triphenylphosphine)palladium (84 mg, 0.07 mmol) was added, and the suspension was degassed and refilled with argon again (3 cycles). The reaction mixture was heated to 75 °C under argon and monitored by LC-MS. After reacting overnight, the reaction mixture was cooled, diluted with EtOAc, filtered through celite, and the filtrate was washed with water, brine, and dried over sodium sulfate. The residue was purified by silica gel column to give the title compound. (130 mg, 56% yield). 1H NMR (DMSO-d6, 400MHz): δH 1.37 (3H, d, J = 7.0Hz), 1.68 (4H, d, J = 30.1Hz), 2.25 (2H, s), 3.76-3.60 (2H, m), 4.80 (1 H, d, J = 7.9Hz), 5.03 (1H, t, J = 5.5Hz), 6.74 (1H, s), 7.82 (1H, d, J = 4.1Hz), 8.46 (1H, s). MS(m / z): 320.1[M+H]+.

[1096] Step 2. Preparation of (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 (188)

[1097]

[1098] To a flame-dried pressure vial equipped with a stir bar under air was added (S)-6-chloro-8-(cyclohex-1-en-1-yl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (120 mg, 0.38 mmol), potassium phosphate (399 mg, 1.88 mmol), (2-dicyclohexylphosphino-2',4',6'-tri-dopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride [Xphos Pd G1] (28 mg, 0.38 mmol) and 5-trichloromethyl-2-pyridineboronic acid MIDA ester (170 mg, 0.56 mmol), diethanolamine (79 mg, 0.75 mmol). 2 mL of NMP was added and the vial was degassed, then Cu(OAc)2 (68 mg, 0.38 mmol) was added. The vial was heated to 108°C while stirring for 15h. The reaction mixture was then cooled, diluted with EtOAc and filtered through a celite pad. The filtrate was washed with saturated NaHCO3, water, concentrated and purified by normal phase plus reverse phase combi-flash to give the title compound. (100 mg, 62% yield). 1 H NMR (CH3OH-d4, 400MHz): δH1.56 (3H, d, J = 7.1Hz), 1.78 (2H, d, J = 7.1Hz), 1.86 (2H, d, J = 7.1Hz), 2.34 (2H, s), 2.72 (2H, s), 3.84 (1H, dd, J = 11.9, 4.1Hz) , 3.96 (1H, dd, J = 11.8, 6.7Hz), 4.96 (1H, d, J = 7.8Hz), 6.73 (1H, s), 8.19 (1H , d, J = 8.4Hz), 8.38 (1H, s), 8.60 (1H, d, J = 8.4Hz), 8.92 (1H, s), 8.95 (1H, s). MS (m / z): 431.2 [M+H]+. 98% purity.

[1099] Step 3. Preparation of (S)-8-cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (189)

[1100]

[1101] By (S) -8- (cyclohex-1-ene-1-yl) -3- (1-hydroxypropyl-2-yl) -6-5- (trifluoromethyl) pyridin-2-yl) pyrido [3,4-d] pyrimidine -4 (3H) -one (76mg, 0.18mmol) and PtO (4mg, 0.018mmol) dissolved in 17mL EtOH. The suspension is degassed and refilled with H gas (in a balloon) for 3 cycles. The reaction mixture is stirred at room temperature under H gas (in a balloon) and monitored by LC-MS. The reaction is stopped after 24h and filtered through diatomaceous earth. The filtrate was concentrated and purified by normal phase and reverse phase combi-flash to give the title compound: (S)-8-cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (189) (18 mg, 24% yield). 1H NMR (DMSO-d6, 400MHz): δH 1.34 (1H, s), 1.41 (3H, d, J = 7.0Hz), 1.47 (2H, d, J = 13.5Hz), 1.76 (3H, t, J = 12.2Hz), 1.89 (4H, t, J = 14.9Hz), 3.66-3.63 (1H, m), 3, 76 (1H, s), 3.84 (1H, s), 4.88 (1H, s), 5.05 (1H, d, J = 5.8Hz), 8.39 (1H, d, J = 8.4Hz), 8.57 (1H, s), 8.66 (1H, d, J = 8.4Hz), 8.87 (1H, s), 9.11 (1H, s). MS (m / z): 433-2 [M+H]+; 96% purity; (S)-8-cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one (22 mg, 29% yield). 1H NMR (DMSO-d6, 400 MHz): δH 1.14 (3H, d, J=6.9 Hz), 1.27 (1H, d, J=15.6 Hz), 1.44 (2H, d, J=14.2 Hz), 1.61 (2H, t, J=12.4 Hz), 1.73 (1H, br s), 1.82 (4H, brs), 2.90 (1H,, s), 3.49 (2H, d, J = 6.8Hz), 4.54 (JH, d, J = 8.2Hz), 4.62 (2H, s), 4.85 (1 H, d, J = 5.8Hz), 7.11 (1H, s), 8.24 (1H, d, J = 8.5Hz), 8.43 (1H, d, J = 8.5Hz), 8.52 (1H, s), 8.96 (1H, s). MS (m / z): 435.2 [M+H]+; 99% purity.

[1102] Preparation of (S)-3-(1-hydroxypropan-2-yl)-N,N-dimethyl-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido-3,4-d]pyrimidine-6-carboxamide (190)

[1103]

[1104] To a mixture of (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (200 mg, 1 eq.), dimethylamine hydrochloride (77 mg, 1.5 eq.), molybdenum hexacarbonyl (166 mg, 1 eq.) and XPhos (60 mg, 0.2 eq.) was added dioxane (6 mL). The suspension was degassed and refilled with nitrogen (3 cycles). Palladium (II) acetate (15 mg, 0.1 eq.) and K3PO4 were added and the suspension was degassed and refilled with nitrogen again (3 cycles). The reaction mixture was heated to 100 ° C and monitored by LC-MS. After overnight, the reaction mixture was filtered through celite, washed with EtOAc, MeOH and the filtrate was concentrated. The crude product (190) was first purified by silica gel column chromatography eluting with DCM / MeOH from 0% to 10% MeOH in 25 min, followed by reverse phase with water / acetonitrile to give the desired product (90 mg, 40%). 1 HNMR (DMSO-d6, 400MHz): δ H 1.40 (3H, d, J=7.0Hz), 3.05 (7H, s), 3.66 (1H, s), 3.76 (1H, s), 4.88-4.83 (1H, m), 5.05 (1H, t, J=5.3Hz), 7 .55 (1H, t, J = 6.3Hz), 8.16 (1H, s), 8.41 (1H, d, J = 8.0Hz), 8.58 (1H, s), 8.66 (1H, d, J = 4.8Hz), 9.21 (1H, s). MS(m / z):488.0[M+H] + ;>99% purity.

[1105] Preparation of (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 (191):

[1106] Compound 191 was prepared according to the same procedure as general scheme IV above and the following protection strategy.

[1107]

[1108] Solution VI

[1109] Table 29 describes the intermediates synthesized via general scheme VI.

[1110] Table 29

[1111]

[1112] Table 30 lists the compounds synthesized according to the above Synthesis Scheme VI.

[1113]

[1114] Preparation of (S)-3-(1-hydroxypropan-2-yl)-6-(2-methoxyethyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (192)

[1115]

[1116] Into an oven-dried microwave vial were introduced bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (5.6 mg, 0.05 mmol), trifluoro(2-methoxyethyl)-λ4-borane potassium salt (40 mg, 0.24 mmol), Cs2CO3 (154 mg, 0.47 mmol) and (S)-6-fluoro-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (50 mg, 0.16 mmol). The vial was sealed, degassed and heated to 40 ℃ for 2 h. 2 Refill. Degassed dioxane-H2O (4:1, 1 mL) was added via a syringe. The reaction mixture was then placed in an oil bath preheated to 100°C and stirred at this temperature for 24 h. Upon completion, the reaction mixture was cooled to room temperature, diluted with EtOAc, and filtered through a celite pad. The filtrate was washed with water, brine, dried over sodium sulfate, concentrated, and purified by normal phase chromatography to give the title compound (192). 1 H NMR (DMSO-d6, 400MHz): δH 1.39 (3H, d, J = 7.0Hz), 3.17 (2H, t, J = 6.4Hz), 3.24 (3H, s), 3.64-3.61 (1H, m), 3.77 (3H, t, J = 6.7Hz), 4.85 (1H, s), 5.03 (1H , t, J=5.5Hz), 7.53 (1H, t, J=6.2Hz), 7.93 (1H, s), 8.40 (1H, d, J=7.9Hz), 8.47 (1H, s), 8.64 (1H, d, J=4.6Hz), 9.20 (1H, s). MS (m / z): 341.1 [M+H]+; 96% purity.

[1117] Preparation of (S)-3-(1-hydroxypropan-2-yl)-8-(2-methoxyethyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (193)

[1118] Compound 193 was prepared according to the same procedure as general scheme IV above and following the alkyl-aryl coupling step according to the procedure of compound 192.

[1119]

[1120] Scheme VII

[1121] Table 31 describes the intermediates synthesized via general scheme VII.

[1122] Table 31

[1123]

[1124] Table 32 lists the compounds synthesized according to the above Synthesis Scheme VII.

[1125]

[1126] Example 2: DRE-luciferase reporter gene assay

[1127] AHR binds to the dioxin response element (DRE) upstream of the gene it activates. One measure of AHR activity is the activation of a reporter gene such as luciferase downstream of one or more DRE elements. Luciferase activity will reflect the activation and inhibition of AHR in cells expressing its reporter gene. 20,000 human HepG2 liver cancer-AhR-Lucia reporter cells or human HT29 colon adenocarcinoma-AhR reporter cells or other cell lines stably transfected with DRE-luciferase reporter genes were plated in Eagle's minimum essential medium, 10% heat-inactivated FBS, 1X non-essential amino acids Pen-Strep (10,000U / mL) and Normocin (100ug / mL) plates (96-well, 384-well or other plates) and incubated overnight at 37°C in a CO2 incubator and treated with and without AhR antagonists at logarithmic dilutions starting at 100uM.

[1128] One hour after cell plating, AHR activating ligands such as TCDD, kynurenine, ITE (2-(1H-indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester), VAF347, BNF (β-naphthoflavone), FICZ (6-formylindole (3,2-b) carbazole) or other AHR ligands were added to the cells at their specific EC values. 50 concentrations were added to cells with or without AHR antagonists.

[1129] The cells were incubated for 24 or 48 hours or another time point, and the supernatants were then analyzed to determine luciferase activity as a readout for AHR activation or inhibition. The commercial kit QUANTI-Luc from Invivogen was used according to the manufacturer's instructions. TM The assay solution kit measures luciferase.

[1130] The level of luciferase when only the agonist ligand is added is the maximum signal, while the level of luciferase when no antagonist is added is the minimum signal. 50 The IC value was determined as the concentration that inhibited the luciferase activity by half. 50 The levels are reported in Table 33. “A” indicates IC 50 Values ​​less than 100 nM, "B" indicates IC 50 Between 100 and 500 nM, “C” indicates IC 50 Above 500 nM, and "D" indicates that an IC50 value could not be generated from the data.

[1131]

[1132]

[1133]

[1134]

[1135] Example 3: CYP1A1 gene expression assay

[1136] Human and mouse colorectal cancer (CRC) cell lines from the American Type Culture Collection (ATCC), HT29 and HT26, respectively, were cultured at 8.0 × 10 5Cells / well were plated in sterile tissue culture treated 96-well plates (ThermoFisher) and grown overnight in DMEM complete medium (Gibco) at 37°C, 5% CO2 to achieve confluence. After aspirating the incubation medium from the cell monolayer, the tissue was then washed with 200 μL of warm PBS solution, followed by adding 190 μL of pre-warmed growth medium to each well. The AhR antagonist of interest was diluted at 20X concentration in growth medium containing 2% DMSO, and 10 μL of the compound solution was added to the corresponding wells in triplicate. After 1 hour, AHR activating ligands such as TCDD, kynurenine, ITE (2-(1H-indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester), VAF347, BNF (β-naphthoflavone), FICZ (6-formylindole (3,2-b) carbazole) or other AHR ligands were added with or without AHR antagonists for 24 hours, after which the medium was removed and stored at -80°C for later cytokine analysis. At the end of the incubation, the medium was aspirated from the CRC cells and the cells were washed with 100 μL of cold PBS solution. The PCR products were analyzed by TaqMan according to the manufacturer's protocol. TM Gene Expression Cells-to-CT TM RNA was extracted using the QuantStudio 6 Flex (Applied Biosciences) kit (Thermo Fisher Scientific). CYP1A1 mRNA levels were analyzed using GAPDH as an endogenous control. TM Probe sets were purchased from Thermo Fisher Scientific. Samples were run in triplicate and data were analyzed using QuantStudio software and reported as linear and log2 (ΔΔCT) values. Statistical analysis was performed using a two-tailed t-test to compare CYP1A1 levels in the presence of each individual compound to the vehicle negative control. Further evaluation of IC 50 Compounds in the nanomolar concentration range. This assay can be used to confirm the inhibitory effect of a compound prior to testing using in vivo models.

[1137] Example 4: Human PBMC (CD8+) assay

[1138] Human donor blood (8 mL) was collected in sodium citrate CPT tubes and centrifuged at 1,600 × g for 20 minutes at room temperature. The buffy coat containing PBMCs was collected at room temperature and transferred to a 50 mL conical tube containing 30 mL RPMI-1640 medium (supplemented with penicillin-streptomycin). The PBMC samples were centrifuged at 400 × g for 10 minutes at 10 ° C. The precipitated PBMCs were washed twice in 10 ml RPMI-1640 medium (supplemented with penicillin-streptomycin) and then resuspended in RPMI-1640 medium (supplemented with penicillin-streptomycin, fetal bovine serum and L-glutamine: RPMI-1640 complete medium). The PBMCs were filtered through a 70 micron mesh to remove any cell debris. The volume was adjusted to 1.66×106 cells / mL, from which 180 μl (300,000 PBMCs) were added to each well of a 96-well plate (sterile, tissue culture treated, round bottom). The PBMCs in the 96-well plate were incubated in a 37°C, 5% CO2 incubator for 30 minutes and then treated with 10 μl of the indicated compound. For CD8+ (killer T cell) differentiation assays, PMBCs (1-10×10 4 Cells) were cultured in RPMI-1640 complete medium for 2, 4 and 6 days and stimulated with 5uL / ml ImmunoCultTM Human CD3 / CD28 / CD2 T Cell Activator (Stemcell #10990) with or without AhR antagonist compounds. Cell viability was determined using a 1:500 dilution of viability dye (eBioscience Fixable Viability Dye eFluor 780: ThermoFisher 65-0865-14). Cells were gated for CD8+, defined as live, CD11c-, CD14-, CD19-, CD8+, CD4-, CD3+. Percent (%) CD8+ was calculated as the percentage of CD8+ cells to total live T cells. Statistical analysis was performed using one-way ANOVA using GraphPadPrism software.

[1139] Example 5: Human PBMC cytokine assay

[1140] Human donor blood (8 mL) was collected in sodium citrate CPT tubes and centrifuged at 1,600 × g for 20 minutes at room temperature. The buffy coat containing PBMCs was collected at room temperature and transferred to a 50 mL conical tube containing 30 mL RPMI-1640 medium (supplemented with penicillin-streptomycin). The PBMC samples were centrifuged at 400 × g for 10 minutes at 10 ° C. The precipitated PBMCs were washed twice in 10 ml RPMI-1640 medium (supplemented with penicillin-streptomycin) and then resuspended in RPMI-1640 medium (supplemented with penicillin-streptomycin, fetal bovine serum and L-glutamine: RPMI-1640 complete medium). The PBMCs were filtered through a 70 micron mesh to remove any cell debris. The volume was adjusted to reach 1.66×106 cells / mL, from which 180 μl (300,000 PBMCs) were added to each well of a 96-well plate (sterile, tissue culture treated, round bottom). The PBMCs in the 96-well plate were left to stand in a 37°C, 5% CO2 incubator for 30 minutes and then treated with 10 μl of the specified compound. For cytokine secretion assays, PMBCs (1-10×104 cells) were cultured in RPMI-1640 complete medium for 2, 4, and 6 days and stimulated with 5uL / ml ImmunoCultTM human CD3 / CD28 / CD2 T cell activator (Stem Cell Company #10990) with or without AhR antagonist compounds. After incubation for 2, 4, and 6 days at 37°C, 5% CO2, 100 μL of cell supernatant was collected and transferred to a 96-well plate (untreated with tissue, flat bottom). The plate was centrifuged at 350 × g for 5 min at room temperature and the clear supernatant was transferred to a new 96-well plate (untreated with tissue, flat bottom). The viability of the remaining cells was tested by luminescent cell viability assay (Promega). IL22 and IFg in the supernatant were analyzed using Luminex immunoassay technology (MAGPIX system). Cytokine levels of DMSO control samples treated with PBMCs were set to 100%, and compound-treated samples were expressed relative to this value.

[1141] Example 6: Solubility Determination Assay

[1142] Stock solutions of the test compound and control compound progesterone were prepared in DMSO at a concentration of 10mM. 15 μL of stock solution (10mM) of each sample was placed in their appropriate 96-well racks in sequence. 485 μL of PBS with a pH of 1.6 and a pH of 7.4 was added to each vial of the uncapped solubility sample plate. The assay was performed in a singlet state. A stirring bar was added to each vial, and the vial was then sealed using a molded PTFE / silicone plug. The solubility sample plate was then transferred to an Eppendorf Thermomixer Comfort Plate Oscillator and shaken at 1100rpm for 2 hours at 25°C. After 2 hours, the stopper was removed and the stirring bar was removed using a large magnet. The samples from the solubility sample plate were transferred to a filter plate. All samples were filtered using a vacuum manifold. A 5 μL aliquot was taken from the filtrate, followed by a mixture of 495 μL of H2O and acetonitrile containing an internal standard (1:1). The diluent was diluted with a certain proportion of ultrapure water according to the peak shape. The dilution factor varies depending on the solubility value and the LC-MS signal response.

[1143] From the 10mM DMSO STD plate, 6 μL was transferred to the remaining empty plate, and then 194 μL DMSO was added to the plate to make the STD concentration 300 μM. From the 300 μM DMSO STD plate, 5 μL was transferred to the remaining empty plate, and then 495 μL of a mixture of H2O and acetonitrile (1:1) containing the internal standard was added to the plate to make the final STD concentration 3 μM. Use a certain ratio of ultrapure water to dilute the diluent according to the peak shape. The concentration of the standard sample varies according to the LC-MS signal response.

[1144] The plate was placed in a well plate autosampler. The samples were evaluated by LC-MS / MS analysis.

[1145] All calculations were performed using Microsoft Excel.

[1146] The filtrate was analyzed and quantified against standards of known concentration using LC coupled with mass spectrometry peak identification and quantification. The solubility values ​​for the test and control compounds were calculated as follows:

[1147]

[1148] Any value for a compound not within the specified limits was rejected and the test repeated.

[1149] The solubility of compounds of the present disclosure in pH 1.6 and 7.4 buffers is reported in Table 34. "+++" indicates a solubility value equal to or greater than 1 μM, "++" indicates a solubility value between 0.1 and 1 μM, and "+" indicates a solubility value less than 0.1 μM.

[1150] Table 34

[1151]

[1152]

[1153]

[1154] BLD: below the limit of detection.

[1155] Example 7: Hepatocyte stability assay

[1156] Preparation of working solutions: Prepare 10 mM stock solutions of test compounds and positive controls in DMSO. In separate conical tubes, dilute the 10 mM test compound solutions and positive controls to 100 μM by mixing 198 μL of 50% acetonitrile / 50% water and 2 μL of the 10 mM stock solution.

[1157] Preparation of hepatocytes: Place incubation medium (William's E medium supplemented with GlutaMAX) and hepatocyte thawing medium in a 37°C water bath and warm for at least 15 minutes before use. Transfer a vial of cryopreserved hepatocytes from storage, ensuring that the vial remains cold until the thawing process subsequently occurs. Thaw the cells by placing the vial in a 37°C water bath and gently shaking the vial for 2 minutes. Once thawing is complete, spray the vial with 70% ethanol and transfer to a biosafety cabinet. Use a wide-bore pipette tip to transfer the hepatocytes to a 50mL conical tube containing thawing medium. Place the 50mL conical tube in a centrifuge and centrifuge at 100g for 10 minutes. After centrifugation is complete, aspirate the thawing medium and resuspend the hepatocytes in enough incubation medium to approximately 1.5×10 6 Cells / mL were counted using AO / PI staining to determine viable cell density. Cells with poor viability (<75% viability) were determined to be unusable. Cells were diluted to 0.5×10 6 The working cell density was 10 viable cells / mL.

[1158] Stability assay procedure: 198 μL of hepatocytes are pipetted into each well of a 96-well uncoated plate. The plate is placed in an incubator to warm the hepatocytes for 10 minutes. 2 μL of 100 μM test compound or positive control solution is pipetted into the corresponding well of a 96-well uncoated plate to start the reaction. The plate is returned to the incubator at the designed time point. The well contents are transferred in 25 μL aliquots at 0, 15, 30, 60, 90 and 120 minutes. The aliquots are then mixed with 6 volumes (150 μL) of acetonitrile containing internal standard IS (100 nM alprazolam, 200 nM caffeine and 100 nM tolbutamide) to terminate the reaction. The mixture is vortexed for 5 minutes. The sample is centrifuged at 3,220 g for 45 minutes. An aliquot of 100 μL of supernatant is diluted with 100 μL ultrapure water, and the mixture is used for LC / MS / MS analysis. All incubations are performed in duplicate.

[1159] Data Analysis: All calculations were performed using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. In vitro half-lives (t 1 / 2 ) was determined by regression analysis of the maternal disappearance percentage versus time curve.

[1160] In vitro half-life (in vitro t 1 / 2 ) is determined by the slope value:

[1161] In vitro 1 / 2 =0.693 / k

[1162] The in vitro t 1 / 2 (in min) converted to in vitro intrinsic clearance (in vitro CL int , the unit is μL / min / 1×10 6 cells):

[1163] In vitro CL int =kV / N

[1164] V = incubation volume (0.2 mL);

[1165] N = number of hepatocytes per well (0.1×10 6 cells).

[1166] Data processing rules: Data processing rules are shown in Table 35.

[1167] Table 35

[1168]

[1169] The human and rat hepatocyte clearance of the compounds of the present disclosure are reported in Table 36. "+++" indicates CL intThe value is less than 20mL / min / Kg, "++" indicates CL int Between 20 and 50 mL / min / Kg, and "+" indicates CL int Higher than 50mL / min / Kg.

[1170] Table 36

[1171]

[1172]

[1173]

[1174] Example 8: Liver microsome stability assay

[1175] Prepare the master solution according to Table 37.

[1176] Table 37

[1177] Reagents Stock concentration volume Final concentration Phosphate buffered saline 100mM 210μL 100mM Microsomes 20mg / mL 6.25μL 0.5mg / mL

[1178] Two separate experiments were performed as follows.

[1179] Utilizing cofactor (NADPH): 25 μL of 10 mM NADPH was added to the culture. The final concentrations of microsomes and NADPH were 0.5 mg / mL and 1 mM, respectively. The final concentration of microsomes was 0.5 mg / mL. The mixture was preheated at 37°C for 10 minutes. The reaction was started by adding 2.5 μL of 100 μM control compound or test compound solution. Verapamil was used as a positive control in this study. The final concentration of the test compound or control compound was 1 μM. The incubation solution was incubated in water at 37°C in batches. 25 μL aliquots were taken from the reaction solution at 0.5, 5, 15, 30 and 60 minutes. The reaction was terminated by adding 5 volumes of cold acetonitrile containing IS (200 nM caffeine and 100 nM tolbutamide). The sample was centrifuged at 3,220 g for 40 minutes. An aliquot of 100 μL of the supernatant was mixed with 100 μL of ultrapure H 2 O and then used for LC-MS / MS analysis.

[1180] Data Analysis: All calculations were performed using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. K values ​​were determined by linear regression of the natural logarithm of the percentage remaining of the parent drug versus incubation time curve.

[1181] In vitro half-life (in vitro t 1 / 2 ) is determined by the slope value:

[1182] In vitro 1 / 2 =-(0.693 / k)

[1183] The in vitro t 1 / 2 (min) converted to in vitro intrinsic clearance (in vitro CL int , unit is μL / min / mg protein):

[1184]

[1185] Enlarge CL int Calculations of CLH (mL / min / kg), predicted CLH (mL / min / kg), and EH were performed using the following equations:

[1186] Enlarge CL int =(0.693 / t 1 / 2 )×(1 / (microsomal protein concentration (0.5 mg / mL)))×scaling factor:

[1187] Predicted CLH = (QH × enlarged CL int ×f ub ) / (QH+enlarged CL int ×f ub );

[1188] EH=predicted CLH / QH

[1189] where QH is hepatic blood flow (mL / min / kg) (Table 32),

[1190] f ub is the fraction of unbound drug in plasma, which is assumed to be 1.

[1191] The scaling factors for the prediction of intrinsic clearance in human and mouse microsomes are reported in Table 38.

[1192] Table 38

[1193]

[1194] * Scaling factor = (microsomal protein per gram of liver) x (liver weight per kilogram of body weight)

[1195] Data processing rules: Data processing rules are shown in Table 39.

[1196] Table 39

[1197]

[1198] Human and rat liver microsomal clearance of compounds of the present disclosure are reported in Table 40. "+++" indicates Cl int The value is less than 10mL / min / Kg, "++" indicates Cl intBetween 10 and 20 mL / min / Kg, and "+" indicates Cl int Higher than 20mL / min / Kg.

[1199] Table 40

[1200]

[1201] Example 9: Caco-2 permeability assay

[1202] Preparation of Caco-2 cells: Add 50 μL and 25 mL of cell culture medium to each well of the Transwell insert and reservoir, respectively. Incubate the HTS Transwell plate at 37°C, 5% CO2 for 1 hour before cell seeding. Dilute Caco-2 cells to 6.86 × 10 5 Cells / mL were added and 50 μL of cell suspension was dispensed into the filter wells of a 96-well HTS Transwell plate. Cells were cultured in a cell culture incubator at 37°C, 5% CO2, and 95% relative humidity for 14-18 days. Cell culture medium was changed every other day, starting no later than 24 hours after initial plating.

[1203] Cell monolayer integrity assessment: Remove the culture medium from the reservoir and each Transwell insert and replace it with pre-warmed fresh culture medium. The transepithelial resistance (TEER) across the monolayer was measured using the Millicell Epithelial Volt-Ohm Measurement System (Millipore, USA). Once the measurement is completed, the plate is returned to the incubator. The TEER value is calculated according to the following equation:

[1204] TEER measurement value (ohm) × membrane area (cm 2 ) = TEER value (ohm cm 2 )

[1205] TEER value should be greater than 230ohm·cm 2 , which indicates that the Caco-2 monolayer is of good quality.

[1206] Preparation of solutions: Prepare a 2 mM stock solution of the control compound in DMSO and dilute it with HBSS (10 mM HEPES, pH 7.4) to obtain a 10 μM working solution. Prepare a 0.2 mM stock solution of the test compound in DMSO and dilute it with HBSS (10 mM HEPES, pH 7.4, containing 0.5% BSA) to obtain a 1 μM working solution. Metoprolol, erythromycin and cimetidine were used as control compounds.

[1207] Drug transport assay was performed: The Caco-2 plate was removed from the incubator. The monolayer was washed twice with preheated HBSS (10 mM HEPES, pH 7.4). The plate was incubated at 37°C for 30 minutes. To determine the drug transport rate from the apical to the basolateral direction, 125 μL of working solution was added to the Transwell insert (apical compartment). Immediately transfer 50 μL of sample from the apical compartment to 200 μL of acetonitrile containing IS (100 nM alprazolam, 200 nM caffeine and 100 nM tolbutamide) in a new 96-well plate as the initial donor sample (AB) and vortex it at 1000 rpm for 10 minutes. Fill the wells in the receiving plate (basolateral compartment) with 235 μL of transport buffer. To determine the drug transport rate from the basolateral to the apical direction, 285 μL of working solution was added to the receiving plate wells (basolateral compartment). Immediately transfer 50 μL of sample from the basolateral compartment to 200 μL of acetonitrile containing IS (100 nM alprazolam, 200 nM caffeine and 100 nM tolbutamide) in a new 96-well plate as the initial donor sample (BA) and vortex it at 1000 rpm for 10 minutes. Fill the Transwell insert (apical compartment) with 75 μL of transport buffer. The apical to basolateral direction and the basolateral to apical direction need to be performed simultaneously. Incubate the plate at 37°C for 2 hours. At the end of the incubation, transfer 50 μL of samples from the donor side (apical compartment for Ap→B1 flux and basolateral compartment for B1→Ap) and the receiving side (basolateral compartment for Ap→B1 flux and apical compartment for B1→Ap) to the wells of a new 96-well plate, and then add 4 volumes of acetonitrile containing IS (100 nM alprazolam, 200 nM caffeine and 100 nM tolbutamide). The samples were vortexed for 10 minutes and 50 μL of the sample was transferred to a well of a new 96-well plate, followed by the addition of 50 μL of Hepes and 200 μL of IS. All samples were vortexed for 10 minutes and then centrifuged at 3,220 g for 40 minutes. An aliquot of 150 μL of the supernatant was mixed with an appropriate volume of ultrapure water prior to LC-MS / MS analysis.

[1208] Data Analysis: All calculations were performed using Microsoft Excel. Peak areas were determined from the extracted ion chromatograms. Lucifer yellow leakage from the monolayer was calculated using the following equation:

[1209]

[1210] Among them I 受体 is the fluorescence intensity in the acceptor well (0.3 mL), and

[1211] I 供体is the fluorescence intensity in the donor well (0.1 mL) and is expressed as leakage %.

[1212] The percent lucifer yellow transport value should be less than 1.5%. However, if the percent lucifer yellow transport value for a particular transwell is higher than 1.5, but the digoxigenin P measured in that transwell app Qualitatively similar to that measured in duplicate trame, the monolayer was considered acceptable based on the scientific judgment of the responsible scientist.

[1213] The apparent permeability (Papp) for drug transport assays can be calculated using the following equation:

[1214] Where P app yes Apparent permeability (cm / s×10 -6 );

[1215] dQ / dt is the drug transport rate (pmol / s);

[1216] A is the surface area of ​​the membrane (cm2);

[1217] D0 is the initial donor concentration (nM; pmol / cm3).

[1218] The efflux rate can be determined using the following equation:

[1219]

[1220] Where P app(B-A) Indicates the apparent permeability coefficient from the basolateral to the apical direction,

[1221] P app(A-B) Indicates the apparent permeability coefficient in the apical to basolateral direction.

[1222] The apparent permeabilities of the compounds of the present disclosure are reported in Table 41. "A" indicates P app Value greater than 10*10 -6 cm / s, "B" indicates P app Between 2 and 10*10 -6 cm / s, and "C" indicates P app Less than 2*10 -6 cm / s.

[1223] Table 41

[1224]

[1225]

[1226] Example 10: Determination of plasma protein binding using ultracentrifugation

[1227] Frozen plasma (stored at -80°C) was thawed in a 37°C water bath and subsequently centrifuged at 3,220g for 10 minutes to remove clots. The supernatant was transferred to a new tube as centrifuged plasma. The centrifuged plasma was preheated in a 37°C water bath for 10 minutes. The stock solution of the test compound was diluted to 200 μM in DMSO and then spiked into the plasma. Two samples were prepared. The final concentration of the compound was 1.0 μM. The final concentration of the organic solvent was 0.5%. Warfarin was used as a positive control in the assay. 1.0 mL of spiked plasma was transferred to a new balanced ultracentrifuge tube. The sample was incubated at 37°C, 5% CO2 for 30 minutes. After incubation, the balanced ultracentrifuge tube was centrifuged at 600,000g for 5.5 hours at 37°C. After centrifugation, 50 μL of solution was taken from the center of the ultracentrifuge tube as the post-ultracentrifugation sample, followed by the addition of 50 μL of blank plasma and 400 μL of quenching solution (acetonitrile containing internal standard (IS, 100 nM alprazolam, 500 nM labetalol and 2 μM ketoprofen)) to precipitate the protein and release the compound. The sample was vortexed for 2 minutes and then centrifuged at 20,000 g for 15 minutes at room temperature. The supernatant was diluted with ultrapure water and then used for LC-MS / MS analysis. Stability samples were prepared by transferring 50 μL of spiked plasma to a 0.6 mL tube and incubating at 37°C, 5% CO2 for 0.5 and 6 hours. After incubation, 50 μL of PBS (100 mM, pH 7.4) and 400 μL of quenching solution were added to the stability sample. The stability sample was then treated in the same manner as the post-ultracentrifugation sample. The supernatant was diluted with ultrapure water and then used for LC-MS / MS analysis. The 0.5 hour time point sample was also used as a non-centrifuged control. The time 0 sample was prepared by transferring 50 μL of spiked plasma into a 0.6 mL tube containing 50 μL of PBS, followed by the addition of 400 μL of quench solution to precipitate proteins and release compounds. These samples were then processed in the same manner as the ultracentrifuged samples. The supernatant was diluted with ultrapure water and then used for LC-MS / MS analysis.

[1228] Data Analysis: All calculations were performed using Microsoft Excel. The concentration of the test compound in the plasma samples and in the plasma after ultracentrifugation was determined from the peak areas. The percentage of test compound binding was calculated as follows:

[1229] Unbound % = (peak area after ultracentrifugation / peak area of ​​non-centrifuged control) × 100%

[1230] % bound = 100% - % unbound

[1231] Remaining % at 0.5 hours = 0.5 hour area ratio / 0 hour area ratio × 100%

[1232] Remaining % at 6 hours = 6 hour area ratio / 0 hour area ratio × 100%

[1233]

[1234] The binding levels of the compounds of the present disclosure to human, rat and mouse plasma proteins are reported in Table 42. "+++" indicates a % binding value of less than 50, "++" indicates a % binding value between 50 and 75, and "+" indicates a % binding value above 75.

[1235] Table 42

[1236]

[1237]

[1238] Example 11: CYP inhibition assay

[1239] Stock solutions of test compounds were prepared at a concentration of 10 mM in DMSO. The stock solutions were diluted to 2 mM with acetonitrile. The final concentration of the test compounds was 10 μM. The concentrations of the positive inhibitors are listed in Table 43. For stock solution preparation, if the positive control was not well dissolved in the highest concentration of DMSO and acetonitrile (1:4), another mixture of acetonitrile and DMSO, i.e., a mixture of acetonitrile and H2O or DMSO, was used to dissolve the compound.

[1240] Table 43

[1241]

[1242] Details of the preparation of these substrates are given in Table 44. The substrate solutions were stored in a -20°C freezer and allowed to warm to room temperature before use.

[1243] Table 44

[1244]

[1245] Preparation of phosphate buffer (100mmol / L, pH 7.4): To prepare solution A, weigh 7.098g of disodium hydrogen phosphate and add to 500mL of pure water, then sonicate to dissolve the contents. To prepare solution B, weigh 3,400g of potassium dihydrogen phosphate and add to 250mL of pure water, then sonicate to dissolve the contents. Place solution A on a stirrer and slowly add solution B to solution A until the pH reaches 7.4. Preparation of 10mmol / L NADPH solution: Dissolve NADPH in phosphate buffer at 8.334mg / mL; this solution was prepared fresh before use.

[1246] Prepare the master solution according to Table 45. Incubation was performed in a 96-deep well plate. The following volumes were dispensed into each well of the incubation plate: 179 μL of substrate and HLM mixture in phosphate buffer, 1 μL of compound working solution, or vehicle (a mixture of DMSO and acetonitrile (1:4)). The incubation plate was placed in a water bath and preheated at 37°C for 15 minutes, and then the reaction was started by adding 20 μL of 10 mmol / L NADPH solution in phosphate buffer. After the addition of NADPH, the incubation plate was incubated at 37°C for the corresponding time. The assay was performed in duplicate.

[1247] Table 45

[1248]

[1249] The reaction was quenched by adding 1.5 volumes (300 μL) of cold acetonitrile containing 3% formic acid and internal standards (200 nM labetalol, 200 nM alprazolam, and 200 nM tolbutamide). The plate was centrifuged at 3,220 g for 40 minutes. 100 μL of supernatant was transferred to a new plate. The supernatant was diluted with 100 μL of purified water. The samples were mixed thoroughly and analyzed using UPLC / MS / MS.

[1250] Data Analysis: Automatic peak integration areas were checked for all samples. Analyte peak areas and internal standard peak areas were exported to an Excel spreadsheet. Inhibition of each P450 enzyme in human liver microsomes was measured as the percent reduction in activity of the labeled metabolite formed compared to the uninhibited control (=100% activity).

[1251] The percentage of remaining activity is calculated as follows:

[1252] Area ratio = analyte peak area / internal standard peak area

[1253] Remaining activity (%) = test compound area ratio / vehicle area ratio * 100%

[1254] Inhibition % = 100 - Remaining activity (%)

[1255] The % inhibition of CYP2D6 and CYP3A4 by the compounds of the present disclosure is reported in Table 46.

[1256] Table 46

[1257]

[1258] NA = Not applicable

[1259] Example 12: hERG inhibition assay

[1260] HEK 293 cell line stably expressing hERG (Catalog No. K1236) was purchased from Invitrogen. Cells were cultured in 85% DMEM, 10% dialyzed FBS, 0.1 mM NEAA, 25 mM HEPES, 100 U / mL penicillin-streptomycin, 5 μg / mL blasticidin, and 400 μg / mL geneticin. TrypLE TM The cells were split approximately three times and maintained at a confluence between approximately 40% and approximately 80%. Prior to the assay, the cells were plated on coverslips at 5×105 cells / 6 cm cell culture dish and induced with 1 μg / mL of doxycycline for 48 hours.

[1261] External solution (mM); 132 NaCl, 4 KCl, 3 CaCl2, 0.5 MgCl2, 11.1 glucose and 10 HEPES (pH adjusted to 7.35 with NaOH). Internal solution (mM): 140 KCl, 2 MgCl2, 10 EGTA, 10 HEPES and 5 MgATP (pH adjusted to 7.35 with KOH). Preparation of working solutions of test compounds: First, prepare the test compounds in DMSO at a final concentration of 10 mM as stock solutions. The stock solution of each compound was serially diluted with DMSO at a ratio of 1:3 to prepare 3 additional intermediate solutions, including 3.33, 1.11 and 0.37 mM.

[1262] Prior to the hERG assay, working solutions were prepared by diluting 10, 3.33, 1.11, and 0.37 mM intermediate solutions 1000-fold with extracellular solution, and 30 μM working solutions were prepared by diluting 10 mM DMSO stock solution 333.333-fold. The final concentrations of the working solutions were 30, 10, 3.33, 1.11, and 0.37 μM. The final DMSO concentration in the working solution was maintained within the range of 1.1%-0.3% (v / v).

[1263] Experimental Procedure: Remove the coverslip from the cell culture dish and place it on the microscope stage in the bath. Use the ×10 objective to locate the desired cell. Position the tip of the electrode under the microscope using the ×10 objective by focusing above the plane of the cell. Once the tip is in focus, use coarse control of the manipulator to advance the electrode down toward the cell while moving the objective to keep the tip in focus. When directly above the cell, use fine control of the manipulator to approach the cell surface in small steps by using the ×40 objective. Apply gentle suction through the side port of the electrode holder to form a gigaohm seal.

[1264] Cfast is used to remove capacitive currents that coincide with the voltage step. Whole-cell configuration is achieved by repeated, short, strong pumping until the membrane patch ruptures. The membrane potential is then set to -60mV to ensure that the hERG channels do not open. Cslow on the amplifier is then used to remove spikes in capacitive currents.

[1265] The holding potential was set at -90 mV for 500 ms; currents were recorded at 20 kHz and filtered at 10 kHz. Leakage currents were tested at -80 mV for 500 ms.

[1266] hERG current is induced by depolarizing at +30mV for 4.8 seconds, and then the voltage is restored to 50mV for 5.2 seconds to eliminate inactivation and observe the deactivation tail current. The maximum amount of tail current size is used to determine the hERG current amplitude. Record current for 120 seconds to evaluate current stability. Only stable cells with recording parameters above the threshold are further drug administration. The vehicle control is applied to the cell to establish a baseline. Once it is found that the hERG current is stable for 5 minutes, the working solution is applied. Record the hERG current for about 5 minutes in the presence of the test compound to reach a steady state, and then capture 5 scans. For dose response testing, 5 doses of test compounds are cumulatively applied to cells from low concentration to high concentration. In order to ensure the good performance of cultured cells and operation, 5 doses of positive control dofetilide are also used to test the cells of the same batch.

[1267] The following criteria were used to determine data acceptability: initial seal resistance >1 GΩ; leak current <50% of control peak tail current at any time; peak tail amplitude >300 pA; membrane resistance Rm >500 MΩ; access resistance (Ra) <15 MΩ; and a significant decrease in peak current of <2.5% per minute.

[1268] Data that met the above hERG current quality criteria were further analyzed as follows. The percent current inhibition was calculated using the following equation: (Note: Peak currents were extracted from raw data using PatchMaster or Clampfit software).

[1269]

[1270] Dose response curves of test compounds were plotted versus % inhibition relative to test compound concentration using Graphpad Prism 6.0, and the data were fit to a sigmoidal dose response curve with a variable slope.

[1271] IC of the compounds disclosed herein 50 Reported in Table 47.

[1272] Table 47

[1273]

[1274]

[1275] Example 13: In vivo rat PK study

[1276] These studies were conducted in male Sprague Dawley rats, three rats per group, or in male CD1 mice, three mice per group. Compounds were dosed at 1.0 mg / Kg intravenously (vehicle ethanol:% PEG400 in deionized water, ratio appropriate for dosing clear solution) and 3.0 mg / kg or 10 mg / kg orally (vehicle: 1% methylcellulose: 1,500 cP in DI water (w / v)). All animals had free access to food and water. Rat intravenous PK time points: plasma: 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 h; rat oral PK time points: plasma: 0.25, 0.5, 1, 2, 4, 8 and 24 h. Mouse intravenous injection PK time points: plasma: 0.083, 0.25, 0.5, 1, 2, 4, 8, 24 and 48 h; mouse oral PK time points: plasma: 0.25, 0.5, 1, 2, 4, 8, 24 and 48 h. The concentration of the compound in the plasma sample was analyzed using the LC-MS / MS method. WinNonlin (PhoenixTM, version 6.1) or other similar software was used for pharmacokinetic calculations.

[1277] Data from Mouse and Rat PK Studies Pharmacokinetic data are shown below in Tables 48 to 51. PK data in mice dosed IV at 1 mg / mL of a compound of the disclosure are reported in Table 48. PK data in mice dosed PO at 10 mg / mL of a compound of the disclosure are reported in Table 49. PK data in rats dosed IV at 1 mg / mL of a compound of the disclosure are reported in Table 50. PK data in rats dosed PO at 3 or 10 mg / mL of a compound of the disclosure are reported in Table 51.

[1278]

[1279]

[1280]

[1281]

[1282] In vivo models

[1283] Efficacy of AHR antagonists and checkpoint inhibitor anti-PD-1 in the murine colorectal cancer model CT26 in Balb / c mice

[1284] Female mice aged six to eight weeks were obtained from Charles River Laboratory (C57BL / 6NCrl). The mouse tumor cell line WT-CT26 was obtained from the American Type Culture Collection, tested for mycoplasma and other pathogens at the Charles River Research Animal Diagnostic Service, and cultured according to its guidelines. All studies were conducted in accordance with the CRADL policy on the care, welfare, and treatment of laboratory animals. From the date of tumor inoculation, the mice were monitored at least three times a week by researchers or veterinary staff for clinical abnormalities that may require euthanasia. These include chronic and / or severe diarrhea leading to moderate to severe dehydration, evidence of infection that is not easily treated, hunchback with fatigue or other clinical symptoms lasting more than three days, inability / reluctance to walk to obtain food or water, or other clinical signs judged by experienced technicians to indicate illness or moribund conditions. Mice that showed a net weight loss of >20% compared to baseline weight measurements were euthanized.

[1285] CT26 is a murine colon cancer cell line obtained from ATCC. CT26 cells were cultured in RPMI supplemented with 10% FBS. Low-passage CT26 cells were plated at 5 × 10 5 100 cells / ml were resuspended in 100 μL PBS and implanted subcutaneously into the shaved right lower flank of 6-8 week old Balb / c mice. The day of subcutaneous tumor cell implantation was defined as day 0.

[1286] Once inclusion criteria were met, animals were assigned to treatment groups so that the mean tumor burden in each group was within 10% of the overall mean. Mice were dosed individually according to body weight on the day of treatment.

[1287] One week after inoculation, the average tumor size was about 60 mm 3 Mice were randomly assigned and treatment started. Figure 1 ) AhR antagonists were orally administered at 1 mg / kg, 3 mg / kg or 10 mg / kg daily (QD) for 14 days. Starting from day 14, anti-PD-1 (BioXcell RMP1-14) or anti-PD-L1 was intraperitoneally administered at 100 μg / kg three times every three days.

[1288] Tumors were monitored by vertical tumor diameter measurement and using the formula (mm 3 )=0.52×(length)×(width) 2 Body weight was measured three times a week and calculated daily by caliper measurements. At the end of the experiment, tumors were recovered and analyzed for infiltrating tumor immune cells by flow cytometry and / or IHC.

[1289] Expression of AHR-dependent genes in tumors, spleen, and liver

[1290] AHR dependent gene expression will be measured in tissue samples such as tumors or liver. RNA will be extracted from tissues via an RNA isolation kit (such as Qiagen). RNA extraction is performed from total cells or cells after sorting a specific cell population, such as tumor cells, tumor associated T cells, tumor associated myeloid cells, tumor associated macrophages or other cells. Gene expression will be determined by quantitative RT-PCR using probes for specific genes including housekeeping genes (such as Gapdh) for standardization. The AHR dependent genes to be examined include, but are not limited to: CYP1A1, CYP1B1, AHRR, IDO1, IDO2, IL22, IL6, VEGFA, STAT3, cdc2, MMP13, MMP-9.

[1291] Example 14: Drug metabolism and pharmacokinetic properties of compounds No. 9 and 46

[1292] Compounds No. 9 and 46 had the following in vitro DMPK properties.

[1293] Table 52

[1294]

[1295] Compounds No. 9 and 46 had the following in vivo DMPK properties.

[1296] Table 53

[1297]

[1298]

[1299] The mean plasma concentrations of Compound No. 46 over time after 1 mg / kg IV and 10 mg / kg PO administration in CD1 mice are shown in Fig. Fig.14 The mean plasma concentrations of Compound No. 46 over time after 1 mg / kg IV and 3 mg / kg PO administration in SD rats are shown in the graph Fig.15 middle.

[1300] The mean plasma concentrations of Compound 9 over time after 1 mg / kg IV and 10 mg / kg PO administration in CD1 mice are shown in Fig. Fig.16 The mean plasma concentrations of Compound 9 over time after 1 mg / kg IV and 3 mg / kg PO administration in SD rats are shown in FIG. Fig.17 middle.

[1301] Example 15: Combination therapy with immune checkpoint inhibitors (ICIs)

[1302] A study was conducted to identify potent, selective, low-dose modulators of the aryl hydrocarbon receptor that could antagonize tryptophan metabolite activity in a variety of cancers, either alone or in combination with checkpoint inhibitors (ICIs).

[1303] Antitumor efficacy of Compound No. 7 in the CT26 syngeneic model. CT26 cells were implanted subcutaneously in Balb / c mice, which were then randomized and treated with PD-L1 antibody alone or in combination with PD-L1 antibody and Compound No. 7. Compound No. 7 was administered PO at 3 mg / kg once daily in combination with anti-PD-L1 antibody administered IP at 10 mg / kg every 3 days for 14 days of dosing. Tumor growth curves of vehicle versus single agent PD-L1 antibody or PD-L1 antibody with Compound No. 7 are shown in Figure 2 The co-administration of Compound No. 7 and PD-L1 antibody showed a reduction in tumor volume p=0.0039 (Mann-Whitney, nonparametric test). In addition, the tumor weight at the end of the study of vehicle relative to single agent PD-L1 antibody or PD-L1 antibody and Compound No. 7 is shown in Figure 3 Co-administration of compound No. 7 with PD-L1 antibody showed a reduction in tumor weight p=0.041 (Mann-Whitney, non-parametric test).

[1304] Antitumor efficacy of Compound No. 30 in the CT26 syngeneic model. CT26 cells were implanted subcutaneously in Balb / c mice, which were then randomized and treated with Compound No. 30 alone, PD-L1 antibody alone, or PD-L1 antibody in combination with Compound No. 30. Compound No. 30 was administered PO at 10 mg / kg once daily in combination with anti-PD-L1 antibody administered IP at 10 mg / kg every 3 days for 14 days of dosing. Tumor growth curves of vehicle versus single agent PD-L1 antibody or Compound No. 30 alone or PD-L1 antibody and Compound No. 30 are shown in Figure 4 and Figure 6 The co-administration of compound No. 30 and PD-L1 antibody showed a decrease in tumor volume p=0.039 ( Figure 4 , Mann-Whitney, nonparametric test) and p = 0.350 ( Figure 6 , Kruskal Wallis test followed by nonparametric Dunn's multiple comparison test). In addition, tumor weights at the end of the study for vehicle versus single agent PD-L1 antibody or Compound No. 30 alone, or PD-L1 antibody and Compound No. 30 are shown in Figure 5 and Figure 7 The co-administration of compound No. 30 and PD-L1 antibody showed a decrease in tumor weight p=0.067 ( Figure 5, Mann-Whitney, nonparametric test) and p = 0.0004 ( Figure 7 , Kruskal-Wallis test followed by nonparametric Dunn's multiple comparison test).

[1305] Antitumor efficacy of Compound 9 in the CT26 syngeneic model. CT26 cells were implanted subcutaneously in Balb / c mice, which were then randomized and treated with Compound 9 alone, PD-L1 antibody alone, or PD-L1 antibody in combination with Compound 9. Compound 9 was administered PO once daily at 10 mg / kg ( Figure 8 ) or 1mg / kg( Fig.10 ), combined with anti-PD-L1 antibody administered at 10 mg / kg IP every 3 days. Tumor growth curves of vehicle versus single agent PD-L1 antibody or Compound No. 9 alone or PD-L1 antibody and Compound No. 9 are shown in Figure 8 and Fig.10 The co-administration of compound No. 9 and PD-L1 antibody showed a decrease in tumor volume p=0.0070 ( Figure 8 , Mann-Whitney, nonparametric test) and p = 0.0039 ( Fig.10 , Kruskal Wallis test, followed by nonparametric Dunn's multiple comparison test). In addition, the tumor weight at the end of the study of vehicle relative to single agent PD-L1 antibody or Compound No. 9 alone, or PD-L1 antibody and Compound No. 9 is shown in Fig. 9 and Fig.11 The co-administration of compound No. 9 and PD-L1 antibody showed a decrease in tumor weight p=0.0114 ( Fig. 9 , Mann-Whitney, nonparametric test) and p = 0.0029 ( Fig.11 , Kruskal Wallis test followed by nonparametric Dunn's multiple comparison test). In conclusion, Compound 9 in combination with PD-L1 reduced tumor volume and weight compared with PD-L1 alone.

[1306] Antitumor efficacy of Compound No. 46 in the CT26 syngeneic model. CT26 cells were implanted subcutaneously in Balb / c mice, which were then randomized and treated with Compound No. 46 alone, PD-L1 antibody alone, or PD-L1 antibody in combination with Compound No. 46. Compound No. 46 was administered PO at 10 mg / kg once daily in combination with anti-PD-L1 antibody administered IP at 10 mg / kg every 3 days for 14 days of dosing. Tumor growth curves of vehicle versus single agent PD-L1 antibody or Compound No. 46 alone or PD-L1 antibody and Compound No. 46 are shown in Fig.12 In. Co-administration of Compound No. 46 with PD-L1 antibody showed a reduction in tumor volume. In addition, the tumor weight at the end of the study of vehicle relative to single agent PD-L1 antibody or Compound No. 46 alone, or PD-L1 antibody and Compound No. 46 is shown in Fig.13 Co-administration of compound No. 46 with PD-L1 antibody showed a reduction in tumor weight.

[1307] Table 54 - In vivo pharmacology data of CT26 model

[1308]

Claims

1. A compound of formula Ia or a pharmaceutically acceptable salt thereof, in: Ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyrrolyl, furanyl, furazanyl, thienyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, aza cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyrrolyl, furanyl, furazanyl, thienyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, aza R, tetrahydropyranyl and tetrahydrofuranyl are independently optionally substituted by 1 to 5 R A Instances of ; Ring B is selected from phenyl, benzodioxol, pyrrolyl, furanyl, furazanyl, thienyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyridonyl and pyrimidinyl, wherein each phenyl, benzodioxol, pyrrolyl, furanyl, furazanyl, thienyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyridonyl and pyrimidinyl is independently optionally substituted by 1 to 5 R B Instances of ; Or ring B is selected from R is selected from hydrogen, C 1 -C 10 alkyl, 6-10 membered aryl, 3-10 membered cycloalkyl, 5-10 membered heteroaryl and 3-10 membered heterocycloalkyl, wherein each C 1 -C 10 alkyl, 6-10 membered aryl, 3-10 membered cycloalkyl, 5-10 membered heteroaryl and 3-10 membered heterocycloalkyl are independently optionally substituted by 1 to 5 R C Instances of ; Each R A Independently selected from halo, C 1 -C 10 Alkyl, C 1 -C 10 Haloalkyl and C 1 -C 10 Haloalkoxy; Each R B Independently selected from halo, C 1 -C 10 Alkyl and C 1 -C 10 Haloalkyl; Each R C Independently selected from halo, hydroxy and C 1 -C 10 Alkoxy.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from A Examples of substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted with 1 to 3 R A Examples of substituted phenyl groups.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of pyrrolyl, furanyl, furazanyl, thienyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, wherein each of pyrrolyl, furanyl, furazanyl, thienyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl is independently optionally substituted by 1 to 3 R A Instances of .

5. The compound according to claim 1 or 4, or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted with 1 to 3 R A Examples of substituted pyridinyl.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, aza yl, tetrahydropyranyl and tetrahydrofuranyl, Among them, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, aza Each of tetrahydropyranyl, tetrahydrofuranyl and tetrahydropyranyl is independently optionally substituted by 1 to 3 R A Instances of .

7. The compound according to claim 1 or 6, or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted with 1 to 3 R A Examples of are substituted piperidinyl or morpholinyl.

8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is optionally substituted with 1 to 3 R B Examples of substituted phenyl groups.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from benzodioxolyl, pyrrolyl, furanyl, furazanyl, thienyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyridonyl and pyrimidinyl, wherein each of benzodioxolyl, pyrrolyl, furanyl, furazanyl, thienyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl is independently optionally substituted by 1 to 3 R B Instances of .

10. The compound according to claim 1 or 9, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl and thienyl, wherein each of pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl and thienyl is independently optionally substituted by 1 to 3 R B Instances of .

11. The compound according to any one of claims 1 and 8 to 10, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from 12. The compound of any one of claims 1 and 8-10, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from 13. The compound of any one of claims 1 and 8-10, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from 14. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from 15. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from 16. The compound of any one of claims 1 to 7 or 14, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from 17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R is selected from methyl, 18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R is selected from methyl, 19. A compound selected from the following or a pharmaceutically acceptable salt thereof: (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; (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; (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-morpholinyl-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; (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) (S)-5-(3-(1-hydroxypropan-2-yl)-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)picolinic acid methyl ester (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)-one (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)-one (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)-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 (c) (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 (ci) (R)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cii) (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 (ciii) 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 (civ) 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 (cv) 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 (cvi) 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 (cvii) (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 (cviii) (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 (cix)(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 (cx)(R)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxi)(S)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxii) 6-(4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxiii) 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 (cxiv) Methyl (S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoate (cxv) 6-(4-chlorophenyl)-3-(4-hydroxy-1-methylpyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxvi) 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxvii) (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 (cxviii) (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 (cxix) 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 (cxx) 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 (cxxi) 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 (cxxii) 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 (cxxiii) (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 (cxxiv) (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 (cxxv) (S)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxvi) (R)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxvii) 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 (cxxviii) (S)-3-(2-Hydroxypropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxix) (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 (cxxx)(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 (cxxxi) 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 (cxxxii) 6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxiii) 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 (cxxxiv) (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 (cxxxv) (S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoic acid (cxxxvi) (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 (cxxxvii) (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 (cxxxviii) 3-(2-Hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxix) 3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxl) 3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxli)(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 (cxlii) (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 (cxliii) (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 (cxliv)(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 (cxlv)(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 (cxlvi) (S)-8-(diethylamino)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlvii) (S)-3-(1-hydroxypropan-2-yl)-8-(piperidin-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlviii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyrrolidin-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlix)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(piperidin-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cl)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cli)(S)-6-cyclohexyl-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clii)(S)-3-(1-hydroxypropan-2-yl)-6-(pyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cliii)(S)-3-(1-hydroxypropan-2-yl)-6-(2-methylthiazol-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cliv)(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 (clv)(R)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (clvi) (S)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (clvii) (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 (clviii) 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 (clix)(S)-3-(1-hydroxypropan-2-yl)-6-(2-methylpyrimidin-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clx) 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 (clxi)(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 (clxii) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxiii) (S)-5-(3-(1-hydroxypropan-2-yl)-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)picolinic acid (clxiv) (S)-3-(1-hydroxypropan-2-yl)-6-(6-methylpyridin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxv) 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 (clxvi) 3,8-di(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxvii) 8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxviii) 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 (clxix) 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 (clxx)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 (clxxi) 3-cyclopentyl-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxii) 3-phenyl-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxiii) 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 (clxxiv) 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 (clxxv)(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 (clxxvi) 3-(2-Hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxvii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxviii) (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 (clxxix) 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 (clxxx) 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 (clxxxi) 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 (clxxxii) 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)-one (clxxxiii) 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 (clxxxiv) (S)-3-(1-hydroxypropan-2-yl)-8-morpholinyl-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxv) 3-(2-Hydroxy-2-methylpropyl)-8-(piperidin-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxvi) (S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxvii) (S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyrimidin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxviii) (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 (clxxxix)(S)-8-cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxc)(S)-3-(1-Hydroxypropan-2-yl)-N,N-dimethyl-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidine-6-carboxamide (cxci)(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 (cxcii)(S)-3-(1-hydroxypropan-2-yl)-6-(2-methoxyethyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxciii) (S)-3-(1-hydroxypropan-2-yl)-8-(2-methoxyethyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one.

20. A compound selected from the following structural formula: (3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one); (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.

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

22. Use of a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, in the preparation of a medicament for treating a disease or condition mediated by AhR signaling, wherein the disease is selected from digestive tract cancer and metastasis of any of the aforementioned diseases.

23. Use of a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, in the preparation of a medicament for treating a disease or condition associated with abnormal AhR signaling, wherein the disease is selected from digestive tract cancer and metastasis of any of the aforementioned diseases.

24. The use according to claim 22 or 23, wherein the disease is selected from colon cancer.

25. Use of a compound as described in any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 21, in the preparation of a medicament for treating cancer, wherein the medicament can be administered together with at least one additional therapy, wherein the at least one additional therapy is selected from a programmed death-1 pathway inhibitor, and the cancer is colorectal cancer.

26. The use according to claim 25, wherein the programmed death-1 pathway inhibitor is selected from anti-PD-1 antibodies.

27. The use of claim 26, wherein the anti-PD-1 antibody is nivolumab.

28. The use of claim 26, wherein the anti-PD-1 antibody is pembrolizumab.

29. The use of claim 26, wherein the anti-PD-1 antibody is cemiplimab.

30. The use of claim 26, wherein the anti-PD-1 antibody is camrelizumab.

31. The use according to claim 26, wherein the anti-PD-1 antibody is sintilimab.

32. The use of claim 26, wherein the anti-PD-1 antibody is spartalizumab.

33. The use of claim 26, wherein the anti-PD-1 antibody is tislelizumab.

34. The use of claim 26, wherein the anti-PD-1 antibody is BCD-100.

35. The use of claim 26, wherein the anti-PD-1 antibody is JS001.

36. The use according to claim 25, wherein the programmed death-1 pathway inhibitor is selected from an anti-PD-L1 antibody.

37. The use of claim 36, wherein the anti-PD-L1 antibody is atezolizumab.

38. The use of claim 36, wherein the anti-PD-L1 antibody is avelumab.

39. The use of claim 36, wherein the anti-PD-L1 antibody is durvalumab.

40. The use of claim 36, wherein the anti-PD-L1 antibody is KN035.

Images