Pyridopyrimidinone derivatives as AHR antagonists

Abstract

To provide pyridopyrimidinone derivatives as AHR antagonists.SOLUTION: The present disclosure relates to compounds of formula (Ia) and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the same, methods of preparing the same, intermediate compounds useful for preparing the same, and methods for treating or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signaling. These compounds may also be useful in treating cancer when administered in combination with at least one additional therapy.SELECTED DRAWING: None

Description

[Technical Field]

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

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

[0003] Aromatic hydrocarbon receptors (AHRs) are ligand-activated transcription factors belonging to the basic helix-loop-helix / Per-Arnt-Sim (bHLH / PAS) family, located in the cytosol. Upon ligand binding, AHRs translocate to the nucleus, where they heterodimerize with ARNT (AHR nuclear transporter) and simultaneously interact with DRE (dioxin response elements) of AHR response genes, regulating their transcription. AHRs are best known for binding to environmental toxins and inducing metabolic mechanisms such as cytochrome P450 enzymes (e.g., CYP1A1, CYP1A2, and CYP1B1) necessary for their removal (Reyes et al., Science, 1992, 256(5060):1 193-5). Activation of AHRs by xenobiotics has demonstrated their role in many cellular processes, including embryogenesis, tumorigenesis, and inflammation.

[0004] AHR is expressed in many cells of the immune system, including dendritic cells (DCs), macrophages, T cells, and NK cells, and plays an important role in immune regulation (Nguyen et al., Front.Immunol., 2014, 5:551). Classical exogenous AHR ligands, TCDD and 3-methylcholanthrene, are known to induce severe immunosuppression, promote carcinogenesis, and induce tumor growth (Gramatzki et al., Oncogene, 2009, 28(28):2593-605;Bui (Wang et al., Oncogene, 2009, 28(41):3642-51; Esser et al., Trends Immunol., 2009, 30:447-454). In immunosuppressive conditions, AHR activation promotes regulatory T cell generation, directly and indirectly inhibits Th1 and Th17 differentiation, and reduces DC activation and maturation (Wang et al., Clin. Exp. Immunol., 2014, 177(2):521-30; Mezrich et al., J. Immunol., 2010, 185(6):3190-8; Wei et al., Lab. Invest., 2014, 94(5):528-35; Nguyen et al., PNAS, 2010, 107(46):19961-6). AHR activation has been shown to modulate the innate immune response, and constitutive AHR expression has been shown to negatively modulate the type 1 interferon response to viral infection (Yamada et al., Nat.Immunol., 2016, 17(6):687-94). Furthermore, mice with spontaneously constitutively activated AHR develop tumors (Andersson et al., PNAS, 2002, 99(15):9990-5).

[0005] In addition to xenobiotics, AHR can also bind to tryptophan degradation metabolites. 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 to AHR, although their physiological roles are currently unknown (Nguyen & Bradfield, Chem. Res. Toxicol., 2008, 21(1):102-116).

[0006] The immunosuppressive effects of kynurenine and tryptophan degradation are well described and are involved in cancer-related 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-discharging lymph nodes reduces the antitumor immune response, and inhibition of IDO can suppress tumorigenesis in animal models (Uyttenhove et al., Nat. Med., 2003, 9(10):1269-74; Liu et al. al.,Blood,2005,115(17):3520-30;Muller et al.,Nat.Med.,11(3):312-9;Metz,Cancer Res.,2007,67(15):7082-7).

[0007] TDO2 is strongly expressed in cancer cells and can lead to the production of immunosuppressive kynurenine. In gliomas, AHR activation by kynurenine downstream of TDO-mediated tryptophan degradation increases tumor growth as a result of inhibiting the anti-tumor immune response and directly promoting tumor cell survival and motility (Opitz et al., Nature, 2011, 478(7368):197-203). Therefore, AHR ligands produced by tumor cells act on tumor cells and lymphocytes, respectively, through both autocrine and paracrine mechanisms to promote tumor growth.

[0008] Additional therapies may be useful in the treatment of cancer in combination with AhR. Immune checkpoint inhibitors (ICIs) have been used in cancer treatment to enhance the host 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).

[0009] PD-1 is highly expressed by activated T cells, B cells, dendritic cells (DCs), and natural killer cells (NKs), while PD-L1 can be expressed on several types of tumor cells. ICI is currently approved by the 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 carcinoma, cervical cancer, mediastinal large B-cell lymphoma, MSI-H / dMMR colorectal cancer, hepatocellular carcinoma, Merkel cell carcinoma, triple-negative breast cancer, and cutaneous squamous cell carcinoma. [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] Reyes et al.,Science,1992,256(5060):1 193-5 [Non-Patent Document 2] Nguyen et al.,Front.Immunol.,2014,5:551 [Non-Patent Document 3] Gramatzki et al.,Oncogene,2009,28(28):2593-605 [Non-Patent Document 4] Bui et al.,Oncogene,2009,28(41):3642-51 [Non-Patent Document 5] Esser et al.,Trends Immunol.,2009,30:447-454 [Non-Patent Document 6] Wang et al.,Clin.Exp.Immunol.,2014,177(2):521-30 [Non-Patent Document 7] Mezrich et al.,J.Immunol.,2010,185(6):3190-8 [Non-Patent Document 8] Wei et al.,Lab.Invest.,2014,94(5):528-35 [Non-Patent Document 9] Nguyen et al.,PNAS,2010,107(46):19961-6 [Non-Patent Document 10] Yamada et al., Nat. Immunol.,2016,17(6):687-94 [Non-Patent Document 11] Andersson et al.,PNAS,2002,99(15):9990-5 [Non-Patent Document 12] DiNatale et al.,Toxicol.Sci.,2010,115(1):89-97 [Non-Patent Document 13] Mezrich et al.,J.Immunol.,2010,185(6):3190-8 [Non-Patent Document 14] Opitz et al.,Nature,2011,478(7368):197-203 [Non-Patent Document 15] Nguyen&Bradfield,Chem.Res.Toxicol.,2008,21(1):102-116 [Overview of the Initiative] [Means for solving the problem]

[0011] This 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. The compounds of this disclosure have been found to remarkably effectively inhibit AHR, and therefore cancer and / or other pathological conditions in which exogenous and endogenous AHR ligands induce dysregulated immune responses, uncontrolled cell growth, tumor cell proliferation and / or survival, immunosuppression in cancerous conditions, inadequate cellular immune responses, or inadequate cellular inflammatory responses, or diseases accompanied by uncontrolled cell growth, tumor cell proliferation and / or survival, immunosuppression in cancerous conditions, inadequate cellular immune responses, or inadequate cellular inflammatory responses, particularly uncontrolled It may be used in the treatment or prevention of diseases in which cell growth, tumor cell proliferation and / or survival, immunosuppression in cancerous conditions, inadequate cellular immune responses, or inadequate cellular inflammatory responses are mediated by AHR, such as 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 / or their metastases.

[0012] This disclosure also relates to a pharmaceutical composition comprising at least one entity selected from compounds of formula (I) or formula (Ia) and pharmaceutically acceptable salts thereof. This disclosure also relates to a method of treatment comprising administering at least one compound of this disclosure, a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition. In some embodiments, this disclosure provides a method for treating a disease or condition mediated by AHR signaling. In some embodiments, this disclosure provides a method for treating a disease or condition associated with abnormal AHR signaling. In some embodiments, this disclosure provides a method for inhibiting cancer cell proliferation mediated by AHR signaling. The present invention provides, for example, the following items: (Item 1) Compounds of formula I: [ka] and its pharmaceutically acceptable salt (In the formula: R 1 and R 2 Each of these is independently selected from optionally substituted alkyls, optionally substituted esters, optionally substituted heteroalkyls, optionally substituted acyls, optionally substituted amides, optionally substituted aryls, optionally substituted heteroaryls, optionally substituted cycloalkyls, optionally substituted amines, and optionally substituted heterocycloalkyls; and R 3 (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, optionally substituted amine, cyano, halo, hydroxy, and -C(O)H). (Item 2) Compounds of formula Ia [ka] or a pharmaceutically acceptable salt thereof (In the formula: Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; Ring B is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; and 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). (Item 3) Ring A is selected from optionally substituted 6-10 member aryl groups, optionally substituted 5-10 member heteroaryl groups, optionally substituted 3-10 member cycloalkyl groups, and optionally substituted 3-10 member heterocycloalkyl groups; Ring B is selected from optionally substituted 6-10 member aryl groups, optionally substituted 5-10 member heteroaryl groups, optionally substituted 3-10 member cycloalkyl groups, and optionally substituted 3-10 member heterocycloalkyl groups; R is replaced by hydrogen, or C1-C as chosen. 10 Alkyl, optionally substituted 6-10 member aryl, -C(O)R', -C(O)NR'R', optionally substituted 3-10 member cycloalkyl, -C(O)OR', optionally substituted C1-C 10 Selected from heteroalkyls, optionally substituted 5-10 member heteroaryls, optionally substituted 3-10 member heterocycloalkyls, amino, cyano, halo, hydroxy, and -C(O)H; and Each R' is replaced by hydrogen, or C1-C as chosen. 10 Alkyl and optionally substituted C1-C 10 A compound listed in item 2, or a pharmaceutically acceptable salt thereof, independently selected from heteroalkyls. (Item 4) Ring A is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl, and each of the 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl groups is used for 1-5 R groups. A It is independently and arbitrarily replaced by; Ring B is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocycloalkyl, and each 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocycloalkyl is independently optionally substituted by 1 to 5 instances of R B ; R is selected from hydrogen, C1-C 10 alkyl, 6- to 10-membered aryl, -C(O)R', -C(O)NR'R', 3- to 10-membered cycloalkyl, -C(O)OR', C1-C 10 heteroalkyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H, and each C1-C 10 alkyl, 6- to 10-membered aryl, 3- to 10-membered cycloalkyl, C1-C 10 heteroalkyl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocycloalkyl is independently optionally substituted by 1 to 5 instances of R C ; each R' is independently selected from hydrogen, C1-C 10 alkyl, C1-C 10 haloalkyl, C1-C 10 hydroxyalkyl, and C1-C 10 heteroalkyl; each R A is independently selected from halo, hydroxy, C1-C 10 alkyl, C1-C 10 haloalkyl, C1-C 10 alkoxy, C1-C 10 haloalkoxy, C1-C 10 hydroxyalkyl, and NR''R''; each R B is independently selected from halo, hydroxy, C1-C 10 alkyl, C1-C 10 haloalkyl, C1-C 10 alkoxy, C1-C 10 haloalkoxy, C1-C 10 hydroxyalkyl, and NR''R''; each RC However, halo, hydroxy, cyano, C1~C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Independently selected from haloalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and Each R'' is hydrogen, C1~C 10 Alkyl, C1-C 10 Haloalkyl, C1~C 10 Hydroxyalkyl, and C1-C 10 A compound described in item 2 or 3, independently selected from heteroalkyls, or a pharmaceutically acceptable salt thereof. (Item 5) Ring A has 1 to 5 cases of R A A compound described in item 4 or a pharmaceutically acceptable salt thereof, selected from a 3- to 10-membered cycloalkyl group optionally substituted by the specified method. (Item 6) Ring A has 1 to 5 cases of R A A compound described in item 4 or 5, or a pharmaceutically acceptable salt thereof, selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, optionally substituted by [the specified agent]. (Item 7) Ring A has 1 to 5 cases of R A A compound described in item 4 or a pharmaceutically acceptable salt thereof, selected from a 6- to 8-membered aryl group optionally substituted by the aforementioned method. (Item 8) Ring A has 1 to 3 cases of R A A compound described in item 4 or 7, or a pharmaceutically acceptable salt thereof, which is a phenyl optionally substituted by [the specified agent]. (Item 9) Ring A has 1 to 5 cases of R A A compound described in item 4 or a pharmaceutically acceptable salt thereof, selected from 5- to 8-membered heteroaryl compounds optionally substituted by the aforementioned method. (Item 10) Ring A is selected from pyrrolyl, furanil, furazanil, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridadinyl, and pyrimidinyl. Each of the following has 1-3 cases of R A A compound or pharmaceutically acceptable salt thereof, as described in item 4 or 9, which is independently and optionally substituted by the specified compound. (Item 11) Ring A has 1 to 3 cases of R A A compound or a pharmaceutically acceptable salt thereof described in any one of items 4, 9, and 10, which is a pyridinyl optionally substituted by. (Item 12) Ring A has 1 to 5 cases of R A A compound described in item 4 or a pharmaceutically acceptable salt thereof, selected from 5- to 8-membered heterocycloalkyl groups optionally substituted by the aforementioned method. (Item 13) Ring A is selected from pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydropyranil, and tetrahydrofuranil. Pyrrolidinil, pyrazolidinil, piperidinil, piperazinil, morpholino, azepinil, tetrahydropyranil, and tetrahydrofuranil each account for 1 to 3 cases of R A A compound or pharmaceutically acceptable salt thereof, as described in item 4 or 12, which is independently and optionally substituted by [the specified compound]. (Item 14) Ring A has 1 to 3 cases of R A A compound or pharmaceutically acceptable salt thereof described in any one of items 4, 12, and 13, which is optionally substituted with piperidinyl or morpholino. (Item 15) Ring B has 1 to 5 cases of R BA compound described in item 4 or a pharmaceutically acceptable salt thereof, selected from a 6- to 8-membered aryl group optionally substituted by the aforementioned method. (Item 16) Ring B has 1-3 cases of R B A compound described in item 4 or 15, or a pharmaceutically acceptable salt thereof, which is a phenyl optionally substituted by [the specified agent]. (Item 17) Ring B has 1 to 5 cases of R B A compound described in item 4, or a pharmaceutically acceptable salt thereof, selected from benzodioxolyl and 5- to 8-membered heteroaryl compounds optionally substituted by the aforementioned method. (Item 18) Ring B is selected from benzodioxolyl, pyrrolyl, furanil, furazanil, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridadinyl, pyridinonyl, and pyrimidinyl. Each of the following has 1-3 cases of R B Compounds described in item 4 or 17, or pharmaceutically acceptable salts thereof, which are independently and optionally substituted by the specified compound. (Item 19) Ring B is selected from pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl. Pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl each account for 1 to 3 cases of R B A compound or a pharmaceutically acceptable salt thereof described in any one of items 4, 17, and 18, which is independently and optionally substituted by. (Item 20) Each R A But, Hello, C1~C 10 Alkyl, C1-C 10Haloalkyl, C1~C 10 Alkoxy, C1-C 10 Selected independently from haloalkoxys and NR''R''; Each R B But, Hello, C1~C 10 Alkyl, and C1-C 10 Independently selected from haloalkyl groups; Each R C However, halo, hydroxy, cyano, C1~C 10 Alkyl, C1-C 10 Independently selected from alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, and 6-8 membered aryl; and Each R'' is hydrogen and C1~C 10 A compound independently selected from alkyl groups, or a pharmaceutically acceptable salt thereof, as described in any one of items 4 to 19. (Item 21) Ring A is [ka] A compound or a pharmaceutically acceptable salt thereof, selected from any one of items 2-4 and 7-20. (Item 22) Ring A is [ka] A compound or a pharmaceutically acceptable salt thereof, selected from any one of items 2-6 and 15-20. (Item 23) Ring A is [ka] A compound or a pharmaceutically acceptable salt thereof, selected from any one of items 2-4 and 7-20. (Item 24) Ring B is [ka] A compound or a pharmaceutically acceptable salt thereof, selected from any one of items 2-4 and 7-20. (Item 25) Ring B is [ka] A compound or a pharmaceutically acceptable salt thereof, selected from any one of items 2-14 and 20. (Item 26) Ring B is [ka] A compound or a pharmaceutically acceptable salt thereof, selected from any one of items 2-4 and 7-20. (Item 27) R is methyl, [ka] A compound or a pharmaceutically acceptable salt thereof, selected from any one of items 2 to 26. (Item 28) R is methyl, [ka] A compound or a pharmaceutically acceptable salt thereof, selected from any one of items 2 to 27. (Item 29) At least one entity selected from the following compounds and a pharmaceutically acceptable salt thereof: (i)(S)-8-(5-fluoropyridine-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (ii)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(6-oxo-1,6-dihydropyridine-3-yl)pyrido[3,4-d]pyrimidine-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]pyrimidine-4(3H)-one; (iv)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (v)(S)-8-(5-fluoropyridine-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (vi)(S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridine-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (vii)(S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (viii)(S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (ix)3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (x)6,8-di(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xi)(S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xii)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xiii)6-(4-chlorophenyl)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xiv)8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xv)6-(4-chlorophenyl)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xvi)3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xvii)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xviii)6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xix)3-(2-hydroxy-2-methylpropyl)-6,8-bis(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xx)(S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxi)6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxii)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxiii)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxiv)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxv)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxvi)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-phenylpyrido[3,4-d]pyrimidine-4(3H)-one; (xxvii)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxviii)3-methyl-8-(pyridine-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxix)Rac-6-(4-chlorophenyl)-3-((trans)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxx)(S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxi)(R)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxii)rac-6-(4-chlorophenyl)-3-((cis)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxiii)(R)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxiv)(S)-3-(3-hydroxy-3-methylbutan-2-yl)-6,8-di(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxv)(S)-6,8-bis(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxvi)(S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxvii)(S)-8-(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxviii)6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(2-hydroxy-2-methylpropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxix)(R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xl)(S)-3-(1-(benzyloxy)propan-2-yl)-8-(3-fluorophenyl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xli)(R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xlii)(S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xliii)(S)-3-(1-hydroxypropan-2-yl)-6-morpholino-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xliv)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazole-1-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xlv)(S)-3-(1-methoxypropan-2-yl)-8-(pyridine-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xlvi)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xlvii)(S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xlviii)(S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xlix)(S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (l)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethoxy)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (li)(S)-3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lii)methyl(S)-5-(3-(1-hydroxypropan-2-yl)-4-oxo-8-(pyridine-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidine-6-yl)picolinate (liii)(S)-3-(1-hydroxypropan-2-yl)-6-(isothiazol-4-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (liv)3-(2-hydroxy-2-methylpropyl)-8-(isothiazol-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lv)(S)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lvi)(S)-3-(1-hydroxypropan-2-yl)-6,8-di(isothiazol-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lvii)(S)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lviii)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lix)3-(2-hydroxy-2-methylpropyl)-6,8-di(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lx)3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxi)6-(4-chloro-2-methylphenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxii)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxiii)(S)-3-(1-hydroxypropan-2-yl)-8-(2-methylpyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxiv)(S)-3-(1-hydroxypropan-2-yl)-8-(4-methylpyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxv)(S)-3-(1-hydroxypropan-2-yl)-6-(4-methylthiazole-5-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxvi)(S)-6-(2-cyclopropylthiazole-5-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxvii)(S)-3-(1-hydroxypropan-2-yl)-6-(2-isopropylthiazole-5-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxviii)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxix)(S)-3-(1-hydroxypropan-2-yl)-6,8-bis(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxx)6-(4-chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxi)6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxii)3-(2-hydroxyethyl)-8-(pyridine-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxiii)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-6-oxo-1,6-dihydropyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxiv)(S)-6-(6-cyclopropylpyridine-3-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxv)(S)-3-(1-hydroxypropan-2-yl)-6-(4-methyl-6-(trifluoromethyl)pyridine-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxvi)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxvii)(S)-6-(cyclohexa-1-en-1-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxviii)(S)-6,8-bis(5-fluoropyridine-3-yl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxix)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxx)3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxi)6-(6-cyclopropylpyridine-3-yl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxii)6-(6-cyclopropylpyridine-3-yl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxiii)(S)-6-(6-cyclopropylpyridine-3-yl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxiv)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxv)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxvi)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)pyrimidine-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxvii)3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxviii)3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxix)(S)-3-(1-hydroxypropan-2-yl)-6-(2-methylthiazole-5-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xc)(S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xci)(S)-3-(1-hydroxypropan-2-yl)-6-(piperidine-1-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xcii)3-(2-hydroxy-2-methylpropyl)-8-(isothiazol-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xciii)(S)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xciv)3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xcv)(S)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xcvi)(3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xcvii)3-(1,1-dioxidetetrahydrothiophen-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xcviii)(R)-3-(1,1-dioxidetetrahydrothiophen-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xcix)(R)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (c)(S)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (ci)(R)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cii)(S)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (ciii)(R)-3-(2-hydroxypropyl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (civ)(R)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cv)3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cvi)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cvii)6-(4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cviii)3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cix)(S)-6-(6-cyclopropylpyridine-3-yl)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one (cx)(R)-6-(6-cyclopropylpyridine-3-yl)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxi)(R)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxii)(R)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxiii)(S)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxiv)6-(4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxv)3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxvi)methyl(S)-2-(4-oxo-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-3(4H)-yl)propanoate (cxvii)6-(4-chlorophenyl)-3-(4-hydroxy-1-methylpyrrolidine-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxviii)6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidine-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxix)(R)-6-(6-cyclopropylpyridine-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxx)(S)-6-(6-cyclopropylpyridine-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxi)3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxii)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxiii)3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxiv)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxv)(R)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxvi)(S)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxvii)(S)-3-(2-hydroxypropyl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxviii)(R)-3-(2-hydroxypropyl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxix)3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxx)(S)-3-(2-hydroxypropyl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxxi)(S)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxxii)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxxiii)3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxxiv)6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxxv)6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxxvi)(R)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxxvii)(S)-2-(4-oxo-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-3(4H)-yl)propanoic acid (cxxxviii)(S)-N-methyl-2-(4-oxo-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-3(4H)-yl)propanamide (cxxxix)(S)-N,N-dimethyl-2-(4-oxo-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-3(4H)-yl)propenamide (cxl)3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxli)3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazole-1-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxlii)3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazole-1-yl)-6-(6-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxliii)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazole-1-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxliv)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazole-1-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxlv)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-1,2,4-triazole-1-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxlvi)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazole-1-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxlvii)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxlviii)(S)-8-(diethylamino)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxlix)(S)-3-(1-hydroxypropan-2-yl)-8-(piperidine-1-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cl)(S)-3-(1-hydroxypropan-2-yl)-8-(pyrrolidine-1-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cli)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(piperidine-1-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clii)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-2-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cliii)(S)-6-cyclohexyl-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cliv)(S)-3-(1-hydroxypropan-2-yl)-6-(pyridine-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clv)(S)-3-(1-hydroxypropan-2-yl)-6-(2-methylthiazole-4-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clvi)(S)-3-(1-hydroxypropan-2-yl)-6-(1-methyl-1H-1,2,3-triazole-5-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clvii)(R)-6-(4-chlorophenyl)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clviii)(S)-6-(4-chlorophenyl)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clix)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1,2,5,6-tetrahydropyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clx)6-(4-chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxi)(S)-3-(1-hydroxypropan-2-yl)-6-(2-methylpyrimidine-5-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxii)3-(2-hydroxy-2-methylpropyl)-8-(1-(trifluoromethyl)-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxiii)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(2-(trifluoromethyl)pyrimidine-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxiv)3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)pyrimidine-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxv)(S)-5-(3-(1-hydroxypropan-2-yl)-4-oxo-8-(pyridine-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidine-6-yl)picolinic acid (clxvi)(S)-3-(1-hydroxypropan-2-yl)-6-(6-methylpyridine-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxvii)3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(2-(trifluoromethyl)pyrimidine-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxviii)3,8-di(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxix)8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxx)3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxi)3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxii)6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxiii)3-Cyclopentyl-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxiv)3-phenyl-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxv)3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxvi)3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxvii)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxviii)(S)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-2-(4-oxo-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-3(4H)-yl)propanamide (clxxix)3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxx)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazole-1-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxxi)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazole-1-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxxii)3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxxiii)3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxxiv)3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxxv)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxxvi)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxxvii)(S)-3-(1-hydroxypropan-2-yl)-8-morpholino-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxxviii)3-(2-hydroxy-2-methylpropyl)-8-(piperidine-1-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxxix)(S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyridine-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxc)(S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyrimidine-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxci)(S)-8-(cyclohexa-1-en-1-yl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxcii)(S)-8-cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxciii)(S)-3-(1-hydroxypropan-2-yl)-N,N-dimethyl-4-oxo-8-(pyridine-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidine-6-carboxamide (cxciv)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxcv)(S)-3-(1-hydroxypropan-2-yl)-6-(2-methoxyethyl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxcvi)(S)-3-(1-hydroxypropan-2-yl)-8-(2-methoxyethyl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one. (Item 30) A pharmaceutical composition comprising at least one entity selected from the compounds and pharmaceutically acceptable salts thereof described in any one of items 1 to 29, and at least one pharmaceutically acceptable excipient. (Item 31) A method for treating a disease or condition mediated by AhR signaling in a subject that requires treatment of the disease or condition mediated by AhR signaling, the method comprising administering to the subject at least one entity selected from a compound according to any one of items 1 to 29 and a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition according to item 30, in a therapeutically effective amount. (Item 32) A method for treating a disease or condition associated with abnormal AhR signaling in a subject that requires treatment of the disease or condition associated with abnormal AhR signaling, the method comprising administering to the subject at least one entity selected from a compound according to any one of items 1 to 29 and a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition according to item 30, in a therapeutically effective amount. (Item 33) The method according to item 31 or 32, wherein the disease is selected from cancer. (Item 34) The method according to item 31 or 32, wherein the disease is selected from liquid tumors and solid tumors. (Item 35) The method according to any one of items 31 to 34, wherein the disease is selected from breast cancer, airway cancer, brain cancer, genital cancer, gastrointestinal cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and metastases of any of the above. (Item 36) The method according to any one of items 31 to 35, wherein the disease is selected from breast cancer, pancreatic cancer, prostate cancer, and colon cancer. (Item 37) <( The method according to any one of items 31 to 34, wherein the disease is selected from lymphoma, sarcoma, melanoma, glioblastoma, and leukemia. (Item 38) A method for inhibiting AHR-mediated cancer cell proliferation in a subject that requires inhibition of AHR-mediated cancer cell proliferation, the method comprising administering to the subject at least one entity selected from the compounds described in any one of items 1 to 29 and pharmaceutically acceptable salts thereof, or at least one pharmaceutical composition described in item 30, in a therapeutically effective amount. (Item 39) A method for inhibiting AHR-mediated tumor cell infiltration or metastasis in a subject that requires inhibition of AHR-mediated tumor cell infiltration or metastasis, the method comprising administering to the subject at least one entity selected from the compounds described in any one of items 1 to 29 and pharmaceutically acceptable salts thereof, or at least one pharmaceutical composition described in item 30, in a therapeutically effective amount. (Item 40) A method for treating cancer in a subject that requires treatment of cancer, the method comprising administering to the subject i) at least one entity selected from the compounds described in any one of items 1 to 29 and pharmaceutically acceptable salts thereof, or at least one pharmaceutical composition described in item 30, in a therapeutically effective amount, and ii) at least one additional therapy in a therapeutically effective amount. (Item 41) The method according to item 40, wherein the at least one additional therapy comprises at least two, at least three, at least four, or at least five additional therapies. (Item 42) The method according to item 40, wherein the administration of the at least one entity selected from the compounds described in any one of items 1 to 29 and pharmaceutically acceptable salts thereof, or at least one pharmaceutical composition described in item 30, is initiated before the administration of the at least one additional therapy. (Item 43) The method according to item 40, wherein at least one entity selected from any one of the compounds described in item 1 to 29 and pharmaceutically acceptable salts thereof, or at least one pharmaceutical composition described in item 30, is administered after the administration of the at least one additional therapy. (Item 44) The method according to item 40, wherein at least one entity selected from any one of the compounds described in item 1 to 29 and pharmaceutically acceptable salts thereof, or at least one pharmaceutical composition described in item 30, is administered concurrently with the administration of the at least one additional therapy. (Item 45) The method according to any one of items 40 to 44, wherein the aforementioned at least one additional therapy is selected from checkpoint inhibitors. (Item 46) The method according to item 45, wherein the subject is intolerant, unresponsive, and / or poorly responsive when the at least one additional therapy is administered alone. (Item 47) The method according to item 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. (Item 48) The method according to item 46, wherein the at least one additional therapy is selected from checkpoint inhibitors targeting CTLA-4, PD-1, and / or PD-L1. (Item 49) The method according to item 46, wherein at least one additional therapy is selected from cytotoxic T lymphocyte-associated antigen 4 pathway inhibitors. (Item 50) The method according to item 49, wherein the cytotoxic T lymphocyte-associated antigen 4 pathway inhibitor is selected from anti-CTLA-4 antibodies. (Item 51) The method according to item 50, wherein the anti-CTLA-4 antibody is ipilimumab. (Item 52) The method according to item 46, wherein at least one additional therapy is selected from programmed death-1 pathway inhibitors. (Item 53) The method according to item 52, wherein the programmed death-1 pathway inhibitor is selected from anti-PD-1 antibodies. (Item 54) The method according to item 52, wherein the anti-PD-1 antibody is nivolumab. (Item 55) The method according to item 52, wherein the anti-PD-1 antibody is pembrolizumab. (Item 56) The method according to item 52, wherein the anti-PD-1 antibody is cemiprimab. (Item 57) The method according to item 52, wherein the anti-PD-1 antibody is camrelizumab. (Item 58) The method according to item 52, wherein the anti-PD-1 antibody is cintilimab. (Item 59) The method according to item 52, wherein the anti-PD-1 antibody is spartalizumab. (Item 60) The method according to item 52, wherein the anti-PD-1 antibody is tislerizumab. (Item 61) The method according to item 52, wherein the anti-PD-1 antibody is BCD-100. (Item 62) The method according to item 52, wherein the anti-PD-1 antibody is JS001. (Item 63) The method according to item 52, wherein the programmed death-1 pathway inhibitor is selected from anti-PD-L1 antibodies. (Item 64) The method according to item 63, wherein the anti-PD-L1 antibody is atezolizumab. (Item 65) The method according to item 63, wherein the anti-PD-L1 antibody is avelumab. (Item 66) The method according to item 63, wherein the anti-PD-L1 antibody is durvalumab. (Item 67) The method according to item 63, wherein the anti-PD-L1 antibody is KN035. (Item 68) The method according to item 46, wherein the at least one additional therapy is selected from lymphocyte activation gene-3 (LAG-3) inhibitors. (Item 69) The method according to item 68, wherein the LAG-3 inhibitor is selected from anti-LAG-3 antibodies. (Item 70) The method according to item 46, wherein the at least one additional therapy is selected from T cell immunoglobulin and mucin domain-containing-3 (TIM-3) inhibitors. (Item 71) The method according to item 70, wherein the TIM-3 inhibitor is selected from anti-TIM-3 antibodies. (Item 72) The method according to item 46, wherein the at least one additional therapy is selected from T cell immunoglobulin and ITIM domain (TIGIT) inhibitors. (Item 73) The method according to item 72, wherein the TIGIT inhibitor is selected from TIGIT antibodies. (Item 74) The method according to item 46, wherein the at least one additional therapy is selected from V domain Ig suppressor of T cell activation (VISTA) inhibitors. (Item 75) The method according to item 74, wherein the VISTA inhibitor is selected from anti-VISTA antibodies. (Item 76) The aforementioned cancers include non-small cell lung cancer (NSCLC); small cell lung cancer; head and neck squamous cell carcinoma; renal cell carcinoma; gastric adenocarcinoma; nasopharyngeal neoplasm; urothelial carcinoma; colorectal cancer; pleural mesothelioma; triple-negative breast cancer (TNBC); esophageal neoplasm; multiple myeloma; gastric and gastroesophageal junction cancer; melanoma; Hodgkin lymphoma; hepatocellular carcinoma; lung cancer; head and neck cancer; non-Hodgkin lymphoma; metastatic clear cell renal cancer; squamous cell lung cancer; mesothelioma; gastric cancer; gastroesophageal junction cancer; metastatic melanoma; metastatic noncutaneous melanoma; urothelial carcinoma; diffuse large B-cell lymphoma; The method according to any one of items 40 to 75, selected from renal cell carcinoma; ovarian cancer, fallopian tube cancer; peritoneal neoplasm; advanced small cell lung cancer; bladder cancer; transitional cell carcinoma; prostate neoplasm; recurrent or metastatic PD-L1-positive or metastatic squamous cell carcinoma of the head and neck (SCCHN); recurrent squamous cell lung cancer; advanced solid malignant tumor; SCCHN; hypopharyngeal squamous cell carcinoma; laryngeal squamous cell carcinoma; unresectable or metastatic melanoma; biliary tract neoplasm; esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, glioblastoma, metastatic cancer, prostate cancer, parenchymal organ cancer; gastric cancer; colon cancer; and liver cancer. [Brief explanation of the drawing]

[0013] [Figure 1] The dosing regimen used in an in vivo syngeneic model study with CT26 Balb / C mice is shown. [Figure 2] This shows tumor growth curves in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy, comparing vehicle-based monotherapy with a PD-L1 antibody or compound 7 combined with a PD-L1 antibody. [Figure 3] This shows the tumor weight at the end of testing in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy, comparing vehicle versus monotherapy with a PD-L1 antibody or compound 7 with a PD-L1 antibody. [Figure 4] This shows tumor growth curves in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy, comparing vehicle-based monotherapy with a PD-L1 antibody or compound 30 combined with a PD-L1 antibody. [Figure 5] This shows the tumor weight at the end of testing in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy, comparing vehicle versus monotherapy with a PD-L1 antibody or compound 30 with a PD-L1 antibody. [Figure 6]This shows tumor growth curves in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy, comparing vehicle-based monotherapy with a PD-L1 antibody or compound 30 combined with a PD-L1 antibody. [Figure 7] This shows the tumor weight at the end of testing in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy, comparing vehicle versus monotherapy with a PD-L1 antibody or compound 30 with a PD-L1 antibody. [Figure 8] This shows tumor growth curves in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy, comparing vehicle-based monotherapy with a PD-L1 antibody or compound 9 combined with a PD-L1 antibody. [Figure 9] This shows the tumor weight at the end of the vehicle-versus-single-agent PD-L1 antibody or PD-L1 antibody combined with compound 9 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy. [Figure 10] This shows tumor growth curves in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy, comparing vehicle-based monotherapy with a PD-L1 antibody or compound 9 combined with a PD-L1 antibody. [Figure 11] This shows the tumor weight at the end of the vehicle-versus-single-agent PD-L1 antibody or PD-L1 antibody combined with compound 9 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy. [Figure 12] This shows tumor growth curves in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy, comparing vehicle-based monotherapy with a PD-L1 antibody or a PD-L1 antibody combined with compound 46. [Figure 13] This shows the tumor weight at the end of testing in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy, comparing vehicle versus monotherapy with a PD-L1 antibody or compound 46 with a PD-L1 antibody. [Figure 14] This shows plots of the mean plasma concentrations of compound 46 over time after 1 mg / kg IV and 10 mg / kg PO in CD1 mice. [Figure 15] This shows plots of the mean plasma concentrations of compound 46 over time after 1 mg / kg IV and 3 mg / kg PO in SD rats. [Figure 16]This shows the time-course mean plasma concentrations of compound 9 after 1 mg / kg IV and 10 mg / kg PO in CD1 mice. [Figure 17] This shows plots of the mean plasma concentrations of compound 9 over time after 1 mg / kg IV and 3 mg / kg PO in SD rats. [Modes for carrying out the invention]

[0014] As used herein, the term “pharmaceutically acceptable salt” means a salt of the parent compound that is pharmaceutically acceptable as defined herein and has the desired pharmacological activity. Non-limiting examples of pharmaceutically acceptable salts include those derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as those derived from organic acids, such as 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.

[0015] Additional non-limiting examples of pharmaceutically acceptable salts include those formed when acidic protons in the parent compound are substituted by metal ions, including, in non-limiting examples, alkali metal ions and alkaline earth metal ions, and those formed when acidic protons present in the parent compound are substituted by ammonium ions, primary ammonium ions, secondary ammonium ions, tertiary ammonium ions, or quaternary ammonium ions. 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.

[0016] The ranges provided herein are understood to be abbreviated representations of all values ​​within that range. For example, the range 1–50 is understood to include all numbers, combinations of numbers, or subranges thereof 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 values ​​within a range are not specifically referred to herein.

[0017] As used herein, the terms “checkpoint inhibitor” and “checkpoint inhibitor therapy” are used interchangeably to refer to any therapeutic agent comprising any small molecule chemical compound, antibody, nucleic acid molecule, or polypeptide, or any fragment thereof, that inhibits one or more inhibitory pathways, thereby enabling greater immune activity. In some embodiments, checkpoint inhibitor therapy comprises administering at least one checkpoint inhibitor to a patient in need of such therapy.

[0018] The term “compound,” as used herein, refers to a group of molecules having the same chemical structure as a group of stereoisomers (e.g., a group of racemates, a group of cis / trans stereoisomers, or a group of (E) and (Z) stereoisomers), unless otherwise specified. Therefore, geometric and conformational mixtures of the compounds and salts are within the scope of this disclosure. Unless otherwise specified, all tautomeral forms of the compounds disclosed are within the scope of this disclosure.

[0019] As used herein, "stereoisomers" refers to enantiomers and diastereomers.

[0020] As used herein, the term "tautomer" refers to one of two or more isomers of a compound that exist together in equilibrium and readily interchange through the movement of atoms or groups within the molecule.

[0021] Unless otherwise indicated, the nomenclature used to describe chemical groups or parts as used herein follows the convention of reading the name from left to right, with the bond point to the rest of the molecule located to the right of the name. For example, the group "(C 1~3 Alkoxy)C 1~3 Alkyl atoms are bonded to the rest of the molecule at their alkyl end. Further examples include methoxyethyl, which has its bond at the ethyl end, and methylamino, which has its bond at the amine end.

[0022] Unless otherwise indicated, if a chemical group is described by its chemical formula or structure having terminal bond portions indicated by "-", it will be understood that "-" represents a bond point. In some embodiments, the dashed line (i.e.) [ka] ) represents the connection point.

[0023] As used herein, “acyl” or “alkanoyl” refers to a functional group having the formula RCO-, where R is bonded to a carbon atom of the carbonyl functional group by a single bond, and “-” indicates a bond to the rest of the molecule. Non-exclusive examples of acyls include formyl (HC(O)-, also called metanoyl), acetyl (CH3C(O)-, also called ethanolyl), and benzoyl (PhC(O)-).

[0024] As used herein, the terms “alkyl” or “aliphatic” mean a substituted or unsubstituted hydrocarbon chain that is fully saturated and has a single bond to the rest of the molecule, whether linear (i.e., unbranched) or branched. Unless otherwise specified, alkyl groups are hydrocarbon chains of 1 to 20 alkyl carbon atoms. In some embodiments, alkyl groups contain 1 to 12 carbon atoms (C1 to C2). 12). In some embodiments, the alkyl group contains 1 to 8 carbon atoms (C1 to C8). In some embodiments, the alkyl group contains 1 to 6 carbon atoms (C1 to C6). In some embodiments, the alkyl group contains 1 to 4 carbon atoms (C1 to C4). In some embodiments, the cyclic alkyl group contains 3 to 6 carbon atoms (C3 to C6). Non-limiting examples of substituted and unsubstituted linear, branched, and cyclic alkyl groups include methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, sec-butyl, iso-butyl, 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.

[0025] As used herein, "alkoxy" refers to the previously defined alkyl group in which an oxygen ("alkoxy") atom is bonded to the main carbon chain.

[0026] As used herein, "halo" and "halogen" are interchangeable and refer to halogen atoms such as fluoro(F), chloro(Cl), bromo(Br), and iod(I).

[0027] "Haloalkyl" refers to an alkyl group substituted with one or more halo atoms (F, Cl, Br, I). For example, "fluoromethyl" refers to a methyl group substituted with one or more fluoro atoms (e.g., monofluoromethyl, difluoromethyl, or trifluoromethyl).

[0028] "Haloalkoxy" refers to an alkoxy group substituted with one or more halo atoms (F, Cl, Br, I). For example, "fluoromethoxy" refers to a methoxy group substituted with one or more fluoro atoms (e.g., monofluoromethoxy, difluoromethoxy, or trifluoromethoxy).

[0029] "Hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl groups (-OH).

[0030] In this specification, the terms “cycloalkyl” and “cycloalkyl” are used interchangeably to refer to a cyclic saturated monovalent hydrocarbon group of 3 to 12 carbon atoms having a single bond site to the rest of the molecule. Cycloalkyls may be unsubstituted or substituted. In some embodiments, cycloalkyls contain 3 to 8 carbon atoms (C3 to C8). In some embodiments, cycloalkyls contain 3 to 6 carbon atoms (C3 to C6). Non-limiting examples of substituted and unsubstituted cycloalkyls include cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0031] The terms "alkylene" and "alkylene group," as used interchangeably in this specification, refer to a group of 1 to 12 carbon atoms (C1 to C12). 12 This refers to a saturated divalent (i.e., having two bonding points to the rest of the molecule) hydrocarbon group containing ) ). The alkylene group may be linear, branched, or cyclic. The alkylene group may be unsubstituted or substituted. In some embodiments, the alkylene group contains 1 to 8 carbon atoms (C1 to C8). In some embodiments, the alkylene group contains 1 to 6 carbon atoms (C1 to C6). In some embodiments, the alkylene group contains 1 to 4 carbon atoms (C1 to C4). Non-limiting examples of alkylene groups include methylene and ethylene.

[0032] The terms “alkenyl” and “alkenyl group,” as used interchangeably herein, refer to a monovalent (i.e., having one bond site to the rest of the molecule) hydrocarbon group containing 2 to 8 carbon atoms (C2 to C8) and having at least one unsaturated site (i.e., an sp2 carbon-carbon double bond). The alkenyl group may be linear, branched, or cyclic. The alkenyl group may be unsubstituted or substituted. In some embodiments, the alkenyl group contains 2 to 6 carbon atoms (C2 to C6). In some embodiments, the alkenyl group contains 2 to 4 carbon atoms (C2 to C4). The alkenyl group may have either an E configuration or a Z configuration. Non-limiting examples of alkenyl groups include ethenyl (also called vinyl), 1-propenyl, iso-propenyl, and 2-chloroethenyl.

[0033] In this specification, the terms “alkenylene” and “alkenylene group” are interchangeable and refer to a divalent (i.e., having two bonding sites to the rest of the molecule) hydrocarbon group of 2 to 8 carbon atoms (C2 to C8) having at least one unsaturated site (e.g., an sp2 carbon-carbon double bond). Alkenylene groups may be linear, branched, or cyclic. Alkenylene groups may be unsubstituted or substituted. In some embodiments, alkylene groups contain 2 to 6 carbon atoms (C2 to C6). In some embodiments, alkylene groups contain 2 to 4 carbon atoms (C2 to C4). Alkylene groups may have either an E configuration or a Z configuration. A non-limiting example of an alkenyl group is ethenylene (also called vinylene).

[0034] The terms “alkynyl” and “alkynyl group,” as used interchangeably herein, refer to a monovalent (i.e., having one bond site to the rest of the molecule) hydrocarbon group comprising 2 to 8 carbon atoms (C2 to C8) having at least one unsaturated site (i.e., an sp-carbon triple bond). The alkynyl group may be linear or branched. The alkynyl group may be unsubstituted or substituted. In some embodiments, the alkynyl group contains 2 to 6 carbon atoms (C2 to C6). In some embodiments, the alkynyl group contains 2 to 4 carbon atoms (C2 to C4). A non-limiting example of an alkynyl group is ethynyl.

[0035] The terms "alkylene" and "alkylene group," as used interchangeably herein, refer to a divalent (i.e., having two bonding sites to the rest of the molecule) hydrocarbon group of 2 to 8 carbon atoms (C2 to C8) having at least one unsaturated site (i.e., an sp-carbon triple bond). The alkylene group may be linear or branched. The alkylene group may be unsubstituted or substituted. In some embodiments, the alkylene group contains 2 to 6 carbon atoms (C2 to C6). In some embodiments, the alkylene group contains 2 to 4 carbon atoms (C2 to C4). A non-limiting example of the alkylene group is ethynylene.

[0036] As used herein, "aromatic group" or "aromatic ring" refers to a chemical group containing a conjugated planar ring system having a delocalized π-electron orbital composed of [4n+2] p-orbital electrons, where n is an integer from 0 to 6. Non-restrictive examples of aromatic groups include aryl and heteroaryl groups.

[0037] The terms "aryl" and "aryl group," as used interchangeably in this specification, refer to a group of 6 to 20 carbon atoms (C6 to C6). 20This refers to a monovalent (i.e., having one bond site to the rest of the molecule) aromatic hydrocarbon group. The aryl group may be unsubstituted or substituted. Non-restrictive 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 These include 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.

[0038] 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. Heteroalkyl groups may be unsubstituted or substituted.

[0039] The terms “heterocycloalkyl,” “heterocycle,” “heterocyclyl,” and “heterocyclic group,” as used interchangeably herein, refer to a saturated or partially unsaturated cyclic system of 3 to 20 atoms in which at least one of the ring atoms is a heteroatom such as nitrogen, oxygen, phosphorus, and sulfur. Heterocycloalkyl groups may be unsubstituted or substituted. In some embodiments, heterocycloalkyl groups contain 3 to 10 atoms. In some embodiments, heterocycloalkyl groups contain 3 to 7 atoms. In some embodiments, heterocycloalkyl groups are monocyclic. In some embodiments, heterocycloalkyl groups are bicyclic. In some embodiments, heterocycloalkyl groups contain a fused ring. Non-limiting examples of unsubstituted and substituted heterocycloalkyl groups include pyrrolidinyl, N-methylpyrrolidinyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 3-hydroxypyrrolidinyl, 3-methoxypyrrolidinyl, and benzodioxolyl.

[0040] In this specification, the terms “heteroaryl” and “heteroaryl group” refer to an aromatic ring system of 3 to 20 atoms in which at least one of the ring atoms is a heteroatom such as nitrogen, oxygen, phosphorus, and sulfur. Heteroaryl groups may be unsubstituted or substituted. In some embodiments, heteroaryl groups contain 5 to 20 atoms. In some embodiments, heteroaryl groups contain 5 to 9 atoms. In some embodiments, heteroaryl groups contain 5 atoms. In some embodiments, heteroaryl groups contain 6 atoms. In some embodiments, heteroaryl groups contain 7 atoms. In some embodiments, heteroaryl groups are monocyclic. In some embodiments, heteroaryl groups are bicyclic. In some embodiments, heteroaryl groups contain fused rings. Non-restrictive examples of heteroaryl groups include pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, 2-thienyl, 3-thienyl, isoxazolyl, thiazolyl, oxadiazolyl, 3-methyl-1,2,4-oxadiazolyl, 3-phenyl-1,2,4-oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, and These include soquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolidinyl, phthalazinyl, pyridadinyl, triazinyl, thiadiazolyl, flazanyl, benzoflazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthylidinyl, phlopyridinyl, and 1H-pyrrolo[2,3-b]pyridinyl. Non-limiting examples of heteroaryl groups include: [ka] There is.

[0041] As used herein, the phrase "optionally substituted" means that a group may or may not be substituted. As used herein, the term "substituted" refers to the substitution of one or more hydrogen atoms on a group (such as on an alkyl group, alkylene group, alkenyl group, alkenylene group, alkynyl group, alkynylene group, aryl group, heterocycloalkyl group, or heteroaryl group) with one or more substituents. Non-limiting examples of substituents that replace one hydrogen atom include halogens, hydroxyls, and aminos. Non-limiting examples of substituents that replace two hydrogen atoms include oxo and methenes. Non-limiting examples of substituents that replace three hydrogen atoms include nitriles.

[0042] An unrestricted example of adding substituents is C1-C6 linear, branched, and cyclic alkyl groups, non-limiting examples of which include methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, cyclobutyl, cyclopentyl, and cyclohexyl; C2-C8 straight-chain, branched-chain, and cyclic alkenyl groups, non-limiting examples of which include ethenyl (also called vinyl), 1-propenyl, and iso-propenyl; C2-C8 linear and branched alkynyl groups, a non-limiting example being ethynyl groups; Substituted and unsubstituted aryl groups, non-limiting examples thereof, include phenyl, 2-fluorophenyl, 3-methylphenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 3,4-difluorophenyl, 3-hydroxyphenyl, 4-cyanophenyl, 2-dimethylaminophenyl, 3-methylsulfonylphenyl, 4-trifluoromethylphenyl, 3-isopropylphenyl, 1-naphthyl, and 2-naphthyl; Substituted and unsubstituted heterocyclic groups, non-limiting examples thereof, include pyrrolidinyl, N-methylpyrrolidinyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 3-hydroxypyrrolidinyl, and 3-methoxypyrrolidinyl; Replacement and non-replacement heteroaryl groups, and non-limiting examples thereof include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, furyl, 2-thienyl, 3-thienyl, isoxazolyl, thiazolyl, oxadiazolyl, 3-methyl-1,2,4-oxadiazolyl, 3-phenyl-1,2,4-oxadiazolyl, indolyl, benzothiazolyl, and 1H-pyrrolo[2,3-b]pyridinyl; -(CR a R b ) z OR c , and non-limiting examples thereof include -OH, -OCH3, -OCH2OH, and -OCH2CH3; -(CR a R b )zN(R c )(R d ), and non-limiting examples thereof include -NH2, -NHCH3, -N(CH3)2, -CH2NH2, -CH2NHCH3, Halogen atoms, and non-limiting examples thereof include fluorine atom (-F) and chlorine atom (-Cl); -(CR a R b ) z CN; -(CR a R b ) z NO2; -CH x X y (wherein X is a halogen atom, and x + y totals 3), and non-limiting examples thereof include -CH2F, -CHF2, and -CF3; -(CR a R b ) z C(O)R c , and non-limiting examples thereof include -COCH3, -COCH2CH3, and -CH2COCH3; -(CR a R b ) z C(O)OR c , and non-limiting examples include CO2H, -CO2CH3, -CO2CH2CH3, and -CH2CO2CH3, -(CR aR b ) z C(O)N(R c )(R d )、and non-limiting examples thereof include -CONH2, -CONHCH3, -CON(CH3)2, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2; -(CR a R b ) z SO2R c ; non-limiting examples thereof include -SO2H, -SO2CH3, -CH2SO2H, -CH2SO2CH3, -SO2C6H5, and -CH2SO2C6H5; and -(CR a R b ) z SO3R c ; non-limiting examples thereof include -SO3H, -SO3CH3, -CH2SO3H, -CH2SO3CH3, -SO3C6H5, and -CH2SO3C6H5; wherein each of R a and R b is independently selected from hydrogen and substituted or unsubstituted C1-C6 linear, branched, or cyclic alkyl, and each of R c and R d is selected from hydrogen, substituted or unsubstituted C1-C6 linear, branched, or cyclic alkyl, and aryl, or R c and R d together form a ring system containing 3-7 atoms, and z is selected from 0, 1, 2, 3, and 4.

[0043] As used herein, the term "pharmaceutical composition" refers to a preparation in a form in which the biological activity of the active ingredient is effective and which contains no additional ingredients that are unacceptably toxic to the subject to whom the composition will be administered. In some embodiments, such compositions may be sterilized.

[0044] As used herein in relation to "pharmaceutically acceptable salts" and "pharmaceutically acceptable excipients," the term "pharmaceutically acceptable" refers to an ingredient that, within the bounds of sound medical judgment, is suitable for use in contact with human and other mammalian tissues without excessive toxicity, irritation, or allergic reactions, and that has a reasonable benefit-risk ratio.

[0045] The phrase “pharmaceutically acceptable excipients” is used herein to refer to pharmaceutically acceptable materials selected from solvents, dispersions, diluents, dispersions, suspension aids, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, polymers, peptides, proteins, cells, hyaluronidases, and mixtures thereof. In some embodiments, the solvent is an aqueous solvent.

[0046] "Treatment," "to treat," and "to treat" refer to reversing, alleviating (e.g., alleviating one or more symptoms) and / or slowing the progression of any medical condition or disorder described herein.

[0047] The terms “disease” and “disorder” are used interchangeably herein and refer to any alteration of the condition of any part of the body or organ that interrupts or impairs the function and / or causes symptoms such as discomfort, dysfunction, pain, or even death in the person who has the disorder or who comes into contact with the person who has the disorder. Disorder or disorder may also be related to distemper, ailing, ailment, malady, sickness, illness, complaint, indisposition, or affection.

[0048] As used herein, "subject" refers to animal subjects, such as mammals, and especially to humans.

[0049] As used herein, the term “administer” means the placement of a compound, a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition into the tissue or subject of a mammal by a method or route that results in at least partial localization of the compound, salt, and / or composition at a desired site or tissue location.

[0050] As used herein, the term “therapeutically effective dose” refers to the amount of compound or salt that produces the desired effect for which it is administered (e.g., improvement of symptoms of a disease or condition mediated by AhR signaling, reduction of the severity of such disease or condition or its symptoms, and / or reduction of the progression of any one of the above). The exact amount of an effective dose depends on the therapeutic purpose and will be verifiable by those skilled in the art using known techniques (e.g., Lloyd (1999) The Art, Science and Technology of (See Pharmaceutical Compounding.)

[0051] Those skilled in the art will recognize that, when a quantity of a compound is disclosed, the relevant quantity of a pharmaceutically acceptable salt form of the compound is equal to the quantity of the free base of the compound. The quantities of compounds and pharmaceutically acceptable salts disclosed herein are based on the free base form of the relevant compound. For example, "at least one entity selected from the compound of formula I or Ia and its pharmaceutically acceptable salts" means an amount of pharmaceutically acceptable salt of the compound of formula I or Ia equal to 10 mg of the compound of formula I or Ia or 10 mg of the relevant compound of formula I or Ia.

[0052] The “effectiveness” of the compounds or compositions of this disclosure can be evaluated by any method known to those skilled in the art, including those described in the examples of this disclosure. Effectiveness can be established in vitro (biochemical and / or biological) and / or in vivo. In vitro effectiveness can be used to extrapolate or predict, to some extent, in vivo effectiveness in animals or in human subjects. Criteria, standards, or comparisons may be used. In the context of this disclosure and claims, the term “effective” for inhibiting signaling mediated by receptors (such as AhR) and / or enzymes means reducing / activating receptor activity and / or signaling pathway activation and propagation by a detectable or measurable amount relative to baseline activity, in units of downstream molecule activation or known biological effect. This can be evaluated in vitro or in vivo, and, in some cases, can be extrapolated to the extent that the activity or benefit may be in vivo. In some embodiments, the reduction or activation is measured in units of the percentage of reduction or activation relative to the activity in the absence of exposure to the compound of the Disclosure, including, for example, at least 5%, at least 10%, 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or about 100%. The activity may also fall within a range, for example, 5–10%, 10–20%, and any other range interval between 1% and 100%. A certain amount is “effective” in vivo if the compound or salt produces any benefit to the subject to which it is administered.

[0053] Compound of formula (I): [ka] and pharmaceutically acceptable salts thereof are disclosed herein. (In the formula: R 1 and R 2Each of these is independently selected from optionally substituted alkyls, optionally substituted esters, optionally substituted heteroalkyls, optionally substituted acyls, optionally substituted amides, optionally substituted aryls, optionally substituted heteroaryls, optionally substituted cycloalkyls, optionally substituted amines, and optionally substituted heterocycloalkyls; and R 3 (which is independently 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, optionally substituted amine, cyano, halo, hydroxy, and -C(O)H).

[0054] In some embodiments, R 2 is a dialkylamine. In some embodiments, R 2 It is diethylamine.

[0055] Compounds of formula Ia: [ka] and pharmaceutically acceptable salts thereof are also disclosed herein. (In the formula: Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; Ring B is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; and 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).

[0056] 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, where each of the 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl is 1 to 5 instances of R A It is being replaced independently and arbitrarily by [the specified method / function].

[0057] 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, where each of the 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl is one to five examples of R B It is being replaced independently and arbitrarily by [the specified method / function].

[0058] In some embodiments, R is 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 Selected from heteroalkyl, 5-10 member heteroaryl, 3-10 member heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H, where each C1-C 10 Alkyl, 6-10 membered aryl, 3-10 membered cycloalkyl, C1-C 10 Heteroalkyls, 5-10 membered heteroaryls, and 3-10 membered heterocycloalkyls are 1-5 R CIt is being replaced independently and arbitrarily by [the specified method / function].

[0059] In some embodiments, each R' is hydrogen, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1~C 10 Hydroxyalkyl, and C1-C 10 It is independently selected from heteroalkyl groups.

[0060] In some embodiments, each R A Halo, hydroxy, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1~C 10 Alkoxy, C1-C 10 Haloalkoxy, C1~C 10 It is independently selected from hydroxyalkyl and NR''R''.

[0061] In some embodiments, each R B Halo, hydroxy, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1~C 10 Alkoxy, C1-C 10 Haloalkoxy, C1~C 10 It is independently selected from hydroxyalkyl and NR''R''.

[0062] In some embodiments, each R C Halo, hydroxy, cyano, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 The following are independently selected from haloalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl.

[0063] In some embodiments, each R'' is hydrogen, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1~C 10 Hydroxyalkyl, and C1-C 10It is independently selected from heteroalkyl groups.

[0064] 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, where each of the 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl is one to five examples of R A It is independently and arbitrarily replaced by; Ring B is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl, where each of the 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl groups is 1-5 R B It is independently and arbitrarily replaced by; R is 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 Selected from heteroalkyl, 5-10 member heteroaryl, 3-10 member heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H, where each C1-C 10 Alkyl, 6-10 membered aryl, 3-10 membered cycloalkyl, C1-C 10 Heteroalkyls, 5-10 membered heteroaryls, and 3-10 membered heterocycloalkyls are 1-5 R C It is independently and arbitrarily replaced by; Each R' is a hydrogen, C1~C 10 Alkyl, C1-C 10 Haloalkyl, C1~C 10 Hydroxyalkyl, and C1-C 10 Independently selected from heteroalkyl groups; Each R A Halo, hydroxy, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1~C 10 Alkoxy, C1-C 10 Haloalkoxy, C1~C10 Independently selected from hydroxyalkyl and NR''R''; Each R B Halo, hydroxy, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1~C 10 Alkoxy, C1-C 10 Haloalkoxy, C1~C 10 Independently selected from hydroxyalkyl and NR''R''; Each R C Halo, hydroxy, cyano, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Independently selected from haloalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and Each R'' is a hydrogen, C1~C 10 Alkyl, C1-C 10 Haloalkyl, C1~C 10 Hydroxyalkyl, and C1-C 10 It is independently selected from heteroalkyl groups.

[0065] In some embodiments, ring A is 1 to 5 R A Selected from 3- to 10-membered cycloalkyl groups optionally substituted by [the specified group]. In some embodiments, ring A is one to five examples of R A The following are optionally substituted for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, ring A is 1 to 5 R A Selected from 6-8 membered aryls which are optionally substituted by. In some embodiments, ring A is one- to three examples of R A It is a phenyl compound optionally substituted by R. In some embodiments, ring A is 1 to 5 R A It is selected from 5- to 8-membered heteroaryls that have been optionally substituted.

[0066] In some embodiments, ring A is selected from pyrrolyl, furanil, flazanil, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyrazinyl, pyridadinyl, and pyrimidinyl, where each of pyrrolyl, furanil, flazanil, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyrazinyl, pyridadinyl, and pyrimidinyl is one to three examples of R A It is being replaced independently and arbitrarily by [the specified method / function].

[0067] In some embodiments, ring A is one to three R A It is a pyridinyl optionally substituted by [the specified agent]. In some embodiments, ring A is 1 to 5 R[the specified agent]. A The ring A is selected from 5- to 8-membered heterocycloalkyl groups that are optionally substituted by R. In some embodiments, ring A is selected from pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydropyranil, and tetrahydrofuranil, where each of pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydropyranil, and tetrahydrofuranil is one to three examples of R A It is independently and optionally substituted by. In some embodiments, ring A is replaced by 1 to 3 R A It is piperidinyl or morpholino that has been optionally substituted by [the specified agent].

[0068] In some embodiments, each R A Ha, C1~C 10 Alkyl, C1-C 10 Haloalkyl, C1~C 10 Alkoxy, C1-C 10 A haloalkoxy and NR''R'' are independently selected. In some embodiments, each R B Ha, C1~C 10Alkyl, and C1-C 10 Independently selected from haloalkyl groups. In some embodiments, each R C Halo, hydroxy, cyano, C1-C 10 Alkyl, C1-C 10 The following can be independently selected from alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, and 6-8 membered aryl. In some embodiments, each R'' is hydrogen and C1-C 10 It is selected independently of alkyl.

[0069] In some embodiments, each R A Ha, C1~C 10 Alkyl, C1-C 10 Haloalkyl, C1~C 10 Alkoxy, C1-C 10 Selected independently from haloalkoxys and NR''R''; Each R B Ha, C1~C 10 Alkyl, and C1-C 10 Independently selected from haloalkyl groups; Each R C Halo, hydroxy, cyano, C1-C 10 Alkyl, C1-C 10 Independently selected from alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, and 6-8 membered aryl; and Each R'' is hydrogen and C1~C 10 It is selected independently of alkyl.

[0070] In some embodiments, ring B is one to five R B Selected from 6-8 membered aryls which are optionally substituted by. In some embodiments, ring B is one- to three examples of R B It is a phenyl compound optionally substituted by R. In some embodiments, ring B is 1 to 5 R BThe ring B is selected from 5- to 8-membered heteroaryls that are optionally substituted by R. In some embodiments, ring B is selected from pyrrolyl, furanil, furazanil, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyridinonyl, and pyrimidinyl, where each of pyrrolyl, furanil, furazanil, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyridazinyl, and pyrimidinyl is one to three R B It is independently and optionally substituted by. In some embodiments, ring B is selected from pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl, where each of pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl is one to three examples of R B It is being replaced independently and arbitrarily by [the specified method / function].

[0071] In some embodiments, ring A is [ka] Selected from.

[0072] In some embodiments, ring A is [ka] Selected from.

[0073] In some embodiments, ring A is [ka] Selected from.

[0074] In some embodiments, ring B is [ka] Selected from.

[0075] In some embodiments, ring B is [ka] It is from.

[0076] In some embodiments, ring B is [ka] Selected from.

[0077] In some embodiments, R is methyl, [ka] Selected from.

[0078] In some embodiments, R is methyl, [ka] Selected from.

[0079] Compounds of formula Ib: [ka] and pharmaceutically acceptable salts thereof are also disclosed herein. (In the formula: Ring A is selected from optionally substituted heteroaryls and optionally substituted heterocycloalkyls; Ring B is selected from optionally substituted heteroaryls and optionally substituted heterocycloalkyls; and 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).

[0080] In some embodiments, this disclosure relates to one or more compounds listed in Table 1.

[0081] [Table 1]

[0082] [Table 2]

[0083] [Table 3]

[0084] [Table 4]

[0085] [Table 5]

[0086] [Table 6]

[0087] [Table 7]

[0088] [Table 8]

[0089] Table 9

[0090] Table 10

[0091] Table 11

[0092] Table 12

[0093] Table 13

[0094] Table 14

[0095] Table 15

[0096] Table 16

[0097] Table 17

[0098] Table 18

[0099] [Table 19]

[0100] [Table 20]

[0101] [Table 21]

[0102] [Table 22]

[0103] [Table 23]

[0104] [Table 24]

[0105] [Table 25]

[0106] [Table 26]

[0107] [Table 27]

[0108] In some embodiments, this disclosure relates to one or more compounds selected from the following compounds and their pharmaceutically acceptable salts: (i)(S)-8-(5-fluoropyridine-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (ii)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(6-oxo-1,6-dihydropyridine-3-yl)pyrido[3,4-d]pyrimidine-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]pyrimidine-4(3H)-one; (iv)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (v)(S)-8-(5-fluoropyridine-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (vi)(S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridine-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (vii)(S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (viii)(S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (ix)3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (x)6,8-di(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xi)(S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xii)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xiii)6-(4-chlorophenyl)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xiv)8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xv)6-(4-chlorophenyl)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xvi)3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xvii)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xviii)6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xix)3-(2-hydroxy-2-methylpropyl)-6,8-bis(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xx)(S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxi)6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxii)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxiii)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxiv)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxv)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxvi)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-phenylpyrido[3,4-d]pyrimidine-4(3H)-one; (xxvii)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxviii)3-methyl-8-(pyridine-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxix)Rac-6-(4-chlorophenyl)-3-((trans)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxx)(S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxi)(R)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxii)rac-6-(4-chlorophenyl)-3-((cis)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxiii)(R)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxiv)(S)-3-(3-hydroxy-3-methylbutan-2-yl)-6,8-di(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxv)(S)-6,8-bis(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxvi)(S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxvii)(S)-8-(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxviii)6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(2-hydroxy-2-methylpropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxix)(R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xl)(S)-3-(1-(benzyloxy)propan-2-yl)-8-(3-fluorophenyl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xli)(R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xlii)(S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xliii)(S)-3-(1-hydroxypropan-2-yl)-6-morpholino-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xliv)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazole-1-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xlv)(S)-3-(1-methoxypropan-2-yl)-8-(pyridine-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xlvi)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xlvii)(S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xlviii)(S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xlix)(S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (l)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethoxy)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (li)(S)-3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lii)methyl(S)-5-(3-(1-hydroxypropan-2-yl)-4-oxo-8-(pyridine-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidine-6-yl)picolinate (liii)(S)-3-(1-hydroxypropan-2-yl)-6-(isothiazol-4-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (liv)3-(2-hydroxy-2-methylpropyl)-8-(isothiazol-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lv)(S)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lvi)(S)-3-(1-hydroxypropan-2-yl)-6,8-di(isothiazol-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lvii)(S)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lviii)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lix)3-(2-hydroxy-2-methylpropyl)-6,8-di(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lx)3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxi)6-(4-chloro-2-methylphenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxii)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxiii)(S)-3-(1-hydroxypropan-2-yl)-8-(2-methylpyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxiv)(S)-3-(1-hydroxypropan-2-yl)-8-(4-methylpyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxv)(S)-3-(1-hydroxypropan-2-yl)-6-(4-methylthiazole-5-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxvi)(S)-6-(2-cyclopropylthiazole-5-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxvii)(S)-3-(1-hydroxypropan-2-yl)-6-(2-isopropylthiazole-5-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxviii)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxix)(S)-3-(1-hydroxypropan-2-yl)-6,8-bis(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxx)6-(4-chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxi)6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxii)3-(2-hydroxyethyl)-8-(pyridine-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxiii)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-6-oxo-1,6-dihydropyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxiv)(S)-6-(6-cyclopropylpyridine-3-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxv)(S)-3-(1-hydroxypropan-2-yl)-6-(4-methyl-6-(trifluoromethyl)pyridine-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxvi)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxvii)(S)-6-(cyclohexa-1-en-1-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxviii)(S)-6,8-bis(5-fluoropyridine-3-yl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxix)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxx)3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxi)6-(6-cyclopropylpyridine-3-yl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxii)6-(6-cyclopropylpyridine-3-yl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxiii)(S)-6-(6-cyclopropylpyridine-3-yl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxiv)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxv)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxvi)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)pyrimidine-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxvii)3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxviii)3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxix)(S)-3-(1-hydroxypropan-2-yl)-6-(2-methylthiazole-5-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xc)(S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xci)(S)-3-(1-hydroxypropan-2-yl)-6-(piperidine-1-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xcii)3-(2-hydroxy-2-methylpropyl)-8-(isothiazol-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xciii)(S)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xciv)3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xcv)(S)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xcvi)(3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xcvii)3-(1,1-dioxidetetrahydrothiophen-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xcviii)(R)-3-(1,1-dioxidetetrahydrothiophen-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xcix)(R)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (c)(S)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (ci)(R)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cii)(S)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (ciii)(R)-3-(2-hydroxypropyl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (civ)(R)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cv)3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cvi)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cvii)6-(4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cviii)3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cix)(S)-6-(6-cyclopropylpyridine-3-yl)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one (cx)(R)-6-(6-cyclopropylpyridine-3-yl)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxi)(R)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxii)(R)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxiii)(S)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxiv)6-(4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxv)3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxvi)methyl(S)-2-(4-oxo-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-3(4H)-yl)propanoate (cxvii)6-(4-chlorophenyl)-3-(4-hydroxy-1-methylpyrrolidine-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxviii)6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidine-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxix)(R)-6-(6-cyclopropylpyridine-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxx)(S)-6-(6-cyclopropylpyridine-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxi)3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxii)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxiii)3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxiv)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxv)(R)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxvi)(S)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxvii)(S)-3-(2-hydroxypropyl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxviii)(R)-3-(2-hydroxypropyl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxix)3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxx)(S)-3-(2-hydroxypropyl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxxi)(S)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxxii)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxxiii)3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxxiv)6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxxv)6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxxvi)(R)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxxvii)(S)-2-(4-oxo-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-3(4H)-yl)propanoic acid (cxxxviii)(S)-N-methyl-2-(4-oxo-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-3(4H)-yl)propanamide (cxxxix)(S)-N,N-dimethyl-2-(4-oxo-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-3(4H)-yl)propenamide (cxl)3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxli)3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazole-1-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxlii)3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazole-1-yl)-6-(6-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxliii)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazole-1-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxliv)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazole-1-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxlv)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-1,2,4-triazole-1-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxlvi)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazole-1-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxlvii)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxlviii)(S)-8-(diethylamino)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxlix)(S)-3-(1-hydroxypropan-2-yl)-8-(piperidine-1-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cl)(S)-3-(1-hydroxypropan-2-yl)-8-(pyrrolidine-1-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cli)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(piperidine-1-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clii)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-2-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cliii)(S)-6-cyclohexyl-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cliv)(S)-3-(1-hydroxypropan-2-yl)-6-(pyridine-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clv)(S)-3-(1-hydroxypropan-2-yl)-6-(2-methylthiazole-4-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clvi)(S)-3-(1-hydroxypropan-2-yl)-6-(1-methyl-1H-1,2,3-triazole-5-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clvii)(R)-6-(4-chlorophenyl)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one (clviii)(S)-6-(4-chlorophenyl)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one (clix)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1,2,5,6-tetrahydropyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clx)6-(4-chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxi)(S)-3-(1-hydroxypropan-2-yl)-6-(2-methylpyrimidine-5-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxii)3-(2-hydroxy-2-methylpropyl)-8-(1-(trifluoromethyl)-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxiii)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(2-(trifluoromethyl)pyrimidine-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxiv)3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)pyrimidine-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxv)(S)-5-(3-(1-hydroxypropan-2-yl)-4-oxo-8-(pyridine-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidine-6-yl)picolinic acid (clxvi)(S)-3-(1-hydroxypropan-2-yl)-6-(6-methylpyridine-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxvii)3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(2-(trifluoromethyl)pyrimidine-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxviii)3,8-di(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxix)8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxx)3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxi)3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxii)6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxiii)3-Cyclopentyl-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxiv)3-phenyl-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxv)3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxvi)3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxvii)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxviii)(S)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-2-(4-oxo-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-3(4H)-yl)propanamide (clxxix)3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxx)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazole-1-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxxi)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazole-1-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxxii)3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxxiii)3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxxiv)3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxxv)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxxvi)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxxvii)(S)-3-(1-hydroxypropan-2-yl)-8-morpholino-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxxviii)3-(2-hydroxy-2-methylpropyl)-8-(piperidine-1-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxxix)(S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyridine-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxc)(S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyrimidine-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxci)(S)-8-(cyclohexa-1-en-1-yl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxcii)(S)-8-cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxciii)(S)-3-(1-hydroxypropan-2-yl)-N,N-dimethyl-4-oxo-8-(pyridine-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidine-6-carboxamide (cxciv)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxcv)(S)-3-(1-hydroxypropan-2-yl)-6-(2-methoxyethyl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxcvi)(S)-3-(1-hydroxypropan-2-yl)-8-(2-methoxyethyl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one.

[0109] 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 compounds of formula I or formula Ia and pharmaceutically acceptable salts thereof. In some embodiments, the disclosure relates to pharmaceutical compositions comprising at least one entity selected from compounds of formula I or formula Ia and pharmaceutically acceptable salts thereof.

[0110] In some embodiments, at least one entity selected from compounds of formula I or formula Ia and pharmaceutically acceptable salts thereof can be administered in combination with at least one additional therapy. In some embodiments, at least one additional therapy is selected from immune checkpoint inhibitors (ICIs).

[0111] In some embodiments, at least one additional therapy is selected from anti-CTLA-4 compounds, anti-PD-1 compounds, and anti-PDL-1 compounds. In some embodiments, at least one additional therapy is selected from pembrolizumab (Keytruda); nivolumab (Opdivo); ipilimumab (Yervoy); avelumab (Bavencio); atezolizumab (Tecentriq); durvalumab (Imfinzi); semiprimab (LBTAYO); cintilimab (Tyvyt); tripalimab (Tuoyi); camrelizumab (AiRuiKa); spartalizumab; and tisrelizumab. In some embodiments, 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 (T cell activation V domain Ig suppressor) compounds; or combinations thereof. Non-limiting examples of anti-LAG-3 compounds include IMP321 (eftilagimod alfa), relatrimab (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, and RO7121661. Non-limiting examples of anti-TIGIT compounds include MK-7684, etigirimab (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.

[0112] In some embodiments, the pharmaceutical composition comprises at least one entity selected from compounds of formula I or formula Ia and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient. pharmaceutically acceptable excipients are well known to those skilled in the art and are described, in non-limiting examples, in Remington: The Science and Practice of Pharmacy, 22nd Edition, Lippincott Williams & Wilkins, Philadelphia, Pa. (2013) and any other editions, which are incorporated herein by reference. In some embodiments, the pharmaceutical composition further comprises at least one additional therapy.

[0113] The present disclosure comprises the compounds of the present disclosure, pharmaceutically acceptable salts thereof, and / or at least one entity selected from the compounds of formula I or formula Ia and pharmaceutically acceptable salts thereof, optionally comprising at least one at A pharmaceutical composition further comprising at least one additional therapy may be used in therapeutic treatment.

[0114] Compounds, pharmaceutically acceptable salts, additional therapies, and / or pharmaceutical compositions may be administered in units of dosage to mammalian subjects, including humans. Preferred non-limiting examples of units of dosage include orally administered forms and parenteral / systemic administration forms, non-limiting examples of which include inhalation, subcutaneous administration, intramuscular administration, intravenous administration, intradermal administration, and intravitreous administration.

[0115] In some embodiments, pharmaceutical compositions suitable for oral administration may 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 compounds of the Disclosure and / or pharmaceutically acceptable salts of the compounds of the Disclosure are mixed with one or more inert diluents, non-limiting examples of which include starch, cellulose, sucrose, lactose, and silica. In some embodiments, such pharmaceutical compositions may further include one or more substances other than diluents, such as lubricants, colorants, coatings, or varnishes (as non-limiting examples). In some embodiments, such pharmaceutical compositions may further include at least one additional therapy.

[0116] In some embodiments, the pharmaceutical composition for parenteral administration may be in the form of an aqueous solution, a non-aqueous solution, a suspension, an emulsion, an intravenous solution, or any combination thereof. In some embodiments, such a pharmaceutical composition may comprise one or more of water, a pharmaceutically acceptable glycol, a pharmaceutically acceptable oil, a pharmaceutically acceptable organic ester, or other pharmaceutically acceptable solvent. In some embodiments, such a pharmaceutical composition may further comprise at least one additional therapy.

[0117] In some embodiments, methods for inhibiting AhR are disclosed herein, comprising administering to a subject requiring such inhibition at least one entity selected from compounds of formula I or formula Ia and pharmaceutically acceptable salts thereof. In some embodiments, methods for reducing AhR activity are disclosed herein, comprising administering to a subject requiring such reduction at least one entity selected from compounds of formula I or formula Ia and pharmaceutically acceptable salts thereof. In some embodiments, such pharmaceutical compositions may further comprise at least one additional therapy.

[0118] In some embodiments, methods for treating cancer are disclosed herein, comprising administering to a subject in need of such treatment at least one entity selected from compounds of formula I or formula Ia and pharmaceutically acceptable salts thereof. In some embodiments, cancer is selected from liquid tumors and solid tumors. In some embodiments, cancer is selected from breast cancer, airway cancer, brain cancer, genital cancer, gastrointestinal cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and metastases of any of the above. In some embodiments, cancer is selected from breast cancer, pancreatic cancer, prostate cancer, and colon cancer. In some embodiments, cancer is selected from lymphoma, sarcoma, and leukemia.

[0119] In some embodiments, methods for treating cancer are disclosed herein, comprising administering to a subject in need of such treatment at least one entity selected from compounds of formula I or formula Ia and pharmaceutically acceptable salts thereof, as well as at least one additional therapy. In some embodiments, cancer is defined as non-small cell lung cancer (NSCLC); small cell lung cancer; head and neck squamous cell carcinoma; renal cell carcinoma; gastric adenocarcinoma; nasopharyngeal neoplasm; urothelial carcinoma; colorectal cancer; pleural mesothelioma; triple-negative breast cancer (TNBC); esophageal neoplasm; multiple myeloma; gastric and gastroesophageal junction cancer; melanoma; Hodgkin lymphoma; hepatocellular carcinoma; lung cancer; head and neck cancer; non-Hodgkin lymphoma; metastatic clear cell renal cancer; 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 neoplasm; extensive-stage small cell lung cancer; bladder cancer; transitional cell carcinoma; prostate neoplasm; recurrent or metastatic PD-L1 The following are selected from: positive or negative head and neck squamous cell carcinoma (SCCHN); recurrent squamous cell lung cancer; advanced solid malignant tumors; SCCHN; hypopharyngeal squamous cell carcinoma; laryngeal squamous cell carcinoma; unresectable or metastatic melanoma; biliary tract neoplasms; esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, glioblastoma, metastatic cancer, prostate cancer, parenchymal organ cancer; gastric cancer; colon cancer; and liver cancer.

[0120] In some embodiments, methods for treating eye diseases are disclosed herein, comprising administering to a subject in need at least one entity selected from compounds of formula I or formula Ia and pharmaceutically acceptable salts thereof, and optionally at least one additional therapy.

[0121] With respect to the methods disclosed herein, the mode of administration (or modes), dosage (or dosages), and dosage form (or dosage forms) can be determined, in non-limiting examples, according to criteria generally considered during the establishment of treatment for a patient, such as the potency of the compound and / or pharmaceutically acceptable salts of the compound, at least one additional therapy (if any), the patient's age, the patient's weight, the severity of the patient's condition (or conditions), the patient's tolerance to treatment, and secondary effects observed during treatment. Determining the effective dosage to produce a therapeutic effect with a specific mode and frequency of administration is within the capabilities of those skilled in the art.

[0122] In some embodiments, the compound of formula I or formula Ia and / or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount ranging from 5 μg to 2,000 mg. In some embodiments, the compound of the disclosure and / or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount ranging from 5 μg to 1,000 mg. In some embodiments, the compound of the disclosure and / or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount ranging from 5 μg to 500 mg. In some embodiments, the compound of the disclosure and / or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount ranging from 5 μg to 250 mg. In some embodiments, the compound of the disclosure and / or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount ranging from 5 μg to 100 mg. In some embodiments, the compound of the disclosure and / or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount ranging from 5 μg to 50 mg.

[0123] In some embodiments, the compounds of the Disclosure and / or their pharmaceutically acceptable salts are present in the pharmaceutical composition in amounts ranging from 1 mg to 5,000 mg. In some embodiments, the compounds of the Disclosure and / or their pharmaceutically acceptable salts are present in the pharmaceutical composition in amounts ranging from 1 mg to 3,000 mg. In some embodiments, the compounds of the Disclosure and / or their pharmaceutically acceptable salts are present in the pharmaceutical composition in amounts ranging from 1 mg to 2,000 mg. In some embodiments, the compounds of the Disclosure and / or their pharmaceutically acceptable salts are present in the pharmaceutical composition in amounts ranging from 1 mg to 1,000 mg. In some embodiments, the compounds of the Disclosure and / or their pharmaceutically acceptable salts are present in the pharmaceutical composition in amounts ranging from 1 mg to 500 mg. In some embodiments, the compounds of the Disclosure and / or their pharmaceutically acceptable salts are present in the pharmaceutical composition in amounts ranging from 1 mg to 250 mg. In some embodiments, the compounds of the Disclosure and / or pharmaceutically acceptable salts thereof are present in the pharmaceutical composition in amounts ranging from 1 mg to 100 mg. In some embodiments, the compounds of the Disclosure and / or pharmaceutically acceptable salts thereof are present in the pharmaceutical composition in amounts ranging from 1 mg to 50 mg.

[0124] In some embodiments, the compounds of this disclosure and / or pharmaceutically acceptable salts thereof are present in pharmaceutical compositions in amounts 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, 500mg, 1,600mg, 1,700mg, 1,800mg, 1,900mg, 2,000mg, 2,100mg, 2,200mg, 2,300mg, 2,4 00mg, 2,500mg, 2,600mg, 2,700mg, 2,800mg, 2,900mg, 3,000mg, 3,100mg, 3,200mg, 3,300 It exists in amounts of mg, 3,400 mg, 3,500 mg, 3,600 mg, 3,700 mg, 3,800 mg, 3,900 mg, 4,000 mg, 4,100 mg, 4,200 mg, 4,300 mg, 4,400 mg, 4,500 mg, 4,600 mg, 4,700 mg, 4,800 mg, 4,900 mg, or 5,000 mg.

[0125] Effective doses and dosages can initially be estimated from in vitro assays. For example, the initial dose for use in animals can be determined by the IC of a particular compound measured in an in vitro assay. 50 The above-mentioned active compounds can be formulated to achieve circulating blood or serum concentrations. Calculating the dose to achieve such circulating blood or serum concentrations, taking into account the bioavailability of a particular compound, is well within the capabilities of those skilled in the art. For guidance, readers should refer to Goodman and Gilman's *The Pharmaceutical Basis of*. See Fingl & Woodbury, “General Principles” in Therapeutics, Chapter 1, pp. 1-46, latest edition, Pergamagon Press, and the references cited therein; these methods are incorporated herein by reference as a whole. Initial doses can also be estimated from in vivo data, such as animal models. Animal models useful for testing the efficacy of compounds for treating or preventing the various diseases described herein are well known in the art.

[0126] In some embodiments, the administered dose ranges from 0.0001 or 0.001 or 0.01 mg / kg / day to 100 mg / kg / day, but may be higher or lower depending on other factors, including the compound's activity, its bioavailability, mode of administration, and various factors discussed earlier. Dosage and intervals can be individually adjusted to provide plasma levels of the compound sufficient to maintain a therapeutic or prophylactic effect. For example, the compound may be administered once per week, several times per week (e.g., every other day), once daily, or multiple times per day, depending, among other things, on the mode of administration, the specific indication being treated, and the prescribing physician's discretion. In the case of topical administration or selective uptake, such as topical application, the effective local concentration of the active compound may not be related to the plasma concentration. Those skilled in the art will be able to optimize the effective local dose without excessive experimentation.

[0127] Non-limiting embodiments of this disclosure include: 1. Compounds of formula I: [ka] and its pharmaceutically acceptable salt (In the formula: R 1 and R 2Each of these is independently selected from optionally substituted alkyls, optionally substituted esters, optionally substituted heteroalkyls, optionally substituted acyls, optionally substituted amides, optionally substituted aryls, optionally substituted heteroaryls, optionally substituted cycloalkyls, optionally substituted amines, and optionally substituted heterocycloalkyls; and R 3 (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, optionally substituted amine, cyano, halo, hydroxy, and -C(O)H).

[0128] 2. Compounds of formula Ia [ka] or a pharmaceutically acceptable salt thereof (In the formula: Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; Ring B is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; and 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).

[0129] 3. Ring A is selected from optionally substituted 6-10 membered aryls, optionally substituted 5-10 membered heteroaryls, optionally substituted 3-10 membered cycloalkyls, and optionally substituted 3-10 membered heterocycloalkyls; Ring B is selected from optionally substituted 6-10 member aryl groups, optionally substituted 5-10 member heteroaryl groups, optionally substituted 3-10 member cycloalkyl groups, and optionally substituted 3-10 member heterocycloalkyl groups; R is replaced by hydrogen, or C1-C as chosen. 10 Alkyl, optionally substituted 6-10 member aryl, -C(O)R', -C(O)NR'R', optionally substituted 3-10 member cycloalkyl, -C(O)OR', optionally substituted C1-C 10 Selected from heteroalkyls, optionally substituted 5-10 member heteroaryls, optionally substituted 3-10 member heterocycloalkyls, amino, cyano, halo, hydroxy, and -C(O)H; and Each R' is replaced by hydrogen, or C1-C as chosen. 10 Alkyl and optionally substituted C1-C 10 A compound of Embodiment 2 or a pharmaceutically acceptable salt thereof, independently selected from heteroalkyl groups.

[0130] 4. Ring A is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl, where each of the 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl groups is used for 1-5 R groups. A It is independently and arbitrarily replaced by; Ring B is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl, where each of the 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl groups is one to five R groups. B It is independently and arbitrarily replaced by; R is hydrogen, C1~C 10Alkyl, 6-10 membered aryl, -C(O)R', -C(O)NR'R', 3-10 membered cycloalkyl, -C(O)OR', C1-C 10 Selected from heteroalkyl, 5-10 member heteroaryl, 3-10 member heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H, where each C1-C 10 Alkyl, 6-10 membered aryl, 3-10 membered cycloalkyl, C1-C 10 Heteroalkyls, 5-10 member heteroaryls, and 3-10 member heterocycloalkyls are found in 1-5 R C It is independently and arbitrarily replaced by; Each R' is a hydrogen atom, C1~C 10 Alkyl, C1-C 10 Haloalkyl, C1~C 10 Hydroxyalkyl, and C1-C 10 Independently selected from heteroalkyl groups; Each R A However, halo, hydroxy, C1~C 10 Alkyl, C1-C 10 Haloalkyl, C1~C 10 Alkoxy, C1-C 10 Haloalkoxy, C1~C 10 Independently selected from hydroxyalkyl and NR''R''; Each R B However, halo, hydroxy, C1~C 10 Alkyl, C1-C 10 Haloalkyl, C1~C 10 Alkoxy, C1-C 10 Haloalkoxy, C1~C 10 Independently selected from hydroxyalkyl and NR''R''; Each R C However, halo, hydroxy, cyano, C1~C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Independently selected from haloalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and Each R'' is hydrogen, C1~C 10 Alkyl, C1-C10 Haloalkyl, C1~C 10 Hydroxyalkyl, and C1-C 10 A compound of Embodiment 2 or 3, or a pharmaceutically acceptable salt thereof, independently selected from heteroalkyls.

[0131] 5. Ring A has 1 to 5 cases of R A A compound of Embodiment 4 or a pharmaceutically acceptable salt thereof, selected from 3- to 10-membered cycloalkyl groups optionally substituted by the above.

[0132] 6. Ring A has 1 to 5 cases of R A A compound of Embodiment 4 or 5, or a pharmaceutically acceptable salt thereof, selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, optionally substituted by [the specified agent].

[0133] 7. Ring A has 1 to 5 cases of R A A compound of Embodiment 4 or a pharmaceutically acceptable salt thereof, selected from 6- to 8-membered aryl compounds optionally substituted by the aforementioned method.

[0134] 8. Ring A has 1-3 cases of R A A compound of Embodiment 4 or 7, or a pharmaceutically acceptable salt thereof, wherein the phenyl is optionally substituted by [the specified agent].

[0135] 9. Ring A has 1 to 5 cases of R A A compound of Embodiment 4 or a pharmaceutically acceptable salt thereof, selected from 5- to 8-membered heteroaryl compounds optionally substituted by the aforementioned method.

[0136] 10. Ring A is selected from pyrrolyl, furanil, furazanil, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridadinyl, and pyrimidinyl. Here, each of the following is R in 1 to 3 cases: pyrrolyl, furanil, furazanil, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridadinyl, and pyrimidinyl A Compounds of Embodiment 4 or 9, or pharmaceutically acceptable salts thereof, which are independently and optionally substituted by [the specified agent].

[0137] 11. Ring A has 1-3 cases of R A A compound from any one of Embodiments 4, 9, or 10, or a pharmaceutically acceptable salt thereof, which is a pyridinyl optionally substituted by [the specified agent].

[0138] 12. Ring A has 1 to 5 cases of R A A compound of Embodiment 4 or a pharmaceutically acceptable salt thereof, selected from 5- to 8-membered heterocycloalkyl groups optionally substituted by [the specified agent].

[0139] 13. Ring A is selected from pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydropyranil, and tetrahydrofuranil. Here, pyrrolidinil, pyrazolidinil, piperidinil, piperazinil, morpholino, azepinil, tetrahydropyranil, and tetrahydrofuranil each account for 1 to 3 cases of R A Compounds of Embodiment 4 or 12, or pharmaceutically acceptable salts thereof, which are independently and optionally substituted by [the specified agent].

[0140] 14. Ring A has 1-3 cases of R A A compound from any one of Embodiments 4, 12, or 13, or a pharmaceutically acceptable salt thereof, which is optionally substituted with piperidinyl or morpholino.

[0141] 15. Ring B has 1 to 5 cases of R B A compound of Embodiment 4 or a pharmaceutically acceptable salt thereof, selected from 6- to 8-membered aryl compounds optionally substituted by the aforementioned method.

[0142] 16. Ring B has 1-3 cases of R B A compound of Embodiment 4 or 15, or a pharmaceutically acceptable salt thereof, which is a phenyl optionally substituted by [the specified agent].

[0143] 17. Ring B has 1 to 5 cases of R B A compound of Embodiment 4 or a pharmaceutically acceptable salt thereof, selected from benzodioxolyl and 5-8 membered heteroaryl compounds optionally substituted by the above.

[0144] 18. Ring B is selected from benzodioxolyl, pyrrolyl, furanil, furazanil, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridadinyl, pyridinonyl, and pyrimidinyl. Here, each of the following is a case of R: benzodioxolyl, pyrrolyl, furanil, flazanil, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridadinyl, and pyrimidinyl. B Compounds of Embodiment 4 or 17, or pharmaceutically acceptable salts thereof, which are independently and optionally substituted by [the specified agent].

[0145] 19. Ring B is selected from pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl. Here, pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl each have 1 to 3 cases of R B A compound from any one of Embodiments 4, 17, or 18, or a pharmaceutically acceptable salt thereof, which is independently and optionally substituted by [the specified agent].

[0146] 20.Each R A But, Hello, C1~C 10 Alkyl, C1-C 10 Haloalkyl, C1~C 10Alkoxy, C1-C 10 Selected independently from haloalkoxys and NR''R''; Each R B But, Hello, C1~C 10 Alkyl, and C1-C 10 Independently selected from haloalkyl groups; Each R C However, halo, hydroxy, cyano, C1~C 10 Alkyl, C1-C 10 Independently selected from alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, and 6-8 membered aryl; and Each R'' is hydrogen and C1~C 10 A compound from any one of Embodiments 4 to 19, independently selected from alkyl groups, or a pharmaceutically acceptable salt thereof.

[0147] 21. Ring A is, [ka] A compound selected from any one of embodiments 2-4 and 7-20, or a pharmaceutically acceptable salt thereof.

[0148] 22. Ring A is, [ka] A compound selected from any one of embodiments 2-6 and 15-20, or a pharmaceutically acceptable salt thereof.

[0149] 23. Ring A is [ka] A compound selected from any one of embodiments 2-4 and 7-20, or a pharmaceutically acceptable salt thereof.

[0150] 24. Ring B is, [ka] A compound selected from any one of embodiments 2-4 and 7-20, or a pharmaceutically acceptable salt thereof.

[0151] 25. Ring B is, [ka] A compound selected from any one of embodiments 2 to 14 and 20, or a pharmaceutically acceptable salt thereof.

[0152] 26. Ring B is, [ka] A compound selected from any one of embodiments 2-4 and 7-20, or a pharmaceutically acceptable salt thereof.

[0153] 27. R is methyl, [ka] A compound selected from any one of embodiments 2 to 26, or a pharmaceutically acceptable salt thereof.

[0154] 28. R is methyl, [ka] A compound selected from any one of embodiments 2 to 27, or a pharmaceutically acceptable salt thereof.

[0155] 29. At least one entity selected from the following compounds and a pharmaceutically acceptable salt thereof: (i)(S)-8-(5-fluoropyridine-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (ii)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(6-oxo-1,6-dihydropyridine-3-yl)pyrido[3,4-d]pyrimidine-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]pyrimidine-4(3H)-one; (iv)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (v)(S)-8-(5-fluoropyridine-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (vi)(S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridine-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (vii)(S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (viii)(S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (ix)3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (x)6,8-di(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xi)(S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xii)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xiii)6-(4-chlorophenyl)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xiv)8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xv)6-(4-chlorophenyl)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xvi)3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xvii)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xviii)6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xix)3-(2-hydroxy-2-methylpropyl)-6,8-bis(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xx)(S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxi)6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxii)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxiii)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxiv)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxv)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxvi)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-phenylpyrido[3,4-d]pyrimidine-4(3H)-one; (xxvii)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxviii)3-methyl-8-(pyridine-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxix)Rac-6-(4-chlorophenyl)-3-((trans)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxx)(S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxi)(R)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxii)rac-6-(4-chlorophenyl)-3-((cis)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxiii)(R)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxiv)(S)-3-(3-hydroxy-3-methylbutan-2-yl)-6,8-di(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxv)(S)-6,8-bis(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxvi)(S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxvii)(S)-8-(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxviii)6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(2-hydroxy-2-methylpropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxix)(R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xl)(S)-3-(1-(benzyloxy)propan-2-yl)-8-(3-fluorophenyl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xli)(R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xlii)(S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xliii)(S)-3-(1-hydroxypropan-2-yl)-6-morpholino-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xliv)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazole-1-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xlv)(S)-3-(1-methoxypropan-2-yl)-8-(pyridine-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xlvi)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xlvii)(S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xlviii)(S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xlix)(S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (l)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethoxy)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (li)(S)-3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lii)methyl(S)-5-(3-(1-hydroxypropan-2-yl)-4-oxo-8-(pyridine-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidine-6-yl)picolinate (liii)(S)-3-(1-hydroxypropan-2-yl)-6-(isothiazol-4-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (liv)3-(2-hydroxy-2-methylpropyl)-8-(isothiazol-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lv)(S)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lvi)(S)-3-(1-hydroxypropan-2-yl)-6,8-di(isothiazol-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lvii)(S)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lviii)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lix)3-(2-hydroxy-2-methylpropyl)-6,8-di(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lx)3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxi)6-(4-chloro-2-methylphenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxii)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxiii)(S)-3-(1-hydroxypropan-2-yl)-8-(2-methylpyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxiv)(S)-3-(1-hydroxypropan-2-yl)-8-(4-methylpyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxv)(S)-3-(1-hydroxypropan-2-yl)-6-(4-methylthiazole-5-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxvi)(S)-6-(2-cyclopropylthiazole-5-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxvii)(S)-3-(1-hydroxypropan-2-yl)-6-(2-isopropylthiazole-5-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxviii)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxix)(S)-3-(1-hydroxypropan-2-yl)-6,8-bis(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxx)6-(4-chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxi)6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxii)3-(2-hydroxyethyl)-8-(pyridine-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxiii)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-6-oxo-1,6-dihydropyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxiv)(S)-6-(6-cyclopropylpyridine-3-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxv)(S)-3-(1-hydroxypropan-2-yl)-6-(4-methyl-6-(trifluoromethyl)pyridine-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxvi)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxvii)(S)-6-(cyclohexa-1-en-1-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxviii)(S)-6,8-bis(5-fluoropyridine-3-yl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxix)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxx)3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxi)6-(6-cyclopropylpyridine-3-yl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxii)6-(6-cyclopropylpyridine-3-yl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxiii)(S)-6-(6-cyclopropylpyridine-3-yl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxiv)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxv)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxvi)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)pyrimidine-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxvii)3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxviii)3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxix)(S)-3-(1-hydroxypropan-2-yl)-6-(2-methylthiazole-5-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xc)(S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xci)(S)-3-(1-hydroxypropan-2-yl)-6-(piperidine-1-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xcii)3-(2-hydroxy-2-methylpropyl)-8-(isothiazol-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xciii)(S)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xciv)3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xcv)(S)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xcvi)(3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xcvii)3-(1,1-dioxidetetrahydrothiophen-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xcviii)(R)-3-(1,1-dioxidetetrahydrothiophen-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xcix)(R)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (c)(S)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (ci)(R)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cii)(S)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (ciii)(R)-3-(2-hydroxypropyl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (civ)(R)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cv)3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cvi)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cvii)6-(4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cviii)3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cix)(S)-6-(6-cyclopropylpyridine-3-yl)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one (cx)(R)-6-(6-cyclopropylpyridine-3-yl)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxi)(R)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxii)(R)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxiii)(S)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxiv)6-(4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxv)3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxvi)methyl(S)-2-(4-oxo-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-3(4H)-yl)propanoate (cxvii)6-(4-chlorophenyl)-3-(4-hydroxy-1-methylpyrrolidine-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxviii)6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidine-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxix)(R)-6-(6-cyclopropylpyridine-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxx)(S)-6-(6-cyclopropylpyridine-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxi)3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxii)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxiii)3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxiv)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxv)(R)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxvi)(S)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxvii)(S)-3-(2-hydroxypropyl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxviii)(R)-3-(2-hydroxypropyl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxix)3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxx)(S)-3-(2-hydroxypropyl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxxi)(S)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxxii)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxxiii)3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxxiv)6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxxv)6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxxvi)(R)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxxvii)(S)-2-(4-oxo-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-3(4H)-yl)propanoic acid (cxxxviii)(S)-N-methyl-2-(4-oxo-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-3(4H)-yl)propanamide (cxxxix)(S)-N,N-dimethyl-2-(4-oxo-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-3(4H)-yl)propenamide (cxl)3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxli)3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazole-1-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxlii)3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazole-1-yl)-6-(6-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxliii)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazole-1-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxliv)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazole-1-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxlv)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-1,2,4-triazole-1-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxlvi)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazole-1-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxlvii)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxlviii)(S)-8-(diethylamino)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxlix)(S)-3-(1-hydroxypropan-2-yl)-8-(piperidine-1-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cl)(S)-3-(1-hydroxypropan-2-yl)-8-(pyrrolidine-1-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cli)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(piperidine-1-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clii)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-2-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cliii)(S)-6-cyclohexyl-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cliv)(S)-3-(1-hydroxypropan-2-yl)-6-(pyridine-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clv)(S)-3-(1-hydroxypropan-2-yl)-6-(2-methylthiazole-4-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clvi)(S)-3-(1-hydroxypropan-2-yl)-6-(1-methyl-1H-1,2,3-triazole-5-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clvii)(R)-6-(4-chlorophenyl)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clviii)(S)-6-(4-chlorophenyl)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clix)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1,2,5,6-tetrahydropyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clx)6-(4-chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clxi)(S)-3-(1-hydroxypropan-2-yl)-6-(2-methylpyrimidine-5-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clxii)3-(2-hydroxy-2-methylpropyl)-8-(1-(trifluoromethyl)-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clxiii)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(2-(trifluoromethyl)pyrimidine-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clxiv)3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)pyrimidine-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clxv)(S)-5-(3-(1-hydroxypropan-2-yl)-4-oxo-8-(pyridine-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidine-6-yl)picolinic acid; (clxvi)(S)-3-(1-hydroxypropan-2-yl)-6-(6-methylpyridine-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clxvii)3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(2-(trifluoromethyl)pyrimidine-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clxviii)3,8-di(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clxix)8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clxx)3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clxxi)3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clxxii)6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clxxiii)3-cyclopentyl-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clxxiv)3-phenyl-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clxxv)3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clxxvi)3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clxxvii)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clxxviii)(S)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-2-(4-oxo-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-3(4H)-yl)propanamide (clxxix)3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clxxx)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazole-1-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clxxxi)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazole-1-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clxxxii)3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clxxxiii)3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clxxxiv)3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clxxxv)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clxxxvi)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clxxxvii)(S)-3-(1-hydroxypropan-2-yl)-8-morpholino-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clxxxviii)3-(2-hydroxy-2-methylpropyl)-8-(piperidine-1-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clxxxix)(S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyridine-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (cxc)(S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyrimidine-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (cxci)(S)-8-(cyclohexa-1-en-1-yl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (cxcii)(S)-8-cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (cxciii)(S)-3-(1-hydroxypropan-2-yl)-N,N-dimethyl-4-oxo-8-(pyridine-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidine-6-carboxamide; (cxciv)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (cxcv)(S)-3-(1-hydroxypropan-2-yl)-6-(2-methoxyethyl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; and (cxcvi)(S)-3-(1-hydroxypropan-2-yl)-8-(2-methoxyethyl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxcvii).

[0156] 30. A pharmaceutical composition comprising at least one entity selected from any one compound of Embodiments 1 to 29 and a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0157] 31. A method for treating an AhR signaling-mediated disease or condition in a subject requiring treatment of an AhR signaling-mediated disease or condition, comprising administering to the subject a therapeutically effective amount of at least one entity selected from any one compound of Embodiments 1 to 29 and a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition of Embodiment 30.

[0158] 32. A method for treating a disease or condition associated with abnormal AhR signaling in a subject requiring treatment for such a disease or condition, comprising administering to the subject a therapeutically effective amount of at least one entity selected from any one compound of Embodiments 1 to 29 and a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition of Embodiment 30.

[0159] 33. The method of Embodiment 31 or 32, wherein the disease is selected from cancer.

[0160] 34. The method of Embodiment 31 or 32, wherein the disease is selected from liquid tumors and solid tumors.

[0161] 35. Any one of embodiments 31 to 34, wherein the disease is selected from breast cancer, airway cancer, brain cancer, reproductive organ cancer, gastrointestinal cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and any metastasis of the above.

[0162] 36. Any one of embodiments 31 to 35, wherein the disease is selected from breast cancer, pancreatic cancer, prostate cancer, and colon cancer.

[0163] 37. Any one of embodiments 31 to 34, wherein the disease is selected from lymphoma, sarcoma, melanoma, glioblastoma, and leukemia.

[0164] 38. A method for inhibiting AhR signaling-mediated cancer cell proliferation in a subject requiring inhibition of AhR signaling-mediated cancer cell proliferation, comprising administering to the subject a therapeutically effective amount of at least one entity selected from any one compound of Embodiments 1 to 29 and a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition of Embodiment 30.

[0165] 39. A method for inhibiting AhR signaling-mediated tumor cell invasion or metastasis in a subject requiring inhibition of AhR signaling-mediated tumor cell invasion or metastasis, comprising administering to the subject a therapeutically effective amount of at least one entity selected from any one compound of Embodiments 1 to 29 and a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition of Embodiment 30.

[0166] 40. A method for treating cancer in a subject requiring treatment for cancer, comprising administering to the subject a therapeutically effective amount of i) at least one entity selected from any one compound of Embodiments 1 to 29 and a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition of Embodiment 30, and ii) at least one therapeutically effective amount of an additional therapy.

[0167] 41. The method of Embodiment 40, wherein at least one additional therapy comprises at least two, at least three, at least four, or at least five additional therapies.

[0168] 42. The method of Embodiment 40, wherein administration of at least one entity selected from any one compound of Embodiments 1 to 29 and a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition of Embodiment 30, is initiated before the administration of at least one additional therapy.

[0169] 43. The method of Embodiment 40, wherein at least one entity selected from any one compound of Embodiments 1 to 29 and a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition of Embodiment 30, is administered after the administration of at least one additional therapy.

[0170] 44. The method of Embodiment 40, wherein at least one entity selected from any one compound of Embodiments 1 to 29 and a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition of Embodiment 30, is administered concurrently with the administration of at least one additional therapy.

[0171] 45. Any one of embodiments 40 to 44, wherein at least one additional therapy is selected from checkpoint inhibitors.

[0172] 46. ​​The method of Embodiment 45, wherein, when at least one additional therapy is administered alone, the subject is intolerant, unresponsive, and / or poorly responsive to at least one additional therapy.

[0173] 47. The method of Embodiment 46, wherein 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.

[0174] 48. The method of Embodiment 46, wherein at least one additional therapy is selected from checkpoint inhibitors targeting CTLA-4, PD-1, and / or PD-L1.

[0175] 49. The method of Embodiment 46, wherein at least one additional therapy is selected from cytotoxic T lymphocyte-associated antigen 4 pathway inhibitors.

[0176] 50. The method of Embodiment 49, wherein the cytotoxic T lymphocyte-associated antigen 4 pathway inhibitor is selected from anti-CTLA-4 antibodies.

[0177] 51. The method of Embodiment 50, wherein the anti-CTLA-4 antibody is ipilimumab.

[0178] 52. The method of Embodiment 46, wherein at least one additional therapy is selected from programmed death-1 pathway inhibitors.

[0179] 53. The method of Embodiment 52, wherein a programmed death-1 pathway inhibitor is selected from an anti-PD-1 antibody.

[0180] 54. The method of Embodiment 52, wherein the anti-PD-1 antibody is nivolumab.

[0181] 55. The method of Embodiment 52, wherein the anti-PD-1 antibody is pembrolizumab.

[0182] 56. The method of Embodiment 52, wherein the anti-PD-1 antibody is cemiprimab.

[0183] 57. The method of Embodiment 52, wherein the anti-PD-1 antibody is camrelizumab.

[0184] 58. The method of Embodiment 52, wherein the anti-PD-1 antibody is cintilimab.

[0185] 59. The method of Embodiment 52, wherein the anti-PD-1 antibody is spartalizumab.

[0186] 60. The method of Embodiment 52, wherein the anti-PD-1 antibody is tislerizumab.

[0187] 61. The method of Embodiment 52, wherein the anti-PD-1 antibody is BCD-100.

[0188] 62. The method of Embodiment 52, wherein the anti-PD-1 antibody is JS001.

[0189] 63. The method of Embodiment 52, wherein a programmed death-1 pathway inhibitor is selected from an anti-PD-L1 antibody.

[0190] 64. The method of Embodiment 63, wherein the anti-PD-L1 antibody is atezolizumab.

[0191] 65. The method of Embodiment 63, wherein the anti-PD-L1 antibody is avelumab.

[0192] 66. The method of Embodiment 63, wherein the anti-PD-L1 antibody is durvalumab.

[0193] 67. The method of Embodiment 63, wherein the anti-PD-L1 antibody is KN035.

[0194] 68. The method of Embodiment 46, wherein at least one additional therapy is selected from lymphocyte-activating gene-3 (LAG-3) inhibitors.

[0195] 69. The method of Embodiment 68, wherein the LAG-3 inhibitor is selected from an anti-LAG-3 antibody.

[0196] 70. The method of Embodiment 46, wherein at least one additional therapy is selected from T cell immunoglobulin and mucin domain-containing TIM-3 (TIM-3) inhibitors.

[0197] 71. The method of Embodiment 70, wherein the TIM-3 inhibitor is selected from an anti-TIM-3 antibody.

[0198] 72. The method of Embodiment 46, wherein at least one additional therapy is selected from T cell immunoglobulin and ITIM domain (TIGIT) inhibitors.

[0199] 73. The method of Embodiment 72, wherein the TIGIT inhibitor is selected from the TIGIT antibody.

[0200] 74. The method of Embodiment 46, wherein at least one additional therapy is selected from T-cell activation V-domain Ig suppressor (VISTA) inhibitors.

[0201] 75. The method of Embodiment 74, wherein the VISTA inhibitor is selected from anti-VISTA antibodies.

[0202] 76. Cancers include non-small cell lung cancer (NSCLC); small cell lung cancer; head and neck squamous cell carcinoma; renal cell carcinoma; gastric adenocarcinoma; nasopharyngeal neoplasm; urothelial carcinoma; colorectal cancer; pleural mesothelioma; triple-negative breast cancer (TNBC); esophageal neoplasm; multiple myeloma; gastric and gastroesophageal junction cancer; melanoma; Hodgkin lymphoma; hepatocellular carcinoma; lung cancer; head and neck cancer; non-Hodgkin lymphoma; metastatic clear cell renal cancer; squamous cell lung cancer; mesothelioma; gastric cancer; gastroesophageal junction cancer; metastatic melanoma; metastatic noncutaneous melanoma; urothelial carcinoma; diffuse large B-cell lymphoma A method of any one of embodiments 40 to 75, selected from: renal cell carcinoma; ovarian cancer, fallopian tube cancer; peritoneal neoplasm; advanced small cell lung cancer; bladder cancer; transitional cell carcinoma; prostate neoplasm; recurrent or metastatic PD-L1 positive or negative squamous cell carcinoma of the head and neck (SCCHN); recurrent squamous cell lung cancer; advanced solid malignant tumor; SCCHN; hypopharyngeal squamous cell carcinoma; laryngeal squamous cell carcinoma; unresectable or metastatic melanoma; biliary tract neoplasm; esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, glioblastoma, metastatic cancer, prostate cancer, parenchymal organ cancer; gastric cancer; colon cancer; and liver cancer. [Examples]

[0203] The following non-limiting examples and data illustrate various aspects and features relating to the compounds and / or methods of this disclosure, including the preparation of various compounds available by the synthetic methods described herein. Compared to the prior art, in some embodiments, the compounds and / or methods provide surprising, unexpected, and contrasting results and data. The usefulness of this disclosure is illustrated by the use of several compounds and moieties / groups that can be used with them, but it will be understood by those skilled in the art that equivalent results can be obtained with various other compounds, moieties, and / or groups equivalent to the scope of this disclosure.

[0204] Example 1. Synthesis of pyridopyrimidinone compounds The compounds contained herein are outlined in Scheme I and can be prepared by the procedures described in the following examples. [ka]

[0205] Preparation of tert-butyl N-[(1S)-2-benzyloxy-1-methyl-ethyl]carbamate: [ka] To a solution of tert-butyl N-[(1S)-2-hydroxy-1-methyl-ethyl]carbamate (8, 10 g, 57 mmol, 1 equivalent) in THF (300 mL), NaH (2.51 g, 62.78 mmol, 60% purity, 1.1 equivalent) was added at 0°C, and the mixture was stirred at 0°C for 30 minutes. BnBr (11.71 g, 68.48 mmol, 8.13 mL, 1.2 equivalents) and tetrabutylammonium iodide (210.80 mg, 570.69 mmol, 0.01 equivalent) were added to the mixture at 0°C, and the mixture was then 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 the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain the labeled 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).

[0206] Preparation of (2S)-1-benzyloxypropane-2-aminetrifluoroacetic acid: [ka] To a solution of tert-butyl N-[(1S)-2-benzyloxy-1-methyl-ethyl]carbamate (9, 12 g, 45.22 mmol, 1 equivalent) in DCM (100 mL), TFA (30.80 g, 270.12 mmol, 20 mL, 5.97 equivalents) was added dropwise. The mixture was stirred at 25°C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain the labeled compound (10, 10 g, 35.81 mmol, yield 79.18%, TFA), which was used directly.

[0207] Preparation of (S)-8-(5-fluoropyridine-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one(1) Step 1. Preparation of (S)-3-amino-2,6-dichloro-N-(1-hydroxypropan-2-yl)isonicotinamide (intermediate A1): [ka] A mixture of 3-amino-2,6-dichloroisonicotinic acid (2.0 g, 9.66 mmol) and (S)-2-aminopropan-1-ol (reaction product 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 mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with water and partitioned between ethyl acetate and water. The organic phase was separated, washed with saturated ammonium chloride aqueous solution, then saturated sodium bicarbonate aqueous solution, dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was purified by silica gel chromatography using ethyl acetate / hexane to yield the marked compound (1.82 g, 6.89 mmol, yield 71%). 1 H NMR(CH3OH-d4,400MHz)δ 1.21(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] + .

[0208] Table 2 lists intermediates produced by a procedure similar to that described in Step 1 above.

[0209] [Table 28]

[0210] [Table 29]

[0211] [Table 30]

[0212] [Table 31]

[0213] Preparation of 3-amino-2,6-dichloro-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)isonicotinamide (A16) [ka] Propylphosphonic anhydride (T3P, 64.6 g, 101 mmol, 60.3 mL, 50% purity, 1.05 equivalents) was added all at once to a 150 mL solution of 3-amino-2,6-dichloroisonicotinic acid (Reagent 1, 20 g, 96.6 mmol, 1 equivalent), (3S,4R)-4-aminotetrahydrofuran-3-ol (10.5 g, 101 mmol, 1.05 equivalents), and triethylamine (29.3 g, 290 mmol, 40.3 mL, 3 equivalents) in HCl (150 mL). The resulting solution was stirred at 25°C for 1 hour. The reaction mixture was poured into water (100 mL). The organic phase was collected, and the aqueous phase was extracted with HCl (30 mL x 2). The combined organic phases were washed with brine (100 mL) and concentrated under vacuum to yield the marked compound 3-amino-2,6-dichloro-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)isonicotinamide (A16, 25 g, 85.6 mmol, yield 88.6%) as a grayish-white solid. The crude product was used in the next step without purification. 1 H-NMR (400 MHz, CD3OD): δ Hppm 7.49(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] + .

[0214] Step 2. Preparation of (S)-6,8-dichloro-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (intermediate B1): [ka] (S)-3-amino-2,6-dichloro-N-(1-hydroxypropan-2-yl)isonicotinamide (A1, 2.54 g, 9.66 mmol) in a flask was mixed with 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, the solid was recovered by vacuum filtration, washed with water, and dried under high vacuum to obtain the labeled compound (B1, 1.82 g, 6.64 mmol, yield 69%). 1H NMR(CH3OH-d4,400MHz)δ 1.51(3H,d,J=7.1Hz),3.80(1H,dd,J=11.9,4.2Hz),3.92(1H,dd,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]+.

[0215] Preparation of 3-[(1S)-2-benzyloxy-1-methyl-ethyl]-6,8-dichloropyrido[3,4-d]pyrimidine-4-one (intermediate B11) [ka] Formic acid (18.94 g, 411.41 mmol, 15.52 mL, 1.5 equivalents) was added dropwise to acetyl acetate (28 g, 274.27 mmol, 25.69 mL, 1 equivalent) at 0°C, and the mixture was stirred at 60°C for 2 hours under an N2 atmosphere. A colorless liquid solution was obtained (41 mL, 6.65 M), which was used in the next step without further purification. To a solution of 3-amino-N-[(1S)-2-benzyloxy-1-methyl-ethyl]-2,6-dichloropyridine-4-carboxamide (A11, 4.5 g, 12.70 mmol, 1 equivalent) in THF (50 mL), formyl acetate solution (6.65 M, 41 mL, 21.47 equivalents) was added at 25°C, and the mixture was stirred at 60°C for 30 minutes. The mixture was then stirred at 100°C for 9.5 hours. LC-MS indicated the detection of the desired compound. The reaction mixture was concentrated under reduced pressure to yield a residue. The residue was diluted with ¼ (50 mL), sequentially washed with saturated NaHCO₃ (200 mL), water (50 mL), and brine (50 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to yield another residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1 / 0~1 / 1) to obtain the labeled compound (B11, 2.4 g, 6.59 mmol, yield 51.88%). 1 H NMR(400MHz,CDCl3)δ ppm MS:M+H + ,364.0.

[0216] Table 3 lists intermediates prepared by a procedure similar to that described for the synthesis of intermediate B1 above.

[0217] [Table 32]

[0218] [Table 33]

[0219] [Table 34]

[0220] [Table 35]

[0221] Preparation of (S)-6,8-dichloro-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (B10) [ka] 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-methylbutan-2-yl)isonicotinamide (1.2 g, 4.11 mmol) in trimethyl orthoformate (10 mL), and the mixture was degassed and nitrogen-purged three times. The mixture was stirred under a nitrogen atmosphere at 120 °C for 8 hours. TLC showed that the starting reaction products remained and two new spots were formed. The solvent was evaporated, the residue was absorbed into ethyl acetate (20 mL), washed three times with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. Purification of the residue by preparative HPLC yielded the compound (S)-6,8-dichloro-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (600 mg, 1.99 mmol, yield 48%). 1 H-NMR (400 MHz, DMSO-d6):δ H ppm 8.60(s,1H),8.05(s,1H),5.02(d,J=3.2Hz,1H),4.19-4.56(m,1H),3.85-3.97(m,1H),3.74(q,J=11 .8Hz,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.

[0222] Step 3. Preparation of (S)-6-chloro-8-(5-fluoropyridine-3-yl)-3-(1--2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (intermediate C1): [ka] A mixture of (S)-6,8-dichloro-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (B1, 0.10 g, 0.37 mmol), (5-fluoropyridine-3-yl)boronic acid (reaction product 2, 0.057 g, 0.401 mmol), sodium carbonate (0.16 g, 1.46 mmol), and tetrakis(triphenylphosphine)palladium (0.042 g, 0.036 mmol) in a sealed tube was purged with argon. Toluene (3.0 mL) and ethanol (1.5 mL) were added, and the resulting mixture was stirred at 75°C for 15 hours. The mixture was cooled to room temperature, filtered through Celite, the Celite pad was washed with ethyl acetate, and the filtrate was concentrated to dryness. Purification of the residue by silica gel chromatography using methanol / dichloromethane yielded the indicated compound (C1, 0.078 g, 0.19 mmol, 53% yield). NMR(DMSO-d6,300MHz):δ 1.41(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(1H,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]+.

[0223] Table 4 lists intermediates produced by a procedure similar to that described in Step 3 above.

[0224] [Table 36]

[0225] Table 37

[0226] Table 38

[0227] Table 39

[0228] Table 40

[0229] Table 41

[0230] Table 42

[0231] Table 43

[0232] Table 44

[0233] Table 45

[0234] Table 46

[0235] [Table 47]

[0236] [Table 48]

[0237] [Table 49]

[0238] Step 4. Preparation of (S)-8-(5-fluoropyridine-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one(1): [ka] A mixture of (S)-6-chloro-8-(5-fluoropyridine-3-yl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidine-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) in a sealed tube was purged with argon. Toluene (1.0 mL) and ethanol (0.5 mL) were added, and the resulting mixture was stirred at 75°C for 15 hours. The mixture was cooled to room temperature, filtered through Celite, the Celite pad was washed with ethyl acetate, and the filtrate was evaporated. Purification of the residue by silica gel chromatography using methanol / dichloromethane yielded the indicated compound (0.022 g, 0.047 mmol, 68% yield). 1H NMR(DMSO-d6,400MHz):δ 1.44(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.

[0239] Table 5 lists compounds prepared by a procedure similar to that described for reactants 1, 2, and 3, with the indicated groups replaced.

[0240] [Table 50]

[0241] [Table 51]

[0242] [Table 52]

[0243] [Table 53]

[0244] [Table 54]

[0245] [Table 55]

[0246] [Table 56]

[0247] Table 57

[0248] Table 58

[0249] Table 59

[0250] Table 60

[0251] Table 61

[0252] Table 62

[0253] Table 63

[0254] Table 64

[0255] Table 65

[0256] Table 66

[0257] Table 67

[0258] Table 68

[0259] Table 69

[0260] Table 70

[0261] Table 71

[0262] Table 72

[0263] Table 73

[0264] Table 74

[0265] Table 75

[0266] Table 76

[0267] Table 77

[0268] Table 78

[0269] Table 79

[0270] Table 80

[0271] Table 81

[0272] Table 82

[0273] Table 83

[0274] Table 84

[0275] Table 85

[0276] Table 86

[0277] Table 87

[0278] Table 88

[0279] Table 89

[0280] Table 90

[0281] Table 91

[0282] Table 92

[0283] Table 93

[0284] Table 94

[0285] Table 95

[0286] Table 96

[0287] Table 97

[0288] Table 98

[0289] Table 99

[0290] Table 100

[0291] Table 101

[0292] Table 102

[0293] Table 103

[0294] Table 104

[0295] Table 105

[0296] Table 106

[0297] Table 107

[0298] Table 108

[0299] Table 109

[0300] Table 110

[0301] Table 111

[0302] Table 112

[0303] Table 113

[0304] Table 114

[0305] Table 115

[0306] Table 116

[0307] Table 117

[0308] Table 118

[0309] [Table 119]

[0310] [Table 120]

[0311] [Table 121]

[0312] [Table 122]

[0313] [Table 123]

[0314] Preparation of 3-((S)-1-hydroxypropan-2-yl)-8-(1-methylpiperidine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one [ka] To a solution of (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1,2,5,6-tetrahydropyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (60 mg, 0.135 mmol) in EtOH (1 mL), PtO2 (15 mg, 0.088 mmol) was added. The flask was degassed and exposed to H2 gas in a balloon. After one night, the reaction mixture was filtered through Celite®, thoroughly washed with methanol, concentrated, and purified by reverse-phase chromatography eluting with 0.1% formic acid and acetonitrile in H2O, yielding the desired product as a diastereomer mixture (4 mg, 7%). 1 1H 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.

[0315] Preparation of (S)-3-(1-hydroxypropan-2-yl)-6-morpholino-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(43) [ka] (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (11, 0.060 g, 0.19 mmol) and potassium carbonate (0.011 g, 0.76 mmol) were added in a sealed tube, to which dimethylformamide (2.0 ml) was added, followed by morpholine (0.038 g, 0.38 mmol). The resulting mixture was stirred at 120°C. After 24 hours, a further amount of morpholine (38.1 mg, 0.38 mmol) was added, and stirring was continued for another 24 hours at 120°C. The reaction mixture was allowed to cool to room temperature and then partitioned between water and ethyl acetate. The organic layer was separated, dried over sodium sulfate, and concentrated. Purification of the residue by silica gel chromatography using methanol / dichloromethane yielded the indicated compound (0.026 g, 0.071 mmol, 37% yield). 1 H NMR(DMSO-d6,400MHz):δ 1.38(3H,d,J=7.04Hz),3.58-3.65(5H,m),3.76(5H,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.

[0316] The compounds listed in Table 6 below were prepared according to a method similar to that of compound 43 mentioned earlier.

[0317] [Table 124]

[0318] Preparation of (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazole-1-yl)-6-(4-(trifluoromethoxy)-phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one(44): Step 1. Preparation of (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(1H-imidazole-1-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (C23): [ka] In resealable Schlenk tubes and screw-cap test tubes, CuI (4 mg, 0.02 mmol), imidazole (25 mg, 0.37 mmol), cesium carbonate (250 mg, 0.77 mmol), and a stirring bar were added. After degassing the tubes, (S)-6,8-dichloro-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (100 mg, 0.37 mmol), 1,10-phenanthroline (7 mg, 0.04 mmol), and anhydrous dioxane (2 mL) were added under an argon stream. The reaction tubes were degassed, refilled with argon, and stirred at 90°C for 24 hours. The reaction mixture was allowed to cool to room temperature. The solution was diluted with ethyl acetate (2-3 mL), filtered through a Celite plug, and eluted with additional ethyl acetate (10-20 mL). The filtrate was washed with water and brine, dried over Na2SO4, and concentrated. The resulting residue was purified by silica gel column chromatography (CH2Cl2 / MeOH) to yield the labeled compound (C23, 20 mg, 0.06 mmol, yield 18%). 1 ¹H NMR (CHCl3-d3 with 10% CH3OH-d4, 400MHz): δH 1.46 (3H,dd,J=16.4,7.1Hz), 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, probably due to complexation with copper.

[0319] Step 2. Preparation of (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazole-1-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one(44): [ka] (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(1H-imidazole-1-yl)pyrido[3,4-d]pyrimidine-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, the suspension was degassed, and refilled with argon (3 cycles). The reaction mixture was stirred overnight under argon at 85°C. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate. The solution was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH) followed by C18 column chromatography to yield the TFA salt of (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazole-1-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one, which was washed with saturated Na2CO3 to obtain the free base of the indicated compound 44 (11 mg, 0.026 mmol, yield 26%). 1 H NMR(CH3OH-d4,400MHz):δ 1.56(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%.

[0320] Preparation of (S)-3-(1-methoxypropan-2-yl)-8-(pyridine-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H)-one(45) [ka] (S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H)-one (17, 20 mg, 0.05 mmol) was dissolved in anhydrous THF, and the resulting solution was cooled in an ice bath. Then, t-BuOK (6 mg, 0.05 mmol) was added, followed by CH3I (8 mg, 0.05 mmol). The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched by the addition of methanol and diluted with ethyl acetate. This solution was washed with water and brine, dried over Na2SO4, concentrated, and purified by HPLC to give the TFA salt of (S)-3-(1-methoxypropan-2-yl)-8-(pyridine-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H)-one, which was then washed with saturated Na2CO3 aqueous solution to give the free base of the indicated compound 45 (2 mg, 0.005 mmol, yield 10%). 1 H NMR(CH3OH-d4,400MHz):δ 1.55(3H,d,J=7.1Hz),2.41(3H,s),3.36(3H,s),3.68(1H,dd,J=10.5,4.2 Hz),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),8.5 0(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%.

[0321] Preparation of (S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(46) [ka] (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (11, 50 mg, 0.15 mmol) was dissolved in toluene. After degassing the solution, Pd(dppf)Cl2·CH2Cl2 (13 mg, 0.016 mmol), LiCl (26 mg, 4 equivalents), CuI (6 mg, 0.032 mmol), and 2-(tributylstannyl)-5-(trifluoromethyl)pyridine (83 mg, 0.19 mmol) were added. The solution was degassed again and stirred overnight at 80°C. LC-MS monitoring of the reaction mixture showed incomplete conversion to the expected product, so 30 mg of CuI was added and the reaction was allowed to proceed for a further 6 hours at 80°C. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate. This solution was washed with water and 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-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one. Washing with saturated aqueous Na2CO3 solution yielded the free base of the indicated compound (8 mg, 0.019 mmol, yield 12%). 1 H NMR(CH3OH-d4,400MHz):δ 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):428.1 [M+H]+;Purity 99%.

[0322] Preparation of (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(47): [ka] (S)-6-chloro-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (C1, 50 mg, 0.15 mmol) was dissolved in toluene, degassed, and then Pd(dppf)Cl2·CH2Cl2 (24 mg, 0.18 mg), LiCl (26 mg, 0.6 mmol), CuI (29 mg, 0.15 mmol), and 2-(tributylstannyl)-5-(trifluoromethyl)pyridine (79 mg, 0.18 mmol) were added. The solution was degassed again and stirred overnight at 80°C. The reaction mixture was diluted with Â, washed with water and brine, and dried over Na2SO4. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (CH2Cl2 / MeOH) followed by C18 column chromatography to yield the TFA salt of (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one. Washing with saturated Na2CO3 yielded the free base of the indicated compound (19 mg, 0.04 mmol, yield 25%). 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%.

[0323] Compounds prepared by a method similar to that described in 47 are listed in Table 7 below.

[0324] [Table 125]

[0325] [Table 126]

[0326] [Table 127]

[0327] Preparation of 8-(3-fluorophenyl)-3-[(1S)-2-hydroxy-1-methyl-ethyl]-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4-one (48) [ka] A mixture of 3-[(1S)-2-benzyloxy-1-methyl-ethyl]-8-(3-fluorophenyl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4-one (40 mg, 160 mg, 333.65 umol, 1 equivalent) and Pd / C (80 mg, 333.65 umol, purity 10%, 1.00 equivalent) in MeOH (25 mL) and siRNA (25 mL) was degassed, replaced three times with H2 (15 psi), and then stirred at 80°C for 15 hours under an H2 atmosphere. LCMS showed detection of the desired compound. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to yield the residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1:1) to obtain the labeled compound (47 mg, 120.69 umol, yield 36.17%). 1H NMR(400MHz,DMSO-d6)δ ppm 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.

[0328] Preparation of 8-(3-fluorophenyl)-3-[(1S)-2-hydroxy-1-methyl-ethyl]-6-[4-(trifluoromethoxy)phenyl]pyrido[3,4-d]pyrimidine-4-one (49) Step 1.3 Preparation of [(1S)-2-benzyloxy-1-methyl-ethyl]-8-(3-fluorophenyl)-6-[4-(trifluoromethoxy)phenyl]pyrido[3,4-d]pyrimidine-4-one (precursor 1) [ka] 3-[(1S)-2-benzyloxy-1-methyl-ethyl]-6-chloro-8-(3-fluorophenyl)pyrido[3,4-d]pyrimidine-4-one (C21, 460 mg, 1.09 mmol, 1 equivalent) and [4-(trifluoromethoxy)phenyl]boronic acid (268.18 mg, 1.30 mmol, 1.2 equivalents) were dissolved in toluene (8 mL) and EtOH (4 mL). Na2CO3 (460.10 mg, 4.34 mmol, 4 equivalents) and Pd(PPh3)4 (125.41 mg, 108.52 mmol, 0.1 equivalent) were added. The mixture was packed into a microwave tube. The sealed tube was heated under microwave at 100°C for 1 hour. LCMS showed that the desired compound was detected. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain the indicated compound (400 mg, 727.92 umol, yield 67.07%). MS: M+H+, 550.1.

[0329] Step 2. Preparation of 8-(3-fluorophenyl)-3-[(1S)-2-hydroxy-1-methyl-ethyl]-6-[4-(trifluoromethoxy)phenyl]pyrido[3,4-d]pyrimidine-4-one (49) [ka] To a solution of 3-[(1S)-2-benzyloxy-1-methyl-ethyl]-8-(3-fluorophenyl)-6-[4-(trifluoromethoxy)phenyl]pyrido[3,4-d]pyrimidine-4-one (precursor 1, 290 mg, 527.74 umol, 1 equivalent) in siRNA (20 mL) and MeOH (20 mL), Pd(OH)2 / C (130 mg, 527.74 umol, purity 10%, 1.00 equivalent) was added. The mixture was stirred under H2 (15 psi) at 25°C for 6 hours. LC-MS showed that the desired mass was detected. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1:1) to obtain the labeled compound 49 (22 mg, 47.41 umol, yield 8.98%). 1 H NMR(400MHz,CDCl3)δ ppm 1.61(d,J=7.1Hz,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=8.4Hz) ,2H),7.46-7.54(m,1H),7.94-8.07(m,2H),8.26(d,J=8.4Hz,2H),8.32(s,1H),8.53(s,1H).MS:M+H+,460.1;99% purity.

[0330] The compounds contained herein are outlined in Scheme II and can be prepared by the procedures described in the following examples. [ka]

[0331] Preparation of 3-(1,1-dioxidetetrahydrothiophen-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(106) Step 1. Preparation of methyl 3-amino-6-chloro-[2,3'-bipyridine]-4-carboxylate (precursor 2): [ka] Precursor 2 was prepared according to the procedure reported for step 3 of the synthesis of 1. 1 1H NMR (CHCl3-d, 400MHz):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] + .

[0332] Table 8 lists intermediates produced by a procedure similar to that described in Step 1 above.

[0333] [Table 128]

[0334] Step 2. Preparation of methyl 3'-amino-6''-(trifluoromethyl)-[3,2':6',3''-terpyridine]-4'-carboxylate (precursor 3): [ka] Precursor 3 was prepared according to the procedure reported for step 3 of the synthesis of 1. 1 1H NMR (CHCl3-d, 400MHz):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] + .

[0335] Table 9 lists intermediates produced by procedures similar to those described above.

[0336] [Table 129]

[0337] [Table 130]

[0338] [Table 131]

[0339] Step 3. Preparation of 3'-amino-N-(1,1-dioxidetetrahydrothiophen-3-yl)-6''-(trifluoromethyl)-[3,2':6',3''-terpyridine]-4'-carboxamide (precursor 4) [ka] 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 mixture was stirred at 0°C for 1 hour and then stirred overnight at room temperature. The reaction mixture was acidified to pH 4 using 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 yield 3'-amino-6''-(trifluoromethyl)-[3,2':6',3''-terpyridine]-4'-carboxylic acid (3.0 g, 7.91 mmol, yield 95%, purity 95%). MS(m / z):361.1[M+H] + The acid intermediate was directly subjected to the next step.

[0340] A mixture of 3'-amino-6''-(trifluoromethyl)-[3,2':6',3''-terpyridine]-4'-carboxylic acid (0.6 g, 1.67 mmol) and 3-aminotetrahydrothiophene 1,1-dioxide HCl (0.314 g, 1.83 mmol) 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 mixture was stirred at 0°C for 1 hour and then stirred overnight at room temperature. The reaction mixture was quenched with water and partitioned between ethyl acetate and water. The organic phase was separated and washed with saturated ammonium chloride aqueous solution, and then with saturated sodium bicarbonate aqueous solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to yield the compound 3'-amino-N-(1,1-dioxidetetrahydrothiophen-3-yl)-6''-(trifluoromethyl)-[3,2':6',3''-terpyridine]-4'-carboxamide (precursor 4, 0.58 g, yield 66%, purity >90%). MS(m / z): 478.1[M+H] + The crude product was subjected to the next step without purification.

[0341] Table 10 lists intermediates produced by procedures similar to those described above.

[0342] [Table 132]

[0343] [Table 133]

[0344] [Table 134]

[0345] [Table 135]

[0346] Table 136

[0347] Table 137

[0348] Table 138

[0349] Table 139

[0350] Table 140

[0351] Table 141

[0352] Table 142

[0353] Table 143

[0354] Table 144

[0355] Table 145

[0356] Preparation of 3'-amino-6''-(trifluoromethyl)-[3,2':6',3''-terpyridine]-4'-carboxamide (F30) [ka] 300 mg, 0.801 mmol of methyl 3'-amino-6''-(trifluoromethyl)-[3,2':6',3''-terpyridine]-4'-carboxylate (in a vial) was mixed with a 7 M ammonia (MeOH) solution, sealed, and heated overnight at 65°C. After evaporation of the solvent, 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.

[0357] Step 4-3-(1,1-dioxidetetrahydrothiophen-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(106) [ka] Triethyl orthoformate (10 mL) was added to 3'-amino-N-(1,1-dioxidetetrahydrothiophen-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 overnight at 95°C. The mixture was concentrated, followed by the addition of saturated NaHCO3, and the solid was recovered by vacuum filtration, washed with water, and dried. Purification of the residue by normal-phase chromatography yielded the compound 3-(1,1-dioxidetetrahydrothiophen-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (10⁶, 0.13 g, yield 43%). 1H NMR(DMSO-d6,300MHz):δH 2.70-2.67(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.

[0358] Preparation of (R)-3-(1,1-dioxidetetrahydrothiophen-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(107) [ka] Dioxane (7 mL) and triethyl orthoformate (1.2 mL, 7.02 mmol) were added to the intermediate (R)-3'-amino-N-(1,1-dioxidetetrahydrothiophen-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. Purification of the residue by silica gel column chromatography yielded the compound (R)-3-(1,1-dioxidetetrahydrothiophen-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (98 1.82 g, yield 69%). 1 1H NMR (DMSO-d6, 400MHz):δ H3.25-3.18(2H,m),3.90-3.87(1H,m),4.25-4.12(3H,m),5.96(1H,t,J=8.5Hz),8.16(1H,d,J=6.7Hz),8.62(1H,d,J=8.3H z),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

[0359] Table 11 lists compounds prepared by a procedure similar to that described for 98, with the groups indicated for reactants 4, 5, and 6 being replaced.

[0360] [Table 146]

[0361] [Table 147]

[0362] [Table 148]

[0363] [Table 149]

[0364] [Table 150]

[0365] [Table 151]

[0366] Preparation of (S)-6-(6-cyclopropylpyridine-3-yl)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one(120) as a white solid. [ka] 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 hour, DMF (0.5 ml) was added, and the reaction mixture was heated to 40°C and stirred for 48 hours. 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 yield the compound (S)-6-(6-cyclopropylpyridine-3-yl)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one as a white solid (120, 115 mg, 37%). 1 H NMR(DMSO-d6,400MHz):δ 1.02(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.

[0367] Table 12 lists compounds prepared by a procedure similar to that described for 120, with the indicated groups replaced for reactants 4, 5, and 6.

[0368] [Table 152]

[0369] Preparation of (R)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(108) [ka] Compound 108 was prepared according to the procedure reported for step 2 (synthesis of intermediate B1) of the synthesis of compound 1. 1 1H NMR (DMSO-d6, 400MHz):δ H 1.17(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),8.0 3(1H,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.

[0370] Table 13 lists compounds prepared by a procedure similar to that described for 108, with the indicated groups replaced for reactants 4, 5, and 6.

[0371] [Table 153]

[0372] [Table 154]

[0373] Table 155

[0374] Table 156

[0375] Table 157

[0376] Table 158

[0377] Table 159

[0378] Table 160

[0379] Table 161

[0380] Table 162

[0381] Table 163

[0382] Table 164

[0383] Preparation of K-0004422 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidine-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(134) Step 1. Preparation of tert-butyl(3R,4R)-3-(6-(4-chlorophenyl)-4-oxo-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-3(4H)-yl)-4-hydroxypyrrolidine-1-carboxylate (precursor 5) [ka] When the above procedure was carried out according to the procedure reported for 108, a mixture of tert-butyl(3R,4R)-3-(6-(4-chlorophenyl)-4-oxo-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-3(4H)-yl)-4-hydroxypyrrolidine-1-carboxylate (precursor 5) and 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidine-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (134) was obtained.

[0384] Step 2.6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidine-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(134) [ka] A mixture of precursors 5 and 134 (218 mg, 0.43 mmol) is dissolved in 3.0 mL of 4M solution. The compound was dissolved in a HCl solution of dioxane and stirred at room temperature for 1 hour. Diethyl ether (2.0 ml) was added, the solid was centrifuged, decanted, tritulate with ether, and dried. The solid was purified by reverse-phase column chromatography, giving the compound 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidine-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (134, 120 mg, 0.29, yield 67%) as a white solid. 1 1H NMR (DMSO-d6, 400MHz):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=8.4Hz),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.

[0385] Manufacturing of (R)-6-(6-cyclopropylpyridine-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one(135): [ka] Triethyl orthoformate (1.74 ml, 10.5 mmol) and 12.1N HCl (115 μl, 1.39 mmol) were added to a solution of (R)-5-amino-6'-cyclopropyl-6-(1-methyl-1H-pyrazole-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). After 1 hour, DMF (0.5 ml) was added, and the reaction mixture was stirred at room temperature for 24 hours. 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 yield the labeled compound (R)-6-(6-cyclopropylpyridine-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one (135, 152 mg, 48%). 1 H NMR(DMSO-d6,400MHz):δ 1.03-1.00(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),7.4 6(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.

[0386] Table 14 lists compounds prepared by a procedure similar to that described for 139, with the groups indicated for reactants 4, 5, and 6 being replaced.

[0387] [Table 165]

[0388] The compounds contained herein are outlined in Scheme III and can be prepared by the procedures described in the following examples. [ka]

[0389] Preparation of 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(137) Step 1. Preparation of 3-amino-6-chloro-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-2-(1-methyl-1H-pyrazole-4-yl)isonicotinamide (intermediate G1) [ka] Intermediate G1 was prepared according to step 3 of synthesis 114. MS(m / z):338.0[M+H] + .

[0390] Table 15 shows the intermediates produced according to the process described above.

[0391] [Table 166]

[0392] [Table 167]

[0393] [Table 168]

[0394] [Table 169]

[0395] [Table 170]

[0396] [Table 171]

[0397] Step 2. Preparation of 6-chloro-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (intermediate H1) [ka] Intermediate H1 was synthesized according to the final step of the 98-step synthesis. 1 H-NMR (DMSO-d6, 400MHz):δ H 3.62-3.55(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(1 H,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.

[0398] The intermediates in Table 16 were synthesized according to the process described above.

[0399] [Table 172]

[0400] [Table 173]

[0401] [Table 174]

[0402] Table 17 shows the intermediates synthesized according to the final step of the synthesis of 108.

[0403] [Table 175]

[0404] [Table 176]

[0405] [Table 177]

[0406] [Table 178]

[0407] Step 3. Method A: Preparation of 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(137): [ka] 6-Chloro-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (H1, 200 mg, 0.575 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II)[Xphos Pd G1], (22.24 mg, 0.029 mmol), and 5-trifluoromethyl-2-pyridylboronic acid MIDA ester (260 mg, 0.863 mmol) were added to a 10 mL pressure vial that had been heated and dried with a stirring bar under air. A vial was filled with argon, then 1-methyl-2-pyrrolidone (NMP) (4 mL) was added, followed by diethanolamine (0.055 mL, 0.575 mmol), K3PO4 (610 mg, 2.87 mmol), and Cu(OAc)2 (52.2 mg, 0.288 mmol). The vial was then sealed with a cap. 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 minutes. Then 1N NaOH (12 mL) was added, and the resulting solution was stirred for 20 minutes. The formed precipitate was filtered, collected, and dried. Purification of the precipitate by silica gel column chromatography yielded the compound 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (137, 151 mg, yield 57%). 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.

[0408] Table 18 lists compounds prepared by a procedure similar to that described for 137, with the indicated groups replaced in the reactants 6 and 7.

[0409] [Table 179]

[0410] [Table 180]

[0411] [Table 181]

[0412] [Table 182]

[0413] [Table 183]

[0414] [Table 184]

[0415] [Table 185]

[0416] [ka] Table 19 lists the compounds synthesized according to the procedure used in the final step of the synthesis of 137 compounds.

[0417] [Table 186]

[0418] The compounds contained herein are outlined in Scheme V and can be prepared by the procedures described in the following examples. [ka]

[0419] Preparation of 6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one 18(152): [ka] 152 was synthesized according to step 4 of the synthesis of 1. 1 H NMR(DMSO-d6,400MHz):δ 3.63(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=4.4 Hz),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.

[0420] Table 20 lists compounds prepared by a procedure similar to that described for 152, with the groups indicated for reactants 6, 7, and 8 being replaced.

[0421] [Table 187]

[0422] Manufacturing of (S)-2-(4-oxo-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-3(4H)-yl)propanoic acid (155) [ka] Methyl(S)-2-(4-oxo-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-3(4H)-yl)propanoate (127, 70 mg, 0.15 mmol) was dissolved in 0.5 THF, and 0.5 mL of 1 M LiOH was added dropwise. The reaction mixture was stirred at room temperature. After completion, the solution was acidified with Amberlite-IR120[H], filtered, concentrated, and the residue was purified by reverse-phase chromatography to yield the marked compound (S)-2-(4-oxo-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-3(4H)-yl)propanoic acid (155, 32 mg, 0.073 mmol, yield 47%). 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%.

[0423] Preparation of (S)-N-methyl-2-(4-oxo-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-3(4H)-yl)propanamide (156) [ka] (S)-2-(4-oxo-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-3(4H)-yl)propanoic acid (155 mg, 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 bath and HATU (155 mg, 0.408 mmol) was added. The reaction mixture was allowed to stand and warm to room temperature, and kept stirred at room temperature. After completion, the reaction mixture was quenched with water and diluted with ethyl acetate. The organic phase was washed with saturated NaHCO3 and brine, dried over anhydrous sodium sulfate, and concentrated. Purification of the residue by normal-phase chromatography yielded the labeled compound (S)-N-methyl-2-(4-oxo-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-3(4H)-yl)propanamide (156 mg, 94 mg, 0.21 mmol, yield 61%). 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=8.3Hz),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%.

[0424] Preparation of (S)-N,N-dimethyl-2-(4-oxo-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-3(4H)-yl)propenamide (157) [ka] Compound 157 was synthesized according to the procedure reported for compound 156. 1H-NMR (DMSO-d6, 400MHz):δ H 1.66(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=8.3Hz),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%.

[0425] Preparation of (S)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-2-(4-oxo-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-3(4H)-yl)propenamide (158) [ka] Compound 158 was synthesized following the procedure reported for compound 138. 1 H-NMR(DMSO-d6,400MHz):δ 1.68(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(1 H,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%

[0426] Preparation of 3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (159) Step 1. Preparation of 6-chloro-3-(2-hydroxy-2-methylpropyl)-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (precursor 6) [ka] 6-Chloro-3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (C23, 140 mg, 0.44 mmol) was suspended in anhydrous THF (4.4 mL), and the mixture was cooled in an ice bath. NaH (60% dispersion in oil, 26 mg, 1.10 mmol) was added, and the mixture was stirred for 10 minutes, after which SEMCl (0.19 mL, 1.10 mmol) was added. After completion, the reaction was quenched with saturated NH4Cl aqueous solution (25 mL) and water (10 mL). The aqueous layer was separated and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the residue by normal-phase chromatography yielded the labeled compound 6-chloro-3-(2-hydroxy-2-methylpropyl)-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (6, 170 mg, 0.38 mmol, yield 86%). 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] + .

[0427] Step 2. Preparation of 3-(2-hydroxy-2-methylpropyl)-6-(5-(trifluoromethyl)pyridine-2-yl)-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (precursor 7) [ka] Precursor 7 was prepared according to the procedure reported above. 1 H-NMR (CHCl3-d, 400MHz):δ H -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(2H,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] + .

[0428] Step 3. Preparation of 3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (159) [ka] 3-(2-hydroxy-2-methylpropyl)-6-(5-(trifluoromethyl)pyridine-2-yl)-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (precursor 7, 90 mg, 0.16 mmol) was dissolved in 1.6 mL of anhydrous DCM, and the solution was cooled in an ice bath. Trifluoroacetic acid (0.61 mL, 8.0 mmol) was added. The reaction mixture was stirred at 0°C for 30 minutes and then warmed to room temperature. After completion, volatiles were removed under reduced pressure. The residue was absorbed into ethyl acetate, washed with saturated NaHCO3 and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by normal-phase chromatography and subsequently recrystallized in MeOH to yield the compound 3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (159 mg, 35 mg, yield 51%). 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%.

[0429] Preparation of 3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazole-1-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(160) Step 1. Preparation of 6-chloro-3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazole-1-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (precursor 8) [ka] In a screw-cap test tube dried in an oven, 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]pyrimidine-4(3H)-one (B2, 400 mg, 1.4 mmol), poly(ethylene glycol) (233 mg, 0.07 mmol), Cs2CO3 (908 mg, 2.8 mmol), and a magnetic stirring bar were placed. Then, anhydrous NMP (7 mL) was added, and a rubber septum was attached to the reaction vessel. The vessel was vacuumed and refilled with argon for three 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 celite plug, and eluted with additional dichloromethane. The filtrate was washed with saturated NaHCO3 and brine, dried over anhydrous sodium sulfate, concentrated, and the resulting residue was purified by normal-phase chromatography to yield the compound 6-chloro-3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazole-1-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (precursor 8, 200 mg, yield 45%). 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] + .

[0430] Step 2. Preparation of 3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazole-1-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(160) [ka] Compound 160 was prepared according to the procedure reported for compound 121. 1H-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%.

[0431] Preparation of 3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazole-1-yl)-6-(6-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(161) [ka] Compound 161 was synthesized according to step 4 of the synthesis of compound 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(1 H,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%.

[0432] Preparation of (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazole-1-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(162) Step 1. Preparation of (S)-3-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6,8-dichloropyrido[3,4-d]pyrimidine-4(3H)-one (precursor 9) [ka] Imidazole (99 mg, 1.5 mmol) was added to a solution of (S)-6,8-dichloro-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (B1, 200 mg, 0.73 mmol) in anhydrous DMF. The solution was cooled in an ice bath and TBDMSCl (132 mg, 0.88 mmol) was added. The reaction mixture was allowed to stand and warmed to room temperature, with stirring for 2 hours. After completion, the reaction was quenched with methanol. The reaction mixture was diluted with ELISA and washed sequentially with saturated NaHCO3 and water. The organic phase was dried over anhydrous sodium sulfate and concentrated to yield the compound (S)-3-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6,8-dichloropyrido[3,4-d]pyrimidine-4(3H)-one (precursor 9,280 mg, yield 99%). 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] + .

[0433] Step 2. Preparation of (S)-3-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6-chloro-8-(1H-imidazole-1-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (P1) [ka] Intermediate P1 was synthesized according to the procedure reported in step 1 of the synthesis of 160. MS(m / z): 420.0[M+H].

[0434] Table 21 shows the intermediates synthesized according to the process described above.

[0435] [Table 188]

[0436] Step 3. Preparation of (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(1H-imidazole-1-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (Q1) [ka] (S)-3-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6-chloro-8-(1H-imidazole-1-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (intermediate P1, 460 mg, 1.1 mmol) was dissolved in anhydrous THF (11 mL) and cooled in an ice bath. Tetrabutylammonium fluoride (1.0 M in THF, 1.3 mL, 1.3 mmol) was added dropwise, and the solution was stirred for 10 minutes. After completion, the reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The organic phase was recovered, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was absorbed with MeOH, and the precipitate was collected and dried to yield the marked compound, which was used in the next step without further purification: (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(1H-imidazole-1-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (intermediate Q1, 340 mg, 1.1 mmol, quantitative 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,m),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] + .

[0437] Table 22 lists the intermediates synthesized according to the process described above.

[0438] [Table 189]

[0439] Step 4. Preparation of (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazole-1-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(162) [ka] 162 was prepared according to the procedure reported for 137. 1 H-NMR (CH3OH-d4, 400MHz):δ H 1.57(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),8.2 8(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%.

[0440] Preparation of (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazole-1-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(163) [ka] (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(1H-imidazole-1-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (intermediate Q1, 85 mg, 0.28 mmol) and 2-trifluoromethylpyridine-5-boronic acid (80 mg, 0.42 mmol) were dissolved in 2 mL of 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, the suspension was degassed, and refilled with argon (3 cycles). The reaction mixture was heated to 85°C under argon and stirred overnight. After completion, the reaction mixture was cooled, diluted in ethylethanol, and 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 yield the compound (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazole-1-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (163, 52 mg, 45% yield). ¹H-NMR (CH3OH-d4, 300 MHz):δ H 0.08(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%.

[0441] Table 23 lists the compounds synthesized according to the reported synthesis procedure for 163, with the reactants in step 2 being replaced.

[0442] [Table 190]

[0443] [Table 191]

[0444] Preparation of (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(168) [ka] (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-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 layer was dried over anhydrous magnesium sulfate, concentrated, and purified by silica gel column chromatography to yield (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (168 mg, 28 mg, yield 20%). 1 H NMR(DMSO-d6,400MHz):δ 1.45(3H,d,J=7.0Hz),3.71-3.66(1H,m),3.82-3.77(1H,m),3.97(3H,s),4.92-4.87(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.

[0445] Table 24 lists the compounds synthesized according to synthesis scheme V, which involves carrying out the steps in accordance with the procedure reported in 168.

[0446] [Table 192]

[0447] [Table 193]

[0448] [Table 194]

[0449] The compounds contained herein are outlined in Scheme V and can be prepared by the procedures described in the following examples. [ka]

[0450] Preparation of (S)-8-(diethylamino)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(174) Step 1. Preparation of (S)-6-chloro-8-(diethylamino)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (intermediate S1) [ka] Dimethylformamide (2.0 ml) was added to (S)-6,8-dichloro-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidine-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. Purification of the residue by silica gel column chromatography yielded the compound (S)-6-chloro-8-(diethylamino)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (intermediate S1, 0.062 g, yield 27%). 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] + .

[0451] Table 25 lists the intermediates synthesized according to the process described above.

[0452] [Table 195]

[0453] Step 2. Preparation of (S)-8-(diethylamino)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (174) [ka] The above steps for preparing 174 were carried out according to the procedure reported in Final Step 1.

[0454] Table 26 lists the compounds synthesized according to the reported synthesis procedure for 174, with the reactants in Step 1 and Step 2 being replaced.

[0455] [Table 196]

[0456] [Table 197]

[0457] [Table 198]

[0458] Preparation of (S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-2-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(180) Step 1. Preparation of (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (precursor 10) [ka] (S)-6,8-dichloro-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (intermediate B1, 200 mg, 0.73 mmol) was dissolved in toluene, degassed, and then PdCl2 (2.62 mg, 0.015 mmol), CsF (0.222 g, 1.46 mmol), CuI (0.056 g, 0.292 mmol), tri-tertiary butylphosphine (0.292 μl, 0.292 mmol, 1.0 M in THF), and 2-(tributylstannyl)pyridine (0.348 mg, 0.803 mmol) were added. The solution was degassed again and stirred overnight at 50°C. The reaction mixture was diluted with RINKAN, washed with water and brine, and then dried over anhydrous sodium sulfate. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (CH2Cl2 / MeOH) to yield (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (precursor 10, 55.6 mg, yield 24%). 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=7.3,1.9Hz),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] + .

[0459] Step 2. Preparation of (S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-2-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(180) [ka] The above steps for preparing 180 were carried out according to the procedure reported in the final step of 1. 1 H-NMR (DMSO-d6, 300MHz):δ H1.44-1.40(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.

[0460] Preparation of (S)-6-cyclohexyl-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(181) [ka] (S)-6-(cyclohexa-1-en-1-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-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, refilled with argon, and purged with hydrogen gas. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 3 days. The reaction mixture was filtered through Celite, the filtrate was concentrated, and purified by silica gel column chromatography to yield (S)-6-cyclohexyl-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (181, 46.0 mg, yield 60%). 1H-NMR(CHCl3-d,300MHz):δ 1.81-1.29(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.

[0461] Preparation of (S)-3-(1-hydroxypropan-2-yl)-6-(pyridine-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(182) [ka] When the above procedure was carried out according to the procedure reported for step 1 of the synthesis of 180, (S)-3-(1-hydroxypropan-2-yl)-6-(pyridine-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-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 ),8.00(1H,td,J=7.8,1.7Hz),8.60-8.54(3H,m),8.69(1H,dd,J=4.8,1.7Hz),8.77-8.75(1H,m),9.02(1H,s),9.36(1H,s);MS(m / z):360.0 [M+H] + ;99% purity.

[0462] Table 27 lists the compounds synthesized according to the reported synthetic procedure for 180.

[0463] [Table 199]

[0464] Preparation of (S)-3-(1-hydroxypropan-2-yl)-6-(1-methyl-1H-1,2,3-triazole-5-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(184) [ka] When the above procedure was carried out according to the procedure reported for the synthesis of 47, (S)-3-(1-hydroxypropan-2-yl)-6-(1-methyl-1H-1,2,3-triazole-5-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one was obtained (184, 40 mg, 18%). 1 H-NMR(DMSO-d6,300MHz):δ 1.44(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.

[0465] Preparation of (R)-6-(4-chlorophenyl)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one (185 enantiomer 1) and (S)-6-(4-chlorophenyl)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one (185 enantiomer 2) [ka] Racemic 6-(4-chlorophenyl)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one (rac-185, 20 mg, 0.045 mmol) was purified by SFC to yield the marked compound: (R)-6-(4-chlorophenyl)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one (6.9 mg, yield 35%). 1 H-NMR (CH3OH-d4, 400MHz):δ H 3.98(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-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one (6.4 mg, yield 32%). 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%.

[0466] Preparation of (S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyridine-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(186) [ka] (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (100 mg, 1 equivalent) and 5-methyl-2-(tributylstannyl)pyridine (145 mg, 0.131 mL, 1.2 equivalents) were dissolved in toluene (3 mL). The suspension was degassed and refilled with argon (3 cycles). Tetrakis(triphenylphosphine)palladium (73 mg, 0.2 equivalents) was added, the suspension was degassed, and refilled with argon (3 cycles). The reaction mixture was heated to 100 °C under argon and monitored by LC-MS. After 24 hours, KF and water / MeOH were added to the reaction mixture and stirred overnight. The reaction mixture was passed through a celite filter, concentrated, and purified using Combi-Flash® with DCM / MeOH to a concentration of 0-10% MeOH over 25 minutes. The resulting product (100 mg, 84% yield) was further purified by reverse-phase chromatography to give (S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyridine-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (186) as a white solid. 1 1H NMR (DMSO-d6, 400MHz):δ H1.42(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%.

[0467] Table 28 lists the compounds synthesized according to the reported synthetic procedure for 186.

[0468] [Table 200]

[0469] Preparation of (S)-8-cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(189) [ka] Step 1. Preparation of (S)-6-chloro-8-(cyclohexa-1-en-1-yl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one [ka] (S)-6,8-dichloro-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (intermediate B1 200 mg, 0.73 mmol) and cyclohexa-1-en-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, the suspension was degassed, and refilled with argon (3 cycles). The reaction mixture was heated to 75°C under argon and monitored by LC-MS. After the reaction overnight, the reaction mixture was cooled, diluted with ethyl acetate, filtered through celite, washed with water and brine, and dried over sodium sulfate. Purification of the residue by silica column chromatography yielded the indicated compound (130 mg, 56% yield). ¹H NMR (DMSO-d6, 400 MHz): δH 1.37 (3H, d, J = 7.0 Hz), 1.68 (4H, d, J = 30.1 Hz), 2.25 (2H, s), 3.76-3.60 (2H, m), 4.80 (1H, d, J = 7.9 Hz), 5.03 (1H, t, J = 5.5 Hz), 6.74 (1H, s), 7.82 (1H, d, J = 4.1 Hz), 8.46 (1H, s). MS (m / z): 320.1 [M + H] +.

[0470] Step 2. Preparation of (S)-8-(cyclohexa-1-en-1-yl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(188) [ka] (S)-6-chloro-8-(cyclohexa-1-en-1-yl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (120 mg, 0.38 mmol), potassium phosphate (399 mg, 1.88 mmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride [Xphos Pd G1] (28 mg, 0.38 mmol), and 5-trifluoromethyl-2-pyridylboronic acid MIDA ester (170 mg, 0.56 mmol), and diethanolamine (79 mg, 0.75 mmol) were added to a heat-dried pressure vial equipped with a stirring bar under air. 2 mL of NMP was added, the vial was degassed, and Cu(OAc)2 (68 mg, 0.38 mmol) was added. The vial was heated to 108°C for 15 hours with stirring. The reaction mixture was then cooled, diluted with siRNA, and filtered through a celite pad. The filtrate was washed with saturated NaHCO3 and water, concentrated, and purified by normal-phase and reverse-phase combi-flash® to obtain the labeled compound (100 mg, 62% yield). 1 1H NMR (CH3OH-d4, 400MHz): δH 1.56(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),8.6 0(1H,d,J=8.4Hz),8.92(1H,s),8.95(1H,s).MS(m / z):431.2[M+H]+.98% purity.

[0471] Step 3. Preparation of (S)-8-cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (189) [ka] (S)-8-(cyclohexa-1-en-1-yl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (76 mg, 0.18 mmol) and PtO2 (4 mg, 0.018 mmol) were dissolved in 17 mL of EtOH. The suspension was degassed for 3 cycles and refilled with H2 gas (in a balloon). The reaction mixture was stirred at room temperature under H2 gas (in a balloon) and monitored by LC-MS. The reaction was stopped after 24 hours and filtered through celite. The filtrate was concentrated and purified by normal-phase and reverse-phase combi-flash® to obtain the marked compound: (S)-8-cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (189) (18 mg, yield 24%). 1H NMR (DMSO-d6, 400 MHz): 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(1 H,s), 8.66(1H,d,J=8.4Hz), 8.87(1H,s), 9.11(1H,s).MS(m / z):433.2[M+H]+; Purity 96%; (S)-8-cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)-2,3-dihydropyrido[3,4-d]pyrimidine-4(1H)-one (22 mg, yield 29%) was administered.1H NMR (DMSO-d6,400MHz): δH 1.14(3H,d,J=6.9Hz),1.27(1H,d,J=15.6Hz),1.44(2H,d,J=14.2Hz),1.61(2H,t,J=12.4Hz),1.73(1H,br s),1.82(4H,br s),2.90(1H,s),3.49(2H,d,J=6.8Hz),4.54(1H,d,J=8.2Hz),4.62(2H,s),4.85(1H,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.

[0472] Preparation of (S)-3-(1-hydroxypropan-2-yl)-N,N-dimethyl-4-oxo-8-(pyridine-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidine-6-carboxamide (190) [ka] Dioxane (6 mL) was added to a mixture of (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (200 mg, 1 equivalent), dimethylamine HCl (77 mg, 1.5 equivalents), molybdenum hexacarbonyl (166 mg, 1 equivalent), and XPhos (60 mg, 0.2 equivalents). The suspension was degassed and refilled with nitrogen (3 cycles). Palladium(II) acetate (15 mg, 0.1 equivalents) and K3PO4 were added, the suspension was degassed, and refilled with nitrogen (3 cycles). The reaction mixture was heated at 100°C and monitored by LC-MS. After overnight, the reaction mixture was filtered through celite, washed with ethylethanol and MeOH, and the filtrate was concentrated. The crude product (190) was first eluted by silica gel column chromatography using DCM / MeOH to a concentration of 0-10% MeOH over 25 minutes, followed by purification by reverse-phase chromatography using water / acetonitrile to obtain the desired product (90 mg, 40%). 11H NMR (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.

[0473] Preparation of (S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(191): Compound 191 was prepared according to the same procedure as in General Scheme IV above and the following protection strategy. [ka]

[0474] Table 29 lists the intermediates synthesized using general scheme VI.

[0475] [Table 201]

[0476] Table 30 lists the compounds synthesized according to the above synthesis scheme VI.

[0477] [Table 202]

[0478] Preparation of (S)-3-(1-hydroxypropan-2-yl)-6-(2-methoxyethyl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(192) [ka] 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-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (50 mg, 0.16 mmol) were introduced into microwave vials dried in an oven. The vials were sealed, degassed, and then re-isolated with N2. 2 The mixture was filled with [amount]. Degassed dioxane-H2O (4:1, 1 mL) was added by syringe. The reaction mixture was then placed in an oil bath preheated to 100°C and stirred at this temperature for 24 hours. After completion, the reaction mixture was cooled to room temperature, diluted with dimethyl acetate, and filtered through a celite pad. The filtrate was washed with water and brine, dried over sodium sulfate, concentrated, and purified by normal-phase chromatography to give the labeled 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.

[0479] Preparation of (S)-3-(1-hydroxypropan-2-yl)-8-(2-methoxyethyl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one(193) Compound 193 was prepared according to the same procedure as in General Scheme IV described above, following the alkyl-aryl coupling step according to the procedure for Compound 192. [ka]

[0480] Table 31 lists the intermediates synthesized by general scheme VII.

[0481] [Table 203]

[0482] Table 32 lists the compounds synthesized according to the above synthesis scheme VII.

[0483] [Table 204]

[0484] Example 2: DRE-luciferase reporter assay AHRs bind to dioxin response elements (DREs) upstream of the genes they activate. One measure of AHR activity is the activation of reporter genes, such as luciferases, downstream of one or more DRE elements. Luciferase activity would reflect the activation and inhibition of AHRs in cells expressing their reporter. 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 a DRE-luciferase reporter were seeded in Eagle's Minimum Essential Medium, 10% heat-inactivated FBS, 1X non-essential amino acids, Pen-Strep (10,000 U / mL) and Normocin (100 ug / mL) in plates (96-well, 384-well, or other plates), incubated overnight at 37°C in a CO2 incubator, and treated with or without logarithmically diluted AhR antagonists starting at 100 uM.

[0485] One hour after seeding the cells, AHR activating ligands such as TCDD, kynurenine, ITE (2-(1H-indole-3-ylcarbonyl)-4-thiazole carboxylate methyl ester), VAF347, BNF (β-naphthoflavone), FICZ (6-formylindro(3,2-b)carbazole), or other AHR ligands are used in their specific EC (Emission Control). 50 The solution was added to cells with or without the AHR antagonist at various concentrations.

[0486] Cells were incubated for 24 or 48 hours or at another time point, and the supernatant was then analyzed for the measurement of luciferase activity as an AHR activation or inhibition reading. Luciferase was measured using Invivogen's commercially available QUANTI-Luc® assay solution kit, according to the manufacturer's instructions.

[0487] The level of luciferase with only the agonist ligand added showed the maximum signal, while luciferase without the antagonist showed the lowest signal. 50 The value was determined as the concentration that inhibits half of the luciferase activity. IC of the luciferase of the compounds disclosed herein. 50 Report the level in Table 33. "A" indicates ICs with a impedance of less than 100 nM. 50 The values ​​are shown, and "B" indicates an IC with a capacitance of 100-500 nM. 50 This indicates that "C" represents an IC with a minimum impedance of over 500 nM. 50 This indicates that "D" is IC 50 This indicates that the value could not be generated from the data.

[0488] [Table 205]

[0489] [Table 206]

[0490] [Table 207]

[0491] Example 3: CYP1A1 gene expression assay Human and mouse colorectal cancer (CRC) cell lines, HT29 and HT26, respectively, and the American Type Culture Collection (ATCC) were placed in sterile, tissue-culture-treated 96-well plates (ThermoFisher) at a rate of 8.0 × 10⁴ per well. 5Cells are seeded and grown overnight in DMEM complete medium (Gibco) at 37°C and 5% CO2 to achieve confluence. After incubation, the medium is aspirated from the cell monolayer, the tissue is washed with 200 μL of warmed PBS solution, and then 190 μL of pre-warmed growth medium is added to each well. The target AhR antagonist is diluted 20-fold in growth medium containing 2% DMSO, and 10 μL of the compound solution is added in triplicate to each well. After 1 hour, AHR activating ligands such as TCDD, kynurenine, ITE (2-(1H-indole-3-ylcarbonyl)-4-thiazole carboxylate methyl ester), VAF347, BNF (β-naphthoflavone), FICZ (6-formylindro(3,2-b)carbazole), or other AHR ligands, with or without the AHR antagonist, will be added for 24 hours, after which the medium will be removed and stored at -80°C for subsequent cytokine analysis. At the end of incubation, the medium will be aspirated from the CRC cells and the cells will be washed with 100 μL of cold PBS solution. RNA will be extracted using a TaqMan® Gene Expression Cells-to-CT® Kit (ThermoFisher) according to the manufacturer's protocol. QuantStudio 6 Flex (Applied) Using Biosciences, we will analyze CYP1A1 mRNA levels with GAPDH as the endogenous control. TaqMan® probe sets for both genes will be purchased from ThermoFisher. Samples will be tested in triplicate, and data will be analyzed using QuantStudio software and reported as linear and log2(ΔΔCT) values. Statistical analysis will be performed using a two-sided t-test comparing CYP1A1 levels in the presence of each individual compound relative to the vehicle-negative control. IC50 will be used in the nanomolar concentration range. 50 Compounds possessing this characteristic will be investigated for further evaluation. This assay can be used to confirm the inhibitory effect of a compound before testing it using an in vivo model.

[0492] Example 4: Human PBMC (CD8+) assay Human donor blood (8 mL) is collected in a sodium citrate CPT tube and centrifuged at 1,600 × g for 20 minutes at room temperature. The buffy coat containing PBMCs is collected and transferred to a 50 mL conical tube containing 30 mL of RPMI-1640 medium (supplemented with penicillin-streptomycin) at room temperature. The PBMC sample is centrifuged at 400 × g for 10 minutes at 10°C. The pelletized PBMCs are washed twice in 10 mL of 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 are filtered through a 70 micron mesh to remove cellular debris. The volume is adjusted to achieve 1.66 × 10⁶ cells / mL, and then 180 μl (300,000 PBMCs) is added to each well in a 96-well plate (sterilized, tissue culture-treated, round-bottom). The PBMCs in the 96-well plate are incubated in a 5% CO₂ incubator at 37°C for 30 minutes, and then treated with 10 μl of the indicated compound. For the CD8+ (Killing T cell) differentiation assay, PBMCs are cultured in RPMI-1640 complete medium for 2, 4, and 6 days (1–10 × 10⁶ cells). 4 Cells were stimulated with 5 μL / ml ImmunoCult® Human CD3 / CD28 / CD2 T Cell Activator (Stemcell 10990) with or without an AhR antagonist compound. Cell viability was measured using a 1:500 dilution of viability dye (eBioscience Fixable Viability Dye eFluor 780: ThermoFisher 65-0865-14). Cells were defined as Live, CD11c-, CD14-, CD19-, CD8+, CD4-, and CD3+, and gated for CD8+. CD8+ percentage (%) was calculated as the percentage of CD8+ cells relative to the total number of live T cells. Statistical analysis was performed using one-way ANOVA with GraphPad Prism software.

[0493] Example 5: Human PBMC cytokine assay Human donor blood (8 mL) is collected in a sodium citrate CPT tube and centrifuged at 1,600 × g for 20 minutes at room temperature. The buffy coat containing PBMCs is collected and transferred to a 50 mL conical tube containing 30 mL of RPMI-1640 medium (supplemented with penicillin-streptomycin) at room temperature. The PBMC sample is centrifuged at 400 × g for 10 minutes at 10°C. The pelletized PBMCs are washed twice in 10 mL of 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 are filtered through a 70 micron mesh to remove cellular debris. The volume is adjusted to achieve 1.66 × 10⁶ cells / mL, and then 180 μl (300,000 PBMCs) is added to each well in a 96-well plate (sterilized, tissue culture-treated, round-bottom). The PBMCs in the 96-well plate are incubated in a 5% CO₂ incubator at 37°C for 30 minutes, and then treated with 10 μl of the indicated compound. For cytokine secretion assays, PBMCs are cultured in RPMI-1640 complete medium for 2, 4, and 6 days (1–10 × 10⁴ cells) and stimulated with / without the AhR antagonist compound using 5 μL / ml ImmunoCult® Human CD3 / CD28 / CD2 T Cell Activator (Stemcell 10990). After incubation at 37°C and 5% CO2 for 2, 4, and 6 days, 100 μL of cell supernatant is collected and transferred to a 96-well plate (non-tissue treated, flat-bottomed). The plate is centrifuged at 350 × g for 5 minutes at room temperature, and the clear supernatant is then transferred to a new 96-well plate (non-tissue treated, flat-bottomed). The remaining cells are tested for viability using CellTiter-Glo® Luminescent Cell Viability Assay (Promega). The supernatant is tested for IL22 and IFg) using Luminex Immunoassay Technology (MAGPIX System). The cytokine levels of the PBMC-treated DMSO control sample are set to 100%, and the compound-treated samples are represented relative to this.

[0494] Example 6: Solubility Measurement Assay Stock solutions of the test compound and the control compound progesterone were prepared in DMSO at a concentration of 10 mM. 15 μL of each sample's stock solution (10 mM) was placed sequentially in the appropriate 96-well rack. 485 μL of PBS pH 1.6 and pH 7.4 were added to each vial of the solubility sample plate without caps. The assay was performed in single-row configuration. One stirring bar was added to each vial, and the vials were then sealed using molded PTFE / silicone plugs. The solubility sample plates were then transferred to an Eppendorf Thermomixer Comfort plate shaker and shaken at 1100 rpm for 2 hours at 25°C. After 2 hours, the plugs were removed and the stirring bars were removed using a large magnet. The samples from the solubility sample plates were transferred to a filter plate. The entire sample was filtered using a vacuum manifold. A 5 μL aliquot was taken from the filtrate, followed by the addition of a 495 μL mixture of H2O and acetonitrile (1:1) containing an internal standard. The diluent was diluted using ultrapure water at specific ratios according to the peak shape. The dilution factor was varied according to the solubility value and LC-MS signal response.

[0495] From a 10 mM DMSO STD plate, 6 μL was transferred to the remaining empty plate, and then 194 μL of DMSO was added to the plate to obtain a 300 μM STD concentration. From a 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 an internal standard was added to the plate to obtain a final STD concentration of 3 μM. The diluents were diluted according to the peak shape using ultrapure water at specific ratios. The concentration of the standard sample was varied according to the LC-MS signal response.

[0496] The plate was placed in a well-plate autosampler. The sample was evaluated by LC-MS / MS analysis.

[0497] All calculations were performed using Microsoft Excel.

[0498] The filtrate was analyzed and quantified against a known concentration standard using LC coupled with mass spectrometry identification and quantification. The solubility values ​​of the test compound and control compound were calculated as follows.

number

[0499] We eliminated all values ​​for compounds that were outside the explicitly stated limits and repeated the experiment.

[0500] The solubility of the compounds of this disclosure in pH 1.6 and 7.4 buffer solutions is reported in Table 34. "+++" indicates a solubility value of 1 μM or greater, "++" indicates a solubility value of 0.1 to 1 μM, and "+" indicates a solubility value of less than 0.1 μM.

[0501] [Table 208]

[0502] [Table 209]

[0503] [Table 210]

[0504] Example 7: Hepatocyte Stability Assay Preparation of the solutions: 10 mM stock solutions of the test compound and positive control were prepared in DMSO. In a separate conical tube, the 10 mM solutions of the test compound and positive control were diluted to 100 μM by combining 2 μL of 10 mM stock with 198 μL of 50% acetonitrile / 50% water.

[0505] Preparation of hepatocytes: The incubation medium (William's E medium supplemented with GlutaMAX) and hepatocyte thawing medium were placed in a 37°C water bath and warmed for at least 15 minutes before use. The cryopreserved hepatocyte vials were moved from storage, ensuring that the vials remained at a cryogenic temperature until the thawing process was complete. The cells were thawed by placing the vials in a 37°C water bath and gently shaking the vials for 2 minutes. After thawing was complete, the vials were sprayed with 70% ethanol and transferred to a safety cabinet. Using a wide-bore pipette tip, the hepatocytes were transferred to a 50 mL conical tube containing the thawing medium. The 50 mL conical tube was placed in a centrifuge and rotated at 100 g for 10 minutes. After rotation was complete, the thawing medium was aspirated, and the hepatocytes were resuspended in sufficient incubation medium for approximately 1.5 × 10⁶ cells. 6 Cells / mL were obtained. Cell counting was performed using AO / PI staining to determine the viable cell density. Cells with poor viability (<75% viability) were deemed unacceptable for use. Cells were incubated in incubation medium for 0.5 × 10⁶ cells. 6 Diluted to the cell density used (live cells / mL).

[0506] Stability measurement procedure: 198 μL of hepatocytes were pipettered into each well of a 96-well uncoated plate. The plate was placed in an incubator and the hepatocytes were warmed for 10 minutes. 2 μL of 100 μM test compound or positive control solution was pipettered into each well of the 96-well uncoated plate to initiate the reaction. The plate was returned to the incubator at the specified time points. The well contents were transferred to 25 μL aliquots at 0, 15, 30, 60, 90, and 120 minutes. The aliquots were then mixed with 6 volumes (150 μL) of acetonitrile containing the internal standard, IS (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide) to terminate the reaction. The mixture was vortexed for 5 minutes. The sample was centrifuged at 3,220 g for 45 minutes. A 100 μL aliquot of the supernatant was diluted with 100 μL of ultrapure water, and the mixture was used for LC / MS / MS analysis. All incubations were performed in a double-row setup.

[0507] Data Analysis: All calculations were performed using Microsoft Excel. Peak area was determined from the extracted ion chromatogram. In vitro half-life (t) of the parent compound. 1 / 2 This was determined by regression analysis of the parental disappearance percentage versus time curve.

[0508] In vitro half-life (in vitro t 1 / 2 The slope value was determined from the following: In Vitro T 1 / 2 =0.693 / k

[0509] In Vitro T 1 / 2 (expressed in minutes), in vitro specific clearance (in vitro CL) int , μL / min / 1×10 6 The conversion to (represented as cells) was performed using the following equation (average of two measurements): In Vitro CL int =kV / N V = incubation volume (0.2 mL); N = Number of liver cells per well (0.1 × 10⁻¹⁰) 6 cell).

[0510] Data Processing Rules: The data processing rules are shown in Table 35.

[0511] [Table 211]

[0512] Table 36 reports the human and rat liver cell clearance of the compounds disclosed herein. "+++" indicates clearance less than 20 mL / min / kg. int The values ​​are shown, and "++" indicates a CL of 20-50 mL / min / kg. int This indicates that the CL exceeds 50 mL / min / kg. int This indicates.

[0513] [Table 212]

[0514] [Table 213]

[0515] [Table 214]

[0516] Example 8: Liver Microsome Stability Assay The master solution was prepared according to Table 37.

[0517] [Table 215]

[0518] Two other experiments were conducted as follows.

[0519] With cofactor (NADPH): 25 μL of 10 mM NADPH was added to the incubation. 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 pre-warmed at 37°C for 10 minutes. The reaction was initiated by adding 2.5 μL of 100 μM control compound or test compound solution. Verapamil was used as a positive control in this test. The final concentration of the test compound or control compound was 1 μM. The incubation solution was incubated in a water batch at 37°C. 25 μL aliquots were taken from the reaction solution at 0.5, 5, 15, 30, and 60 minutes. The reaction was stopped by adding 5 volumes of cold acetonitrile containing IS (200 nM caffeine and 100 nM tolbutamide). The samples were centrifuged at 3,220 g for 40 minutes. A 100 μL aliquot of the supernatant was mixed with 100 μL of ultrapure water and then used for LC-MS / MS analysis.

[0520] Data Analysis: All calculations were performed using Microsoft Excel. Peak area was determined from the extracted ion chromatogram. The slope value, k, was determined by linear regression of the natural logarithm of the residual percentage of the parent drug versus the incubation time curve.

[0521] In vitro half-life (in vitro t 1 / 2 The slope value was determined from the following: In Vitro T 1 / 2 =-(0.693 / k)

[0522] In Vitro T 1 / 2 (minutes), in vitro specific clearance (in vitro CL int The conversion to (expressed in μL / min / mg protein) was performed using the following equation (average of two measurements):

number

[0523] Scaled-up CL int The calculations for (mL / min / kg), predicted CLH (mL / min / kg), and EH were performed using the following equation: Scaled-up CL int =(0.693 / t 1 / 2 ) × (1 / (microsome protein concentration (0.5 mg / mL))) × scaling factor; Predicted CLH = (QH × scaled-up CL) int ×f ub ) / (QH+scaled-up CL int ×f ub ); EH = Predicted CLH / QH Here, QH is liver blood flow (mL / min / kg) (Table 32), f ub This is the fraction of unbound drug in plasma, which is assumed to be 1.

[0524] Table 38 reports the scaling factors for predicting intrinsic clearance in human and mouse microsomes.

[0525] [Table 216]

[0526] Data Processing Rules: The data processing rules are shown in Table 39.

[0527] [Table 217]

[0528] Table 40 reports the human and rat liver microsomal clearance of the compounds disclosed herein. "+++" indicates a clearance of less than 10 mL / min / kg. int The values ​​are shown, and "++" indicates Cl of 10-20 mL / min / kg. int This indicates that the Cl flow rate exceeds 20 mL / min / kg. int This indicates.

[0529] [Table 218]

[0530] Example 9: Caco-2 permeability assay Preparation of Caco-2 cells: 50 μL and 25 mL of cell medium were added to each well of the Transwell insert and reservoir, respectively. The HTS Transwell plate was incubated at 37°C in 5% CO2 for 1 hour, after which the cells were seeded. Caco-2 cells were cultured in medium at a rate of 6.86 × 10⁶. 5 The cell suspension was diluted to cells / mL and dispensed into 50 μL of filter wells in 96-well HTS Transwell plates. The cells were cultured in a cell culture incubator at 37°C, 5% CO2, and 95% relative humidity for 14–18 days. The cell medium was changed every other day, starting within 24 hours of initial seeding.

[0531] Evaluation of cell monolayer integrity: The culture medium was removed from the reservoir and each Transwell insert and replaced with pre-warmed fresh medium. The transepithelial electrical resistance (TEER) of the monolayer was measured using the Millicell Epithelial Volt-Ohm measurement system (Millipore, USA). After measurement, the plate was returned to the incubator. The TEER value was calculated according to the following equation: TEER measurement value (ohms) × membrane area (cm²) 2 ) = TEER value (ohms·cm) 2 )

[0532] The TEER value is 230 ohms / cm². 2 It should exceed this value, which indicates a suitable Caco-2 monolayer.

[0533] Solution preparation: A 2 mM stock solution of the control compound was prepared in DMSO and diluted with HBSS (10 mM HEPES, pH 7.4) to obtain a 10 μM working solution. A 0.2 mM stock solution of the test compound was prepared in DMSO and diluted with HBSS (10 mM HEPES containing 0.5% BSA, pH 7.4) to obtain a 1 μM working solution. Metoprolol, erythromycin, and cimetidine were used as control compounds.

[0534] Perform the drug transport assay: Remove the Caco-2 plate from the incubator. Wash the monolayer twice with pre-warmed HBSS (10 mM HEPES, pH 7.4). Incubate the plate at 37°C for 30 minutes. To measure the rate of drug transport from the apical to the lateral to the basal side, 125 μL of the working solution was added to the Transwell insert (apical compartment). Immediately transfer 50 μL of the 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 at 1000 rpm for 10 minutes. Fill the wells in the receiver plate (lateral compartment) with 235 μL of transport buffer. To measure the rate of drug transport from the lateral-bottom to the apical direction, 285 μL of the working solution was added to the receiver plate well (lateral-bottom compartment). 50 μL of the sample was immediately transferred from the lateral-bottom 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 vortexed at 1000 rpm for 10 minutes. The Transwell insert (apical compartment) was filled with 75 μL of transport buffer. The apical-to-lateral-bottom and lateral-bottom-to-apical directions must be performed simultaneously. The plate was incubated at 37°C for 2 hours. At the end of incubation, 50 μL samples from the donor side (apical compartment for Ap→Bl flow, and lateral / bottom compartment for Bl→Ap flow) and receiver side (lateral / bottom compartment for Ap→Bl flow, and apical compartment for Bl→Ap flow) were transferred to the wells of a new 96-well plate, followed by the addition of four 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 samples were transferred to the wells 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, followed by centrifugation at 3,220 g for 40 minutes. A 150 μL aliquot of the supernatant was mixed with an appropriate volume of ultrapure water, and then LC-MS / MS analysis was performed.

[0535] Data Analysis: All calculations were performed using Microsoft Excel. Peak areas were determined from the extracted ion chromatogram. Leakage of the single layer of Lucifer Yellow can be calculated using the following equation:

number

[0536] The transported percentage of Lucifer Yellow must be less than 1.5%. However, if the transported percentage of Lucifer Yellow in a particular transwell is higher than 1.5%, the measured digoxin P in that transwell may be higher. app If the results are qualitatively similar to those measured in a repeatable transwell, the single layer is considered acceptable, based on the scientific judgment of the responsible scientist.

[0537] Apparent transparency (P app ) can be calculated for drug transport assays using the following equation:

number

[0538] The emission ratio can be determined using the following equation:

number

[0539] The apparent permeability ratios of the compounds disclosed herein are reported in Table 41. "A" represents 10 × 10 -6 P exceeding cm / second app The values ​​are shown, and "B" is 2 to 10 × 10 -6 P in cm / second app This indicates that "C" is 2 × 10 -6 P less than cm / sec app This indicates.

[0540] [Table 219]

[0541] Example 10: Measurement of plasma protein binding by ultracentrifugation. Frozen plasma (stored at -80°C) was thawed in a 37°C water bath, followed by centrifugation at 3,220 g for 10 minutes to remove blood clots. The supernatant was removed and the centrifuged plasma was placed in a new tube. The centrifuged plasma was pre-warmed in a 37°C water bath for 10 minutes. The stock solution of the test compound was diluted to 200 μM with 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 and 5% CO2 for 30 minutes. After incubation, the balanced ultracentrifuge tube was centrifuged at 600,000 g at 37°C for 5.5 hours. After centrifugation, 50 μL of the solution was removed from the center of the ultracentrifugation tube as the post-ultracentrifugation sample. Subsequently, 50 μL of blank plasma and 400 μL of quench solution (acetonitrile containing internal standards (IS, 100 nM alprazolam, 500 nM labetalol, and 2 μM ketoprofen)) were added to precipitate the proteins and release the compounds. The sample was vortexed for 2 minutes, followed by centrifugation 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 and 5% CO2 for 0.5 and 6 hours. After incubation, 50 μL of PBS (100 mM, pH 7.4) and 400 μL of quench solution were used for the stability samples. The stability samples were then processed in the same manner as the post-ultracentrifugation samples. The supernatant was diluted with ultrapure water and then used for LC-MS / MS analysis. The 0.5-hour sample was also used as a no-spun control. The time 0 sample was prepared by transferring 50 μL of spiked plasma to 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 samples after ultracentrifugation. The supernatant was diluted with ultrapure water and then used for LC-MS / MS analysis.

[0542] Data Analysis: All calculations were performed using Microsoft Excel. The concentrations of the test compounds in plasma samples and plasma after ultracentrifugation were determined from the peak area. The percentage of bound test compounds was calculated as follows: Unbound % = (Peak area after ultracentrifugation / Peak area without centrifugation control) × 100% Combined%=100%-Uncombined% Percentage remaining after 0.5 hours = Peak area after 0.5 hours / Peak area at 0 hours × 100% Percentage remaining after 6 hours = Peak area after 6 hours / Peak area at 0 hours × 100%

number

[0543] The binding levels of the compounds disclosed herein to human, rat, and mouse plasma proteins are reported in Table 42. "+++" indicates a binding percentage of less than 50, "++" indicates a binding percentage of 50 to 75, and "+" indicates a binding percentage of greater than 75.

[0544] [Table 220]

[0545] Example 11: CYP Inhibition Assay A stock solution of the test compound was prepared in DMSO at a concentration of 10 mM. The stock solution was diluted to 2 mM with acetonitrile. The final concentration of the test compound was 10 μM. The concentrations of the positive inhibitors are listed in Table 43. For the preparation of the stock solution, if the positive control could not be sufficiently dissolved at the highest concentration in the DMSO and acetonitrile (1:4) mixture, another mixture of acetonitrile and DMSO, or a mixture of acetonitrile and H2O or DMSO, would be used to dissolve the compound.

[0546] [Table 221]

[0547] Details of the preparation of these substrates are given in Table 44. Store the substrate solutions in a -20°C freezer and warm them to room temperature before use.

[0548] [Table 222]

[0549] Preparation of phosphate buffer (100 mmol / L, pH 7.4): To prepare solution A, 7.098 g of disodium hydrogen phosphate was weighed and added to 500 mL of distilled water, then sonicated to dissolve the contents. To prepare solution B, 3.400 g of potassium dihydrogen phosphate was weighed and added to 250 mL of distilled water, then sonicated to dissolve the contents. Solution A was placed on a stirrer, and solution B was slowly added to solution A until the pH reached 7.4. Preparation of 10 mmol / L NADPH solution: NADPH was dissolved in phosphate buffer at a concentration of 8.334 mg / mL; the solution was freshly prepared before use.

[0550] Master solutions were prepared 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, after which 20 μL of 10 mmol / L solution was added. The reaction was initiated by adding a phosphate buffer solution of NADPH. After adding NADPH, the incubation plate was incubated at 37°C for the appropriate time. The assay was performed in double series.

[0551] [Table 223]

[0552] The reaction mixture 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 pure water. The sample was thoroughly mixed and analyzed using UPLC / MS / MS.

[0553] Data Analysis: Check the automated peak integration area for all samples. Export the analyte peak area and internal standard peak area to an Excel spreadsheet. Measure the inhibition of each P450 enzyme in human liver microsomes as the percentage reduction in marker metabolite formation activity compared to the non-inhibited control (=100% activity).

[0554] The percentage of residual activity was calculated as follows: Area ratio = Peak area of ​​analyte / Peak area of ​​internal standard Residual activity (%) = Area ratio of test compound / Area ratio of vehicle × 100% Inhibition %=100-residual activity (%)

[0555] The inhibition percentages of CYP2D6 and CYP3A4 by the compounds disclosed herein are reported in Table 46.

[0556] [Table 224]

[0557] Example 12: hERG Inhibition Assay We purchased the stably expressed hERG HEK 293 cell line (catalog number K1236) from Invitrogen. Cells were cultured in 85% DMEM, 10% dialyzed FBS, 0.1 mM NEAA, 25 mM HEPES, 100 U / mL penicillin-streptomycin, and 5 μg / mL blastosidine and 400 μg / mL geneticin. Cells were split approximately three times per week using TrypLE® Express, maintaining a confluence of approximately 40% to 80%. Prior to the assay, cells were placed on coverslips at 5 × 10⁵ cells per 6 cm cell culture dish and induced with 1 μg / mL doxycycline for 48 hours.

[0558] External solution (in mM): 132 NaCl, 4 KCl, 3 CaCl2, 0.5 MgCl2, 11.1 glucose, and 10 HEPES (adjusted to pH 7.35 with NaOH). Internal solution (in mM): 140 KCl, 2 MgCl2, 10 EGTA, 10 HEPES, and 5 MgATP (adjusted to pH 7.35 with KOH). Preparation of test compound solutions: The test compounds were first prepared as stock solutions in DMSO at a final concentration of 10 mM. The stock solutions of each compound were serially diluted with DMSO in a 1:3 ratio to prepare three additional intermediate solutions containing concentrations of 3.33, 1.11, and 0.37 mM.

[0559] Before performing the hERG assay, the working solutions were prepared using extracellular fluid by 1000-fold dilutions of 10, 3.33, 1.11, and 0.37 mM intermediate solutions, with final concentrations of 30, 10, 3.33, 1.11, and 0.37 μM. The 30 μM working solution was prepared by a 333.333-fold dilution of 10 mM DMSO stock. The final DMSO concentration in the working solutions was maintained within the range of 0.1–0.3% (v / v).

[0560] Experimental Procedure: The coverslip was removed from the cell culture dish and placed on the microscope stage in the bath chamber. The desired cells were located using a 10x objective lens. The tip of the electrode was located below the microscope by focusing on the surface of the cells using the 10x objective lens. Once the tip was in focus, the electrode was advanced downwards toward the cells, using coarse adjustments of the manipulator while simultaneously moving the objective lens to maintain focus on the tip. When directly above the cells, the electrode was gradually brought closer to the cell surface by using a 40x objective lens, utilizing fine adjustments of the manipulator. A gigaohm seal was formed by applying gentle aspiration through the side port of the electrode holder.

[0561] Cfast was used to remove the capacitive current that coincided with the voltage step. A whole-cell configuration was obtained by repeatedly applying short bursts of strong suction until the membrane patch burst. The membrane potential was set to -60mV at this point to ensure that the hERG channel was not open. The capacitive current spikes were then canceled by using Cslow on the amplifier.

[0562] The holding potential was set to -90mV for 500ms; the current was recorded at 20kHz and filtered at 10kHz. The leakage current was tested at -80mV for 500ms.

[0563] The hERG current was induced by depolarizing at +30mV for 4.8 seconds, then the voltage was returned to -50mV for 5.2 seconds to remove inactivation, and the deactivating tail current was observed. The hERG current amplitude was determined using the maximum tail current size. The current stability was evaluated by recording the current for 120 seconds. Only stable cells with recording parameters exceeding the threshold proceeded to further drug administration. A vehicle control was applied to the cells to establish a baseline. Once it was confirmed that the hERG current stabilized for 5 minutes, the solution of use was applied. The hERG current in the presence of the test compound was recorded for approximately 5 minutes to reach a steady state, and then five sweeps were incorporated. For dose-response testing, five doses of the test compound were applied to the cells in an escalating manner from low to high concentrations. To ensure good performance of the cultured cells and the procedure, a positive control, dofetilide, was also used to test the same batch of cells at five doses.

[0564] The following criteria were used to determine the validity of the data: initial seal resistance > 1 GΩ; leakage current < always 50% of the reference peak tail current; peak tail amplitude > 300 pA; film resistance Rm > 500 MΩ; access resistance (Ra) < 15 MΩ; apparent peak current attenuation < 2.5% per minute.

[0565] Data meeting the above criteria for hERG current quality were further analyzed according to the following procedure. The current inhibition percentage was calculated using the following equation: (Note: Peak current was extracted from the original data using PatchMaster or Clampfit software).

number

[0566] The dose-response curves of the test compounds were plotted against the inhibition percentage relative to the concentration of the test compound using GraphPad Prism 6.0, and the data were fitted to an S-shaped dose-response curve with a variable slope.

[0567] Compound ICs of this disclosure50 This is reported in Table 47.

[0568] [Table 225]

[0569] Example 13: In vivo rat PK test The study was conducted using male Sprague Dolly rats, with 3 rats per group, or male CD1 mice, with 3 mice per group. The compound was administered intravenously at 1.0 mg / kg (vehicle: ethanol: deionized water %PEG400, in a ratio suitable for administration of a clear solution) and orally at 3.0 mg / kg or 10 mg / kg (vehicle: 1% methylcellulose: deionized water 1,500 cP (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 hours; rat oral PK time points: plasma: 0.25, 0.5, 1, 2, 4, 8, and 24 hours. Mouse intravenous PK time points: plasma: 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, and 48 hours; mouse oral PK time points: plasma: 0.25, 0.5, 1, 2, 4, 8, 24, and 48 hours. Compound concentrations in plasma samples were analyzed using LC-MS / MS. WinNonlin (Phoenix®, version 6.1) or other similar software was used for pharmacokinetic calculations.

[0570] Mouse and rat PK study data: Pharmacokinetic data are shown in Tables 48-51 below. PK data for mice administered 1 mg / mL IV of the compound disclosed herein are reported in Table 48. PK data for mice administered 10 mg / mL PO of the compound disclosed herein are reported in Table 49. PK data for rats administered 1 mg / mL IV of the compound disclosed herein are reported in Table 50. PK data for rats administered 3 or 10 mg / mL PO of the compound disclosed herein are reported in Table 51.

[0571] [Table 226]

[0572] [Table 227]

[0573] [Table 228]

[0574] [Table 229]

[0575] InVivo Model Efficacy study of AHR antagonists and checkpoint inhibitors against PD-1 in the CT26 mouse colorectal cancer model in Balb / c mice. Female mice aged 6-8 weeks were obtained from the Charles River Laboratory (C57BL / 6NCrl). The mouse tumor cell line WT-CT26 was obtained from the American type culture collection, and for mycoplasma and other pathogens, Charles The tests were performed at River Research Animal Diagnostics services, and cultures were performed according to their guidelines. All tests were conducted according to the CRADL Policy. The procedure was carried out in accordance with the Care, Welfare and Treatment of Laboratory Animals guidelines. From the day of tumor inoculation, mice were monitored at least three times a week by the principal investigator or veterinary staff for clinical abnormalities that could warrant euthanasia. These included chronic and / or severe diarrhea resulting in moderate to severe dehydration, evidence of an infection that is not readily treatable, kyphosis in combination with other clinical signs of weakness or prolonged periods exceeding three days, inability to walk to access food or water, or other clinical signs that an experienced technical staff judged to indicate a pathological or mortal state. Mice showing a net weight loss of more than 20% compared to baseline weight were euthanized.

[0576] CT26 is a mouse colon cancer cell line obtained from ATCC. CT26 cells were cultured in RPMI supplemented with 10% FBS. 5 × 10⁶ low-passage CT26 cells were cultured. 5 The cells were resuspended in 100 μL of PBS at a concentration of cells / ml and subcutaneously transplanted into the shaved right lower flank of 6-8 week old Balb / c mice. The day of subcutaneous tumor cell transplantation was defined as day 0.

[0577] Once the registration criteria were met, the animals were allocated to treatment groups so that the average tumor volume in each group was within 10% of the overall average. The treatment was administered individually to the mice based on their body weight on the day of treatment.

[0578] Approximately 60 mm one week after vaccination. 3 Mice with average-sized tumors were randomized and made available for initiation of treatment (Figure 1). AhR antagonists were administered orally daily (QD) at 1 mg / kg, 3 mg / kg, or 10 mg / kg for 14 days. Anti-PD-1 (BioXcell RMPl-14) or anti-PD-L1 was administered intraperitoneally at 100 μg / kg every 3 days for 3 doses, starting from day 14.

[0579] The tumor is monitored by measuring the vertica...

Claims

1. Compound of formula Ia 【Chem.99】 or a method for preparing a pharmaceutically acceptable salt thereof, (In the formula: Ring A is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl, and each of the 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl groups is used for 1-5 examples of R Ａ It is independently and arbitrarily replaced by; Ring B is selected from 6-10 member aryl, 5-10 member heteroaryl, 3-10 member cycloalkyl, and 3-10 member heterocycloalkyl, and each of the 6-10 member aryl, 5-10 member heteroaryl, 3-10 member cycloalkyl, and 3-10 member heterocycloalkyl is used for 1-5 examples of R Ｂ It is independently and arbitrarily replaced by; R is hydrogen, C １ ~C １０ alkyl, 6- to 10-membered aryl, -C(O)R', -C(O)NR'R', 3- to 10-membered cycloalkyl, -C(O)OR', C １ ~C １０ heteroalkyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H, and each C １ ~C １０ alkyl, 6- to 10-membered aryl, 3- to 10-membered cycloalkyl, C １ ~C １０ heteroalkyl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocycloalkyl are independently optionally substituted by 1 to 5 examples of R Ｃ ; Each R' is hydrogen, C １ ~C １０ Alkyl, C １ ~C １０ Haloalkyl, C １ ~C １０ Hydroxyalkyl, and C １ ~C １０ Independently selected from heteroalkyl groups; Each R Ａ However, halo, hydroxy, C １ ~C １０ Alkyl, C １ ~C １０ Haloalkyl, C １ ~C １０ Alkoxy, C １ ~C １０ Haloalkoxy, C １ ~C １０ Independently selected from hydroxyalkyl and NR''R''; Each R Ｂ However, halo, hydroxy, C １ ~C １０ Alkyl, C １ ~C １０ Haloalkyl, C １ ~C １０ Alkoxy, C １ ~C １０ Haloalkoxy, C １ ~C １０ Independently selected from hydroxyalkyl and NR''R''; Each R Ｃ However, halo, hydroxy, cyano, C １ ~C １０ Alkyl, C １ ~C １０ Alkoxy, C １ ~C １０ Independently selected from haloalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and Each R'' is hydrogen, C １ ~C １０ Alkyl, C １ ~C １０ Haloalkyl, C １ ~C １０ Hydroxyalkyl, and C １ ~C １０ (Independently selected from heteroalkyl groups) The method described above is (1) 3-amino-2,6-dichloroisonicotinic acid is reacted with a compound of RNH2, 【Chemistry 141】 The process of forming the compound; （２） 【Chemistry 142】 The above compound is reacted with triethyl orthoformate, 【Chemistry 143】 The process of forming the compound; （３） 【Chemistry 144】 The aforementioned compound is reacted with the compound of Ar-B(OH)2, 【Chemistry 145】 The process of forming the compound; （４） 【Chemistry 146】 The step of reacting the aforementioned compound with the Ar'-B(OH)2 compound to form the aforementioned compound of formula Ia. Including, here, Each X is chloro; R is as described with respect to equation Ia; Ar is ring B; Ar' is ring A; and Each B (OH) ２ A method in which the active ingredients are, independently, boronic acid, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, or tributylstannyl.

2. Compound of formula Ia 【Chem.99】 or a method for preparing a pharmaceutically acceptable salt thereof, (In the formula: Ring A is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl, and each of the 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl groups is used for 1-5 examples of R Ａ It is independently and arbitrarily replaced by; Ring B is selected from 6-10 member aryl, 5-10 member heteroaryl, 3-10 member cycloalkyl, and 3-10 member heterocycloalkyl, and each of the 6-10 member aryl, 5-10 member heteroaryl, 3-10 member cycloalkyl, and 3-10 member heterocycloalkyl is used for 1-5 examples of R Ｂ It is independently and arbitrarily replaced by; R is hydrogen, C １ ~C １０ Alkyl, 6-10 membered aryl, -C(O)R', -C(O)NR'R', 3-10 membered cycloalkyl, -C(O)OR', C １ ~C １０ Selected from heteroalkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H, each C １ ~C １０ Alkyl, 6-10 membered aryl, 3-10 membered cycloalkyl, C １ ~C １０ Heteroalkyls, 5-10 member heteroaryls, and 3-10 member heterocycloalkyls are found in 1-5 R Ｃ It is independently and arbitrarily replaced by; Each R' is hydrogen, C １ ~C １０ Alkyl, C １ ~C １０ Haloalkyl, C １ ~C １０ Hydroxyalkyl, and C １ ~C １０ Independently selected from heteroalkyl groups; Each R Ａ However, halo, hydroxy, C １ ~C １０ Alkyl, C １ ~C １０ Haloalkyl, C １ ~C １０ Alkoxy, C １ ~C １０ Haloalkoxy, C １ ~C １０ Independently selected from hydroxyalkyl and NR''R''; Each R Ｂ is independently selected from halo, hydroxy, C １ to C １０ alkyl, C １ to C １０ haloalkyl, C １ to C １０ alkoxy, C １ to C １０ haloalkoxy, C １ to C １０ hydroxyalkyl, and NR''R''; Each R Ｃ However, halo, hydroxy, cyano, C １ ~C １０ Alkyl, C １ ~C １０ Alkoxy, C １ ~C １０ Independently selected from haloalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and Each R'' is hydrogen, C １ ~C １０ Alkyl, C １ ~C １０ Haloalkyl, C １ ~C １０ Hydroxyalkyl, and C １ ~C １０ (Independently selected from heteroalkyl groups) The method described above is （１） 【Chemistry 147】 The compound is reacted with the compound Ar-B(OH)2, 【Chemistry 148】 The process of forming the compound; （２） 【Chemistry 149】 The above compound is reacted with Ar'-B(OH)2, [Chemical 150] The process of forming the compound; （３） 【Chemistry 151】 The aforementioned compound is reacted with LiOH, and then with the RNH2 compound in the presence of HATU. 【Chemistry 152】 The process of forming the compound; （４） 【Chemistry 153】 The step of reacting the aforementioned compound with triethyl orthoformate to form the compound of formula Ia. Including, here, R is as described with respect to equation Ia; Ar is ring B; Ar' is ring A; and Each B (OH) ２ A method in which the active ingredients are, independently, boronic acid, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, or tributylstannyl.

3. Compound of formula Ia 【Chem.99】 or a method for preparing a pharmaceutically acceptable salt thereof, (In the formula: Ring A is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl, and each of the 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl groups is used for 1-5 examples of R Ａ It is independently and arbitrarily replaced by; Ring B is selected from 6-10 member aryl, 5-10 member heteroaryl, 3-10 member cycloalkyl, and 3-10 member heterocycloalkyl, and each of the 6-10 member aryl, 5-10 member heteroaryl, 3-10 member cycloalkyl, and 3-10 member heterocycloalkyl is used for 1-5 examples of R Ｂ It is independently and arbitrarily replaced by; R is hydrogen, C １ ~C １０ Alkyl, 6-10 membered aryl, -C(O)R', -C(O)NR'R', 3-10 membered cycloalkyl, -C(O)OR', C １ ~C １０ Selected from heteroalkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H, each C １ ~C １０ Alkyl, 6-10 membered aryl, 3-10 membered cycloalkyl, C １ ~C １０ Heteroalkyls, 5-10 member heteroaryls, and 3-10 member heterocycloalkyls are found in 1-5 R Ｃ It is independently and arbitrarily replaced by; Each R' is hydrogen, C １ ~C １０ Alkyl, C １ ~C １０ Haloalkyl, C １ ~C １０ Hydroxyalkyl, and C １ ~C １０ Independently selected from heteroalkyl groups; Each R Ａ However, halo, hydroxy, C １ ~C １０ Alkyl, C １ ~C １０ Haloalkyl, C １ ~C １０ Alkoxy, C １ ~C １０ Haloalkoxy, C １ ~C １０ Independently selected from hydroxyalkyl and NR''R''; Each R Ｂ However, halo, hydroxy, C １ ~C １０ Alkyl, C １ ~C １０ Haloalkyl, C １ ~C １０ Alkoxy, C １ ~C １０ Haloalkoxy, C １ ~C １０ Independently selected from hydroxyalkyl and NR''R''; Each R Ｃ However, halo, hydroxy, cyano, C １ ~C １０ Alkyl, C １ ~C １０ Alkoxy, C １ ~C １０ Independently selected from haloalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and Each R'' is hydrogen, C １ ~C １０ Alkyl, C １ ~C １０ Haloalkyl, C １ ~C １０ Hydroxyalkyl, and C １ ~C １０ (Independently selected from heteroalkyl groups) The method described above is （１） 【Chemistry 154】 The compound is reacted with the compound Ar-B(OH)2, 【Chemistry 155】 The process of forming the compound; （２） 【Chemistry 156】 The aforementioned compound is reacted with LiOH, and then with the RNH2 compound in the presence of HATU. 【Chemistry 157】 The process of forming the compound; （３） 【Chemistry 158】 The above compound is reacted with triethyl orthoformate, 【Chemistry 159】 The process of forming the compound; （４） [Chemical 160] The step of reacting the aforementioned compound with Ar'-B(OH)2 to form the compound of formula Ia. Including, here, R is as described with respect to equation Ia; Ar is ring B; Ar' is ring A; and Each B (OH) ２ A method in which the active ingredients are, independently, boronic acid, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, or tributylstannyl.

4. Compound of formula Ia 【Chem.99】 or a method for preparing a pharmaceutically acceptable salt thereof, (In the formula: Ring A is 【Chemistry 126】 And; Ring B is selected from 6-10 member aryl, 5-10 member heteroaryl, 3-10 member cycloalkyl, and 3-10 member heterocycloalkyl, and each of the 6-10 member aryl, 5-10 member heteroaryl, 3-10 member cycloalkyl, and 3-10 member heterocycloalkyl is used for 1-5 examples of R Ｂ It is independently and arbitrarily replaced by; R is hydrogen, C １ ~C １０ Alkyl, 6-10 membered aryl, -C(O)R', -C(O)NR'R', 3-10 membered cycloalkyl, -C(O)OR', C １ ~C １０ Selected from heteroalkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H, each C １ ~C １０ Alkyl, 6-10 membered aryl, 3-10 membered cycloalkyl, C １ ~C １０ Heteroalkyls, 5-10 member heteroaryls, and 3-10 member heterocycloalkyls are found in 1-5 R Ｃ It is independently and arbitrarily replaced by; Each R' is hydrogen, C １ ~C １０ Alkyl, C １ ~C １０ Haloalkyl, C １ ~C １０ Hydroxyalkyl, and C １ ~C １０ Independently selected from heteroalkyl groups; Each R Ｂ However, halo, hydroxy, C １ ~C １０ Alkyl, C １ ~C １０ Haloalkyl, C １ ~C １０ Alkoxy, C １ ~C １０ Haloalkoxy, C １ ~C １０ Independently selected from hydroxyalkyl and NR''R''; Each R Ｃ However, halo, hydroxy, cyano, C １ ~C １０ Alkyl, C １ ~C １０ Alkoxy, C １ ~C １０ Independently selected from haloalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and Each R'' is hydrogen, C １ ~C １０ Alkyl, C １ ~C １０ Haloalkyl, C １ ~C １０ Hydroxyalkyl, and C １ ~C １０ (Independently selected from heteroalkyl groups) The method described above is （１） 【Chemistry 161】 The aforementioned compound is reacted with LiOH, and then with the RNH2 compound in the presence of HATU. 【Chemistry 162】 The process of forming the compound; （２） 【Chemistry 163】 The above compound is reacted with triethyl orthoformate, 【Chemistry 164】 The process of forming the compound; （３） 【Chemistry 165】 The above compound 【Chemistry 166】 A step of reacting with a compound to form the compound of formula Ia. Including, here, X is Chlorophyll; R is as described with respect to formula Ia; and Ar is ring B. method.

5. Compound of formula Ia 【Chem.99】 or a method for preparing a pharmaceutically acceptable salt thereof, (In the formula: Ring A is 【Chemistry 128】 And; Ring B is selected from 6-10 member aryl, 5-10 member heteroaryl, 3-10 member cycloalkyl, and 3-10 member heterocycloalkyl, and each of the 6-10 member aryl, 5-10 member heteroaryl, 3-10 member cycloalkyl, and 3-10 member heterocycloalkyl is used for 1-5 examples of R Ｂ It is independently and arbitrarily replaced by; R is hydrogen, C １ ~C １０ Alkyl, 6-10 membered aryl, -C(O)R', -C(O)NR'R', 3-10 membered cycloalkyl, -C(O)OR', C １ ~C １０ Selected from heteroalkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H, each C １ ~C １０ Alkyl, 6-10 membered aryl, 3-10 membered cycloalkyl, C １ ~C １０ Heteroalkyls, 5-10 member heteroaryls, and 3-10 member heterocycloalkyls are found in 1-5 R Ｃ It is independently and arbitrarily replaced by; Each R' is hydrogen, C １ ~C １０ Alkyl, C １ ~C １０ Haloalkyl, C １ ~C １０ Hydroxyalkyl, and C １ ~C １０ Independently selected from heteroalkyl groups; Each R Ｂ However, halo, hydroxy, C １ ~C １０ Alkyl, C １ ~C １０ Haloalkyl, C １ ~C １０ Alkoxy, C １ ~C １０ Haloalkoxy, C １ ~C １０ Independently selected from hydroxyalkyl and NR''R''; Each R Ｃ However, halo, hydroxy, cyano, C １ ~C １０ Alkyl, C １ ~C １０ Alkoxy, C １ ~C １０ Independently selected from haloalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and Each R'' is hydrogen, C １ ~C １０ Alkyl, C １ ~C １０ Haloalkyl, C １ ~C １０ Hydroxyalkyl, and C １ ~C １０ (Independently selected from heteroalkyl groups) The method described above is （１） 【Chemistry 167】 The compound is reacted with the compound of RNH2, 【Chemical 168】 The process of forming the compound; （２） 【Chemistry 169】 The above compound is reacted with triethyl orthoformate, 【Chemistry 170】 The process of forming the compound; （３） 【Chemistry 171】 The aforementioned compound is reacted with the compound of Ar-B(OH)2, 【Chemistry 172】 The process of forming the compound; （４） 【Chemistry 173】 The above compound 【Chemistry 174】 A step of reacting with a compound to form the compound of formula Ia. Including, here, R is as described with respect to equation Ia; Ar is ring B; and A way for Ar' to be ring A.

6. Ring A has 1 to 5 cases of R Ａ 6- to 8-membered aryls or 1 to 5 Rs are optionally substituted by Ａ The method according to any one of claims 1 to 3, wherein a 5- to 8-membered heteroaryl is selected by any choice of substitution.

7. Ring A has 1 to 3 cases of R Ａ Phenyl or 1 to 3 R compounds optionally substituted by Ａ The method according to any one of claims 1 to 3 and 6, wherein the pyridinyl is optionally substituted by the pyridinyl.

8. Ring B has 1 to 5 cases of R Ｂ The method according to any one of claims 1 to 7, wherein benzodioxolyl and 5- to 8-membered heteroaryls are optionally substituted by the method.

9. Ring B is selected from pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl. Pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl each have 1 to 3 cases of R Ｂ The method according to any one of claims 1 to 8, wherein the substitution is independently and optionally performed by the method described above.

10. Each R Ａ But, hello, C １ ~C １０ Alkyl, C １ ~C １０ Haloalkyl, C １ ~C １０ Alkoxy, C １ ~C １０ Selected independently from haloalkoxys and NR''R''; Each R Ｂ But, hello, C １ ~C １０ Alkyl and C １ ~C １０ Independently selected from haloalkyl groups; Each R Ｃ However, halo, hydroxy, cyano, C １ ~C １０ Alkyl, C １ ~C １０ Independently selected from alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, and 6-8 membered aryl; and Each R'' is hydrogen and C １ ~C １０ The method according to any one of claims 1 to 9, independently selected from alkyl.

11. Ring A is 【Chemistry 130】 【Chemistry 131】 The method according to any one of claims 1 to 3, selected from the following.

12. Ring A is 【Chemistry 132】 【Chemistry 133】 The method according to claim 11, selected from the following.

13. Ring B is 【Chemistry 134】 【Chemistry 135】 The method according to any one of claims 1 to 7 and 10 to 12, selected from among them.

14. Ring B is 【Transformation 136】 The method according to claim 13, selected from the following.

15. R is methyl, 【Chemistry 137】 【Chemistry 138】 The method according to any one of claims 1 to 14, selected from the following.

16. R is methyl, 【Chemistry 139】 The method according to claim 15, selected from the following.

17. The compound of formula Ia above, (i)(S)-8-(5-fluoropyridine-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (ii)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(6-oxo-1,6-dihydropyridine-3-yl)pyrido[3,4-d]pyrimidine-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]pyrimidine-4(3H)-one; (iv)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (v)(S)-8-(5-fluoropyridine-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (vi)(S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridine-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (vii)(S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (viiii)(S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (ix)3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (x) 6,8-di(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xi)(S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xi)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xiiii)6-(4-chlorophenyl)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xiv)8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xv)6-(4-chlorophenyl)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xvi)3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xvii)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xviiii)6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xix)3-(2-hydroxy-2-methylpropyl)-6,8-bis(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xx)(S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxi)6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxii)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxiii)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxiv)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxv)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxvi)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-phenylpyrido[3,4-d]pyrimidine-4(3H)-one; (xxvii)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxviiii)3-methyl-8-(pyridine-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxix)Rac-6-(4-chlorophenyl)-3-((trans)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxx)(S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxi)(R)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxii)rac-6-(4-chlorophenyl)-3-((cis)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxiii)(R)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxiv)(S)-3-(3-hydroxy-3-methylbutan-2-yl)-6,8-di(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxv)(S)-6,8-bis(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxvi)(S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxvii)(S)-8-(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxviiii)6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(2-hydroxy-2-methylpropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xxxix)(R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xl)(S)-3-(1-(benzyloxy)propan-2-yl)-8-(3-fluorophenyl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xli)(R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xli)(S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xliiii)(S)-3-(1-hydroxypropan-2-yl)-6-morpholino-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xliv)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazole-1-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xlv)(S)-3-(1-methoxypropan-2-yl)-8-(pyridine-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xlvi)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xlvii)(S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xlviii)(S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (xlix)(S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (l)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethoxy)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (li)(S)-3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lii)methyl(S)-5-(3-(1-hydroxypropan-2-yl)-4-oxo-8-(pyridine-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidine-6-yl) picolinate (liiii)(S)-3-(1-hydroxypropan-2-yl)-6-(isothiazole-4-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (liv)3-(2-hydroxy-2-methylpropyl)-8-(isothiazol-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lv)(S)-3-(1-hydroxypropan-2-yl)-8-(isothiazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lvi)(S)-3-(1-hydroxypropan-2-yl)-6,8-di(isothiazol-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lvi)(S)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lviiii)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lix)3-(2-hydroxy-2-methylpropyl)-6,8-di(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lx)3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxi)6-(4-chloro-2-methylphenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxii)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxiii)(S)-3-(1-hydroxypropan-2-yl)-8-(2-methylpyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxiv)(S)-3-(1-hydroxypropan-2-yl)-8-(4-methylpyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxv)(S)-3-(1-hydroxypropan-2-yl)-6-(4-methylthiazole-5-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxvii)(S)-3-(1-hydroxypropan-2-yl)-6-(2-isopropylthiazole-5-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxviiii)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxix)(S)-3-(1-hydroxypropan-2-yl)-6,8-bis(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxx)6-(4-chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxi)6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxii)3-(2-hydroxyethyl)-8-(pyridine-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxiii)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-6-oxo-1,6-dihydropyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxv)(S)-3-(1-hydroxypropan-2-yl)-6-(4-methyl-6-(trifluoromethyl)pyridine-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxvi)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxvii)(S)-6-(cyclohexa-1-en-1-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxviiii)(S)-6,8-bis(5-fluoropyridine-3-yl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxix)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxx)3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxiv)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxv)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxvi)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)pyrimidine-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxvii)3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxviiii)3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (lxxxix)(S)-3-(1-hydroxypropan-2-yl)-6-(2-methylthiazole-5-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xc)(S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xci)(S)-3-(1-hydroxypropan-2-yl)-6-(piperidine-1-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xcii)3-(2-hydroxy-2-methylpropyl)-8-(isothiazol-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xciiii)(S)-3-(1-hydroxypropan-2-yl)-8-(isothiazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xciv)3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xcv)(S)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xcvi)(3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xcvii)3-(1,1-dioxidetetrahydrothiophen-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xcviii)(R)-3-(1,1-dioxidetetrahydrothiophen-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (xcix)(R)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (c)(S)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (ci)(R)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cii)(S)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (Ciii)(R)-3-(2-hydroxypropyl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (Civ)(R)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cv)3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cvi)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cvii)6-(4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cviii)3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxi)(R)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxi)(R)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxiii)(S)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxiv)6-(4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxv)3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxvii)6-(4-chlorophenyl)-3-(4-hydroxy-1-methylpyrrolidine-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxviiii)6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidine-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxi)3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxii)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxiii)3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxiv)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxv)(R)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxvi)(S)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxvii)(S)-3-(2-hydroxypropyl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxviiii)(R)-3-(2-hydroxypropyl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxix)3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxx)(S)-3-(2-hydroxypropyl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxxi)(S)-8-(1-methyl-1H-pyrazole-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxxii)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxxiii)3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxxiv)6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxxv)6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxxxvi)(R)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxl)3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxli)3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazole-1-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxli)3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazole-1-yl)-6-(6-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxliiii)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazole-1-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxliv)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazole-1-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxlv)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-1,2,4-triazole-1-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxlvi)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazole-1-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxlvii)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxlix)(S)-3-(1-hydroxypropan-2-yl)-8-(piperidine-1-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cl)(S)-3-(1-hydroxypropan-2-yl)-8-(pyrrolidine-1-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cli)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(piperidine-1-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clii)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridine-2-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cliiii)(S)-6-cyclohexyl-3-(1-hydroxypropan-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clv)(S)-3-(1-hydroxypropan-2-yl)-6-(pyridine-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clv)(S)-3-(1-hydroxypropan-2-yl)-6-(2-methylthiazole-4-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clvi)(S)-3-(1-hydroxypropan-2-yl)-6-(1-methyl-1H-1,2,3-triazole-5-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clvii)(R)-6-(4-chlorophenyl)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clviiii)(S)-6-(4-chlorophenyl)-8-(pyridine-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)-one; (clix)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1,2,5,6-tetrahydropyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clx)6-(4-chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxi)(S)-3-(1-hydroxypropan-2-yl)-6-(2-methylpyrimidine-5-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxii)3-(2-hydroxy-2-methylpropyl)-8-(1-(trifluoromethyl)-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxiii)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(2-(trifluoromethyl)pyrimidine-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxiv)3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)pyrimidine-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxv)(S)-5-(3-(1-hydroxypropan-2-yl)-4-oxo-8-(pyridine-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidine-6-yl) picolinic acid (clxvi)(S)-3-(1-hydroxypropan-2-yl)-6-(6-methylpyridine-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxvii)3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(2-(trifluoromethyl)pyrimidine-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxviiii)3,8-di(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxix)8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxx)3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxi)3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxii)6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxiii)3-cyclopentyl-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxiv)3-phenyl-8-(pyridine-3-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxv)3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxvi)3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxix)3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxx)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazole-1-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxxi)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazole-1-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxxii)3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxxiii)3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxxiv)3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxxv)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxxvi)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(2-(trifluoromethyl)thiazole-5-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxxvii)(S)-3-(1-hydroxypropan-2-yl)-8-morpholino-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxxviiii)3-(2-hydroxy-2-methylpropyl)-8-(piperidine-1-yl)-6-(6-(trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (clxxxix)(S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyridine-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxc)(S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyrimidine-2-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxci)(S)-8-(cyclohexa-1-en-1-yl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxcii)(S)-8-cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxciv)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazole-4-yl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxcv)(S)-3-(1-hydroxypropan-2-yl)-6-(2-methoxyethyl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (cxcvi)(S)-3-(1-hydroxypropan-2-yl)-8-(2-methoxyethyl)-6-(5-(trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one The method according to any one of claims 1 to 3, selected from the following.

18. The compound of formula Ia above, 【Chemistry 116】 (3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(6-trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one); 【Chemistry 117】 (6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one); 【Chemistry 118】 (3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazole-4-yl)-6-(6-trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one); 【Chemical 119】 (3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)-6-(6-trifluoromethyl)pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one); 【Chemical 120】 (3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3-yl)-6-(5-trifluoromethyl)pyridine-2-yl)pyrido[3,4-d]pyrimidine-4(3H)-one); or 【Chemistry 121】 (6-(4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine-3-yl)pyrido[3,4-d]pyrimidine-4(3H)-one) The method according to any one of claims 1 to 3, selected from the following.

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