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 November 22, 2019, U.S. Patent Application No. 63 / 050,416, filed July 10, 2020, and U.S. Patent Application No. 63 / 091,192, filed October 13, 2020, which are incorporated by reference in their entireties herein.

[0002] Disclosed herein are novel 3,6,8-trisubstituted pyrido[3,4-d]pyrimidin-4(3H)-one compounds of formula (Ia) and pharma- ceutically acceptable salts thereof, methods for preparing said compounds and salts, intermediate compounds useful for preparing said compounds and salts, pharmaceutical compositions comprising said compounds and salts, and methods of using said compounds and salts for the treatment or prevention of diseases, particularly cancer or pathologies with 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 pharma- ceutically acceptable salt thereof and at least one additional therapy, and methods of treating cancer comprising administering at least one such compound and / or a pharma- ceutically acceptable salt thereof and at least one additional therapy. [ka] [Background technology]

[0003] The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor belonging to the basic helix-loop-helix / Per-Arnt-Sim (bHLH / PAS) family located in the cytosol. Upon ligand binding, AHR translocates to the nucleus where it heterodimerizes with ARNT (AHR nuclear transporter) and simultaneously interacts with DREs (dioxin response elements) of AHR-responsive genes to regulate their transcription. AHR is best known for binding environmental toxins and inducing metabolic machinery such as cytochrome P450 enzymes (e.g., CYP1A1, CYP1A2, and CYP1B1) required for their elimination (Reyes et al., Science, 1992, 256(5060):1 193-5). Activation of AHR by xenobiotics has demonstrated its role in many cellular processes such as embryonic development, 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, for example, are known to induce profound immunosuppression, promote carcinogenesis, and induce tumor growth (Gramatzki et al., Oncogene, 2009, 28(28):2593-605; Bui et al., 2009, 28(28):2593-605). et al., Oncogene, 2009, 28(41):3642-51; Esser et al., Trends Immunol., 2009, 30:447-454). In the context of immunosuppression, AHR activation promotes regulatory T cell generation, 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 regulates innate immune responses, and constitutive AHR expression has been shown to negatively regulate type 1 interferon responses to viral infection (Yamada et al., Nat. Immunol., 2016, 17(6):687-94). Furthermore, mice with naturally constitutively active AHR develop tumors (Andersson et al., PNAS, 2002, 99(15):9990-5).

[0005] In addition to xenobiotics, the AHR can also bind metabolic products of tryptophan degradation. Tryptophan metabolites such as kynurenine and kynurenic acid are endogenous AHR ligands that activate the AHR under physiological conditions (DiNatale et al., Toxicol. Sci., 2010, 115(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 the AHR, although their physiological roles are currently unknown (Nguyen & Bradfield, Chem. Res. Toxicol., 2008, 21(1):102-116).

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

[0007] TDO2 is also strongly expressed in cancers 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 antitumor immune responses and directly promoting tumor cell survival and motility (Opitz et al., Nature, 2011, 478(7368):197-203). Thus, AHR ligands produced by tumor cells act in both autocrine and paracrine ways on tumor cells and lymphocytes, respectively, 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 increase the host's immune response. Non-limiting examples of ICI targets include programmed death 1 (PD-1), PD-1 ligand (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4).

[0009] PD-1 is highly expressed by activated T cells, B cells, dendritic cells (DCs), and natural killer cells (NKs), whereas PD-L1 can be expressed on some types of tumor cells. ICIs are currently approved by the Food and Drug Administration for the treatment of melanoma, non-small cell lung cancer, renal cell carcinoma, squamous cell carcinoma of the head and neck, Hodgkin lymphoma, urothelial carcinoma, small cell lung cancer, esophageal squamous cell carcinoma, cervical cancer, primary mediastinal large B-cell lymphoma, MSI-H / dMMR colorectal cancer, hepatocellular carcinoma, Merkel cell carcinoma, 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 Summary of the Invention [Means for solving the problem]

[0011] The present disclosure relates to novel 3,6,8-trisubstituted pyrido[3,4-d]pyrimidin-4(3H)-ones of formula (I) or formula (Ia) and / or pharma- ceutically acceptable salts thereof. The compounds of the present disclosure have surprisingly been found to effectively inhibit AHR and thus are useful in treating cancer and / or other pathologies in which exogenous and endogenous AHR ligands induce dysregulated immune responses, uncontrolled cell growth, tumor cell proliferation and / or survival, immunosuppression in the context of cancer, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases involving uncontrolled cell growth, tumor cell proliferation and / or survival, immunosuppression in the context of cancer, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, in particular in the context of cancer and / or other pathologies in which exogenous and endogenous AHR ligands induce dysregulated immune responses, ... The present invention may be used to treat or prevent diseases in which cell growth, proliferation and / or survival of tumor cells, immunosuppression in the context of cancer, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses are mediated by AHR, such as liquid and solid tumors, and / or metastases thereof, 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 metastases thereof.

[0012] The present disclosure also relates to pharmaceutical compositions comprising at least one entity selected from compounds of formula (I) or formula (Ia) and pharma- ceutically acceptable salts thereof. The present disclosure also relates to methods of treatment comprising administering at least one compound of the present disclosure, a pharma- ceutically acceptable salt thereof, and / or a pharmaceutical composition. In some embodiments, the present disclosure provides methods of treating a disease or condition mediated by AHR signaling. In some embodiments, the present disclosure provides methods of treating a disease or condition associated with aberrant AHR signaling. In some embodiments, the present disclosure provides methods of 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 pharma- ceutically acceptable salts thereof. (In the formula: R 1 and R 2 are independently selected from optionally substituted alkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted amine, and optionally substituted heterocycloalkyl; and R 3 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, optionally substituted amine, cyano, halo, hydroxy, and -C(O)H. (Item 2) Compound of Formula Ia [ka] or a pharma- ceutically 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 amido, 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- to 10-membered aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 3- to 10-membered cycloalkyl, and optionally substituted 3- to 10-membered heterocycloalkyl; Ring B is selected from optionally substituted 6- to 10-membered aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 3- to 10-membered cycloalkyl, and optionally substituted 3- to 10-membered heterocycloalkyl; R is hydrogen, optionally substituted C 1 ~C 10 Alkyl, optionally substituted 6-10 membered aryl, -C(O)R', -C(O)NR'R', optionally substituted 3-10 membered cycloalkyl, -C(O)OR', optionally substituted C 1 ~C 10 selected from heteroalkyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H; and Each R' is hydrogen, optionally substituted C 1 ~C 10 Alkyl and optionally substituted C 1 ~C 10 3. The compound according to claim 2, or a pharma- ceutically acceptable salt thereof, wherein: (Item 4) Ring A is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocycloalkyl, each of which is selected from 1 to 5 instances of R A and 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, each of which is selected from 1 to 5 instances of R B and 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 heteroalkyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H; 1 ~C 10 Alkyl, 6-10 membered aryl, 3-10 membered cycloalkyl, C 1 ~C 10 Heteroalkyl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocycloalkyl are each independently selected from 1 to 5 instances of R C 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 heteroalkyl; Each R A But halo, hydroxy, C 1 ~C 10 Alkyl, C 1 ~C 10 Haloalkyl, C 1 ~C10 Alkoxy, C 1 ~C 10 Haloalkoxy, C 1 ~C 10 is independently selected from hydroxyalkyl, and NR"R"; Each R B But 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 is independently selected from hydroxyalkyl, and NR"R"; Each R C But halo, hydroxy, cyano, C 1 ~C 10 Alkyl, C 1 ~C 10 Alkoxy, C 1 ~C 10 independently selected from haloalkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 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 4. The compound according to claim 2 or 3, or a pharma- ceutically acceptable salt thereof, wherein: (Item 5) Ring A is R in 1 to 5 cases A or a pharma- ceutically acceptable salt thereof. (Item 6) Ring A is R in 1 to 5 cases A6. The compound according to item 4 or 5, wherein the aryl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, optionally substituted by: or a pharma- ceutically acceptable salt thereof. (Item 7) Ring A is R in 1 to 5 cases A or a pharma- ceutically acceptable salt thereof. (Item 8) Ring A is R in 1 to 3 cases A or a pharma- ceutically acceptable salt thereof. (Item 9) Ring A is R in 1 to 5 cases A or a pharma- ceutically acceptable salt thereof. (Item 10) Ring A is selected from pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl; pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl each represent 1 to 3 instances of R A 10. The compound according to item 4 or 9, optionally substituted independently by: or a pharma- ceutically acceptable salt thereof. (Item 11) Ring A is R in 1 to 3 cases A or a pharma- ceutically acceptable salt thereof. (Item 12) Ring A is R in 1 to 5 cases Aor a pharma- ceutically acceptable salt thereof. (Item 13) Ring A is selected from pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydropyranyl, and tetrahydrofuranyl; pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydropyranyl, and tetrahydrofuranyl each have 1 to 3 instances of R A 13. The compound according to item 4 or 12, optionally substituted independently by: (Item 14) Ring A is R in 1 to 3 cases A or morpholino, optionally substituted with: (Item 15) Ring B is R in 1-5 cases B or a pharma- ceutically acceptable salt thereof. (Item 16) Ring B is R in 1-3 cases B 16. The compound according to item 4 or 15, wherein R is phenyl optionally substituted by: or a pharma- ceutically acceptable salt thereof. (Item 17) Ring B is R in 1-5 cases B 5. The compound according to item 4, wherein the compound is selected from benzodioxolyl and 5-8 membered heteroaryl optionally substituted by: or a pharma- ceutically acceptable salt thereof. (Item 18) Ring B is selected from benzodioxolyl, pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyridinonyl, and pyrimidinyl; Benzodioxolyl, pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl each represent one to three instances of R B 18. The compound according to item 4 or 17, optionally substituted independently by: (Item 19) Ring B is selected from pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl; Each of pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl has 1 to 3 instances of R B 19. The compound according to any one of items 4, 17, and 18, optionally substituted independently by: or a pharma- ceutically acceptable salt thereof. (Item 20) Each R A But, Halo, C 1 ~C 10 Alkyl, C 1 ~C 10 Haloalkyl, C 1 ~C 10 Alkoxy, C 1 ~C 10 independently selected from haloalkoxy, and NR"R"; Each R B But, Halo, C 1 ~C 10 Alkyl, and C 1 ~C 10 haloalkyl; Each R C But halo, hydroxy, cyano, C 1 ~C 10 Alkyl, C 1 ~C 10 independently selected from alkoxy, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocycloalkyl, and 6- to 8-membered aryl; and Each R″ is hydrogen and C 1 ~C 1020. The compound according to any one of items 4 to 19, or a pharma- ceutically acceptable salt thereof, wherein each of the following is independently selected from alkyl: (Item 21) Ring A is [ka] The compound according to any one of items 2 to 4 and 7 to 20, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of: (Item 22) Ring A is [ka] The compound according to any one of items 2 to 6 and 15 to 20, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of: (Item 23) Ring A is [ka] The compound according to any one of items 2 to 4 and 7 to 20, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of: (Item 24) Ring B is [ka] The compound according to any one of items 2 to 4 and 7 to 20, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of: (Item 25) Ring B is [ka] 21. The compound according to any one of items 2 to 14 and 20, or a pharma- ceutically acceptable salt thereof, selected from: (Item 26) Ring B is [ka] The compound according to any one of items 2 to 4 and 7 to 20, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of: (Item 27) R is methyl, [ka] 27. The compound according to any one of items 2 to 26, or a pharma- ceutically acceptable salt thereof, selected from: (Item 28) R is methyl, [ka] 28. The compound according to any one of items 2 to 27, or a pharma- ceutically acceptable salt thereof, selected from: (Item 29) At least one entity selected from the following compounds and pharma- ceutically acceptable salts thereof: (i) (S)-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (ii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(6-oxo-1,6-dihydropyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (iii) (S)-8-(benzo[d][1,3]dioxol-4-yl)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (iv) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (v) (S)-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (vi) (S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (vii) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (viii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (ix) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (x) 6,8-di(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xi) (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xiii) 6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xiv) 8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xv) 6-(4-chlorophenyl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xvi) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xvii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xviii) 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xix) 3-(2-hydroxy-2-methylpropyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xx) (S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxi) 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxiii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxiv) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxv) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxvi) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-phenylpyrido[3,4-d]pyrimidin-4(3H)-one; (xxvii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxviii) 3-methyl-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxix) Rac-6-(4-chlorophenyl)-3-((trans)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxx) (S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxi) (R)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxii) rac-6-(4-chlorophenyl)-3-((cis)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxiii) (R)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxiv) (S)-3-(3-hydroxy-3-methylbutan-2-yl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxv) (S)-6,8-bis(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxvi) (S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxvii) (S)-8-(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxviii) 6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(2-hydroxy-2-methylpropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxix) (R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xl) (S)-3-(1-(benzyloxy)propan-2-yl)-8-(3-fluorophenyl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xli) (R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlii) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xliii) (S)-3-(1-hydroxypropan-2-yl)-6-morpholino-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xliv) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlv) (S)-3-(1-methoxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlvi) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlvii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlviii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlix) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (l) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethoxy)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (li) (S)-3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lii) Methyl (S)-5-(3-(1-hydroxypropan-2-yl)-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)picolinate (liii) (S)-3-(1-hydroxypropan-2-yl)-6-(isothiazol-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (liv) 3-(2-hydroxy-2-methylpropyl)-8-(isothiazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lv) (S)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lvi) (S)-3-(1-hydroxypropan-2-yl)-6,8-di(isothiazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lvii) (S)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lviii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lix) 3-(2-hydroxy-2-methylpropyl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lx) 3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxi) 6-(4-chloro-2-methylphenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxii) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxiii) (S)-3-(1-hydroxypropan-2-yl)-8-(2-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxiv) (S)-3-(1-hydroxypropan-2-yl)-8-(4-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxv) (S)-3-(1-hydroxypropan-2-yl)-6-(4-methylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxvi) (S)-6-(2-cyclopropylthiazol-5-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxvii) (S)-3-(1-hydroxypropan-2-yl)-6-(2-isopropylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxviii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxix) (S)-3-(1-hydroxypropan-2-yl)-6,8-bis(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxx) 6-(4-chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxi) 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxii) 3-(2-hydroxyethyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxiii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxiv) (S)-6-(6-cyclopropylpyridin-3-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxv) (S)-3-(1-hydroxypropan-2-yl)-6-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxvi) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxvii) (S)-6-(cyclohex-1-en-1-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxviii) (S)-6,8-bis(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxix) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxx) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxi) 6-(6-cyclopropylpyridin-3-yl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxii) 6-(6-cyclopropylpyridin-3-yl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxiii) (S)-6-(6-cyclopropylpyridin-3-yl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxiv) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxv) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxvi) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxvii) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxviii) 3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxix) (S)-3-(1-hydroxypropan-2-yl)-6-(2-methylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xc) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xci) (S)-3-(1-hydroxypropan-2-yl)-6-(piperidin-1-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcii) 3-(2-hydroxy-2-methylpropyl)-8-(isothiazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xciii) (S)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xciv) 3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcv) (S)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcvi) (3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcvii) 3-(1,1-dioxidetetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcviii) (R)-3-(1,1-dioxidetetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcix) (R)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (c) (S)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (ci) (R)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cii) (S)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (ciii) (R)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (civ) (R)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cv) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cvi) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cvii) 6-(4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cviii) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cix) (S)-6-(6-cyclopropylpyridin-3-yl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cx) (R)-6-(6-cyclopropylpyridin-3-yl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxi) (R)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxii) (R)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxiii) (S)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxiv) 6-(4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxv) 3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxvi) Methyl (S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoate (cxvii) 6-(4-chlorophenyl)-3-(4-hydroxy-1-methylpyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxviii) 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxix) (R)-6-(6-cyclopropylpyridin-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxx) (S)-6-(6-cyclopropylpyridin-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxi) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxii) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxiii) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxiv) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxv) (R)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxvi) (S)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxvii) (S)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxviii) (R)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxix) 3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxx) (S)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxi) (S)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxiii) 3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxiv) 6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxv) 6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxvi) (R)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxvii) (S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoic acid (cxxxviii) (S)-N-Methyl-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanamide (cxxxix) (S)-N,N-Dimethyl-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propenamide (cxl) 3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxli) 3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlii) 3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxliii) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxliv) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlv) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-1,2,4-triazol-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlvi) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlvii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlviii) (S)-8-(diethylamino)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlix) (S)-3-(1-hydroxypropan-2-yl)-8-(piperidin-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cl) (S)-3-(1-hydroxypropan-2-yl)-8-(pyrrolidin-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cli)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(piperidin-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (S)-6-Cyclohexyl-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (S)-3-(1-hydroxypropan-2-yl)-6-(pyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clv) (S)-3-(1-hydroxypropan-2-yl)-6-(2-methylthiazol-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clvi) (S)-3-(1-hydroxypropan-2-yl)-6-(1-methyl-1H-1,2,3-triazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clvii) (R)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (clviii) (S)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clx) 6-(4-chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxi) (S)-3-(1-hydroxypropan-2-yl)-6-(2-methylpyrimidin-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxii) 3-(2-hydroxy-2-methylpropyl)-8-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxiii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxiv) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxv) (S)-5-(3-(1-hydroxypropan-2-yl)-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)picolinic acid (clxvi) (S)-3-(1-hydroxypropan-2-yl)-6-(6-methylpyridin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxvii) 3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxviii) 3,8-di(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxix) 8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxx) 3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxi) 3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxii) 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxiii) 3-Cyclopentyl-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxiv) 3-phenyl-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxv) 3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxvi) 3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxvii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxviii) (S)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanamide (clxxix) 3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxx) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxi) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxii) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxiii) 3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxiv) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxv) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxvi) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxvii) (S)-3-(1-hydroxypropan-2-yl)-8-morpholino-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxviii) 3-(2-hydroxy-2-methylpropyl)-8-(piperidin-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxix) (S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxc) (S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyrimidin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxci) (S)-8-(cyclohex-1-en-1-yl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxcii) (S)-8-Cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxciii) (S)-3-(1-hydroxypropan-2-yl)-N,N-dimethyl-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidine-6-carboxamide (cxciv) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxcv) (S)-3-(1-hydroxypropan-2-yl)-6-(2-methoxyethyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxcvi) (S)-3-(1-hydroxypropan-2-yl)-8-(2-methoxyethyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one. (Item 30) A pharmaceutical composition comprising at least one entity selected from the compounds according to any one of items 1 to 29 and their pharma- ceutically acceptable salts, and at least one pharma- ceutically acceptable excipient. (Item 31) A method for treating a disease or condition mediated by AhR signaling in a subject in need of such treatment, comprising administering to said subject a therapeutically effective amount of at least one entity selected from the compounds described in any one of items 1 to 29 and their pharma- ceutically acceptable salts or at least one pharmaceutical composition described in item 30. (Item 32) A method for treating a disease or condition associated with abnormal AhR signaling in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of at least one entity selected from the compounds described in any one of items 1 to 29 and their pharma- ceutically acceptable salts or at least one pharmaceutical composition described in item 30. (Item 33) 33. The method according to item 31 or 32, wherein the disease is selected from cancer. (Item 34) 33. The method according to item 31 or 32, wherein the disease is selected from liquid tumors and solid tumors. (Item 35) 35. The method according to any one of items 31 to 34, wherein the disease is selected from breast cancer, cancer of the respiratory tract, brain cancer, cancer of the reproductive organs, cancer of the digestive tract, cancer of the urinary tract, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and metastasis of any of the above. (Item 36) 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) 35. 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 cancer cell proliferation mediated by AHR signaling in a subject in need of inhibition of cancer cell proliferation mediated by AHR signaling, comprising administering to said subject a therapeutically effective amount of at least one entity selected from the compounds according to any one of items 1 to 29 and their pharma- ceutically acceptable salts or at least one pharmaceutical composition according to item 30. (Item 39) A method for inhibiting tumor cell invasion or metastasis mediated by AhR signaling in a subject in need of inhibition of tumor cell invasion or metastasis mediated by AhR signaling, comprising administering to the subject a therapeutically effective amount of at least one entity selected from the compounds described in any one of items 1 to 29 and their pharma- ceutically acceptable salts or at least one pharmaceutical composition described in item 30. (Item 40) A method for treating cancer in a subject in need of such treatment, comprising administering to said subject a therapeutically effective amount of i) at least one entity selected from the compounds according to any one of items 1 to 29 and their pharma- ceutically acceptable salts or at least one pharmaceutical composition according to item 30, and ii) a therapeutically effective amount of at least one additional therapy. (Item 41) 41. The method of claim 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 according to any one of items 1 to 29 and pharma- ceutically acceptable salts thereof or the at least one pharmaceutical composition according to item 30 is initiated prior to the administration of the at least one additional therapy. (Item 43) The method according to item 40, wherein the at least one entity selected from the compounds according to any one of items 1 to 29 and pharma- ceutically acceptable salts thereof or the at least one pharmaceutical composition according to item 30 is administered after administration of the at least one additional therapy. (Item 44) The method according to item 40, wherein the at least one entity selected from the compounds according to any one of items 1 to 29 and pharma- ceutically acceptable salts thereof or the at least one pharmaceutical composition according to item 30 is administered simultaneously with the administration of the at least one additional therapy. (Item 45) 45. The method of any one of items 40 to 44, wherein the at least one additional therapy is selected from a checkpoint inhibitor. (Item 46) 46. ​​The method of claim 45, wherein the subject is intolerant, refractory, and / or poorly responsive to the at least one additional therapy when administered alone. (Item 47) 47. The method of claim 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) 47. The method of claim 46, wherein the at least one additional therapy is selected from checkpoint inhibitors targeting CTLA-4, PD-1, and / or PD-L1. (Item 49) 47. The method of claim 46, wherein the at least one additional therapy is selected from a cytotoxic T-lymphocyte-associated antigen 4 pathway inhibitor. (Item 50) 50. The method of claim 49, wherein the cytotoxic T-lymphocyte-associated antigen 4 pathway inhibitor is selected from an anti-CTLA-4 antibody. (Item 51) 51. The method of claim 50, wherein the anti-CTLA-4 antibody is ipilimumab. (Item 52) 47. The method of claim 46, wherein the at least one additional therapy is selected from a programmed death-1 pathway inhibitor. (Item 53) 53. The method of claim 52, wherein the programmed death-1 pathway inhibitor is selected from an anti-PD-1 antibody. (Item 54) 53. The method of item 52, wherein the anti-PD-1 antibody is nivolumab. (Item 55) 53. The method of claim 52, wherein the anti-PD-1 antibody is pembrolizumab. (Item 56) 53. The method of claim 52, wherein the anti-PD-1 antibody is cemiplimab. (Item 57) 53. The method of claim 52, wherein the anti-PD-1 antibody is camrelizumab. (Item 58) 53. The method of item 52, wherein the anti-PD-1 antibody is sintilimab. (Item 59) 53. The method of claim 52, wherein the anti-PD-1 antibody is spartalizumab. (Item 60) 53. The method of claim 52, wherein the anti-PD-1 antibody is tislelizumab. (Item 61) 53. The method of claim 52, wherein the anti-PD-1 antibody is BCD-100. (Item 62) 53. The method of item 52, wherein the anti-PD-1 antibody is JS001. (Item 63) 53. The method of claim 52, wherein the programmed death-1 pathway inhibitor is selected from an anti-PD-L1 antibody. (Item 64) 64. The method of claim 63, wherein the anti-PD-L1 antibody is atezolizumab. (Item 65) 64. The method of claim 63, wherein the anti-PD-L1 antibody is avelumab. (Item 66) 64. The method of item 63, wherein the anti-PD-L1 antibody is durvalumab. (Item 67) 64. The method of item 63, wherein the anti-PD-L1 antibody is KN035. (Item 68) 47. The method of claim 46, wherein the at least one additional therapy is selected from a lymphocyte-activation gene-3 (LAG-3) inhibitor. (Item 69) 69. The method of claim 68, wherein the LAG-3 inhibitor is selected from an anti-LAG-3 antibody. (Item 70) 47. The method of claim 46, wherein the at least one additional therapy is selected from a T-cell immunoglobulin and a mucin domain-containing-3 (TIM-3) inhibitor. (Item 71) 71. The method of claim 70, wherein the TIM-3 inhibitor is selected from an anti-TIM-3 antibody. (Item 72) 47. The method of claim 46, wherein the at least one additional therapy is selected from T cell immunoglobulin and ITIM domain (TIGIT) inhibitors. (Item 73) 73. The method of claim 72, wherein the TIGIT inhibitor is selected from a TIGIT antibody. (Item 74) 47. The method of claim 46, wherein the at least one additional therapy is selected from V domain Ig suppressor of T cell activation (VISTA) inhibitors. (Item 75) 75. The method of claim 74, wherein the VISTA inhibitor is selected from an anti-VISTA antibody. (Item 76) The cancer may be non-small cell lung cancer (NSCLC); small cell lung cancer; head and neck squamous cell carcinoma; renal cell carcinoma; gastric adenocarcinoma; nasopharyngeal neoplasms; urothelial carcinoma; colorectal cancer; pleural mesothelioma; triple-negative breast cancer (TNBC); esophageal neoplasms; multiple myeloma; gastric and esophagogastric junction cancer; melanoma; Hodgkin's lymphoma; hepatocellular carcinoma; lung cancer; head and neck cancer; non-Hodgkin's lymphoma; metastatic clear cell renal carcinoma; squamous cell lung carcinoma; mesothelioma; gastric cancer; esophagogastric 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, wherein the cancer is selected from renal cell carcinoma; ovarian cancer, fallopian tube cancer; peritoneal neoplasms; extensive small cell lung cancer; bladder cancer; transitional cell carcinoma; prostate neoplasms; recurrent or metastatic PD-L1 positive or negative squamous cell carcinoma of the head and neck (SCCHN); recurrent squamous cell type 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. [Brief description of the drawings]

[0013] [Figure 1] 1 shows the dosing regimen for an in vivo syngeneic model study using CT26 Balb / C mice. [Diagram 2] Figure 2 shows tumor growth curves of vehicle versus single agent PD-L1 antibody or PD-L1 antibody together with compound #7 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy. [Diagram 3] Figure 1 shows tumor weights at the end of a study of vehicle versus single agent PD-L1 antibody or PD-L1 antibody together with Compound #7 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy. [Figure 4] Figure 2 shows tumor growth curves of vehicle versus single agent PD-L1 antibody or PD-L1 antibody together with Compound #30 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy. [Diagram 5] Figure 2 shows tumor weights at the end of a study of vehicle versus single agent PD-L1 antibody or PD-L1 antibody together with Compound #30 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy. [Figure 6] Figure 2 shows tumor growth curves of vehicle versus single agent PD-L1 antibody or PD-L1 antibody together with compound #30 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy. [Figure 7] Figure 2 shows tumor weights at the end of a study of vehicle versus single agent PD-L1 antibody or PD-L1 antibody together with Compound #30 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy. [Figure 8] Figure 1 shows tumor growth curves of vehicle versus single agent PD-L1 antibody or PD-L1 antibody together with compound #9 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy. [Figure 9] Figure 1 shows tumor weights at the end of a study of vehicle versus single agent PD-L1 antibody or PD-L1 antibody together with Compound #9 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy. [Figure 10] Figure 1 shows tumor growth curves of vehicle versus single agent PD-L1 antibody or PD-L1 antibody together with compound #9 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy. [Figure 11] Figure 1 shows tumor weights at the end of a study of vehicle versus single agent PD-L1 antibody or PD-L1 antibody together with Compound #9 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy. [Figure 12] Figure 2 shows tumor growth curves of vehicle versus single agent PD-L1 antibody or PD-L1 antibody together with compound #46 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy. [Figure 13] Figure 2 shows tumor weights at the end of a study of vehicle versus single agent PD-L1 antibody or PD-L1 antibody together with Compound #46 in a syngeneic colon cancer mouse model resistant to anti-PD-L1 therapy. [Figure 14] FIG. 1 shows a plot of the mean plasma concentration over time of Compound #46 after 1 mg / kg IV and 10 mg / kg PO in CD1 mice. [Figure 15] 1 shows a plot of the mean plasma concentration over time of Compound #46 after 1 mg / kg IV and 3 mg / kg PO in SD rats. [Figure 16] FIG. 1 shows a plot of the mean plasma concentration over time of Compound #9 after 1 mg / kg IV and 10 mg / kg PO in CD1 mice. [Figure 17] 1 shows a plot of the mean plasma concentration over time of Compound #9 after 1 mg / kg IV and 3 mg / kg PO in SD rats. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] As used herein, the term "pharmaceutical acceptable salt" refers to a salt that is pharmaceutically acceptable as defined herein and has the desired pharmacological activity of the parent compound.Non-limiting examples of pharmaceutically acceptable salts include those derived from inorganic acids, including but not limited to hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and those derived from organic acids, including but not limited to 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 an acidic proton in a parent compound is replaced by a metal ion, including but not limited to alkali metal ions and alkaline earth metal ions, and those formed when an acidic proton present in a parent compound is replaced by an ammonium ion, a primary ammonium ion, a secondary ammonium ion, a tertiary ammonium ion, or a quaternary ammonium ion. Non-limiting examples of alkali metals and alkaline earth metals include sodium, potassium, lithium, calcium, aluminum, magnesium, copper, zinc, iron, and manganese. Additional non-limiting examples of pharmaceutically acceptable salts include those that include one or more counterions and zwitterions.

[0016] Ranges provided herein are understood to be shorthand expressions of all values ​​within the range. For example, the range of 1 to 50 is understood to include any number, combination 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 rule applies to any other ranges described herein, even if the values ​​within the 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, including any small molecule chemical compound, antibody, nucleic acid molecule, or polypeptide, or any fragment thereof, that inhibits one or more inhibitory pathways, thereby allowing greater immune activity. In some embodiments, checkpoint inhibitor therapy comprises administering at least one checkpoint inhibitor to a patient in need of such treatment.

[0018] The term "compound" as used herein, unless otherwise specified, 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). Thus, geometric and conformational mixtures of the compounds and salts are within the scope of the disclosure. Unless otherwise specified, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.

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

[0020] The term "tautomer" as used herein refers to one of two or more isomers of a compound that exist together in equilibrium and readily interchange by shifting of atoms or groups within the molecules.

[0021] Unless otherwise indicated, the nomenclature used to describe chemical groups or moieties used herein follows the convention that the name is read from left to right and the point of attachment to the remainder of the molecule is to the right of the name. For example, the group "(C 1~3 Alkoxy)C 1~3 The "alkyl" is attached to the remainder of the molecule at the alkyl end. Further examples include methoxyethyl, where the point of attachment is at the ethyl end, and methylamino, where the point of attachment is at the amine end.

[0022] Unless otherwise indicated, when a chemical group is described by its formula or structure having a terminal attachment portion designated by a "-", it will be understood that the "-" represents the point of attachment. [ka] ) represents the attachment point.

[0023] As used herein, "acyl" or "alkanoyl" is a functional group having the formula RCO-, where R is attached by a single bond to the carbon atom of a carbonyl functional group and the "-" indicates the point of attachment to the remainder of the molecule. Non-limiting examples of acyls include formyl (HC(O)-, also known as methanoyl), acetyl (CH 3 C(O)-, also known as ethanoyl), and benzoyl (PhC(O)-).

[0024] The term "alkyl" or "aliphatic" as used herein means a straight (i.e. unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated and has a single point of attachment to the remainder of the molecule. Unless otherwise specified, an alkyl group is a hydrocarbon chain of 1 to 20 alkyl carbon atoms. In some embodiments, an alkyl group contains 1 to 12 carbon atoms (C 1 ~C 12 In some embodiments, the alkyl group contains 1 to 8 carbon atoms (C 1 ~C 8 In some embodiments, the alkyl group contains 1 to 6 carbon atoms (C 1 ~C 6 In some embodiments, the alkyl group contains 1 to 4 carbon atoms (C 1 ~C 4 In some embodiments, the cyclic alkyl group contains 3 to 6 carbon atoms (C 3 ~C 6 Non-limiting examples of substituted and unsubstituted straight chain, branched chain, 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 an alkyl group, as defined above, attached to the main carbon chain by an oxygen ("alkoxy") atom.

[0026] As used herein, "halo" and "halogen" are interchangeable and refer to halogen atoms such as fluoro (F), chloro (Cl), bromo (Br), and iodo (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 substituted with one or more hydroxy groups (-OH).

[0030] The terms "cycloalkyl" and "cycloalkyl group", as used interchangeably herein, refer to a cyclic saturated monovalent hydrocarbon group of 3 to 12 carbon atoms having a single point of attachment to the remainder of the molecule. Cycloalkyl groups can be unsubstituted or substituted. In some embodiments, cycloalkyl groups contain 3 to 8 carbon atoms (C 3 ~C 8 In some embodiments, the cycloalkyl group contains 3 to 6 carbon atoms (C 3 ~C 6). 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 herein refer to alkylene groups having 1 to 12 carbon atoms (C 1 ~C 12 Alkylene refers to a saturated divalent (i.e., having two points of attachment to the rest of the molecule) hydrocarbon group containing 1 to 8 carbon atoms (C 1 ~C 8 In some embodiments, the alkylene group contains 1 to 6 carbon atoms (C 1 ~C 6 In some embodiments, the alkylene group contains 1 to 4 carbon atoms (C 1 ~C 4 ). Non-limiting examples of alkylene groups include methylene and ethylene.

[0032] The terms "alkenyl" and "alkenyl group" as used interchangeably herein refer to alkenyl groups containing 2 to 8 carbon atoms (C 2 ~C 8 ) refers to a monovalent (i.e., having one point of attachment to the remainder of the molecule) hydrocarbon group with at least one site of unsaturation (i.e., an sp2 carbon-carbon double bond). Alkenyl groups can be straight chain, branched chain, or cyclic. Alkenyl groups can be unsubstituted or substituted. In some embodiments, alkenyl groups contain from 2 to 6 carbon atoms (C 2 ~C 6 In some embodiments, the alkenyl group contains 2 to 4 carbon atoms (C 2 ~C 4). Alkenyl groups can have either the E or Z configuration. Non-limiting examples of alkenyl groups include ethenyl (also called vinyl), 1-propenyl, iso-propenyl, and 2-chloroethenyl.

[0033] The terms "alkenylene" and "alkenylene group", as used interchangeably herein, refer to an alkenylene group having 2 to 8 carbon atoms (C 2 ~C 8 Alkenylene groups can be straight chain, branched chain, or cyclic. Alkenylene groups can be unsubstituted or substituted. In some embodiments, an alkylene group contains 2 to 6 carbon atoms (C 2 ~C 6 In some embodiments, the alkylene group contains 2 to 4 carbon atoms (C 2 ~C 4 ). Alkylene groups can have either the E or 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 alkynyl groups having 2 to 8 carbon atoms (C 2 ~C 8 Alkynyl groups refer to a monovalent (i.e., having one point of attachment to the rest of the molecule) hydrocarbon group. Alkynyl groups can be straight or branched chain. Alkynyl groups can be unsubstituted or substituted. In some embodiments, alkynyl groups contain from 2 to 6 carbon atoms (C 2 ~C 6 In some embodiments, the alkynyl group contains 2 to 4 carbon atoms (C 2 ~C 4 A non-limiting example of an alkynyl group is ethynyl.

[0035] The terms "alkynylene" and "alkynylene group", as used interchangeably herein, refer to alkynylene groups having 2 to 8 carbon atoms (C 2 ~C 8 Alkynylene groups can be straight or branched chain. Alkynylene groups can be unsubstituted or substituted. In some embodiments, an alkynylene group contains 2 to 6 carbon atoms (C 2 ~C 6 In some embodiments, the alkynylene group contains 2 to 4 carbon atoms (C 2 ~C 4 A non-limiting example of an alkynylene group is ethynylene.

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

[0037] The terms "aryl" and "aryl group" as used interchangeably herein refer to aryl groups having 6 to 20 carbon atoms (C 6 ~C 20Aryl groups refer to a monovalent (i.e., having one point of attachment to the remainder of the molecule) aromatic hydrocarbon group. Aryl groups can be unsubstituted or substituted. Non-limiting examples of unsubstituted and substituted aryl groups include phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 3,4-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-phenoxyphenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, Examples of aryl include aryl, 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 of the carbon atoms in the chain is replaced with a heteroatom, such as nitrogen, oxygen, phosphorus, and sulfur. Heteroalkyl groups can be unsubstituted or substituted.

[0039] The terms "heterocycloalkyl", "heterocycle", "heterocyclyl", and "heterocyclic group", used interchangeably herein, refer to a saturated or partially unsaturated 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. Heterocycloalkyl groups can 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 fused rings. Non-limiting examples of unsubstituted and substituted heterocycloalkyl groups include pyrrolidinyl, N-methylpyrrolidinyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 3-hydroxypyrrolidinyl, 3-methoxypyrrolidinyl, and benzodioxolyl.

[0040] The terms "heteroaryl" and "heteroaryl group", used interchangeably herein, 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 can 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-limiting 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, isoaryl, ... Non-limiting examples of heteroaryl groups include isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and 1H-pyrrolo[2,3-b]pyridinyl. [ka] There is.

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

[0042] Additional non-limiting examples of substituents include C 1 ~C 6 Straight chain, branched chain, 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; C 2 ~C 8 Straight chain, branched chain, and cyclic alkenyl groups, non-limiting examples of which include ethenyl (also called vinyl), 1-propenyl, and iso-propenyl; C 2 ~C 8 Straight chain and branched chain alkynyl groups, a non-limiting example of which is ethynyl; Substituted and unsubstituted aryl groups, non-limiting examples of which include phenyl, 2-fluorophenyl, 3-methylphenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 3,4-difluorophenyl, 3-hydroxyphenyl, 4-cyanophenyl, 2-dimethylaminophenyl, 3-methylsulfonylphenyl, 4-trifluoromethylphenyl, 3-isopropylphenyl, 1-naphthyl, and 2-naphthyl; Substituted and unsubstituted heterocyclic groups, non-limiting examples of which include pyrrolidinyl, N-methylpyrrolidinyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 3-hydroxypyrrolidinyl, and 3-methoxypyrrolidinyl; Substituted and unsubstituted heteroaryl groups, non-limiting examples of which include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, furyl, 2-thienyl, 3-thienyl, isoxazolyl, thiazolyl, oxadiazolyl, 3-methyl-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 Non-limiting examples of which include -OH, -OCH 3 , -OCH 2 OH and -OCH 2 CH 3 There is; -(CR a R b )zN(R c )(R d ), non-limiting examples of which include -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 2 NH 2 , -CH 2 NHCH 3 There is, halogen atoms, non-limiting examples of which include fluorine atoms (-F) and chlorine atoms (-Cl); -(CR a R b ) z CN; -(CR a R b ) z NO 2 ; -CH x X y (wherein X is a halogen atom and x+y equals 3 in total), non-limiting examples of which include -CH 2F, -CHF 2 , and -CF 3 There is; -(CR a R b ) z C(O)R c , non-limiting examples of which include -COCH 3 , -COCH 2 CH 3 , and -CH 2 COCH 3 There is; -(CR a R b ) z C(O)OR c , non-limiting examples include CO 2 H, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , and -CH 2 CO 2 CH 3 There is, -(CR a R b ) z C(O)N(R c )(R d ), non-limiting examples of which include -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2 , -CH 2 CONH 2 , -CH 2 CONHCH 3 , -CH 2 CON(CH 3 ) 2 There is; -(CR a R b ) z SO 2 R c non-limiting examples of which include -SO 2 H, -SO 2 CH 3 , -CH 2 SO 2 H, -CH 2 SO 2 CH 3, -SO 2 C 6 H 5 , and -CH 2 SO 2 C 6 H 5 There is; -(CR a R b ) z SO 3 R c non-limiting examples of which include -SO 3 H, -SO 3 CH 3 , -CH 2 SO 3 H, -CH 2 SO 3 CH 3 , -SO 3 C 6 H 5 , and -CH 2 SO 3 C 6 H 5 There is; There are In the formula, R a and R b Each of the formulas is selected from hydrogen and substituted or unsubstituted C 1 ~C 6 R is independently selected from linear, branched, or cyclic alkyl; c and R d Each of 1 ~C 6 or R is selected from linear, branched, or cyclic alkyl, and aryl; c and R d together form a ring system containing 3 to 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 which the biological activity of the active ingredient is in a form such that it is effective and does not contain additional ingredients that are unacceptably toxic to a subject to which the composition will be administered. In some embodiments, such compositions may be sterile.

[0044] As used herein, the term "pharmaceutically acceptable" in "pharmaceutically acceptable salts" and "pharmaceutically acceptable excipients" refers to those components which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio.

[0045] The phrase "pharmaceutically acceptable excipient" is used herein to refer to a pharma- ceutically acceptable material selected from a solvent, dispersion medium, diluent, dispersion fluid, suspending aid, surfactant, isotonicity agent, thickening or emulsifying agent, preservative, polymer, peptide, protein, cell, hyaluronidase, and mixtures thereof. In some embodiments, the solvent is an aqueous solvent.

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

[0047] The terms "disease" and "disorder" are used interchangeably herein and refer to any alteration in the state of a part of the body or organ that interrupts or interferes with the performance of a function and / or causes symptoms such as discomfort, dysfunction, pain, or even death in the afflicted person or in people who come into contact with the person. A disease or disorder can also be associated with distemper, ailing, ailment, malady, sickness, illness, complaint, indisposition, or affection.

[0048] As used herein, "subject" refers to animal subjects, such as mammalian subjects, and in particular humans.

[0049] As used herein, the term "administering" refers to the placement of a compound, its pharma- ceutically acceptable salt, and / or pharmaceutical composition into a mammalian tissue or subject by a method or route that results in at least partial localization of the compound, salt, and / or composition at a desired site or tissue location.

[0050] As used herein, the term "therapeutically effective amount" refers to the amount of a compound or salt that produces the desired effect for which it is administered (e.g., amelioration of symptoms of a disease or condition mediated by AhR signaling, reducing the severity of such disease or condition or its symptoms, and / or reducing the progression of any one of the above). The exact amount of an effective dosage will depend on the purpose of the treatment and will be ascertainable by one of skill in the art using known techniques (see, for example, Lloyd (1999) The Art, Science and Technology of (See Pharmaceutical Compounding).

[0051] Those skilled in the art will recognize that when the amount of a compound is disclosed, the relevant amount of a pharma- ceutically acceptable salt form of the compound is an amount equivalent to the amount of the free base of the compound. The amount of the compounds and pharma- ceutically acceptable salts disclosed herein is based on the free base form of the relevant compound. For example, "10 mg of at least one entity selected from the compound of formula I or Ia and its pharma- ceutically acceptable salt" refers to an amount of the pharma- ceutically acceptable salt of the compound of formula I or Ia equivalent 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 a compound or composition of the present disclosure can be evaluated by any method known to those skilled in the art, including those described in the examples of the present disclosure. Effectiveness can be established in vitro (biochemical and / or biological in cultured cells) and / or in vivo. In vitro effectiveness can be used to extrapolate or predict some degree of in vivo effectiveness in animals or in human subjects. A standard or standard or comparison can be used. The term "effective" of inhibiting receptor (such as AhR) and / or enzyme-mediated signaling in the context of the present disclosure and claims means reducing / activating the activity of the receptor and / or activation and propagation of signaling pathways by a detectable or measurable amount relative to baseline activity, in terms of activation of downstream molecules or known biological effects. This can be evaluated in vitro or in vivo, and in some cases can be extrapolated by those skilled in the art to the extent that the activity or benefit may be in vivo. In some embodiments, the reduction or activation is measured in terms of a percentage of the reduction or activation relative to activity in the absence of exposure to a compound of the present disclosure, including, for example, at least 5%, at least 10%, 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or about 100%. Activity can also fall within a range, for example, 5-10%, 10-20%, and any other range interval between 1% and 100%. An amount is "effective" in vivo if it produces some benefit to the subject to whom the compound or salt is administered.

[0053] Compounds of formula (I): [ka] and pharma- ceutically acceptable salts thereof are disclosed herein. (In the formula: R 1 and R 2are independently selected from optionally substituted alkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted amine, and optionally substituted heterocycloalkyl; and R 3 are 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 is diethylamine.

[0055] Compounds of formula Ia: [ka] and pharma- ceutically 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 amido, 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, wherein each of 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl is selected from 1 to 5 instances of R A is optionally substituted independently by:

[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, wherein each of 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl is selected from 1-5 instances of R B is optionally substituted independently by:

[0058] In some embodiments, 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 is selected from heteroalkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H, where each C 1 ~C 10 Alkyl, 6-10 membered aryl, 3-10 membered cycloalkyl, C 1 ~C 10Heteroalkyl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocycloalkyl are each independently selected from 1 to 5 instances of R C is optionally substituted independently by:

[0059] In some embodiments, each R′ is hydrogen, C 1 ~C 10 Alkyl, C 1 ~C 10 Haloalkyl, C 1 ~C 10 Hydroxyalkyl and C 1 ~C 10 heteroalkyl.

[0060] In some embodiments, each R A is 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 is independently selected from hydroxyalkyl, and NR″R″.

[0061] In some embodiments, each R B is 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 is independently selected from hydroxyalkyl, and NR″R″.

[0062] In some embodiments, each R C is halo, hydroxy, cyano, C 1 ~C 10 Alkyl, C 1 ~C 10Alkoxy, C 1 ~C 10 and independently selected from haloalkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl.

[0063] In some embodiments, each R″ is hydrogen, C 1 ~C 10 Alkyl, C 1 ~C 10 Haloalkyl, C 1 ~C 10 Hydroxyalkyl and C 1 ~C 10 heteroalkyl.

[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, wherein each of 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl is selected from 1-5 instances of R A and 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, wherein each of the 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocycloalkyl is selected from 1 to 5 instances of R B and 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 is selected from heteroalkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H, where each C 1 ~C 10 Alkyl, 6-10 membered aryl, 3-10 membered cycloalkyl, C 1 ~C10 Heteroalkyl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocycloalkyl are each independently selected from 1 to 5 instances of R C 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 heteroalkyl; Each R A is 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 is independently selected from hydroxyalkyl, and NR"R"; Each R B is 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 is independently selected from hydroxyalkyl, and NR"R"; Each R C is halo, hydroxy, cyano, C 1 ~C 10 Alkyl, C 1 ~C 10 Alkoxy, C 1 ~C 10 independently selected from haloalkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; and Each R'' is hydrogen, C 1 ~C10 Alkyl, C 1 ~C 10 Haloalkyl, C 1 ~C 10 Hydroxyalkyl and C 1 ~C 10 heteroalkyl.

[0065] In some embodiments, ring A is selected from 1 to 5 instances of R A In some embodiments, ring A is selected from 1 to 5 instances of R A In some embodiments, ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, optionally substituted with 1 to 5 instances of R A In some embodiments, ring A is selected from 6-8 membered aryl optionally substituted with 1-3 instances of R A In some embodiments, ring A is phenyl optionally substituted with 1 to 5 instances of R A and wherein the aryl is 5 to 8 membered heteroaryl optionally substituted by

[0066] In some embodiments, Ring A is selected from pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazoyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl, wherein each of pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl is selected from 1 to 3 instances of R A is optionally substituted independently by:

[0067] In some embodiments, ring A is selected from 1 to 3 instances of R AIn some embodiments, ring A is pyridinyl optionally substituted with 1 to 5 instances of R A In some embodiments, Ring A is selected from pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydropyranyl, and tetrahydrofuranyl, wherein each of pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydropyranyl, and tetrahydrofuranyl is selected from 1 to 3 instances of R A In some embodiments, ring A is optionally substituted independently with 1 to 3 instances of R A or morpholino, optionally substituted by

[0068] In some embodiments, each R A Halo, C 1 ~C 10 Alkyl, C 1 ~C 10 Haloalkyl, C 1 ~C 10 Alkoxy, C 1 ~C 10 In some embodiments, each R B Halo, C 1 ~C 10 Alkyl, and C 1 ~C 10 In some embodiments, each R C is halo, hydroxy, cyano, C 1 ~C 10 Alkyl, C 1 ~C 10 In some embodiments, each R″ is independently selected from hydrogen and C 1 ~C 10 alkyl.

[0069] In some embodiments, each RA Halo, C 1 ~C 10 Alkyl, C 1 ~C 10 Haloalkyl, C 1 ~C 10 Alkoxy, C 1 ~C 10 independently selected from haloalkoxy, and NR"R"; Each R B Halo, C 1 ~C 10 Alkyl, and C 1 ~C 10 haloalkyl; Each R C is halo, hydroxy, cyano, C 1 ~C 10 Alkyl, C 1 ~C 10 independently selected from alkoxy, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocycloalkyl, and 6- to 8-membered aryl; and Each R″ is hydrogen and C 1 ~C 10 alkyl.

[0070] In some embodiments, ring B is selected from 1 to 5 instances of R B In some embodiments, ring B is selected from 6-8 membered aryl optionally substituted with 1-3 instances of R B In some embodiments, ring B is phenyl optionally substituted with 1 to 5 instances of R BIn some embodiments, Ring B is selected from pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyridinonyl, and pyrimidinyl, wherein each of pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl is selected from 1 to 3 instances of R B In some embodiments, Ring B is selected from pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl, wherein each of pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl is independently selected from 1 to 3 instances of R B is optionally substituted independently by:

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

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

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

[0074] In some embodiments, Ring B is [ka] is selected from.

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

[0076] In some embodiments, Ring B is [ka] is selected from.

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

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

[0079] Compounds of formula Ib: [ka] and pharma- ceutically acceptable salts thereof are also disclosed herein. (In the formula: Ring A is selected from optionally substituted heteroaryl and optionally substituted heterocycloalkyl; Ring B is selected from optionally substituted heteroaryl and optionally substituted heterocycloalkyl; and R is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amido, 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, the 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, the present disclosure relates to one or more compounds selected from the following compounds and pharma- ceutically acceptable salts thereof: (i) (S)-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (ii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(6-oxo-1,6-dihydropyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (iii) (S)-8-(benzo[d][1,3]dioxol-4-yl)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (iv) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (v) (S)-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (vi) (S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (vii) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (viii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (ix) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (x) 6,8-di(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xi) (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xiii) 6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xiv) 8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xv) 6-(4-chlorophenyl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xvi) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xvii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xviii) 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xix) 3-(2-hydroxy-2-methylpropyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xx) (S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxi) 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxiii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxiv) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxv) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxvi) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-phenylpyrido[3,4-d]pyrimidin-4(3H)-one; (xxvii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxviii) 3-methyl-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxix) Rac-6-(4-chlorophenyl)-3-((trans)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxx) (S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxi) (R)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxii) rac-6-(4-chlorophenyl)-3-((cis)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxiii) (R)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxiv) (S)-3-(3-hydroxy-3-methylbutan-2-yl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxv) (S)-6,8-bis(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxvi) (S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxvii) (S)-8-(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxviii) 6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(2-hydroxy-2-methylpropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxix) (R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xl) (S)-3-(1-(benzyloxy)propan-2-yl)-8-(3-fluorophenyl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xli) (R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlii) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xliii) (S)-3-(1-hydroxypropan-2-yl)-6-morpholino-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xliv) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlv) (S)-3-(1-methoxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlvi) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlvii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlviii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlix) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (l) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethoxy)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (li) (S)-3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lii) Methyl (S)-5-(3-(1-hydroxypropan-2-yl)-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)picolinate (liii) (S)-3-(1-hydroxypropan-2-yl)-6-(isothiazol-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (liv) 3-(2-hydroxy-2-methylpropyl)-8-(isothiazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lv) (S)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lvi) (S)-3-(1-hydroxypropan-2-yl)-6,8-di(isothiazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lvii) (S)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lviii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lix) 3-(2-hydroxy-2-methylpropyl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lx) 3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxi) 6-(4-chloro-2-methylphenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxii) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxiii) (S)-3-(1-hydroxypropan-2-yl)-8-(2-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxiv) (S)-3-(1-hydroxypropan-2-yl)-8-(4-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxv) (S)-3-(1-hydroxypropan-2-yl)-6-(4-methylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxvi) (S)-6-(2-cyclopropylthiazol-5-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxvii) (S)-3-(1-hydroxypropan-2-yl)-6-(2-isopropylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxviii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxix) (S)-3-(1-hydroxypropan-2-yl)-6,8-bis(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxx) 6-(4-chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxi) 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxii) 3-(2-hydroxyethyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxiii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxiv) (S)-6-(6-cyclopropylpyridin-3-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxv) (S)-3-(1-hydroxypropan-2-yl)-6-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxvi) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxvii) (S)-6-(cyclohex-1-en-1-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxviii) (S)-6,8-bis(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxix) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxx) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxi) 6-(6-cyclopropylpyridin-3-yl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxii) 6-(6-cyclopropylpyridin-3-yl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxiii) (S)-6-(6-cyclopropylpyridin-3-yl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxiv) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxv) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxvi) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxvii) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxviii) 3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxix) (S)-3-(1-hydroxypropan-2-yl)-6-(2-methylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xc) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xci) (S)-3-(1-hydroxypropan-2-yl)-6-(piperidin-1-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcii) 3-(2-hydroxy-2-methylpropyl)-8-(isothiazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xciii) (S)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xciv) 3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcv) (S)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcvi) (3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcvii) 3-(1,1-dioxidetetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcviii) (R)-3-(1,1-dioxidetetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcix) (R)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (c) (S)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (ci) (R)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cii) (S)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (ciii) (R)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (civ) (R)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cv) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cvi) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cvii) 6-(4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cviii) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cix) (S)-6-(6-cyclopropylpyridin-3-yl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cx) (R)-6-(6-cyclopropylpyridin-3-yl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxi) (R)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxii) (R)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxiii) (S)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxiv) 6-(4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxv) 3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxvi) Methyl (S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoate (cxvii) 6-(4-chlorophenyl)-3-(4-hydroxy-1-methylpyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxviii) 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxix) (R)-6-(6-cyclopropylpyridin-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxx) (S)-6-(6-cyclopropylpyridin-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxi) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxii) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxiii) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxiv) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxv) (R)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxvi) (S)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxvii) (S)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxviii) (R)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxix) 3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxx) (S)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxi) (S)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxiii) 3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxiv) 6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxv) 6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxvi) (R)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxvii) (S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoic acid (cxxxviii) (S)-N-Methyl-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanamide (cxxxix) (S)-N,N-Dimethyl-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propenamide (cxl) 3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxli) 3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlii) 3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxliii) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxliv) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlv) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-1,2,4-triazol-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlvi) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlvii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlviii) (S)-8-(diethylamino)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlix) (S)-3-(1-hydroxypropan-2-yl)-8-(piperidin-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cl) (S)-3-(1-hydroxypropan-2-yl)-8-(pyrrolidin-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cli)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(piperidin-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (S)-6-Cyclohexyl-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (S)-3-(1-hydroxypropan-2-yl)-6-(pyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clv) (S)-3-(1-hydroxypropan-2-yl)-6-(2-methylthiazol-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clvi) (S)-3-(1-hydroxypropan-2-yl)-6-(1-methyl-1H-1,2,3-triazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clvii) (R)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (clviii) (S)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clx) 6-(4-chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxi) (S)-3-(1-hydroxypropan-2-yl)-6-(2-methylpyrimidin-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxii) 3-(2-hydroxy-2-methylpropyl)-8-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxiii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxiv) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxv) (S)-5-(3-(1-hydroxypropan-2-yl)-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)picolinic acid (clxvi) (S)-3-(1-hydroxypropan-2-yl)-6-(6-methylpyridin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxvii) 3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxviii) 3,8-di(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxix) 8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxx) 3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxi) 3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxii) 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxiii) 3-Cyclopentyl-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxiv) 3-phenyl-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxv) 3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxvi) 3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxvii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxviii) (S)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanamide (clxxix) 3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxx) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxi) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxii) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxiii) 3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxiv) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxv) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxvi) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxvii) (S)-3-(1-hydroxypropan-2-yl)-8-morpholino-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxviii) 3-(2-hydroxy-2-methylpropyl)-8-(piperidin-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxix) (S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxc) (S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyrimidin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxci) (S)-8-(cyclohex-1-en-1-yl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxcii) (S)-8-Cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxciii) (S)-3-(1-hydroxypropan-2-yl)-N,N-dimethyl-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidine-6-carboxamide (cxciv) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxcv) (S)-3-(1-hydroxypropan-2-yl)-6-(2-methoxyethyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxcvi) (S)-3-(1-hydroxypropan-2-yl)-8-(2-methoxyethyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one.

[0109] The compounds of formula I or formula Ia and their pharmaceutically acceptable salts can be incorporated into pharmaceutical compositions. In some embodiments, the present disclosure relates to pharmaceutical compositions comprising at least one entity selected from the compounds of formula I or formula Ia and their pharmaceutically acceptable salts. In some embodiments, the present disclosure relates to pharmaceutical compositions consisting essentially of at least one entity selected from the compounds of formula I or formula Ia and their pharmaceutically acceptable salts.

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

[0111] In some embodiments, the at least one additional therapy is selected from an anti-CTLA-4 compound, an anti-PD-1 compound, and an anti-PDL-1 compound. In some embodiments, the at least one additional therapy is selected from pembrolizumab (Keytruda); nivolumab (Opdivo); ipilimumab (Yervoy); avelumab (Bavencio); atezolizumab (Tecentriq); durvalumab (Imfinzi); cemiplimab (LBTAYO); sintilimab (Tyvyt); toripalimab (Tuoyi); camrelizumab (AiRuiKa); spartalizumab; and tislelizumab. In some embodiments, the at least one additional therapy is selected from an anti-LAG-3 (lymphocyte activation gene-3) compound; an anti-TIM-3 (T cell immunoglobulin and mucin domain containing-3) compound; an anti-TIGIT (T cell immunoglobulin and ITIM domain) compound; an anti-VISTA (V domain Ig suppressor of T cell activation) compound; or a combination thereof. Non-limiting examples of anti-LAG-3 compounds include IMP321 (eftiragimoda alpha), leratolimab (BMS-986016), LAG525, MK-4280, REGN3767, TSR-033, BI754111, Sym022, FS118, and MGD013. Non-limiting examples of anti-TIM-3 compounds include TSR-022, MBG453, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, RO7121661. Non-limiting examples of anti-TIGIT compounds include MK-7684, etigilimab (OMP-313), tiragolumab (MTIG7192A, RG-6058), BMS-986207, AB-154, and ASP-8374. Non-limiting examples of anti-VISTA compounds include JNJ-61610588 and CA-170.

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

[0113] The compound of the present disclosure, a pharma- ceutically acceptable salt thereof, and / or at least one entity selected from the compounds of formula I or formula Ia and pharma- ceutically acceptable salts thereof, optionally comprising at least one The pharmaceutical composition further comprising at least one additional therapy can be used for therapeutic treatment.

[0114] The compounds, pharma- ceutically acceptable salts, additional therapies, and / or pharmaceutical compositions can be administered to a mammalian subject, including a human, in a unit of administration form. Suitable, non-limiting examples of unit of administration forms include those administered orally and those administered by parenteral / systemic routes, non-limiting examples of which include inhalation, subcutaneous administration, intramuscular administration, intravenous administration, intradermal administration, and intravitreal 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 present disclosure and / or pharma- ceutically acceptable salts of the compounds of the present 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 (non-limiting examples) lubricants, colorants, coatings, or varnishes. In some embodiments, such pharmaceutical compositions may further include at least one additional therapy.

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

[0117] In some embodiments, disclosed herein is a method for inhibiting AhR, comprising administering to a subject in need thereof at least one entity selected from a compound of formula I or formula Ia and its pharmaceutically acceptable salts. In some embodiments, disclosed herein is a method for decreasing the activity of AhR, comprising administering to a subject in need thereof at least one entity selected from a compound of formula I or formula Ia and its pharmaceutically acceptable salts. In some embodiments, such pharmaceutical compositions may further comprise at least one additional therapy.

[0118] In some embodiments, disclosed herein is a method of treating cancer, comprising administering to a subject in need thereof at least one entity selected from a compound of Formula I or Formula Ia and its pharma- ceutically acceptable salts. In some embodiments, the cancer is selected from liquid tumors and solid tumors. In some embodiments, the cancer is selected from breast cancer, cancer of the respiratory tract, brain cancer, cancer of the reproductive organs, cancer of the digestive tract, cancer of the urinary tract, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and metastases of any of the above. In some embodiments, the cancer is selected from breast cancer, pancreatic cancer, prostate cancer, and colon cancer. In some embodiments, the cancer is selected from lymphoma, sarcoma, and leukemia.

[0119] In some embodiments, disclosed herein is a method of treating cancer comprising administering to a subject in need thereof at least one entity selected from the compounds of Formula I or Formula Ia and pharma- ceutically acceptable salts thereof, and at least one additional therapy. In some embodiments, the cancer is selected from the group consisting of non-small cell lung cancer (NSCLC); small cell lung cancer; head and neck squamous cell carcinoma; renal cell carcinoma; gastric adenocarcinoma; nasopharyngeal neoplasms; urothelial carcinoma; colorectal cancer; pleural mesothelioma; triple-negative breast cancer (TNBC); esophageal neoplasms; multiple myeloma; gastric and esophagogastric junction cancer; melanoma; Hodgkin's lymphoma; hepatocellular carcinoma; lung cancer; head and neck cancer; non-Hodgkin's lymphoma; metastatic clear cell renal carcinoma; squamous cell lung carcinoma; mesothelioma; gastric cancer; esophagogastric junction cancer; metastatic melanoma; metastatic non-cutaneous melanoma; urothelial carcinoma; diffuse large B-cell lymphoma; renal cell carcinoma; ovarian cancer, fallopian tube cancer; peritoneal neoplasms; extensive small cell lung cancer; bladder cancer; transitional cell carcinoma; prostate neoplasms; recurrent or metastatic PD-L1. Selected from positive or negative squamous cell carcinoma of the head and neck (SCCHN); recurrent squamous cell lung cancer; advanced solid malignancies; SCCHN; hypopharyngeal squamous cell carcinoma; laryngeal squamous cell carcinoma; unresectable or metastatic melanoma; biliary tract neoplasms; esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, glioblastoma, metastatic cancer, prostate cancer, parenchymal cancer; gastric cancer; colon cancer; and liver cancer.

[0120] In some embodiments, disclosed herein is a method of treating an ocular disease, comprising administering to a subject in need thereof at least one entity selected from the compounds of Formula I or Formula Ia and pharma- ceutically acceptable salts thereof, and optionally at least one additional therapy.

[0121] For the methods disclosed herein, the mode (or modes), dose (or doses), and dosage form (or dosage forms) of administration can be determined according to criteria commonly considered during the establishment of treatment of a patient, such as, by way of non-limiting example, the potency of the compound and / or a pharma- ceutically acceptable salt 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 the treatment, and secondary effects observed during treatment. Determination of an effective dosage to provide a therapeutic effect for a particular mode and frequency of administration is within the capabilities of one of ordinary skill in the art.

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

[0123] In some embodiments, the compound of the present disclosure and / or its pharma- ceutically acceptable salt is present in the pharmaceutical composition in an amount ranging from 1 mg to 5,000 mg. In some embodiments, the compound of the present disclosure and / or its pharma- ceutically acceptable salt is present in the pharmaceutical composition in an amount ranging from 1 mg to 3,000 mg. In some embodiments, the compound of the present disclosure and / or its pharma- ceutically acceptable salt is present in the pharmaceutical composition in an amount ranging from 1 mg to 2,000 mg. In some embodiments, the compound of the present disclosure and / or its pharma- ceutically acceptable salt is present in the pharmaceutical composition in an amount ranging from 1 mg to 1,000 mg. In some embodiments, the compound of the present disclosure and / or its pharma- ceutically acceptable salt is present in the pharmaceutical composition in an amount ranging from 1 mg to 500 mg. In some embodiments, the compound of the present disclosure and / or its pharma- ceutically acceptable salt is present in the pharmaceutical composition in an amount ranging from 1 mg to 250 mg. In some embodiments, the compound of the present disclosure and / or its pharma- ceutically acceptable salt is present in the pharmaceutical composition in an amount ranging from 1 mg to 100 mg.In some embodiments, the compound of the present disclosure and / or its pharma- ceutically acceptable salt is present in the pharmaceutical composition in an amount ranging from 1 mg to 50 mg.

[0124] In some embodiments, the compounds of the present disclosure and / or pharma- ceutically acceptable salts thereof are present in the pharmaceutical composition at 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 1,000 mg, 1,100 mg, 1,200 mg, 1,300 mg, 1,400 mg, 1,500 mg, 1,600 mg, 1,700 mg, 1,800 mg, 1,900 mg, 2,100 mg, 2,200 mg, 2,300 mg, 2,400 mg, 2,500 mg, 3,600 mg, 3,700 mg, 3,800 mg, 4,100 mg, 4,200 mg, 4,300 mg, 5,400 mg, 5,500 mg, 6,100 mg, 7,200 mg, 8,300 mg, 9,400 mg, 1,100 mg, 1,200 mg, 1,300 mg, 1,400 mg, 1,500 mg, 1,600 mg, 1,700 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 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 amounts and doses can be estimated initially from in vitro assays. For example, initial doses for use in animals may be determined based on the IC 50 The dosage form may be formulated to achieve a circulating or serum concentration of the active compound that is equal to or greater than 100 mg / kg. It is well within the ability of one of ordinary skill in the art to calculate the dose that will achieve such a circulating or serum concentration, taking into account the bioavailability of a particular compound. For guidance, the reader is referred 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 references cited therein, the methods of which are incorporated herein by reference in their entirety. 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 various diseases described in this disclosure are well known in the art.

[0126] In some embodiments, the dosage administered 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, among other factors, the activity of the compound, its bioavailability, the mode of administration, and the various factors discussed above. The dosage amount and interval can be individually adjusted to provide a plasma level of the compound that is sufficient to maintain a therapeutic or prophylactic effect. For example, the compound can be administered once a week, several times a week (e.g., every other day), once a day, or multiple times a day, depending, among other things, on the mode of administration, the specific indication being treated, and the judgment of the prescribing physician. In cases of local administration or selective uptake, such as topical administration, 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 undue experimentation.

[0127] Non-limiting embodiments of the present disclosure include: 1. Compound of Formula I: [ka] and pharma- ceutically acceptable salts thereof. (In the formula: R 1 and R 2are independently selected from optionally substituted alkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted amine, and optionally substituted heterocycloalkyl; and R 3 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, optionally substituted amine, cyano, halo, hydroxy, and -C(O)H.

[0128] 2. Compound of formula Ia [ka] or a pharma- ceutically 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 amido, 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 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered cycloalkyl, and optionally substituted 3-10 membered heterocycloalkyl; Ring B is selected from optionally substituted 6- to 10-membered aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 3- to 10-membered cycloalkyl, and optionally substituted 3- to 10-membered heterocycloalkyl; R is hydrogen, optionally substituted C 1 ~C 10 Alkyl, optionally substituted 6-10 membered aryl, -C(O)R', -C(O)NR'R', optionally substituted 3-10 membered cycloalkyl, -C(O)OR', optionally substituted C 1 ~C 10 selected from heteroalkyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H; and Each R' is hydrogen, optionally substituted C 1 ~C 10 Alkyl and optionally substituted C 1 ~C 10 The compound of embodiment 2, or a pharma- ceutically acceptable salt thereof, wherein:

[0130] 4. Ring A is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl, wherein each of the 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl is selected from 1-5 instances of R A and Ring B is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl, wherein each of the 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl is selected from 1-5 instances of R Band 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 is selected from heteroalkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H, where each C 1 ~C 10 Alkyl, 6-10 membered aryl, 3-10 membered cycloalkyl, C 1 ~C 10 Heteroalkyl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocycloalkyl are each independently selected from 1 to 5 instances of R C 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 heteroalkyl; Each R A But 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 is independently selected from hydroxyalkyl, and NR"R"; Each R B But 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 is independently selected from hydroxyalkyl, and NR"R"; Each R C But halo, hydroxy, cyano, C 1 ~C 10 Alkyl, C 1 ~C 10 Alkoxy, C 1 ~C 10 independently selected from haloalkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 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 The compound of embodiment 2 or 3, or a pharma- ceutically acceptable salt thereof, independently selected from heteroalkyl.

[0131] 5. Ring A is R in 1 to 5 cases A or a pharma- ceutically acceptable salt thereof.

[0132] 6. Ring A is R in 1 to 5 cases A or a pharma- ceutically acceptable salt thereof. The compound of embodiment 4 or 5, wherein R is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, optionally substituted by:

[0133] 7. Ring A is R in 1 to 5 cases A or a pharma- ceutically acceptable salt thereof.

[0134] 8. Ring A is R in 1 to 3 cases. A or a pharma- ceutically acceptable salt thereof.

[0135] 9. Ring A is R in 1 to 5 cases A or a pharma- ceutically acceptable salt thereof.

[0136] 10. Ring A is selected from pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl; wherein each of pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl is 1 to 3 times R A or a pharma- ceutically acceptable salt thereof.

[0137] 11. Ring A is R in 1 to 3 cases. A or a pharma- ceutically acceptable salt thereof. The compound of any one of embodiments 4, 9, or 10, wherein R is 0 or 1;

[0138] 12. Ring A is R in 1 to 5 cases. A or a pharma- ceutically acceptable salt thereof.

[0139] 13. Ring A is selected from pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydropyranyl, and tetrahydrofuranyl; wherein pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydropyranyl, and tetrahydrofuranyl each represent one to three instances of R Aor a pharma- ceutically acceptable salt thereof.

[0140] 14. Ring A is R in 1 to 3 cases. A or morpholino optionally substituted with: Figure imgf000023_0001 or a pharma- ceutically acceptable salt thereof.

[0141] 15. Ring B is R in 1 to 5 cases. B or a pharma- ceutically acceptable salt thereof.

[0142] 16. Ring B is R in 1-3 cases B or a pharma- ceutically acceptable salt thereof.

[0143] 17. Ring B is R in 1 to 5 cases. B or a pharma- ceutically acceptable salt thereof.

[0144] 18. Ring B is selected from benzodioxolyl, pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyridinonyl, and pyrimidinyl; wherein each of benzodioxolyl, pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl is selected from 1 to 3 instances of R B or a pharma- ceutically acceptable salt thereof.

[0145] 19. Ring B is selected from pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl; wherein each of pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl is selected from 1 to 3 instances of R B or a pharma- ceutically acceptable salt thereof.

[0146] 20.Each R A But, Halo, C 1 ~C 10 Alkyl, C 1 ~C 10 Haloalkyl, C 1 ~C 10 Alkoxy, C 1 ~C 10 independently selected from haloalkoxy, and NR"R"; Each R B But, Halo, C 1 ~C 10 Alkyl, and C 1 ~C 10 haloalkyl; Each R C But halo, hydroxy, cyano, C 1 ~C 10 Alkyl, C 1 ~C 10 independently selected from alkoxy, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocycloalkyl, and 6- to 8-membered aryl; and Each R″ is hydrogen and C 1 ~C 10 20. The compound of any one of embodiments 4-19, or a pharma- ceutically acceptable salt thereof, wherein:

[0147] 21. Ring A is [ka] or a pharma- ceutically acceptable salt thereof.

[0148] 22. Ring A is [ka] or a pharma- ceutically acceptable salt thereof.

[0149] 23. Ring A is [ka] or a pharma- ceutically acceptable salt thereof.

[0150] 24. Ring B is [ka] or a pharma- ceutically acceptable salt thereof.

[0151] 25. Ring B is [ka] 21. The compound of any one of embodiments 2-14 and 20, selected from: or a pharma- ceutically acceptable salt thereof.

[0152] 26. Ring B is [ka] or a pharma- ceutically acceptable salt thereof.

[0153] 27. R is methyl; [ka] or a pharma- ceutically acceptable salt thereof.

[0154] 28. R is methyl; [ka] or a pharma- ceutically acceptable salt thereof.

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

[0156] 30. A pharmaceutical composition comprising at least one entity selected from the compound of any one of embodiments 1 to 29 and its pharma- ceutically acceptable salts, and at least one pharma- ceutically acceptable excipient.

[0157] 31. A method for treating a disease or condition mediated by AhR signaling in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of at least one entity selected from the compounds of any one of embodiments 1 to 29 and their pharma- ceutically acceptable salts 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 in need of such treatment, comprising administering to the subject a therapeutically effective amount of at least one entity selected from the compounds of any one of embodiments 1 to 29 and pharma- ceutically acceptable salts 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. The method of any one of embodiments 31-34, wherein the disease is selected from breast cancer, cancer of the respiratory tract, brain cancer, cancer of the reproductive organs, cancer of the digestive tract, cancer of the urinary tract, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and metastases of any of the above.

[0162] 36. The method of any one of embodiments 31-35, wherein the disease is selected from breast cancer, pancreatic cancer, prostate cancer, and colon cancer.

[0163] 37. The method of any one of embodiments 31-34, wherein the disease is selected from lymphoma, sarcoma, melanoma, glioblastoma, and leukemia.

[0164] 38. A method for inhibiting cancer cell proliferation mediated by AhR signaling in a subject in need of inhibition of cancer cell proliferation mediated by AhR signaling, comprising administering to the subject a therapeutically effective amount of at least one entity selected from the compounds of any one of embodiments 1 to 29 and pharma- ceutically acceptable salts thereof or at least one pharmaceutical composition of embodiment 30.

[0165] 39. A method for inhibiting tumor cell invasion or metastasis mediated by AhR signaling in a subject in need of inhibition of tumor cell invasion or metastasis mediated by AhR signaling, comprising administering to the subject a therapeutically effective amount of at least one entity selected from the compounds of any one of embodiments 1 to 29 and pharma- ceutically acceptable salts thereof or at least one pharmaceutical composition of embodiment 30.

[0166] 40. A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of i) at least one entity selected from the compounds of any one of embodiments 1-29 and pharma- ceutically acceptable salts thereof, or at least one pharmaceutical composition of embodiment 30, and ii) a therapeutically effective amount of at least one additional therapy.

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

[0168] 42. The method of embodiment 40, wherein administration of at least one entity selected from the compounds of any one of embodiments 1 to 29 and pharma- ceutically acceptable salts thereof or at least one pharmaceutical composition of embodiment 30 is initiated prior to administration of at least one additional therapy.

[0169] 43. The method of embodiment 40, wherein at least one entity selected from the compounds of any one of embodiments 1 to 29 and pharma- ceutically acceptable salts thereof or at least one pharmaceutical composition of embodiment 30 is administered after administration of at least one additional therapy.

[0170] 44. The method of embodiment 40, wherein at least one entity selected from the compounds of any one of embodiments 1 to 29 and pharma- ceutically acceptable salts thereof or at least one pharmaceutical composition of embodiment 30 is administered simultaneously with the administration of at least one additional therapy.

[0171] 45. The method of any one of embodiments 40-44, wherein at least one additional therapy is selected from a checkpoint inhibitor.

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

[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 a cytotoxic T-lymphocyte-associated antigen 4 pathway inhibitor.

[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 a programmed death-1 pathway inhibitor.

[0179] 53. The method of embodiment 52, wherein the programmed death-1 pathway inhibitor is selected from anti-PD-1 antibodies.

[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 cemiplimab.

[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 sintilimab.

[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 tislelizumab.

[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 the programmed death-1 pathway inhibitor is selected from anti-PD-L1 antibodies.

[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-activation gene-3 (LAG-3) inhibitors.

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

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

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

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

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

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

[0201] 75. The method of embodiment 74, wherein the VISTA inhibitor is selected from an anti-VISTA antibody.

[0202] 76. Cancer includes: 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 esophagogastric junction cancer; melanoma; Hodgkin lymphoma; hepatocellular carcinoma; lung cancer; head and neck cancer; non-Hodgkin lymphoma; metastatic clear cell renal carcinoma; squamous cell lung carcinoma; mesothelioma; gastric cancer; esophagogastric junction cancer; metastatic melanoma; metastatic noncutaneous melanoma; urothelial carcinoma; diffuse large B-cell lymphoma ;renal cell carcinoma;ovarian cancer, fallopian tube cancer;peritoneal neoplasms;extensive small cell lung cancer;bladder cancer;transitional cell carcinoma;prostate neoplasms;recurrent or metastatic PD-L1 positive or negative squamous cell carcinoma of the head and neck (SCCHN);recurrent squamous cell lung cancer;advanced solid malignancies;SCCHN;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. EXAMPLES

[0203] The following non-limiting examples and data illustrate various aspects and features associated with the compounds and / or methods of the present disclosure, including the preparation of various compounds that can be utilized by the synthetic methods described herein. In some embodiments, the compounds and / or methods provide results and data that are surprising, unexpected, and in contrast to the prior art. Although the utility of the present disclosure is illustrated by the use of several compounds and moieties / groups that can be used therewith, it will be understood by those skilled in the art that equivalent results can be obtained with a variety of other compounds, moieties, and / or groups that are within the scope of the present disclosure.

[0204] Example 1. Synthesis of pyridopyrimidinone compounds Compounds encompassed within this disclosure can be prepared by the procedures outlined in Scheme I and described in the Examples below. [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 equiv.) in THF (300 mL), NaH (2.51 g, 62.78 mmol, 60% purity, 1.1 equiv.) was added at 0° C., and the mixture was stirred at 0° C. for 30 min. BnBr (11.71 g, 68.48 mmol, 8.13 mL, 1.2 equiv.) and tetrabutylammonium iodide (210.80 mg, 570.69 umol, 0.01 equiv.) were added to the mixture at 0° C., and the mixture was then stirred at 25° C. for 3 h. The reaction mixture was quenched by the addition of MeOH (50 mL) at 0° C., then filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give the title compound (12 g, 45.22 mmol, 79% yield). 1H NMR (400 MHz, CDCl3), δ ppm 1.20 (d, J = 6.8 Hz, 3H), 1.45 (s, 9H), 3.35-3.48 (m, 2H), 3.80-3.94 (m, 1H), 4.48 (q, J = 12.0, 17.6 Hz, 2H), 4.67-4.80 (m, 1H), 7.27-7.38 (m, 5H).

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

[0207] Preparation of (S)-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (1) 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 (reactant 1, 0.80 g, 10.63 mmol) was dissolved in DMF (32.2 mL) and the reaction mixture was cooled to 0° C. Diisopropylethylamine (3.37 mL, 19.3 mmol) and HATU (4.41 g, 11.59 mmol) were added and the reaction was stirred at 0° C. for 1 h. The reaction was quenched with water and partitioned between ethyl acetate and water. The organic phase was separated, washed with saturated aqueous ammonium chloride, then saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using ethyl acetate / hexane to give the title compound (1.82 g, 6.89 mmol, 71% yield). 1 H NMR(CH 3 OH-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 that were prepared by procedures similar to those 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 equiv) was added in one portion to a solution of 3-amino-2,6-dichloroisonicotinic acid (Reagent 1, 20 g, 96.6 mmol, 1 equiv), (3S,4R)-4-aminotetrahydrofuran-3-ol (10.5 g, 101 mmol, 1.05 equiv), and triethylamine (29.3 g, 290 mmol, 40.3 mL, 3 equiv) in EtOAc (150 mL). The resulting solution was stirred at 25° C. for 1 h. The reaction was poured into water (100 mL). The organic phase was collected and the aqueous phase was extracted with EtOAc (30 mL×2). The combined organic phase was washed with brine (100 mL) and concentrated in vacuo to give the title compound 3-amino-2,6-dichloro-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)isonicotinamide (A16, 25 g, 85.6 mmol, 88.6% yield) as an off-white solid. The crude product was used in the next step without purification. 1 H-NMR (400MHz, CD 3 O.D.):δ H ppm 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]pyrimidin-4(3H)-one (Intermediate B1): [ka] To (S)-3-amino-2,6-dichloro-N-(1-hydroxypropan-2-yl)isonicotinamide (A1, 2.54 g, 9.66 mmol) in a flask was added triethyl orthoformate (20 mL). Concentrated hydrochloric acid (0.8 mL, 9.7 mmol) was slowly added dropwise at room temperature and the resulting mixture was stirred for 2 h. The mixture was concentrated and the solid was collected by vacuum filtration, washed with water and dried under high vacuum to give the title compound (B1, 1.82 g, 6.64 mmol, 69% yield). 1H NMR(CH3OH-d4,400MHz)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-dichloro-pyrido[3,4-d]pyrimidin-4-one (Intermediate B11) [ka] Formic acid (18.94 g, 411.41 mmol, 15.52 mL, 1.5 equiv.) was added dropwise to acetyl acetate (28 g, 274.27 mmol, 25.69 mL, 1 equiv.) at 0 °C and heated at 60 °C for 2 h under N 2Stirred under atmospheric pressure. A solution was obtained as a colorless liquid (41 mL, 6.65 M) and used in the next step without further purification. To a solution of 3-amino-N-[(1S)-2-benzyloxy-1-methyl-ethyl]-2,6-dichloro-pyridine-4-carboxamide (A11, 4.5 g, 12.70 mmol, 1 equiv.) in THF (50 mL), formyl acetate solution (6.65 M, 41 mL, 21.47 equiv.) was added at 25° C. and stirred at 60° C. for 30 min. Then the mixture was stirred at 100° C. for 9.5 h. LCMS showed that the desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with EtOAc (50 mL) and washed with saturated NaHCO 3 (200 mL), water (50 mL), and brine (50 mL) were successively washed with Na 2 SO 4 The mixture was dried at 40° C., filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 1 / 1) to give the title compound (B11, 2.4 g, 6.59 mmol, yield 51.88%). 1 H NMR (400 MHz, CDCl 3 )δ ppm MS:M+H + ,364.0.

[0216] Table 3 lists intermediates that were prepared by procedures similar to those 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]pyrimidin-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 degassed and purged with nitrogen three times. The mixture was stirred at 120° C. for 8 hours under nitrogen atmosphere. TLC showed starting reactant remained and two new spots formed. The solvent was evaporated and the residue was taken up in ethyl acetate (20 mL), washed three times with brine (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by preparative HPLC to give the title compound (S)-6,8-dichloro-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (600 mg, 1.99 mmol, 48% yield). 1 H-NMR (400MHz, DMSO-d 6 ):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-fluoropyridin-3-yl)-3-(1-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate C1): [ka] A mixture of (S)-6,8-dichloro-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (B1, 0.10 g, 0.37 mmol), (5-fluoropyridin-3-yl)boronic acid (reactant 2, 0.057 g, 0.401 mmol), sodium carbonate (0.16 g, 1.46 mmol), and tetrakis(triphenylphosphine)palladium (0.042 g, 0.036 mmol) in a sealed tube was purged with argon. Toluene (3.0 mL) and ethanol (1.5 mL) were added, and the resulting mixture was stirred at 75° C. for 15 hours. The mixture was cooled to room temperature, filtered through Celite, 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 gave the title 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 that were prepared by procedures similar to those 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-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (1): [ka] A mixture of (S)-6-chloro-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (C1, 0.023 g, 0.069 mmol), (4-(trifluoromethoxy)phenyl)boronic acid (reactant 3, 0.016 g, 0.076 mmol), sodium carbonate (0.029 g, 0.275 mmol), and tetrakis(triphenylphosphine)palladium (0.008 g, 0.007 mmol) 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 gave the title compound (0.022 g, 0.047 mmol, 68% yield). 1 H NMR (DMSO-d 6,400MHz):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 that were prepared by procedures similar to those described for 1, substituting the indicated groups for reactants 1, 2, and 3.

[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-methylpiperidin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] N 2 To a solution of (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (60 mg, 0.135 mmol) in EtOH (1 mL), PtO 2 (15 mg, 0.088 mmol) was added. The flask was evacuated and the H 2 After overnight, the reaction mixture was filtered through Celite®, washed thoroughly with methanol, concentrated, and purified with H 2Purification by reverse-phase chromatography eluting with 0.1% formic acid in O and acetonitrile gave the desired product as a diastereomeric mixture (4 mg, 7%). 1 H NMR(CH 3 OH-d 4 ,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-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (43) [ka] To (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (11, 0.060 g, 0.19 mmol), potassium carbonate (0.011 g, 0.76 mmol) in a sealed tube was added dimethylformamide (2.0 ml) followed by morpholine (0.038 g, 0.38 mmol). The resulting mixture was stirred at 120° C. After 24 h, additional morpholine (38.1 mg, 0.38 mmol) was added and stirring was continued for another 24 h 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 gave the title compound (0.026 g, 0.071 mmol, 37% yield). 1 H NMR (DMSO-d 6,400MHz):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 below in Table 6 were prepared following methods similar to 43 immediately above.

[0317] [Table 124]

[0318] Preparation of (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(4-(trifluoromethoxy)-phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (44): Step 1. Preparation of (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (C23): [ka] To a resealable Schlenk, screw-capped test tube was added CuI (4 mg, 0.02 mmol), imidazole (25 mg, 0.37 mmol), cesium carbonate (250 mg, 0.77 mmol), and a stir bar. The tube was degassed, then (S)-6,8-dichloro-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (100 mg, 0.37 mmol), 1,10-phenanthroline (7 mg, 0.04 mmol), and anhydrous dioxane (2 mL) were added under a stream of argon. The reaction tube was degassed and backfilled with argon, then stirred at 90 °C for 24 h. The reaction mixture was allowed to cool to room temperature. The solution was diluted with ethyl acetate (2-3 mL) and filtered through a plug of Celite, eluting with additional ethyl acetate (10-20 mL). The filtrate was washed with water, brine and Na 2 SO 4 The resulting residue was purified by silica gel column chromatography (CH 2 Cl 2 / MeOH) to give the title compound (C23, 20 mg, 0.06 mmol, 18% yield). 1 H NMR (CHCl 3 -d 3 with 10% CH 3 OH-d 4 , 400 MHz): δH 1.46 (3H, dd, J=16.4, 7.1 Hz), 3.81 (2H, s), 4.94 (1H, s), 5.24 (1H, s), 7.94 (1H, s), 8.31 (1H, s); MS (m / z): 306.1 [M+H]+. The imidazole protons were not observed, probably due to complexation with copper.

[0319] Step 2. Preparation of (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (44): [ka] (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (C23, 30 mg, 0.1 mmol) and (4-(trifluoromethoxy)phenyl)boronic acid (30 mg, 0.15 mmol) were dissolved in 1 mL of toluene-EtOH (2:1) and sodium carbonate (42 mg, 0.4 mmol) was added. The suspension was degassed and backfilled with argon (3 cycles). Tetrakis(triphenylphosphine)palladium (12 mg, 0.01 mmol) was added and the suspension was degassed and backfilled with argon (3 cycles). The reaction mixture was stirred overnight at 85° C. under argon. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate. The solution was washed with water, brine and Na 2 SO 4 The residue was purified by silica gel column chromatography (CH 2 Cl 2 / MeOH) followed by purification on a C18 column gave the TFA salt of (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, which was washed with saturated Na2CO3 to give the free base of the title compound 44 (11 mg, 0.026 mmol, 26% yield). 1 H NMR(CH 3 OH-d 4 ,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-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one (45) [ka] (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one (17, 20 mg, 0.05 mmol) was dissolved in anhydrous THF and the resulting solution was cooled in an ice-water bath. t-BuOK (6 mg, 0.05 mmol) was then added, followed by CH 3 I (8 mg, 0.05 mmol) was added. The reaction mixture was stirred for 1 h at 0° C. The reaction was quenched by the addition of methanol and diluted with EtOAc. The solution was washed with water, brine and added with Na 2 SO 4 The mixture was dried over 1000 cc, concentrated and purified by HPLC to give the TFA salt of (S)-3-(1-methoxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one, which was washed with saturated Na 2 CO 3 Washing with aqueous solution gave the free base of the title compound 45 (2 mg, 0.005 mmol, 10% yield). 1 H NMR(CH 3 OH-d 4 ,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-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (46) [ka] (S)-6-Chloro-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (11, 50 mg, 0.15 mmol) was dissolved in toluene. The solution was degassed and then diluted with Pd(dppf)Cl. 2 ·CH 2 Cl 2 (13 mg, 0.016 mmol), LiCl (26 mg, 4 equiv), 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 at 80° C. overnight. LCMS 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 an additional 6 h at 80° C. The reaction mixture was allowed to cool to room temperature and it was diluted with EtOAc. The solution was washed with water, brine, and Na 2 SO 4 The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (CH 2 Cl 2 / MeOH) followed by purification by C18 column chromatography to give the TFA salt of (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, which was purified by elution with saturated Na 2 CO 3 Washing with aqueous solution gave the free base of the title compound (8 mg, 0.019 mmol, 12% yield). 1 H NMR(CH 3 OH-d 4,400MHz):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)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (47): [ka] (S)-6-chloro-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (C1, 50 mg, 0.15 mmol) was dissolved in toluene, degassed, and then diluted with Pd(dppf)Cl 2 ·CH 2 Cl 2 (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 at 80° C. overnight. The reaction mixture was diluted with EtOAc, washed with water, brine, and added with Na 2 SO 4 The solvent was removed under vacuum and the residue was purified by silica gel column chromatography (CH 2 Cl 2 / MeOH) followed by purification on a C18 column gave the TFA salt of (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, which was purified by elution with saturated Na2 CO 3 Washing with gave the free base of the title compound (19 mg, 0.04 mmol, 25% yield). 1 H NMR(CH 3 OH-d 4 ,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 in a similar manner to 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]pyrimidin-4-one (48) [ka] A mixture of 3-[(1S)-2-benzyloxy-1-methyl-ethyl]-8-(3-fluorophenyl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4-one (40, 160 mg, 333.65 umol, 1 equiv.) and Pd / C (80 mg, 333.65 umol, 10% purity, 1.00 equiv.) in MeOH (25 mL) and EtOAc (25 mL) was degassed and diluted with H 2 (15 psi) three times, and then the mixture was heated at 80° C. for 15 h. 2 Stirred under atmospheric pressure. LCMS showed that the desired compound was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was analyzed by preparative TLC (SiO 2 , petroleum ether / ethyl acetate=1:1) to give the title compound (47 mg, 120.69 umol, 36.17% yield). 1 H NMR (400MHz, DMSO-d 6 )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]pyrimidin-4-one (49) Step 1. Preparation of 3-[(1S)-2-benzyloxy-1-methyl-ethyl]-8-(3-fluorophenyl)-6-[4-(trifluoromethoxy)phenyl]pyrido[3,4-d]pyrimidin-4-one (Precursor 1) [ka] To a solution of 3-[(1S)-2-benzyloxy-1-methyl-ethyl]-6-chloro-8-(3-fluorophenyl)pyrido[3,4-d]pyrimidin-4-one (C21, 460 mg, 1.09 mmol, 1 equiv.) and [4-(trifluoromethoxy)phenyl]boronic acid (268.18 mg, 1.30 mmol, 1.2 equiv.) in toluene (8 mL) and EtOH (4 mL) was added Na 2 CO 3 (460.10 mg, 4.34 mmol, 4 equiv.) and Pd(PPh 3 ) 4 (125.41 mg, 108.52 umol, 0.1 equiv) was added. The mixture was taken up into a microwave tube. The sealed tube was heated under microwave at 100° C. for 1 h. LCMS showed that the desired compound was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 The mixture was purified by hexane / petroleum ether / ethyl acetate (1 / 0 to 0 / 1) to give the title compound (400 mg, 727.92 umol, 67.07% yield). MS: M+H+, 550.1.

[0329] Step 2. Preparation of 8-(3-fluorophenyl)-3-[(1S)-2-hydroxy-1-methyl-ethyl]-6-[4-(trifluoromethoxy)phenyl]pyrido[3,4-d]pyrimidin-4-one (49) [ka] To a solution of 3-[(1S)-2-benzyloxy-1-methyl-ethyl]-8-(3-fluorophenyl)-6-[4-(trifluoromethoxy)phenyl]pyrido[3,4-d]pyrimidin-4-one (precursor 1, 290 mg, 527.74 umol, 1 equiv.) in EtOAc (20 mL) and MeOH (20 mL) was added Pd(OH) 2 130 mg / C (527.74 umol, 10% purity, 1.00 equiv.) was added. The mixture was incubated at 25° C. for 6 h under H 2The mixture was stirred under reduced pressure (15 psi). LCMS showed that the desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO 2 , petroleum ether / ethyl acetate=1:1) to give the title compound 49 (22 mg, 47.41 umol, 8.98% yield). 1 H NMR (400 MHz, CDCl 3 )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] Compounds encompassed within the present disclosure can be prepared by the procedures outlined in Scheme II and described in the Examples below. [ka]

[0331] Preparation of 3-(1,1-dioxidotetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (106) Step 1. Preparation of methyl 3-amino-6-chloro-[2,3'-bipyridine]-4-carboxylate (Precursor 2): [ka] Precursor 2 was prepared following the procedure reported for step 3 of the synthesis of 1. 1 H NMR (CHCl 3 -d,400MHz):δ H3.95(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 that were prepared by procedures similar to those 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 following the procedure reported for step 3 of the synthesis of 1. 1 H NMR (CHCl 3 -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 that were prepared 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-dioxidotetrahydrothiophen-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 was stirred at 0°C for 1 h and at room temperature overnight. The reaction mixture was acidified to pH 4 with Amberlite IR120, followed by addition of ethyl acetate and MeOH. The solution was filtered to remove the resin and the solvent was evaporated to give 3'-amino-6''-(trifluoromethyl)-[3,2':6',3''-terpyridine]-4'-carboxylic acid (3.0 g, 7.91 mmol, 95% yield, >95% purity). MS (m / z): 361.1 [M+H] + The acid intermediate was carried on directly 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 was stirred at 0° C. for 1 h and at room temperature overnight. The reaction was quenched with water and partitioned between ethyl acetate and water. The organic phase was separated and washed with saturated aqueous ammonium chloride solution followed by saturated aqueous sodium bicarbonate solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to give the title compound 3'-amino-N-(1,1-dioxidotetrahydrothiophen-3-yl)-6''-(trifluoromethyl)-[3,2':6',3''-terpyridine]-4'-carboxamide (Precursor 4, 0.58 g, 66% yield, >90% purity). MS(m / z): 478.1[M+H] + The crude product was carried onto the next step without purification.

[0341] Table 10 lists intermediates that were prepared by procedures similar to those described in the steps 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] To methyl 3'-amino-6''-(trifluoromethyl)-[3,2':6',3''-terpyridine]-4'-carboxylate (300 mg, 0.801 mmol) in a vial was added 7M ammonia in MeOH, sealed, and heated at 65° C. overnight. Evaporation of the solvent afforded compound F30 as a white solid, which was used without further purification (270 mg, 89%). MS (m / z): 488.0 [M+H] + ;95% purity.

[0357] Step 4 - Preparation of 3-(1,1-dioxidotetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (106) [ka] Triethyl orthoformate (10 mL) was added to 3'-amino-N-(1,1-dioxidotetrahydrothiophen-3-yl)-6''-(trifluoromethyl)-[3,2':6',3''-terpyridine]-4'-carboxamide (precursor 4, 0.3 g, 0.618 mmol) in a sealed tube. Acetic acid (1 mL, 10% v / v) was added at room temperature and the resulting mixture was heated at 95 °C overnight. The mixture was concentrated followed by addition of saturated NaHCO 3 was added, and the solid was collected by vacuum filtration, washed with water, and dried. The residue was purified by normal phase chromatography to give the title compound 3-(1,1-dioxidotetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (106, 0.13 g, 43% yield). 1 H NMR (DMSO-d 6,300MHz):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-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-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-dioxidotetrahydrothiophen-3-yl)-6''-(trifluoromethyl)-[3,2':6',3''-terpyridine]-4'-carboxamide (F1, 0.67 g, 1.4 mmol) in a flask. p-Toluenesulfonic acid (0.267 mg, 1.4 mmol) was added at room temperature and the resulting mixture was stirred overnight. The mixture was concentrated followed by addition of saturated NaHCO 3 The solid formed was collected by vacuum filtration, washed with water and dried. The residue was purified by silica gel column chromatography to give the title compound (R)-3-(1,1-dioxidetetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (98 1.82 g, yield 69%). 1 H NMR (DMSO-d 6 ,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 that were prepared by procedures similar to those described for 98, substituting the indicated groups for reactants 4, 5, and 6.

[0360] [Table 146]

[0361] [Table 147]

[0362] [Table 148]

[0363] [Table 149]

[0364] [Table 150]

[0365] [Table 151]

[0366] Preparation of (S)-6-(6-cyclopropylpyridin-3-yl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (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 h, DMF (0.5 ml) was added and the reaction mixture was heated to 40° C. and stirred for 48 h. The reaction mixture was quenched with sodium bicarbonate (pH>11). Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, concentrated and purified by silica gel column chromatography to give the title compound (S)-6-(6-cyclopropylpyridin-3-yl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one as a white solid (120, 115 mg, 37%). 1 H NMR (DMSO-d 6 ,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 that were prepared by procedures similar to those described for 120, substituting the indicated groups for reactants 4, 5, and 6.

[0368] [Table 152]

[0369] Preparation of (R)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (108) [ka] 108 was prepared following the procedure reported for step 2 of the synthesis of 1 (synthesis of intermediate B1). 1 H NMR (DMSO-d 6 ,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 that were prepared by procedures similar to those described for 108, substituting the indicated groups 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] K-0004422 Preparation of 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (134) Step 1. Preparation of tert-butyl (3R,4R)-3-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)-4-hydroxypyrrolidine-1-carboxylate (Precursor 5) [ka] The above procedure was carried out according to the procedure reported for 108 to give a mixture of tert-butyl (3R,4R)-3-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)-4-hydroxypyrrolidine-1-carboxylate (precursor 5) and 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (134).

[0384] Step 2. 6-(4-Chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (134) [ka] A mixture of precursors 5 and 134 (218 mg, 0.43 mmol) was dissolved in 3.0 mL of 4 M The solid was dissolved in HCl in dioxane and stirred at room temperature for 1 hour. Diethyl ether (2.0 ml) was added and the solid was centrifuged, decanted, triturated with ether and dried. The solid was purified by reverse phase column chromatography to give the title compound 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (134, 120 mg, 0.29, 67% yield) as a white solid. 1 H NMR (DMSO-d 6 ,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] Preparation of (R)-6-(6-cyclopropylpyridin-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (135): [ka] Triethyl orthoformate (1.74 ml, 10.5 mmol) and 12.1 N HCl (115 μl, 1.39 mmol) were added to a solution of (R)-5-amino-6'-cyclopropyl-6-(1-methyl-1H-pyrazol-4-yl)-N-(3,3,3-trifluoro-2-hydroxypropyl)-[2,3'-bipyridine]-4-carboxamide (F19, 311 mg, 0.697 mmol) in dioxane (3.5 ml). After 1 h, DMF (0.5 ml) was added and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with sodium bicarbonate (pH>>11). Water was added and extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, concentrated and purified by silica gel column chromatography to give the title compound (R)-6-(6-cyclopropylpyridin-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (135, 152 mg, 48%). 1 H NMR (DMSO-d 6 ,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 that were prepared by procedures similar to those described for 139, substituting the indicated groups for reactants 4, 5, and 6.

[0387] [Table 165]

[0388] Compounds encompassed within the present disclosure can be prepared by the procedures outlined in Scheme III and described in the Examples below. [ka]

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

[0390] Table 15 shows intermediates prepared according to the steps set forth 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-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate H1) [ka] Intermediate H1 was synthesized according to the final step of the synthesis of 98. 1 H-NMR (DMSO-d 6 ,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 procedures described above.

[0399] [Table 172]

[0400] [Table 173]

[0401] [Table 174]

[0402] Table 17 shows the intermediates synthesized according to the final steps 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-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (137): [ka] 6-Chloro-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (H1, 200 mg, 0.575 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[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 heat-dried 10 mL pressure vial equipped with a stir bar under air. The vial was filled with argon and then 1-methyl-2-pyrrolidone (NMP) (4 mL) was added, followed by diethanolamine (0.055 ml, 0.575 mmol), K 3 PO 4 (610 mg, 2.87 mmol), and Cu(OAc) 2 (52.2 mg, 0.288 mmol) was added and the vial was 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 precipitate that formed was filtered, collected and dried. Purification of the precipitate by silica gel column chromatography gave the title compound 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (137, 151 mg, 57% yield). 1 H-NMR (DMSO-d 6 ,400MHz):δ H3.64(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 that were prepared by procedures similar to those described for 137, substituting the indicated groups for 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 that were synthesized according to the procedure used in the final step of the synthesis of 137.

[0417] [Table 186]

[0418] Compounds encompassed within this disclosure can be prepared by the procedures outlined in Scheme V and described in the Examples below. [ka]

[0419] Preparation of 6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one 18 (152): [ka] 152 was synthesized according to step 4 of the synthesis of 1. 1 H NMR (DMSO-d 6 ,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 that were prepared by procedures similar to those described for 152, substituting the indicated groups for reactants 6, 7, and 8.

[0421] [Table 187]

[0422] Preparation of (S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoic acid (155) [ka] Methyl (S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-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 left stirring 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 give the title compound (S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoic acid (155, 32 mg, 0.073 mmol, 47% yield). 1 H-NMR(CH 3 OH-d 4 ,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-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanamide (156) [ka] (S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoic acid (155, 150 mg, 0.34 mmol) and methylamine hydrochloride (35 mg, 0.51 mmol) were dissolved in 1.1 mL of anhydrous NMP. N,N-Diisopropylethylamine (0.18 mL, 1.02 mmol) was added. The solution was cooled in an ice-water bath and HATU (155 mg, 0.408 mmol) was added. The reaction mixture was allowed to warm to room temperature and left stirring at room temperature. Upon completion, the reaction was quenched with water and diluted with EtOAc. The organic phase was washed with saturated NaHCO 3 The residue was purified by normal phase chromatography to give the title compound (S)-N-methyl-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanamide (156, 94 mg, 0.21 mmol, 61% yield). 1 H-NMR(CH 3 OH-d 4 ,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-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propenamide (157) [ka] 157 was synthesized following the procedure reported for 156. 1 H-NMR (DMSO-d 6 ,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-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propenamide (158) [ka] 158 was synthesized following the procedure reported for 138. 1H-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-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (159) Step 1. Preparation of 6-chloro-3-(2-hydroxy-2-methylpropyl)-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Precursor 6) [ka] 6-Chloro-3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-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-water bath. NaH (60% dispersion in oil, 26 mg, 1.10 mmol) was added and the mixture was stirred for 10 min before adding SEMCl (0.19 mL, 1.10 mmol). Upon completion, the reaction was quenched with saturated NH 4Quenched with aqueous Cl (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. The residue was purified by normal phase chromatography to give the title compound 6-chloro-3-(2-hydroxy-2-methylpropyl)-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (6, 170 mg, 0.38 mmol, 86% yield). 1 H-NMR (CHCl 3 -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)pyridin-2-yl)-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Precursor 7) [ka] Precursor 7 was prepared according to the procedure reported above. 1 H-NMR (CHCl 3 -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-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (159) [ka] 3-(2-Hydroxy-2-methylpropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Precursor 7, 90 mg, 0.16 mmol) was dissolved in 1.6 mL of anhydrous DCM and the solution was cooled by ice-water bath. Trifluoroacetic acid (0.61 mL, 8.0 mmol) was added. The reaction mixture was left stirring at 0° C. for 30 min and warmed to room temperature. After completion, the volatiles were removed under reduced pressure. The residue was taken up in EtOAc and washed with saturated NaHCO 3 The residue was purified by normal phase chromatography followed by recrystallization in MeOH to give the title compound 3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (159, 35 mg, 51% yield). 1 H-NMR(CH 3 OH-d 4 ,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-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (160) Step 1. Preparation of 6-chloro-3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Precursor 8) [ka] In an oven-dried screw-cap test tube, add CuI (53 mg, 0.28 mmol), 4,7-dimethoxy-1,10-phenanthroline (134 mg, 0.56 mmol), imidazole (95 mg, 1.4 mmol), 6,8-dichloro-3-(2-hydroxy-2-methylpropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (B2, 400 mg, 1.4 mmol), poly(ethylene glycol) (233 mg, 0.07 mmol), and Cs 2 CO 3 (908 mg, 2.8 mmol), and a magnetic stir bar were added. Anhydrous NMP (7 mL) was then added and the reaction vessel was fitted with a rubber septum. The vessel was evacuated and backfilled with argon for three cycles. The reaction mixture was heated at 108 °C for 2-3 h. Upon completion, the reaction mixture was cooled to room temperature, diluted with dichloromethane, and filtered through a plug of celite, eluting with additional dichloromethane. The filtrate was washed with saturated NaHCO 3, washed with brine, dried over anhydrous sodium sulfate, concentrated, and the resulting residue was purified by normal phase chromatography to give the title compound 6-chloro-3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (precursor 8, 200 mg, 45% yield). 1 H-NMR(CH 3 OH-d 4 ,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-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (160) [ka] Compound 160 was prepared following the procedure reported for 121. 1 H-NMR(CH 3 OH-d 4 ,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-imidazol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (161) [ka] 161 was synthesized according to step 4 of the synthesis of 1. 1 H-NMR(CH 3 OH-d 4 ,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-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (162) Step 1. Preparation of (S)-3-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6,8-dichloropyrido[3,4-d]pyrimidin-4(3H)-one (Precursor 9) [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]pyrimidin-4(3H)-one (B1, 200 mg, 0.73 mmol) in anhydrous DMF. The solution was cooled in an ice-water bath and TBDMSCl (132 mg, 0.88 mmol) was added. The reaction mixture was allowed to warm to room temperature and left stirring for 2 hours. Upon completion, the reaction was quenched with methanol. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO 3 and water successively. The organic phase was dried over anhydrous sodium sulfate and concentrated to give the title compound (S)-3-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6,8-dichloropyrido[3,4-d]pyrimidin-4(3H)-one (precursor 9, 280 mg, 99% yield). 1 H-NMR (DMSO-d 6,400MHz):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-imidazol-1-yl)pyrido[3,4-d]pyrimidin-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 intermediates synthesized according to the above steps.

[0435] [Table 188]

[0436] Step 3. Preparation of (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Q1) [ka] (S)-3-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6-chloro-8-(1H-imidazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate P1, 460 mg, 1.1 mmol) was dissolved in anhydrous THF (11 mL) and cooled in an ice-water 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. Upon completion, the reaction mixture was diluted with saturated NH 4The mixture was quenched with Cl and extracted with EtOAc. The organic phase was collected, washed with water, brine, dried over anhydrous sodium sulfate and concentrated. The residue was taken up in MeOH and the precipitate was collected and dried to give the title compound, which was used in the next step without further purification, (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate Q1, 340 mg, 1.1 mmol, quantitative yield). 1 H-NMR (DMSO-d 6 ,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 above steps.

[0438] [Table 189]

[0439] Step 4. Preparation of (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (162) [ka] 162 was prepared following the procedure reported for 137. 1 H-NMR(CH 3 OH-d 4 ,400MHz):δ H1.57(3H,d,J=7.1Hz),3.87(1H,dd,J=11.9,4.3Hz),3.97(1H,dd,J=11.9,6.9Hz),5.01(1H,td,J=7.1,4.4Hz),7.19(1H,s),8.2 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-imidazol-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (163) [ka] (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (intermediate Q1, 85 mg, 0.28 mmol) and 2-trifluoromethyl-pyridine-5-boronic acid (80 mg, 0.42 mmol) were dissolved in 2 mL of toluene-EtOH (2:1) and sodium carbonate (118 mg, 1.1 mmol) was added. The suspension was degassed and backfilled with argon (3 cycles). Tetrakis(triphenylphosphine)palladium (32 mg, 0.028 mmol) was added and the suspension was degassed and backfilled with argon (3 cycles). The reaction mixture was heated to 85° C. under argon and left stirring overnight. After completion, the reaction mixture was cooled, diluted in EtOAc 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 give the title compound (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (163, 52 mg, 45% yield). H-NMR (CH 3OH-d 4 ,300MHz):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 compounds that were synthesized following the synthetic procedure reported for 163, varying the reactants in step 2.

[0442] [Table 190]

[0443] [Table 191]

[0444] Preparation of (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (168) [ka] (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (C10, 100 mg, 0.313 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)thiazole (96.0 mg, 0.344 mmol) were dissolved in dioxane. Pd(OAc) 2 (7.02 mg, 0.031 mmol), triphenylphosphine (16.4 mg, 0.063 mmol) and K 3 PO4 (266 mg, 1.25 mmol) was added to the solution. The suspension was degassed and backfilled with argon (3 cycles). The reaction mixture was heated to 90° C. and stirred for 16 h. The reaction mixture was extracted with ethyl acetate and washed with water and brine. The combined organic layers were dried over anhydrous magnesium sulfate, concentrated and purified by silica gel column chromatography to give (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (168, 28 mg, 20% yield). 1 H NMR (DMSO-d 6 ,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 that were synthesized according to Synthetic Scheme V, in which the steps are carried out according to the procedure reported in 168.

[0446] [Table 192]

[0447] [Table 193]

[0448] [Table 194]

[0449] Compounds encompassed within this disclosure can be prepared by the procedures outlined in Scheme V and described in the Examples below. [ka]

[0450] Preparation of (S)-8-(diethylamino)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (174) Step 1. Preparation of (S)-6-chloro-8-(diethylamino)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-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]pyrimidin-4(3H)-one (B1, 0.200 g, 0.73 mmol) and potassium carbonate (0.403 g, 2.92 mmol) in a sealed tube. Diethylamine (0.0586 g, 0.803 mmol) was added and the reaction mixture was stirred at 120° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added and the mixture was partitioned with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated. Purification of the residue by silica gel column chromatography gave the title compound (S)-6-chloro-8-(diethylamino)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (intermediate S1, 0.062 g, yield 27%). 1 H-NMR (DMSO-d 6 ,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 above steps.

[0452] [Table 195]

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

[0454] Table 26 lists compounds that were synthesized following the synthetic procedure reported for 174, varying the reactants in step 1 and step 2.

[0455] [Table 196]

[0456] [Table 197]

[0457] [Table 198]

[0458] Preparation of (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (180) Step 1. Preparation of (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Precursor 10) [ka] (S)-6,8-Dichloro-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate B1, 200 mg, 0.73 mmol) was dissolved in toluene, degassed, and then diluted with PdCl 2 (2.62 mg, 0.015 mmol), CsF (0.222 g, 1.46 mmol), CuI (0.056 g, 0.292 mmol), tri-tertiarybutylphosphine (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 at 50° C. overnight. The reaction mixture was diluted with EtOAc, washed with water, brine, and then dried over anhydrous sodium sulfate. The solvent was removed under vacuum and the residue was purified by silica gel column chromatography (CH 2 Cl 2 Purification by hexane / MeOH) gave (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (precursor 10, 55.6 mg, 24% yield). 1 H-NMR (CHCl 3 -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-(pyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (180) [ka] The above steps to prepare 180 were carried out according to the procedure reported for the final step of 1. 1 H-NMR (DMSO-d 6 ,300MHz):δ H 1.44-1.40(3H,m),3.79-3.64(2H,m),4.91(1H,s),5.09-5.04(1H,m),7.55-7.50(1H,m),7.92-7.89(1H,m),7.99-7.95(1H,m),8.07 -8.02(1H,m),8.51(1H,t,J=0.9Hz),8.77-8.74(1H,m),8.81(1H,t,J=0.8Hz),8.89-8.85(1H,m),9.60-9.58(1H,m);MS(m / z):427.9 [M+H] + ;99% purity.

[0460] Preparation of (S)-6-cyclohexyl-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (181) [ka] (S)-6-(cyclohex-1-en-1-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (77, 76.2 mg, 0.210 mmol) and PtO 2 (4.77 mg, 0.021 mmol) was dissolved in EtOH (3 ml). The suspension was degassed, backfilled with argon, and replaced with hydrogen gas. The reaction mixture was stirred under hydrogen atmosphere for 3 days at room temperature. The reaction mixture was filtered through Celite, and the filtrate was concentrated and purified by silica gel column chromatography to give (S)-6-cyclohexyl-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (181, 46.0 mg, 60% yield). 1 H-NMR (CHCl 3-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-(pyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (182) [ka] The above procedure was carried out according to the procedure reported for step 1 of the synthesis of 180 to give (S)-3-(1-hydroxypropan-2-yl)-6-(pyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (182). 1 H-NMR (DMSO-d 6 ,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 compounds that were synthesized according to the synthetic procedures reported for 180.

[0463] [Table 199]

[0464] Preparation of (S)-3-(1-hydroxypropan-2-yl)-6-(1-methyl-1H-1,2,3-triazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (184) [ka] The above procedure was carried out according to the procedure reported for the synthesis of 47 to give (S)-3-(1-hydroxypropan-2-yl)-6-(1-methyl-1H-1,2,3-triazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (184, 40 mg, 18%). 1 H-NMR (DMSO-d 6 ,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-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (185 enantiomer 1) and (S)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (185 enantiomer 2) [ka] Racemic 6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (rac-185, 20 mg, 0.045 mmol) was purified by SFC to give the title compound: (R)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (6.9 mg, 35% yield). 1 H-NMR(CH 3 OH-d 4 ,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-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (6.4 mg, 32% yield). 1 H-NMR(CH 3 OH-d 4 ,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-methylpyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (186) [ka] (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (100 mg, 1 eq.) and 5-methyl-2-(tributylstannyl)pyridine (145 mg, 0.131 mL, 1.2 eq.) were dissolved in toluene (3 mL). The suspension was degassed and backfilled with argon (3 cycles). Tetrakis(triphenylphosphine)palladium (73 mg, 0.2 eq.) was added and the suspension was degassed and backfilled with argon (3 cycles). The reaction mixture was heated to 100° C. under argon and monitored by LC-MS. After 24 h, the reaction was added with KF and water / MeOH and stirred overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated and purified by Combi-Flash® using DCM / MeOH 0-10% MeOH over 25 min. The resulting product (100 mg, 84% yield) was further purified by reverse phase chromatography to give (S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (186) as a white solid. 1 H NMR (DMSO-d 6 ,,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 compounds that were synthesized according to the synthetic procedure reported for 186.

[0468] [Table 200]

[0469] Preparation of (S)-8-cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (189) [ka] Step 1. Preparation of (S)-6-chloro-8-(cyclohex-1-en-1-yl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] (S)-6,8-dichloro-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate B1 200 mg, 0.73 mmol) and cyclohex-1-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 backfilled with argon (3 cycles). Tetrakis(triphenylphosphine)palladium (84 mg, 0.07 mmol) was added and the suspension was degassed and backfilled with argon (3 cycles). The reaction mixture was heated to 75° C. under argon and monitored by LC-MS. After overnight reaction, the reaction mixture was cooled, diluted with EtOAc, filtered through celite, and the filtrate was washed with water, brine and dried over sodium sulfate. The residue was purified by silica column to give the title compound (130 mg, 56% yield). 1H NMR (DMSO-d6, 400MHz): δH 1.37 (3H, d, J = 7.0Hz), 1.68 (4H, d, J = 30.1Hz), 2.25 (2H, s), 3.76-3.60 (2H, m), 4.80 (1H, d, J = 7.9Hz), 5.03 (1H, t, J = 5.5Hz), 6.74 (1H, s), 7.82 (1H, d, J = 4.1Hz), 8.46 (1H, s). MS (m / z): 320.1 [M+H]+.

[0470] Step 2. Preparation of (S)-8-(cyclohex-1-en-1-yl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (188) [ka] To a heat-dried pressure vial equipped with a stir bar under air was added (S)-6-chloro-8-(cyclohex-1-en-1-yl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (120 mg, 0.38 mmol), potassium phosphate (399 mg, 1.88 mmol), (2-dicyclohexylphosphino-2',4',6'-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), diethanolamine (79 mg, 0.75 mmol). 2 mL of NMP was added and the vial was degassed before adding Cu(OAc)2 (68 mg, 0.38 mmol). The vial was heated to 108° C. with stirring for 15 h. The reaction mixture was then cooled, diluted with EtOAc and filtered through a pad of celite. The filtrate was washed with saturated NaHCO 3 It was washed with water, concentrated and purified by normal phase as well as reverse phase combi-flash® to give the title compound (100 mg, 62% yield). 1 H NMR(CH 3 OH-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)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (189) [ka] (S)-8-(cyclohex-1-en-1-yl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (76 mg, 0.18 mmol) and PtO2 (4 mg, 0.018 mmol) were dissolved in 17 mL of EtOH. The suspension was degassed for three cycles and then cooled to room temperature with H2O (in a balloon). 2 The reaction mixture was then filled with H 2Stirred under gas at room temperature and monitored by LC-MS. The reaction was stopped after 24 hours and filtered through celite. The filtrate was concentrated and purified by normal and reverse phase combi-flash® to give the title compound: (S)-8-cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (189) (18 mg, 24% yield). 1H NMR (DMSO-d 6,400 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=8.4 Hz), 8.87 (1H,s), 9.11 (1H,s). MS (m / z): 433.2 [M+H]+; purity 96%; to give (S)-8-cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one (22 mg, 29% yield). 1H NMR (DMSO-d6,400MHz): 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-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidine-6-carboxamide (190) [ka] To a mixture of (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (200 mg, 1 equiv.), dimethylamine.HCl (77 mg, 1.5 equiv.), molybdenum hexacarbonyl (166 mg, 1 equiv.) and XPhos (60 mg, 0.2 equiv.) was added dioxane (6 mL). The suspension was degassed and backfilled with nitrogen (3 cycles). Palladium(II) acetate (15 mg, 0.1 equiv.) and K 3 PO 4 was added and the suspension was degassed and backfilled 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 EtOAc, MeOH and the filtrate was concentrated. The crude product (190) was purified first by silica gel column chromatography eluting with DCM / MeOH 0-10% MeOH over 25 min followed by reverse phase using water / acetonitrile to give the desired product (90 mg, 40%). 1 H NMR (DMSO-d 6 ,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-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (191): Compound 191 was prepared following the same procedure as in general Scheme IV above and the following protection strategy. [ka]

[0474] Table 29 lists intermediates synthesized according to general Scheme VI.

[0475] [Table 201]

[0476] Table 30 lists the compounds synthesized according to Synthetic Scheme VI above.

[0477] [Table 202]

[0478] Preparation of (S)-3-(1-hydroxypropan-2-yl)-6-(2-methoxyethyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (192) [ka] An oven-dried microwave vial was charged with bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (5.6 mg, 0.05 mmol), trifluoro(2-methoxyethyl)-λ-borane, potassium salt (40 mg, 0.24 mmol), CsCO (154 mg, 0.47 mmol) and (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (50 mg, 0.16 mmol). The vial was sealed, degassed and refilled with N. 2 The flask was filled with 100 ml of ethyl acetate. Degassed dioxane-H2O (4:1, 1 mL) was added via syringe. The reaction mixture was then placed in a preheated oil bath at 100 °C and stirred at this temperature for 24 h. Upon completion, the reaction mixture was cooled to room temperature, diluted with EtOAc, and filtered through a celite pad. The filtrate was washed with water, brine, dried over sodium sulfate, concentrated, and purified by normal phase chromatography to give the title compound (192). 1 H NMR(DMSO-d6,400MHz):δH 1.39(3H,d,J=7.0Hz),3.17(2H,t,J=6.4Hz),3.24(3H,s),3.64-3.61(1H,m),3.77(3H,t,J=6.7Hz),4.85(1H,s),5.03(1H,t,J=5 .5Hz),7.53(1H,t,J=6.2Hz),7.93(1H,s),8.40(1H,d,J=7.9Hz),8.47(1H,s),8.64(1H,d,J=4.6Hz),9.20(1H,s).MS(m / z):341.1 [M+H]+;96% purity.

[0479] Preparation of (S)-3-(1-hydroxypropan-2-yl)-8-(2-methoxyethyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (193) Compound 193 was prepared following the same procedures as in general Scheme IV above, following the alkyl-aryl coupling step as in compound 192. [ka]

[0480] Table 31 lists intermediates synthesized according to general Scheme VII.

[0481] [Table 203]

[0482] Table 32 lists the compounds synthesized according to Synthetic Scheme VII above.

[0483] [Table 204]

[0484] Example 2: DRE-luciferase reporter assay AHR binds to dioxin response elements (DRE) upstream of the genes it activates. One measure of AHR activity is the activation of a reporter gene, such as luciferase, downstream of one or more DRE elements. Luciferase activity will reflect the activation and inhibition of AHR in cells expressing the his reporter. 20,000 human HepG2 hepatoma-AhR-Lucia reporter cells or human HT29 colon adenocarcinoma-AhR reporter cells or other cell lines stably transfected with the DRE-luciferase reporter were seeded in plates (96-well, 384-well, or other plates) in Eagle's minimum essential medium, 10% heat-inactivated FBS, 1X non-essential amino acids, Pen-Strep (10,000U / mL) and Normocin (100ug / mL) and incubated at 4°C for 1 h at 20°C for 30 min at 20°C. 2 The cells were incubated overnight at 37° C. in an incubator and treated with or without AhR antagonists in log dilutions starting at 100 uM.

[0485] One hour after seeding the cells, AHR activating ligands such as TCDD, kynurenine, ITE (2-(1H-indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester), VAF347, BNF (β-naphthoflavone), FICZ (6-formylindolo(3,2-b)carbazole), or other AHR ligands were administered at their specific EC 50 Concentrations of 100 mM NaCl, 10 mM MHC class II, 10 mM NaCl, 10 mM MHC class III, 10 mM NaCl, and 10 mM MHC class II were added to cells with or without AHR antagonist.

[0486] Cells were incubated for 24 or 48 hours or other time points, and then the supernatants were analyzed for measurement of luciferase activity as a readout of AHR activation or inhibition. Luciferase was measured by a commercial kit QUANTI-Luc™ Assay Solution Kit from Invivogen according to the manufacturer's instructions.

[0487] The level of luciferase where only agonist ligand was added gave the highest signal, whereas luciferase without antagonist gave the lowest signal. IC 50 The luciferase IC value was determined as the concentration that inhibited half of the luciferase activity. 50 Levels are reported in Table 33. "A" indicates IC<100 nM 50 values, and "B" indicates IC values ​​between 100 and 500 nM. 50 "C" indicates IC > 500 nM 50 "D" stands for IC 50 Indicates that a 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 colon cancer (CRC) cell lines, HT29 and HT26, respectively, American Type Culture Collection (ATCC), were plated in sterile tissue culture-treated 96-well plates (ThermoFisher) at 8.0 × 10 cells per well. 5 Seed the cells and incubate at 37 °C and 5% CO to achieve confluence. 2The AhR cells are grown overnight in DMEM complete medium (Gibco) at 4°C for 12 h. After incubation, the medium is aspirated from the cell monolayer and the tissue is then washed with 200 μL of pre-warmed PBS solution, after which 190 μL of pre-warmed growth medium is added to each well. AhR antagonists of interest are diluted at 20-fold concentration in growth medium containing 2% DMSO, and 10 μL of compound solution is added to each well in triplicate. After 1 hour, AHR activating ligands such as TCDD, kynurenine, ITE (2-(1H-indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester), VAF347, BNF (β-naphthoflavone), FICZ (6-formylindolo(3,2-b)carbazole) or other AHR ligands will be added with or without AHR antagonists for 24 hours, after which the medium will be removed and stored at -80 degrees for later cytokine analysis. At the end of the 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 by TaqMan™ Gene Expression Cells-to-CT™ Kit (ThermoFisher) according to the manufacturer's protocol. QuantStudio 6 Flex (Applied CYP1A1 mRNA levels are analyzed using a ELISA kit (Diamond Biosciences) with GAPDH as an endogenous control. TaqMan™ probe sets for both genes are purchased from ThermoFisher. Samples are run in triplicate and data are analyzed using QuantStudio software and reported as linear and log2(ΔΔCT) values. Statistical analysis is performed using two-tailed t-tests comparing CYP1A1 levels in the presence of each individual compound versus vehicle negative control. IC values ​​are calculated in the nanomolar range. 50 Compounds having the following structure are considered for further evaluation: This assay can be used to confirm the inhibitory effects of compounds prior to testing using in vivo models.

[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 x 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 x g for 10 minutes at 10°C. The pelleted 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. Adjust the volume to achieve 1.66 x 106 cells / mL and then add 180 μl (300,000 PBMCs) to each well in a 96-well plate (sterile, tissue culture treated, round bottom). Incubate the PBMCs in the 96-well plate at 37°C in 5% CO 2 The cells were placed in an incubator for 30 min and then treated with 10 μl of the indicated compound. For CD8+ (Killing T cell) differentiation assay, PMBCs were cultured in RPMI-1640 complete medium for 2, 4, and 6 days (1-10×10 4 Cells) and stimulated with 5uL / ml ImmunoCult™ Human CD3 / CD28 / CD2 T Cell Activator (Stemcell #10990) with / without AhR antagonist compounds. Cell viability was measured using a viability dye (eBioscience Fixable Viability Dye eFluor 780: ThermoFisher 65-0865-14) at 1:500 dilution. Cells were gated for CD8+, defined as Live, CD11c-, CD14-, CD19-, CD8+, CD4-, CD3+. Percent CD8+ was calculated as the percentage of CD8+ cells relative to total 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 x 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 x g for 10 minutes at 10°C. The pelleted 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. Adjust the volume to achieve 1.66×106 cells / mL and then add 180 μl (300,000 PBMCs) to each well in a 96-well plate (sterile, tissue culture treated, round bottom). The PBMCs in the 96-well plate are incubated at 37° C. in 5% CO 2 The cells were placed in an incubator for 30 minutes and then treated with 10 μl of the indicated compounds. For cytokine secretion assays, PMBCs were cultured (1-10×104 cells) in RPMI-1640 complete medium for 2, 4, and 6 days and stimulated with 5 uL / ml ImmunoCult™ Human CD3 / CD28 / CD2 T Cell Activator (Stemcell #10990) with or without AhR antagonist compounds. Incubated at 37° C., 5% CO 2After 2, 4, and 6 days of incubation at 4°C, 100 μL of cell supernatant is collected and transferred to a 96-well plate (non-tissue treated, flat bottom). 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 bottom). The remaining cells are tested for viability using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega). The supernatant is tested for IL22 and IFg) using Luminex Immunoassay Technology (MAGPIX System). Cytokine levels of PBMC-treated DMSO control samples are set to 100% and compound-treated samples are represented relative to this.

[0494] Example 6: Solubility measurement assay Stock solutions of the test compounds and the control compound progesterone were prepared in DMSO at a concentration of 10 mM. 15 μL of each sample stock solution (10 mM) was placed in its appropriate 96-well rack in order. 485 μL of PBS pH 1.6 and pH 7.4 was added into each vial of the uncapped solubility sample plate. Assays were performed in replicates. One stir bar was added to each vial, which was then sealed using a molded PTFE / silicone plug. The solubility sample plate was then transferred to an Eppendorf Thermomixer Comfort plate shaker and shaken at 1100 rpm for 2 hours at 25° C. After the completion of the 2 hours, the plugs were removed and the stir bars were removed using a large magnet. The samples from the solubility sample plate were transferred to a filter plate. All samples were filtered using a Vacuum Manifold. A 5 μL aliquot was taken from the filtrate followed by the addition of 495 μL of a mixture of H2O and acetonitrile (1:1) containing the internal standard. Specific proportions of ultrapure water were used to dilute the dilutions depending on the peak shape. The dilution factor was varied depending on the solubility value and LC-MS signal response.

[0495] From the 10 mM DMSO STD plate, 6 μL was transferred to the remaining blank plate, then 194 μL of DMSO was added to the plate to have a STD concentration of 300 μM. From the 300 μM DMSO STD plate, 5 μL was transferred to the remaining blank plate, then 495 μL of a mixture of H2O and acetonitrile (1:1) containing the internal standard was added to the plate to have a final STD concentration of 3 μM. The dilutions were diluted according to the peak shape using ultrapure water in a specific ratio. The concentration of the standard samples was varied according to the LC-MS signal response.

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

[0497] All calculations were performed using Microsoft Excel.

[0498] The filtrate was analyzed and quantified against standards of known concentration using LC coupled to mass spectrometric identification and quantification. The solubility values ​​of the test and control compounds were calculated as follows:

number

[0499] Any values ​​of the compounds that were not within the stated limits were eliminated and the experiment was repeated.

[0500] The solubilities of compounds of the present disclosure in pH 1.6 and 7.4 buffers are reported in Table 34. "+++" indicates a solubility value of 1 μM or greater, "++" indicates a solubility value between 0.1 and 1 μM, and "+" indicates a solubility value below 0.1 μM.

[0501] [Table 208]

[0502] [Table 209]

[0503] [Table 210]

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

[0505] Preparation of Hepatocytes: 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. A vial of cryopreserved hepatocytes was removed from storage, ensuring that the vial remained at cryogenic temperature until the thawing process occurred. The cells were thawed by placing the vial in a 37°C water bath and gently shaking the vial for 2 minutes. After thawing was complete, the vial was 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 thawing medium. The 50 mL conical tube was placed in a centrifuge and spun at 100 g for 10 minutes. Once the spin was complete, the thawing medium was aspirated and the hepatocytes were resuspended in enough incubation medium to obtain approximately 1.5 x 10 6 Cells were counted using AO / PI staining to determine viable cell density. Cells with poor viability (<75% viability) were determined to be unacceptable for use. Cells were diluted to 0.5×10 6 Diluted to a working cell density of 100 viable cells / mL.

[0506] Stability measurement procedure: 198 μL of hepatocytes were pipetted into each well of a 96-well non-coated plate. The plate was placed in an incubator to allow the hepatocytes to warm for 10 minutes. 2 μL of 100 μM test compound or positive control solution was pipetted into each well of the 96-well non-coated plate to initiate the reaction. The plate was returned to the incubator at the designated time points. The well contents were transferred into 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 standards, IS (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide), to terminate the reaction. The mixture was vortexed for 5 minutes. The samples were 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 duplicate.

[0507] Data analysis: All calculations were performed using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. The in vitro half-life (t 1 / 2 ) was determined by regression analysis of the parental percent disappearance versus time curves.

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

[0509] In vitro 1 / 2 In vitro specific clearance (in vitro CL int , μL / min / 1×10 6 Conversion to (expressed in cells) was performed using the following equation (average of duplicate determinations): In vitro CL int = kV / N V = incubation volume (0.2 mL); N = number of hepatocytes per well (0.1 x 10 6 cell).

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

[0511] [Table 211]

[0512] Human and rat liver hepatocyte clearance of compounds of the present disclosure is reported in Table 36. "+++" indicates a CL of less than 20 mL / min / Kg. int The value is indicated, and "++" indicates a CL of 20-50 mL / min / Kg. int indicates CL over 50mL / min / Kg, and "+" indicates CL over 50mL / min / Kg int Shows.

[0513] [Table 212]

[0514] [Table 213]

[0515] [Table 214]

[0516] Example 8: Liver microsome stability assay A master solution was prepared according to Table 37.

[0517] [Table 215]

[0518] Two separate experiments were carried out 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 for 10 min at 37° C. The reaction was started by the addition of 2.5 μL of 100 μM control or test compound solution. Verapamil was used as a positive control in this study. The final concentration of test or control compound was 1 μM. The incubation solution was incubated in a water batch at 37° C. Aliquots of 25 μL were taken from the reaction solution at 0.5, 5, 15, 30, and 60 min. The reaction was stopped by the addition of 5 volumes of cold acetonitrile with IS (200 nM caffeine and 100 nM tolbutamide). The samples were centrifuged at 3,220 g for 40 min. An aliquot of 100 μL 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 areas were determined from extracted ion chromatograms. Slope values, k, were determined by linear regression of the natural logarithm of the percentage of parent drug remaining versus incubation time curves.

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

[0522] In vitro 1 / 2 (min), in vitro specific clearance (in vitro CL int Conversion to RT (expressed in μL / min / mg protein) was performed using the following equation (average of duplicate determinations):

number

[0523] Scaled-up CL intCalculations of predicted CLH (mL / min / kg) and EH were performed using the following equations: Scaled-up CL int =(0.693 / t 1 / 2 ) × (1 / (microsomal 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 where QH is the hepatic blood flow (mL / min / kg) (Table 32); f ub is the fraction of unbound drug in plasma, assumed to be 1.

[0524] Scaling factors for predicting intrinsic clearance in human and mouse microsomes are reported in Table 38.

[0525] [Table 216]

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

[0527] [Table 217]

[0528] Human and rat hepatic microsomal clearance of compounds of the present disclosure are reported in Table 40. "+++" indicates Cl < 10 mL / min / Kg int "++" indicates 10-20mL / min / Kg Cl int "+" indicates Cl over 20mL / min / Kg int Shows.

[0529] [Table 218]

[0530] Example 9: Caco-2 permeability assay Preparation of Caco-2 cells: 50 μL and 25 mL of cell culture medium were added to each well of the Transwell insert and reservoir, respectively. The HTS transwell plate was incubated at 37 °C and 5% CO 2 After incubation at 4°C for 1 h, the cells were seeded. Caco-2 cells were diluted with medium at 6.86 × 10 5 The cells were diluted to 1000 cells / mL and 50 μL of the cell suspension was dispensed into the filter wells of a 96-well HTS Transwell plate. The cells were incubated at 37°C, 5% CO in a cell culture incubator. 2 The cells were cultured at 20°C for 14–18 days at 95% relative humidity. The cell medium was changed every other day starting within 24 h of initial seeding.

[0531] Assessment of cell monolayer integrity: 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 a Millicell Epithelial Volt-Ohm measurement system (Millipore, USA). Once measurements were performed, the plates were returned to the incubator. TEER values ​​were calculated according to the following equation: TEER measurement (ohms) x membrane area (cm 2 ) = TEER value (ohm cm 2 )

[0532] The TEER value is 230 ohm cm 2 , which is indicative of a suitable Caco-2 monolayer.

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

[0534] Performing the drug transport assay: Caco-2 plates were removed from the incubator. Monolayers were washed twice with pre-warmed HBSS (10 mM HEPES, pH 7.4). Plates were incubated at 37° C. for 30 min. To measure the rate of drug transport from the apical to basolateral direction, 125 μL of working solution was added to the Transwell insert (apical compartment). 50 μL of sample was immediately transferred 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), which was vortexed at 1000 rpm for 10 min. The wells in the receiver plate (basolateral compartment) were filled with 235 μL of transport buffer. To measure the rate of drug transport from the basolateral to apical direction, 285 μL of working solution was added to the receiver plate wells (basolateral compartment). 50 μL of sample was immediately transferred from the basolateral compartment to 200 μL of acetonitrile containing IS (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide) in a new 96-well plate as the initial donor sample (BA), which was vortexed at 1000 rpm for 10 min. Transwell inserts (apical compartment) were filled with 75 μL of transport buffer. The apical to basolateral and basolateral to apical directions should be performed simultaneously. The plate was incubated at 37° C. for 2 h. At the end of the incubation, 50 μL samples from the donor side (apical compartment for Ap→Bl flow and basolateral compartment for Bl→Ap) and receiver side (basolateral compartment for Ap→Bl flow and apical compartment for Bl→Ap) were transferred to wells of a new 96-well plate, followed by addition of 4 volumes of acetonitrile containing IS (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide). Samples were vortexed for 10 min and 50 μL samples were transferred to wells of a new 96-well plate, followed by addition of 50 μL Hepes and 200 μL IS.All samples were vortexed for 10 min and then centrifuged at 3,220 g for 40 min. An aliquot of 150 μL of the supernatant was mixed with an appropriate volume of ultrapure water before LC-MS / MS analysis.

[0535] Data Analysis: All calculations were performed using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. The leakage of Lucifer Yellow from the monolayer can be calculated using the following equation:

number

[0536] The percentage amount of Lucifer Yellow transported should be less than 1.5%. However, if the percentage amount of Lucifer Yellow transported for a particular transwell is greater than 1.5, but the measured digoxin P in that transwell is greater than 1.5, the app If is qualitatively similar to that measured in replicate transwells, based on the scientific judgment of the responsible scientist, the monolayer is considered acceptable.

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

number

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

number

[0539] The apparent permeability ratios of the compounds of the present disclosure are reported in Table 41. "A" is 10 x 10 -6 P in excess of cm / sec app value, "B" is 2 to 10 x 10 -6 P in cm / sec app indicates that "C" is 2 x 10 -6 P in less than cm / sec app Shows.

[0540] [Table 219]

[0541] Example 10: Plasma protein binding assay by ultracentrifugation Frozen plasma (stored at -80°C) was thawed in a 37°C water bath followed by centrifugation at 3,220g for 10 min to remove clots. The supernatant was removed and placed in a new tube as spun plasma. The spun plasma was pre-warmed in a 37°C water bath for 10 min. Stock solutions of test compounds were diluted to 200 μM in DMSO and then spiked into the plasma. Duplicate samples were prepared. The final concentration of compound was 1.0 μM. The final concentration of 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. Samples were incubated at 37°C, 5% CO 2The balanced ultracentrifuge tubes were incubated at 600,000g for 5.5 hours at 37°C after incubation. After centrifugation, 50 μL solution was removed from the center of the ultracentrifuge tube as a post-ultracentrifugation sample, followed by the addition of 50 μL blank plasma and 400 μL quench solution (acetonitrile containing internal standards (IS, 100 nM alprazolam, 500 nM labetalol, and 2 μM ketoprofen)) to precipitate proteins and release compounds. The samples were vortexed for 2 minutes, followed by centrifugation at 20,000g 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 into a 0.6 mL tube and incubated at 37°C, 5% CO 2 The plasma was incubated at 4°C for 0.5 and 6 h at 25°C. 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 treated similarly to the post-ultracentrifugation samples. The supernatant was diluted with ultrapure water and then used for LC-MS / MS analysis. The 0.5 h time point 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 the proteins and release the compound. These samples were then treated similarly to the post-ultracentrifugation samples. 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 test compounds in plasma samples and in plasma after ultracentrifugation were determined from peak areas. The percentage of bound test compound was calculated as follows: % unbound = (peak area after ultracentrifugation / peak area of ​​uncentrifuged control) x 100% Combined%=100%-Uncombined% % remaining at 0.5 hours = peak area at 0.5 hours / peak area at 0 hours × 100% % remaining at 6 hours = peak area at 6 hours / peak area at 0 hours × 100%

number

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

[0544] [Table 220]

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

[0546] [Table 221]

[0547] Preparation details for these substrates are given in Table 44. The substrate solutions are stored in a -20°C freezer and allowed to warm 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 purified 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 purified 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 8.334 mg / mL; the solution was freshly prepared before use.

[0550] Master solutions were prepared according to Table 45. Incubations were performed in 96 deep-well plates. 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 pre-warmed at 37° C. for 15 min before adding 20 μL of 10 mmol / L The reaction was initiated by the addition of NADPH in phosphate buffer. After addition of NADPH, the incubation plates were incubated for the corresponding time at 37° C. Assays were performed in duplicate.

[0551] [Table 223]

[0552] Reactions were quenched by the addition of 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 min. 100 μL of the supernatant was transferred to a new plate. The supernatant was diluted with 100 μL pure water. The samples were mixed thoroughly and analyzed using UPLC / MS / MS.

[0553] Data analysis: Automated peak integration areas are checked for all samples. Analyte and internal standard peak areas are exported to an excel spreadsheet. Inhibition of each P450 enzyme in human liver microsomes is measured as the percentage reduction in activity of marker metabolite formation compared to the uninhibited control (=100% activity).

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

[0555] The % inhibition of CYP2D6 and CYP3A4 for compounds of the present disclosure is reported in Table 46.

[0556] [Table 224]

[0557] Example 12: hERG Inhibition Assay The HEK 293 cell line (catalog number K1236) stably expressed hERG was purchased from Invitrogen. Cells are cultured in 85% DMEM, 10% dialyzed FBS, 0.1 mM NEAA, 25 mM HEPES, 100 U / mL penicillin-streptomycin, and 5 μg / mL blasticidin and 400 μg / mL geneticin. Cells are split approximately three times per week using TrypLE™ Express and maintained at approximately 40% to approximately 80% confluence. Prior to the assay, cells were plated on cover slips 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). Test compound working solution preparation: 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 in DMSO at a ratio of 1:3 to prepare three additional intermediate solutions containing 3.33, 1.11, and 0.37 mM.

[0559] Prior to performing the hERG assay, working solutions were prepared by 1000-fold dilution of the 10, 3.33, 1.11, and 0.37 mM intermediate solutions using extracellular solution such that the final concentrations of the working solutions were 30, 10, 3.33, 1.11, and 0.37 μM, whereas the 30 μM working solution was prepared by 333.333-fold dilution of the 10 mM DMSO stock. The final DMSO concentration in the working solutions was kept in 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 a bath chamber. The desired cell was found using a 10x objective. The tip of the electrode was found under the microscope by focusing above the plane of the cell using the 10x objective. Once the tip was in focus, the electrode was advanced downwards towards the cell using the coarse adjustment of the manipulator while simultaneously moving the objective to keep the tip in focus. When directly above the cell, the surface of the cell was gradually approached by using the 40x objective, utilizing the fine adjustment of the manipulator. Gentle suction was applied by the side port of the electrode holder to form a gigaohm seal.

[0561] Cfast was used to eliminate the capacitive current that coincided with the voltage step. The whole-cell configuration was obtained by repeatedly applying short periods of strong suction until the membrane patch ruptured. The membrane potential was set to -60 mV at this point to ensure that the hERG channels were not open. The amplifier's Cslow was then used to cancel out the capacitive current spikes.

[0562] The holding potential was set at -90 mV for 500 ms; currents were recorded at 20 kHz and filtered at 10 kHz. Leak currents were tested at -80 mV for 500 ms.

[0563] hERG currents were evoked by depolarizing at +30mV for 4.8 seconds, then the voltage was returned to -50mV for 5.2 seconds to remove inactivation and observe the deactivating tail current. The maximum tail current size was used to determine the hERG current amplitude. Currents were recorded for 120 seconds to assess current stability. Only stable cells with recording parameters above threshold were advanced to further drug administration. Vehicle control was applied to the cells to establish a baseline. Once the hERG current was found to be stabilized for 5 minutes, the working solution was applied. hERG currents in the presence of test compounds were recorded for approximately 5 minutes to reach a steady state, and then five sweeps were taken. For dose-response testing, five doses of test compounds were applied to the cells, increasing from low to high concentrations. To ensure good performance of the cultured cells and manipulations, the 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; leak current always <50% of control peak tail current; peak tail amplitude >300 pA; membrane resistance Rm >500 MΩ; access resistance (Ra) <15 MΩ; apparent decay of peak current <2.5% per minute.

[0565] Data meeting the above criteria of hERG current quality were further analyzed as follows: Percent current inhibition was calculated using the following equation: (Note: Peak currents were extracted from the raw data using PatchMaster or Clampfit software).

number

[0566] Dose-response curves for test compounds were plotted by % inhibition versus test compound concentration using GraphPad Prism 6.0, and data were fitted to a sigmoidal dose-response curve with variable slope.

[0567] IC of compounds of the present disclosure 50 are reported in Table 47.

[0568] [Table 225]

[0569] Example 13: In vivo rat PK study The study was carried out in male Sprague-Dawley rats, 3 rats per group, or in male CD1 mice, 3 mice per group. Compounds were administered intravenously at 1.0 mg / Kg (vehicle ethanol:% PEG400 in deionized water, suitable ratio for dosing clear solutions) and orally at 3.0 mg / kg or 10 mg / kg (vehicle: 1% methylcellulose:1,500 cP (w / v) in deionized water). 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. The concentration of the compound in the plasma samples was analyzed using an LC-MS / MS method. WinNonlin (Phoenix™, version 6.1) or other similar software was used for pharmacokinetic calculations.

[0570] Pharmacokinetic data from mouse and rat PK studies are shown in Tables 48-51 below. PK data for mice administered 1 mg / mL IV of a compound of the present disclosure is reported in Table 48. PK data for mice administered 10 mg / mL PO of a compound of the present disclosure is reported in Table 49. PK data for rats administered 1 mg / mL IV of a compound of the present disclosure is reported in Table 50. PK data for rats administered 3 or 10 mg / mL PO of a compound of the present disclosure is reported in Table 51.

[0571] [Table 226]

[0572] [Table 227]

[0573] [Table 228]

[0574] [Table 229]

[0575] In vivo model Testing the efficacy of AHR antagonists and checkpoint inhibitors against PD-1 in the murine colon cancer model CT26 in Balb / c mice Female mice aged 6 to 8 weeks were obtained from Charles River Laboratory (C57BL / 6NCrl). The mouse tumor cell line WT-CT26 was obtained from the American Type Culture Collection and was cultured at Charles River for mycoplasma and other pathogens. All studies were performed at River Research Animal Diagnostics services and cultured according to their guidelines. All studies were performed in accordance with the Care, Welfare and Treatment of Laboratory Animals. From the day of tumor inoculation, mice were monitored a minimum of three times a week by the investigator or veterinary staff for clinical abnormalities that may require euthanasia. These included chronic and / or severe diarrhea resulting in moderate to severe dehydration, evidence of infection that was not easily treatable, hunched posture in conjunction with other clinical signs if emaciation or prolonged for more than 3 days, inability / unwillingness to ambulate to reach food or water, or other clinical signs judged by experienced technical staff to be indicative of a morbid or moribund state. Mice showing a net weight loss of more than 20% compared to baseline weight measurements were euthanized.

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

[0577] Once the enrollment criteria were met, animals were distributed into treatment groups such that the mean tumor burden in each group was within 10% of the overall mean. Mice were dosed individually by body weight on the day of treatment.

[0578] One week after vaccination, approximately 60 mm 3 Mice bearing tumors of an average size of 100 μg / kg were available for randomization and treatment initiation (Figure 1). AhR antagonists were administered orally at 1 mg / kg, 3 mg / kg, or 10 mg / kg daily (QD) for 14 days. Anti-PD-1 (BioXcell RMP1-14) or anti-PD-L1 was administered intraperitoneally at 100 μg / kg every 3 days for three doses starting on day 14.

[0579] Tumors were monitored by perpendicular tumor diameter measurements and expressed as (mm 3 ) = 0.52 x (length) x (width) 2 The tumors were counted daily by caliper measurement using a CT scan and body weight was measured three times a week. At the end point, tumors were harvested and analyzed for infiltrating tumor immune cells by flow cytometry and / or IHC.

[0580] AHR-dependent gene expression in tumors, spleen and liver AHR-dependent gene expression will be measured in tissue samples such as tumor or liver. RNA will be extracted from tissues by RNA isolation kits such as Qiagen. RNA extraction will be performed from whole cells or cells after sorting of specific cell populations such as tumor cells, tumor-associated T cells, tumor-associated bone marrow cells, tumor-associated macrophages, or others. Gene expression will be determined by quantitative RT-PCR using probes of specific genes, including housekeeping genes such as Gapdh for normalization. AHR-dependent genes that will be investigated include, but are not limited to, CYP1A1, CYP1B1, AHRR, IDOL, IDO2, IL22, IL6, VEGFA, STAT3, cdc2, MMP13, MMP-9.

[0581] Example 14: Drug metabolism and pharmacokinetic profiles of compounds no. 9 and no. 46 Compounds no. 9 and no. 46 have the following in vitro DMPK profiles:

[0582] [Table 230]

[0583] Compounds no. 9 and no. 46 have the following in vivo DMPK profiles:

[0584] [Table 231]

[0585] A plot of the mean plasma concentration over time of Compound #46 after 1 mg / kg IV and 10 mg / kg PO in CD1 mice is shown in Figure 14. A plot of the mean plasma concentration over time of Compound #46 after 1 mg / kg IV and 3 mg / kg PO in SD rats is shown in Figure 15.

[0586] A plot of the mean plasma concentration over time of Compound #9 after 1 mg / kg IV and 10 mg / kg PO in CD1 mice is shown in Figure 16. A plot of the mean plasma concentration over time of Compound #9 after 1 mg / kg IV and 3 mg / kg PO in SD rats is shown in Figure 17.

[0587] Example 15: Combination therapy with immune checkpoint inhibitors (ICIs) A study was conducted to identify potent, selective, low-dose modulators of the aryl hydrocarbon receptor that antagonized the activity of tryptophan metabolites alone or in combination with checkpoint inhibitors (ICIs) across multiple cancer types.

[0588] Antitumor efficacy of compound #7 in the CT26 syngeneic model. CT26 cells were implanted subcutaneously into Balb / c mice, and the mice were then randomized to be treated with either PD-L1 antibody alone or PD-L1 antibody in combination with compound #7. Compound #7 was administered orally at 3 mg / kg once daily for 14 days of dosing in combination with anti-PD-L1 antibody administered intraperitoneally at 10 mg / kg every 3 days. Tumor growth curves of vehicle vs. single agent PD-L1 antibody or PD-L1 antibody together with compound #7 are shown in Figure 2. Co-administration of compound #7 with PD-L1 antibody showed a reduction in tumor volume, p=0.0039 (Mann-Whitney, non-parametric test). Tumor weights at the end of the study of vehicle vs. single agent PD-L1 antibody or PD-L1 antibody together with compound #7 are also shown in Figure 3. Co-administration of compound #7 with PD-L1 antibody showed a reduction in tumor weight, p=0.041 (Mann-Whitney, non-parametric test).

[0589] Antitumor efficacy of compound #30 in the CT26 syngeneic model. CT26 cells were implanted subcutaneously into Balb / c mice, and then the mice were randomized and treated with either compound #30 alone, PD-L1 antibody alone, or PD-L1 antibody in combination with compound #30. Compound #30 was administered orally at 10 mg / kg once daily for 14 days of dosing in combination with anti-PD-L1 antibody administered intraperitoneally at 10 mg / kg every 3 days. Tumor growth curves of vehicle versus single agent PD-L1 antibody or compound #30 alone or PD-L1 antibody together with compound #30 are shown in Figures 4 and 6. Co-administration of compound #30 and PD-L1 antibody showed a reduction in tumor volume with p=0.039 (Figure 4, Mann-Whitney, nonparametric test) and p=0.350 (Figure 6, Kruskal-Wallis test followed by nonparametric Dunn's multiple comparison test). Tumor weights at the end of the study for vehicle versus single agent PD-L1 antibody, or compound #30 alone, or PD-L1 antibody together with compound #30, are also shown in Figures 5 and 7. Co-administration of compound #30 with PD-L1 antibody demonstrated a reduction in tumor weight, p=0.067 (Figure 5, Mann-Whitney, nonparametric test) and p=0.0004 (Figure 7, Kruskal-Wallis test followed by nonparametric Dunn's multiple comparison test).

[0590] Anti...

Claims

[Claim 1] The invention described in the specification.

Images