Purinones as ubiquitin-specific protease 1 inhibitors

Abstract

To provide purinones as ubiquitin-specific protease 1 inhibitors. The present application relates to inhibitors of USP1 useful for the treatment of cancer and other USP1-associated diseases and disorders, having formula (I): 3’ , R4, R5, X1, X2, X3, X4, and n are as described herein. This application is directed to inhibitors of ubiquitin-specific protease 1 (USP1), which are useful for treating diseases or disorders associated with the USP1 enzyme. In particular, this application relates to compounds and compositions thereof that inhibit USP1, methods for treating diseases or disorders associated with USP1, and methods for synthesizing these compounds. TIFF2023011899000384.tif4885

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 62 / 258,162, filed November 20, 2015, the entire contents of which are incorporated herein by reference.

[0002] Field of Disclosure This application is directed to inhibitors of ubiquitin-specific protease 1 (USP1), which are useful in treating diseases or disorders associated with the USP1 enzyme. In particular, this application relates to compounds and compositions thereof that inhibit USP1, methods of treating diseases or disorders associated with USP1, and methods of synthesizing these compounds. [Background technology]

[0003] Ubiquitination is a reversible process involving a family of deubiquitinating enzymes (DUBs), which regulate various cellular processes by releasing ubiquitin from its substrate. DUBs are encoded by approximately 100 human genes and are classified into six families, the largest of which is the ubiquitin-specific protease (USP), which comprises more than 50 proteases. DUBs and their substrate proteins are often deregulated in cancer, supporting the hypothesis that targeting enzymes belonging to specific DUB families may result in antitumor activity by enhancing the ubiquitination and subsequent degradation of tumorigenic substrates and the activity of other important proteins involved in tumor growth, survival, differentiation, and maintenance of the tumor microenvironment (Hussain, S., et al., "DUBs and cancer: The role of deubiquitinating enzymes as oncogenes, non-oncogenes, and tumor suppressors." Cell Cycle 8,1688-1697 (2009)).

[0004] USP1 is a cysteine ​​isopeptidase of the USP subfamily of DUBs (Nijman, S.M.B., et al. "The deubiquitinating enzyme USP1 regulates the Fanconi anemia"). pathway.”Mol.Cell 17,331-339 (2005)).Full length Human USP1 consists of 785 amino acids, including the catalytic triad consisting of Cys90, His593, and Asp751 (Villamil, MA, et al., "Serine phosphorylation is critical for the activation of ubiquitin-specific protease 1 and its interaction with WD40-repeat protein UAF1." Biochem. 51, 9112-9113 (2012)). USP1 is relatively inactive by itself and achieves full enzymatic activity only when bound in a heterodimeric complex with UAF1, a cofactor that also binds to and regulates the activity of USP12 and USP46 (Cohn, MA, et al., "A UAF1-Containing Multisubunit Protein Complex Regulates the Fanconi Anemia Pathway." Mol. Cell 28, 786-797 (2007)).

[0005] USP1 deubiquitinates various cellular targets involved in various processes related to cancer. For example, USP1 deubiquitinates PCNA (proliferating cell nuclear antigen), a key protein in translesion synthesis (TLS), and FANCD2 (Fanconi anemia complementation group D2), a key protein in the Fanconi anemia (FA) pathway (Nijma et al., 2014). n,SMB et al., "The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway." Mol. Cell 17, 331-339 (2005); Huang,TT et al., "Regulation of monoubiquitinated PCNA by DUB autocleavage." Nat. Cell Biol. 8, 339-347 (2006)). These DNA damage response (DDR) pathways are crucial for repair of DNA damage induced by DNA cross-linking agents such as cisplatin, mitomycin C, diepoxybutane, ionizing radiation, and ultraviolet irradiation.

[0006] In vivo studies in mouse embryonic fibroblasts (MEFs) from USP1-deficient mice have revealed increased levels of Ub-PCNA and Ub-FANCD2 in chromatin, impaired FANCD2 foci assembly, and defects in homologous recombination repair. Disruption of the USP1 gene in chicken cells (DT40) has been shown to result in hypersensitivity to DNA cross-linking agents (Oestergaard, VHet al. Deubiquitination of FANCD2 Is Required for DNA Crosslink Repair. Mol. Cell 28, 798-809 (2007)). Furthermore, depletion of USP1 in human cell lines by siRNA results in increased Ub-PCNA levels accompanied by increased recruitment of DNA polymerases specialized for translesion synthesis (Cohn, MA et al., "A UAF1-Containing Multisubunit Protein Complex" Regulations the Fanconi Anemia Pathway.”Mol.Cell 28,786-797 (2007);Huang,TTet al.,“Regulation of monoubiquitinated PCNA by DUB autocleavage.”Nat.Cell Biol.8,339-347 (2006)).

[0007] In addition to regulating protein dynamics in the DDR pathway, USP1 promotes tumor stem cell maintenance and radioresistance in glioblastoma through stabilization of ID1 and CHEK1, and is involved in regulating proliferation and differentiation by deubiquitinating and stabilizing the inhibitor of DNA binding (ID), which antagonizes basic helix-loop-helix (bHLH) transcription factors (Lee, J.-K. et al., "USP1 targeting impedes GBM growth by inhibiting stem cell maintenance and radioresistance." Neuro. Oncol. 1-11 (2015). doi:10.1093 / neuonc / nov091). ShRNA knockdown of USP1 in U2OS cells induces cell cycle arrest mediated by ID proteins, and shRNA knockdown of USP1 in 143B human osteosarcoma xenografts suppresses tumor growth (Williams, SA et al., "USP1 deubiquitinates ID proteins to preserve a mesenchymal stem cell program in osteosarcoma." Cell 146, 918-930 (2011)). Therefore, inhibition of USP1 with small molecule inhibitors has the potential to be a therapeutic approach for cancer and other disorders. For this reason, there remains a great need for potent small molecule inhibitors of USP1. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Hussain, S., et.al., “DUBs and cancer: The role of deubiquitinating enzymes as oncogenes, non-oncogenes and tumor suppressors.” Cell Cycle 8, 1688-1697 (2009) [Non-patent document 2] Nijman, SMB, et al. “The deubiquitinating enzyme USP1 regulates the fanconi anemia pathway.” Mol. Cell 17, 331-339 (2005) [Non-patent document 3] Villamil, MA, et al., “Serine phosphorylation is critical for the activation of ubiquitin-specific protease 1 and its interaction with WD40-repeat protein UAF1.”Biochem.51,9112-9113 (2012) [Non-patent document 4] Cohn, MA, et al., “A UAF1-Containing Multisubunit Protein Complex Regulates the Fanconi Anemia Pathway.” Mol. Cell 28, 786-797 (2007) [Non-Patent Document 5] Huang, TT et al., “Regulation of monoubiquitinated PCNA by DUB autocleavage.” Nat. Cell Biol. 8, 339-347 (2006) [Non-patent document 6] Oestergaard,VHet al.Deubiquitination of FANCD2 Is Required for DNA Crosslink Repair.Mol.Cell 28,798-809 (2007) [Non-Patent Document 7] Lee, J.-K. et al., “USP1 targeting impedes GBM growth by inhibiting stem cell maintenance and radioresistance.” Neuro.Oncol.1-11 (2015).doi:10.1093 / neuonc / nov091 [Non-patent document 8] Williams, SAet al., “USP1 deubiquitinates ID proteins to preserve a mesenchymal stem cell program in osteosarcoma.”Cell 146,918-930 (2011) Summary of the Invention [Means for solving the problem]

[0009] The first aspect of the present application is a compound of formula (I): [ka] and pharmaceutically acceptable salts, hydrates, solvates, isotopes, prodrugs, stereoisomers, and tautomers thereof, wherein X1 is CR6 or N, X2 is CR7 or N, X3 is CR8 or N, X4 is CR9 or N, R1 is H, -CD3, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, (C2-C6) hydroxyalkyl, (C3-C8) cycloalkyl, or heterocycloalkyl, provided that the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally selected from halogen, -OR 20 , -C(O)R 20 , -CO2R 20 , -NR 18 R 19 , -NR 20C(O)R 21 , -C(O)NR 20 R 21 , -NR 20 C(O)NR 21 R 22 , -NR 20 S(O) r R 21 , -S(O) r R 20 R 21 , -NR 20 S(O) r R 21 R 22 , -S(O) r R 20 , -P(O)R 20 R 21 , oxo, and -Si((C1-C4)alkyl)3; R2 is (C6~C 14 ) aryl, heteroaryl, (C3-C 10 ) cycloalkyl, or heterocycloalkyl, provided that the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each independently selected from one or more R 10 is replaced by R3 is H, D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, heterocycloalkyl, halogen, —C(O)OH, —C(O)NH2, or CN; R 3’ is H, D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, heterocycloalkyl, halogen, —C(O)OH, —C(O)NH2, or CN; R3 and R 3’ form a (C3-C7) cycloalkyl ring together with the carbon atoms to which they are attached, or R3 and R 3’ together with the carbon atoms to which they are attached form a heterocycloalkyl ring; R4 is (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C3-C8) cycloalkyl, -O-(C0-C2)-alkylene-(C3-C8) cycloalkyl, heterocycloalkyl, -O-(C0-C2)-alkylene-heterocycloalkyl, halogen, -OH, -NH2, CN, -C(O)(C1-C4) alkyl, -C(O)O(C1-C4) alkyl, -NR 20 C(O)O(C1~C4)alkyl, -Si(CH3)3, -SF5, -S(O) P (C1-C4) alkyl, -S(O) P (NH)(C1-C4)alkyl, -NH(C1-C4)alkyl, -N((C1-C4)alkyl)2, -NH-(C0-C2)-alkylene-(C3-C8)cycloalkyl, or -NH-(C0-C2)-alkylene-heterocycloalkyl, provided that the alkyl, alkenyl, alkynyl, and alkoxy are optionally selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, halogen, -OH, -S(O) r (C1-C4) alkyl, -S(O) r substituted with one or more substituents selected from (NH)(C1-C4)alkyl, -SF5, -Si(CH3)3, -NH2, -NH(C1-C4)alkyl, -N((C1-C4)alkyl)2, -C(O)NH2, -C(O)NH(C1-C4)alkyl, and -C(O)NH((C1-C4)alkyl)2, wherein said cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, and halogen; R and X, together with the atoms to which they are attached, may optionally be one or more R 17 (C6~C 14 ) form an aryl ring, or R and X on adjacent atoms, together with the atoms to which they are attached, may optionally be joined by one or more R 17or R and X together with the atoms to which they are attached form a heteroaryl ring substituted with one or more R 17 or R and X on adjacent atoms together with the atoms to which they are attached form a (C5-C7)cycloalkyl ring substituted with one or more R 17 forming a heterocycloalkyl ring substituted with R5 is H, D, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) Alkynyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkoxy, halogen, (C3-C6)cycloalkyl, heterocycloalkyl, -C(O)O(C1-C4)alkyl, -C(O)(C1-C4)alkyl, -C(O)NR 13 R 14 , -OH, -NH2, CN, -NH(C1-C4) alkyl, -N((C1-C4) alkyl)2 or -NR 13 C(O)R 14 or R1 and R5 together with the atoms to which they are attached form a heterocycloalkyl ring; each of R6, R7, R8, and R9, independently at each occurrence, is H, D, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, (C3-C8)cycloalkyl ring, heterocycloalkyl, or halogen, wherein said alkyl is optionally substituted with one or more (C1-C6)alkoxy; Each R 10 is independently in each occurrence D, -CD3, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -C(O)R 14 , -C(O)OR 13 , -NR 13 R 14 , -NR13 C(O)R 14 , -NR 13 C(O)NR 13 R 14 , -C(O)NR 13 R 14 , -S(O) p R 14 , -NR 13 S(O) p R 14 , -S(O) p NR 13 R 14 , -CN, -(C0-C2)-alkylene-(C6-C 14 )aryl, -(C0-C2)-alkylene-heteroaryl, -(C0-C2)-alkylene-(C3-C8)cycloalkyl, -(C0-C2)-alkylene-heterocycloalkyl, -O-(C0-C2)-alkylene-aryl, -O-(C0-C2)-alkylene-heteroaryl, -O-(C0-C2)-alkylene-(C3-C8)cycloalkyl, or -O-(C0-C2)-alkylene-heterocycloalkyl, provided that the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl may optionally be selected from the group consisting of one or more R 11 wherein the alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more R 12 is replaced by, or 2 R on adjacent atoms 10 together with the atoms to which they are attached, optionally one or more R 11 (C6~C 14 ) forming an aryl ring or two R on adjacent atoms 10 together with the atoms to which they are attached, optionally one or more R 11 or two R on adjacent atoms to form a heteroaryl ring substituted with 10 together with the atoms to which they are attached, optionally one or more R 11 Form a (C3-C8) cycloalkyl ring substituted with, or two R on adjacent atoms 10 together with the atoms to which they are attached, optionally one or more R 11or two R 10 and the above two Rs are bonded to the same atom. 10 optionally one or more R 11 or two R 10 and the above two Rs are bonded to the same atom. 10 optionally one or more R 11 forming a spiroheterocycloalkyl ring substituted with Each R 11 is independently in each occurrence D, -CD3, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, CN, -OH, -NH2, -NH(C1-C4)alkyl, -N((C1-C4)alkyl)2, -C(O)O(C1-C4)alkyl, -S(O) q (C1-C4) alkyl, -C(O)NH2, -C(O)NH(C1-C4) alkyl, -C(O)N((C1-C4) alkyl)2, -NHC(O)(C1-C4) alkyl, -N((C1-C4) alkyl)C(O)(C1-C4) alkyl, (C6-C 14 )aryl, heteroaryl, (C3-C8)cycloalkyl, or heterocycloalkyl, provided that the alkyl, alkoxy, (C3-C8)cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, —C(O)OH, —C(O)O(C1-C4)alkyl, —C(O)(C1-C4)alkyl, —S(O) q (C1~C 4) substituted with one or more substituents selected from alkyl, —C(O)NH(C1-C4)alkyl, —C(O)N((C1-C4)alkyl)2, —OH, —NH2, —CN, —NH(C1-C4)alkyl, and —N((C1-C4)alkyl)2; or 2 R on adjacent atoms 11 form a heterocycloalkyl ring together with the atom to which they are attached, or two R on adjacent atoms11 form a (C5-C8) cycloalkyl ring together with the atom to which they are attached, or two R on adjacent atoms 11 However, along with the atoms to which they are bonded (C6 to C 14 ) forming an aryl ring or two R on adjacent atoms 11 together with the atoms to which they are attached form a heteroaryl ring, or R of 2 11 form C=O with the atoms to which they are attached, Each R 12 is independently in each occurrence (C1-C6)alkoxy, -NR 15 R 16 , -NR 15 C(O)NR 15 R 16 , -NR 15 C(O)R 16 , -NR 15 S(O) m R 16 or —C(O)NH(C3-C8)cycloalkyl; Each R 13 is independently in each occurrence H or (C1-C4) alkyl; Each R 14 is independently in each occurrence H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, -(C0-C2)-alkylene-(C3-C8) cycloalkyl, -(C0-C2)-alkylene-heterocycloalkyl, -(C0-C2)-alkylene-(C6-C 14 )aryl, or -(C0-C2)-alkylene-heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally (C1-C4)alkoxy, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C6-C 14) substituted with one or more substituents selected from aryl, heteroaryl, halogen, —OH, —NH2, CN, —C(O)NH2, —C(O)NH(C1-C4)alkyl, —C(O)N((C1-C4)alkyl)2, —NH(C1-C4)alkyl, and (C1-C4)alkyl substituted with —N((C1-C4)alkyl)2; or R 13 and R 14 together with the nitrogen atom to which they are attached, optionally one or more R 23 forming a heterocycloalkyl ring substituted with Each R 15 is independently in each occurrence H or (C1-C4) alkyl; Each R 16 is independently in each occurrence H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C2-C6)haloalkyl, (C3-C8)cycloalkyl, or -(C0-C2)-alkylene-heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heteroaryl are optionally substituted with one or more substituents independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, and halogen; Each R 17 is independently in each occurrence (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, —OH, —NH2, or CN; R 18 and R 19 each of is independently in each occurrence H or (C1-C4) alkyl; R 18 and R 19 together with the nitrogen atom to which they are attached form a heterocycloalkyl ring; R 20 , R 21 and R22 each in each occurrence is independently H, (C1-C4) alkyl, or (C6-C 14 ) aryl, Each R 23 is (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, -C(O)(C1-C4) alkyl, -C(O)O( independently selected from (C1-C4)alkyl, —C(O)(C3-C8)cycloalkyl, —C(O)heterocycloalkyl, —OH, —NH2, and CN, wherein said alkyl and alkoxy are optionally substituted with one or more substituents selected from (C1-C4)alkoxy and —OH; or R of 2 23 and the above two Rs are bonded to the same atom. 23 form a spiroheterocycloalkyl ring, Each of m, n, p, q, and r is independently 0, 1, or 2.

[0010] Another aspect of the present application relates to a method for treating or preventing a disease or disorder associated with the inhibition of ubiquitin-specific protease 1 (USP1), comprising administering to a patient in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0011] Another aspect of the present application is directed to a method for inhibiting ubiquitin-specific protease 1 (USP1), comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0012] Another aspect of the present application relates to a method for treating or preventing cancer, said method comprising administering to a patient in need of cancer treatment an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0013] Another aspect of the present application relates to a method for treating cancer, comprising administering to a patient in need of cancer treatment an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0014] Another aspect of the present application relates to a method for treating or preventing a disease or disorder associated with DNA damage, said method comprising administering to a patient in need of treatment for a disease or disorder associated with DNA damage an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0015] Another aspect of the present application relates to a method for inhibiting or reducing DNA repair activity regulated by ubiquitin-specific protease 1 (USP1), comprising administering to a patient in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0016] Another aspect of the present application is directed to a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, which may further comprise an excipient, diluent, or surfactant.

[0017] Another aspect of the present application relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for use in a method for the treatment or prevention of diseases associated with the inhibition of USP1.

[0018] Another aspect of the present application relates to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in a method for the treatment or prevention of cancer.

[0019] Another aspect of the present application relates to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in a method for the treatment or prevention of a disease or disorder associated with DNA damage.

[0020] Another aspect of the present application relates to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in a method of inhibiting or reducing DNA repair activity regulated by ubiquitin-specific protease 1 (USP1).

[0021] Another aspect of the present application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the manufacture of a medicament for the treatment or prevention of a disease associated with the inhibition of USP1.

[0022] Another aspect of the present application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the manufacture of a medicament for the treatment or prevention of cancer.

[0023] Another aspect of the present application relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with DNA damage.

[0024] Another aspect of the present application relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for inhibiting or reducing DNA repair activity regulated by ubiquitin-specific protease 1 (USP1).

[0025] The present application further provides methods for treating diseases or disorders associated with the regulation of ubiquitin-specific protease 1 (USP1), including, but not limited to, cancer, comprising administering a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, to a patient suffering from at least one of the diseases or disorders.

[0026] The present application provides inhibitors of ubiquitin-specific protease 1 (USP1) that are therapeutic agents in the treatment of diseases such as cancer and other diseases associated with the regulation of USP1.

[0027] The present application further provides compounds and compositions with improved efficacy and safety profiles compared to known USP1 inhibitors. The present disclosure also provides agents with novel mechanisms of action against the USP1 enzyme in the treatment of various types of diseases, including cancer. Ultimately, the present application provides the medical community with novel pharmacological strategies for the treatment of diseases and disorders associated with the USP1 enzyme. The present invention provides, for example: (Item 1) Formula (I) [ka] or pharmaceutically acceptable salts, hydrates, solvates, isotopes, prodrugs, stereoisomers, and tautomers thereof, wherein X1 is CR6 or N, X2 is CR7 or N, X3 is CR8 or N, X4 is CR9 or N, R1 is H, -CD3, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, (C2-C6) hydroxyalkyl, (C3-C8) cycloalkyl, or heterocycloalkyl, provided that said alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally selected from halogen, -OR 20 , -C(O)R 20 , -CO2R 20 , -NR 18 R 19 , -NR 20 C(O)R 21 , -C(O)NR 20 R 21 , -NR 20 C(O)NR 21 R 22 , -NR 20 S(O) r R 21 , -S(O) r R 20 R 21 , -NR 20 S(O) r R 21 R 22 , -S(O) r R 20 , -P(O)R 20 R 21 , oxo, and -Si((C1-C4)alkyl)3; R2 is (C6~C 14 ) aryl, heteroaryl, (C3-C 10 ) cycloalkyl, or heterocycloalkyl, provided that the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each independently selected from one or more R 10 is replaced by R3 is H, D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, heterocycloalkyl, halogen, —C(O)OH, —C(O)NH2, or CN; R 3’is H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, heterocycloalkyl, —C(O)OH, —C(O)NH2, or CN; or R3 and R 3’ may form a (C3-C7) cycloalkyl ring together with the carbon atom to which they are attached, or R3 and R 3’ may together with the carbon atoms to which they are attached form a heterocycloalkyl ring; R4 is (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C3-C8) cycloalkyl, -O-(C0-C2)-alkylene-(C3-C8) cycloalkyl, heterocycloalkyl, -O-(C0-C2)-alkylene-heterocycloalkyl, halogen, -OH, -NH2, CN, -C(O)(C1-C4) alkyl, -C(O)O(C1-C4) alkyl, -NR 20 C(O)O(C1~C4)alkyl, -Si(CH3)3, -SF5, -S(O) P (C1-C4) alkyl, -S(O) P (NH)(C1-C4)alkyl, —NH(C1-C4)alkyl, —N((C1-C4)alkyl)2, —NH—(C0-C2)-alkylene-(C3-C8)cycloalkyl, or —NH—(C0-C2)-alkylene-heterocycloalkyl, wherein said alkyl, alkenyl, alkynyl, and alkoxy are optionally (C1-C 6) Alkyl, (C1-C6) alkoxy, (C3-C8) cycloalkyl, halogen, -OH, -S(O) r (C1-C4) alkyl, -S(O) rsubstituted with one or more substituents selected from (NH)(C1-C4)alkyl, -SF5, -Si(CH3)3, -NH2, -NH(C1-C4)alkyl, -N((C1-C4)alkyl)2, -C(O)NH2, -C(O)NH(C1-C4)alkyl, and -C(O)NH((C1-C4)alkyl)2, wherein said cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, and halogen; R and X, together with the atoms to which they are attached, may optionally be one or more R 17 (C6~C 14 ) may form an aryl ring, or R and X on adjacent atoms together with the atoms to which they are attached may optionally form one or more R 17 or R and X together with the atoms to which they are attached may optionally form a heteroaryl ring substituted with one or more R 17 or R and X on adjacent atoms together with the atoms to which they are attached may optionally form a (C5-C7)cycloalkyl ring substituted with one or more R 17 may form a heterocycloalkyl ring substituted with R5 is H, D, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) hydroxyalkyl, (C1-C6) haloalkoxy, halogen, (C3-C6) cycloalkyl, heterocycloalkyl, -C(O)O(C1-C4) alkyl, -C(O)(C1-C4) alkyl, -C(O)NR 13 R 14 , -OH, -NH2, CN, -NH(C1-C4) alkyl, -N((C1-C4) alkyl)2 or -NR 13 C(O)R 14 or R1 and R5 together with the atoms to which they are attached form a heterocycloalkyl ring; each of R6, R7, R8, and R9, independently at each occurrence, is H, D, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, (C3-C8)cycloalkyl ring, heterocycloalkyl, or halogen, wherein said alkyl is optionally substituted with one or more (C1-C6)alkoxy; Each R 10 is independently in each occurrence D, -CD3, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -C(O)R 14 , -C(O)OR 13 , -NR 13 R 14 , -NR 13 C(O)R 14 , -NR 13 C(O)NR 13 R 14 , -C(O)NR 13 R 14 , -S(O) p R 14 , -NR 13 S(O) p R 14 , -S(O) p NR 13 R 14 , -CN, -(C0-C2)-alkylene-(C6-C 14 )aryl, -(C0-C2)-alkylene-heteroaryl, -(C0-C2)-alkylene-(C3-C8)cycloalkyl, -(C0-C2)-alkylene-heterocycloalkyl, -O-(C0-C2)-alkylene-aryl, -O-(C0-C2)-alkylene-heteroaryl, -O-(C0-C2)-alkylene-(C3-C8)cycloalkyl, or -O-(C0-C2)-alkylene-heterocycloalkyl, wherein said aryl, heteroaryl, cycloalkyl and heterocycloalkyl may optionally be selected from the group consisting of one or more R 11wherein said alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more R 12 is replaced by, or 2 R on adjacent atoms 10 together with the atoms to which they are attached, optionally one or more R 11 (C6~C 14 ) may form an aryl ring, or two R on adjacent atoms 10 together with the atoms to which they are attached, optionally one or more R 11 or two R on adjacent atoms may form a heteroaryl ring substituted with 10 together with the atoms to which they are attached, optionally one or more R 11 or two R on adjacent atoms may form a substituted (C3-C8) cycloalkyl ring. 10 but , together with the atoms to which they are attached, optionally one or more R 11 or two R 10 and the two R are on the same atom to which they are attached. 10 optionally one or more R 11 or two R 10 and the two R are on the same atom to which they are attached. 10 optionally one or more R 11 and optionally forming a spiroheterocycloalkyl ring substituted with Each R 11 is independently in each occurrence D, -CD3, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, CN, -OH, -NH2, -NH(C1-C4)alkyl, -N((C1-C4)alkyl)2, -C(O)O(C1-C4)alkyl, -S(O) q(C1-C4) alkyl, -C(O)NH2, -C(O)NH(C1-C4) alkyl, -C(O)N((C1-C4) alkyl)2, -NHC(O)(C1-C4) alkyl, -N((C1-C4) alkyl)C(O)(C1-C4) alkyl, (C6-C 14 )aryl, heteroaryl, (C3-C8)cycloalkyl, or heterocycloalkyl, provided that said alkyl, alkoxy, (C3-C8)cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, —C(O)OH, —C(O)O(C1-C4)alkyl, —C(O)(C1-C4)alkyl, —S(O) q substituted with one or more substituents selected from (C1-C4)alkyl, —C(O)NH(C1-C4)alkyl, —C(O)N((C1-C4)alkyl)2, —OH, —NH2, —CN, —NH(C1-C4)alkyl, and —N((C1-C4)alkyl)2; 2 R on adjacent atoms 11 may form a heterocycloalkyl ring together with the atom to which they are attached, or two R on adjacent atoms may 11 may form a (C5-C8) cycloalkyl ring together with the atom to which they are attached, or two R on adjacent atoms 11 However, along with the atoms to which they are bonded (C6 to C 14 ) may form an aryl ring, or two R on adjacent atoms 11 may together with the atoms to which they are attached form a heteroaryl ring, or R of 2 11 may form C=O together with the atom to which they are attached, Each R 12 is independently in each occurrence (C1-C6)alkoxy, -NR 15 R 16 , -NR 15 C(O)NR 15 R 16 , -NR 15 C(O)R 16 , -NR 15 S(O)m R 16 or —C(O)NH(C3-C8)cycloalkyl; Each R 13 is independently in each occurrence H or (C1-C4) alkyl; Each R 14 is independently in each occurrence H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, -(C0-C2)-alkylene-(C3-C8) cycloalkyl, -(C0-C2)-alkylene-heterocycloalkyl, -(C0-C2)-alkylene-(C6-C 14 )aryl, or -(C0-C2)-alkylene-heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally (C1-C4)alkoxy, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C6-C 14 ) substituted with one or more substituents selected from aryl, heteroaryl, halogen, —OH, —NH2, CN, —C(O)NH2, —C(O)NH(C1-C4)alkyl, —C(O)N((C1-C4)alkyl)2, —NH(C1-C4)alkyl, and (C1-C4)alkyl substituted with —N((C1-C4)alkyl)2; or R 13 and R 14 together with the nitrogen atom to which they are attached, optionally one or more R 23 may form a heterocycloalkyl ring substituted with Each R 15 is independently in each occurrence H or (C1-C4) alkyl; Each R 16is independently in each occurrence H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C2-C6)haloalkyl, (C3-C8)cycloalkyl, or -(C0-C2)-alkylene-heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heteroaryl are optionally substituted with one or more substituents independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, and halogen; Each R 17 is independently in each occurrence (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, —OH, —NH2, or CN; R 18 and R 19 each of is independently in each occurrence H or (C1-C4) alkyl; R 18 and R 19 may together with the nitrogen atom to which they are attached form a heterocycloalkyl ring; R 20 , R 21 and R 22 each in each occurrence is independently H, (C1-C4) alkyl, or (C6-C 14 ) aryl, Each R 23 are independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, halogen, —C(O)(C1-C4)alkyl, —C(O)O(C1-C4)alkyl, —C(O)(C3-C8)cycloalkyl, —C(O)heterocycloalkyl, —OH, —NH2, and CN, wherein said alkyl and alkoxy are optionally substituted with one or more substituents selected from (C1-C4)alkoxy and —OH; or R of 2 23 and the two R are on the same atom to which they are attached.23 may form a spiroheterocycloalkyl ring; each of m, n, p, q, and r is independently 0, 1, or 2; The compound, or pharmaceutically acceptable salts, hydrates, solvates, isotopes, prodrugs, stereoisomers, and tautomers thereof. (Item 2) X1 is CR6 or N, X2 is CR7 or N, X3 is CR8 or N, X4 is CR9 or N, R1 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, (C2-C6) hydroxyalkyl, or heterocycloalkyl, provided that said alkyl, alkenyl, alkynyl, and heterocycloalkyl are optionally selected from halogen, -OR 20 , -C(O)R 20 , -CO2R 20 , -NR 18 R 19 , -NR 20 C(O)R 21 , -C(O)NR 20 R 21 , -NR 20 C(O)NR 21 R 22 , -NR 20 S(O) r R 21 , -S(O) r R 20 R 21 , -NR 20 S(O) r R 21 R 22 , -S(O) r R 20 , -P(O)R 20 R 21 and -Si((C1-C4)alkyl)3, R2 is (C6~C 14)aryl, heteroaryl, (C-C)cycloalkyl, or heterocycloalkyl, provided that the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each independently selected from one or more R 10 is replaced by R3 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, heterocycloalkyl, —C(O)OH, —C(O)NH2, or CN; R 3’ is H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) hydroxyalkyl, (C1-C6) aminoalkyl, heterocycloalkyl, -C(O )OH, —C(O)NH2, or CN, or R3 and R 3’ may form a (C3-C7) cycloalkyl ring together with the carbon atom to which they are attached, or R3 and R 3’ may together with the carbon atoms to which they are attached form a heterocycloalkyl ring; R4 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C3-C8)cycloalkyl, halogen, -OH, -NH2, CN, -C(O)(C1-C4)alkyl, -NH(C1-C4)alkyl, or -N((C1-C4)alkyl)2, wherein said alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, -OH, -NH2, -NH(C1-C4)alkyl, and -N((C1-C4)alkyl)2; or R and X, together with the atoms to which they are attached, may optionally be one or more R 17 (C6~C 14 ) may form an aryl ring, or R and X on adjacent atoms together with the atoms to which they are attached may optionally form one or more R 17or R and X together with the atoms to which they are attached may optionally form a heteroaryl ring substituted with one or more R 17 or R and X on adjacent atoms together with the atoms to which they are attached may optionally form a (C5-C7)cycloalkyl ring substituted with one or more R 17 may form a heterocycloalkyl ring substituted with R5 is H, each of R6, R7, R8, and R9 independently, at each occurrence, is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, or halogen, wherein said alkyl is optionally substituted with one or more (C1-C6)alkoxy; Each R 10 is independently in each occurrence (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -C(O)R 14 , -C(O)OR 13 , -NR 13 R 14 , -NR 13 C(O)R 14 , -NR 13 C(O)NR 13 R 14 , -C(O)NR 13 R 14 , -S(O) p R 14 , -NR 13 S(O) p R 14 , -S(O) p NR 13 R 14 , -CN, -(C0-C2)-alkylene-(C6-C 14)aryl, -(C0-C2)-alkylene-heteroaryl, -(C0-C2)-alkylene-(C3-C8)cycloalkyl, -(C0-C2)-alkylene-heterocycloalkyl, -O-(C0-C2)-alkylene-aryl, -O-(C0-C2)-alkylene-heteroaryl, -O-(C0-C2)-alkylene-(C3-C8)cycloalkyl, or -O-(C0-C2)-alkylene-heterocycloalkyl, wherein said aryl, heteroaryl, cycloalkyl and heterocycloalkyl may optionally be selected from the group consisting of one or more R 11 wherein said alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more R 12 is replaced by, or 2 R on adjacent atoms 10 together with the atoms to which they are attached, optionally one or more R 11 (C6~C 14 ) may form an aryl ring, or two R on adjacent atoms 10 together with the atoms to which they are attached, optionally one or more R 11 or two R on adjacent atoms may form a heteroaryl ring substituted with 10 together with the atoms to which they are attached, optionally one or more R 11 or two R on adjacent atoms may form a substituted (C5-C7) cycloalkyl ring. 10 together with the atoms to which they are attached, optionally one or more R 11 or two R 10 and the two R are on the same atom to which they are attached. 10 optionally one or more R 11 Spirochlore substituted with Alternatively, two R 10 and the two R are on the same atom to which they are attached. 10 optionally one or more R 11 and optionally forming a spiroheterocycloalkyl ring substituted with Each R 11 is independently in each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, CN, -OH, -NH2, -NH(C1-C4) alkyl, -N((C1-C4) alkyl)2, -C(O)O(C1-C4) alkyl, -S(O) q (C1-C4) alkyl, -C(O)NH2, -C(O)NH(C1-C4) alkyl, -C(O)N((C1-C4) alkyl)2, -NHC(O)(C1-C4) alkyl, -N((C1-C4) alkyl)C(O)(C1-C4) alkyl, (C6-C 14 )aryl, heteroaryl, (C3-C8)cycloalkyl, or heterocycloalkyl, provided that said alkyl, alkoxy, (C3-C8)cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, —C(O)OH, —C(O)O(C1-C4)alkyl, —C(O)(C1-C4)alkyl, —S(O) q substituted with one or more substituents selected from (C1-C4)alkyl, —C(O)NH(C1-C4)alkyl, —C(O)N((C1-C4)alkyl)2, —OH, —NH2, —CN, —NH(C1-C4)alkyl, and —N((C1-C4)alkyl)2; 2 R on adjacent atoms 11 may form a heterocycloalkyl ring together with the atom to which they are attached, or two R on adjacent atoms may 11 may form a (C5-C8) cycloalkyl ring together with the atom to which they are attached, or two R on adjacent atoms 11 However, along with the atoms to which they are bonded (C6 to C 14 ) may form an aryl ring, or two R on adjacent atoms 11 may together with the atoms to which they are attached form a heteroaryl ring, or R of 2 11 may form C=O together with the atom to which they are attached, Each R12 is independently in each occurrence (C1-C6)alkoxy, -NR 15 R 16 , -NR 15 C(O)NR 15 R 16 , -NR 15 C(O)R 16 , -NR 15 S(O) m R 16 or —C(O)NH(C3-C8)cycloalkyl; Each R 13 is independently in each occurrence H or (C1-C4) alkyl; Each R 14 is independently in each occurrence H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, -(C0-C2)-alkylene-(C3-C8) cycloalkyl, -(C0-C2)-alkylene-heterocycloalkyl, -(C0-C2)-alkylene-(C6-C 14 )aryl, or -(C0-C2)-alkylene-heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally (C1-C4)alkoxy, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C6-C 14 ) substituted with one or more substituents selected from aryl, heteroaryl, halogen, —OH, —NH2, CN, —C(O)NH2, —C(O)NH(C1-C4)alkyl, —C(O)N((C1-C4)alkyl)2, —NH(C1-C4)alkyl, and (C1-C4)alkyl substituted with —N((C1-C4)alkyl)2; or R 13 and R 14 together with the nitrogen atom to which they are attached, optionally one or more R 23 may form a heterocycloalkyl ring substituted with Each R 15 is independently in each occurrence H or (C1-C4) alkyl; Each R 16 is independently in each occurrence H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C2-C6)haloalkyl, (C3-C8)cycloalkyl, or -(C0-C2)-alkylene-heteroaryl, provided that said alkyl, alkenyl, alkynyl, cycloalkyl, and heteroaryl is optionally substituted with one or more substituents independently selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, and halogen; Each R 17 is independently in each occurrence (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, —OH, —NH2, or CN; R 18 and R 19 each of which is independently in each occurrence H or (C1-C4) alkyl; R 18 and R 19 may together with the nitrogen atom to which they are attached form a heterocycloalkyl ring; R 20 , R 21 and R 22 each of which is independently in each occurrence H or (C1-C4) alkyl; Each R 23 are independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, halogen, —C(O)(C1-C4)alkyl, —C(O)O(C1-C4)alkyl, —C(O)(C3-C8)cycloalkyl, —C(O)heterocycloalkyl, —OH, —NH2, and CN, wherein said alkyl and alkoxy are optionally substituted with one or more substituents selected from (C1-C4)alkoxy and —OH; or R of 2 23and the two R are on the same atom to which they are attached. 23 may form a spiroheterocycloalkyl ring; each of m, n, p, q, and r is independently 0, 1, or 2; The compound according to item 1. (Item 3) R1 is H, (C2-C6) hydroxyalkyl, heterocycloalkyl, or optionally -CO2H, -NH2, and N((C l (C -C4) alkyl)2 substituted with one or two substituents selected from l 1-C6) alkyl. (Item 4) R2 is (C6)aryl, 5- or 6-membered heteroaryl, (C3-C6)cycloalkyl, or 5- or 6-membered heterocycloalkyl, provided that the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each independently selected from one or more R 10 4. The compound according to any one of items 1 to 3, substituted with (Item 5) R2 is phenyl, pyrazolyl, pyridinyl, pyridin-2-onyl, pyrimidinyl, cyclobutyl, cyclohexyl, piperidinyl, piperidinonyl, pyridinonyl, or pyrrolinyl, provided that each R2 is 1 to 3 R 10 5. The compound according to any one of items 1 to 4, substituted with (Item 6) R3 and R 3’ are each independently H or (C1-C6) alkyl. (Item 7) The compound according to any one of items 1 to 6, wherein R4 is (C1-C6)alkyl, halogen, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or (C1-C6)alkoxy optionally substituted with (C1-C6)alkoxy. (Item 8) The compound according to any one of items 1 to 7, wherein X1 is CR6 and R6 is H or halogen. (Item 9) X2 is CR7, and R7 is H or halogen. The compounds listed above. (Item 10) The compound according to any one of items 1 to 9, wherein X3 is CR8 and R8 is H or halogen. (Item 11) 11. The compound according to any one of items 1 to 10, wherein X4 is N. (Item 12) 11. The compound according to any one of items 1 to 10, wherein X4 is CR9 and R9 is H, F, or Cl. (Item 13) 13. The compound according to any one of items 1 to 12, wherein n is 1. (Item 14) The compound according to any one of items 1 to 4 or 6 to 12, wherein n is 0. (Item 15) Formula (Ia) or Formula (Ib) [ka] Item 1. The compound according to item 1, having the formula: (Item 16) Formula (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ix), (Ij), (Ik), (Iz), (Im), (Io), (Ip), (Iq), (Ir), or (Iu) [ka] [ka] [ka] Item 1. The compound according to item 1, having the formula: (Item 17) Item 16. The compound according to item 15, wherein R3 is H or (C1-C6) alkyl. (Item 18) R 3’ 18. The compound according to any one of items 15 to 17, wherein is H. (Item 19) R3 and R 3’ together with the carbon atoms to which they are attached form a (C3-C7)cycloalkyl ring; R1 is H or (C1-C6)alkyl. (Item 20) 20. The compound according to any one of items 15 to 19, wherein R1 is H or (C1-C6) alkyl. (Item 21) 21. The compound according to any one of items 15 to 20, wherein R4 is (C1-C6)alkyl, halogen, (C1-C6)haloalkoxy, or (C1-C6)alkoxy optionally substituted with (C1-C6)alkoxy. (Item 22) 22. The compound according to any one of items 15 to 21, wherein X4 is N. (Item 23) 23. The compound according to any one of items 15 to 22, wherein X4 is CR9 and R9 is H or halogen. (Item 24) 24. The compound according to any one of items 17 to 23, wherein R6 is H or halogen. (Item 25) R 10 25. The compound according to any one of items 17 to 24, wherein is heteroaryl. (Item 26) The compound according to item 1, selected from the group consisting of: 9-(4-(3,5-dimethyl-1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(2H-1,2,3-triazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(2H-1,2,3-triazol-2-yl)benzyl)-2-(2-(difluoromethoxy)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(2H-1,2,3-triazol-2-yl)benzyl)-2-(2-isobutoxypyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl) nyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(3-fluoro-2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(5-fluoro-2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(4-fluoro-2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-fluoro-6-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, (S)-9-(1-(4-(1H-pyrazol-1-yl)phenyl)ethyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, (R)-9-(1-(4-(1H-pyrazol-1-yl)phenyl)ethyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(2H-1,2,3-triazol-2-yl)benzyl)-2-(4-fluoro-2-isopropoxyphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(2H-1,2,3-triazol-2-yl)benzyl)-2-(3-fluoro-2-methoxyphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(4-isopropylpyridin-3-yl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-(2,2,2-trifluoroethoxy)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-ethoxypyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-(2-methoxyethoxy)phenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-propoxyphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-(2,2,2-trifluoroethoxy)phenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-(cyclopropylmethoxy)phenyl)-7,9-dihydro-8H-purin-8-one, 9-((1R,2S)-2-(4-(1H-pyrazol-1-yl)phenyl)cyclobutyl)-2-(2-(2,2,2-trifluoroethoxy)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(2,2,2-trifluoroethoxy)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-ethylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(4-isopropylpyrazole) imidin-5-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(1-methyl-1H-indol-7-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-cyclopropylpyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(difluoromethyl)phenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-cyclopropylpyridin-3-yl)-9-(4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(1-methylindolin-7-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-(difluoromethoxy)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(trifluoromethoxy)phenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-acetylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-2-(2-(2,2,2-trifluoroethoxy)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-2-(2-(2,2,2-trifluoroethoxy)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(1-(2-methoxyethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(1-methyl-1H-indazol-7-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(1-methyl-1H-indol-7-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro -8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1,4-dimethyl-1H-pyrazol-3-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-(difluoromethoxy)pyridin-3-yl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(trifluoromethoxy)phenyl)-7,9-dihydro-8H-purin-8-one, 7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(2,2,2-trifluoroethoxy)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)cyclopropyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-chloro-5-methyl-1H-pyrazol-1-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(5-chloro-3-methyl-1H-pyrazol-1-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(2-methyl-1H-pyrrol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, (R)-2-(2-(1-methoxyethyl)phenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, (S)-2-(2-(1-methoxyethyl)phenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-fluoropyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-fluoro-1H-pyrazol-1-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-ethylpyridin-3-yl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-methylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro- 8H-purin-8-one, 2-(2-(difluoromethyl)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(3-fluoro-2-isopropylphenyl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(6-fluoro-2-methylpyridin-3-yl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(5-fluoro-2-isopropylpyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-(azetidin-1-yl)-5-methyl-1H-pyrazol-1-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(5-fluoro-2-isopropylpyridin-3-yl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-cyclopropylphenyl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-cyclopropylpyridin-3-yl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(difluoromethyl)pyridin-3-yl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(6-methoxy-2-methylpyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-fluoro-6-isopropoxypyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-fluoro-6-methoxypyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(5-morpholino-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(3-methoxy-5-methyl-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, (R)-2-(2-isopropylpyridin-3-yl)-9-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-7,9-dihydro-8H-purin-8-one, (S)-2-(2-isopropylpyridin-3-yl)-9-(1-(4-(1-methyl) (4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(1-(methyl-d3)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(3,5-difluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(2,6-difluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(methylsulfinyl)phenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(4-(difluoromethyl)-1-methyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-(difluoromethoxy)pyridin-3-yl)-9-(4-(3-fluoro-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(difluoromethoxy)phenyl)-9-(4-(3-fluoro-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(dimethylamino)phenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-isopropyl-3-methylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-isopropyl-3-methoxyphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(3-chloro-2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-cyclopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(5-chloro-2-cyclopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-fluoro-6-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-cyclopropyl-5-(trifluoromethyl)phenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-cyclopropylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 1-(4-((2-(2-cyclopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-3-methyl-1H-pyrazole-5- ethyl carboxylate, 7-cyclopropyl-2-(2-cyclopropylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 7-cyclopropyl-2-(2-cyclopropylpyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)benzyl)-2-(3-fluoro-2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)benzyl)-2-(3-fluoro-2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-(2-hydroxyethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-7-(2-(dimethylamino)ethyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-7-methyl-9-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)cyclopropyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-(azetidin-1-yl)-5-methyl-1H-pyrazol-1-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(((1S,4S)-4-(3,5-dimethyl-1H-pyrazol-1-yl)cyclohexyl)methyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(((1R,4R)-4-(3,5-dimethyl-1H-pyrazol-1-yl)cyclohexyl)methyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-7-methyl-9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7-methyl-7,9-dihydro-8H-purin-8-one, (R)-2-(2-isopropylpyridin-3-yl)-7-methyl-9-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-7,9-dihydro-8H-purin-8-one, (S)-2-(2-isopropylpyridin-3-yl)-7-methyl-9-(1-(4 -(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-7-methyl-9-(4-(5-morpholino-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(3-methoxy-5-methyl-1H-pyrazol-1-yl)benzyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7-(oxetan-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-7-(2-methoxyethyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 7-(1,1-dioxidothietan-3-yl)-2-(2-isopropylpyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one, 7-(2-hydroxyethyl)-2-(2-isopropylpyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-7-methyl-9-(4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(3,5-difluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(2,6-difluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-7-(methyl-d3)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-7-(methyl-d3)-9-(4-(1-(methyl-d3)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-7-methyl-9-(4-(1-(methyl-d3)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(2-hydroxypropan-2-yl)phenyl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-morpholinopyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-(3-fluoroazetidin-1-yl)pyridin-3-yl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(3-(trifluoromethyl)azetidin-1-yl)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-cyclopropoxypyridin-3-yl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-1,2,3-triazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(2H-1,2,3-triazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (S)-9-(1-(4-(2H-1,2,3-triazol-2-yl)phenyl)ethyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (R)-9-(1-(4-(2H-1,2,3-triazol-2-yl)phenyl)ethyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-((1-(pyridin-3-yl)piperidin-4-yl)methyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(1-(pyridin-3-yl)piperidin-4-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (S)-9-(1-(4-(1H-1,2,3-triazol-1-yl)phenyl)ethyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (R)-9-(1-(4-(1H-1,2,3-triazol-1-yl)phenyl)ethyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(5-methyl-1,3,4-oxadiazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)benzonitrile, 2-(2-isopropylphenyl)-9-(4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(morpholinomethyl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-1,2,4-triazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (R)-2-(2-isopropylphenyl)-9-(1-phenylethyl)-7,9-dihydro-8H-purin-8-one, (S)-2-(2-isopropylphenyl)-9-(1-phenylethyl)-7,9-dihydro-8H-purin-8-one, (S)-9-(1-(4-(1H-pyrazol-1-yl)phenyl)ethyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (R)-9-(1-(4-(1H-pyrazol-1-yl)phenyl)ethyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (R)-9-(chroman-4-yl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-methyl-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(2-(1-(pyridin-3-yl)piperidin-4-yl)ethyl)-7,9-dihydro-8H-purin-8-one, 9-(2-chloro-4-(1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-((1R,2S)-2-(4-(1H-pyrazol-1-yl)phenyl)cyclobutyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-((1S,2R)-2-(4-(1H-pyrazol-1-yl)phenyl)cyclobutyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-1,2,3-triazol-1-yl)benzyl)-2-(3-fluoro-2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(2H-1,2,3-triazol-2-yl)benzyl)-2-(3-fluoro-2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(5-methyl-2H-tetrazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(oxazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(3-fluoro-2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-benzyl-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(3-fluoro-2-isopropylphenyl)-9-(4-(1-methyl-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-(4-methylpiperazin-1-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-morpholino-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(4-methyl-1H-1,2,3-triazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(5-fluoro-1-methyl-1H-imidazol-2-yl)benzyl) -2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(3-fluoro-4-(1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (R)-9-(1-(4-fluorophenyl)ethyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (S)-9-(1-(4-fluorophenyl)ethyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (S)-9-(1-(4-fluorophenyl)-2-hydroxyethyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (S)-9-(2-hydroxy-1-phenylethyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-((1-methyl-1H-benzo[d]imidazol-5-yl)methyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(methylsulfonyl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(5-methyl-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(5-methyl-1H-1,2,3-triazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-((2-methyl-1-oxoisoindolin-5-yl)methyl)-7,9-dihydro-8H-purin-8-one, 6-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one, 2-(3-fluoro-2-isopropylphenyl)-9-(4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(3-fluoro-2-isopropylphenyl)-9-(4-(5-methyl-1,3,4-oxadiazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, (R)-9-(1-(4-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)ethyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (S)-9-(1-(4-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)ethyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(3-fluoro-2-isopropylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 1-(4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-1H-pyrazole-3-carbonitrile , 9-(3-(1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(4-chloro-1-methyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 1-(4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-1H-pyrazole-3,5-dicarbonitrile, 9-(4-(2,5-dimethyloxazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(3-fluoro-2-isopropylphenyl)-9-(4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(3-fluoro-2-isopropylphenyl)-9-(4-(4-methyl-1-(oxetan-3-yl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-((6-(1,4-dimethyl-1H-imidazol-2-yl)pyridin-3-yl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-methoxy-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(2-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(5-methoxy-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 1-(4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-5-methyl-1H-pyrazole-3-carbonitrile, 1-(4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-3-methyl-1H-pyrazole-5-carbonitrile, 2-(2-isopropylphenyl)-9-(4-(1-methyl-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-chloro-5-methyl-1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(5-chloro-3-methyl-1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(((1S,4S)-4-(3,5-dimethyl-1H-pyrazol-1-yl)cyclohexyl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(((1R,4R)-4-(3,5-dimethyl-1H-pyrazol-1-yl)cyclohexyl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (R)-2-(2-isopropylphenyl)-9-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-7,9-dihydro-8H-purin-8-one, (S)-2-(2-isopropylphenyl)-9-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-7,9- dihydro-8H-purin-8-one, 9-(4-(3,3-dimethyloxetan-2-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, N-(3-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)acetamide, N-(4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)acetamide, 2-(2-isopropylphenyl)-9-(4-(1-methyl-5-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, tert-butyl 4-fluoro-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)piperidine-1-carboxylate, 2-(2-isopropylphenyl)-9-(4-(4-(piperidin-4-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-(pyrrolidin-3-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-(piperidin-3-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, (R)-2-(2-isopropylphenyl)-9-(4-(3-(piperidin-3-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, (S)-2-(2-isopropylphenyl)-9-(4-(3-(piperidin-3-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(1-(4-(1H-pyrazol-1-yl)phenyl)cyclopropyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(1-(4-fluorophenyl)cyclopropyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(cyclopropylmethoxy)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-((tetrahydrofuran-3-yl)methoxy)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-((1-methylpiperidin-3-yl)methoxy)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(pyridin-2-ylmethoxy)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-((1-methyl-1H-imidazol-5-yl)methoxy)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(2-(dimethylamino)ethoxy)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(3-(dimethylamino)propoxy)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-((5-methylisoxazol-3-yl)methoxy)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(2-ethoxyethoxy)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-Cyclobutoxybenzyl)-2-(2-isopropylphenyl)-7-methyl 7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(3-(cyclopropylmethoxy)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(3-((tetrahydrofuran-3-yl)methoxy)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(3-((1-methylpiperidin-3-yl)methoxy)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(3-(pyridin-2-ylmethoxy)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(3-((1-methyl-1H-imidazol-5-yl)methoxy)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(3-(2-(dimethylamino)ethoxy)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(3-(3-(dimethylamino)propoxy)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(3-cyclobutoxybenzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(pyrazin-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-((3'-(2-(dimethylamino)ethyl)-[1,1'-biphenyl]-4-yl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-((4'-(2-(dimethylamino)ethyl)-[1,1'-biphenyl]-4-yl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(6-morpholinopyrimidin-4-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-methyl-1H-imidazol-5-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1,5-dimethyl-1H-pyrazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3,5-dimethylisoxazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(4-(4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-1-methyl-1H-pyrazol-5-yl)acetic acid, 2-(2-isopropylphenyl)-9-(4-(pyrimidin-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-methyl-1H-pyrazol-5-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(1-methyl-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1,4-dimethyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-((2'-(2-(dimethylamino)ethoxy)-[1,1'-biphenyl]-4 -yl)methyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-((3'-(2-(dimethylamino)ethoxy)-[1,1'-biphenyl]-4-yl)methyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-((4'-(2-(dimethylamino)ethoxy)-[1,1'-biphenyl]-4-yl)methyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-((4'-(2-(dimethylamino)ethyl)-[1,1'-biphenyl]-4-yl)methyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(6-morpholinopyrimidin-4-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(1-methyl-1H-imidazol-5-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-([1,2,4]triazolo[1,5-a]pyridin-5-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(benzo[d]isoxazol-7-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-indazol-7-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(imidazo[1,2-a]pyridin-8-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(imidazo[1,2-a]pyridin-5-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(1-methyl-1H-imidazol-4-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(1-methyl-1H-1,2,4-triazol-3-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-methyl-1H-imidazol-4-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-methyl-1H-1,2,4-triazol-3-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-isopropyl-1H-imidazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1,2-dimethyl-1H-imidazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1-isopropyl-1H-imidazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 3-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-1-methyl-1H-1,2,4-triazole-5-carboxamide, 9-(4-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)benzyl 2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(1-methyl-5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(5-methoxy-1-methyl-1H-1,2,4-triazol-3-yl)benzyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(1-methyl-5-morpholino-1H-1,2,4-triazol-3-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1-isopropyl-1H-pyrazol-5-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(1-methyl-1H-1,2,3-triazol-5-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-([1,2,4]triazolo[4,3-a]pyridin-3-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(5-(hydroxymethyl)-1-methyl-1H-imidazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(imidazo[1,2-a]pyrazin-8-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(4-methyloxazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(imidazo[1,2-a]pyrazin-8-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-methyl-5-morpholino-1H-1,2,4-triazol-3-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-methyl-5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(5-methoxy-1-methyl-1H-1,2,4-triazol-3-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(5-(hydroxymethyl)-1-methyl-1H-imidazol-4-yl )benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-methyl-1H-1,2,3-triazol-5-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-isopropyl-1H-pyrazol-5-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(5-methylthiazol-4-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(2,5-dimethylthiazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(5-(hydroxymethyl)thiazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(5-methylthiazol-4-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(2,5-dimethylthiazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(5-(hydroxymethyl)thiazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(6-methylimidazo[1,2-a]pyrazin-8-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1,4-dimethyl-1H-imidazol-2-yl)benzyl)-2-(3-fluoro-2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(3-fluoro-2-isopropylphenyl)-9-(4-(1-methyl-1H-imidazol-4-yl)benzyl)-7,9-dihydro-8H-purin-8-one, (R)-2-(2-isopropylphenyl)-9-(1-(4-(1-methyl-1H-imidazol-2-yl)phenyl)ethyl)-7,9-dihydro-8H-purin-8-one, (S)-2-(2-isopropylphenyl)-9-(1-(4-(1-methyl-1H-imidazol-2-yl)phenyl)ethyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(methylamino)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-(ethylamino)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(isopropylamino)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(cyclopropylamino)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-((2-ethoxyethyl)amino)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(cyclobutylamino)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-((1-methoxypropan-2-yl)amino)pyridin-3-yl)-9 -(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, N,N-dimethyl-2-((3-(9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyridin-2-yl)amino)acetamide, (R)-2-(2-((1-methoxypropan-2-yl)amino)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(((tetrahydrofuran-2-yl)methyl)amino)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, (S)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-((tetrahydrofuran-3-yl)amino)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-(dimethylamino)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(diethylamino)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(pyrrolidin-1-yl)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(piperidin-1-yl)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-((2-methoxyethyl)(methyl)amino)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(4-methylpiperazin-1-yl)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-(isopropyl(methyl)amino)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(ethyl(methyl)amino)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(methyl(2,2,2-trifluoroethyl)amino)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-morpholinopyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-(3-fluoroazetidin-1-yl)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(azetidin-1-yl)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(3-(trifluoromethyl)azetidin-1-yl)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(4-(2-aminopropan-2-yl)-1H-1,2,3-triazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(4-((dimethylamino)methyl)-1H-1,2,3-triazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(4-(2-hydroxyethyl)-1H-1,2,3-triazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(4-((diethylamino)methyl)-1H-1,2,3-triazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (R)-9-(4-(4-(1-hydroxyethyl)-1H-1,2,3-triazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(4-(3-aminopentan-3-yl)-1H-1,2,3-triazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(4-((methylsulfonyl)methyl)-1H-1,2,3-triazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-methylbenzamide, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-(2-methoxyethyl)benzamide, N-cyclopropyl-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)benzamide, N-(4-fluorobenzyl)-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)benzamide, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N,N-dimethylbenzamide, N-isopropyl-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)benzamide, N-isobutyl-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)benzamide, N-cyclopentyl-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)benzamide, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-(1-phenylcyclopentyl)benzamide, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-((1-methyl-1H-imidazol-2-yl)methyl)benzamide, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)benzamide, N,N-diethyl-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)benzamide, 2-(2-isopropylphenyl)-9-(4-(morpholine-4-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, N-cyclohexyl-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-methylbenzamide, N-(4-fluorobenzyl)-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-methylbenzamide, 2-(2-isopropylphenyl)-9-(4-(4-methylpiperidine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)benzamide, 2-(2-isopropylphenyl)-9-(4-(3-(methoxymethyl)piperidine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, (R)-2-(2-isopropylphenyl)-9-(4-(2-methylpyrrolidine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, N-isopropyl-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-(2-methoxyethyl)benzamide, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-methyl-N-((2-methylthiazol-4-yl)methyl)benzamide, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-(1-methyl-1H-imidazol-2-yl)benzoate Zuamide, N-ethyl-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-methylbenzamide, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-methyl-N-propylbenzamide, N-isopropyl-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-methylbenzamide, N-(2-hydroxyethyl)-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-methylbenzamide, 9-(4-(3-hydroxyazetidine-1-carbonyl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (S)-9-(4-(3-hydroxypyrrolidine-1-carbonyl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, N-cyclopropyl-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-methylbenzamide, N-(2-(dimethylamino)-2-oxoethyl)-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-methylbenzamide, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-(oxetan-3-yl)benzamide, (S)-9-(4-(2-(hydroxymethyl)pyrrolidine-1-carbonyl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(4-acetylpiperazine-1-carbonyl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (S)-2-(2-isopropylphenyl)-9-(4-(3-(2-methoxyethoxy)pyrrolidine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-((2R,6S)-2,6-dimethylmorpholine-4-carbonyl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-fluoroazetidine-1-carbonyl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, N-((1R,2S)-2-hydroxycyclopentyl)-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)benzamide, 9-(4-(4,4-difluoropiperidine-1-carbonyl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(pyrrolidine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(2-methylpyrrolidine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-(1-(methoxymethyl)cyclopropyl)-N-methylbenzamide, 9-(4-(3,3-difluoropyrrolidine-1-carbonyl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(5-oxa-2-azaspiro[3.4]octane-2-carbonyl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one hmm, 9-(4-(6-oxa-2-azaspiro[3.4]octane-2-carbonyl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (S)-2-(2-isopropylphenyl)-9-(4-(2-methylpyrrolidine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, (S)-2-(2-isopropylphenyl)-9-(4-(2-(methoxymethyl)pyrrolidine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(2-ethylpiperidine-1-carbonyl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(2-methylpiperidine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-methylpiperidine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(2-(methoxymethyl)piperidine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-methoxypiperidine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-methyl-N-(tetrahydrofuran-3-yl)benzamide, (R)-2-(2-isopropylphenyl)-9-(4-(2-(methoxymethyl)pyrrolidine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, (R)-2-(2-isopropylphenyl)-9-(4-(3-methylmorpholine-4-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, (S)-2-(2-isopropylphenyl)-9-(4-(3-methylmorpholine-4-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-methyl-N-(2,2,2-trifluoroethyl)benzamide, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-(2-methoxyethyl)-N-methylbenzamide, N-(2-(dimethylamino)ethyl)-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)benzamide, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-(2-(piperidin-1-yl)ethyl)benzamide, 2-(2-isopropylphenyl)-9-(4-(4-methylpiperazine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(2-oxa-5-azaspiro[3.4]octane-5-carbonyl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-methoxypyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-propoxypyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-(cyclopropylmethoxy)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9 -dihydro-8H-purin-8-one, 2-(2-(2-ethoxyethoxy)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropoxypyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(sec-butoxy)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-cyclobutoxypyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-cyclopropoxypyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-ethoxypyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isobutoxypyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(2-methoxyethoxy)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-((tetrahydrofuran-2-yl)methoxy)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-((tetrahydrofuran-3-yl)methoxy)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-(3-methoxybutoxy)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(pentan-3-yloxy)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-((1-methoxybutan-2-yl)oxy)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(2-(dimethylamino)ethoxy)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-(azetidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-(piperidin-4-yl)-1 H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-(piperazin-1-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(3-(piperidin-4-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(3-fluoro-2-isopropylphenyl)-9-(4-(3-(piperidin-4-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(3-(piperidin-4-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-(azetidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(1-(1-methylazetidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-(1-methylpiperidin-4-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-(1-methylpyrrolidin-3-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(3-fluoro-2-isopropylphenyl)-9-(4-(3-(1-methylpiperidin-4-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(3-(1-methylpiperidin-4-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-(1-methylpiperidin-4-yl)-1H-pyrazol-1-yl)benzyl)-2-(2-(2,2,2-trifluoroethoxy)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-(1-methylpiperidin-3-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-methyl-4-(1-methylpiperidin-4-yl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-methyl-5-(1-methylpiperidin-4-yl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-(1-methylazetidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(1-(1-methylazetidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-((1-(pyridin-3-ylsulfonyl)piperidin-4-yl)methyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-((1-(isopropylsulfonyl)piperidin-4-yl)methyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-((1-((1-methyl-1H-imidazol-2-yl)sulfonyl)piperidin-4-yl)methyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(2-(isopropylsulfonyl)-2-azaspiro[3.3]heptan-5-yl)-7,9-dihydro-8H-purin-8-one, N-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-1-methyl-1H-pyrazole-3-sulfonamide, N-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-1-methyl-1H-imidazole-2-sulfonamide, N-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-1,2-dimethyl-1H-imidazole-4-sulfonamide, N-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-N,1-dimethyl-1H-pyrazole-3-sulfonamide, N-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-N,1-dimethyl-1H-imidazole-2-sulfonamide, N-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-N,1,2-trimethyl-1H-imidazole-4-sulfonamide, N-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-N-methylmethanesulfonamide, 9-((1-(cyclopropylsulfonyl)-4-fluoropiperidin-4-yl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-((1-(cyclopropylsulfonyl)piperidin-4-yl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-((1-isobutyrylpiperidin-4-yl)methyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(3-(1-acetylpiperidin-4-yl)-1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-(1-acetylpiperidin-4-yl)-1H-pyrazol-1-yl)benzyl)-2-(3-fluoro-2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-(1-acetylpiperidin-4-yl)-1H-pyrazol-1-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-(1-acetylpiperidin-4-yl)-1H-pyrazol-1-yl)benzyl)-2-(2-(2,2,2-trifluoroethoxy)pyridin-3-yl )-7,9-dihydro-8H-purin-8-one, 9-(4-(3-(1-acetylpyrrolidin-3-yl)-1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-(1-acetylpiperidin-3-yl)-1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, N-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide, N-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-N,5-dimethyl-1H-pyrazole-3-carboxamide, N-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-N,1,3-trimethyl-1H-pyrazole-5-carboxamide, 9-(4-(4-(1-acetylpiperidin-4-yl)-1-methyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(5-(1-acetylpiperidin-4-yl)-1-methyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-(1-acetylpiperidin-4-yl)-1H-pyrazol-1-yl)benzyl)-2-(2-fluoro-6-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-((4-fluoro-1-isobutyrylpiperidin-4-yl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-(1-acetylazetidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-(1-acetylazetidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, N-isopropyl-4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)piperidine-1-carboxamide, N-cyclopropyl-4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)piperidine-1-carboxamide, 4-(1-(4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-1H-pyrazol-3-yl)-N-methylpiperidine-1-carboxamide, 1-isopropyl-3-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)urea, 1-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-3-(2-methoxyethyl)urea, 1-cyclopropyl-3-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)urea, 3-Isopropyl-1-(4-((2-(2-isopropylphenyl)-7-methyl- 8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-1-methylurea, 1-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-3-(2-methoxyethyl)-1-methylurea, 3-cyclopropyl-1-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-1-methylurea, 4-fluoro-N-isopropyl-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)piperidine-1-carboxamide, 9-(4-((cyclopropylmethyl)amino)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-((2-methoxyethyl)amino)benzyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-((cyclopropylmethyl)(methyl)amino)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-((2-methoxyethyl)(methyl)amino)benzyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-((1-(1,3,4-thiadiazol-2-yl)piperidin-4-yl)methyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)-7,9-dihydro-8H-purin-8-one, 9-((1-(2,5-dimethylthiazol-4-yl)piperidin-4-yl)methyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(2-(pyridin-3-yl)-2-azaspiro[3.3]heptan-5-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-ethyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1-isopropyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-(2-methoxyethyl)-1H-imidazol-2-yl)benzyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(1-(piperidin-4-yl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-(difluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-((1-(1,4-dimethyl-1H-imidazol-2-yl)piperidin-4-yl)methyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-((1-(4-(trifluoromethyl)pyrimidin-2-yl)azetidin-3-yl)methyl)-7,9-dihydro-8H-purin-8-one, 1-(4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro- 9H-purin-9-yl)methyl)phenyl)-N,N,5-trimethyl-1H-pyrazole-3-carboxamide, 1-(4-((2-(2-cyclopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-N,N,5-trimethyl-1H-pyrazole-3-carboxamide, 9-((4-fluoro-1-(pyridin-3-yl)piperidin-4-yl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-(2-hydroxyethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 7-ethyl-2-(2-isopropylpyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-((5-(1H-pyrazol-1-yl)pyrazin-2-yl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-((5-(1H-pyrazol-1-yl)pyrimidin-2-yl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-((5-(3,5-dimethyl-1H-pyrazol-1-yl)pyrazin-2-yl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-((5-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidin-2-yl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(2-oxopyrrolidin-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-tetrazol-5-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-((1-(2,5-dimethylthiazol-4-yl)-4-fluoropiperidin-4-yl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(4-cyclopropyl-1-methyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(3-isopropylpyridin-4-yl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(3-isopropylpyridin-2-yl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-(2-(dimethylamino)ethyl)-1H-1,2,3-triazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purine On-8-on, 9-(4-(2H-1,2,3-triazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)benzoate methyl 2-(2-(2-hydroxypropan-2-yl)phenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(1-hydroxycyclopropyl)phenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-propionylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-(2-hydroxypropan-2-yl)phenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-8-oxo-8,9-dihydro-7H-purin-7-yl)propanoic acid, 2-(2-(difluoromethoxy)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(methylamino)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(methylamino)-7,9-dihydro-8H-purin-8-one, 6-(dimethylamino)-2-(2-isopropylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 6-acetyl-2-(2-isopropylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-6-methoxy-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-isopropyl-5-methyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-isopropyl-4-methyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, N-(2-(4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-1-methyl-1H-imidazol-4-yl)acetamide, 9-(4-(1H-pyrazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8 -dihydro-9H-purin-9-yl)methyl)phenyl)-1-methyl-1H-imidazole-4-carbonitrile, 2-(2-cyclopropylphenyl)-9-(4-(5-(hydroxymethyl)-3-methyl-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, Methyl 4-(1-(4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-1H-pyrazol-3-yl)piperidine-1-carboxylate, and 2-(2-(1-hydroxyethyl)phenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one. (Item 27) 27. A pharmaceutical composition comprising a compound according to any one of items 1 to 26 and a pharmaceutically acceptable carrier. (Item 28) 27. A method for treating or preventing a disease or disorder associated with the regulation of ubiquitin-specific protease 1 (USP1), comprising administering to a patient in need thereof an effective amount of a compound according to any one of items 1 to 26. (Item 29) 27. A method for treating or preventing a disease or disorder associated with the inhibition of ubiquitin-specific protease 1 (USP1), comprising administering to a patient in need thereof an effective amount of a compound according to any one of items 1 to 26. (Item 30) A method for treating or preventing cancer, the method comprising administering an effective amount of a compound according to any one of items 1 to 26 to a patient in need thereof. (Item 31) A method for treating cancer, comprising administering an effective amount of a compound according to any one of items 1 to 26 to a patient in need thereof. (Item 32) 27. A method for treating or preventing a disease or disorder associated with DNA damage, the method comprising administering an effective amount of a compound according to any one of items 1 to 26 to a patient in need of the method. (Item 33) 27. A method for inhibiting or reducing DNA repair activity regulated by ubiquitin-specific protease 1 (USP1), comprising administering to a patient in need thereof an effective amount of a compound according to any one of items 1 to 26. (Item 34) 27. The compound according to any one of items 1 to 26 for use in a method for the treatment or prevention of diseases which are associated with the inhibition of ubiquitin-specific protease 1 (USP1). (Item 35) 27. A compound according to any one of items 1 to 26 for use in a method for treating or preventing cancer. (Item 36) 27. The compound according to any one of items 1 to 26 for use in a method for the treatment or prevention of a disease or disorder associated with DNA damage. (Item 37) 27. The compound according to any one of items 1 to 26, for use in a method for inhibiting or reducing DNA repair activity regulated by ubiquitin-specific protease 1 (USP1). (Item 38) 27. Use of a compound according to any one of items 1 to 26 in the manufacture of a medicament for the treatment or prevention of diseases which are associated with the inhibition of ubiquitin-specific protease 1 (USP1). (Item 39) 27. Use of a compound according to any one of items 1 to 26 in the manufacture of a medicament for the treatment or prevention of cancer. (Item 40) 27. Use of a compound according to any one of items 1 to 26 in the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with DNA damage. (Item 41) 27. Use of a compound according to any one of items 1 to 26 in the manufacture of a medicament for inhibiting or reducing DNA repair activity regulated by ubiquitin-specific protease 1 (USP1). DETAILED DESCRIPTION OF THE INVENTION

[0028] This application relates to compounds and compositions capable of inhibiting the activity of USP1. This application features a method for treating, preventing, or ameliorating a disease or disorder involving USP1 by administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, to a patient in need thereof. The method of this application can be used to treat various USP1-dependent diseases and disorders by inhibiting the activity of the USP1 enzyme. Inhibition of USP1 provides a novel approach to the treatment, prevention, or amelioration of diseases, including, but not limited to, cancer.

[0029] In a first aspect of the present application, a compound of formula (I) [ka] and pharmaceutically acceptable salts, hydrates, solvates, isotopes, prodrugs, stereoisomers, and tautomers thereof, wherein R, R, R, R 3’ , R4, R5, X1, X2, X3, X4, and n are as defined herein above.

[0030] Details of the present application are set forth in the description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, illustrative methods and materials are described herein. Other features, objects, and advantages of the present application will become apparent from the specification and claims. In this specification and the appended claims, the singular encompasses the plural unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. All patents and publications cited herein are incorporated by reference in their entirety.

[0031] definition As used herein, the articles "a" and "an" refer to one or more (i.e., at least (Also used to refer to the grammatical object of the article in question. By way of example, "an element" means one element or more than one element.

[0032] In this disclosure, the term "and / or" is used to mean either "and" or "or" unless otherwise indicated.

[0033] The term "optionally substituted" should be understood to mean that a given chemical moiety (e.g., an alkyl group) may (but is not required to) be bonded to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group may be a fully saturated alkyl chain (i.e., pure hydrocarbon). Alternatively, the same optionally substituted alkyl group may have a substituent other than hydrogen. For example, an optionally substituted alkyl group may be bonded at any point along the chain to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety may contain other functional groups, but does not necessarily have to have any additional functional groups. Suitable substituents for optional substitution of the groups described include halogen, oxo, -OH, -CN, -COOH, -CHCN, -O-(C1-C6)alkyl, (C1-C6)alkyl, C1-C6alkoxy, (C1-C6)haloalkyl, C1-C6 haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -OH, -OP(O)(OH), -OC( Examples of the alkyl group include, but are not limited to, —O)(C1-C6)alkyl, —C(O)(C1-C6)alkyl, —OC(O)O(C1-C6)alkyl, —NH, —NH((C1-C6)alkyl), —N((C1-C6)alkyl), —NHC(O)(C1-C6)alkyl, —C(O)NH(C1-C6)alkyl, —S(O)(C1-C6)alkyl, —S(O)NH(C1-C6)alkyl, and S(O)N((C1-C6)alkyl). The above substituents may themselves be optionally substituted. As used herein, “optionally substituted” also means substituted or unsubstituted, the meaning of which is explained below.

[0034] As used herein, the term "substituted" means that the specified group or moiety has one or more optional substituents that can be attached to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl is attached to the aryl at one atom of the aryl by one bond, or is fused to the aryl and attached to the aryl by sharing two or more common atoms.

[0035] As used herein, the term "unsubstituted" means that the specified group bears no substituents.

[0036] Unless expressly defined otherwise, the term "aryl" refers to a cyclic, aromatic hydrocarbon group having one to three aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (e.g., bicyclic), the aromatic rings of the aryl group may be attached at a single point (e.g., biphenyl) or may be fused (e.g., naphthyl). The aryl group may be optionally substituted at any point of attachment with one or more substituents, e.g., one to five substituents. Exemplary substituents include: -H, -halogen, -O-(C1-C6)alkyl, (C1-C6)alkyl, -O-(C2-C6)alkenyl, -O-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, NH2, NH((C1-C6)alkyl), N((C1-C6)alkyl)2, Examples of aryl groups include, but are not limited to, -S(O)-(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl, and -S(O)N((C1-C6)alkyl). The above substituents may themselves be optionally substituted. Furthermore, aryl groups, as defined herein, when containing two fused rings, may have an unsaturated or partially saturated ring fused to a fully saturated ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.

[0037] Unless expressly defined otherwise, "heteroaryl" refers to a monovalent, monocyclic or polycyclic aromatic group of 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, or S, with the remaining ring atoms being carbon. As defined herein, heteroaryl also refers to a bicyclic heteroaromatic group in which the heteroatoms are selected from N, O, or S. The aromatic group is optionally substituted independently with one or more substituents described herein. Examples include furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, and triazinyl. , imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl , indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quina Zolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1λ 2-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3 [-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore, aryl groups as defined herein, when they contain two fused rings, can have an unsaturated or partially saturated ring fused to a fully saturated ring. Exemplary ring systems of these heteroaryl groups include indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl, and dihydrobenzoxanyl. can be done.

[0038] Halogen or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0039] Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms. Examples of (C1-C6) alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0040] "Alkoxy" refers to a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms containing a terminal "O" in the chain, i.e., -O(alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[0041] "Alkenyl" refers to a straight-chain or branched-chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. The "alkenyl" group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. Alkenyl groups can be unsubstituted or substituted. As defined herein, alkenyl can be straight-chain or branched.

[0042] "Alkynyl" refers to a straight-chain or branched unsaturated hydrocarbon containing 2 to 12 carbon atoms. The "alkynyl" group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. Alkynyl groups can be unsubstituted or substituted.

[0043] The term "alkylene" or "alkylenyl" refers to a divalent alkyl group. Any of the monovalent alkyl groups described above can be converted to an alkylene by abstracting a second hydrogen atom from the alkyl. As defined herein, alkylene can also be a C1-C6 alkylene. Additionally, alkylene can be a C1-C4 alkylene. Common alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.

[0044] As used herein, the term "aminoalkyl" refers to an alkyl group, as defined herein, substituted with one or more amino groups. Examples of aminoalkyl groups include, but are not limited to, aminomethyl, diaminomethyl, aminoethyl, 1,2-diaminoethyl, and the like.

[0045] "Cycloalkyl" refers to alkyl groups containing 3 to 18 carbon atoms (e.g., C3-C 10 ) means a mono- or polycyclic saturated carbocyclic ring (e.g., fused, bridged, or spirocyclic). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.

[0046] "Heterocyclyl" or "heterocycloalkyl" means a heterocyclic group consisting of carbon and oxygen, nitrogen, or means a monocyclic or polycyclic ring (e.g., fused, bridged, or spiro) containing a heteroatom selected from , and sulfur, wherein there are no delocalized π-electrons (aromaticity) shared between ring carbons or ring heteroatoms. The heterocycloalkyl may be a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring. The heterocycloalkyl ring structure may be substituted with one or more substituents, which may themselves be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl. According to the present application, 3- to 10-membered heterocyclyl refers to a saturated or partially saturated non-aromatic ring structure containing 3 to 10 atoms in which at least one heteroatom selected from the group N, O, and S is present.

[0047] The term "hydroxyalkyl" refers to an alkyl group as defined above that is substituted with one or more -OH groups. Examples of hydroxyalkyl groups include HO-CH2-, HO-CH2-CH2-, and CH3-CH(OH)-.

[0048] As used herein, the term "haloalkyl" refers to an alkyl group, as defined herein, substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, and the like.

[0049] As used herein, the term "haloalkoxy" refers to an alkoxy group, as defined herein, substituted with one or more halogens. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, and the like.

[0050] As used herein, the term "cyano" refers to a substituent having a carbon atom triple bonded to a nitrogen atom, ie, C≡N.

[0051] As used herein, the term "amine" refers to primary (R-NH, R≠H), secondary (R-NH, R≠H), and tertiary (R-N, R≠H) amines. By substituted amine is intended an amine in which at least one hydrogen atom has been replaced with a substituent.

[0052] As used herein, the term "amino" refers to a substituent containing at least one nitrogen atom. Specifically, NH, -NH(alkyl) or alkylamino, -N(alkyl) i.e., dialkylamino, amido, carbamido, urea, and sulfamido substituents are encompassed by the term "amino."

[0053] As used herein, the term "dialkylamino" refers to an amino in which both hydrogen atoms are replaced with alkyl groups as defined hereinabove, i.e., NH, i.e., -N(alkyl). The alkyl groups on said dialkylamino group can be the same or different alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino (i.e., -N(CH), diethylamino, dipropylamino, di-isopropylamino, di-n-butylamino, di-sec-butylamino, di-tert-butylamino, methyl(ethyl)amino, methyl(butyl)amino, and the like.

[0054] As used herein, the term "oxo" refers to the group "=O".

[0055] "Spirocycloalkyl" or "spirocyclyl" refers to a carbobicyclic ring system in which both rings are bonded through a single atom. The rings may be different in size and nature or may be identical in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both rings in the spiro ring may be fused to another carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more carbon atoms in the spiro ring may be replaced with a heteroatom (e.g., O, N, S, or P). (C3-C 12 ) Spirocycloalkyl is a spiro ring containing 3 to 12 carbon atoms, one or more of which may be replaced by a heteroatom.

[0056] The terms "spiroheterocycloalkyl" or "spiroheterocyclyl" shall be understood to mean a spirocycle in which at least one of the rings is a heterocycle (e.g., at least one of the rings is furanyl, morpholinyl, or piperazinyl).

[0057] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and a solvent. For purposes of this application, such a solvent should not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are generally referred to as hydrates. Hydrates encompass compositions containing not only stoichiometric amounts of water, but also compositions containing variable amounts of water.

[0058] The term "isomer" refers to compounds that are identical in composition and molecular weight but have different physical and / or chemical properties. The structural difference may be in configuration (geometric isomers) or in ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, the compounds of formula (I) may have one or more asymmetric carbon atoms and may exist as racemates, racemic mixtures, and as individual enantiomers or diastereomers.

[0059] The present disclosure also encompasses pharmaceutical compositions comprising an effective amount of the disclosed compounds and a pharmaceutically acceptable carrier. Representative "pharmaceutically acceptable salts" include, for example, acetate, amsonate (4,4'-diaminostilbene-2,2'-disulfonate), benzenesulfonate, benzoate, bicarbonate, hydrogensulfate, bitartrate, borate, bromide, butyrate, calcium salt, calcium edetate, camsylate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, lauric acid, and the like. Water-soluble and water-insoluble salts include ammonium salts such as ammonium salts, magnesium salts, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salts, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate), embonate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

[0060] A "patient" or "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a non-human primate such as a monkey, chimpanzee, baboon, or rhesus monkey.

[0061] An "effective amount" when used in reference to a compound is an amount effective to treat or prevent a disease of interest as described herein.

[0062] In this disclosure, the term "carrier" encompasses carriers, excipients, and diluents and means a substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a pharmaceutical agent from one organ or part of a subject's body to another organ or part of the body.

[0063] The term "treatment" with respect to a subject refers to ameliorating at least one symptom of a disorder in the subject. Treatment includes curing, ameliorating, or at least partially ameliorating the disorder.

[0064] In this disclosure, the term "disorder" is used to mean, and is used interchangeably with, the terms disease, illness, or illness, unless otherwise indicated.

[0065] In this disclosure, the terms "administer," "administering," or "administration" refer to either administering a disclosed compound or a pharmaceutically acceptable salt of said disclosed compound or composition directly to a subject, or administering to said subject a prodrug derivative or analog of said compound or a pharmaceutically acceptable salt of said compound or composition that is capable of forming an equivalent amount of the active compound in said subject's body.

[0066] As used herein, the term "prodrug" means a compound that is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound.

[0067] The term "cancer" includes, but is not limited to, the following cancers: adrenocortical carcinoma, AIDS-related lymphoma, AIDS-related malignancies, anal cancer, cerebellar astrocytoma, extrahepatic bile duct cancer, bladder cancer, osteosarcoma / malignant fibrous histiocytoma, brain stem glioma, ependymoma, optic tract hypothalamic glioma, breast cancer, bronchial adenoma / bronchial carcinoid, carcinoid tumor, gastrointestinal carcinoid, carcinoma, adrenocortical carcinoma, pancreatic islet cell carcinoma, primary central nervous system lymphoma, cerebellar astrocytoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia Hematologic malignancies, clear cell sarcoma of tendon sheath, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma / Ewing's tumor, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer including intraocular melanoma and retinoblastoma, gallbladder cancer, gastrointestinal carcinoid, ovarian germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, Hodgkin's disease, hypopharyngeal carcinoma, hypothalamic optic tract glioma, intraocular melanoma, Kaposi's sarcoma, pharyngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, liver cancer, non-small cell lung cancer, small cell Lung cancer, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, malignant mesothelioma, malignant thymoma, osteoblastoma, melanoma, intraocular melanoma, Merkel cell carcinoma, metastatic squamous cell carcinoma of the neck with unknown primary origin, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, chronic myeloid leukemia, myeloid leukemia, multiple myeloma, myeloproliferative disorders, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, oral cavity cancer, oral cavity and lip cancer, oropharyngeal cancer, osteosarcoma / malignant fibrous histiocytoma of bone, ovarian cancer, ovarian hypoplasia Malignant tumors include pancreatic cancer, cancer of the paranasal sinuses and nasal cavity, parathyroid cancer, penile cancer, pheochromocytoma, pituitary tumors, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, transitional cell carcinoma (e.g., renal pelvis and ureter), retinoblastoma, rhabdomyosarcoma, salivary gland cancer, malignant fibrous histiocytoma of bone, soft tissue sarcoma, Sezary syndrome, skin cancer, small intestine cancer, gastric cancer, supratentorial primitive neuroectodermal tumor and pineal tumor, cutaneous T-cell lymphoma, testicular cancer, malignant thymoma, thyroid cancer, gestational trophoblastic tumor, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms' tumor. In this embodiment, the cancer is non-small cell lung cancer.

[0068] In any of the embodiments of the present application, the cancer may be any cancer in any organ, for example, the cancer is selected from the group consisting of glioma, thyroid cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, gastric cancer, colon cancer, gastrointestinal stromal tumor, pancreatic cancer, bile duct cancer, CNS cancer, ovarian cancer, endometrial cancer, prostate cancer, renal cancer, anaplastic large cell lymphoma, leukemia, multiple myeloma, mesothelioma, and melanoma, and combinations thereof.

[0069] This application relates to compounds capable of inhibiting USP1, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, that are useful for treating diseases and disorders associated with the regulation of the USP1 enzyme. This application also relates to compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof that are useful for inhibiting USP1.

[0070] In one embodiment, the compound of formula (I) has the formula (Ia) [ka] and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

[0071] In another embodiment, the compound of formula (I) has the formula (Ib) [ka] and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

[0072] In one embodiment, the compound of formula (I) has formula (Ic) or formula (Id): [ka] and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

[0073] In another embodiment, the compound of formula (I) is of formula (Ie), formula (If), formula (Ig), or formula (Ih): [ka] and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

[0074] In another embodiment, the compound of formula (I) is of formula (Ix), formula (Ij), formula (Ik), or formula (Iz): [ka] and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

[0075] In another embodiment, the compound of formula (I) has the formula (Im) or the formula (Io) [ka] and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof, wherein R3 is (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, heterocycloalkyl, —C(O)OH, —C(O)NH2, or CN.

[0076] In another embodiment, the compound of formula (I) is of formula (Ip), formula (Iq), formula (Ir), or formula (Iu) [ka] [ka] and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof, wherein R3 is (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, heterocycloalkyl, —C(O)OH, —C(O)NH2, or CN.

[0077] In some embodiments of the above formula, R1 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, (C1-C6) hydroxyalkyl, or heterocycloalkyl, provided that the alkyl, alkenyl, alkynyl, and heterocycloalkyl are optionally selected from halogen, -OR 20 , -C(O)R 20 , -CO2R 20 , -NR 18 R 19 , -NR 20 C(O)R 21 , -C(O)NR 20 R 21 , -NR 20 C(O)NR 21 R 22 , -NR 20 S(O) r R 21 , -S(O) r R 20 R 21 , -NR 20 S(O) r R 21 R 22 , -S(O) r R 20 , -P(O)R 20 R 21 and -Si((C1-C4)alkyl)3, R2 is (C6~C 14 ) aryl, heteroaryl, (C3-C 10) cycloalkyl, or heterocycloalkyl, provided that the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each independently selected from one or more R 10 is replaced by R3 is H, D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, heterocycloalkyl, halogen, —C(O)OH, —C(O)NH2, or CN; R 3’ is H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, heterocycloalkyl, —C(O)OH, —C(O)NH2, or CN; or R3 and R 3’ may form a (C3-C7) cycloalkyl ring together with the carbon atom to which they are attached, or R3 and R 3’ may together with the carbon atoms to which they are attached form a heterocycloalkyl ring; R4 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C3-C8)cycloalkyl, -O-(C0-C2)-alkylene-(C3-C8)cycloalkyl, halogen, -OH, -NH2, CN, -C(O)(C1-C4)alkyl, -NH(C1-C4)alkyl, or -N((C1-C4)alkyl)2, wherein said alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, -OH, -NH2, -NH(C1-C4)alkyl, and -N((C1-C4)alkyl)2; R and X, together with the atoms to which they are attached, may optionally be one or more R 17 (C6~C 14 ) may form an aryl ring, or R and X on adjacent atoms together with the atoms to which they are attached may optionally form one or more R 17or R4 and X4 may form a heteroaryl ring substituted with and optionally one or more R 17 or R and X on adjacent atoms together with the atoms to which they are attached may optionally form a (C5-C7)cycloalkyl ring substituted with one or more R 17 may form a heterocycloalkyl ring substituted with R5 is H, (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C1-C4) alkoxy, (C1-C4) hydroxyalkyl, (C1-C4) haloalkoxy, halogen, (C3-C6) cycloalkyl, heterocycloalkyl, -OH, -NH2, CN, -NH(C1-C4) alkyl, -N((C1-C4) alkyl)2, or -NR 13 C(O)R 14 and each of R6, R7, R8, and R9 is independently, at each occurrence, H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, or halogen, wherein said alkyl is optionally substituted with one or more (C1-C6)alkoxy; Each R 10 is independently in each occurrence (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -C(O)R 14 , -C(O)OR 13 , -NR 13 R 14 , -NR 13 C(O)R 14 , -NR 13 C(O)NR 13 R 14 , -C(O)NR 13 R 14 , -S(O) p R 14 , -NR13 S(O) p R 14 , -S(O) p NR 13 R 14 , -CN, -(C0-C2)-alkylene-(C6-C 14 )aryl, -(C0-C2)-alkylene-heteroaryl, -(C0-C2)-alkylene-(C3-C8)cycloalkyl, -(C0-C2)-alkylene-heterocycloalkyl, -O-(C0-C2)-alkylene-aryl, -O-(C0-C2)-alkylene-heteroaryl, -O-(C0-C2)-alkylene-(C3-C8)cycloalkyl, or -O-(C0-C2)-alkylene-heterocycloalkyl, provided that the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl may optionally be selected from the group consisting of one or more R 11 wherein the alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more R 12 is replaced by, or 2 R on adjacent atoms 10 together with the atoms to which they are attached, optionally one or more R 11 (C6~C 14 ) may form an aryl ring, or two R on adjacent atoms 10 together with the atoms to which they are attached, optionally one or more R 11 or two R on adjacent atoms may form a heteroaryl ring substituted with 10 together with the atoms to which they are attached, optionally one or more R 11 or two R on adjacent atoms may form a substituted (C3-C8) cycloalkyl ring. 10 together with the atoms to which they are attached, optionally one or more R 11 or two R 10 and the above two Rs are bonded to the same atom. 10 optionally one or more R 11 or two R 10and the above two Rs are bonded to the same atom. 10 optionally one or more R 11 and optionally forming a spiroheterocycloalkyl ring substituted with Each R 11 is independently in each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, CN, -OH, -NH2, -NH(C1-C4) alkyl, -N((C1-C4) alkyl)2, -C(O)O(C1-C4) alkyl, -S(O) q (C1-C4) alkyl, -C(O)NH2, -C(O)NH(C1-C4) alkyl, -C(O)N((C1-C4) alkyl)2, -NHC(O)(C1-C4) alkyl, -N((C1-C4) alkyl)C(O)(C1-C4) alkyl, (C6-C 14 ) aryl, heteroaryl, (C3-C8) cycloalkyl, or heterocycloalkyl, provided that the above alkyl, alkoxy, (C3-C8) cycloalkyl, heterocycloalkyl, aryl Aryl and heteroaryl are optionally selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, -C(O)OH, -C(O)O(C1-C4) alkyl, -C(O)(C1-C4) alkyl, -S(O) q substituted with one or more substituents selected from (C1-C4)alkyl, —C(O)NH(C1-C4)alkyl, —C(O)N((C1-C4)alkyl)2, —OH, —NH2, —CN, —NH(C1-C4)alkyl, and —N((C1-C4)alkyl)2; 2 R on adjacent atoms 11 may form a heterocycloalkyl ring together with the atom to which they are attached, or two R on adjacent atoms may 11 may form a (C5-C8) cycloalkyl ring together with the atom to which they are attached, or two R on adjacent atoms 11 However, along with the atoms to which they are bonded (C6 to C 14 ) may form an aryl ring, or two R on adjacent atoms11 may together with the atoms to which they are attached form a heteroaryl ring, or R of 2 11 may form C=O together with the atom to which they are attached, Each R 12 is independently in each occurrence (C1-C6)alkoxy, -NR 15 R 16 , -NR 15 C(O)NR 15 R 16 , -NR 15 C(O)R 16 , -NR 15 S(O) m R 16 or —C(O)NH(C3-C8)cycloalkyl; Each R 13 is independently in each occurrence H or (C1-C4) alkyl; Each R 14 is independently in each occurrence H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, -(C0-C2)-alkylene-(C3-C8) cycloalkyl, -(C0-C2)-alkylene-heterocycloalkyl, -(C0-C2)-alkylene-(C6-C 14 )aryl, or -(C0-C2)-alkylene-heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally (C1-C4)alkoxy, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C6-C 14 ) substituted with one or more substituents selected from aryl, heteroaryl, halogen, —OH, —NH2, CN, —C(O)NH2, —C(O)NH(C1-C4)alkyl, —C(O)N((C1-C4)alkyl)2, —NH(C1-C4)alkyl, and (C1-C4)alkyl substituted with —N((C1-C4)alkyl)2; or R 13 and R 14together with the nitrogen atom to which they are attached, optionally one or more R 23 may form a heterocycloalkyl ring substituted with Each R 15 is independently in each occurrence H or (C1-C4) alkyl; Each R 16 is independently in each occurrence H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C2-C6)haloalkyl, (C3-C8)cycloalkyl, or -(C0-C2)-alkylene-heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heteroaryl are optionally substituted with one or more substituents independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, and halogen; Each R 17 is independently in each occurrence (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, —OH, —NH2, or CN; R 18 and R 19 each of is independently in each occurrence H or (C1-C4) alkyl; R 18 and R 19 may together with the nitrogen atom to which they are attached form a heterocycloalkyl ring; R 20 , R 21 and R 22 Each of these is independent in its existence, H, (C1~ C4) alkyl, or (C6-C 14 ) aryl, Each R 23are independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, halogen, —C(O)(C1-C4)alkyl, —C(O)O(C1-C4)alkyl, —C(O)(C3-C8)cycloalkyl, —C(O)heterocycloalkyl, —OH, —NH2, and CN, wherein said alkyl and alkoxy are optionally substituted with one or more substituents selected from (C1-C4)alkoxy and —OH; or R of 2 23 and the above two Rs are bonded to the same atom. 23 may form a spiroheterocycloalkyl ring; Each of m, n, p, q, and r is independently 0, 1, or 2.

[0078] In some embodiments of the above formula, R1 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, (C2-C6) hydroxyalkyl, or heterocycloalkyl, provided that the alkyl, alkenyl, alkynyl, and heterocycloalkyl are optionally selected from halogen, -OR 20 , -C(O)R 20 , -CO2R 20 , -NR 18 R 19 , -NR 20 C(O)R 21 , -C(O)NR 20 R 21 , -NR 20 C(O)NR 21 R 22 , -NR 20 S(O) r R 21 , -S(O) r R 20 R 21 , -NR 20 S(O) r R 21 R 22 , -S(O) r R 20 , -P(O)R 20 R 21and -Si((C1-C4)alkyl)3, R2 is (C6~C 14 )aryl, heteroaryl, (C-C)cycloalkyl, or heterocycloalkyl, provided that the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each independently selected from one or more R 10 is replaced by R3 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, heterocycloalkyl, —C(O)OH, —C(O)NH2, or CN; R 3’ is H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, heterocycloalkyl, —C(O)OH, —C(O)NH2, or CN; or R3 and R 3’ form a (C3-C7) cycloalkyl ring together with the carbon atoms to which they are attached, or R3 and R 3’ together with the carbon atoms to which they are attached form a heterocycloalkyl ring; R4 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C3-C8)cycloalkyl, halogen, -OH, -NH2, CN, -C(O)(C1-C4)alkyl, -NH(C1-C4)alkyl, or -N((C1-C4)alkyl)2, wherein said alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, -OH, -NH2, -NH(C1-C4)alkyl, and -N((C1-C4)alkyl)2; R and X, together with the atoms to which they are attached, may optionally be one or more R 17 (C6~C 14) R and X on adjacent atoms together with the atoms to which they are attached may optionally form an aryl ring. 17 or R and X together with the atoms to which they are attached form a heteroaryl ring substituted with one or more R 17 or R and X on adjacent atoms together with the atoms to which they are attached form a (C5-C7)cycloalkyl ring substituted with one or more R 17 forming a heterocycloalkyl ring substituted with R5 is H, Each of R6, R7, R8, and R9 independently, in each occurrence, is selected from H, (C (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, or halogen, wherein said alkyl is optionally substituted with one or more (C1-C6)alkoxy; Each R 10 is independently in each occurrence (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -C(O)R 14 , -C(O)OR 13 , -NR 13 R 14 , -NR 13 C(O)R 14 , -NR 13 C(O)NR 13 R 14 , -C(O)NR 13 R 14 , -S(O) p R 14 , -NR 13 S(O) p R 14 , -S(O) p NR 13 R 14 , -CN, -(C0-C2)-alkylene-(C6-C 14)aryl, -(C0-C2)-alkylene-heteroaryl, -(C0-C2)-alkylene-(C3-C8)cycloalkyl, -(C0-C2)-alkylene-heterocycloalkyl, -O-(C0-C2)-alkylene-aryl, -O-(C0-C2)-alkylene-heteroaryl, -O-(C0-C2)-alkylene-(C3-C8)cycloalkyl, or -O-(C0-C2)-alkylene-heterocycloalkyl, provided that the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl may optionally be selected from the group consisting of one or more R 11 wherein the alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more R 12 is replaced by, or 2 R on adjacent atoms 10 together with the atoms to which they are attached, optionally one or more R 11 (C6~C 14 ) forming an aryl ring or two R on adjacent atoms 10 together with the atoms to which they are attached, optionally one or more R 11 or two R on adjacent atoms to form a heteroaryl ring substituted with 10 together with the atoms to which they are attached, optionally one or more R 11 Form a (C5-C7) cycloalkyl ring substituted with, or two R on adjacent atoms 10 together with the atoms to which they are attached, optionally one or more R 11 or two R 10 and the above two Rs are bonded to the same atom. 10 optionally one or more R 11 or two R 10 and the above two Rs are bonded to the same atom. 10 optionally one or more R 11 forming a spiroheterocycloalkyl ring substituted with Each R 11is independently in each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, CN, -OH, -NH2, -NH(C1-C4) alkyl, -N((C1-C4) alkyl)2, -C(O)O(C1-C4) alkyl, -S(O) q (C1-C4) alkyl, -C(O)NH2, -C(O)NH(C1-C4) alkyl, -C(O)N((C1-C4) alkyl)2, -NHC(O)(C1-C4) alkyl, -N((C1-C4) alkyl)C(O)(C1-C4) alkyl, (C6-C 14 )aryl, heteroaryl, (C3-C8)cycloalkyl, or heterocycloalkyl, provided that the alkyl, alkoxy, (C3-C8)cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, —C(O)OH, —C(O)O(C1-C4)alkyl, —C(O)(C1-C4)alkyl, —S(O) q substituted with one or more substituents selected from (C1-C4)alkyl, —C(O)NH(C1-C4)alkyl, —C(O)N((C1-C4)alkyl)2, —OH, —NH2, —CN, —NH(C1-C4)alkyl, and —N((C1-C4)alkyl)2; 2 R on adjacent atoms 11 form a heterocycloalkyl ring together with the atom to which they are attached, or two R on adjacent atoms 11 form a (C5-C8) cycloalkyl ring together with the atom to which they are attached, or two R on adjacent atoms 11 However, along with the atoms to which they are bonded (C6 to C 14 ) forming an aryl ring or two R on adjacent atoms 11 together with the atoms to which they are attached form a heteroaryl ring, or R of 2 11 form C=O with the atoms to which they are attached, Each R 12 is independently in each occurrence (C1-C6)alkoxy, -NR15 R 16 , -NR 15 C(O)NR 15 R 16 , -NR 15 C(O)R 16 , -NR 15 S(O) m R 16 or —C(O)NH(C3-C8)cycloalkyl; Each R 13 is independently in each occurrence H or (C1-C4) alkyl; Each R 14 is independently in each occurrence H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, -(C0-C2)-alkylene-(C3-C8) cycloalkyl, -(C0-C2)-alkylene-heterocycloalkyl, -(C0-C2)-alkylene-(C6-C 14 )aryl, or -(C0-C2)-alkylene-heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally (C1-C4)alkoxy, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C6-C 14 ) substituted with one or more substituents selected from aryl, heteroaryl, halogen, —OH, —NH2, CN, —C(O)NH2, —C(O)NH(C1-C4)alkyl, —C(O)N((C1-C4)alkyl)2, —NH(C1-C4)alkyl, and (C1-C4)alkyl substituted with —N((C1-C4)alkyl)2; or R 13 and R 14 together with the nitrogen atom to which they are attached, optionally one or more R 23 forming a heterocycloalkyl ring substituted with Each R 15 is independently in each occurrence H or (C1-C4) alkyl; Each R 16is independently in each occurrence H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C2-C6)haloalkyl, (C3-C8)cycloalkyl, or -(C0-C2)-alkylene-heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heteroaryl are optionally substituted with one or more substituents independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, and halogen; Each R 17 is independently in each occurrence (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, —OH, —NH2, or CN; R 18 and R 19 each of is independently in each occurrence H or (C1-C4) alkyl; R 18 and R 19 together with the nitrogen atom to which they are attached form a heterocycloalkyl ring; R 20 , R 21 and R 22 each of is independently in each occurrence H or (C1-C4) alkyl; Each R 23 are independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, halogen, —C(O)(C1-C4)alkyl, —C(O)O(C1-C4)alkyl, —C(O)(C3-C8)cycloalkyl, —C(O)heterocycloalkyl, —OH, —NH2, and CN, wherein said alkyl and alkoxy are optionally substituted with one or more substituents selected from (C1-C4)alkoxy and —OH; or R of 2 23 and the above two Rs are bonded to the same atom. 23form a spiroheterocycloalkyl ring, Each of m, n, p, q, and r is independently 0, 1, or 2.

[0079] In some embodiments of the above formula, R1 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, (C2-C6) hydroxyalkyl, or heterocycloalkyl, provided that the alkyl, alkenyl, alkynyl, and heterocycloalkyl are optionally selected from halogen, -OR 20 , -C(O)R 20 , -CO2R 20 , -NR 18 R 19 , -NR 20 C(O)R 21 , -C(O)NR 20 R 21 , -NR 20 C(O)NR 21 R 22 , -NR 20 S(O) r R 21 , -S(O) r R 20 R 21 , -NR 20 S(O) r R 21 R 22 , -S(O) r R 20 , -P(O)R 20 R 21 and -Si((C1-C4)alkyl)3, R2 is (C6~C 14 )aryl, heteroaryl, (C-C)cycloalkyl, or heterocycloalkyl, provided that the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each independently selected from one or more R 10 is replaced by R3 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, heterocycloalkyl, —C(O)OH, —C(O)NH2, or CN; R 3’ is H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, heterocycloalkyl, —C(O)OH, —C(O)NH2, or CN; or R3 and R 3’ form a (C3-C7) cycloalkyl ring together with the carbon atoms to which they are attached, or R3 and R 3’ together with the carbon atoms to which they are attached form a heterocycloalkyl ring; R4 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C3-C8)cycloalkyl, halogen, -OH, -NH2, CN, -C(O)(C1-C4)alkyl, -NH(C1-C4)alkyl, or -N((C1-C4)alkyl)2, wherein said alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, -OH, -NH2, -NH(C1-C4)alkyl, and -N((C1-C4)alkyl)2; R and X, together with the atoms to which they are attached, may optionally be one or more R 17 (C6~C 14 ) form an aryl ring, or R and X on adjacent atoms, together with the atoms to which they are attached, may optionally be joined by one or more R 17 or R and X together with the atoms to which they are attached form a heteroaryl ring substituted with one or more R 17 or R and X on adjacent atoms together with the atoms to which they are attached form a (C5-C7)cycloalkyl ring substituted with one or more R 17forming a heterocycloalkyl ring substituted with R5 is H, each of R6, R7, R8, and R9 is independently, at each occurrence, H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, or halogen, wherein said alkyl is optionally substituted with one or more (C1-C6)alkoxy; Each R 10 is independently in each occurrence (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -C(O)R 14 , -C(O)OR 13 , -NR 13 R 14 , -NR 13 C(O)R 14 , -NR 13 C(O)NR 13 R 14 , -C(O)NR 13 R 14 , -S(O) p R 14 , -NR 13 S(O) p R 14 , -S(O) p NR 13 R 14 , -CN, -(C0-C2)-alkylene-(C6-C 14 )aryl, -(C0-C2)-alkylene-heteroaryl, -(C0-C2)-alkylene-(C3-C8)cycloalkyl , —(C0-C2)-alkylene-heterocycloalkyl, —O—(C0-C2)-alkylene-aryl, —O—(C0-C2)-alkylene-heteroaryl, —O—(C0-C2)-alkylene-(C3-C8)cycloalkyl, or —O—(C0-C2)-alkylene-heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl may optionally be selected from the group consisting of one or more R 11 wherein the alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more R 12 is replaced by, or 2 R on adjacent atoms 10 together with the atoms to which they are attached, optionally one or more R 11 (C6~C 14 ) forming an aryl ring or two R on adjacent atoms 10 together with the atoms to which they are attached, optionally one or more R 11 or two R on adjacent atoms to form a heteroaryl ring substituted with 10 together with the atoms to which they are attached, optionally one or more R 11 Form a (C5-C7) cycloalkyl ring substituted with, or two R on adjacent atoms 10 together with the atoms to which they are attached, optionally one or more R 11 or two R 10 and the above two Rs are bonded to the same atom. 10 optionally one or more R 11 or two R 10 and the above two Rs are bonded to the same atom. 10 optionally one or more R 11 forming a spiroheterocycloalkyl ring substituted with Each R 11is independently in each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, CN, -OH, -NH2, -NH(C1-C4) alkyl, -N((C1-C4) alkyl)2, -C(O)O(C1-C4) alkyl, -S(O) q (C1-C4) alkyl, -C(O)NH2, -C(O)NH(C1-C4) alkyl, -C(O)N((C1-C4) alkyl)2, -NHC(O)(C1-C4) alkyl, -N((C1-C4) alkyl)C(O)(C1-C4) alkyl, (C6-C 14 )aryl, heteroaryl, (C3-C8)cycloalkyl, or heterocycloalkyl, provided that the alkyl, alkoxy, (C3-C8)cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, —C(O)OH, —C(O)O(C1-C4)alkyl, —C(O)(C1-C4)alkyl, —S(O) q substituted with one or more substituents selected from (C1-C4)alkyl, —C(O)NH(C1-C4)alkyl, —C(O)N((C1-C4)alkyl)2, —OH, —NH2, —CN, —NH(C1-C4)alkyl, and —N((C1-C4)alkyl)2; 2 R on adjacent atoms 11 form a heterocycloalkyl ring together with the atom to which they are attached, or two R on adjacent atoms 11 form a (C5-C8) cycloalkyl ring together with the atom to which they are attached, or two R on adjacent atoms 11 However, along with the atoms to which they are bonded (C6 to C 14 ) forming an aryl ring or two R on adjacent atoms 11 together with the atoms to which they are attached form a heteroaryl ring, or R of 2 11 form C=O with the atoms to which they are attached, Each R 12 is independently in each occurrence (C1-C6)alkoxy, -NR15 R 16 , -NR 15 C(O)NR 15 R 16 , -NR 15 C(O)R 16 , -NR 15 S(O) m R 16 or —C(O)NH(C3-C8)cycloalkyl; Each R 13 is independently in each occurrence H or (C1-C4) alkyl; Each R 14 is independently in each occurrence H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, -(C0-C2)-alkylene-(C3-C8) cycloalkyl, -(C0-C2)-alkylene-heterocycloalkyl, -(C0-C2)-alkylene-(C6-C 14 )aryl, or -(C0-C2)-alkylene-heteroaryl, provided that the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optional. optionally (C1-C4)alkoxy, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C6-C 14 ) substituted with one or more substituents selected from aryl, heteroaryl, halogen, —OH, —NH2, CN, —C(O)NH2, —C(O)NH(C1-C4)alkyl, —C(O)N((C1-C4)alkyl)2, —NH(C1-C4)alkyl, and (C1-C4)alkyl substituted with —N((C1-C4)alkyl)2; or R 13 and R 14 together with the nitrogen atom to which they are attached, optionally one or more R 23 forming a heterocycloalkyl ring substituted with Each R 15 is independently in each occurrence H or (C1-C4) alkyl; Each R 16is independently in each occurrence H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C2-C6)haloalkyl, (C3-C8)cycloalkyl, or -(C0-C2)-alkylene-heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heteroaryl are optionally substituted with one or more substituents independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, and halogen; Each R 17 is independently in each occurrence (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, —OH, —NH2, or CN; R 18 and R 19 each of is independently in each occurrence H or (C1-C4) alkyl; R 18 and R 19 together with the nitrogen atom to which they are attached form a heterocycloalkyl ring; R 20 , R 21 and R 22 each of is independently in each occurrence H or (C1-C4) alkyl; Each R 23 are independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, halogen, —C(O)(C1-C4)alkyl, —C(O)O(C1-C4)alkyl, —C(O)(C3-C8)cycloalkyl, —C(O)heterocycloalkyl, —OH, —NH2, and CN, wherein said alkyl and alkoxy are optionally substituted with one or more substituents selected from (C1-C4)alkoxy and —OH; R of 2 23 and the above two Rs are bonded to the same atom. 23form a spiroheterocycloalkyl ring, Each of m, n, p, q, and r is independently 0, 1, or 2.

[0080] In some embodiments of the above formula, X1 is CR6, X2 is CR7, X3 is CR8, and X4 is CR9. In other embodiments, X1 is CR6, X2 is CR7, X3 is CR8, and X4 is N. In other embodiments, X1 is CR6, X2 is CR7, X3 is N, and X4 is CR9. In other embodiments, X1 is CR6, X2 is N, X3 is CR8, and X4 is CR9. In other embodiments, X1 is N, X2 is CR7, X3 is CR8, and X4 is CR9.

[0081] In some embodiments of the above formula, R1 is H, (C1-C6) alkyl, (C2-C6) hydroxyalkyl, or heterocycloalkyl, wherein the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 In another embodiment, R is substituted with one or more substituents selected from H, methyl, —CHCHOH, —CHCHNH, —CH( CH3)C(O)OH, or optionally -C(O)R 20 In yet another embodiment, R1 is H or methyl.

[0082] In some embodiments of the above formula, R3 is H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)hydroxyalkyl, (C1-C3)aminoalkyl, heterocycloalkyl, -C(O)OH, -C(O)NH2, or CN. In yet other embodiments, R3 is H, (C1-C2)alkyl, (C1-C2)hydroxyalkyl, -C(O)OH, -C(O)NH2, or CN. In other embodiments, R3 is H or (C1)alkyl.

[0083] In some embodiments of the above formula, R 3’ is H, (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) hydroxyalkyl, (C1-C3) aminoalkyl, heterocycloalkyl, halogen, —C(O)OH, —C(O)NH, or CN. 3’ is H, (C1-C2) alkyl, (C1-C2) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN. 3’ is H or methyl.

[0084] In another embodiment, R and R 3’ together with the carbon atoms to which they are attached form a (C-C) cycloalkyl ring. 3’ together with the carbon atoms to which they are attached form a heterocycloalkyl ring. 3’ together with the carbon atoms to which they are attached form a (C3-C4) cycloalkyl ring.

[0085] In some embodiments of the above formula, R4 is (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C3-C6)cycloalkyl, halogen, —NH2, —C(O)(C1-C4)alkyl, —O—(C0-C2)-alkylene-(C3-C8)cycloalkyl, —NH(C1-C4)alkyl, or —N((C1-C4)alkyl)2, wherein the alkyl and alkoxy are optionally substituted with 1 to 3 substituents selected from (C1-C4)alkyl, (C1-C4)alkoxy, —OH, —NH2, —NH(C1-C4)alkyl, and —N((C1-C4)alkyl)2. In another embodiment, R4 is (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C3-C6)cycloalkyl, halogen, —NH2, or —C(O)(C1-C4)alkyl, wherein said alkyl is optionally substituted with 1 to 3 substituents (C1-C4)alkoxy. In another embodiment, R4 is heterocycloalkyl. In another embodiment, R4 is pyrrolidinyl, piperazinyl, or piperidinyl.

[0086] In another embodiment, R and X, together with the atoms to which they are attached, optionally include one or more R 17 (C6~C 14 In yet another embodiment, R and X on adjacent atoms, together with the atom to which they are attached, optionally form one or more R 17 In another embodiment, R and X, together with the atom to which they are attached, optionally form a heteroaryl ring substituted with one or more R 17 In yet another embodiment, R and X on adjacent atoms, together with the atom to which they are attached, form a (C5-C7)cycloalkyl ring substituted with one or more R 17 forming a heterocycloalkyl ring substituted with

[0087] In some embodiments of the above formula, R5 is H, (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C1-C4) alkoxy, (C1-C4) hydroxyalkyl, (C1-C4) haloalkoxy, halogen, —OH, —NH2 , CN, -NH(C1-C4)alkyl, -N((C1-C4)alkyl)2 or -NR 13 C(O)R 14 In another embodiment, R5 is H.

[0088] In some embodiments of the above formula, R6 is H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, or halogen, wherein said alkyl is optionally substituted with one to three (C1-C6)alkoxy. In other embodiments, R6 is H, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C1-C4)hydroxyalkyl, or halogen, wherein said alkyl is optionally substituted with one to three (C1-C6)alkoxy. In other embodiments, R6 is H, (C1-C4)alkyl, or halogen.

[0089] In some embodiments of the above formula, R7 is H, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, or halogen, wherein the alkyl is optionally substituted with one to three (C1-C6) alkoxy. In other embodiments, R7 is H, (C1-C4) alkyl, (C1-C4) haloalkyl, or halogen. In yet other embodiments, R7 is H, (C1-C4) haloalkyl, or halogen.

[0090] In some embodiments of the above formula, R8 is H, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, (C1-C4) hydroxyalkyl, or halogen, wherein the alkyl is optionally substituted with 1 to 3 (C1-C6) alkoxy. In other embodiments, R8 is H, (C1-C4) alkoxy, or halogen.

[0091] In some embodiments of the above formula, R9 is H, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C1-C4)hydroxyalkyl, or halogen, wherein the alkyl is optionally substituted with 1 to 3 (C1-C4)alkoxy. In other embodiments, R9 is H, (C1-C4)alkyl, (C1-C4)alkoxy, or halogen.

[0092] In some embodiments of the above formula, R 10 is (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -C(O)R 14 , -C(O)OR 13 , -NR 13 R 14 , -NR 13 C(O)R 14 , -NR 13 C(O)NR 13 R 14 , -C(O)NR 13 R 14 , -S(O) p R 14 , -NR 13 S(O) p R 14 , -S(O) p NR 13 R 14 or CN, wherein the alkyl, alkenyl, alkynyl, and alkoxy groups are optionally selected from 1 to 3 R 12 In another embodiment, R 10 HA-C(O)R 14, -C(O)OR 13 , -NR 13 R 14 , -NR 13 C(O)R 14 , -NR 13 C(O)NR 13 R 14 , -C(O)NR 13 R 14 , -S(O) p R 14 , -NR 13 S(O) p R 14 , -S(O) p NR 13 R 14 or CN. In another embodiment, R 10 -(C0-C2)-alkylene-(C6-C 14 )aryl, -(C0-C2)-alkylene-heteroaryl, -(C0-C2)-alkylene-(C3-C8)cycloalkyl, -(C0-C2)-alkylene-heterocycloalkyl, -O-(C0-C2)-alkylene-aryl, -O-(C0-C2)-alkylene-heteroaryl, -O-(C0-C2)-alkylene-(C3-C8)cycloalkyl, or -O-(C0-C2)-alkylene-heterocycloalkyl, provided that the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl may optionally be substituted with 1 to 3 R 11 is replaced by

[0093] In another embodiment, two R on adjacent atoms 10 together with the atoms to which they are attached, optionally one or more R 11 (C6~C 14 ) form an aryl ring. In yet another embodiment, two R on adjacent atoms 10 together with the atoms to which they are attached, optionally one or more R 11 In another embodiment, two R on adjacent atoms form a heteroaryl ring substituted with 10 together with the atoms to which they are attached, optionally one or more R 11In yet another embodiment, two R on adjacent atoms form a (C3-C8)cycloalkyl ring substituted with 10 together with the atoms to which they are attached, optionally one or more R 11 In another embodiment, two R 10 and the above two Rs are bonded to the same atom. 10 optionally one or more R 11 In yet another embodiment, two R 10 and the above two Rs are bonded to the same atom. 10 optionally one or more R 11 Forms a spiroheterocycloalkyl ring substituted with

[0094] In some embodiments of the above formula, R 11 are (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, CN, -OH, -NH2, -NH(C1-C4) alkyl, -N((C1-C4) alkyl)2, -C(O)O(C1-C4) alkyl, -S(O) q (C1-C4) alkyl, -C(O)NH2, -C(O)NH(C1-C4) alkyl, -C(O)N((C1-C4) alkyl)2, -NHC(O)(C1-C4) alkyl, -N((C1-C4) alkyl)C(O)(C1-C4) alkyl, (C6-C 14 )aryl, heteroaryl, (C3-C8)cycloalkyl, or heterocycloalkyl, provided that the alkyl, alkoxy, (C3-C8)cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, —C(O)OH, —C(O)O(C1-C4)alkyl, —C(O)(C1-C4)alkyl, —S(O) qIn another embodiment, R is substituted with 1 to 3 substituents selected from (C1-C4)alkyl, —C(O)NH(C1-C4)alkyl, —C(O)N((C1-C4)alkyl), —OH, —NH, CN, —NH(C1-C4)alkyl, and —N((C1-C4)alkyl). 11 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or halogen, provided that the alkyl and alkoxy are optionally selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, —C(O)OH, —C(O)O(C1-C4)alkyl, —C(O)(C1-C4)alkyl, —S(O) q In another embodiment, R is substituted with 1 to 3 substituents selected from (C1-C4)alkyl, —C(O)NH(C1-C4)alkyl, —C(O)N((C1-C4)alkyl), —OH, —NH, CN, —NH(C1-C4)alkyl, and —N((C1-C4)alkyl). 11 are CN, -OH, -NH2, -NH(C1-C4) alkyl, -N((C1-C4) alkyl)2, -C(O)O(C1-C4) alkyl, -S(O) q (C1-C4)alkyl, —C(O)NH, —C(O)NH(C1-C4)alkyl, —C(O)N((C1-C4)alkyl) —NHC(O)(C1-C4)alkyl, or —N((C1-C4)alkyl)C(O)(C1-C4)alkyl. In another embodiment, R 11 (C6~C 14 )aryl, heteroaryl, (C3-C8)cycloalkyl, or heterocycloalkyl, provided that (C3-C8)cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, —C(O)OH, —C(O)O(C1-C4)alkyl, —C(O)(C1-C4)alkyl, —S(O) qSelected from (C1-C4) alkyl, -C(O)NH(C1-C4) alkyl, -C(O)N((C1-C4) alkyl)2, -OH, -NH2, CN, -NH(C1-C4) alkyl, and -N((C1-C4) alkyl)2 The group is substituted with 1 to 3 substituents.

[0095] In another embodiment, two R on adjacent atoms 11 together with the atoms to which they are attached form a heterocycloalkyl ring. 11 together with the atom to which they are attached form a (C5-C8)cycloalkyl ring. In another embodiment, two R on adjacent atoms 11 However, along with the atoms to which they are bonded (C6 to C 14 ) form an aryl ring. In yet another embodiment, two R on adjacent atoms 11 together with the atoms to which they are attached form a heteroaryl ring.

[0096] In another embodiment, R 11 but form C=O with the atom to which they are attached.

[0097] In some embodiments of the above formula, R 12 Ha-NR 15 R 16 , -NR 15 C(O)NR 15 R 16 , -NR 15 C(O)R 16 , -NR 15 S(O) m R 16 or —C(O)NH(C-C)cycloalkyl. In another embodiment, R 12 Ha-NR 15 R 16 , -NR 15 C(O)NR 15 R 16 , -NR 15 C(O)R 16 , or -NR 15 S(O) m R 16In yet another embodiment, R 12 is (C1-C6)alkoxy or —C(O)NH(C3-C8)cycloalkyl.

[0098] In some embodiments of the above formula, R 13 is H, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, or i-butyl.

[0099] In some embodiments of the above formula, R 14 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, -(C0-C2)-alkylene-(C3-C8) cycloalkyl, -(C0-C2)-alkylene-heterocycloalkyl, -(C0-C2)-alkylene-(C6-C 14 )aryl, or -(C0-C2)-alkylene-heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally (C1-C4)alkoxy, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C6-C 14 ) is substituted with 1 to 3 substituents selected from aryl, heteroaryl, halogen, —OH, —NH2, CN, —C(O)NH2, —C(O)NH(C1-C4)alkyl, —C(O)N((C1-C4)alkyl)2, —NH(C1-C4)alkyl, and (C1-C4)alkyl substituted with —N((C1-C4)alkyl)2. In another embodiment, R 14 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, or (C1-C6) haloalkyl, wherein said alkyl is optionally (C1-C4) alkoxy, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, (C6-C 14) is substituted with 1 to 3 substituents selected from aryl, heteroaryl, halogen, —OH, —NH2, CN, —C(O)NH2, —C(O)NH(C1-C4)alkyl, —C(O)N((C1-C4)alkyl)2, —NH(C1-C4)alkyl, and (C1-C4)alkyl substituted with —N((C1-C4)alkyl)2. In yet another embodiment, R 14 -(C0-C2)-alkylene-(C3-C8)cycloalkyl, -(C0-C2)-alkylene-heterocycloalkyl, -(C0-C2)-alkylene-(C6-C 14 )aryl, or -(C0-C2)-alkylene-heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally (C1-C4)alkoxy, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C6-C 14 ) aryl, heteroaryl, halogen, -OH, -NH2, CN, -C(O)NH2, -C(O)NH(C1-C4) alkyl, -C(O)N((C1-C4) alkyl)2, -NH(C1-C4) alkyl, and -N((C1-C4) alkyl )2-substituted (C1-C4) alkyl.

[0100] In another embodiment, R 13 and R 14 together with the nitrogen atom to which they are attached, optionally one or more R 23 In another embodiment, R 13 and R 14 together with the nitrogen atom to which they are attached, optionally 1 to 3 R 23 forming a heterocycloalkyl ring substituted with

[0101] In some embodiments of the above formula, R 15 is H, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, or i-butyl.

[0102] In some embodiments of the above formula, R 16 is H, (C1-C6)alkyl, (C2-C6)haloalkyl, (C3-C8)cycloalkyl, or -(C0-C2)-alkylene-heteroaryl, wherein said alkyl, cycloalkyl, and heteroaryl are optionally substituted with 1 to 3 substituents independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, and halogen.

[0103] In some embodiments of the above formula, R 17 is (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, —OH, —NH2, or CN.

[0104] In some embodiments of the above formula, R 18 is H, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, or i-butyl.

[0105] In some embodiments of the above formula, R 19 is H, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, or i-butyl.

[0106] In another embodiment, R 18 and R 19 together with the nitrogen atom to which they are attached form a heterocycloalkyl ring.

[0107] In some embodiments of the above formula, R 20 is H, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, or i-butyl.

[0108] In some embodiments of the above formula, R 21is H, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, or i-butyl.

[0109] In some embodiments of the above formula, R 22 is H, (C1-C4) alkyl, or (C6-C 14 ) aryl. In yet another embodiment, R 22 is H, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, or i-butyl. 22 (C6~C 10 ) aryl.

[0110] In some embodiments of the above formula, R 23 is selected from (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, halogen, —C(O)(C1-C4)alkyl, —C(O)O(C1-C4)alkyl, —C(O)(C3-C8)cycloalkyl, —C(O)heterocycloalkyl, —OH, —NH2, and CN, wherein said alkyl and alkoxy are optionally substituted with 1 to 3 substituents selected from (C1-C4)alkoxy and —OH. 23 is selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, and halogen, wherein the alkyl and alkoxy are optionally selected from (C1-C4 ) alkoxy and -OH. In another embodiment, R 23 is selected from —C(O)(C1-C4)alkyl, —C(O)O(C1-C4)alkyl, —C(O)(C3-C8)cycloalkyl, —C(O)heterocycloalkyl, —OH, —NH2, and CN.

[0111] In another embodiment, R 23 and the above two Rs are bonded to the same atom. 23 forms a spiroheterocycloalkyl ring.

[0112] In some embodiments of the above formula, m is 0 or 1. In yet other embodiments, m is 1 or 2. In other embodiments, m is 0. In yet other embodiments, m is 1. In other embodiments, m is 2.

[0113] In some embodiments of the above formula, n is 0 or 1. In yet other embodiments, n is 1 or 2. In other embodiments, n is 0. In yet other embodiments, n is 1. In other embodiments, n is 2.

[0114] In some embodiments of the above formula, p is 0 or 1. In yet other embodiments, p is 1 or 2. In other embodiments, p is 0. In yet other embodiments, p is 1. In other embodiments, p is 2.

[0115] In some embodiments of the above formula, q is 0 or 1. In yet other embodiments, q is 1 or 2. In other embodiments, q is 0. In yet other embodiments, q is 1. In other embodiments, q is 2.

[0116] In some embodiments of the above formula, r is 0 or 1. In yet other embodiments, r is 1 or 2. In other embodiments, r is 0. In yet other embodiments, r is 1. In other embodiments, r is 2.

[0117] In some embodiments of the above formula, R1 is H, -CD3, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, (C2-C6) hydroxyalkyl, (C3-C8) cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally selected from the group consisting of halogen, -OR 20 , -C(O)R 20 , -CO2R 20 , -NR18 R 19 , -NR 20 C(O)R 21 , -C(O)NR 20 R 21 , -NR 20 C(O)NR 21 R 22 , -NR 20 S(O) r R 21 , -S(O) r R 20 R 21 , -NR 20 S(O) r R 21 R 22 , -S(O) r R 20 , -P(O)R 20 R 21 and -Si((C1-C4)alkyl)3, where R4 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C3-C8)cycloalkyl, -O-(C0-C2)-alkylene-(C3-C8)cycloalkyl, heterocycloalkyl, halogen, -OH, -NH2, CN, -C(O)(C1-C4)alkyl, -C(O)O(C1-C4)alkyl, -NR 20 C(O)O(C1~C4)alkyl, -Si(CH3)3, -SF5, -S(O) P (C1-C4) alkyl, -S(O) P (NH)(C1-C4)alkyl, -NH(C1-C4)alkyl, or -N((C1-C4)alkyl)2, provided that the alkyl, alkenyl, alkynyl, and alkoxy are optionally (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, -OH, -S(O) r (C1-C4) alkyl, -S(O) r substituted with one or more substituents selected from (NH)(C1-C4)alkyl, -SF5, -Si(CH3)3, -NH2, -NH(C1-C4)alkyl, and -N((C1-C4)alkyl)2, or and X4, together with the atoms to which they are attached, may optionally be one or more R 17 (C6~C 14 ) form an aryl ring, or R and X on adjacent atoms, together with the atoms to which they are attached, may optionally be joined by one or more R 17 or R and X together with the atoms to which they are attached form a heteroaryl ring substituted with one or more R 17 or R and X on adjacent atoms together with the atoms to which they are attached form a (C5-C7)cycloalkyl ring substituted with one or more R 17 forming a heterocycloalkyl ring substituted with

[0118] In some embodiments of the above formula, R2 is [ka] [ka] where each R2 is one or more R 10 is replaced by

[0119] In some embodiments of the above formula, R2 is [ka] [ka] where each R2 is optionally R 10 is further substituted with

[0120] In some embodiments of the above formula, R2 is [ka] where each is optionally 1 to 2 R11 is further substituted with

[0121] In some embodiments of the above formula, R2 is [ka] [ka] where each is optionally 1 to 2 R 11 is further substituted with

[0122] In some embodiments of the above formula, R2 is [ka] where each is optionally 1 to 2 R 10 is further substituted with

[0123] In some embodiments of the above formula, n is 1 and R2 is [ka] where each is optionally 1 to 2 R 10 is further substituted with

[0124] In some embodiments of the above formula, n is 0 and R2 is [ka] where each is optionally 1 to 2 R 10 is further substituted with

[0125] In some embodiments of the above formula, n is 2 and R2 is [ka] where each is optionally 1 to 2 R 10 is further substituted with

[0126] In some embodiments of the above formula, R 10 teeth [ka] However, each R 10 is optional, R from 1 to 3 11 is replaced by

[0127] In some embodiments of the above formula, R 10 teeth [ka] However, each R 10 is optional, R from 1 to 3 11 is replaced by

[0128] In some embodiments of Formula (I), X1 is CR6. In other embodiments, X1 is CR6 and X2 is CR7. In yet other embodiments, X1 is CR6, X2 is CR7, and X3 is CR8. In other embodiments, X1 is CR6, X2 is CR7, X3 is CR8, and X4 is CR9. In other embodiments, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, and R5 is H. In yet other embodiments, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, and R6 is H, (C1-C6) alkyl, or halogen. In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, and R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen. In yet another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, and R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen.

[0129] In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy. In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 In yet another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6) alkyl, or halogen, R7 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, or halogen, R8 is H, (C1-C6) alkyl, (C1-C6) alkoxy, or halogen, R9 is H, (C1-C6) alkyl, (C1-C6) alkoxy, or halogen, and R1 is H, (C1-C6) alkyl, (C2-C6) hydroxyalkyl, or heterocycloalkyl, with the proviso that the alkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R 3’ is H.

[0130] In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein said alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R 3’ is H, and R3 is H, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, -C(O)OH, -C(O)NH2, or CN. In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, provided that the alkyl and heterocycloalkyl are optionally selected from -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R 3’ is H, R3 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN, and R2 is one or more R 10 (C6~C14 ) aryl.

[0131] In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein said alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR1 8th Race 19 and R 3’ is H, R3 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN, and R2 is one or more R 10 (C6~C 14 )aryl. In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R3’ is H, R3 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN, and R2 is one or more R 10 (C6~C 14 ) aryl.

[0132] In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein said alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R 3’ is H, R3 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN, and R2 is one or more R 10 (C6~C 14 ) aryl, and R 10 (C6~C 14 ) aryl, heteroaryl, or heterocycloalkyl, wherein the aryl, heteroaryl, and heterocycloalkyl optionally include one or more R 11 is replaced by

[0133] In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein said alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R 3’ is H, R3 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN, and R2 is one or more R 10 In yet another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R 3’is H, R3 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN, and R2 is one or more R 10 heteroaryl substituted with R 10 (C6~C 14 ) aryl, heteroaryl, or heterocycloalkyl, wherein the aryl, heteroaryl, and heterocycloalkyl optionally include one or more R 11 is replaced by

[0134] In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein said alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R 3’ is H, R3 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN, and R2 is one or more R 10 is a (C3-C8)cycloalkyl substituted with

[0135] In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein said alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R 3’ is H, R3 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN, and R2 is one or more R 10 is (C-C)cycloalkyl substituted with R 10 (C6~C 14 ) aryl, heteroaryl, or heterocycloalkyl, wherein the aryl, heteroaryl, and heterocycloalkyl optionally include one or more R 11 is replaced by

[0136] In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein said alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20, -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R 3’ is H, R3 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN, and R2 is one or more R 10 In yet another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6) alkyl, or halogen, R7 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, or halogen, and R8 is H, (C1-C6) alkyl, (C1 R9 is H, (C1-C6) alkyl, (C1-C6) alkoxy, or halogen; R1 is H, (C1-C6) alkyl, (C2-C6) hydroxyalkyl, or heterocycloalkyl, with the proviso that said alkyl and heterocycloalkyl are optionally selected from -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R 3’ is H, R3 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN, and R2 is one or more R 10 and R is a heterocycloalkyl substituted with 10 (C6~C 14 ) aryl, heteroaryl, or heterocycloalkyl, wherein the aryl, heteroaryl, and heterocycloalkyl optionally include one or more R 11 is replaced by

[0137] In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, and R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen. In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein said alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R and R are substituted with one or more substituents selected from 3’ together with the carbon atoms to which they are attached form a (C3-C7) cycloalkyl ring.

[0138] In yet another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R20 , and -NR 18 R 19 and R and R are substituted with one or more substituents selected from 3’ together with the carbon atoms to which they are attached form a (C3-C7) cycloalkyl ring, and R2 is one or more R 10 (C6~C 14 ) aryl.

[0139] In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein said alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R and R are substituted with one or more substituents selected from 3’ together with the carbon atoms to which they are attached form a (C3-C7) cycloalkyl ring, and R2 is one or more R 10 (C6~C 14 ) aryl, and R 10 (C6~C 14 ) Ant aryl, heteroaryl, or heterocycloalkyl, wherein the aryl, heteroaryl, and heterocycloalkyl may optionally be one or more R 11 is replaced by

[0140] In yet another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R and R are substituted with one or more substituents selected from 3’ together with the carbon atoms to which they are attached form a (C3-C7) cycloalkyl ring, and R2 is one or more R 10 In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R and R are substituted with one or more substituents selected from 3’ together with the carbon atoms to which they are attached form a (C3-C7) cycloalkyl ring, and R2 is one or more R 10 heteroaryl substituted with R10 (C6~C 14 ) aryl, heteroaryl, or heterocycloalkyl, wherein the aryl, heteroaryl, and heterocycloalkyl optionally include one or more R 11 is replaced by

[0141] In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein said alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R and R are substituted with one or more substituents selected from 3’ together with the carbon atoms to which they are attached form a (C3-C7) cycloalkyl ring, and R2 is one or more R 10 is a (C3-C8)cycloalkyl substituted with

[0142] In yet another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R and R are substituted with one or more substituents selected from 3’ Is that together with the carbon atom to which they are attached form a (C3-C7) cycloalkyl ring, and R2 is one or more R 10 is (C-C)cycloalkyl substituted with R 10 (C6~C 14 ) aryl, heteroaryl, or heterocycloalkyl, wherein the aryl, heteroaryl, and heterocycloalkyl optionally include one or more R 11 is replaced by

[0143] In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein said alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R20 , -CO2R 20 , and -NR 18 R 19 and R and R are substituted with one or more substituents selected from 3’ together with the carbon atoms to which they are attached form a (C3-C7) cycloalkyl ring, and R2 is one or more R 10 In yet another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, with the proviso that the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R and R are substituted with one or more substituents selected from 3’ together with the carbon atoms to which they are attached form a (C3-C7) cycloalkyl ring, and R2 is one or more R 10 and R is a heterocycloalkyl substituted with 10 (C6~C 14 ) aryl, heteroaryl, or heterocycloalkyl, wherein the aryl, heteroaryl, and heterocycloalkyl optionally include one or more R 11 is replaced by

[0144] In some embodiments of Formula (I), X1 is CR6. In other embodiments, X1 is CR6 and X2 is CR7. In yet other embodiments, X1 is CR6, X2 is CR7, and X3 is CR8. In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, and X4 is N. In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, and R5 is H. In yet other embodiments, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, and R6 is H, (C1-C6) alkyl, or halogen. In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6) alkyl, or halogen, and R7 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, or halogen.

[0145] In yet another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6) alkyl, or halogen, R7 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, or halogen, and R8 is H, (C1-C6) alkyl, (C1-C6) alkoxy, or halogen. In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6) alkyl, or halogen, and R7 is H, (C1-C6) alkyl, (C1-C6) R8 is H, (C1-C6) alkyl, (C1-C6) alkoxy, or halogen; R1 is H, (C1-C6) alkyl, (C2-C6) hydroxyalkyl, or heterocycloalkyl, provided that the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19In yet another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6) alkyl, or halogen, R7 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, or halogen, R8 is H, (C1-C6) alkyl, (C1-C6) alkoxy, or halogen, and R1 is H, (C1-C6) alkyl, (C2-C6) hydroxyalkyl, or heterocycloalkyl, with the proviso that the alkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R 3’ is H.

[0146] In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R 3’is H, and R3 is H, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, -C(O)OH, -C(O)NH2, or CN. In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, provided that the alkyl and heterocycloalkyl are optionally selected from -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R 3’ is H, R3 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN, and R2 is one or more R 10 (C6~C 14 ) aryl.

[0147] In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R 3’is H, R3 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN, and R2 is one or more R 10 (C6~C 14 ) aryl, and R 10 (C6~C 14 ) aryl, heteroaryl, or heterocycloalkyl, wherein the aryl, heteroaryl, and heterocycloalkyl optionally include one or more R 11 is replaced by

[0148] In another embodiment, X1 is CR6, X2 is CR7, and X3 is CR8. X4 is N, R5 is H, R6 is H, (C1-C6) alkyl, or halogen, R7 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, or halogen, R8 is H, (C1-C6) alkyl, (C1-C6) alkoxy, or halogen, and R1 is H, (C1-C6) alkyl, (C2-C6) hydroxyalkyl, or heterocycloalkyl, with the proviso that the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R 3’ is H, R3 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN, and R2 is one or more R 10In yet another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R 3’ is H, R3 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN, and R2 is one or more R 10 heteroaryl substituted with R 10 (C6~C 14 ) aryl, heteroaryl, or heterocycloalkyl, wherein the aryl, heteroaryl, and heterocycloalkyl optionally include one or more R 11 is replaced by

[0149] In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19and R 3’ is H, R3 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN, and R2 is one or more R 10 In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, provided that the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R 3’ is H, R3 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN, and R2 is one or more R 10 is (C-C)cycloalkyl substituted with R 10 (C6~C 14 ) aryl, heteroaryl, or heterocycloalkyl, wherein the aryl, heteroaryl, and heterocycloalkyl optionally include one or more R 11 is replaced by

[0150] In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6) alkyl, or halogen, and R7 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, or R8 is H, (C1-C6) alkyl, (C1-C6) alkoxy, or halogen; R1 is H, (C1-C6) alkyl, (C2-C6) hydroxyalkyl, or heterocycloalkyl, provided that the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R 3’ is H, R3 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN, and R2 is one or more R 10 In yet another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, with the proviso that said alkyl and heterocycloalkyl are optionally selected from -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R 3’ is H, R3 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN, and R2 is one or more R 10 and R is a heterocycloalkyl substituted with 10 (C6~C 14 ) aryl, heteroaryl, or heterocycloalkyl, wherein the aryl, heteroaryl, and heterocycloalkyl optionally include one or more R 11 is replaced by

[0151] In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6) alkyl, or halogen, R7 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, or halogen, and R8 is H, (C1-C6) alkyl, (C1-C6) alkoxy, or halogen. In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R and R are substituted with one or more substituents selected from 3’ together with the carbon atoms to which they are attached form a (C3-C7) cycloalkyl ring.

[0152] In yet another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R and R are substituted with one or more substituents selected from3’ together with the carbon atoms to which they are attached form a (C3-C7) cycloalkyl ring, and R2 is one or more R 10 (C6~C 14 )aryl. In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl. wherein the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R and R are substituted with one or more substituents selected from 3’ together with the carbon atoms to which they are attached form a (C3-C7) cycloalkyl ring, and R2 is one or more R 10 (C6~C 14 ) aryl, and R 10 (C6~C 14 ) aryl, heteroaryl, or heterocycloalkyl, wherein the aryl, heteroaryl, and heterocycloalkyl optionally include one or more R 11 is replaced by

[0153] In yet another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R and R are substituted with one or more substituents selected from 3’ together with the carbon atoms to which they are attached form a (C3-C7) cycloalkyl ring, and R2 is one or more R 10 In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R and R are substituted with one or more substituents selected from 3’ together with the carbon atoms to which they are attached form a (C3-C7) cycloalkyl ring, and R2 is one or more R 10 heteroaryl substituted with R 10 (C6~C 14) aryl, heteroaryl, or heterocycloalkyl, wherein the aryl, heteroaryl, and heterocycloalkyl optionally include one or more R 11 is replaced by

[0154] In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R and R are substituted with one or more substituents selected from 3’ together with the carbon atoms to which they are attached form a (C3-C7) cycloalkyl ring, and R2 is one or more R 10 In yet another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, with the proviso that the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R and R are substituted with one or more substituents selected from 3’together with the carbon atoms to which they are attached form a (C3-C7) cycloalkyl ring, and R2 is one or more R 10 Substituted with (C3~C8) is cycloalkyl, and R 10 (C6~C 14 ) aryl, heteroaryl, or heterocycloalkyl, wherein the aryl, heteroaryl, and heterocycloalkyl optionally include one or more R 11 is replaced by

[0155] In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R and R are substituted with one or more substituents selected from 3’ together with the carbon atoms to which they are attached form a (C3-C7) cycloalkyl ring, and R2 is one or more R 10 In yet another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, with the proviso that said alkyl and heterocycloalkyl are optionally selected from -OR 20 , -C(O)R20 , -CO2R 20 , and -NR 18 R 19 and R and R are substituted with one or more substituents selected from 3’ together with the carbon atoms to which they are attached form a (C3-C7) cycloalkyl ring, and R2 is one or more R 10 and R is a heterocycloalkyl substituted with 10 (C6~C 14 ) aryl, heteroaryl, or heterocycloalkyl, wherein the aryl, heteroaryl, and heterocycloalkyl optionally include one or more R 11 is replaced by

[0156] In yet another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R and R are substituted with one or more substituents selected from 3’ together with the carbon atoms to which they are attached form a (C3-C7) cycloalkyl ring, and R2 is one or more R 10In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R and R are substituted with one or more substituents selected from 3’ together with the carbon atoms to which they are attached form a (C3-C7) cycloalkyl ring, and R2 is one or more R 10 heteroaryl substituted with R 10 (C6~C 14 ) aryl, heteroaryl, or heterocycloalkyl, wherein the aryl, heteroaryl, and heterocycloalkyl optionally include one or more R 11 is replaced by

[0157] In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19and R and R are substituted with one or more substituents selected from 3’ together with the carbon atoms to which they are attached form a (C3-C7) cycloalkyl ring, and R2 is one or more R 10 In yet another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, with the proviso that the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R and R are substituted with one or more substituents selected from 3’ together with the carbon atoms to which they are attached form a (C3-C7) cycloalkyl ring, and R2 is one or more R 10 is (C-C)cycloalkyl substituted with R 10 (C6~C 14 ) aryl, heteroaryl, or heterocycloalkyl, wherein the aryl, heteroaryl, and heterocycloalkyl optionally include one or more R 11 is replaced by

[0158] In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R and R are substituted with one or more substituents selected from 3’ together with the carbon atoms to which they are attached form a (C3-C7) cycloalkyl ring, and R2 is one or more R 10 In yet another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, with the proviso that said alkyl and heterocycloalkyl are optionally selected from -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R and R are substituted with one or more substituents selected from 3’ together with the carbon atoms to which they are attached form a (C3-C7) cycloalkyl ring, and R2 is one or more R 10 and R is a heterocycloalkyl substituted with 10 (C6~C 14) aryl, heteroaryl, or heterocycloalkyl, wherein the aryl, heteroaryl, and heterocycloalkyl optionally include one or more R 11 is replaced by

[0159] In some embodiments of formula (I), X1 is CR6. In another embodiment, X1 is CR6 and X2 is CR7. In yet another embodiment, X1 is CR6, X2 is CR7, and X3 is N. In another embodiment, X1 is CR6, X2 is CR7, X3 is N, and X4 is CR9. In another embodiment, X1 is CR6, X2 is CR7, X3 is N, X4 is CR9, and R5 is H. In yet another embodiment, X1 is CR6, X2 is CR7, X3 is N, X4 is CR9, R5 is H, and R6 is H, (C1-C6) alkyl, or halogen. In another embodiment, X1 is CR6, X2 is CR7, X3 is N, X4 is CR9, R5 is H, R6 is H, (C1-C6) alkyl, or halogen, and R7 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, or halogen. In another embodiment, X1 is CR6, X2 is CR7, X3 is N, X4 is CR9, R5 is H, R6 is H, (C1-C6) alkyl, or halogen, R7 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, or halogen, and R9 is H, (C1-C6) alkyl, (C1-C6) alkoxy, or halogen. In another embodiment, X1 is CR6, X2 is CR7, X3 is N, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein said alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20, -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 is substituted with one or more substituents selected from:

[0160] In yet another embodiment, X1 is CR6, X2 is CR7, X3 is N, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R 3’ is H and R3 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN, or R3 and R 3’ together with the carbon atoms to which they are attached form a (C3-C7)cycloalkyl ring. In another embodiment, X1 is CR6, X2 is CR7, X3 is N, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, with the proviso that the alkyl and heterocycloalkyl are optionally selected from -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19and R 3’ is H and R3 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN, or R3 and R 3’ form a (C3-C7) cycloalkyl ring together with the carbon atoms to which they are attached, and R2 is (C6-C 14 )aryl, heteroaryl, (C3-C8)cycloalkyl, heterocycloalkyl, provided that the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each independently selected from one or more R 10 is replaced by

[0161] In another embodiment, X1 is CR6, X2 is CR7, X3 is N, X4 is CR9, R5 is H, R6 is H, (C1-C6) alkyl, or halogen, R7 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, or halogen, and R9 is H, (C1-C6) alkyl, (C1-C6) alkoxy, or halogen, and R1 is H, (C1-C6) alkyl, (C2-C6) hydroxyalkyl, or heterocycloalkyl, provided that the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R 3’ is H and R3 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN, or R3 and R 3’ form a (C3-C7) cycloalkyl ring together with the carbon atoms to which they are attached, and R2 is (C6-C 14 )aryl, heteroaryl, (C3-C8)cycloalkyl, heterocycloalkyl, provided that the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each independently selected from one or more R 10 is replaced by R 10 (C6~C14 ) aryl, heteroaryl, or heterocycloalkyl, wherein the aryl, heteroaryl, and heterocycloalkyl optionally contain one or more R 11 is replaced by

[0162] In some embodiments of Formula (I), X1 is CR6. In other embodiments, X1 is CR6 and X2 is N. In yet other embodiments, X1 is CR6, X2 is N, and X3 is CR8. In another embodiment, X1 is CR6, X2 is N, X3 is CR8, and X4 is CR9. In another embodiment, X1 is CR6, X2 is N, X3 is CR8, X4 is CR9, and R5 is H. In yet other embodiments, X1 is CR6, X2 is N, X3 is CR8, X4 is CR9, R5 is H, and R6 is H, (C1-C6) alkyl, or halogen. In another embodiment, X1 is CR6, X2 is N, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, and R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen. In another embodiment, X1 is CR6, X2 is N, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen. In another embodiment, X1 is CR6, X2 is N, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein said alkyl and heterocycloalkyl are optionally selected from -OR 20 , -C(O)R20 , -CO2R 20 , and -NR 18 R 19 is substituted with one or more substituents selected from:

[0163] In another embodiment, X1 is CR6, X2 is N, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R 3’ is H and R3 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN, or R3 and R 3’ together with the carbon atoms to which they are attached form a (C3-C7)cycloalkyl ring. In another embodiment, X1 is CR6, X2 is N, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, and R8 is H, (C R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen; R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, provided that the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19and R 3’ is H and R3 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN, or R3 and R 3’ form a (C3-C7) cycloalkyl ring together with the carbon atoms to which they are attached, and R2 is (C6-C 14 )aryl, heteroaryl, (C3-C8)cycloalkyl, heterocycloalkyl, provided that the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each independently selected from one or more R 10 is replaced by

[0164] In another embodiment, X1 is CR6, X2 is N, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6)alkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein the alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R 3’ is H and R3 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN, or R3 and R 3’ form a (C3-C7) cycloalkyl ring together with the carbon atoms to which they are attached, and R2 is (C6-C 14 )aryl, heteroaryl, (C3-C8)cycloalkyl, heterocycloalkyl, provided that the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each independently selected from one or more R 10 is replaced by R 10 (C6~C 14) aryl, heteroaryl, or heterocycloalkyl, wherein the aryl, heteroaryl, and heterocycloalkyl optionally contain one or more R 11 is replaced by

[0165] In some embodiments of Formula (I), X1 is N. In other embodiments, X1 is N and X2 is CR7. In yet other embodiments, X1 is N, X2 is CR7, and X3 is CR8. In another embodiment, X1 is N, X2 is CR7, X3 is CR8, and X4 is CR9. In another embodiment, X1 is N, X2 is CR7, X3 is CR8, X4 is CR9, and R5 is H. In yet other embodiments, X1 is N, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, and R7 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, or halogen. In yet another embodiment, X1 is N, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R7 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, or halogen, and R8 is H, (C1-C6) alkyl, (C1-C6) alkoxy, or halogen.

[0166] In another embodiment, X1 is N, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R7 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, or halogen, R8 is H, (C1-C6) alkyl, (C1-C6) alkoxy, or halogen, and R9 is H, (C1-C6) alkyl, (C1-C6) alkoxy, or halogen. In another embodiment, X1 is N, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R7 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, or halogen, and R8 is H, (C1-C6) alkyl, (C1-C6) alkoxy, or halogen; R9 is H, (C1-C6) alkyl, (C1-C6) alkoxy, or halogen; R1 is H, (C1-C6) alkyl, (C2-C6) hydroxyalkyl, or heterocycloalkyl, provided that the alkyl and heterocycloalkyl are optionally selected from -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 In yet another embodiment, X1 is N, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R7 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, or halogen, R8 is H, (C1-C6) alkyl, (C1-C6) alkoxy, or halogen, R9 is H, (C1-C6) alkyl, (C1-C6) alkoxy, or halogen, and R1 is H, (C1-C6) alkyl, (C2-C6) hydroxyalkyl, or heterocycloalkyl, with the proviso that the alkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R 3’ is H and R3 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN, or R3 and R 3’ together with the carbon atoms to which they are attached form a (C3-C7) cycloalkyl ring.

[0167] In another embodiment, X1 is N, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein said alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R 20 , and -NR 18 R 19 and R 3’ is H and R3 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN, or R3 and R 3’ form a (C3-C7) cycloalkyl ring together with the carbon atoms to which they are attached, and R2 is (C6-C 14 )aryl, heteroaryl, (C3-C8)cycloalkyl, heterocycloalkyl, provided that the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each independently selected from one or more R 10 is replaced by

[0168] In another embodiment, X1 is N, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R7 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen, R8 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, R9 is H, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen, and R1 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, or heterocycloalkyl, wherein said alkyl and heterocycloalkyl are optionally selected from the group consisting of -OR 20 , -C(O)R 20 , -CO2R20 , and -NR 18 R 19 and R 3’ is H and R3 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, —C(O)OH, —C(O)NH2, or CN, or R3 and R 3’ form a (C3-C7) cycloalkyl ring together with the carbon atoms to which they are attached, and R2 is (C6-C 14 )aryl, heteroaryl, (C3-C8)cycloalkyl, heterocycloalkyl, provided that the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each independently selected from one or more R 10 is replaced by R 10 (C6~C 14 ) aryl, heteroaryl, or heterocycloalkyl, wherein the aryl, heteroaryl, and heterocycloalkyl optionally contain one or more R 11 is replaced by

[0169] In some embodiments of the above formula, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6) alkyl, or halogen, R7 is H, (C1-C6) alkyl, or halogen, R8 is H, (C1-C6) alkyl, or halogen, and R1 is H or (C1-C6) alkyl. In other embodiments, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6) alkyl, or halogen, R7 is H, (C1-C6) alkyl, or halogen, R8 is H, (C1-C6) alkyl, or halogen, R9 is H, (C1-C6) alkyl, or halogen, R1 is H or (C1-C6) alkyl, and R3 is H or (C1-C6) alkyl. In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6) alkyl, or halogen, R7 is H, (C1-C6) alkyl, or halogen, R8 is H, (C1-C6) alkyl, or halogen, R9 is H, (C1-C6) alkyl, or halogen, R1 is H or (C1-C6) alkyl, R3 is H or (C1-C6) alkyl, and R 3’ is H or (C1-C6) alkyl. In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6) alkyl, or halogen, R7 is H, (C1-C6) alkyl, or halogen, R8 is H, (C1-C6) alkyl, or halogen, R9 is H, (C1-C6) alkyl, or halogen, R1 is H or (C1-C6) alkyl, R3 is H or (C1-C6) alkyl, and R 3’is H or (C1-C6)alkyl, and R4 is (C1-C6)alkyl, (C1-C6)alkoxy, -O-(C0-C2)-alkylene-(C3-C8)cycloalkyl, -O-(C0-C2)-alkylene-heterocycloalkyl, -NH-(C0-C2)-alkylene-(C3-C8)cycloalkyl, or -NH-(C0-C2)-alkylene-heterocycloalkyl.

[0170] In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is N, R5 is H, R6 is H, (C1-C6) alkyl, or halogen, R7 is H, (C1-C6) alkyl, or halogen, R8 is H, (C1-C6) alkyl, or halogen, R9 is H, (C1-C6) alkyl, or halogen, R1 is H or (C1-C6) alkyl, R3 is H or (C1-C6) alkyl, and R 3’ is H or (C1-C6)alkyl, and R4 is -O-(C0-C2)-alkylene-(C3-C8)cycloalkyl, -O-(C0-C2)-alkylene-heterocycloalkyl, -NH-(C0-C2)-alkylene-(C3-C8)cycloalkyl, or -NH-(C0-C2)-alkylene-heterocycloalkyl.

[0171] In some embodiments of the above formula, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6) alkyl, or halogen, R7 is H, (C1-C6) alkyl, or halogen, R8 is H, (C1-C6) alkyl, or halogen, R9 is H, (C1-C6) alkyl, or halogen, and R1 is H or (C1-C6) alkyl. In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6) alkyl, or halogen, R7 is H, (C1-C6) alkyl, or halogen, R8 is H, (C1-C6) alkyl, or halogen, R9 is H, (C1-C6) alkyl, or halogen, R1 is H or (C1-C6) alkyl, and R3 is H or (C1-C6) alkyl. In another embodiment, X1 is CR6 and X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6) alkyl, or halogen, R7 is H, (C1-C6) alkyl, or halogen, R8 is H, (C1-C6) alkyl, or halogen, R9 is H, (C1-C6) alkyl, or halogen, R1 is H or (C1-C6) alkyl, R3 is H or (C1-C6) alkyl, R 3’ is H or (C1-C6) alkyl. In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6) alkyl, or halogen, R7 is H, (C1-C6) alkyl, or halogen, R8 is H, (C1-C6) alkyl, or halogen, R9 is H, (C1-C6) alkyl, or halogen, R1 is H or (C1-C6) alkyl, R3 is H or (C1-C6) alkyl, and R 3’is H or (C1-C6)alkyl, and R4 is (C1-C6)alkyl, (C1-C6)alkoxy, -O-(C0-C2)-alkylene-(C3-C8)cycloalkyl, -O-(C0-C2)-alkylene-heterocycloalkyl, -NH-(C0-C2)-alkylene-(C3-C8)cycloalkyl, or -NH-(C0-C2)-alkylene-heterocycloalkyl.

[0172] In another embodiment, X1 is CR6, X2 is CR7, X3 is CR8, X4 is CR9, R5 is H, R6 is H, (C1-C6) alkyl, or halogen, R7 is H, (C1-C6) alkyl, or halogen, R8 is H, (C1-C6) alkyl, or halogen, R9 is H, (C1-C6) alkyl, or halogen, R1 is H or (C1-C6) alkyl, R3 is H or (C1-C6) alkyl, and R 3’ is H or (C1-C6)alkyl, and R4 is -O-(C0-C2)-alkylene-(C3-C8)cycloalkyl, -O-(C0-C2)-alkylene-heterocycloalkyl, -NH-(C0-C2)-alkylene-(C3-C8)cycloalkyl, or -NH-(C0-C2)-alkylene-heterocycloalkyl.

[0173] Non-limiting illustrative compounds of the present application include: [ka] [ka] [ka] [ka]

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[0174] In another embodiment of the present application, the compound of formula (I) is an enantiomer. In some embodiments, the compound is the (S)-enantiomer. In other embodiments, the compound is the (R)-enantiomer. In still other embodiments, the compound of formula (I) may be the (+) or (-) enantiomer.

[0175] It is to be understood that the present application encompasses all isomeric forms, including mixtures thereof. When the compound contains a double bond, the substituent may be in the E or Z configuration. When the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may be ci. It may have the s or trans configuration. All tautomers are intended to be included.

[0176] The compounds of the present application, and their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, and prodrugs, may exist in their tautomeric form (for example, as an amide or imino ether), and all such tautomeric forms are contemplated herein as part of this application.

[0177] The compounds of the present application may contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present application, as well as mixtures thereof, including racemic mixtures, are intended to form part of this application. This application also encompasses all geometric and positional isomers. For example, if a compound of the present application contains a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are encompassed within the scope of this application. Each compound disclosed herein encompasses all enantiomers consistent with the generic structure of the compound. The compounds may be in racemic or enantiomerically pure form, or any other form in terms of stereochemistry. Assay results may reflect data obtained for the racemic, enantiomerically pure, or any other form in terms of stereochemistry.

[0178] Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as, for example, chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers into their corresponding pure enantiomers (e.g., by hydrolysis). Some of the compounds of the present application may also be atropisomers (e.g., substituted biaryls), and are considered part of this application. Enantiomers can also be separated using chiral HPLC columns.

[0179] It is also possible that the compounds of the present application may exist in different tautomeric forms, and all such forms are included within the scope of the present application. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the present application.

[0180] All stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the present compounds (including the salts, solvates, esters and prodrugs of the present compounds, and stereoisomers of the salts, solvates and esters of the above prodrugs), such as stereoisomers that may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of an asymmetric carbon), rotamer forms, atropisomers, and diastereomeric forms, are contemplated within the scope of the present application, as are positional isomers (e.g., 4-pyridyl and 3-pyridyl, etc.). (For example, if a compound of Formula (I) contains a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are encompassed within the scope of this application. Also, for example, all keto-enol and imine-enamine forms of the compounds are encompassed within the scope of this application.) Individual stereoisomers of the compounds of this application may, for example, be substantially free of other isomers, or may be, for example, as a racemate or in a mixture with all other or selected stereoisomers. Chiral centers of the present application may have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of terms such as "salt," "solvate," "ester," "prodrug," and the like applies equally to enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates, or prodrug salts, solvates, esters, and prodrugs of the compounds of the invention. It is intended that

[0181] Compounds of formula (I) may form salts, which are also within the scope of this application. Reference herein to a compound of formula (I) should be understood to include reference to its salts, unless otherwise indicated.

[0182] The present application relates to compounds that are modulators of USP1. In one embodiment, the compounds of the present application are inhibitors of USP1.

[0183] In some embodiments, the compounds of the present application are selective over other USP enzymes, including, but not limited to, USP2, USP4, USP5, USP6, USP7, USP8, USP9x, and USP12 / 46. As used herein, "selective," "selective USP1 inhibitor," or "selective USP1 compound" refers to a compound of the present application that effectively inhibits USP1 to a greater extent than any other USP enzyme (i.e., USP2, USP5, USP7, USP8, USP11, USP14, USP15, USP16, USP19, USP20, USP21, USP25, USP28, USP30, USP35, USP36, USP45, and USP12 / 46).

[0184] A "selective USP1 inhibitor" can be identified, for example, by comparing the ability of a compound to inhibit USP1 enzyme activity with its ability to inhibit other USP enzymes. For example, a substance may be assayed for its ability to inhibit USP1 as well as for its ability to modulate (i.e., inhibit or activate) USP2, USP5, USP7, USP8, USP11, USP14, USP15, USP16, USP19, USP20, USP21, USP25, USP28, USP30, USP35, USP36, USP45, and USP12 / 46.

[0185] In certain embodiments, the compounds of the present application exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater selectivity over one or more other USP enzymes (i.e., USP2, USP5, USP7, USP8, USP11, USP14, USP15, USP16, USP19, USP20, USP21, USP25, USP28, USP30, USP35, USP36, USP45, and USP12 / 46). In various embodiments, the compounds of the present application exhibit up to 1000-fold greater selectivity over one or more other USP enzymes.

[0186] In certain embodiments, the compounds of the present application exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater selectivity over other USP enzymes (i.e., USP2, USP5, USP7, USP8, USP11, USP14, USP15, USP16, USP19, USP20, USP21, USP25, USP28, USP30, USP35, USP36, USP45, and USP12 / 46). In various embodiments, the compounds of the present application exhibit up to 1000-fold greater selectivity over other USP enzymes.

[0187] In certain embodiments, the compounds of the present application exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater selectivity than USP2, USP5, USP7, USP8, USP11, USP14, USP15, USP16, USP19, USP20, USP21, USP25, USP28, USP30, USP35, USP36, USP45, and USP12 / 46. In various embodiments, the compounds of the present application exhibit up to 1000-fold greater selectivity than USP2, USP5, USP7, USP8, USP11, USP14, USP15, USP16, USP19, USP20, USP21, USP25, USP28, USP30, USP35, USP36, USP45, and USP12 / 46.

[0188] This application is directed to the compounds described herein and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, and to pharmaceutical compositions comprising one or more compounds described herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof.

[0189] Methods for preparing compounds The compounds of the present application may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are shown in the following schemes.

[0190] Compounds of formula (I) may be prepared by methods known in the art of organic synthesis, as illustrated in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary based on general principles or chemistry. Protecting groups may be used in accordance with standard methods of organic synthesis (T.W. Greene, and P.G.M. Butts, "Protective Groups in Organic Synthesis," Third Edition, Wiley, New York 1999). These groups are removed at a convenient stage in the synthesis of the compound in question using methods readily apparent to those skilled in the art. The selected processes as well as the reaction conditions and the order in which they are carried out must be consistent with the preparation of compounds of formula (I).

[0191] Those skilled in the art will recognize whether a stereocenter exists in compounds of formula (I). Accordingly, the present application encompasses both possible stereoisomers (unless otherwise specified in the synthesis), encompassing not only the racemates but also the individual enantiomers and / or diastereomers. When a compound is desired as a single enantiomer or diastereomer, the compound may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, intermediate, or starting material may be affected by any suitable method known in the art. For example, see "Stereochemistry of Organic Compounds" by EL Eliel, See SHWilen, and LN Mander (Wiley-Interscience, 1994).

[0192] The compounds described herein may be prepared from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes.

[0193] The compounds of the present application can be prepared by several methods well known to those skilled in the art of organic synthesis. By way of example, the compounds of the present application can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof recognized by those skilled in the art. Preferred methods include, but are not limited to, those described below. The compounds of the present application can be synthesized by following the steps outlined in General Schemes 1-5, which include different procedures for assembling intermediates 2-a to 2-n. Starting materials are either commercially available or prepared by known procedures previously published or described herein.

[0194] General Scheme 1 [ka] (n is 1, and R2, R3, R 3’, R4, R5, and X1 to X4 are as defined in formula (I). A general method for preparing compounds of Formula (I) using intermediates 2-a, 2-b, 2-c, 2-d, 2-e, and 2-f is outlined in General Scheme 1. Amination of 2-a with 2-b in acetonitrile (MeCN) using a base such as N,N-diisopropylethylamine (DIEA) provides 2-c. Coupling of 2-c with aryl or heteroaryl boronic acids / esters 2-d in 1,4-dioxane using a catalytic amount of a palladium catalyst, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride·dichloromethane (Pd(dppf)Cl2·CHCl2), and a base such as potassium carbonate (K2CO3) or cesium carbonate (Cs2CO3), at elevated temperatures provides 2-e. Reduction of intermediate 2-e with a metal (i.e., iron (Fe) powder) and ammonium chloride in solvents such as tetrahydrofuran (THF), ethanol (EtOH), and / or water provides amine 2-f. Alternatively, reduction of intermediate 2-e with a metal catalyst and hydrogen (H) gas in solvents such as methanol (MeOH) or ethyl acetate (EtOAc) provides amine 2-f. Cyclization of 2-f with carbonyldiimidazole (CDI) in solvents such as dichloromethane (DCM) provides the desired compound of Formula (I).

[0195] General Scheme 2 [ka] (n is 1, and R2, R3, R 3’ , R4, R5, and X1 to X4 are as defined in formula (I). Alternatively, compounds of Formula (I) can be prepared using intermediates 2-a, 2-b, 2-c, 2-d, 2-g, and 2-h as outlined in General Scheme 2. Amination of 2-a with 2-b using a base, i.e., N,N-diisopropylethylamine (DIEA), in a solvent, i.e., acetonitrile (MeCN) provides 2-c. Reduction of intermediate 2-c with a metal (i.e., iron (Fe) powder) and ammonium chloride in a solvent, i.e., tetrahydrofuran (THF), ethanol (EtOH), and / or water, provides amine 2-g. Alternatively, reduction of intermediate 2-c with a metal catalyst and hydrogen (H) gas in a solvent, i.e., methanol (MeOH) or ethyl acetate (EtOAc), can provide amine 2-g. Cyclization of 2-g with carbonyldiimidazole (CDI) in a solvent, i.e., dichloromethane (DCM), provides intermediate 2-h. Coupling of 2-h with aryl or heteroaryl boronic acids / esters 2-d in a solvent such as 1,4-dioxane using a catalytic amount of palladium catalyst, i.e., [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride·dichloromethane (Pd(dppf)Cl2·CH2Cl2), and a base, i.e., potassium carbonate (K2CO3) or cesium carbonate (Cs2CO3), at elevated temperatures provides the desired compounds of formula (I).

[0196] General Scheme 3 [ka] (R1, R2, R3, R 3’ , R4, R5, n, and X1 to X4 are defined as in formula (I). As stated.) Compounds of formula (I) in general scheme 3 can be prepared as outlined above. Alkylation of 2-i with intermediate 2-j (where X is a halogen) using a base, i.e., sodium hydride (NaH) or cesium carbonate (CS2CO3), in a solvent, i.e., dimethylformamide (DMF) provides the desired compound of formula (I). Alternatively, compounds of formula (I) can be obtained by treating intermediates 2-i and 2-j (where X is OH) with diisopropyl azodicarboxylate (DIAD) and triphenylphosphine in a solvent, i.e., tetrahydrofuran (THF).

[0197] General Scheme 4 [ka] (R3, R 3’ , R4, R5, R 10 and X1 to X4 are as defined in formula (I). Compounds of formula (I) can be prepared using intermediates 2-k and 2-l as outlined in General Scheme 4. Coupling of arylboronic acid / ester 2-k with 2-l (Y is -Br or -O-triflate) using a catalytic amount of palladium catalyst, i.e., [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride·dichloromethane (Pd(dppf)Cl2·CHCl2), and a base, i.e., potassium carbonate (K2CO3) or cesium carbonate (Cs2CO3), in a solvent such as 1,4-dioxane at elevated temperatures affords the desired compounds of formula (I).

[0198] General Scheme 5 [ka] (R3, R 3’ , R4, R5, R 10 and X1 to X4 are as defined in formula (I). Alternatively, compounds of formula (I) can be prepared using intermediates 2-m and 2-n as outlined in general scheme 5. In a solvent such as 1,4-dioxane, a catalytic amount of Coupling of aryl bromides / triflates 2-m with 2-n (Y is -BF3K, -B(OH)2, or -(BOR)2, where R forms a boronic ester or MIDA boronic acid) using a palladium catalyst, i.e., [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride·dichloromethane (Pd(dppf)Cl2·CH2Cl2) and a base, i.e., potassium carbonate (K2CO3) or cesium carbonate (Cs2CO3), at elevated temperatures affords the desired compounds of formula (I).

[0199] The mixtures of enantiomers, diastereomers, and cis / trans isomers resulting from the above processes can be separated into the individual components of the mixture by chiral salt techniques, chromatography using normal-phase, reverse-phase, or chiral columns depending on the nature of the separation.

[0200] In the descriptions and formulas set forth above, the various groups R1, R2, R4, R5, and X1-X4, as well as other variables, are as defined above unless otherwise indicated. Furthermore, for synthetic purposes, the compounds of General Schemes 1-5 are merely representative examples, with groups selected to illustrate the general synthetic methodology for compounds of formula (I) defined herein.

[0201] Methods of using the compound Another aspect of the present application relates to a method for treating or preventing a disease or disorder associated with the modulation of ubiquitin-specific protease 1 (USP1), comprising administering to a patient in need of treatment for a disease or disorder associated with the modulation of USP1 an effective amount of the present composition and a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0202] In another aspect, the present application relates to a method for treating, preventing, suppressing, or eliminating a disease or disorder in a patient associated with the inhibition of ubiquitin-specific protease 1 (USP1), comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the disease or disorder is cancer.

[0203] Another aspect of the present application relates to a method for inhibiting ubiquitin-specific protease 1 (USP1), comprising administering to a patient in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0204] In another aspect, the present application relates to a method for treating or preventing cancer, the method comprising administering to a patient in need of cancer treatment an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0205] Another aspect of the present application relates to a method for treating or preventing a disease or disorder associated with DNA damage, the method comprising administering to a patient in need of treatment for a disease or disorder associated with DNA damage an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the disease or disorder is cancer.

[0206] In another aspect, the present application relates to a method for inhibiting or reducing DNA repair activity regulated by ubiquitin-specific protease 1 (USP1), the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solution thereof. This includes administering a solvate, prodrug, stereoisomer, or tautomer.

[0207] Another aspect of the present application relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in a method for the treatment or prevention of a disease associated with the inhibition of USP1. In one embodiment, the disease or disorder is cancer.

[0208] In another aspect, the application relates to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in a method for the treatment or prevention of cancer.

[0209] Another aspect of the present application relates to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in a method for treating or preventing a disease or disorder associated with DNA damage. In one embodiment, the disease or disorder is cancer.

[0210] In another aspect, the application relates to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in a method of inhibiting or reducing DNA repair activity regulated by ubiquitin-specific protease 1 (USP1).

[0211] Another aspect of the present application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the manufacture of a medicament for the treatment or prevention of a disease associated with the inhibition of USP1. In one embodiment, the disease or disorder is cancer.

[0212] In another aspect, the application relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment or prevention of cancer.

[0213] Another aspect of the present application relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with DNA damage. In one embodiment, the disease or disorder is cancer.

[0214] In another aspect, this application relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment of a disease or disorder associated with DNA damage. In one embodiment, the disease or disorder is cancer.

[0215] Another aspect of the present application relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for inhibiting or reducing DNA repair activity regulated by ubiquitin-specific protease 1 (USP1).

[0216] In another embodiment, the present application relates to the use of an inhibitor of USP1 for the preparation of a medicament for use in the treatment, prevention, suppression, or elimination of a disease or disorder related to cancer.

[0217] The present application also relates to a method for the preparation of a medicament comprising a compound of formula (I) for use in the treatment, prevention, suppression or elimination of a disease or disorder mediated by USP1. Regarding use.

[0218] In another aspect, the present application relates to a method for making a medicament comprising a compound of formula (I) for treating, preventing, inhibiting, or eliminating a disease or disorder mediated by USP1.

[0219] In another embodiment, the present application relates to the use of an inhibitor of USP1 for the preparation of a medicament for use in the treatment, prevention, suppression, or elimination of a cancer-related disease or disorder.

[0220] In another embodiment, the present application relates to a composition comprising a compound of formula (I) or a compound of the present application and a pharmaceutically acceptable carrier for use in treating cancer.

[0221] In some embodiments of the methods described herein, the cancer is adrenocortical carcinoma, AIDS-related lymphoma, AIDS-related malignancies, anal cancer, cerebellar astrocytoma, extrahepatic bile duct cancer, bladder cancer, osteosarcoma / malignant fibrous histiocytoma, brain stem glioma, ependymoma, optic tract hypothalamic glioma, breast cancer, bronchial adenoma / bronchial carcinoid, carcinoid tumor, gastrointestinal carcinoid, carcinoma, adrenocortical carcinoma, pancreatic islet cell carcinoma, primary central nervous system lymphoma, cerebellar astrocytoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, tendon sheath specific Alveolar sarcoma, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma / Ewing's tumor, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer including intraocular melanoma and retinoblastoma, gallbladder cancer, gastrointestinal carcinoid, ovarian germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, Hodgkin's disease, hypopharyngeal cancer, hypothalamic optic tract glioma, intraocular melanoma, Kaposi's sarcoma, pharyngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, non-Hodgkin's disease Lymphoma, Waldenstrom's macroglobulinemia, malignant mesothelioma, malignant thymoma, osteoblastoma, melanoma, intraocular melanoma, Merkel cell carcinoma, metastatic squamous cell carcinoma of the neck with unknown primary site, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, chronic myeloid leukemia, myeloid leukemia, multiple myeloma, myeloproliferative disorders, cancer of the nasal cavity and paranasal sinuses, nasopharyngeal carcinoma, neuroblastoma, oral cancer, cancer of the oral cavity and lip, oropharyngeal cancer, osteosarcoma / malignant fibrous histiocytoma of bone, ovarian cancer, ovarian low malignant potential tumor, pancreatic The cancer is selected from cancers of the paranasal sinuses and nasal cavity, parathyroid cancer, penile cancer, pheochromocytoma, pituitary tumor, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, transitional cell carcinoma (e.g., renal pelvis and ureter), retinoblastoma, rhabdomyosarcoma, salivary gland cancer, malignant fibrous histiocytoma of bone, soft tissue sarcoma, Sézary syndrome, skin cancer, small intestine cancer, gastric cancer, supratentorial primitive neuroectodermal tumor and pineal tumor, cutaneous T-cell lymphoma, testicular cancer, malignant thymoma, thyroid cancer, gestational trophoblastic tumor, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms' tumor. In other embodiments, the cancer is non-small cell lung cancer. In other embodiments of the methods described herein, the cancer is a dedifferentiated ID-induced cancer. In yet other embodiments, the cancer is a hematological cancer. In other embodiments, the cancer is a cancer sensitive to USP-1 inhibition.In yet other embodiments, the cancer is a cancer that is sensitive to USP-1 inhibition due to a dysfunctional DNA repair pathway.

[0222] In any embodiment of the present application, the cancer may be a cancer in any organ, for example, the cancer is selected from the group consisting of glioma, thyroid cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, gastric cancer, colon cancer, gastrointestinal stromal tumor, pancreatic cancer, bile duct cancer, CNS cancer, ovarian cancer, endometrial cancer, prostate cancer, renal cancer, anaplastic large cell lymphoma, leukemia, multiple myeloma, mesothelioma, and melanoma, and combinations thereof.

[0223] In other embodiments, the cancer is selected from liposarcoma, neuroblastoma, glioblastoma, bladder cancer, adrenocortical carcinoma, multiple myeloma, colorectal cancer, non-small cell lung cancer, human papillomavirus-associated cervical cancer, oropharyngeal cancer, penile cancer, anal cancer, thyroid cancer, or vaginal cancer, or Epstein-Barr virus-associated nasopharyngeal cancer, gastric cancer, rectal cancer, thyroid cancer, Hodgkin's lymphoma, and diffuse large B-cell lymphoma.

[0224] Another aspect of the present application is directed to a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, which may further comprise an excipient, diluent, or surfactant.

[0225] In one embodiment, a method for treating a disease or disorder associated with the regulation of ubiquitin-specific protease 1 (USP1), including cancer, comprises administering a compound of formula (I) to a patient suffering from at least one of the above diseases or disorders.

[0226] One therapeutic use of the compounds or compositions of the present application that inhibit ubiquitin-specific protease 1 (USP1) is to provide treatment to patients or subjects suffering from cancer.

[0227] The disclosed compounds of the present application can be administered in an effective amount to treat or prevent a disorder and / or prevent its onset in a subject.

[0228] The compounds of the present application can be administered in therapeutically effective amounts in combination therapy with one or more therapeutic agents (pharmaceutical combinations) or in combination therapy with physical therapy, e.g., non-drug therapies. For example, the use of other antiproliferative, anticancer, immunomodulatory, or anti-inflammatory agents may produce synergistic effects. When the compounds of the present application are administered in combination with other therapeutic agents, the dose of the co-administered compound will naturally vary depending on the type of combination drug used, the specific drug used, the disease being treated, etc.

[0229] Combination therapy includes the administration of the subject compound in further combination with other biologically active ingredients (such as, but not limited to, a second and different anti-cancer drug or a second agent targeting a DNA repair mechanism independent of USP-1) and non-drug therapies (such as, but not limited to, surgery or radiation therapy). For example, the compound of the present application can be used in combination with other pharmaceutically active compounds, preferably compounds that can enhance the effects of the compound of the present application. The compound of the present application can be administered simultaneously with other drug therapies (as a single formulation or separate formulations) or physical therapies or sequentially to the drug therapies or physical therapies. Generally, combination therapy envisions the administration of two or more drugs during a single cycle or course of treatment.

[0230] Administration of the disclosed compounds can be carried out via any mode of administration for therapeutic agents, including systemic or local administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal, or topical modes of administration.

[0231] Depending on the intended mode of administration, the disclosed compositions can be in solid, semi-solid, or liquid dosage forms, optionally in unit dosage forms and in accordance with conventional pharmaceutical practice, such as, for example, injectables, tablets, suppositories, pills, sustained-release capsules, elixirs, tinctures, emulsions, syrups, powders, solutions, suspensions, etc. Likewise, the compositions can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0232] An exemplary pharmaceutical composition comprises a compound of the present application and a) a diluent, for example, purified water, hydrogenated or partially hydrogenated vegetable oil or mixtures thereof, triglyceride oil such as corn oil, olive oil, sunflower oil, safflower oil, EPA or DHA or their esters or triglycerides or mixtures thereof, fish oil such as omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol , cellulose, sodium, saccharin, glucose and / or glycine, b) lubricants, for example, silica, talc, stearic acid, magnesium or calcium stearic acid, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol, and for tablets also c) binders, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone, if desired, d) disintegrants, for example, starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures, e) adsorbents, colorants, flavors and sweeteners, f) Tween 80, Labrasol, HPMC, DOSS, caproyl Tablets and gelatin capsules comprising a pharmaceutically acceptable carrier such as an emulsifier or dispersing agent such as 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier, and / or g) an agent that enhances absorption of the compound, such as cyclodextrin, hydroxypropyl cyclodextrin, PEG400, and PEG200.

[0233] Liquid compositions, particularly injectable compositions, can be prepared, for example, by dissolving, dispersing, etc. For example, the disclosed compounds are dissolved in or mixed with pharmaceutically acceptable solvents such as water, physiological saline, aqueous dextrose, glycerin, ethanol, etc., to form an isotonic solution or suspension for injection. Proteins such as albumin, chylomicron particles, or serum proteins may be used to solubilize the disclosed compounds.

[0234] The disclosed compounds may also be formulated as suppositories which can be prepared from fatty emulsions or suspensions, using polyalkylene glycols, such as propylene glycol, as the carrier.

[0235] Parenteral injectable administration is commonly used for subcutaneous, intramuscular, or intravenous injection and infusion. Injectables can be formulated in conventional forms, either as liquid solutions or suspensions, or as solid forms suitable for dissolving in liquid prior to injection.

[0236] Another aspect of the present application is directed to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier, which may further comprise an excipient, diluent, or surfactant.

[0237] Dosage regimens utilizing the disclosed compounds are selected according to a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient; the severity of the disease being treated; the route of administration; the patient's renal or hepatic function; and the particular disclosed compound being used. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the disease.

[0238] When used for the indicated effects, effective doses of the disclosed compounds range from about 0.5 mg to about 5000 mg, as needed to treat the disease. Compositions for in vivo or in vitro use may contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compounds, or may range from one amount to another within the dosage recited above. In one embodiment, the composition may contain a groove for splitting. It is in the form of a tablet which may be marked with [Example]

[0239] The present disclosure is further illustrated by the following examples and synthetic schemes, which should not be construed as limiting the scope or spirit of the disclosure to the specific procedures described herein. It should be understood that these examples are provided to illustrate certain embodiments, and that it is not intended that the scope of the disclosure be limited by these examples. It should be further understood that various other embodiments, modifications, and equivalents of these examples, which may occur to those skilled in the art, may be implemented without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0240] Analytical methods, materials, and devices Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on either a 300 MHz or 400 MHz Bruker or Varian spectrometer. Spectra are reported in ppm (δ), and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as the internal standard. Mass spectra were collected using a Waters ZQ single quadrupole mass spectrometer (ion trap ESI). Purity and low-resolution mass spectral data were measured using a Waters Acquity i-class ultra-performance high-resolution liquid chromatography (UPLC) system equipped with an Acquity photodiode array detector, an Acquity evaporative light scattering detector (ELSD), and a Waters ZQ mass spectrometer. Data were acquired using Waters MassLynx 4.1 software, and purity was characterized by UV wavelength at 220 nm, ELSD, and ESI. Column: Acquity UPLC BEH C18 1.7 μm 2.1 × 50 mm; flow rate: 0.6 mL / min; solvent A (95 / 5 / 0.1 10 mM ammonium formate / acetonitrile / formic acid), solvent B (95 / 5 / 0.09 acetonitrile / water / formic acid); gradient: 5–100% B from 0–2 min, hold at 100% B until 2.2 min, then 5% B at 2.21 min. Purification by preparative HPLC was performed using a Waters SunFire C18 OBD preparative column, 100 Å, 5 μm, 19 mm × 50 mm, with UV detection (Waters 2489 UV / 998 PDA) at 254 nm or 220 nm using a standard solvent gradient program (see HPLC methods 1–8 below). Purification by preparative chiral HPLC was performed on a SunFire C18 OBD preparative column, 100 Å, 5 μm, 19 mm × 150 mm, a Waters XBridge BEH Shield RP18 OBD preparative column, 130 Å, 5 μm, 19 mm × 150 mm, or a Waters XSelect CSH C18 OBD preparative column, 130 Å, 5 μm, 19 mm × 150 mm. Purification by preparative chiral HPLC was performed using either a Phenomenex Lux 5u cellulose-4 column, AXIA-packed 250 mm × 21.2 mm, 5 μm, or a Daicel CHIRALPAK® IC 20 × 250 mm, 5 μm column. The technical specifications used for analytical characterization of compounds are detailed in LCMS Method 1 (Preparation of Intermediates) or LCMS Method 2. [Preparative HPLC aqueous method 1 (ESI, 6-part method)]: Equipment: HPLC: Waters 2545 binary gradient module. MS: Waters 3100 / ZQ mass detector. UV: Waters 2489UV / 998PDA. Conditions: Mobile phase A: water with 0.1% formic acid; Mobile phase B: acetonitrile with 0.1% formic acid. Column: Waters SunFire C18 OBD preparative column, 100 Å, 5 μm, 19 mm × 50 mm. Column temperature: ambient temperature. LC gradient: B held at 0% for 0.9 min, then from 0% to 5% in 0.01 min; then 5% to 35% in 3.84 minutes; then 35% to 100% in 0.01 minutes; hold at 100% for 0.74 minutes, then 100% to 0% in 0.01 minutes; hold at 0% for 0.49 minutes. LC flow rate: 23 mL / min with binary pump and 2 mL / min of acetonitrile for column dilution. UV wavelengths: 220nm and 254nm. Ionization mode: ESI positive / negative. [Preparative HPLC aqueous method 2 (ESI, 6-minute method)]: Equipment: HPLC: Waters 2545 binary gradient module. MS: Waters 3100 / ZQ mass detector. UV: Waters 2489UV / 998PDA. Conditions: Mobile phase A: water containing 0.1% ammonium hydroxide; Mobile phase B: acetonitrile containing 0.1% ammonium hydroxide. Column: Waters XBridge BEH C18 OBD preparative column, 130 Å, 5 μm, 19 mm × 50 mm. Column temperature: ambient temperature. LC gradient: B held at 0% for 0.9 min, then 0% to 5% in 0.01 min; then 5% to 35% in 3.84 min; then 35% to 100% in 0.01 min; hold at 100% for 0.74 min, then 100% to 0% in 0.01 min; hold at 0% for 0.49 min. LC flow rate: 23 mL / min with binary pump and 2 mL / min of acetonitrile for column dilution. UV wavelengths: 220nm and 254nm. Ionization mode: ESI positive / negative. [Preparative HPLC polar method 3 (ESI, 6-separation method)]: Equipment: HPLC: Waters 2545 binary gradient module. MS: Waters 3100 / ZQ mass detector. UV: Waters 2489UV / 998PDA. Conditions: Mobile phase A: water with 0.1% formic acid; Mobile phase B: acetonitrile with 0.1% formic acid. Column: Waters SunFire C18 OBD preparative column, 100 Å, 5 μm, 19 mm × 50 mm. Column temperature: ambient temperature. LC gradient: 15% for 0.9 min, then 15% to 25% in 0.01 min; then 25% to 65% in 3.84 min; and 65% to 100% in 0.01 min; hold at 100% for 0.74 min, then 100% to 0% in 0.01 min; hold at 0% for 0.49 min. LC flow rate: 23 mL / min with binary pump and 2 mL / min of acetonitrile for column dilution. UV wavelengths: 220nm and 254nm. Ionization mode: ESI positive / negative. [Preparative HPLC polarity method 4 (ESI, 6-separation method)]: Equipment: HPLC: Waters 2545 binary gradient module. MS: Waters 3100 / ZQ mass detector. UV: Waters 2489UV / 998PDA. Conditions: Mobile phase A: water containing 0.1% ammonium hydroxide; Mobile phase B: acetonitrile containing 0.1% ammonium hydroxide. Column: Waters XBridge BEH C18 OBD preparative column, 130 Å, 5 μm, 19 mm × 50 mm. Column temperature: ambient temperature. LC gradient: B held at 15% for 0.9 min, then from 15% to 25% in 0.01 min; then from 25% to 65% in 3.84 min; then from 65% to 100% in 0.01 min; held at 100% for 0.74 min, then from 100% to 0% in 0.01 min; then from 0% to 0. Hold for 49 minutes. LC flow rate: 23 mL / min with binary pump and 2 mL / min of acetonitrile for column dilution. UV wavelengths: 220nm and 254nm. Ionization mode: ESI positive / negative. [Preparative HPLC general method 5 (ESI, 6-separation method)]: Equipment: HPLC: Waters 2545 binary gradient module. MS: Waters 3100 / ZQ mass detector. UV: Waters 2489UV / 998PDA. Conditions: Mobile phase A: water with 0.1% formic acid; Mobile phase B: acetonitrile with 0.1% formic acid. Column: Waters SunFire C18 OBD preparative column, 100 Å, 5 μm, 19 mm × 50 mm. Column temperature: ambient temperature. LC gradient: B held at 35% for 0.9 min, then 35% to 45% in 0.01 min; then 45% to 85% in 3.84 min; then 85% to 100% in 0.01 min; hold at 100% for 0.74 min, then 100% to 0% in 0.01 min; hold at 0% for 0.49 min. LC flow rate: 23 mL / min with binary pump and 2 mL / min of acetonitrile for column dilution. UV wavelengths: 220nm and 254nm. Ionization mode: ESI positive / negative. [Preparative HPLC general method 6 (ESI, 6-separation method)]: Equipment: HPLC: Waters 2545 binary gradient module. MS: Waters 3100 / ZQ mass detector. UV: Waters 2489UV / 998PDA. Conditions: Mobile phase A: water containing 0.1% ammonium hydroxide; Mobile phase B: acetonitrile containing 0.1% ammonium hydroxide. Column: Waters XBridge BEH C18 OBD preparative column, 130 Å, 5 μm, 19 mm × 50 mm. Column temperature: ambient temperature. LC gradient: B held at 35% for 0.9 min, then 35% to 45% in 0.01 min; then 45% to 85% in 3.84 min; then 85% to 100% in 0.01 min; hold at 100% for 0.74 min, then 100% to 0% in 0.01 min; hold at 0% for 0.49 min. LC flow rate: 23 mL / min with binary pump and 2 mL / min of acetonitrile for column dilution. UV wavelengths: 220nm and 254nm. Ionization mode: ESI positive / negative. [Preparative HPLC nonpolar method 7 (ESI, 6 preparative methods)]: Equipment: HPLC: Waters 2545 binary gradient module. MS: Waters 3100 / ZQ mass detector. UV: Waters 2489UV / 998PDA. Conditions: Mobile phase A: water with 0.1% formic acid; Mobile phase B: acetonitrile with 0.1% formic acid. Column: Waters SunFire C18 OBD preparative column, 100 Å, 5 μm, 19 mm × 50 mm. Column temperature: ambient temperature. LC gradient: B held at 50% for 0.9 min, then from 50% to 60% in 0.01 min; then from 60% to 100% in 3.84 min; then held at 100% for 0.75 min, then from 100% to 0% in 0.01 min; held at 0% for 0.49 min. LC flow rate: 23 mL / min with binary pump and 2 mL / min of acetonitrile for column dilution. UV wavelengths: 220nm and 254nm. Ionization mode: ESI positive / negative. [Preparative HPLC nonpolar method 8 (ESI, 6-separation method)] Equipment: HPLC: Waters 2545 binary gradient module. MS: Waters 3100 / ZQ mass detector. UV: Waters 2489UV / 998PDA. Conditions: Mobile phase A: water containing 0.1% ammonium hydroxide; Mobile phase B: acetonitrile containing 0.1% ammonium hydroxide. Column: Waters XBridge BEH C18 OBD preparative column, 130 Å, 5 μm, 19 mm × 50 mm. Column temperature: ambient temperature. LC gradient: B held at 50% for 0.9 min, then from 50% to 60% in 0.01 min; then from 60% to 100% in 3.84 min; then held at 100% for 0.75 min, then from 100% to 0% in 0.01 min; held at 0% for 0.49 min. LC flow rate: 23 mL / min with binary pump and 2 mL / min of acetonitrile for column dilution. UV wavelengths: 220nm and 254nm. Ionization mode: ESI positive / negative. [LCMS method 1 (ESI, 2.5 minutes method)]: Equipment: MS: Waters ZQ Mass Detector, HPLC: Waters Acquity Binary Solvent Manager; UV: Waters Acquity PDA; LSD: Waters Acquity ELSD. Conditions: Mobile phase A: 95% water / 5% acetonitrile with 0.1% formic acid in 10 mM ammonium formate; Mobile phase B: 95% acetonitrile / 5% water with 0.09% formic acid. Column: Waters Acquity UPLC BEH C18, 1.7 μm, 2.1 × 50 mm. Column temperature: 35°C. LC gradient: 5 to 100% B over 2.0 min, hold at 100% B until 2.2 min. LC flow rate: 0.6mL / min. UV wavelength: 220nm. Ionization mode: ESI positive / negative. [LCMS method 2 (ESI, 2.5 minutes method)]: Equipment: MS: Waters ZQ Mass Detector, HPLC: Waters Acquity Binary Solvent Manager; UV: Waters Acquity PDA; LSD: Waters Acquity ELSD. Conditions: Mobile phase A: 95% water / 5% acetonitrile with 0.1% formic acid; Mobile phase B: 95% acetonitrile / 5% water with 0.085% formic acid. Column: Waters Acquity UPLC CSH C18, 1.7 μm, 2.1 × 50 mm. Column temperature: 35°C. LC gradient: 5 to 100% B over 2.0 min, hold at 100% B until 2.2 min. LC flow rate: 0.6mL / min. UV wavelength: 220nm. Ionization mode: ESI positive / negative. Abbreviations used in the examples below and elsewhere in this specification are as follows: [Table 1-1] [Table 1-2] [Table 1-3]

[0241] Example 1: Intermediate B-1 2-(3-fluoro-2-isopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Step 1: 3-Fluoro-2-(prop-1-en-2-yl)phenol A mixture of 2-bromo-3-fluorophenol (2 g, 10.47 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.95 g, 11.60 mmol), Pd(dppf)Cl₂·CHCl₂ (858 mg, 1.05 mmol), potassium carbonate (2.90 g, 21.00 mmol), water (4 mL), and 1,4-dioxane (20 mL) was stirred at 60 °C under a nitrogen atmosphere for 16 h. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting with EtOAc / PE (1:2) to give 500 mg (31%) of 3-fluoro-2-(prop-1-en-2-yl)phenol as a light brown oil. MS (ESI) m / z 153 [M+H] + .

[0242] Step 2: 3-Fluoro-2-isopropylphenol A flask containing 3-fluoro-2-(prop-1-en-2-yl)phenol (500 mg, 3.29 mmol) and palladium on carbon (10 wt%, 500 mg) in MeOH (20 mL) was evacuated and backfilled with hydrogen three times, then filled with hydrogen. The resulting mixture was stirred at ambient temperature for 16 hours, then filtered and concentrated under reduced pressure to give 500 mg (99%) of 3-fluoro-2-isopropylphenol. MS (ESI) m / z 155 [M+H] + .

[0243] Step 3: 3-Fluoro-2-isopropylphenyl trifluoromethanesulfonate A solution of 3-fluoro-2-(propan-2-yl)phenol (500 mg, 3.24 mmol) and triethylamine (394 mg, 3.89 mmol) in DCM (8 mL) at 0 °C was treated dropwise with trifluoromethanesulfonic anhydride (1 g, 3.55 mmol). The resulting solution was stirred at 0 °C for 2 h, and the reaction mixture was poured into water (10 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with a gradient of 1–10% EtOAc / PE) to afford 570 mg (61%) of 3-fluoro-2-isopropylphenyl trifluoromethanesulfonate. 1 H NMR (300 MHz, DMSO-d6) δ 7.52-7.43 (m, 1H), 7.40-7.33 (m, 1H), 7.25 (d, J = 8.4 Hz, 1H), 3.29-3.17 (m, 1H), 1.32 (d, J = 6.90 Hz, 3H), 1.31 (d, J = 6.9 Hz, 3H).

[0244] Step 4: 2-(3-fluoro-2-isopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane A mixture of 3-fluoro-2-(propan-2-yl)phenyl trifluoromethanesulfonate (550 mg, 1.92 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (977 mg, 3.85 mmol), Pd(dppf)Cl2·CHCl2 (155 mg, 0.19 mmol), potassium acetate (377 mg, 3.84 mmol), and 1,4-dioxane (20 mL) was stirred at 80 °C for 16 h under a nitrogen atmosphere. The mixture was cooled to ambient temperature, concentrated under reduced pressure, and purified by silica gel chromatography eluting with EtOAc / PE (1 / 100 to 1 / 10) to give 400 mg (79%) of 2-(3-fluoro-2-isopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. MS (ESI) m / z 265 [M+H] + .

[0245] Intermediate B-2 2-Isopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [ka] 2-Isopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was synthesized according to Example 1, replacing 2-bromo-3-fluorophenol with 2-bromopyridin-3-ol. MS (ESI) m / z 248 [M+H] + .

[0246] Intermediate B-3 2-(2-fluoro-6-isopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] 2-(2-Fluoro-6-isopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was synthesized from 2-bromo-6-fluorophenol according to the procedure outlined for Example 1. MS (ESI) m / z 264 [M+H] + .

[0247] Intermediate B-4 2-(2-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] 2-(2-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was prepared from 1-bromo-2-(difluoromethyl)benzene according to Step 4 of Example 1. Purification by preparative TLC (eluted with 2% EtOAc / PE) gave the title compound. MS (ESI) m / z 254.1 [M+H] + .

[0248] Intermediate B-5 1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline [ka] 1-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline was synthesized from 7-bromoindoline according to Step 4 of Example 1. MS (ESI) m / z 259.1 [M+H] + .

[0249] Intermediate B-6 1-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-one [ka] 1-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-one was synthesized from 1-(2-bromophenyl)ethan-1-one according to Step 4 of Example 1. MS (ESI) m / z 246.8 [M+H] + .

[0250] Intermediate B-7 2-(2-(1-methoxyethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Step 1 1-Bromo-2-(1-methoxyethyl)benzene 1-Bromo-2-(1-methoxyethyl)benzene was prepared from 1-(2-bromophenyl)ethan-1-ol according to the conditions in Example 9. MS (ESI) m / z 214.0, 215.9 [M+H] + .

[0251] Step 2: 2-(2-(1-methoxyethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2-(2-(1-methoxyethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was prepared from 1-bromo-2-(1-methoxyethyl)benzene according to Step 4 of Example 1. MS (ESI) m / z 262.1 [M+H] + .

[0252] Intermediate B-8 2-(2-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Step 1 1-Bromo-2-cyclopropylbenzene According to Step 1 of Example 1, 1-bromo-2-cyclopropylbenzene was synthesized using 1-bromo-2-iodobenzene and cyclopropylboronic acid.1 H NMR (400 MHz, CD3OD) δ 7.53-7.49 (m, 1H), 7.24-7.19 (m, 1H), 7.06-6.93 (m, 2H), 2.18-2.10 (m, 1H), 1.01-0.96 (m, 2H), 0.68-0.53 (m, 2H).

[0253] Step 2: 2-(2-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane A mixture of 1-bromo-2-cyclopropylbenzene (11.00 g, 55.82 mmol), Pd(dppf)Cl CHCl (4.56 g, 5.58 mmol), potassium acetate (16.43 g, 167.45 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (17.01 g, 66.98 mmol), and 1,4-dioxane (500 mL) was stirred at 90 °C under a nitrogen atmosphere for 16 h. After cooling to ambient temperature, the reaction mixture was poured into water (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 0% to 0.1% EtOAc / PE), and the product was further purified by C18 reverse-phase silica gel chromatography (eluting with 5% to 100% acetonitrile / aqueous NaHCO3 (10 mmol)), which afforded 6.1 g (44%) of 2-(2-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a yellow oil. 1 H NMR (400 MHz, CD3OD) δ 7.70-7.63 (m, 1H), 7.37-7.19 (m, 1H), 7.18-7.06 (m, 1H), 6.91-6.81 (m, 1H), 2.74-2.62 (m, 1H), 1.38-1.35 (m, 12H), 1.00-0.89 (m, 2H), 0.72-0.60 (m, 2H). MS (ESI) m / z 244.9 [M+H] + .

[0254] Intermediate B-9 2-cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [ka] Step 1 2-Bromopyridin-3-yl trifluoromethanesulfonate A mixture of 2-bromopyridin-3-ol (25 g, 143.68 mmol) and pyridine (145 mL) at 0 °C was treated with the dropwise addition of trifluoromethanesulfonic anhydride (24.2 mL, 143.24 mmol). The resulting solution was stirred at ambient temperature overnight. The reaction mixture was poured into saturated sodium bicarbonate solution (500 mL) and then extracted with DCM (200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by vacuum distillation under reduced pressure (-0.2 MPa). The fraction collected at 130 °C gave 25 g (57%) of 2-bromopyridin-3-yl trifluoromethanesulfonate as a colorless oil. MS (ESI) m / z 304.9, 306.9 [M] + .

[0255] Step 2: 2-Cyclopropylpyridin-3-yl trifluoromethanesulfonate Under nitrogen, a mixture of 2-bromopyridin-3-yl trifluoromethanesulfonate (5.0 g, 16.34 mmol) and tetrakis(triphenylphosphine)palladium(0) (944 mg, 0.82 mmol) in THF (25 mL) was treated with bromo(cyclopropyl)zinc (43 mL of a 0.5 M THF solution, 21.3 mmol) at ambient temperature. The resulting solution was stirred at 70 °C for 16 h. After cooling to ambient temperature, the reaction mixture was poured into saturated sodium bicarbonate solution (100 mL) and extracted with EtOAc (3 × 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 5% EtOAc / PE) to afford 1.9 g (44%) of 2-cyclopropylpyridin-3-yl trifluoromethanesulfonate as a colorless oil. MS (ESI) m / z 267.0 [M+H] + .

[0256] Step 3: 2-Cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Under nitrogen, a mixture of 2-cyclopropylpyridin-3-yl trifluoromethanesulfonate (5 g, 18.71 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (5.71 g, 22.49 mmol), potassium carbonate (5.25 g, 37.99 mmol), and Pd(dppf)Cl.CHCl (1.56 g, 1.91 mmol) in 1,4-dioxane (80 mL) was stirred at 100° C. for 20 h. After cooling to ambient temperature, the reaction mixture was poured into EtOAc (250 mL), washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was first purified by silica gel chromatography (eluting with a gradient of 0–15% EtOAc / PE) and then further purified by C18 reverse-phase silica gel chromatography (eluting with 0%–35% acetonitrile / 10 mmol aq. NH4HCO3) to afford 3 g (65%) of 2-cyclopropyl-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as a brown oil. 1 H NMR (400 MHz, CDCl3) δ 8.46-8.44 (m, 1H), 7.98-7.96 (m, 1H), 7.00-6.97 (m, 1H), 2.84-2.89 (m, 1H), 1.36 (s, 12H), 1.11-1.07 (m, 2H), 0.98-0.95 (m, 2H). MS (ESI) m / z 164.2 [M+H-C6H 10 ] + .

[0257] Example 2: Intermediate B-10 4-(1H-1,2,3-triazol-1-yl)benzonitrile and Intermediate B-11 4-(2H-1,2,3-triazol-2-yl)benzonitrile [ka] A mixture of 4-fluorobenzonitrile (20 g, 165.14 mmol), 1H-1,2,3-triazole (13 g, 188.23 mmol), and potassium carbonate (46 g, 332.83 mmol) in DMF (50 mL) was stirred at 80 °C for 18 h. After cooling to ambient temperature, the reaction mixture was poured into water (200 mL) and then extracted with EtOAc (3 × 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 3:1 EtOAc / PE) to give 10 g (36%) of 4-(1H-1,2,3-triazol-1-yl)benzonitrile as a white solid and 9 g (32%) of 4-(2H-1,2,3-triazol-2-yl)benzonitrile as a white solid.

[0258] Intermediate B-10 4-(1H-1,2,3-triazol-1-yl)benzonitrile (R f =0.2 (in 50% EtOAc / PE): 1 H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 2H), 8.22-8.16 (m, 2H), 8.09-8.00 (m, 2H). MS (ESI) m / z 171 [M+H] + .

[0259] Intermediate B-11 4-(2H-1,2,3-triazol-2-yl)benzonitrile (R f =0.8 (in 50% EtOAc / PE): 1 H NMR (300 MHz, DMSO-d6) δ 9.00 (d, J = 1.2 Hz, 1H), 8.25-8.05 (m, 4H), 8.04 (d, J = 1.2 Hz, 1H). MS (ESI) m / z 171 [M+H] + .

[0260] Example 3: Intermediate B-12 (4-(1H-1,2,3-triazol-1-yl)phenyl)methanamine [ka] A solution of intermediate B-10 (8 g, 47.01 mmol) in THF (20 mL) at 0 °C was treated batchwise with lithium aluminum hydride (5.7 g, 150.20 mmol). After the addition was complete, the resulting solution was stirred at 0 °C for 2 h and then quenched by the addition of sodium sulfate decahydrate. The resulting mixture was filtered, concentrated under reduced pressure, and purified by silica gel chromatography (eluting with 10:1 DCM / MeOH) to give [4-(1H-1,2,3-triazol-1-yl)phenyl]methanamine (7.5 g, white solid, 92%). MS (ESI) m / z 175 [M+H] + .

[0261] Intermediate B-13 (4-(2H-1,2,3-triazol-2-yl)phenyl)methanamine [ka] (4-(2H-1,2,3-triazol-2-yl)phenyl)methanamine was synthesized from 4-(2H-1,2,3-triazol-2-yl)benzonitrile according to Example 3. MS (ESI) m / z 175 [M+H] + .

[0262] Example 4: Intermediate B-14 (2-chloro-4-(1H-pyrazol-1-yl)phenyl)methanamine [ka] Step 1: 2-chloro-4-(1H-pyrazol-1-yl)benzonitrile 4-Bromo-2-chlorobenzonitrile (4.3 g, 19.86 mmol), 1H-pyrazole (2 g, 29.38 mmol), copper(I) iodide (760 mg, 3.99 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (1.2 g, 8.44 mmol), potassium carbonate (5.5 g, 39.79 mmol), and 1,4-dioxane (30 mL) were placed under a nitrogen atmosphere. The resulting mixture was stirred at 110 °C for 16 h. After cooling to ambient temperature, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 1:1 EtOAc / PE) to afford 3 g (74%) of 2-chloro-4-(1H-pyrazol-1-yl)benzonitrile as a yellow solid. MS (ESI) m / z 204 [M+H] + .

[0263] Step 2 (2-chloro-4-(1H-pyrazol-1-yl)phenyl)methanamine A mixture of 2-chloro-4-(1H-pyrazol-1-yl)benzonitrile (3 g, 14.73 mmol), Raney nickel (3 g), and MeOH (40 mL) was evacuated and backfilled with hydrogen several times, then filled with hydrogen. The resulting mixture was stirred at ambient temperature for 2 hours, then filtered and concentrated under reduced pressure to give 1 g (33%) of [2-chloro-4-(1H-pyrazol-1-yl)phenyl]methanamine as a green solid. MS (ESI) m / z 208 [M+H] + .

[0264] Intermediate B-15 (2-fluoro-4-(1H-pyrazol-1-yl)phenyl)methanamine [ka] (2-Fluoro-4-(1H-pyrazol-1-yl)phenyl)methanamine was synthesized from 4-bromo-2-fluorobenzonitrile according to Example 4. MS (ESI) m / z 192 [M+H] + .

[0265] Example 5: Intermediate B-16 1-(4-(1H-pyrazol-1-yl)phenyl)ethan-1-amine [ka] Step 1: 1-(4-(1H-pyrazol-1-yl)phenyl)ethan-1-one 1-(4-(1H-pyrazol-1-yl)phenyl)ethan-1-one was prepared from 1-(4-bromophenyl)ethan-1-one according to Step 1 of Example 4. MS (ESI) m / z 187 [M+H] + .

[0266] Step 2: 1-(4-(1H-pyrazol-1-yl)phenyl)ethan-1-one O-methyloxime A mixture of 1-(4-(1H-pyrazol-1-yl)phenyl)ethan-1-one (3.2 g, 17.30 mmol), O-methylhydroxylamine hydrochloride (2.14 g, 25.62 mmol), acetic acid (6 mL), and EtOH (60 mL) was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and then purified by silica gel chromatography (eluting with 1:1 EtOAc / PE) to afford 3.0 g (81%) of 1-(4-(1H-pyrazol-1-yl)phenyl)ethan-1-one O-methyloxime as a white solid. MS (ESI) m / z 216 [M+H] + .

[0267] Step 3: 1-(4-(1H-pyrazol-1-yl)phenyl)ethan-1-amine A mixture of 1-(4-(1H-pyrazol-1-yl)phenyl)ethan-1-one O-methyloxime (3.0 g, 13.98 mmol) was treated with a solution of borane in THF (1 M, 40 mL, 40 mmol), and the resulting solution was stirred at 80 °C for 16 h. After cooling to ambient temperature, MeOH (20 mL) was added, and the resulting solution was stirred for an additional 3 h. The mixture was concentrated under reduced pressure and purified by silica gel chromatography (eluting with 10:1 DCM / MeOH) to afford 2.0 g (77%) of 1-(4-(1H-pyrazol-1-yl)phenyl)ethan-1-amine as a colorless oil. MS (ESI) m / z 188 [M+H] + .

[0268] Example 6: Intermediate B-17 (4-(1H-pyrazol-1-yl)phenyl)methanamine [ka] Step 1: 4-(1H-pyrazol-1-yl)benzonitrile A mixture of 1H-pyrazole (15 g, 220.34 mmol), 4-fluorobenzonitrile (27 g, 222.93 mmol), and potassium carbonate (60.7 g, 439.19 mmol) in DMF (200 mL) was stirred at 110° C. for 16 h. After cooling to ambient temperature, the reaction mixture was poured into water (500 mL), and the resulting solid was collected by filtration and dried under reduced pressure to give 30 g (80%) of 4-(1H-pyrazol-1-yl)benzonitrile. MS (ESI) m / z 170 [M+H] + .

[0269] Step 2 (4-(1H-pyrazol-1-yl)phenyl)methanamine A mixture of 4-(1H-pyrazol-1-yl)benzonitrile (15 g, 88.66 mmol), Raney nickel (10 g), palladium on carbon (10 wt%, 1 g), and lithium hydroxide (1 g, 41.75 mmol) in EtOAc (200 mL) was evacuated and refilled with hydrogen several times, then filled with hydrogen. The resulting mixture was stirred at ambient temperature for 16 h, then filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with a gradient of 1-10% DCM / MeOH) to afford 8 g (52%) of (4-(1H-pyrazol-1-yl)phenyl)methanamine. MS (ESI) m / z 174 [M+H] + .

[0270] Example 7: Intermediate B-18 tert-butyl 4-(1-(4-(aminomethyl)phenyl)-1H-pyrazol-4-yl)piperidine-1-carboxylate [ka] Step 1: tert-Butyl 4-(1-(4-cyanophenyl)-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate In a 250 mL round-bottom flask purged with and maintained under an inert atmosphere of nitrogen, 4-(4-bromo-1H-pyrazol-1-yl)benzonitrile (prepared from 4-bromo-1H-pyrazole according to Step 1 of Example 6) (2.4 g, 9.67 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3.59 g, 11.61 mmol), Pd(dppf)Cl CHCl (1.19 g, 1.46 mmol), potassium carbonate (4 g, 28.94 mmol), 1,4-dioxane (70 mL), 2 ... A mixture of 1,2-dimethyl-4-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate and water (16 mL) was stirred at 80° C. for 16 hours. After cooling to room temperature, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 1 / 2 ethyl acetate / petroleum ether) to afford 3.3 g (97%) of tert-butyl 4-(1-(4-cyanophenyl)-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate as a brown solid. MS (ESI) m / z 351.0 [M+H] + .

[0271] Step 2: tert-Butyl 4-(1-(4-(aminomethyl)phenyl)-1H-pyrazol-4-yl)piperidine-1-carboxylate A mixture of tert-butyl 4-(1-(4-cyanophenyl)-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1 g, 2.85 mmol), methanol (100 mL), and palladium on carbon (10 wt % supported, 500 mg) was placed under a hydrogen atmosphere and stirred at ambient temperature for 30 minutes. The reaction mixture was filtered and concentrated under reduced pressure. The residue was treated with a solution of ammonia in methanol (7 M, 20 mL) and Raney nickel (500 mg), placed under a hydrogen atmosphere, and stirred at ambient temperature for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to afford 0.8 g (79%) of tert-butyl 4-(1-(4-(aminomethyl)phenyl)-1H-pyrazol-4-yl)piperidine-1-carboxylate as a colorless oil. MS (ESI) m / z 357.2 [M+H] + .

[0272] Example 8: Intermediate B-19 2-(4-(1H-pyrazol-1-yl)phenyl)cyclobutan-1-amine [ka] Step 1: 2-(4-(1H-pyrazol-1-yl)phenyl)cyclobutan-1-one A solution of 4-(1H-pyrazol-1-yl)benzaldehyde (prepared from 4-fluorobenzaldehyde according to Step 1 of Example 6) (1.5 g, 8.71 mmol) and cyclopropyldiphenylsulfonium tetrafluoroborate (2.74 g, 8.72 mmol) in THF (90 mL) was treated with the dropwise addition of a solution of potassium tert-butoxide (1 M in THF, 13 mL, 13 mmol) while stirring at 0 °C. After stirring at 0 °C for 1 h, tetrafluoroborate diethyl ether complex (50-55% w / w, 15 mL) was added, and the resulting mixture was stirred at ambient temperature for 16 h. The reaction mixture was poured into diethyl ether (300 mL), washed with saturated aqueous sodium carbonate (3 × 300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with a gradient of 1-40% EtOAc / PE) to give 1.4 g (76%) of 2-(4-(1H-pyrazol-1-yl)phenyl)cyclobutan-1-one as a yellow solid. MS (ESI) m / z 213 [M+H] + .

[0273] Step 2: 2-(4-(1H-pyrazol-1-yl)phenyl)cyclobutan-1-one oxime A solution of 2-(4-(1H-pyrazol-1-yl)phenyl)cyclobutan-1-one (900 mg, 4.24 mmol), sodium acetate (522 mg, 6.37 mmol), and hydroxylammonium chloride (440 mg, 6.38 mmol) in MeOH (10 mL) was stirred at ambient temperature for 30 minutes. The reaction mixture was then poured into methyl tert-butyl ether (50 mL), washed with water (2 × 50 mL) and brine (2 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with a gradient of 1–30% EtOAc / PE) to afford 320 mg (33%) of 2-(4-(1H-pyrazol-1-yl)phenyl)cyclobutan-1-one oxime as a pale yellow solid. MS (ESI) m / z 228 [M+H] + .

[0274] Step 3: 2-(4-(1H-pyrazol-1-yl)phenyl)cyclobutan-1-amine 2-(4-(1H-pyrazol-1-yl)phenyl)cyclobutan-1-one oxime (820 mg, 3.61 mmol), Raney nickel (800 mg), and ammonia in MeOH (7 M, 40 mL, 28 mmol) were placed under an atmosphere of hydrogen gas and stirred at ambient temperature for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give 750 mg (97%) of 2-(4-(1H-pyrazol-1-yl)phenyl)cyclobutan-1-amine as a greenish oil. MS (ESI) m / z 214 [M+H] + .

[0275] Intermediate B-20 4-(5-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile [ka] A mixture of 3,3-dibromo-1,1,1-trifluoropropan-2-one (6.13 g, 22.72 mmol), sodium acetate (1.88 g, 22.93 mmol), and water (6 mL) was stirred at 100° C. for 45 minutes. After cooling to ambient temperature, this mixture was added to a solution of 4-formylbenzonitrile (3 g, 22.88 mmol) and ammonium hydroxide (20 mL) in MeOH (100 mL), and the resulting mixture was stirred at ambient temperature for 40 minutes and then at 100° C. for 1 hour. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure and then extracted with EtOAc (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with a gradient of 1-50% EtOAc / PE) to give 5 g (92%) of 4-(5-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile as a yellow solid. MS (ESI) m / z 238 [M+H] + .

[0276] Example 9: Intermediate B-21 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile and Intermediate B-22 4-(1-methyl-5-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile [ka] A solution of intermediate B-20 (5.0 g, 21.08 mmol) in THF (100 mL) at 0 °C was treated with sodium hydride (60% dispersion in mineral oil, 844 mg, 21.10 mmol) added portionwise. After stirring at 0 °C for 1 h, iodomethane (2.99 g, 21.07 mmol) was added dropwise, and the resulting mixture was stirred at 0 °C for 2 h. The reaction mixture was poured into water (25 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4.8 g (91%) of a ca. 15:1 mixture of 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile and 4-(1-methyl-5-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile as a yellow oil. MS (ESI) m / z 251.9 [M+H] + .

[0277] NOTE: If desired, the minor isomer, 4-(1-methyl-5-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile, can be separated from the major isomer, 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile, by silica gel chromatography (eluting with a gradient of 0 to 15% EtOAc / PE).

[0278] Example 10: Intermediate B-23 (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine [ka] A mixture of intermediate B-21 (1.5 g, 5.97 mmol) and Raney nickel (1.0 g) in EtOAc (20 mL) was evacuated and refilled with hydrogen several times, then filled with hydrogen. The resulting mixture was stirred at ambient temperature for 2 hours, then filtered and concentrated under reduced pressure to provide 1.5 g (98%) of (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine as a yellow oil. MS (ESI) m / z 256.0 [M+H] + .

[0279] Intermediate B-24 (4-(1-(methyl-d3)-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine [ka] (4-(1-(methyl-d3)-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine was prepared in a manner similar to intermediate B-23, substituting iodomethane with iodomethane-d3. MS (ESI) m / z 259.0 [M+H] + .

[0280] Intermediate B-25 (4-(1-methyl-5-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine [ka] (4-(1-methyl-5-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine was prepared from intermediate B-22 according to Example 10.

[0281] Intermediate B-26 (6-(1H-pyrazol-1-yl)pyridin-3-yl)methanamine [ka] (6-(1H-pyrazol-1-yl)pyridin-3-yl)methanamine was prepared according to Example 6 as a yellow oil. MS (ESI) m / z 175.2 [M+H] + .

[0282] Example 11: Intermediate B-27 tert-butyl 3-(1-(4-(aminomethyl)phenyl)-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate [ka] Step 1 tert-Butyl 3-(1H-pyrazol-3-yl)pyrrolidine-1-carboxylate A mixture of 3-(pyrrolidin-3-yl)-1H-pyrazole hydrochloride (500 mg, 2.88 mmol), triethylamine (873 mg, 8.64 mmol), and di-tert-butyl dicarbonate (753 mg, 3.46 mmol) in DCM (10 mL) was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with DCM (30 mL), washed with water (3 × 30 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 680 mg (99%) of tert-butyl 3-(1H-pyrazol-3-yl)pyrrolidine-1-carboxylate as a colorless oil. MS (ESI) m / z 238 [M+H] + .

[0283] Step 2: tert-Butyl 3-(1-(4-(aminomethyl)phenyl)-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate Tert-butyl 3-(1-(4-(aminomethyl)phenyl)-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate was synthesized from tert-butyl 3-(1H-pyrazol-3-yl)pyrrolidine-1-carboxylate according to Example 6. MS (ESI) m / z 343 [M+H] + .

[0284] Intermediate B-28 (4-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl)methanamine [ka] (4-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl)methanamine was prepared according to the conditions outlined in Example 6. MS (ESI) m / z 188.9 [M+H] + .

[0285] Intermediate B-29 (4-(3-(4-methylpiperazin-1-yl)-1H-pyrazol-1-yl)phenyl)methanamine [ka] Step 1: 4-(3-(4-methylpiperazin-1-yl)-1H-pyrazol-1-yl)benzonitrile 4-(3-iodo-1H-pyrazol-1-yl)benzonitrile (3-iodo-1H-pyrazol-1-yl according to step 1 of Example 6) in 1,4-dioxane (100 mL) under nitrogen. A mixture of RuPhos Pd G3 (prepared from 1H-pyrazol) (2.95 g, 10.00 mmol), 1-methylpiperazine (1.2 g, 12.00 mmol), RuPhos Pd G3 (836 mg, 1.00 mmol), and cesium carbonate (6.52 g, 20.00 mmol) was stirred at 100 °C for 18 h. After cooling to ambient temperature, the reaction mixture was poured into water (100 mL) and then extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with a gradient of 1–5% DCM / MeOH) to afford 700 mg (25%) of 4-(3-(4-methylpiperazin-1-yl)-1H-pyrazol-1-yl)benzonitrile as a white solid. MS (ESI) m / z 268.1 [M+H] + .

[0286] Step 2 (4-(3-(4-methylpiperazin-1-yl)-1H-pyrazol-1-yl)phenyl)methanamine (4-(3-(4-methylpiperazin-1-yl)-1H-pyrazol-1-yl)phenyl)methanamine was synthesized from 4-(3-(4-methylpiperazin-1-yl)-1H-pyrazol-1-yl)benzonitrile according to Step 2 of Example 4. MS (ESI) m / z 272.1 [M+H] + .

[0287] Example 12: Intermediate B-30 (4-(1-methyl-1H-imidazol-2-yl)phenyl)methanamine [ka] Step 1: 4-(1-methyl-1H-imidazol-2-yl)benzonitrile A mixture of 2-bromo-1-methyl-1H-imidazole (12 g, 74.53 mmol), (4-cyanophenyl)boronic acid (13.15 g, 89.44 mmol), Pd(dppf)Cl CHCl (6.09 g, 7.45 mmol), sodium carbonate (15.8 g, 149.06 mmol), 1,4-dioxane (300 mL), and water (60 mL) was stirred under a nitrogen atmosphere at 80 °C for 18 h. After cooling to ambient temperature, the reaction mixture was poured into EtOAc (200 mL), washed with water (2 × 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with a gradient of 1-5% MeOH / DCM) to give 7.8 g (46%) of 4-(1-methyl-1H-imidazol-2-yl)benzonitrile as...

Claims

1. Formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, During the ceremony, X 1 is CR 6 or N, X 2 is CR 7 or N, X 3 is CR 8 or N, X 4 is CR 9 or N, R 1 is H, -CD 3 , (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) haloalkyl, (C 2 ~C 6 ) hydroxyalkyl, (C 3 ~C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally selected from halogen, -OR 20 , -C(O)R 20 , -CO 2 R 20 , -NR 18 R 19 , -NR 20 C(O)R 21 , -C(O)NR 20 R 21 , -NR 20 C(O)NR 21 R 22 , -NR 20 S (O) r R 21 , -S(O) r R 20 R 21 , -NR 20 S (O) r R 21 R 22 , -S(O) r R 20 , -P(O)R 20 R 21 , oxo, and -Si((C 1 ~C 4 ) alkyl) 3 is substituted with one or more substituents selected from R 2 teeth, 【Chemistry 2】 and optionally R 10 is further substituted with R 3 H, D, (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 ) hydroxyalkyl, (C 1 ~C 6 ) Aminoalkyl, heterocycloalkyl, halogen, —C(O)OH, —C(O)NH 2 , or CN, R 3' is H, (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 ) hydroxyalkyl, (C 1 ~C 6 ) Aminoalkyl, heterocycloalkyl, -C(O)OH, -C(O)NH 2 or CN, or R 3 and R 3' together with the carbon atoms to which they are attached (C 3 ~C 7 ) may form a cycloalkyl ring, or R 3 and R 3' may together with the carbon atom to which they are attached form a heterocycloalkyl ring, R 4 (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 ) haloalkoxy, (C 3 ~C 8 ) cycloalkyl, —O—(C 0 ~C 2 )-alkylene-(C 3 ~C 8 ) cycloalkyl, heterocycloalkyl, —O—(C 0 ~C 2 )-alkylene-heterocycloalkyl, halogen, —OH, —NH 2 ,CN,-C(O)(C 1 ~C 4 ) alkyl, —C(O)O(C 1 ~C 4 ) alkyl, -NR 20 C(O)O(C 1 ~C 4 ) alkyl, —Si(CH 3 ) 3 , -SF 5 , -S(O) P (C 1 ~C 4 ) alkyl, -S(O) P (NH)(C 1 ~C 4 ) alkyl, -NH(C 1 ~C 4 ) alkyl, -N((C 1 ~C 4 ) alkyl) 2 , -NH-(C 0 ~C 2 )-alkylene-(C 3 ~C 8 ) cycloalkyl, or —NH—(C 0 ~C 2 )-alkylene-heterocycloalkyl, wherein said alkyl, alkenyl, alkynyl, and alkoxy are optionally selected from the group consisting of (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) alkoxy, (C 3 ~C 8 ) cycloalkyl, halogen, -OH, -S(O) r (C 1 ~C 4 ) alkyl, -S(O) r (NH)(C 1 ~C 4 ) alkyl, -SF 5 , -Si(CH 3 ) 3 , -NH 2 , -NH(C 1 ~C 4 ) alkyl, -N((C 1 ~C 4 ) alkyl) 2 , -C(O)NH 2 , -C(O)NH(C 1 ~C 4 ) alkyl, and -C(O)NH((C 1 ~C 4 ) alkyl) 2 wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from: 1 ~C 6 ) alkyl, (C 1 ~C 6 ) substituted with one or more substituents selected from haloalkyl, and halogen; R 4 and X 4 together with the atoms to which they are attached, optionally one or more R 17 (C 6 ~C 14 ) may form an aryl ring, or R on adjacent atoms 4 and X 4 together with the atoms to which they are attached, optionally one or more R 17 or R 4 and X 4 together with the atoms to which they are attached, optionally one or more R 17 (C 5 ~C 7 ) may form a cycloalkyl ring, or R on adjacent atoms 4 and X 4 together with the atoms to which they are attached, optionally one or more R 17 may form a heterocycloalkyl ring substituted with R 5 H, D, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) hydroxyalkyl, (C 1 ~C 6 ) haloalkoxy, halogen, (C 3 ~C 6 ) cycloalkyl, heterocycloalkyl, —C(O)O(C 1 ~C 4 ) alkyl, —C(O)(C 1 ~C 4 ) alkyl, —C(O)NR 13 R 14 , —OH, —NH 2 , CN, -NH(C 1 ~C 4 ) alkyl, -N((C 1 ~C 4 ) alkyl) 2 Or -NR 13 C(O)R 14 or R 1 and R 5 together with the atoms to which they are attached form a heterocycloalkyl ring; R 6 , R 7 , R 8 , and R 9 Each of the groups independently, in each occurrence, is H, D, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 ) haloalkoxy, (C 1 ~C 6 ) hydroxyalkyl, (C 3 ~C 8 ) cycloalkyl ring, heterocycloalkyl, or halogen, wherein the alkyl is optionally selected from one or more (C 1 ~C 6 ) substituted with alkoxy; Each R 10 are independent in their existence, 【Chemistry 10-1】 【Chemistry 10-2】 where each R 10 is optional, R from 1 to 3 11 is replaced by Each R 11 is independently in each occurrence: D, -CD 3 , (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 ) Haloalkoxy, halogen, CN, -OH, -NH 2 , -NH(C 1 ~C 4 ) alkyl, -N((C 1 ~C 4 ) alkyl) 2 , -C(O)O(C 1 ~C 4 ) alkyl, -S(O) q (C 1 ~C 4 ) alkyl, —C(O)NH 2 , -C(O)NH(C 1 ~C 4 ) alkyl, —C(O)N((C 1 ~C 4 ) alkyl) 2 , -NHC(O)(C 1 ~C 4 ) alkyl, -N((C 1 ~C 4 ) alkyl) C(O)(C 1 ~C 4 ) alkyl, (C 6 ~C 14 ) aryl, heteroaryl, (C 3 ~C 8 ) cycloalkyl, or heterocycloalkyl, provided that the alkyl, alkoxy, (C 3 ~C 8 ) Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally 1 ~C 6 ) alkyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, -C(O)OH, -C(O)O(C 1 ~C 4 ) alkyl, —C(O)(C 1 ~C 4 ) alkyl, -S(O) q (C 1 ~C 4 ) alkyl, —C(O)NH(C 1 ~C 4 ) alkyl, —C(O)N((C 1 ~C 4 ) alkyl) 2 , —OH, —NH 2 , -CN, -NH(C 1 ~C 4 ) alkyl, and -N((C 1 ~C 4 ) alkyl) 2 or Two R on adjacent atoms 11 may form a heterocycloalkyl ring together with the atom to which they are attached, or two R on adjacent atoms may 11 together with the atoms to which they are attached (C 5 ~C 8 ) may form a cycloalkyl ring, or two R on adjacent atoms may 11 together with the atoms to which they are attached (C 6 ~C 14 ) may form an aryl ring, or two R 11 may together with the atoms to which they are attached form a heteroaryl ring, or Each R 11 may form C=O together with the atom to which it is attached, Each R 12 is independently in each occurrence: 1 ~C 6 ) Alkoxy, -NR 15 R 16 , -NR 15 C(O)NR 15 R 16 , -NR 15 C(O)R 16 , -NR 15 S (O) m R 16 or -C(O)NH(C 3 ~C 8 ) cycloalkyl; Each R 13 is independently in each occurrence H or (C 1 ~C 4 ) alkyl; Each R 14 is independently in each occurrence H, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) haloalkyl, -(C 0 ~C 2 )-alkylene-(C 3 ~C 8 ) cycloalkyl, -(C 0 ~C 2 )-alkylene-heterocycloalkyl, -(C 0 ~C 2 )-alkylene-(C 6 ~C 14 ) aryl, or -(C 0 ~C 2 )-alkylene-heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally selected from the group consisting of (C 1 ~C 4 ) alkoxy, (C 1 ~C 4 ) alkoxy, (C 1 ~C 4 ) haloalkyl, (C 1 ~C 4 ) haloalkoxy, (C 6 ~C 14 ) Aryl, heteroaryl, halogen, -OH, -NH 2 , CN, -C(O)NH 2 , -C(O)NH(C 1 ~C 4 ) alkyl, —C(O)N((C 1 ~C 4 ) alkyl) 2 , -NH(C 1 ~C 4 ) alkyl, and -N((C 1 ~C 4 ) alkyl) 2 (C 1 ~C 4 ) alkyl; or R 13 and R 14 together with the nitrogen atom to which they are attached, optionally one or more R 23 may form a heterocycloalkyl ring substituted with Each R 15 is independently in each occurrence H or (C 1 ~C 4 ) alkyl; Each R 16 is independently in each occurrence H, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 2 ~C 6 ) haloalkyl, (C 3 ~C 8 ) cycloalkyl, or -(C 0 ~C 2 )-alkylene-heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heteroaryl are optionally selected from the group consisting of (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) alkoxy, (C 1 ~C 4 ) haloalkyl, (C 1 ~C 4 ) substituted with one or more substituents independently selected from haloalkoxy, and halogen; Each R 17 is independently in each occurrence: 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 ) haloalkoxy, (C 1 ~C 6 ) Hydroxyalkyl, halogen, -OH, -NH 2 or CN, R 18 and R 19 Each of 1 ~C 4 ) alkyl, or R 18 and R 19 may together with the nitrogen atom to which they are attached form a heterocycloalkyl ring; R 20 , R 21 and R 22 Each of 1 ~C 4 ) alkyl, or (C 6 ~C 14 ) aryl; Each R 23 (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) alkoxy, (C 1 ~C 4 ) haloalkoxy, halogen, —C(O)(C 1 ~C 4 ) alkyl, —C(O)O(C 1 ~C 4 ) alkyl, —C(O)(C 3 ~C 8 ) cycloalkyl, —C(O)heterocycloalkyl, —OH, —NH 2 and CN, wherein said alkyl and alkoxy are optionally selected from (C 1 ~C 4 ) substituted with one or more substituents selected from alkoxy and -OH; R of 2 23 and the two R 23 may form a spiroheterocycloalkyl ring, and Each of m, n, p, q, and r is independently 0, 1, or 2; The compound, or a pharma- ceutically acceptable salt thereof.

2. X 1 is CR 6 or N, X 2 is CR 7 or N, X 3 is CR 8 or N, X 4 is CR 9 or N, R 1 H, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) haloalkyl, (C 2 ~C 6 ) hydroxyalkyl, or and heterocycloalkyl, wherein said alkyl, alkenyl, alkynyl, and heterocycloalkyl are optionally selected from halogen, -OR 20 , -C(O)R 20 , -CO 2 R 20 , -NR 18 R 19 , -NR 20 C(O)R 21 , -C(O)NR 20 R 21 , -NR 20 C(O)NR 21 R 22 , -NR 20 S (O) r R 21 , -S(O) r R 20 R 21 , -NR 20 S (O) r R 21 R 22 , -S(O) r R 20 , -P(O)R 20 R 21 , and -Si((C 1 ~C 4 ) alkyl) 3 is substituted with one or more substituents selected from R 2 but 【Chemistry 2】 and optionally further comprising 1 to 2 R 10 is replaced by R 3 H, (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 ) hydroxyalkyl, (C 1 ~C 6 ) Aminoalkyl, heterocycloalkyl, -C(O)OH, -C(O)NH 2 or CN, R 3' H, (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 ) hydroxyalkyl, (C 1 ~C 6 ) Aminoalkyl, heterocycloalkyl, -C(O)OH, -C(O)NH 2 or CN, or R 3 and R 3' together with the carbon atoms to which they are attached (C 3 ~C 7 ) may form a cycloalkyl ring, or R 3 and R 3' may together with the carbon atom to which they are attached form a heterocycloalkyl ring, R 4 But (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 ) haloalkoxy, (C 3 ~C 8 ) Cycloalkyl, halogen, -OH, -NH 2 ,CN,-C(O)(C 1 ~C 4 ) alkyl, -NH(C 1 ~C 4 ) alkyl, or -N((C 1 ~C 4 ) alkyl) 2 wherein the alkyl, alkenyl, alkynyl, and alkoxy are optionally selected from the group consisting of (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) alkoxy, (C 3 ~C 8 ) Cycloalkyl, -OH, -NH 2 , -NH(C 1 ~C 4 ) alkyl, and -N((C 1 ~C 4 ) alkyl) 2 or R 4 and X 4 together with the atoms to which they are attached, optionally one or more R 17 (C 6 ~C 14 ) may form an aryl ring, or R on adjacent atoms 4 and X 4 together with the atoms to which they are attached, optionally one or more R 17 or R 4 and X 4 together with the atoms to which they are attached, optionally one or more R 17 (C 5 ~C 7 ) may form a cycloalkyl ring, or R on adjacent atoms 4 and X 4 together with the atoms to which they are attached, optionally one or more R 17 may form a heterocycloalkyl ring substituted with R 5 is H, R 6 , R 7 , R 8 , and R 9 each independently, in each occurrence, is H, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 ) haloalkoxy, (C 1 ~C 6 ) hydroxyalkyl, or halogen, wherein the alkyl is optionally selected from one or more of (C 1 ~C 6 ) substituted with alkoxy; Each R 10 but independently in each existence, 【Chemistry 10-4】 【Chemistry 10-5】 【Chemistry 10-6】 where each R 10 is optional, R from 1 to 3 11 is replaced by Each R 11 independently in each occurrence, (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 ) Haloalkoxy, halogen, CN, -OH, -NH 2 , -NH(C 1 ~C 4 ) alkyl, -N((C 1 ~C 4 ) alkyl) 2 , -C(O)O(C 1 ~C 4 ) alkyl, -S(O) q (C 1 ~C 4 ) alkyl, —C(O)NH 2 , -C(O)NH(C 1 ~C 4 ) alkyl, —C(O)N((C 1 ~C 4 ) alkyl) 2 , -NHC(O)(C 1 ~C 4 ) alkyl, -N((C 1 ~C 4 ) alkyl) C(O)(C 1 ~C 4 ) alkyl, (C 6 ~C 14 ) aryl, heteroaryl, (C 3 ~C 8 ) cycloalkyl, or heterocycloalkyl, provided that the alkyl, alkoxy, (C 3 ~C 8 ) Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally 1 ~C 6 ) alkyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, -C(O)OH, -C(O)O(C 1 ~C 4 ) alkyl, —C(O)(C 1 ~C 4 ) alkyl, -S(O) q (C 1 ~C 4 ) alkyl, —C(O)NH(C 1 ~C 4 ) alkyl, —C(O)N((C 1 ~C 4 ) alkyl) 2 , —OH, —NH 2 , -CN, -NH(C 1 ~C 4 ) alkyl, and -N((C 1 ~C 4 ) alkyl) 2 or Two R on adjacent atoms 11 may form a heterocycloalkyl ring together with the atom to which they are attached, or two R on adjacent atoms may 11 together with the atoms to which they are attached (C 5 ~C 8 ) may form a cycloalkyl ring, or two R on adjacent atoms may 11 together with the atoms to which they are attached (C 6 ~C 14 ) may form an aryl ring, or two R 11 may together with the atoms to which they are attached form a heteroaryl ring, or Each R 11 may form C=O together with the atom to which it is attached, Each R 12 independently in each occurrence, (C 1 ~C 6 ) Alkoxy, -NR 15 R 16 , -NR 15 C(O)NR 15 R 16 , -NR 15 C(O)R 16 , -NR 15 S (O) m R 16 or -C(O)NH(C 3 ~C 8 ) cycloalkyl; Each R 13 is independently in each occurrence H or (C 1 ~C 4 ) alkyl; Each R 14 independently in each occurrence, H, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) haloalkyl, -(C 0 ~C 2 )-alkylene-(C 3 ~C 8 ) cycloalkyl, -(C 0 ~C 2 )-alkylene-heterocycloalkyl, -(C 0 ~C 2 )-alkylene-(C 6 ~C 14 ) aryl, or -(C 0 ~C 2 )-alkylene-heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally selected from the group consisting of (C 1 ~C 4 ) alkoxy, (C 1 ~C 4 ) alkoxy, (C 1 ~C 4 ) haloalkyl, (C 1 ~C 4 ) haloalkoxy, (C 6 ~C 14 ) Aryl, heteroaryl, halogen, -OH, -NH 2 , CN, -C(O)NH 2 , -C(O)NH(C 1 ~C 4 ) alkyl, —C(O)N((C 1 ~C 4 ) alkyl) 2 , -NH(C 1 ~C 4 ) alkyl, and -N((C 1 ~C 4 ) alkyl) 2 (C 1 ~C 4 ) alkyl; or R 13 and R 14 together with the nitrogen atom to which they are attached, optionally one or more R 23 may form a heterocycloalkyl ring substituted with Each R 15 is independently in each occurrence H or (C 1 ~C 4 ) alkyl; Each R 16 independently in each occurrence, H, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 2 ~C 6 ) haloalkyl, (C 3 ~C 8 ) cycloalkyl, or -(C 0 ~C 2 )-alkylene-heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heteroaryl are optionally selected from the group consisting of (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) alkoxy, (C 1 ~C 4 ) haloalkyl, (C 1 ~C 4 ) substituted with one or more substituents independently selected from haloalkoxy, and halogen; Each R 17 independently in each occurrence, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 ) haloalkoxy, (C 1 ~C 6 ) Hydroxyalkyl, halogen, -OH, -NH 2 or CN, R 18 and R 19 Each of 1 ~C 4 ) alkyl, or R 18 and R 19 may together with the nitrogen atom to which they are attached form a heterocycloalkyl ring; R 20 , R 21 and R 22 Each of 1 ~C 4 ) alkyl; Each R 23 But (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) alkoxy, (C 1 ~C 4 ) haloalkoxy, halogen, —C(O)(C 1 ~C 4 ) alkyl, —C(O)O(C 1 ~C 4 ) alkyl, —C(O)(C 3 ~C 8 ) cycloalkyl, —C(O)heterocycloalkyl, —OH, —NH 2 and CN, wherein said alkyl and alkoxy are optionally selected from (C 1 ~C 4 ) substituted with one or more substituents selected from alkoxy and -OH; R of 2 23 and the two R 23 may form a spiroheterocycloalkyl ring; Each of m, n, p, q, and r is independently 0, 1, or 2; The compound of claim 1.

3. R 1 H, (C 2 ~C 6 ) hydroxyalkyl, heterocycloalkyl, or optionally -CO 2 H, -NH 2 , and -N((C l ~C 4 ) alkyl) 2 (C l ~C 6 3. The compound according to claim 1 or 2, wherein:

4. R 3 and R 3' are each independently H or (C 1 ~C 6 4. The compound according to claim 1, wherein:

5. R 4 But (C 1 ~C 6 ) alkyl, halogen, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 ) haloalkoxy, or optionally (C 1 ~C 6 ) alkoxy-substituted (C 1 ~C 6 5. The compound according to claim 1, wherein the aryl group is aryl, aryl, or aryl.

6. X 1 is CR 6 and R 6 The compound according to any one of claims 1 to 5, wherein is H or halogen.

7. X 2 is CR 7 and R 7 The compound according to any one of claims 1 to 6, wherein is H or halogen.

8. X 3 is CR 8 and R 8 The compound according to any one of claims 1 to 7, wherein is H or halogen.

9. X 4 The compound according to any one of claims 1 to 8, wherein is N.

10. X 4 is CR 9 and R 9 The compound according to any one of claims 1 to 9, wherein is H, F, or Cl.

11. The compound according to any one of claims 1 to 10, wherein n is 1.

12. The compound according to any one of claims 1 to 10, wherein n is 0.

13. Formula (Ia): 【Chemistry 13】 2. The compound of claim 1 having the formula:

14. Formula (Ic), (Im), (Io), (Ip), (Iq), (Ir), or (Iu): 【Chemistry 14-1】 【Chemistry 14-2】 2. The compound of claim 1 having the formula:

15. R 3 is H or (C 1 ~C 6 ) alkyl.

16. R 3' The compound according to any one of claims 13 to 15, wherein is H.

17. R 3 and R 3' together with the carbon atom to which they are attached (C 3 ~C 7 ) forming a cycloalkyl ring, R 1 is H or (C 1 ~C 6 16. The compound according to any one of claims 13 to 15, wherein:

18. R 1 is H or (C 1 ~C 6 18. The compound according to any one of claims 13 to 17, wherein:

19. R 4 But (C 1 ~C 6 ) alkyl, halogen, (C 1 ~C 6 ) haloalkoxy, or optionally (C 1 ~C 6 ) alkoxy-substituted (C 1 ~C 6 20. The compound according to claim 13, wherein:

20. X 4 The compound according to any one of claims 13 to 19, wherein is N.

21. X 4 is CR 9 and R 9 The compound according to any one of claims 13 to 20, wherein is H or halogen.

22. R 6 The compound according to any one of claims 15 to 21, wherein is H or halogen.

23. The compound is selected from the group consisting of: 9-(4-(3,5-dimethyl-1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(2H-1,2,3-triazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(2H-1,2,3-triazol-2-yl)benzyl)-2-(2-(difluoromethoxy)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(2H-1,2,3-triazol-2-yl)benzyl)-2-(2-isobutoxypyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(3-fluoro-2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(5-fluoro-2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(4-fluoro-2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-fluoro-6-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, (S)-9-(1-(4-(1H-pyrazol-1-yl)phenyl)ethyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, (R)-9-(1-(4-(1H-pyrazol-1-yl)phenyl)ethyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(2H-1,2,3-triazol-2-yl)benzyl)-2-(4-fluoro-2-isopropoxyphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(2H-1,2,3-triazol-2-yl)benzyl)-2-(3-fluoro-2-methoxyphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(4-isopropylpyridin-3-yl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-(2,2,2-trifluoroethoxy)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-ethoxypyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-(2-methoxyethoxy)phenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-propoxyphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-(2,2,2-trifluoroethoxy)phenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-(cyclopropylmethoxy)phenyl)-7,9-dihydro-8H-purin-8-one, 9-((1R,2S)-2-(4-(1H-pyrazol-1-yl)phenyl)cyclobutyl)-2-(2-(2,2,2-trifluoroethoxy)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(2,2,2-trifluoroethoxy)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-ethylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(4-isopropylpyrimidin-5-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(1-methyl-1H-indol-7-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-cyclopropylpyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(difluoromethyl)phenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-cyclopropylpyridin-3-yl)-9-(4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(1-methylindolin-7-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-(difluoromethoxy)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-9-( 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(trifluoromethoxy)phenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-acetylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-2-(2-(2,2,2-trifluoroethoxy)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-2-(2-(2,2,2-trifluoroethoxy)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(1-(2-methoxyethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(1-methyl-1H-indazol-7-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(1-methyl-1H-indol-7-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1,4-dimethyl-1H-pyrazol-3-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-(difluoromethoxy)pyridin-3-yl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(trifluoromethoxy)phenyl)-7,9-dihydro-8H-purin-8-one, 7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(2,2,2-trifluoroethoxy)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)cyclopropyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-chloro-5-methyl-1H-pyrazol-1-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(5-chloro-3-methyl-1H-pyrazol-1-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(2-methyl-1H-pyrrol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, (R)-2-(2-(1-methoxyethyl)phenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, (S)-2-(2-(1-methoxyethyl)phenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-fluoropyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-fluoro-1H-pyrazol-1-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-ethylpyridin-3-yl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-methylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(difluoromethyl)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(3-fluoro-2-isopropylphenyl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(6-fluoro-2-methylpyridin-3-yl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(5-fluoro-2-isopropylpyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-(azetidin-1-yl)-5-methyl-1H-pyrazol-1-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(5-fluoro-2-isopropylpyridin-3-yl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-cyclopropylphenyl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-cyclopropylpyridin-3-yl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(difluoromethyl)pyridin-3-yl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(6-methoxy-2-methylpyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-fluoro-6-isopropoxypyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-fluoro-6-methoxypyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(5-morpholino-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(3-methoxy-5-methyl-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, (R)-2-(2-isopropylpyridin-3-yl)-9-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-7,9-dihydro-8H-purin-8-one, (S)-2-(2-isopropylpyridin-3-yl)-9-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(1-(methyl-d 3 )-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(3,5-difluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(2,6-difluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(methylsulfinyl)phenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(4-(difluoromethyl)-1-methyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-(difluoromethoxy)pyridin-3-yl)-9-(4-(3-fluoro-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(difluoromethoxy)phenyl)-9-(4-(3-fluoro-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(dimethylamino)phenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-isopropyl-3-methylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-isopropyl-3-methoxyphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(3-chloro-2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-cyclopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(5-chloro-2-cyclopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-fluoro-6-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-cyclopropyl-5-(trifluoromethyl)phenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-cyclopropylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, Ethyl 1-(4-((2-(2-cyclopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-3-methyl-1H-pyrazole-5-carboxylate, 7-cyclopropyl-2-(2-cyclopropylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 7-cyclopropyl-2-(2-cyclopropylpyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)benzyl)-2-(3-fluoro-2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)benzyl)-2-(3-fluoro-2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-(2-hydroxyethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-7-(2-(dimethylamino)ethyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-7-methyl-9-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)cyclopropyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-(azetidin-1-yl)-5-methyl-1H-pyrazol-1-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(((1S,4S)-4-(3,5-dimethyl-1H-pyrazol-1-yl)cyclohexyl)methyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(((1R,4R)-4-(3,5-dimethyl-1H-pyrazol-1-yl)cyclohexyl)methyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-7-methyl-9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7-methyl-7,9-dihydro-8H-purin-8-one, (R)-2-(2-isopropylpyridin-3-yl)-7-methyl-9-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-7,9-dihydro-8H-purin-8-one, (S)-2-(2-isopropylpyridin-3-yl)-7-methyl-9-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-7-methyl-9-(4-(5-morpholino-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(3-methoxy-5-methyl-1H-pyrazol-1-yl)benzyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7-(oxetan-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-7-(2-methoxyethyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 7-(1,1-dioxidothietan-3-yl)-2-(2-isopropylpyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one, 7-(2-hydroxyethyl)-2-(2-isopropylpyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-7-methyl-9-(4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(3,5-difluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(2,6-difluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-7-(methyl-d 3 )-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-7-(methyl-d 3 )-9-(4-(1-(methyl-d 3 )-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-7-methyl-9-(4-(1-(methyl-d 3 )-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(2-hydroxypropan-2-yl)phenyl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-morpholinopyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-(3-fluoroazetidin-1-yl)pyridin-3-yl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(3-(trifluoromethyl)azetidin-1-yl)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-cyclopropoxypyridin-3-yl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-1,2,3-triazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(2H-1,2,3-triazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (S)-9-(1-(4-(2H-1,2,3-triazol-2-yl)phenyl)ethyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (R)-9-(1-(4-(2H-1,2,3-triazol-2-yl)phenyl)ethyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-((1-(pyridin-3-yl)piperidin-4-yl)methyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(1-(pyridin-3-yl)piperidin-4-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (S)-9-(1-(4-(1H-1,2,3-triazol-1-yl)phenyl)ethyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (R)-9-(1-(4-(1H-1,2,3-triazol-1-yl)phenyl)ethyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(5-methyl-1,3,4-oxadiazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)benzonitrile, 2-(2-isopropylphenyl)-9-(4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(morpholinomethyl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-1,2,4-triazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (R)-2-(2-isopropylphenyl)-9-(1-phenylethyl)-7,9-dihydro-8H-purin-8-one, (S)-2-(2-isopropylphenyl)-9-(1-phenylethyl)-7,9-dihydro-8H-purin-8-one, (S)-9-(1-(4-(1H-pyrazol-1-yl)phenyl)ethyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (R)-9-(1-(4-(1H-pyrazol-1-yl)phenyl)ethyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (R)-9-(chroman-4-yl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-methyl-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(2-(1-(pyridin-3-yl)piperidin-4-yl)ethyl)-7,9-dihydro-8H-purin-8-one, 9-(2-chloro-4-(1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-((1R,2S)-2-(4-(1H-pyrazol-1-yl)phenyl)cyclobutyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-((1S,2R)-2-(4-(1H-pyrazol-1-yl)phenyl)cyclobutyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-1,2,3-triazol-1-yl)benzyl)-2-(3-fluoro-2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(2H-1,2,3-triazol-2-yl)benzyl)-2-(3-fluoro-2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(5-methyl-2H-tetrazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(oxazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(3-fluoro-2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-benzyl-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(3-fluoro-2-isopropylphenyl)-9-(4-(1-methyl-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-(4-methylpiperazin-1-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-morpholino-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(4-methyl-1H-1,2,3-triazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(5-fluoro-1-methyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(3-fluoro-4-(1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (R)-9-(1-(4-fluorophenyl)ethyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (S)-9-(1-(4-fluorophenyl)ethyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (S)-9-(1-(4-fluorophenyl)-2-hydroxyethyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (S)-9-(2-hydroxy-1-phenylethyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-((1-methyl-1H-benzo[d]imidazol-5-yl)methyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(methylsulfonyl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(5-methyl-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(5-methyl-1H-1,2,3-triazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-((2-methyl-1-oxoisoindolin-5-yl)methyl)-7,9-dihydro-8H-purin-8-one, 6-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one, 2-(3-fluoro-2-isopropylphenyl)-9-(4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(3-fluoro-2-isopropylphenyl)-9-(4-(5-methyl-1,3,4-oxadiazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, (R)-9-(1-(4-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)ethyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (S)-9-(1-(4-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)ethyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(3-fluoro-2-isopropylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 1-(4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-1H-pyrazole-3-carbonitrile, 9-(3-(1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(4-chloro-1-methyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 1-(4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-1H-pyrazole-3,5-dicarbonitrile, 9-(4-(2,5-dimethyloxazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(3-fluoro-2-isopropylphenyl)-9-(4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(3-fluoro-2-isopropylphenyl)-9-(4-(4-methyl-1-(oxetan-3-yl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-((6-(1,4-dimethyl-1H-imidazol-2-yl)pyridin-3-yl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-methoxy-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(2-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(5-methoxy-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 1-(4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-5-methyl-1H-pyrazole-3-carbonitrile, 1-(4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-3-methyl-1H-pyrazole-5-carbonitrile, 2-(2-isopropylphenyl)-9-(4-(1-methyl-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-chloro-5-methyl-1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(5-chloro-3-methyl-1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(((1S,4S)-4-(3,5-dimethyl-1H-pyrazol-1-yl)cyclohexyl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(((1R,4R)-4-(3,5-dimethyl-1H-pyrazol-1-yl)cyclohexyl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (R)-2-(2-isopropylphenyl)-9-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-7,9-dihydro-8H-purin-8-one, (S)-2-(2-isopropylphenyl)-9-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3,3-dimethyloxetan-2-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, N-(3-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)acetamide, N-(4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)acetamide, 2-(2-isopropylphenyl)-9-(4-(1-methyl-5-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, tert-butyl 4-fluoro-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)piperidine-1-carboxylate, 2-(2-isopropylphenyl)-9-(4-(4-(piperidin-4-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-(pyrrolidin-3-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-(piperidin-3-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, (R)-2-(2-isopropylphenyl)-9-(4-(3-(piperidin-3-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, (S)-2-(2-isopropylphenyl)-9-(4-(3-(piperidin-3-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(1-(4-(1H-pyrazol-1-yl)phenyl)cyclopropyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(1-(4-fluorophenyl)cyclopropyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(cyclopropylmethoxy)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-((tetrahydrofuran-3-yl)methoxy)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-((1-methylpiperidin-3-yl)methoxy)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(pyridin-2-ylmethoxy)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-((1-methyl-1H-imidazol-5-yl)methoxy)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(2-(dimethylamino)ethoxy)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(3-(dimethylamino)propoxy)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-((5-methylisoxazol-3-yl)methoxy)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(2-ethoxyethoxy)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-cyclobutoxybenzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(3-(cyclopropylmethoxy)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(3-((tetrahydrofuran-3-yl)methoxy)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(3-((1-methylpiperidin-3-yl)methoxy)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(3-(pyridin-2-ylmethoxy)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(3-((1-methyl-1H-imidazol-5-yl)methoxy)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(3-(2-(dimethylamino)ethoxy)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(3-(3-(dimethylamino)propoxy)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(3-cyclobutoxybenzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(pyrazin-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-((3'-(2-(dimethylamino)ethyl)-[1,1'-biphenyl]-4-yl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-((4'-(2-(dimethylamino)ethyl)-[1,1'-biphenyl]-4-yl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(6-morpholinopyrimidin-4-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-methyl-1H-imidazol-5-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1,5-dimethyl-1H-pyrazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3,5-dimethylisoxazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(4-(4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-1-methyl-1H-pyrazol-5-yl)acetic acid, 2-(2-isopropylphenyl)-9-(4-(pyrimidin-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-methyl-1H-pyrazol-5-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(1-methyl-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1,4-dimethyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-((2'-(2-(dimethylamino)ethoxy)-[1,1'-biphenyl]-4-yl)methyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-((3'-(2-(dimethylamino)ethoxy)-[1,1'-biphenyl]-4-yl)methyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-((4'-(2-(dimethylamino)ethoxy)-[1,1'-biphenyl]-4-yl)methyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-((4'-(2-(dimethylamino)ethyl)-[1,1'-biphenyl]-4-yl)methyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(6-morpholinopyrimidin-4-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(1-methyl-1H-imidazol-5-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-([1,2,4]triazolo[1,5-a]pyridin-5-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(benzo[d]isoxazol-7-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-indazol-7-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(imidazo[1,2-a]pyridin-8-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(imidazo[1,2-a]pyridin-5-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(1-methyl-1H-imidazol-4-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(1-methyl-1H-1,2,4-triazol-3-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-methyl-1H-imidazol-4-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-methyl-1H-1,2,4-triazol-3-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-isopropyl-1H-imidazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1,2-dimethyl-1H-imidazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1-isopropyl-1H-imidazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 3-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-1-methyl-1H-1,2,4-triazole-5-carboxamide, 9-(4-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(1-methyl-5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(5-methoxy-1-methyl-1H-1,2,4-triazol-3-yl)benzyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(1-methyl-5-morpholino-1H-1,2,4-triazol-3-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1-isopropyl-1H-pyrazol-5-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(1-methyl-1H-1,2,3-triazol-5-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-([1,2,4]triazolo[4,3-a]pyridin-3-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(5-(hydroxymethyl)-1-methyl-1H-imidazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(imidazo[1,2-a]pyrazin-8-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(4-methyloxazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(imidazo[1,2-a]pyrazin-8-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-methyl-5-morpholino-1H-1,2,4-triazol-3-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-methyl-5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(5-methoxy-1-methyl-1H-1,2,4-triazol-3-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(5-(hydroxymethyl)-1-methyl-1H-imidazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-methyl-1H-1,2,3-triazol-5-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-isopropyl-1H-pyrazol-5-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(5-methylthiazol-4-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(2,5-dimethylthiazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(5-(hydroxymethyl)thiazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(5-methylthiazol-4-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(2,5-dimethylthiazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(5-(hydroxymethyl)thiazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(6-methylimidazo[1,2-a]pyrazin-8-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1,4-dimethyl-1H-imidazol-2-yl)benzyl)-2-(3-fluoro-2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(3-fluoro-2-isopropylphenyl)-9-(4-(1-methyl-1H-imidazol-4-yl)benzyl)-7,9-dihydro-8H-purin-8-one, (R)-2-(2-isopropylphenyl)-9-(1-(4-(1-methyl-1H-imidazol-2-yl)phenyl)ethyl)-7,9-dihydro-8H-purin-8-one, (S)-2-(2-isopropylphenyl)-9-(1-(4-(1-methyl-1H-imidazol-2-yl)phenyl)ethyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(methylamino)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-(ethylamino)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(isopropylamino)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(cyclopropylamino)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-((2-ethoxyethyl)amino)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(cyclobutylamino)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-((1-methoxypropan-2-yl)amino)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, N,N-dimethyl-2-((3-(9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyridin-2-yl)amino)acetamide, (R)-2-(2-((1-methoxypropan-2-yl)amino)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(((tetrahydrofuran-2-yl)methyl)amino)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, (S)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-((tetrahydrofuran-3-yl)amino)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-(dimethylamino)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(diethylamino)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(pyrrolidin-1-yl)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(piperidin-1-yl)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-((2-methoxyethyl)(methyl)amino)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(4-methylpiperazin-1-yl)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-(isopropyl(methyl)amino)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(ethyl(methyl)amino)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(methyl(2,2,2-trifluoroethyl)amino)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-morpholinopyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-(3-fluoroazetidin-1-yl)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(azetidin-1-yl)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(3-(trifluoromethyl)azetidin-1-yl)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(4-(2-aminopropan-2-yl)-1H-1,2,3-triazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(4-((dimethylamino)methyl)-1H-1,2,3-triazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(4-(2-hydroxyethyl)-1H-1,2,3-triazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(4-((diethylamino)methyl)-1H-1,2,3-triazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (R)-9-(4-(4-(1-hydroxyethyl)-1H-1,2,3-triazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(4-(3-aminopentan-3-yl)-1H-1,2,3-triazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(4-((methylsulfonyl)methyl)-1H-1,2,3-triazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-methylbenzamide, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-(2-methoxyethyl)benzamide, N-cyclopropyl-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)benzamide, N-(4-fluorobenzyl)-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)benzamide, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N,N-dimethylbenzamide, N-isopropyl-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)benzamide, N-isobutyl-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)benzamide, N-cyclopentyl-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)benzamide, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-(1-phenylcyclopentyl)benzamide, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-((1-methyl-1H-imidazol-2-yl)methyl)benzamide, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)benzamide, N,N-diethyl-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)benzamide, 2-(2-isopropylphenyl)-9-(4-(morpholine-4-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, N-cyclohexyl-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-methylbenzamide, N-(4-fluorobenzyl)-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-methylbenzamide, 2-(2-isopropylphenyl)-9-(4-(4-methylpiperidine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)benzamide, 2-(2-isopropylphenyl)-9-(4-(3-(methoxymethyl)piperidine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, (R)-2-(2-isopropylphenyl)-9-(4-(2-methylpyrrolidine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, N-isopropyl-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-(2-methoxyethyl)benzamide, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-methyl-N-((2-methylthiazol-4-yl)methyl)benzamide, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-(1-methyl-1H-imidazol-2-yl)benzamide, N-ethyl-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-methylbenzamide, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-methyl-N-propylbenzamide, N-isopropyl-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-methylbenzamide, N-(2-hydroxyethyl)-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-methylbenzamide, 9-(4-(3-hydroxyazetidine-1-carbonyl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (S)-9-(4-(3-hydroxypyrrolidine-1-carbonyl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, N-cyclopropyl-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-methylbenzamide, N-(2-(dimethylamino)-2-oxoethyl)-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-methylbenzamide, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-(oxetan-3-yl)benzamide, (S)-9-(4-(2-(hydroxymethyl)pyrrolidine-1-carbonyl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(4-acetylpiperazine-1-carbonyl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (S)-2-(2-isopropylphenyl)-9-(4-(3-(2-methoxyethoxy)pyrrolidine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-((2R,6S)-2,6-dimethylmorpholine-4-carbonyl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-fluoroazetidine-1-carbonyl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, N-((1R,2S)-2-hydroxycyclopentyl)-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)benzamide, 9-(4-(4,4-difluoropiperidine-1-carbonyl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(pyrrolidine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(2-methylpyrrolidine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-(1-(methoxymethyl)cyclopropyl)-N-methylbenzamide, 9-(4-(3,3-difluoropyrrolidine-1-carbonyl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(5-oxa-2-azaspiro[3.4]octane-2-carbonyl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(6-oxa-2-azaspiro[3.4]octane-2-carbonyl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, (S)-2-(2-isopropylphenyl)-9-(4-(2-methylpyrrolidine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, (S)-2-(2-isopropylphenyl)-9-(4-(2-(methoxymethyl)pyrrolidine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(2-ethylpiperidine-1-carbonyl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(2-methylpiperidine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-methylpiperidine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(2-(methoxymethyl)piperidine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-methoxypiperidine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-methyl-N-(tetrahydrofuran-3-yl)benzamide, (R)-2-(2-isopropylphenyl)-9-(4-(2-(methoxymethyl)pyrrolidine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, (R)-2-(2-isopropylphenyl)-9-(4-(3-methylmorpholine-4-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, (S)-2-(2-isopropylphenyl)-9-(4-(3-methylmorpholine-4-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-methyl-N-(2,2,2-trifluoroethyl)benzamide, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-(2-methoxyethyl)-N-methylbenzamide, N-(2-(dimethylamino)ethyl)-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)benzamide, 4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)-N-(2-(piperidin-1-yl)ethyl)benzamide, 2-(2-isopropylphenyl)-9-(4-(4-methylpiperazine-1-carbonyl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(2-oxa-5-azaspiro[3.4]octane-5-carbonyl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-methoxypyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-propoxypyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-(cyclopropylmethoxy)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(2-ethoxyethoxy)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropoxypyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(sec-butoxy)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-cyclobutoxypyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-cyclopropoxypyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-ethoxypyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isobutoxypyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(2-methoxyethoxy)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-((tetrahydrofuran-2-yl)methoxy)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-((tetrahydrofuran-3-yl)methoxy)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-(3-methoxybutoxy)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-(pentan-3-yloxy)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-((1-methoxybutan-2-yl)oxy)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(2-(dimethylamino)ethoxy)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-(azetidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-(piperidin-4-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-(piperazin-1-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(3-(piperidin-4-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(3-fluoro-2-isopropylphenyl)-9-(4-(3-(piperidin-4-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(3-(piperidin-4-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-(azetidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(1-(1-methylazetidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-(1-methylpiperidin-4-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-(1-methylpyrrolidin-3-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(3-fluoro-2-isopropylphenyl)-9-(4-(3-(1-methylpiperidin-4-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylpyridin-3-yl)-9-(4-(3-(1-methylpiperidin-4-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-(1-methylpiperidin-4-yl)-1H-pyrazol-1-yl)benzyl)-2-(2-(2,2,2-trifluoroethoxy)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(3-(1-methylpiperidin-3-yl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-methyl-4-(1-methylpiperidin-4-yl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-methyl-5-(1-methylpiperidin-4-yl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-(1-methylazetidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(1-(1-methylazetidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-((1-(pyridin-3-ylsulfonyl)piperidin-4-yl)methyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-((1-(isopropylsulfonyl)piperidin-4-yl)methyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-((1-((1-methyl-1H-imidazol-2-yl)sulfonyl)piperidin-4-yl)methyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(2-(isopropylsulfonyl)-2-azaspiro[3.3]heptan-5-yl)-7,9-dihydro-8H-purin-8-one, N-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-1-methyl-1H-pyrazole-3-sulfonamide, N-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-1-methyl-1H-imidazole-2-sulfonamide, N-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-1,2-dimethyl-1H-imidazole-4-sulfonamide, N-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-N,1-dimethyl-1H-pyrazole-3-sulfonamide, N-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-N,1-dimethyl-1H-imidazole-2-sulfonamide, N-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-N,1,2-trimethyl-1H-imidazole-4-sulfonamide, N-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-N-methylmethanesulfonamide, 9-((1-(cyclopropylsulfonyl)-4-fluoropiperidin-4-yl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-((1-(cyclopropylsulfonyl)piperidin-4-yl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-((1-isobutyrylpiperidin-4-yl)methyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(3-(1-acetylpiperidin-4-yl)-1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-(1-acetylpiperidin-4-yl)-1H-pyrazol-1-yl)benzyl)-2-(3-fluoro-2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-(1-acetylpiperidin-4-yl)-1H-pyrazol-1-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-(1-acetylpiperidin-4-yl)-1H-pyrazol-1-yl)benzyl)-2-(2-(2,2,2-trifluoroethoxy)pyridin-3-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-(1-acetylpyrrolidin-3-yl)-1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-(1-acetylpiperidin-3-yl)-1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, N-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide, N-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-N,5-dimethyl-1H-pyrazole-3-carboxamide, N-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-N,1,3-trimethyl-1H-pyrazole-5-carboxamide, 9-(4-(4-(1-acetylpiperidin-4-yl)-1-methyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(5-(1-acetylpiperidin-4-yl)-1-methyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(3-(1-acetylpiperidin-4-yl)-1H-pyrazol-1-yl)benzyl)-2-(2-fluoro-6-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-((4-fluoro-1-isobutyrylpiperidin-4-yl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-(1-acetylazetidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-(1-acetylazetidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7,9-dihydro-8H-purin-8-one, N-isopropyl-4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)piperidine-1-carboxamide, N-cyclopropyl-4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)piperidine-1-carboxamide, 4-(1-(4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-1H-pyrazol-3-yl)-N-methylpiperidine-1-carboxamide, 1-isopropyl-3-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)urea, 1-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-3-(2-methoxyethyl)urea, 1-cyclopropyl-3-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)urea, 3-isopropyl-1-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-1-methylurea, 1-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-3-(2-methoxyethyl)-1-methylurea, 3-cyclopropyl-1-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-1-methylurea, 4-fluoro-N-isopropyl-4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)piperidine-1-carboxamide, 9-(4-((cyclopropylmethyl)amino)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-((2-methoxyethyl)amino)benzyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-((cyclopropylmethyl)(methyl)amino)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-((2-methoxyethyl)(methyl)amino)benzyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-((1-(1,3,4-thiadiazol-2-yl)piperidin-4-yl)methyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)-7,9-dihydro-8H-purin-8-one, 9-((1-(2,5-dimethylthiazol-4-yl)piperidin-4-yl)methyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(2-(pyridin-3-yl)-2-azaspiro[3.3]heptan-5-yl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-ethyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1-isopropyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-(2-methoxyethyl)-1H-imidazol-2-yl)benzyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-7-methyl-9-(4-(1-(piperidin-4-yl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-(difluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-((1-(1,4-dimethyl-1H-imidazol-2-yl)piperidin-4-yl)methyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-((1-(4-(trifluoromethyl)pyrimidin-2-yl)azetidin-3-yl)methyl)-7,9-dihydro-8H-purin-8-one, 1-(4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-N,N,5-trimethyl-1H-pyrazole-3-carboxamide, 1-(4-((2-(2-cyclopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-N,N,5-trimethyl-1H-pyrazole-3-carboxamide, 9-((4-fluoro-1-(pyridin-3-yl)piperidin-4-yl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-(2-hydroxyethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 7-ethyl-2-(2-isopropylpyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-((5-(1H-pyrazol-1-yl)pyrazin-2-yl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-((5-(1H-pyrazol-1-yl)pyrimidin-2-yl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-((5-(3,5-dimethyl-1H-pyrazol-1-yl)pyrazin-2-yl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-((5-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidin-2-yl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(2-oxopyrrolidin-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-tetrazol-5-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-((1-(2,5-dimethylthiazol-4-yl)-4-fluoropiperidin-4-yl)methyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(4-cyclopropyl-1-methyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylpyridin-3-yl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(3-isopropylpyridin-4-yl)-7-methyl-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(3-isopropylpyridin-2-yl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-(2-(dimethylamino)ethyl)-1H-1,2,3-triazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(2H-1,2,3-triazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)benzoate methyl 2-(2-(2-hydroxypropan-2-yl)phenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-(1-hydroxycyclopropyl)phenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(2-propionylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-(2-hydroxypropan-2-yl)phenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, 2-(9-(4-(1H-pyrazol-1-yl)benzyl)-2-(2-isopropylphenyl)-8-oxo-8,9-dihydro-7H-purin-7-yl)propanoic acid, 2-(2-(difluoromethoxy)pyridin-3-yl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(methylamino)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(methylamino)-7,9-dihydro-8H-purin-8-one, 6-(dimethylamino)-2-(2-isopropylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 6-acetyl-2-(2-isopropylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-6-methoxy-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-isopropyl-5-methyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 9-(4-(1-isopropyl-4-methyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, N-(2-(4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-1-methyl-1H-imidazol-4-yl)acetamide, 9-(4-(1H-pyrazol-4-yl)benzyl)-2-(2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, 2-(2-isopropylphenyl)-9-(4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)benzyl)-7,9-dihydro-8H-purin-8-one, 2-(4-((2-(2-isopropylphenyl)-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-1-methyl-1H-imidazole-4-carbonitrile, 2-(2-cyclopropylphenyl)-9-(4-(5-(hydroxymethyl)-3-methyl-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, Methyl 4-(1-(4-((2-(2-isopropylphenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)phenyl)-1H-pyrazol-3-yl)piperidine-1-carboxylate, and 2-(2-(1-hydroxyethyl)phenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one 2. The compound of claim 1, selected from the group consisting of:

24. below: 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(3-fluoro-2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one; 2-(2-isopropylphenyl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one; 2-(3-fluoro-2-isopropylphenyl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one; 2-(2-cyclopropylphenyl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one; 2-(2-cyclopropylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one; 2-(2-isopropylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one; 9-(4-(1H-pyrazol-1-yl)-benzyl)-2-(3-fluoro-2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one; 2-(3-fluoro-2-isopropylphenyl)-9-(4-(1-methyl-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one; 2-(3-fluoro-2-isopropylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one; 2-(2-isopropylphenyl)-9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one; or 2-(2-isopropylphenyl)-9-(4-(1-methyl-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)benzyl)-7,9-dihydro-8H-purin-8-one; and pharma- ceutically acceptable salts thereof.

25. 25. The compound of claim 24, wherein the compound is 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(3-fluoro-2-isopropylphenyl)-7-methyl-7,9-dihydro-8H-purin-8-one, or a pharma- ceutically acceptable salt thereof.

26. 25. The compound of claim 24, wherein the compound is 2-(2-isopropylphenyl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, or a pharma- ceutically acceptable salt thereof.

27. 25. The compound of claim 24, wherein the compound is 2-(3-fluoro-2-isopropylphenyl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, or a pharma- ceutically acceptable salt thereof.

28. 25. The compound of claim 24, wherein the compound is 2-(2-cyclopropylphenyl)-7-methyl-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, or a pharma- ceutically acceptable salt thereof.

29. 25. The compound of claim 24, wherein the compound is 2-(2-cyclopropylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, or a pharma- ceutically acceptable salt thereof.

30. 25. The compound of claim 24, wherein the compound is 2-(2-isopropylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, or a pharma- ceutically acceptable salt thereof.

31. 25. The compound of claim 24, wherein the compound is 9-(4-(1H-pyrazol-1-yl)benzyl)-2-(3-fluoro-2-isopropylphenyl)-7,9-dihydro-8H-purin-8-one, or a pharma- ceutically acceptable salt thereof.

32. 25. The compound of claim 24, wherein the compound is 2-(3-fluoro-2-isopropylphenyl)-9-(4-(1-methyl-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, or a pharma- ceutically acceptable salt thereof.

33. 25. The compound of claim 24, wherein the compound is 2-(3-fluoro-2-isopropylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-one, or a pharma- ceutically acceptable salt thereof.

34. 25. The compound of claim 24, wherein the compound is 2-(2-isopropylphenyl)-9-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-7,9-dihydro-8H-purin-8-one, or a pharma- ceutically acceptable salt thereof.

35. 25. The compound of claim 24, wherein the compound is 2-(2-isopropylphenyl)-9-(4-(1-methyl-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)benzyl)-7,9-dihydro-8H-purin-8-one, or a pharma- ceutically acceptable salt thereof.

36. A pharmaceutical composition comprising a compound according to any one of claims 1 to 35 and a pharma- ceutically acceptable carrier.

37. 37. The pharmaceutical composition of claim 36, wherein the pharma- ceutically acceptable carrier may further comprise an excipient, diluent, or surfactant.

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