Pyrrolo and pyrazolopyrimidines as ubiquitin-specific protease 7 inhibitors

This application is a continuation of U.S. application Ser. No. 15/874,163, now U.S. Pat. No. 10,377,760, filed Jan. 18, 2018, which is a continuation application of U.S. application Ser. No. 14/982,127, now U.S. Pat. No. 9,902,728, filed Dec. 29, 2015, which claims the benefit of and priority to U.S. provisional application No. 62/098,141, filed Dec. 30, 2014, the entire contents of each of which are incorporated herein by reference in its entirety.

The present invention is directed to inhibitors of ubiquitin-specific protease 7 (USP7) useful in the treatment of diseases or disorders associated with USP7 enzymes. Specifically, the invention is concerned with compounds and compositions inhibiting USP7, methods of treating diseases or disorders associated with USP7, and methods of synthesis of these compounds.

Ubiquitination is a post translational modification initially identified as a crucial component of proteasomal degradation in the ubiquitin proteasome system (UPS). Chains of Ubiquitin (Ub(s)), an 8.5 kDa highly conserved protein, are covalently attached to substrates to be degraded in the proteasome. (Finley D. “Recognition and processing of ubiquitin-protein conjugates by the proteasome.” Annual review of biochemistry 78:477-513, (2009)) The molecular mechanisms by which the UPS acts are also varied, with different chain linkages of ubiquitination controlling protein turnover, enzymatic activity, subcellular localization, and protein-protein interactions of substrate proteins. (Komander D., et. al. “The emerging complexity of protein ubiquitination,” Biochem. Soc. Trans. 37(Pt 5):937-53 (2009)).

Ubiquitin-specific protease 7 (USP7) is a Ubiquitin Specific Protease (USP) family deubiquitinase (DUB) that was originally identified as an enzyme that interacted with virally-encoded proteins of the Herpes simplex virus and later the Epstein-Barr virus, (Everett R. D., Meredith M., Orr A., Cross A, Kathoria M., Parkinson J. “A novel ubiquitin-specific protease is dynamically associated with the PML nuclear domain and binds to a herpes virus regulatory protein,” EMBO J. 16(7):1519-30 (1997); Holowaty M. N., Zeghouf M., Wu H., et al. “Protein profiling with Epstein-Barr nuclear antigen-1 reveals an interaction with the herpesvirus-associated ubiquitin-specific protease HAUSP/USP7,” J. Biol. Chem. 278(32):29987-94 (2003)) Ubiquitin Specific Proteases (USPs) specifically cleave the isopeptide bond at the carboxy terminus of ubiquitin. In contrast to other DUB classes, which are thought to generally regulate ubiquitin homeostasis or to be involved in pre-processing of linear ubiquitin chains, USPs remove ubiquitin from specific targets. Given this substrate specificity combined with the numerous roles ubiquitination has in the cell, USPs are important regulators of a multitude of pathways, ranging from preventing the proteolysis of ubquitinated substrates, to controlling their nuclear localization.

USP7 deubiquitinates a variety of cellular targets involved in different processes related to cancer and metastasis, neurodegenerative diseases, immunological disorders, osteoporosis, arthritis inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, and bacterial infections and diseases.

For example, USP7 has been shown to stabilize DNMT1, a DNA methyltransferase that maintain epigenetic silencing, to maintain higher steady state-levels of Claspin, a protein involved in ataxia telangiectasia and Rad3-related (ATR) phosphorylation of Chk1, and to regulate Tip60 protein levels, a histone acetyltransferase and transcriptional coregulator involved fit adipogenesis. (Zhanwen du, Song J., Wang Y., et al. “DNMT1 stability is regulated by proteins coordinating deubiquitination and acetylation-driven ubiquitination,” Science Signaling 3(146) (2010); Faustrup H., Bekker-Jensen S., Bartek J., Lukas J., Mail N., Mailand N “USP7 counteracts SCFbetaTrCP- but not APCCdh1-mediated proteolysis of Claspin,” The Journal of cell biology 184(1):13-9 (2009); Gao Y., Koppen A Rakhsh M., et al. “Early adipogenesis is regulated through USP7-mediated deubiquitination of the histone acetyltransferase TIP60,” Nature Communications 4:2656 (2013).

In addition to regulating the protein stability of poly-ubiquitinated targets, USP7 also acts to control the subcellular localization of proteins. Mono-ubiquitination of PTEN has been shown to effect its cytoplasmic/nuclear partitioning, where nuclear localization of PTEN is important for its tumor suppression activity. (Trotman L. C., Wang X., Alimonti A., et al. “Ubiquitination regulates PTEN nuclear import and tumor suppression,” Cell 128(1):141-56 (2007); Song M. S., Salmena L., Carracedo A., et al. “The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network,” Nature 455(7214):813-7 (2008)) USP7 has also been shown to hind and deubiquitinate FOXO4, a member of the FOXO subfamily of transcription factors involved in a variety of cell processes including metabolism, cell cycle regulation apoptosis, and response to oxidative stress, decreasing its nuclear localization and transcriptional activity. (van der Horst A., van der Horst O., de Vries-Smits A. M. M., et al. “FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP,” Nat. Cell Biol. 8(10):1064-73 (2006)).

Cellular targets of USP7 also include the tumor suppressor p53 and its major E3 ligase, MDM2, stabilizing p53 via the degradation of MDM2. (Li M., Chen D., Shiloh A., et al. “Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization,” Nature 416(6881):1648-53 (2002); Li M., Brooks C. L., Kon Gu W. “A dynamic role of HAUSP in the p53-Mdm2 pathway,” Mol. Cell. 13(6):879-86 (2004)) Structural studies have also shown that the EBNA1 protein encoded by the Epstein-Barr virus interacts at the same binding surface as USP7 on p53, preventing USP7 endogenous cellular activity while recruiting USP7 to viral promoters in order to activate latent viral gene expression. (Saridakis V., et al. “Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediated immortalization,” Mol. Cell. 18(1):25-36 (2005); Sarkari F., Sanchez-Alcaraz T., Wang S., Holowaty M. N., Sheng Y., Frappier L. “EBNA1-mediated recruitment of a histone H2B deubiquitylating complex to the Epstein-Barr virus latent origin of DNA replication,” PLoS pathogens 5(10) (2009); Sheng Y., et al. “Molecular recognition of p53 and MDM2 by USP7/HAUSP,” Nat. Struct. Mol. Biol. 13(3):285-91 (2006)) Similarly, the gene product of TSPYL5, a gene frequently amplified in breast cancer and associated with poor clinical outcome, alters the ubiquitination status of p53 via its interaction with USP7. (Epping M. T., et al. “TSPYL5 suppresses p53 levels and function by physical interaction with USP7,” Nat. Cell Biol. 13(1).102-8 (2011)).

Inhibition of USP7 with small molecule inhibitors therefore has the potential to be a treatment for cancers and other disorders. For this reason, there remains a considerable need for novel and potent small molecule inhibitors of USP7.

A first aspect of the invention relates to compounds of Formula (I):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof,

wherein:

X 1 is C, S, or S(O);

X 2 is CR 7 or N;

R 1 is H, D, —OH, —SH, —NH 2 , —NH(C 1 -C 4 ) alkyl, —N(C 1 -C 4 ) alkyl) 2 , or F;

R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 ;

each R 3 is independently at each occurrence selected from 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, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —CN, —OH, —C(O)R 17 , C(O)OR 17 , —OC(O)OR 17 , —OC(O)NR 17 R 18 , —NR 17 R 18 , —NR 17 C(O)OR 18 , —NR 17 C(O)OR 18 , —C(O)NR 17 R 18 , —NR 17 C(O)NR 17 R 18 , —S(O) q NR 17 R 18 , —SO q R 17 R 18 , —NR 17 S(O) q R 17 R 18 , or halogen, wherein alkyl is optionally substituted with one or more substituents independently selected from —OH or —NH 2 ;

or two R 3 together when on adjacent carbons form a (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 19 ; or two R 3 together form a (C 3 -C 8 ) spirocycloalkyl optionally substituted with one or more R 19 ; or two R 3 together form a spiroheterocyclyl optionally substituted with one or more R 19 ; or two R 3 together when on adjacent carbons form an aryl ring optionally substituted with one or more R 19 ; or two R 3 together when on adjacent carbons form an heteroaryl ring optionally substituted with one or more R 19 ;

R 4 is (C 1 -C 6 ) alkyl, —(C 0 -C 3 ) alkylene-aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, CD 3 or heterocyclyl, wherein aryl, heteroaryl, heterocyclyl and cycloalkyl are optionally substituted with one or more R 12 ;

R 5 and R 5′ are independently 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, or halogen; or

R 5 and R 5′ together form a (C 3 -C 6 ) cycloalkyl or heterocyclyl ring optionally substituted with one or more substituents independently selected from halogen, —CN, (C 1 -C 6 ) alkyl, —OH, —CH 2 OH, —(C 0 -C 2 )-alkylene-O(C 1 -C 6 ) alkyl, or —(C 0 -C 2 )-alkylene-NR 17 R 18 ;

R 6 is independently H, D, halogen, —CN, —NR 17 R 18 , (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, or —OH when X 2 is N;

R 7 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, halogen, aryl, heteroaryl, —CN, or —NR 10 R 11 , wherein aryl and heteroaryl is optionally substituted with one or more R 10 ;

each R 8 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, —(C 1 -C 3 )-alkylene-O(C 1 -C 6 ) alkyl, —(C 0 -C 4 )-alkylene-aryl, —(C 0 -C 4 )-alkylene-heteroaryl, (C 3 -C 10 ) cycloalkyl, heterocyclyl, —(C 0 -C 4 )-alkylene-O-aryl, —(C 0 -C 4 )-alkylene-O-heteroaryl, —O—(C 3 -C 8 )cycloalkyl, —S-heteroaryl, halogen, —CN, —C(O)R 10 , —CO(O)R 10 , —C(O)NR 10 R 11 , —S(O) q R 10 , —S(O) q NR 10 R 11 , —NR 10 S(O) q R 11 , —(C 0 -C 3 )-alkylene-NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 C(O)C(O)R 11 , —NR 10 C(O)NR 10 R 11 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 , or —OH, wherein alkyl, alkylene, aryl, heteroaryl, and heterocyclyl are optionally substituted with one or more R 9 ;

or two R 8 together when on adjacent carbons form an aryl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent carbons form a heterocyclyl ring optionally substituted with one or more R 9 ;

each R 9 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 8 ) cycloalkyl, halogen, aryl, —OH, —CN, —C(O)R 10 , —C(O)NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 R 11 , —S(O) q R 10 , —S(O) q NR 10 R 11 , —NR 10 S(O) q R 11 , oxo, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 , —O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, and cycloalkyl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, halogen, aryl, —NR 14 C(O)R 15 , —NR 14 S(O) q R 15 , —OH or —CN;

or two R 9 together when on adjacent carbons form an aryl ring; or two R 9 together when on adjacent carbons form a heteroaryl ring; or two R 9 together when on adjacent carbons form a (C 3 -C 10 ) cycloalkyl ring;

each R 10 and R 11 is independently at each occurrence selected from H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —(C 0 -C 3 ) alkylene-aryl, —(C 0 -C 4 ) alkylene-(C 3 -C 8 ) cycloalkyl, —(C 0 -C 4 ) alkylene heterocyclyl, —(C 0 -C 4 ) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 3 -C 8 ) cycloalkyl, heterocyclyl, aryl, —S(O) q (C 1 -C 3 ) alkyl, —S(O) q NR 14 R 15 , —NR 14 R 15 , —NR 14 C(O)R 15 , halogen, —OH, or —CN;

or R 10 and R 11 together form a heterocyclyl ring optionally substituted with one or more substituents selected from oxo, —C(O)(C 1 -C 3 ) alkyl or —NR 14 NR 15 ;

each R 12 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, aryl, heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocyclyl, —O—(C 3 -C 8 ) cycloalkyl, —S(O) q R 10 , —(CH 2 ) p C(O)OR 10 , —C(O)NR 14 R 15 , —S(O) q NR 14 R 15 , —NR 14 R 15 , —NR 14 C(O)NR 14 R 15 , —NR 14 C(O)OR 10 , —NR 14 SO q R 10 , —NR 14 COR 10 , halogen, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , SiMe 3 , SF 5 or —OH, wherein alkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl are optionally substituted with one or more R 13 ;

each R 13 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, heterocyclyl, heteroaryl, aryl, —OR 14 , —C(O)R 14 , —C(O)NR 14 R 15 , —NR 14 R 15 , —S(O) q R 14 , —NR 14 S(O) q R 15 , —S(O) q NR 14 R 15 , —NR 14 C(O)NR 14 R 15 , —NR 14 C(O)OR 15 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 or —CN, wherein alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, —NR 14 C(O)R 15 , —OH, —CN, —C(O)R 14 , or —NR 14 R 15 ;

or two R 13 together when on adjacent carbons form a heterocyclyl ring optionally substituted with one or more R 16 ; or two R 13 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R 16 ; or two R 13 together with the carbon to which they are attached can form a spiroheterocyclyl optionally substituted with one or more R 16 ;

each R 14 and R 15 are independently at each occurrence selected from H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —(C 1 -C 4 ) alkylene-(C 3 -C 8 ) cycloalkyl, —(C 0 -C 4 ) alkylene-heterocyclyl, —(C 0 -C 4 ) alkylene-aryl, —(C 0 -C 4 ) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R 16 ;

or R 14 and R 15 together form a heterocyclyl ring optionally substituted with one or more R 16 ;

each R 16 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, —C(O)(C 1 -C 3 ) alkyl, —NHC(O)(C 1 -C 4 ) alkyl, —CN, —CH 2 CN, —CR 10 R 11 NR 10 R 11 , oxo, —NR 10 R 11 , —S(O) q (C 1 -C 6 ) alkyl, —C(O)NR 10 R 11 , —S(O) q NR 10 R 11 , —NR 10 C(O)R 10 R 11 , —NR 10 C(O)NR 10 R 11 , or —OH;

or two R 16 together when on adjacent carbons form an aryl ring; or two R 16 together when on adjacent carbons form a spiroheterocyclyl ring;

each R 17 and R 18 is at each occurrence independently H or (C 1 -C 6 ) alkyl;

R 18 is independently at each occurrence 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, halogen, —CN, or —NR 17 R 18 ;

m is 0, 1 or 2;

n is 0, 1, 2 or 3;

p is 0, 1, or 2; and

each q is 0, 1, or 2.

Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of USP7. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP7 an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention is directed to a method of inhibiting USP7. The method involves 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.

Another aspect of the invention relates to a method of treating cancer. The method comprises 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.

Another aspect of the invention relates to a method of treating a neurodegenerative disease. The method comprises 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.

Another aspect of the invention relates to a method of treating a viral infection or disease. The method comprises 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.

Another aspect of the invention relates to a method of treating an inflammatory disease or condition. The method comprises 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 Another aspect of the invention relates to a method of inducing cell cycle arrest, apoptosis in tumor cells and/or enhanced tumor-specific T-cell immunity. The method comprises contacting the cells with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a disease associated with inhibiting USP7.

Another aspect of the present invention relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease associated with inhibiting USP7.

The present invention further provides methods of treating a disease or disorder associated with modulation of USP7 including, cancer and metastasis, neurodegenerative diseases, immunological disorders, diabetes, bone and joint diseases, osteoporosis, arthritis inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, viral infectivity and/or latency, and bacterial infections and diseases, comprising administering to a patient suffering from at least one of said diseases or disorder a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

The present invention provides inhibitors of USP7 that are therapeutic agents in the treatment of diseases such as cancer and metastasis, neurodegenerative diseases, immunological disorders, diabetes, bone and joint diseases, osteoporosis, arthritis inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, viral infectivity and/or latency, and bacterial infections and diseases.

The present invention further provides compounds and compositions with an improved efficacy and safety profile relative to known USP7 inhibitors. The present disclosure also provides agents with novel mechanisms of action toward USP7 enzymes in the treatment of various types of diseases including cancer and metastasis, neurodegenerative diseases, immunological disorders, diabetes, bone and joint diseases, osteoporosis, arthritis inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, viral infectivity and/or latency, and bacterial infections and diseases. Ultimately the present invention provides the medical community with a novel pharmacological strategy for the treatment of diseases and disorders associated with USP7 enzymes.

The present invention relates to compounds and compositions that are capable of inhibiting the activity USP7. The invention features methods of treating, preventing or ameliorating a disease or disorder in which USP7 plays a role by administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. The methods of the present invention can be used in the treatment of a variety of USP7 dependent diseases and disorders by inhibiting the activity of USP7 enzymes. Inhibition of USP7 provides a novel approach to the treatment, prevention, or amelioration of diseases including, but not limited to, cancer and metastasis, neurodegenerative diseases, immunological disorders, osteoporosis, arthritis inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, and bacterial infections and diseases.

In a first aspect of the invention, the compounds of Formula (I) are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof, wherein m, n, X 1 , X 2 , R 1 -R 5 , R 5′ and R 6 are as described herein above.

The details of the invention are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, 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 invention belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties.

The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

The term “and/or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

The term “optionally substituted” is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, —OH, —CN, —COOH, —CH 2 CN, —O—(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —O—(C 2 -C 6 ) alkenyl, —O—(C 2 -C 6 ) alkynyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —OH, —OP(O)(OH) 2 , —OC(O)(C 1 -C 6 ) alkyl, —C(O)(C 1 -C 6 ) alkyl, —OC(O)O(C 1 -C 6 ) alkyl, —NH 2 , —NH((C 1 -C 6 ) alkyl), —N((C 1 -C 6 ) alkyl) 2 , —NHC(O)(C 1 -C 6 ) alkyl, —C(O)NH(C 1 -C 6 ) alkyl, —S(O) 2 (C 1 -C 6 ) alkyl, —S(O)NH(C 1 -C 6 ) alkyl, and S(O)N((C 1 -C 6 ) alkyl) 2 . The substituents can themselves be optionally substituted. “Optionally substituted” as used herein also refers to substituted or unsubstituted whose meaning is described below.

As used herein, the term “substituted” means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and shaming two or more common atoms.

As used herein, the term “unsubstituted” means that the specified group bears no substituents.

Unless otherwise specifically defined, the term “aryl” refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, —H, -halogen, —O—(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl, —O—(C 2 -C 6 ) alkenyl, —O—(C 2 -C 6 ) alkynyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —OH, —OP(O)(OH) 2 , —OC(O)(C 1 -C 6 ) alkyl, —C(O)(C 1 -C 6 ) alkyl, —OC(O)O(C 1 -C 6 ) alkyl, NH 2 , NH((C 1 -C 6 ) N((C 1 -C 6 ) alkyl) 2 , —S(O) 2 —(C 1 -C 6 ) alkyl, —S(O)NH(C 1 -C 6 ) alkyl, and S(O)N((C 1 -C 5 ) alkyl) 2 . The substituents can themselves be optionally substituted. Furthermore when containing two fused rings the aryl groups herein defined may have an unsaturated or partially saturated ring fused with 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.

Unless otherwise specifically defined, “heteroaryl” means a monovalent monocyclic aromatic radical of 5 to 24 ring atoms or a polycyclic aromatic radical, containing one or more ring heteroatoms selected from N, O, or S, the remaining ring atoms being C. Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, or S. The aromatic radical is optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, 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, 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]naphthyridnyl, thieno[2,3-b]pyrazinyl, quinazolinyl, 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, tetrahydro pyrrolo[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, benzooxazolyl, benzoisoxazolyl, 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 when containing two fused rings the heteroaryl groups herein defined may have an unsaturated or partially saturated ring fused with 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.

Halogen or “halo” refers to fluorine, chlorine, bromine, or iodine.

Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Examples of a (C 1 -C 6 ) alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

“Alkoxy” refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, i.e., —O(alkyl). Examples of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

“Alkenyl” refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 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. An alkenyl group can be unsubstituted or substituted. Alkenyl, as herein defined, may be straight or branched.

“Alkynyl” refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 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. An alkynyl group can be unsubstituted or substituted.

The term “alkylene” or “alkylenyl” refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. As herein defined, alkylene may also be a C 1 -C 6 alkylene. An alkylene may further be a C 1 -C 4 alkylene. Typical alkylene groups include, but are not limited to, —CH 2 —, —CH(CH 3 )—, —C(CH 3 ) 2 —, —CH 2 CH 2 —, —CH 2 CH(CH 3 )—, —CH 2 C(CH 3 ) 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, and the like.

“Cycloalkyl” means monocyclic saturated carbon rings containing 3-18 carbon atoms. Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.

“Cycloalkylalkyl” means monocyclic saturated carbon rings containing 3-24 carbon atoms further substituted with (C 1 -C 6 ) alkyl groups. In general cycloalkylalkyl groups herein described display the following formula

where m is an integer from 1 to 6 and n is an integer from 1 to 16. The cycloalkyl ring or carbocycle may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. The substituents can themselves be optionally substituted. Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.2]octenyl, decahydronaphthalenyl, octahydro-1H-indenyl, cyclopentenyl, cyclohexenyl, cyclohexa-1,4-dienyl, cyclohexa-1,3-dienyl, 1,2,3,4-tetrahydronaphthalenyl, octahydropentalenyl, 3a,4,5,6,7,7a-hexahydro-1H-indenyl, 1,2,3,3a-tetrabydropentalenyl, bicyclo[3 1.0]hexanyl, bicyclo[2.1.0]pentanyl, spiro[3.3]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[2.2.2]octanyl, 6-methylbicyclo[3.1.1]heptanyl, 2,6,6-trimethylbicyclo[3.1.1]heptanyl, and derivatives thereof.

“Heterocyclyl” or “heterocycloalkyl” monocyclic rings containing carbon and heteroatoms taken from oxygen, nitrogen, or sulfur and wherein there is not delocalized π electrons (aromaticity) shared among the ring carbon or heteroatoms. The heterocycloalkyl ring structure may be substituted by one or more substituents. The substituents can themselves be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetadinyl, 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.

The term “hydroxyalkyl” means an alkyl group as defined above, where the alkyl group is substituted with one or more OH groups. Examples of hydroxyalkyl groups include HO—CH 2 , HO—CH 2 —CH 2 — and CH 3 —CH(OH)—.

The term “haloalkyl” as used herein refers to an alkyl group, as defined herein, which is substituted one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

The term “haloalkoxy” as used herein refers to an alkoxy group, as defined herein, which is substituted one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

The term “cyano” as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., C≡N.

The term “amine” as used herein refers to primary (R—NH 2 , R≠H), secondary (R 2 —NH, R 2 ≠H) and tertiary (R 3 —N, R≠H) amines. A substituted amine is intended to mean an amine where at least one of the hydrogen atoms has been replaced by the substituent.

The term “amino” as used herein means a substituent containing at least one nitrogen atom. Specifically, NH 2 , —NH(alkyl) or alkylamino, —N(alkyl) 2 or dialkylamino, amide-, carbamide-, urea, and sulfamide substituents are included in the term “amino”.

The term “dialkylamino” as used herein refers to an amino or NH 2 group where both of the hydrogens have been replaced with alkyl groups, as defined herein above, —N(alkyl) 2 . The alkyl groups on the amino group can be the same or different alkyl groups. Example of alkylamino groups include, but are not limited to, dimethylamino (i.e., —N(CH 3 ) 2 ), diethylamino, dipropylamino, diiso-propylamino, di-n-butylamino, di-sec-butylamino, di-tert-butylamino, methyl(ethyl)amino, methyl(butylamino), etc.

“Spirocycloalkyl” or “spirocyclyl” means carbogenic bicyclic hag systems with both rings connected through a single atom. The ring can be different in size and nature, or identical in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both of the rings in a spirocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more of the carbon atoms in the spirocycle can be substituted with a heteroatom (e.g., O, N, S, or P). A (C 1 -C 12 ) spirocycloalkyl is a spirocycle containing between 3 and 12 carbon atoms. One or more of the carbon atoms can be substituted with a heteroatom.

The term “spiroheterocycloalkyl” or “spiroheterocyclyl” is understood to mean a spirocycle wherein at least one of the rings is a heterocycle (e.g., at least one of the rings is furanyl, morpholinyl, or piperadinyl).

The term “solvate” refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the invention may 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 wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.

The term “isomer” refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the compounds of Formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.

The disclosure also includes pharmaceutical compositions comprising an effective amount of a disclosed compound and a pharmaceutically acceptable carrier. Representative “pharmaceutically acceptable salts” include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumerate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

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

An “effective amount” when used in connection with a compound is an amount effective for treating or preventing a disease in a subject as described herein.

The term “carrier”, as used in this disclosure, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.

The term “treating” with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder.

The term “disorder” is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

The term “administer”, “administering”, or “administration” as used in this disclosure refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.

The term “prodrug,” as used in this disclosure, means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound.

The present invention relates to compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, capable of inhibiting USP7, which are useful for the treatment of diseases and disorders associated with modulation of a USP7 enzyme. The invention further relates to compounds, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, which are useful for inhibiting USP7.

In one embodiment, the compounds of Formula (I) have the structure of Formula (Ia):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof,

wherein:

R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 ;

R 4 is (C 1 -C 6 ) alkyl, —(C 0 -C 8 ) alkylene-aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, CD 3 , or heterocyclyl, wherein aryl, heteroaryl, heterocyclyl and cycloalkyl are optionally substituted with one or more R 12 ;

R 5 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, or halogen; or

R 6 is independently H, D, halogen, —CN, —NR 17 R 18 , (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, or —OH;

each R 8 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, —(C 1 -C 3 )-alkylene-O(C 1 -C 6 ) alkyl, —(C 0 -C 4 )-alkylene-aryl, —(C 0 -C 4 )-alkylene-heteroaryl, (C 3 -C 10 ) cycloalkyl, heterocyclyl, —(C 0 -C 4 )-alkylene-O-aryl, —(C 0 -C 4 )-alkylene-O-heteroaryl, —O—(C 3 -C 8 )cycloalkyl, —S-heteroaryl, halogen, —CN, —C(O)R 10 , —CO(O)R 10 , —C(O)NR 10 R 11 , —S(O) q R 10 , —S(O) q NR 10 R 11 , —NR 10 S(O) q R 11 , —(C 0 -C 3 )-alkylene-NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 C(O)C(O)R 11 , —NR 10 C(O)NR 10 R 11 , —P(O)(C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , SiMe 3 , SF 5 , or —OH, wherein alkyl, alkylene, aryl, heteroaryl, and heterocyclyl are optionally substituted with one or more R 9 ;

or two R 8 together when on adjacent carbons form an aryl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R 8 ; or two R 8 together when on adjacent carbons form a heterocyclyl ring optionally substituted with one or more R 9 ;

each R 9 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 8 ) cycloalkyl, halogen, aryl, —OH, —CN, —C(O)R 10 , —C(O)NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 R 11 , —S(O) q R 10 , —S(O) q NR 10 R 11 , —NR 10 S(O) q R 11 , oxo, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 , —O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, and cycloalkyl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, halogen, aryl, —NR 14 C(O)R 15 , —NR 14 S(O) q R 15 , —OH or —CN;

or two R 9 together when on adjacent carbons form an aryl ring; or two R 9 together when on adjacent carbons form a heteroaryl ring; or two R 9 together when on adjacent carbons form a (C 3 -C 10 ) cycloalkyl ring;

each R 10 and R 11 is independently at each occurrence selected from H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —(C 0 -C 3 ) alkylene-aryl, —(C 0 -C 4 ) alkylene-(C 3 -C 8 ) cycloalkyl, —(C 0 -C 4 ) alkylene-heterocyclyl, —(C 0 -C 4 ) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 3 -C 8 ) cycloalkyl, heterocyclyl, aryl, —S(O) q (C 1 -C 3 ) alkyl, —S(O) q NR 14 R 15 , —NR 14 R 15 , —NR 14 C(O)R 15 , halogen, —OH, or —CN;

or R 10 and R 11 together form a heterocyclyl ring optionally substituted with one or more substituents selected from oxo, —C(O)(C 1 -C 3 ) alkyl or —NR 14 NR 15 ;

each R 12 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, aryl, heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocyclyl, —O—(C 3 -C 8 )cycloalkyl, —S(O) q R 10 ; —(CH 2 ) p C(O)OR 10 , —C(O)NR 14 R 15 , —S(O) q NR 14 R 15 , —NR 14 R 15 , —NR 14 C(O)NR 14 R 15 , —NR 14 C(O)OR 10 , —NR 14 SO q R 10 , —NR 14 COR 10 , halogen, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 or —OH, wherein alkyl, aryl, heteroaryl, and cycloalkyl are optionally substituted with one or more R 13 ;

each R 13 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, heterocyclyl, heteroaryl, aryl, —OR 14 , —C(O)R 14 , —C(O)NR 14 R 15 , —NR 14 R 15 , —S(O) q R 14 , —NR 14 S(O) q R 15 , S(O) q NR 14 R 15 , —NR 14 C(O)NR 14 R 15 , —NR 14 C(O)OR 15 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 or —CN, wherein alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl. —NR 14 C(O)R 15 , —OH, —CN, —C(O)R 14 , or —NR 14 R 15 ;

each R 14 and R 15 are independently at each occurrence selected from H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —(C 1 -C 4 ) alkylene-(C 3 -C 8 ) cycloalkyl, —(C 0 -C 4 ) alkylene-heterocyclyl, —(C 0 -C 4 ) alkylene-aryl, —(C 0 -C 4 ) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R 16 ;

or R 14 and R 15 together form a heterocyclyl ring optionally substituted with one or more R 16 ;

each R 16 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, —C(O)(C 1 -C 3 ) alkyl, —NHC(O)(C 1 -C 4 ) alkyl, —CN, —CH 2 CN, —CR 10 R 11 NR 10 R 11 , oxo, —NR 10 R 11 , —S(O) q (C 1 -C 6 ) alkyl, —C(O)NR 10 R 11 , —S(O) q NR 10 R 11 , —NR 10 C(O)R 10 R 11 , —NR 10 C(O)NR 10 R 11 , or —OH;

or two R 16 together when on adjacent carbons form an aryl ring; or two R 16 together when on adjacent carbons form a spiroheterocyclyl ring;

each R 17 and R 18 is independently at each occurrence H or (C 1 -C 6 ) alkyl;

p is 0, 1, or 2; and

each q is 0, 1 or 2.

In another embodiment, the compounds of Formula (I) have the structure of Formula (Ib):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers thereof,

wherein:

R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 ;

R 4 is (C 1 -C 6 ) alkyl, —(C 0 -C 3 ) alkylene-aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, CD 3 , or heterocyclyl, wherein aryl, heteroaryl, heterocyclyl and cycloalkyl are optionally substituted with one or more R 12 ;

R 5 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, or halogen; or

R 6 is independently H, D, halogen, —CN, —NR 17 R 18 , (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, or —OH when X 2 is N;

R 7 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, halogen, aryl, heteroaryl, —CN, or —NR 10 R 11 , wherein aryl and heteroaryl is optionally substituted with one or more R 10 ;

each R 8 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, —(C 1 -C 3 )-alkylene-O(C 1 -C 6 ) alkyl, —(C 0 -C 4 )-alkylene-aryl, —(C 0 -C 4 )-alkylene-heteroaryl, (C 3 -C 10 ) cycloalkyl, heterocyclyl, —(C 0 -C 4 )-alkylene-O-aryl, —(C 0 -C 4 )-alkylene-O-heteroaryl, —O—(C 3 -C 8 )cycloalkyl, —S-heteroaryl, halogen, —CN, —C(O)R 10 , —CO(O)R 10 , —C(O)NR 10 R 11 , —S(O) q R 10 , —S(O) q NR 10 R 11 , —NR 10 S(O) q R 11 , —(C 0 -C 3 )-alkylene-NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 C(O)C(O)R 11 , —NR 10 C(O)NR 10 R 11 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 , or —OH, wherein alkyl, alkylene, aryl, heteroaryl, and heterocyclyl are optionally substituted with one or more R 9 ;

or two R 8 together when on adjacent carbons form an aryl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent carbons form a heterocyclyl ring optionally substituted with one or more R 9 ;

each R 9 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 8 ) cycloalkyl, halogen, aryl, —OH, —CN, —C(O)R 10 , —C(O)NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 R 11 , —S(O) q R 10 , —S(O) q NR 10 R 11 , —NR 10 S(O) q R 11 , oxo, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe, SF 5 , —O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, and cycloalkyl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, halogen, aryl, —NR 14 C(O)R 15 , —NR 14 S(O) q R 15 , —OH or —CN;

or two R 9 together when on adjacent carbons form an aryl ring; or two R 9 together when on adjacent carbons form a heteroaryl ring; or two R 9 together when on adjacent carbons form a (C 3 -C 10 ) cycloalkyl ring;

each R 10 and R 11 is independently at each occurrence selected from H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —(C 0 -C 3 ) alkylene-aryl, —(C 0 -C 4 ) alkylene-(C 3 -C 8 ) cycloalkyl, —(C 0 -C 4 ) alkylene-heterocyclyl, —(C 0 -C 4 ) alkylene-heteroaryl, —CN, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 3 -C 8 ) cycloalkyl, heterocyclyl, aryl, —S(O) q (C 1 -C 3 ) alkyl, —S(O) q NR 14 R 15 , —NR 14 R 15 , —NR 14 C(O)R 15 , halogen, —OH, or —CN;

or R 10 and R 11 together form a heterocyclyl ring optionally substituted with one or more substituents selected from oxo, —C(O)(C 1 -C 3 ) alkyl or —NR 14 NR 15 ;

each R 12 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, aryl, heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocyclyl, —O—(C 3 -C 8 )cycloalkyl, —S(O) q R 10 , —(CH 2 ) p C(O)OR 10 , —C(O)NR 14 R 15 , —S(O) q NR 14 R 15 , —NR 14 R 15 ; —NR 14 C(O)NR 14 R 15 , NR 14 C(O)OR 10 , —NR 14 SO q R 10 , —NR 14 COR 10 , halogen, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 or —OH, wherein alkyl, aryl, heteroaryl, and cycloalkyl are optionally substituted with one or more R 13 ;

each R 13 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, heterocyclyl, heteroaryl, aryl, —OR 14 , —C(O)R 14 , —C(O)NR 14 R 15 , —NR 14 R 15 , —S(O) q R 14 , —NR 14 S(O) q R 15 , —S(O) q NR 14 R 15 , —NR 14 C(O)NR 14 R 15 , —NR 14 C(O)OR 15 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 or —CN, wherein alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, —NR 14 C(O)R 15 , —OH, —CN, —C(O)R 14 , or —NR 14 R 15 ;

or two R 13 together when on adjacent carbons form a heterocyclyl ring optionally substituted with one or more R 16 ; or two R 13 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R 16 ; or two R 13 together with the carbon to which they are attached can form a spiroheterocyclyl optionally substituted with one or more R 16 ;

each R 14 and R 15 are independently at each occurrence selected from H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 1 -C 6 ) alkynyl, —(C 1 -C 4 ) alkylene-(C 3 -C 8 ) cycloalkyl, —(C 0 -C 4 ) alkylene-heterocyclyl, —(C 0 -C 4 ) alkylene-aryl, —(C 0 -C 4 ) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R 16 ;

or R 14 and R 15 together form a heterocyclyl ring optionally substituted with one or more R 16 ;

each R 16 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, —C(O)(C 1 -C 3 ) alkyl, —NHC(O)(C 1 -C 4 ) alkyl, —CN, —CH 2 CN, —CR 10 R 11 NR 10 R 11 , oxo, —NR 10 R 11 , —S(O) q (C 1 -C 6 ) alkyl, —C(O)NR 10 R 11 , —S(O) q NR 10 R 11 , —NR 10 C(O)R 10 R 11 , —NR 10 C(O)NR 10 R 11 , or —OH;

or two R 16 together when on adjacent carbons form an aryl ring; or two R 16 together when on adjacent carbons form a spiroheterocyclyl ring;

each R 17 and R 18 is at each occurrence independently H or (C 1 -C 6 ) alkyl;

p is 0, 1, or 2; and

each q is 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structure of Formula (Ic):

and pharmaceutically acceptable salts hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof,

wherein:

X 1 is C, S, or S(O);

Y is CH or N;

R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 ;

each R 8 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, —(C 1 -C 3 )-alkylene-O(C 1 -C 6 ) alkyl, —(C 0 -C 4 )-alkylene-aryl, —(C 0 -C 4 )-alkylene-heteroaryl, (C 3 -C 10 ) cycloalkyl, heterocyclyl, —(C 0 -C 4 )-alkylene-O-aryl, —(C 0 -C 4 )-alkylene-O-heteroaryl, —O—(C 3 -C 8 )cycloalkyl, —S-heteroaryl, halogen, —CN, —C(O)R 10 , —CO(O)R 10 , —C(O)NR 10 R 11 , —S(O) q R 10 , —S(O) q NR 10 R 11 , —NR 10 S(O) q R 11 , —(C 0 -C 3 )-alkylene-NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 C(O)C(O)R 11 , —NR 10 C(O)NR 10 R 11 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 , or —OH, wherein alkyl, alkylene, aryl, heteroaryl, and heterocyclyl are optionally substituted with one or more R 9 ;

or two R 8 together when on adjacent carbons form an aryl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent carbons form a heterocyclyl ring optionally substituted with one or more R 9 ;

each R 9 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 8 ) cycloalkyl, halogen, aryl, —OH, —CN, —C(O)R 10 , —C(O)NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 R 11 , —S(O) q R 10 , —S(O) q NR 10 R 11 , —NR 10 S(O) q R 11 , oxo, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 , —O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, and cycloalkyl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, halogen, aryl, —NR 14 C(O)R 15 , —NR 14 S(O) q R 15 , —OH or —CN;

or two R 9 together when on adjacent carbons form an aryl ring; or two R 9 together when on adjacent carbons form a heteroaryl ring; or two R 9 together when on adjacent carbons form a (C 3 -C 10 ) cycloalkyl ring;

each R 10 and R 11 is independently at each occurrence selected from H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —(C 0 -C 3 ) alkylene-aryl, —(C 0 -C 4 ) alkylene-(C 3 -C 8 ) cycloalkyl, —(C 0 -C 4 ) alkylene-heterocyclyl, —(C 0 -C 4 ) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 3 -C 8 ) cycloalkyl, heterocyclyl, aryl, —S(O) q (C 1 -C 3 ) alkyl, —S(O) q NR 14 R 15 , —NR 14 R 15 , —NR 14 C(O)R 15 , halogen, —OH, or —CN;

or R 10 and R 11 together form a heterocyclyl ring optionally substituted with one or more substituents selected from oxo, —C(O)(C 1 -C 3 ) alkyl or —NR 14 NR 15 ;

each R 12 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocyclyl, —O—(C 3 -C 8 ) cycloalkyl, —S(O) q R 10 , —(CH 2 ) p C(O)OR 10 , —C(O)NR 14 R 15 , —S(O) q NR 14 R 15 , —NR 14 R 15 , —NR 14 C(O)NR 14 R 15 , —NR 14 C(O)OR 10 , —NR 14 SO q R 10 , —NR 14 COR 10 , halogen, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 or —OH, wherein alkyl, aryl, heteroaryl, and cycloalkyl are optionally substituted with one or more R 13 ;

each R 13 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, heterocyclyl, heteroaryl, aryl, —OR 14 , —C(O)R 14 , —C(O)NR 14 R 15 , —NR 14 R 15 , —S(O) q R 14 , —NR 14 S(O) q R 15 , —S(O) q NR 14 R 15 , —NR 14 C(O)NR 14 R 15 , —NR 14 C(O)OR 15 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 or —CN, wherein alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, —NR 14 C(O)R 15 , —OH, —CN, —C(O)R 14 , or —NR 14 R 15 ;

or two R 13 together when on adjacent carbons form a heterocyclyl ring optionally substituted with one or more R 16 ; or two R 13 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R 16 ; or two R 13 together with the carbon to which they are attached can form a spiroheterocyclyl optionally substituted with one or more R 16 ;

each R 14 and R 15 are independently at each occurrence selected from H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —(C 1 -C 4 ) alkylene-(C 3 -C 8 ) cycloalkyl, —(C 0 -C 4 ) alkylene-heterocyclyl, —(C 0 -C 4 ) alkylene-aryl, —(C 0 -C 4 ) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R 16 ;

or R 14 and R 15 together form a heterocyclyl ring optionally substituted with one or more R 16 ;

each R 16 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, —C(O)(C 1 -C 3 ) alkyl, —NHC(O)(C 1 -C 4 ) alkyl, —CN, —CH 2 CN, —CR 10 R 11 NR 10 R 11 , oxo, —NR 10 R 11 , —S(O) q (C 1 -C 6 ) alkyl, —C(O)NR 10 R 11 , —S(O) q NR 10 R 11 , —NR 10 C(O)R 10 R 11 , —NR 10 C(O)NR 10 R 11 , or —OH;

or two R 16 together when on adjacent carbons form an aryl ring; or two R 16 together when on adjacent carbons form a spiroheterocyclyl ring;

p is 0, 1, or 2;

each q is 0, 1, or 2; and

r is 1, 2, 3, 4, or 5.

In another embodiment, the compounds of Formula (I) have the structure of Formula (Id):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof,

wherein:

X 1 is C, S, or S(O);

Y is CH or N;

R 2 is (C 1 -C 7 ) alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 ;

each R 8 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 5 ) haloalkoxy, —(C 1 -C 6 )-alkylene-O(C 1 -C 6 ) alkyl, —(C 0 -C 4 )-alkylene-aryl, —(C 0 -C 4 )-alkylene-heteroaryl, (C 3 -C 10 ) cycloalkyl, heterocyclyl, —(C 0 -C 4 )-alkylene-O-aryl, —(C 0 -C 4 )-alkylene-O-heteroaryl, —O—(C 3 -C 8 )cycloalkyl, —S-heteroaryl, halogen, —CN, —C(O)R 10 , —CO(O)R 10 , —C(O)NR 10 R 11 , —S(O) q R 10 , —S(O) q NR 10 R 11 , —NR 10 S(O) q R 11 , —(C 0 -C 3 )-alkylene-NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 C(O)C(O)R 11 , —NR 10 C(O)NR 10 R 11 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl), —SiMe 3 , SF 5 , or —OH, wherein alkyl, alkylene, aryl, heteroaryl, and heterocyclyl are optionally substituted with one or more R 9 ;

or two R 8 together when on adjacent carbons form an aryl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent carbons form a heterocyclyl ring optionally substituted with one or more R 9 ;

each R 9 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 8 ) cycloalkyl, halogen, aryl, —OH, —CN, —C(O)R 10 , —C(O)NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 R 11 , —S(O) q R 10 , —S(O) q NR 10 R 11 , —NR 10 S(O) q R 11 , oxo, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 , —O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, and cycloalkyl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, halogen, aryl, —NR 14 C(O)R 15 , —NR 14 S(O) q R 15 , —OH or —CN;

or two R 9 together when on adjacent carbons form an aryl ring; or two R 9 together when on adjacent carbons form a heteroaryl ring; or two R 9 together when on adjacent carbons form a (C 3 -C 10 ) cycloalkyl ring;

each R 10 and R 11 is independently at each occurrence selected from H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —(C 0 -C 3 ) alkylene-aryl, —(C 0 -C 4 ) alkylene-(C 3 -C 8 ) cycloalkyl, —(C 0 -C 4 ) alkylene-heterocyclyl, —(C 0 -C 4 ) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 3 -C 8 ) cycloalkyl, heterocyclyl, aryl, —S(O) q (C 1 -C 3 ) alkyl, —S(O) q NR 14 R 15 , —NR 14 R 15 , —NR 14 C(O)R 15 , halogen, —OH, or —CN;

or R 10 and R 11 together form a heterocyclyl ring optionally substituted with one or more substituents selected from oxo, —C(O)(C 1 -C 3 ) alkyl or —NR 14 NR 15 ;

each R 12 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, aryl, heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocyclyl, —O—(C 3 -C 8 )cycloalkyl, —S(O) q R 10 , —(CH 2 ) p C(O)OR 10 , —C(O)NR 14 R 15 , —S(O) q NR 14 R 15 , —NR 14 R 15 , —NR 14 C(O)NR 14 R 15 , —NR 14 C(O)OR 19 , —NR 14 SO q R 10 , —NR 14 COR 10 , halogen, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 or —OH, wherein alkyl, aryl, heteroaryl, and cycloalkyl are optionally substituted with one or more R 11 ;

each R 13 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, heterocyclyl, heteroaryl, aryl, —OR 14 , —C(O)R 14 , —C(O)NR 14 R 15 , —NR 14 R 15 , —S(O) q R 14 , —NR 14 S(O) q R 15 , —S(O) q NR 14 R 15 , —NR 14 C(O)NR 14 R 15 , —NR 14 C(O)OR 15 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 or —CN, wherein alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl are substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, —NR 14 C(O)R 15 , —OH, —CN, —C(O)R 14 , or —NR 14 R 15 ;

or two R 13 together when on adjacent carbons form a heterocyclyl ring optionally substituted with one or more R 16 ; or two R 13 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R 16 ; or two R 13 together with the carbon to which they are attached can form a spiroheterocyclyl optionally substituted with one or more R 16 ;

each R 14 and R 15 are independently at each occurrence selected from H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —(C 1 -C 4 ) alkylene, —(C 3 -C 8 ) cycloalkyl, —(C 0 -C 4 ) alkylene-heterocyclyl, —(C 0 -C 4 ) alkylene-aryl, —(C 0 -C 4 ) alkylene-heteroaryl, —CN, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R 16 ;

or R 14 and R 15 together form a heterocyclyl ring optionally substituted with one or more R 16 ;

each R 16 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, —C(O)(C 1 -C 3 ) alkyl, —NHC(O)(C 1 -C 4 ) alkyl, —CN, —CH 2 CN, —CR 10 R 11 NR 10 R 11 , oxo, —NR 10 R 11 , —S(O) q (C 1 -C 6 ) alkyl, —C(O)NR 10 R 11 , —S(O) q NR 10 R 11 , —NR 10 C(O)R 10 R 11 , —NR 10 C(O)NR 10 R 11 , or —OH;

or two R 16 together when on adjacent carbons form an aryl ring; or two R 16 together when on adjacent carbons form a spiroheterocyclyl ring;

p is 0, 1, or 2;

each q is 0, 1, or 2; and

r is 1, 2, 3, 4, or 5.

In another embodiment, the compounds of Formula (I) have the structure of Formula (Ie):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof,

wherein:

X 1 , is C, S, or S(O);

R 1 is H, D, —OH, —SH, —NH 2 , —NH(C 1 -C 4 ) alkyl, —N((C 1 -C 4 ) alkyl) 2 , or F;

R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 1 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 ;

R 5 and R 5′ are independently 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, or halogen; or

R 5 and R 5′ together form a (C 3 -C 6 ) cycloalkyl or heterocyclyl ring optionally substituted with one or more substituents independently selected from halogen, —CN, (C 1 -C 6 ) alkyl, —OH, —CH 2 OH, —(C 0 -C 2 )-alkylene-O(C 1 -C 6 ) alkyl, or —(C 0 -C 2 )-alkylene-NR 17 R 18 ;

R 6 is independently D, halogen, —CN, —NR 17 R 18 , (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, or —OH when X 2 is N;

each R 8 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, —(C 1 -C 3 )-alkylene-O(C 1 -C 6 ) alkyl, —(C 0 -C 4 )-alkylene-aryl, —(C 0 -C 4 )-alkylene-heteroaryl, (C 3 -C 10 ) cycloalkyl, heterocyclyl, —(C 0 -C 4 )-alkylene-O-aryl, —(C 0 -C 4 )-alkylene-O-heteroaryl, —O—(C 3 -C 8 )cycloalkyl, —S-heteroaryl, halogen, —CN, —C(O)R 10 , —CO(O)R) 10 , —C(O)NR 10 R 11 , —S(O) q R 10 , —S(O) q NR 10 R 11 , —NR 10 S(O) q R 11 , —(C 0 -C 3 )-alkylene-NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 C(O)C(O)R 11 , —NR 10 C(O)NR 10 R 11 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 , or —OH, wherein alkyl, alkylene, aryl, heteroaryl, and heterocyclyl are optionally substituted with one or more R 9 ;

or two R 8 together when on adjacent carbons form an aryl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent carbons form a heterocyclyl ring optionally substituted with one or more R 9 ;

each R 9 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 8 ) cycloalkyl, halogen, aryl, —OH, —CN, —C(O)R 10 , —C(O)NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 R 11 , —S(O) q R 10 , —S(O) q NR 10 R 11 , —NR 10 S(O) q R 11 , oxo, —P(O)((C 1 -C 6 )alkyl 2 , —P(O)aryl) 2 , —SiMe 3 , SF 5 , —O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, and cycloalkyl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, halogen, aryl, —NR 14 C(O)R 15 , —NR 14 S(O) q R 15 , —OH or —CN;

or two R 9 together when on adjacent carbons form an aryl ring, or two R 9 together when on adjacent carbons form a heteroaryl ring; or two R 9 together when on adjacent carbons form a (C 3 -C 10 ) cycloalkyl ring;

each R 10 and R 11 is independently at each occurrence selected from H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —(C 0 -C 3 ) alkylene-aryl, —(C 0 -C 4 ) alkylene-(C 3 -C 8 ) cycloalkyl, —(C 0 -C 4 ) alkylene-heterocyclyl, —(C 0 -C 4 ) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 3 -C 8 ) cycloalkyl, heterocyclyl, aryl, —S(O) q (C 1 -C 3 ) alkyl, —S(O) q NR 14 R 15 , —NR 14 R 15 , —NR 14 C(O)R 15 , halogen, —OH, —CN;

or R 10 and R 11 together form a heterocyclyl ring optionally substituted with one or more substituents selected from oxo, —C(O)(C 1 -C 3 ) alkyl or —NR 14 NR 15 ;

each R 14 and R 15 are independently at each occurrence selected from H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —(C 1 -C 4 ) alkylene-(C 3 -C 8 ) cycloalkyl, —(C 0 -C 4 ) alkylene-heterocyclyl, —(C 0 -C 4 ) alkylene-aryl, —(C 0 -C 4 ) alkylene-heteroaryl —CN, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R 16 ;

or R 14 and R 15 together form a heterocyclyl ring optionally substituted with one or more R 16 ;

each R 16 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, —C(O)(C 1 -C 3 ) alkyl, —NHC(O)(C 1 -C 4 ) alkyl, —CN, —CH 2 CN, —CR 10 R 11 NR 10 R 11 , oxo, —NR 10 R 11 , —S(O) q (C 1 -C 6 ) alkyl, —C(O)NR 10 R 11 , —S(O) q NR 10 R 11 , —NR 10 C(O)R 10 R 11 , —NR 10 C(O)NR 10 R 11 , or —OH;

or two R 16 together when on adjacent carbons form an aryl ring; or two R 16 together when on adjacent carbons form a spiroheterocyclyl ring;

each R 17 and R 18 is at each occurrence independently H or (C 1 -C 6 ) alkyl;

p is 0, 1, or 2; and

each q is 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structure of Formula (If):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof,

wherein:

X 1 is C, S, or S(O);

R 1 is D, —OH, —SH, —NH 2 , —NH(C 1 -C 4 ) alkyl, —N((C 1 -C 4 ) alkyl) 2 , or F;

R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 ;

R 5 and R 5′ are independently 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, or halogen; or

R 5 and R 5′ together form a (C 3 -C 6 ) cycloalkyl or heterocyclyl ring optionally substituted with one or more substituents independently selected from halogen, —CN, (C 1 -C 6 ) alkyl, —OH, —CH 2 OH, —(C 0 -C 2 )-alkylene-O(C 1 -C 6 ) alkyl, or —(C 0 -C 2 )-alkylene-NR 17 R 18 ;

R 6 is independently H, D, halogen, —CN, —NR 17 R 18 , (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, or —OH when X 2 , is N;

each R 8 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, —(C 1 -C 3 )-alkylene-O(C 1 -C 6 ) alkyl, —(C 0 -C 4 )-alkylene-aryl, —(C 0 -C 4 )-alkylene-heteroaryl, (C 3 -C 10 ) cycloalkyl, heterocyclyl, —(C 0 -C 4 )-alkylene-O-aryl, —(C 0 -C 4 )-alkylene-O-heteroaryl, —O—(C 3 -C 8 )cycloalkyl, —S-heteroaryl, halogen, —CN, —C(O)R 10 , —CO(O)R 10 , —C(O)NR 10 R 11 , —S(O) q R 10 , —S(O) q NR 10 R 11 , —NR 10 S(O) q R 11 , —(C 0 -C 3 )-alkylene-NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 C(O)C(O)R 11 , —NR 10 C(O)NR 10 R 11 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 , or —OH, wherein alkyl, alkylene, aryl, heteroaryl, and heterocyclyl are optionally substituted with one or more R 9 ;

or two R 8 together when on adjacent carbons form an aryl ring optionally substituted with one or more R 9 , or two R 8 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent carbons form a heterocyclyl ring optionally substituted with one or more R 9 ;

each R 9 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 8 ) cycloalkyl, halogen, aryl, —OH, —CN, —C(O)R 10 , —C(O)NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 R 11 , —S(O) q R 10 , —S(O) q NR 10 R 11 , —NR 10 S(O) q R 11 , oxo, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 , —O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, and cycloalkyl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, halogen, aryl, —NR 14 C(O)R 15 , —NR 14 S(O) q R 15 , —OH or —CN;

or two R 9 together when on adjacent carbons form an aryl ring; or two R 9 together when on adjacent carbons form a heteroaryl ring; or two R 9 together when on adjacent carbons form a (C 3 -C 10 ) cycloalkyl ring;

each R 10 and R 11 is independently at each occurrence selected from H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —(C 0 -C 3 ) alkylene-aryl, —(C 0 -C 4 ) alkylene-(C 3 -C 8 ) cycloalkyl, —(C 0 -C 4 ) alkylene-heterocyclyl, —(C 0 -C 4 ) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 3 -C 8 ) cycloalkyl, heterocyclyl, aryl, —S(O) q (C 1 -C 3 ) alkyl, —S(O) q NR 14 R 15 , —NR 14 R 15 , —NR 14 C(O)R 15 , halogen, —OH, or —CN;

or R 10 and R 11 together form a heterocyclyl ring optionally substituted with one or more substituents selected from oxo, —C(O)(C 1 -C 3 ) alkyl or —NR 14 NR 15 ;

each R 14 and R 15 are independently at each occurrence selected from H, (C 1 -C 6 ) (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —(C 1 -C 4 ) alkylene-(C 3 -C 8 ) cycloalkyl, —(C 0 -C 4 ) alkylene-heterocyclyl, —(C 0 -C 4 ) alkylene-aryl, —(C 0 -C 4 ) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R 16 ;

or R 14 and R 15 together form a heterocyclyl ring optionally substituted with one or more R 16 ;

each R 16 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, —C(O)(C 1 -C 3 ) alkyl, —NHC(O)(C 1 -C 4 ) alkyl, —CN, —CH 2 CN, —CR 10 R 11 NR 10 R 11 , oxo, —NR 10 R 11 , —S(O) q (C 1 -C 6 ) alkyl, —C(O)NR 10 R 11 , —S(O) q NR 10 R 11 , —NR 10 C(O)R 10 R 11 , —NR 10 C(O)NR 10 R 11 , or —OH;

Or two R 16 together when on adjacent carbons form an aryl ring; or two R 16 together when on adjacent carbons form a spiroheterocyclyl ring;

each R 17 and R 18 is at each occurrence independently H or (C 1 -C 6 ) alkyl;

p is 0, 1, or 2; and

each q is 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structure of Formula (Ig):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof,

wherein:

R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 ;

R 4 is (C 1 -C 6 ) alkyl, —(C 0 -C 3 ) alkylene-aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, CD 3 , or heterocyclyl, wherein aryl, heteroaryl, heterocyclyl and cycloalkyl are optionally substituted with one or more R 12 ;

each R 8 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, —(C 1 -C 3 )-alkylene-O(C 1 -C 6 ) alkyl, —(C 0 -C 4 )-alkylene-aryl, —(C 0 -C 4 )-alkylene-heteroaryl, (C 3 -C 10 ) cycloalkyl, heterocyclyl, —(C 0 -C 4 )-alkylene-O-aryl, —(C 0 -C 4 )-alkylene-O-heteroaryl, —O—(C 3 -C 8 )cycloalkyl, —S-heteroaryl, halogen, —CN, —C(O)R 10 , —CO(O)R 10 , —C(O)NR 10 R 11 , —S(O) q R 10 , —S(O) q NR 10 R 11 , —NR 10 S(O) q R 11 , —(C 0 -C 3 )-alkylene-NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 C(O)C(O)R 11 , —NR 10 C(O)NR 10 R 11 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 , or —OH, wherein alkyl, alkylene, aryl, heteroaryl, and heterocyclyl are optionally substituted with one or more R 9 ;

or two R 8 together when on adjacent carbons form an aryl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent carbons form a heterocyclyl ring optionally substituted with one or more R 9 ;

each R 9 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 8 ) cycloalkyl, halogen, aryl, —OH, —CN, —C(O)R 10 , —C(O)NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 R 11 , —S(O) q R 10 , —S(O) q NR 10 R 11 , —NR 10 S(O) q R 11 , oxo, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)aryl) 2 , —SiMe 3 , SF 5 , CN, or —O-heteroaryl, wherein alkyl, aryl, and cycloalkyl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, halogen, aryl, —NR 14 C(O)R 15 , —NR 14 S(O) q R 15 , —OH or —CN;

or two R 9 together when on adjacent carbons form an aryl ring; or two R 9 together when on adjacent carbons form a heteroaryl ring; or two R 9 , together when on adjacent carbons form a (C 3 -C 10 ) cycloalkyl ring;

each R 10 and R 11 is independently at each occurrence selected from H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —(C 0 -C 3 ) alkylene-aryl, —(C 0 -C 4 ) alkylene-(C 3 -C 8 ) cycloalkyl, —(C 0 -C 4 ) alkylene-heterocyclyl, —(C 0 -C 4 ) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 3 -C 8 ) cycloalkyl, heterocyclyl, aryl, —S(O) q (C 1 -C 3 ) alkyl, —S(O) q NR 14 R 15 , —NR 14 R 15 , —NR 14 C(O)R 15 , halogen, —OH, or —CN;

or R 10 and R 11 together form a heterocyclyl ring optionally substituted with one or more substituents selected from oxo, —C(O)(C 1 -C 3 ) alkyl or —NR 14 NR 15 ;

each R 12 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, aryl, heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocyclyl, —O—(C 3 -C 8 ) cycloalkyl, —S(O) q R 10 , —(CH 2 ) p C(O)OR 10 , —C(O)NR 14 R 15 , —S(O) q NR 14 R 15 , —NR 14 R 15 , —NR 14 C(O)NR 14 R 15 , —NR 14 C(O)OR 10 , —NR 14 SO q R 10 , —NR 14 COR 10 , halogen, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 or —OH, wherein alkyl, aryl, heteroaryl, and cycloalkyl are optionally substituted with one or more R 13 ;

each R 13 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, heterocyclyl, heteroaryl, aryl, —OR 14 , —C(O)R 14 , —C(O)NR 14 R 15 , —NR 14 R 15 , —S(O) q R 14 , —NR 14 S(O) q R 15 , —S(O) q NR 14 R 15 , —NR 14 C(O)NR 14 R 15 , —NR 14 C(O)OR 15 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 or —CN, wherein alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, —NR 14 C(O)R 15 , —OH, —CN, —C(O)R 14 , or —NR 14 R 15 ;

or two R 13 together when on adjacent carbons form a heterocyclyl ring optionally substituted with one or more R 16 ; or two R 13 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R 16 ; or two R 13 together with the carbon to which they are attached can form a spiroheterocyclyl optionally substituted with one or more R 16 ;

each R 14 and R 15 are independently at each occurrence selected from H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —(C 1 -C 4 ) alkylene-(C 3 -C 8 ) cycloalkyl, —(C 0 -C 4 ) alkylene-heterocyclyl, —(C 0 -C 4 ) alkylene-aryl, —(C 0 -C 4 ) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R 16 ;

or R 14 and R 15 together form a heterocyclyl ring optionally substituted with one or more R 16 ;

each R 16 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, —C(O)(C 1 -C 3 ) alkyl, —NHC(O)(C 1 -C 4 ) alkyl, —CN, —CH 2 CN, —CR 10 R 11 NR 10 R 11 , oxo, —NR 10 R 11 , —S(O) q (C 1 -C 6 ) alkyl, —C(O)NR 10 R 11 , —S(O) q NR 10 R 11 , —NR 10 C(O)R 10 R 11 , —NR 10 C(O)NR 10 R 11 , or —OH;

or two R 16 together when on adjacent carbons form an aryl ring; or two R 16 together when on adjacent carbons form a spiroheterocyclyl ring;

p is 0, 1, or 2; and

each q is 0, or 2.

In another embodiment, the compounds of Formula (I) have the structure of Formula (Ih):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof,

wherein:

R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 ;

R 4 is (C 1 -C 6 ) alkyl, —(C 0 -C 3 ) alkylene-aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, CD 3 , or heterocyclyl, wherein aryl, heteroaryl, heterocyclyl and cycloalkyl are optionally substituted with one or more R 12 ;

each R 8 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, —(C 1 -C 3 )-alkylene-O(C 1 -C 6 ) alkyl, —(C 0 -C 4 )-alkylene-aryl, —(C 0 -C 4 )-alkylene-heteroaryl, (C 3 -C 10 ) cycloalkyl, heterocyclyl, —(C 0 -C 4 )-alkylene-O-aryl, —(C 0 -C 4 )-alkylene-O-heteroaryl, —O—(C 3 -C 8 )cycloalkyl, —S-heteroaryl, halogen, —CN, —C(O)R 10 , —CO(O)R 10 , —C(O)NR 10 R 11 , —S(O) q R 10 , —S(O) q NR 10 R 11 , —NR 10 S(O) q R 11 , —(C 0 -C 3 )-alkylene-NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 C(O)C(O)R 11 , —NR 10 C(O)NR 10 R 11 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 , or —OH, wherein alkyl, alkylene, heteroaryl and heterocyclyl are optionally substituted with one or more R 9 ;

or two R 8 together when on adjacent carbons form an aryl ring optionally substituted with one or more or two R 8 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent carbons form a heterocyclyl ring optionally substituted with one or more R 9 ;

each R 9 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 8 ) cycloalkyl, halogen, aryl, —OH, —CN, —C(O)R 10 , —C(O)NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 R 11 , —S(O) q R 10 , —S(O) q NR 10 R 11 , —NR 10 S(O) q R 11 , oxo, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 , O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, and cycloalkyl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, halogen, aryl, —NR 14 C(O)R 15 , —NR 14 S(O) q R 15 , —OH or —CN;

or two R 9 together when on adjacent carbons form an aryl ring; or two R 9 together when on adjacent carbons form a heteroaryl ring; or two R 9 together when on adjacent carbons form a (C 3 -C 10 ) cycloalkyl ring;

each R 10 and R 11 is independently at each occurrence selected from H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, —(C 2 -C 6 ) alkynyl, —(C 0 -C 3 ) alkylene-aryl, —(C 0 -C 4 ) alkylene-(C 3 -C 8 ) cycloalkyl, —(C 0 -C 4 ) alkylene-heterocyclyl, —(C 0 -C 4 ) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 3 -C 8 ) cycloalkyl, heterocyclyl, aryl, —S(O) q (C 1 -C 3 ) alkyl, —S(O) q NR 14 R 15 , —NR 14 R 15 , —NR 14 C(O)R 15 , halogen, —OH, or —CN;

or R 10 and R 11 together form a heterocyclyl ring optionally substituted with one or more substituents selected from oxo, —C(O)(C 1 -C 3 ) alkyl or —NR 14 NR 15 ;

each R 12 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, aryl, heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocyclyl, —O—(C 3 -C 8 )cycloalkyl, —S(O) q R 10 , —(CH 2 ) p C(O)OR 10 , —C(O)NR 14 R 15 , —S(O) q NR 14 R 15 , —NR 14 R 15 , —NR 14 C(O)NR 14 R 15 , —NR 14 C(O)OR 10 , —NR 14 SO q R 10 , —NR 14 COR 10 , halogen, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 or —OH, wherein alkyl, aryl, heteroaryl, and cycloalkyl are optionally substituted with one or more R 14 ;

each R 13 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, heterocyclyl, heteroaryl, aryl, —OR 14 , —C(O)R 14 , —C(O)NR 14 R 15 , —NR 14 R 15 , —S(O) q R 14 , —NR 14 S(O) q R 15 , —S(O) q NR 14 R 15 , —NR 14 C(O)NR 14 R 15 , —NR 14 C(O)OR 15 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 or —CN, wherein alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl are substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, —NR 14 C(O)R 15 , —OH, —CN, —C(O)R 14 , or —NR 14 R 15 ;

or two R 13 together when on adjacent carbons form a heterocyclyl ring optionally substituted with one or more R 16 ; or two R 13 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R 16 ; or two R 13 together with the carbon to which they are attached can form a spiroheterocyclyl optionally substituted with one or more R 16 ;

each R 14 and R 15 are independently at each occurrence selected from H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —(C 1 -C 4 ) alkylene-(C 3 -C 8 ) cycloalkyl, —(C 0 -C 4 ) alkylene-heterocyclyl, —(C 0 -C 4 ) alkylene-aryl, —(C 0 -C 4 ) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R 16 ;

or R 14 and R 15 together form a heterocyclyl ring optionally substituted with one or more R 16 ;

each R 16 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, —C(O)(C 1 -C 3 ) alkyl, —NHC(O)(C 1 -C 4 ) alkyl, —CN, —CH 2 CN, —CR 10 R 11 NR 10 R 11 , oxo, —NR 10 R 11 , —S(O) q (C 1 -C 6 ) alkyl, —C(O)NR 10 R 11 , —S(O) q NR 10 R 11 , —NR 10 C(O)NR 10 R 11 , or —OH;

or two R 16 together when on adjacent carbons form an aryl ring; or two R 16 together when on adjacent carbons form a spiroheterocyclyl ring;

p is 0, 1, or 2; and

each q is 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structure of Formula (Ii):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof,

wherein:

Y is CH or N;

R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 ;

each R 8 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, —(C 1 -C 3 )-alkylene-O(C 1 -C 6 ) alkyl, —(C 0 -C 4 )-alkylene-aryl, —(C 0 -C 4 )-alkylene-heteroaryl, (C 3 -C 10 ) cycloalkyl, heterocyclyl, —(C 0 -C 4 )-alkylene-O-aryl, —(C 0 -C 4 )-alkylene-O-heteroaryl, —O—(C 3 -C 8 )cycloalkyl, —S-heteroaryl, halogen, —CN, —C(O)R 10 , —CO(O)R 10 , —C(O)NR 10 R 11 , —S(O) q R 10 , —S(O) q NR 10 R 11 , —NR 10 S(O) q R 11 , —(C 0 -C 3 )-alkylene-NR 10 NR 11 , —NR 10 C(O)R 11 , —NR 10 C(O)C(O)R 11 , —NR 10 C(O)NR 10 R 11 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , SF 5 , —OH, wherein alkyl, alkylene, aryl, heteroaryl, and heterocyclyl are optionally substituted with one or more R 9 ;

or two R 8 together when on adjacent carbons form an aryl ring optionally substituted with one or more R 9 , or two R 8 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent carbons form a heterocyclyl ring optionally substituted with one or more R 9 ;

each R 9 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 8 ) cycloalkyl, halogen, aryl, —OH, —CN, —C(O)R 10 , —C(O)NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 R 11 , —S(O) q R 10 , —S(O) q NR 10 R 11 , —NR 10 S(O) q R 11 , oxo, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 , CN, or —O-heteroaryl, wherein alkyl, aryl and cycloalkyl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, halogen, aryl, —NR 14 C(O)R 15 , —NR 14 S(O) q R 14 , —OH or —CN;

or two R 9 together when on adjacent carbons form an aryl ring; or two R 9 together when on adjacent carbons form a heteroaryl ring; or two R 9 together when on adjacent carbons form a (C 3 -C 10 ) cycloalkyl ring;

each R 10 and R 11 is independently at each occurrence selected from H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —(C 0 -C 3 ) alkylene-aryl, —(C 0 -C 4 ) alkylene-(C 3 -C 9 ) cycloalkyl, —(C 0 -C 4 ) alkylene-heterocyclyl, —(C 0 -C 4 ) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 3 -C 8 ) cycloalkyl, heterocyclyl, aryl, —S(O) q (C 1 -C 3 ) alkyl, —S(O) q NR 14 R 15 , —NR 14 R 15 , —NR 14 C(O)R 15 , halogen, —OH, or —CN;

or R 10 and R 11 together form a heterocyclyl ring optionally substituted with one or more substituents selected from oxo, —C(O)(C 1 -C 3 ) alkyl or —NR 14 NR 15 ;

each R 12 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, aryl, heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocyclyl, —O—(C 3 -C 8 )cycloalkyl, —S(O) q R 10 , —(CH 2 ) p C(O)OR 10 , —C(O)NR 14 R 15 , —S(O) q NR 14 R 14 , —NR 14 R 15 , —NR 14 C(O)NR 14 R 15 , —NR 14 C(O)OR 10 , —NR 14 SO q R 10 , —NR 14 COR 10 , halogen, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 or —OH, wherein alkyl, aryl, heteroaryl, and cycloalkyl are optionally substituted with one or more R 13 ;

each R 13 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, heterocyclyl, heteroaryl, aryl, —OR 14 , —C(O)R 14 , —C(O)NR 14 R 15 , —NR 14 R 15 , —S(O) q R 14 , —NR 14 S(O) q R 15 , —S(O) q NR 14 R 15 , —NR 14 C(O)NR 14 R 15 , —NR 14 C(O)OR 15 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 or —CN, wherein alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, —NR 14 C(O)R 15 , —OH, —CN, —C(O)R 14 , or —NR 14 R 15 ;

or two R 13 together when on adjacent carbons form a heterocyclyl ring optionally substituted with one or more R 16 ; or two R 13 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R 16 ; or two R 13 together with the carbon to which they are attached can form a spiroheterocyclyl optionally substituted with one or more R 16 ;

each R 14 and R 15 are independently at each occurrence selected from H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —(C 1 -C 4 ) alkylene-(C 3 -C 8 ) cycloalkyl, —(C 0 -C 4 ) alkylene-heterocyclyl, —(C 0 -C 4 ) alkylene-aryl, —(C 0 -C 4 ) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R 16 ;

or R 14 and R 15 together form a heterocyclyl ring optionally substituted with one or more R 16 ;

each R 16 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, —C(O)(C 1 -C 3 ) alkyl, —NHC(O)(C 1 -C 4 ) alkyl, —CN, —CH 2 CN, —CR 10 R 11 NR 10 R 11 , oxo, —NR 10 R 11 , —S(O) q (C 1 -C 6 ) alkyl, —C(O)NR 10 R 11 , —S(O) q NR 10 R 11 , —NR 10 C(O)R 10 R 11 , —NR 10 C(O)NR 10 R 11 , or —OH;

or two R 16 together when on adjacent carbons form an aryl ring; or two R 16 together when on adjacent carbons form a spiroheterocyclyl ring;

p is 0, 1, or 2;

each q is 0, 1, or 2 and

r is 0, 1, 2, 3, 4, or 5.

In another embodiment, the compounds of Formula (I) have the structure of Formula (Ij):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof,

wherein:

Y is CH or N;

R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 ;

each R 8 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, —(C 1 -C 3 )-alkylene-O(C 1 -C 6 ) alkyl, —(C 0 -C 4 )-alkylene-aryl, —(C 0 -C 4 )-alkylene-heteroaryl, (C 3 -C 10 ) cycloalkyl, heterocyclyl, —(C 0 -C 4 )-alkylene-O-aryl, —(C 0 -C 4 )-alkylene-O-heteroaryl, —O—(C 3 -C 8 )cycloalkyl, —S-heteroaryl, halogen, —CN, —C(O)R 10 , —CO(O)R 10 , —C(O)NR 10 R 11 , —S(O) q R 10 , —S(O) q NR 10 R 11 , —NR 10 S(O) q R 11 , —(C 0 -C 3 )-alkylene-NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 C(O)C(O)R 11 , —NR 10 C(O)NR 10 R 11 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 , or —OH, wherein alkyl, alkylene, aryl, heteroaryl, and heterocyclyl are optionally substituted with one or more R 9 ;

or two R 8 together when on adjacent carbons form an aryl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent carbons form a heterocyclyl ring optionally substituted with one or more R 9 ;

each R 9 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 8 ) cycloalkyl, halogen, aryl, —OH, —CN, —C(O)R 10 , —C(O)NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 R 11 , —S(O) q R 10 , —S(O) q NR 10 R 11 , —NR 10 S(O) q R 11 , oxo, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 , —O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, and cycloalkyl are optionally, substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, halogen, aryl, —NR 14 C(O)R 15 , —NR 14 S(O) q R 15 , —OH or —CN;

or two R 9 together when on adjacent carbons form an aryl ring; or two R 9 together when on adjacent carbons form a heteroaryl ring; or two R 9 together when on adjacent carbons form a (C 3 -C 10 ) cycloalkyl ring;

each R 10 and R 11 is independently at each occurrence selected from H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —(C 0 -C 3 ) alkylene-aryl, —(C 0 -C 4 ) alkylene-(C 3 -C 8 ) cycloalkyl, —(C 0 -C 4 ) alkylene-heterocyclyl, —(C 0 -C 4 ) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 3 -C 8 ) cycloalkyl, heterocyclyl, aryl, —S(O) q (C 1 -C 3 ) alkyl, —S(O) q NR 14 R 15 , —NR 14 C(O)R 15 , halogen, —OH, or —CN;

or R 10 and R 11 together form a heterocyclyl ring optionally substituted with one or more substituents selected from oxo, —C(O)(C 1 -C 3 ) alkyl or —NR 14 NR 15 ;

each R 12 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, aryl, heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocyclyl, —O—(C 3 -C 9 )cycloalkyl, —S(O) q R 10 , —(CH 2 ) p C(O)OR 10 , —C(O)NR 14 R 15 , —S(O) q NR 14 R 15 , —NR 14 R 15 , —NR 14 C(O)NR 14 R 15 , —NR 14 C(O)OR 10 , —NR 14 SO q R 10 , —NR 14 COR 10 , halogen, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 or —OH, wherein alkyl, aryl, heteroaryl, and cycloalkyl are optionally substituted with one or more R 13 ;

each R 13 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, heterocyclyl, heteroaryl, aryl, —OR 14 , —C(O)R 14 , —C(O)NR 14 R 15 , —NR 14 R 15 , —S(O) q R 14 , —NR 14 S(O) q R 15 , —S(O) q NR 14 R 15 , —NR 14 C(O)NR 14 R 15 , —NR 14 C(O)OR 15 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 or —CN, wherein alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, —NR 14 C(O)R 15 , —OH, —CN, —C(O)R 14 , or —NR 14 R 15 ;

or two R 13 together when on adjacent carbons form a heterocyclyl ring optionally substituted with one or more R 16 ; or two R 13 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R 16 ; or two R 13 together with the carbon to which they are attached can form a spiroheterocyclyl optionally substituted with one or more R 16 ;

each R 14 and R 15 are independently at each occurrence selected from H, (C 1 -C 6 ) (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —(C 1 -C 4 ) alkylene-(C 3 -C 8 ) cycloalkyl, —(C 0 -C 4 ) alkylene-heterocyclyl, —(C 0 -C 4 ) alkylene-aryl, —(C 0 -C 4 ) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R 16 ;

or R 14 and R 15 together form a heterocyclyl ring optionally substituted with one or more R 16 ;

each R 16 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, —C(O)(C 1 -C 3 ) alkyl, —NHC(O)(C 1 -C 4 ) alkyl, —CN, —CH 2 CN, —CR 10 R 11 NR 10 R 11 , oxo, —NR 10 R 11 , —S(O) q (C 1 -C 6 ) alkyl, —C(O)NR 10 R 11 , —S(O) q NR 10 R 11 , —NR 10 C(O)R 10 R 11 , —NR 10 C(O)NR 10 R 11 , or —OH;

or two R 16 together when on adjacent carbons form an aryl ring; or two R 16 together when on adjacent carbons form a spiroheterocyclyl ring;

p is 0, 1, or 2;

each q is 0, 1, or 2 and

r is 0, 1, 2, 3, 4, or 5.

In some embodiments of the Formulae above, X 1 is C, S, or S(O). In another embodiment, X 1 is C. In yet another embodiment, X 1 is S. In another embodiment, X 1 is S(O).

In some embodiments of the Formulae above, X 2 is N. In another embodiment, X 2 is CR 7 .

In some embodiments of the Formulae above, R 1 is H, D, —OH, —SH, —NH 2 , —NH(C 1 -C 4 ) alkyl, —N((C 1 -C 4 ) alkyl) 2 , or F. In another embodiment, R 1 is —OH, —SH, —NH 2 , —NH(C 1 -C 2 ) alkyl, —N((C 1 -C 2 ) alkyl) 2 , or F. In yet another embodiment, R 1 is —OH, —SH, —NH 2 , —NHCH 3 , —NHCH 2 CH 3 , —N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 or F. In another embodiment, R 1 is —OH, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , or F. In yet another embodiment, R 1 is —OH, —NH 2 , or F.

In some embodiments of the Formulae above embodiment, R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or OR 10 . In this embodiment, alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 .

In some embodiments of the Formulae above, R 3 is 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, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —CN, —OH, —C(O)R 17 , —C(O)OR 17 , —OC(O)OR 17 , —OC(O)NR 17 R 18 , —NR 17 R 18 , —NR 17 C(O)R 18 , —NR 17 C(O)OR 18 , —C(O)NR 17 R 18 , —NR 17 C(O)NR 17 R 18 , —S(O) q NR 17 R 18 , —S(O) q R 17 R 18 , —NR 17 S(O) q R 17 R 18 , or halogen. In another embodiment, R 3 is selected from (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, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, or —OH. In yet another embodiment, R 3 is selected from (C 1 -C 6 ) alkyl, (C 3 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, or —OH. In yet another embodiment, R 3 is selected from (C 1 -C 3 ) alkyl, (C 1 -C 3 ) alkoxy, (C 1 -C 3 ) haloalkyl, (C 1 -C 3 ) haloalkoxy, or —OH. In another embodiment, R 3 is selected from (C 1 -C 3 ) alkyl, (C 1 -C 3 ) alkoxy, or —OH. In another embodiment, R 3 is selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, or —OH.

In some embodiments of the Formulae above, two R 3 together when on adjacent carbons can form a (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 19 . In another embodiment, two R 3 together when on adjacent carbons can form a (C 3 -C 8 ) spirocycloalkyl optionally substituted with one or more R 19 . In another embodiment, two R 3 together when on adjacent carbons can form a spiroheterocyclyl optionally substituted with one or more R 19 . In yet another embodiment, two R 3 together when on adjacent carbons can form an aryl ring optionally substituted with one or more R 19 . In another embodiment, two R 3 together when on adjacent carbons can form a heteroaryl ring optionally substituted with one or more R 19 .

In some embodiments of the Formulae above, R 4 is (C 1 -C 6 ) alkyl, —(C 0 -C 3 ) alkylene-aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, CD 3 , or heterocyclyl, where the aryl, heteroaryl, heterocyclyl and cycloalkyl are optionally substituted with one or more R 12 .

In some embodiments of the Formulae above, R 5 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, or halogen. In another embodiment, R 5 is H, D, (C 1 -C 3 ) alkyl, (C 2 -C 3 ) alkenyl, (C 2 -C 3 ) alkynyl, (C 1 -C 3 ) alkoxy, (C 1 -C 3 ) haloalkyl, (C 1 -C 3 ) haloalkoxy, or halogen. In yet another embodiment, R 5 is H, (C 1 -C 3 ) alkyl, (C 1 -C 3 ) alkoxy, (C 1 -C 3 ) haloalkyl, or halogen. In another embodiment, R 5 is H or (C 1 -C 3 ) alkyl. In yet another embodiment, R 5 is H, methyl, ethyl, propyl, or isopropyl.

In some embodiments of the Formulae above, R 5′ 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, or halogen. In another embodiment, R 5′ is H, D, (C 1 -C 3 ) alkyl, (C 2 -C 3 ) alkenyl, (C 2 -C 3 ) alkynyl, (C 1 -C 3 ) alkoxy, (C 1 -C 3 ) haloalkyl, (C 1 -C 3 ) haloalkoxy, or halogen. In yet another embodiment, R 5′ is H, D, (C 1 -C 3 ) alkyl, (C 1 -C 3 ) alkoxy, (C 1 -C 3 ) haloalkyl, or halogen. In another embodiment, R 5′ is H, D, (C 1 -C 3 ) alkyl. In yet another embodiment, R 5′ is H, methyl, ethyl, propyl, or isopropyl.

In some embodiments of the Formulae above, R 5 and R 5′ together can form a (C 3 -C 65 ) cycloalkyl or heterocyclyl ring optionally substituted. The optional substituents can be halogen, —CN, (C 1 -C 6 ) alkyl, —OH, —CH 2 OH, —(C 0 -C 2 )-alkylene-O(C 1 -C 6 ) alkyl, or —(C 0 -C 2 )-alkylene-NR 17 R 18 .

In some embodiments of the Formulae above, R 6 is H, D, halogen, —CN, —NR 17 R 18 , (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, or —OH. In another embodiment, R 6 is H, D, halogen, —CN, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, or —OH. In yet another embodiment, R 6 is H, halogen, or (C 1 -C 3 ) alkyl. In another embodiment, R 6 is H, F, Cl, methyl, ethyl, propyl, or isopropyl.

In some embodiments of the Formulae above, R 7 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, halogen, optionally substituted aryl, optionally substituted heteroaryl, —CN, or —NR 10 R 11 . In another embodiment, R 7 is H, D, (C 3 -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, or halogen. In yet another embodiment, R 7 is H, D, (C 1 -C 3 ) alkyl, (C 2 -C 3 ) alkenyl, (C 2 -C 3 ) alkynyl, (C 1 -C 3 ) alkoxy, (C 1 -C 3 ) haloalkyl, (C 1 -C 3 ) haloalkoxy, or halogen. In another embodiment, R 7 is H, D, (C 1 -C 3 ) alkyl, (C 1 -C 3 ) alkoxy, (C 1 -C 3 ) haloalkyl, (C 1 -C 3 ) haloalkoxy, or halogen. In yet another embodiment, R 7 is H, D, (C 1 -C 3 ) alkyl, (C 1 -C 3 ) alkoxy, (C 1 -C 3 ) haloalkyl, or halogen. In another embodiment, R 7 is H, (C 1 -C 3 ) alkyl, or halogen. In yet another embodiment, R 7 is H, methyl, ethyl, propyl, isopropyl, F or Cl. In another embodiment, R 7 is H or methyl.

In some embodiments of the Formulae above, R 8 is D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, —(C 1 -C 3 )-alkylene-O(C 1 -C 6 ) alkyl, —(C 0 -C 4 )-alkylene-aryl, —(C 0 -C 4 )-alkylene-heteroaryl, (C 3 -C 10 ) cycloalkyl, heterocyclyl, —(C 0 -C 4 )-alkylene-O-aryl, —(C 0 -C 4 )-alkylene-O-heteroaryl, —O—(C 3 -C 8 )cycloalkyl, —S-heteroaryl, halogen, —CN, —C(O)R 10 , —CO(O)R 10 , —C(O)NR 10 R 11 , —S(O) q R 10 , —S(O) q NR 10 R 11 , —NR 10 S(O) q R 11 , —(C 0 -C 3 )-alkylene-NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 C(O)C(O)R 11 , —NR 30 C(O)NR 10 R 11 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 , or —OH. In this embodiment, alkyl, alkylene, aryl, heteroaryl, and heterocyclyl can be optionally substituted with one or more R 9 .

In some embodiments of the Formulae above, two R 8 together when on adjacent carbons can form an aryl ring optionally substituted with one or more R 9 . In yet another embodiment, two R 8 together when on adjacent carbons can form a heteroaryl ring optionally substituted with one or more R 9 . In another embodiment, two R 8 together when on adjacent carbons can form a heterocyclyl ring optionally substituted with one or more R 9 .

In some embodiments of the Formulae above, R 9 is D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 8 ) cycloalkyl, halogen, aryl, —OH, —CN, —C(O)R 10 , —C(O)NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 R 11 , —S(O) q R 10 , —S(O) q NR 10 R 11 , —NR 10 S(O) q R 11 , oxo, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 , —O-aryl, or —O-heteroaryl. The alkyl, aryl, and cycloalkyl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) allyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, halogen, aryl, —NR 14 C(O)R 15 , —NR 14 S(O) q R 15 , —OH or —CN.

In some embodiments of the Formulae above, two R 9 together when on adjacent carbons can form an aryl ring. In another embodiment, two R 9 together when on adjacent carbons can form a heteroaryl ring. In another embodiment, two R 9 together when on adjacent carbons can form a (C 3 -C 10 ) cycloalkyl ring.

In some embodiments of the Formulae above, R 10 (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —(C 0 -C 3 ) alkylene-aryl, —(C 0 -C 4 ) alkylene-(C 3 -C 8 ) cycloalkyl, —(C 0 -C 4 ) alkylene-heterocyclyl, —(C 0 -C 4 ) alkylene-heteroaryl, or —CN. The alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 4 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 3 -C 8 ) cycloalkyl, heterocyclyl, aryl, —S(O) q (C 1 -C 3 ) alkyl, —S(O) q NR 14 R 15 , —NR 14 R 15 , —NR 14 C(O)R 15 , halogen, —OH, or —CN.

In some embodiments of the Formulae above, R 11 is H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —(C 0 -C 3 ) alkylene-aryl, —(C 0 -C 4 ) alkylene-(C 3 -C 8 ) cycloalkyl, —(C 0 -C 4 ) alkylene-heterocyclyl, —(C 0 -C 4 ) alkylene-heteroaryl, or —CN. The alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 3 -C 8 ) cycloalkyl, heterocyclyl, aryl, —S(O) q (C 1 -C 3 ) alkyl, —S(O) q NR 14 R 15 , —NR 14 R 15 , —NR 14 C(O)R 15 , halogen, —OH, or —CN.

In some embodiments of the Formulae above, R 10 and R 11 together when on adjacent carbons can form a heterocyclyl ring optionally substituted with one or more substituents selected from oxo, —C(O)(C 1 -C 3 ) alkyl or —NR 14 NR 15 .

In some embodiments of the Formulae above, R 12 is selected from D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, aryl, heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocyclyl, —O—(C 3 -C 8 )cycloalkyl, —S(O) q R 10 , —(CH 2 ) p C(O)OR 10 , —C(O)NR 14 R 15 , —S(O) q NR 14 R 15 , —NR 14 R 15 , —NR 14 C(O)NR 14 R 15 , —NR 14 C(O)OR 10 , —NR 14 SO q R 10 , —NR 14 COR 10 , halogen, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 or —OH, wherein alkyl, aryl, heteroaryl, and cycloalkyl are optionally substituted with one or more R 13 .

In one embodiment, R 13 is selected from D, (C 1 -C 6 ) alkyl, (C 3 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, (C 3 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, heterocyclyl, heteroaryl, aryl, —OR 14 , —C(O)R 14 , —C(O)NR 14 R 15 , —NR 14 R 15 , —S(O) q R 14 , —NR 14 S(O) q R 15 , —S(O) q NR 14 R 15 , —NR 14 C(O)NR 14 R 15 , —NR 14 C(O)OR 15 , P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , SF 5 or —CN, wherein alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, —NR 14 C(O)R 15 , —OH, —CN, —C(O)R 14 , or —NR 14 R 15 .

In another embodiment, two R 13 together when on adjacent carbons form a heterocyclyl ring optionally substituted with one or more R 16 . To yet another embodiment, two R 13 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R 16 . In another embodiment, two R 13 together with the carbon to which they are attached can form a spiroheterocyclyl optionally substituted with one or more R 16 .

In one embodiment, R 14 is H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —(C 1 -C 4 ) alkylene-(C 3 -C 8 ) cycloalkyl, —(C 0 -C 4 ) alkylene-heterocyclyl, —(C 0 -C 4 ) alkylene-aryl, —(C 0 -C 4 ) alkylene-heteroaryl, or —CN, where the alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R 16 .

In some embodiments of the Formulae above, R 15 is H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —(C 1 -C 4 ) alkylene-(C 3 -C 8 ) cycloalkyl, —(C 0 -C 4 ) alkylene-heterocyclyl, —(C 0 -C 4 ) alkylene-aryl, —(C 0 -C 4 ) alkylene-heteroaryl, or —CN, where the alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R 16 .

In some embodiments of the Formulae above, R 14 and R 15 together can form a heterocyclyl ring optionally substituted with one or more R 16 .

In some embodiments of the Formulae above, R 16 is D, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, —C(O)(C 1 -C 3 ) alkyl, —NHC(O)(C 1 -C 4 ) alkyl, —CN, —CH 2 CN, —CR 10 R 11 NR 10 R 11 , oxo, —NR 10 R 11 , —S(O) q (C 1 -C 6 ) alkyl, —C(O)NR) 10 R 11 , —S(O) q NR 10 R 11 , —NR 10 C(O)R 10 R 11 , —NR 10 C(O)NR 10 R 11 , or —OH. In another embodiment, two R 16 together when on adjacent carbons can form an aryl ring. In yet another embodiment, two R 16 together when on adjacent carbons can form a spiroheterocyclyl ring.

In some embodiments of the Formulae above, R 17 is H or (C 1 -C 6 ) alkyl. In another embodiment, R 17 is independently H or (C 1 -C 4 ) alkyl. In yet another embodiment, R 17 is independently H, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, or tert-butyl.

In some embodiments of the Formulae above, R 18 is H or (C 1 -C 6 ) alkyl. In another embodiment, R 18 is independently H, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, or tert-butyl.

In some embodiments of the Formulae above, R 19 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, halogen, —CN, or —NR 17 R 18 .

In some embodiments of the Formulae above, m is 0, 1 or 2. In another embodiment, m is 0 or 1.

In some embodiments of the Formulae above, m is 0, 1, 2 or 3. In another embodiment, n is 0, 1, or 2. In another embodiment, n is 1.

In some embodiments of the Formulae above, p is 0. In another embodiment, p is 1. In yet another embodiment, p is 2.

In some embodiments of the Formulae above, q is 0, in another embodiment, q is 1. In yet another embodiment, q is 2.

In some embodiments of the Formulae above, X 1 is C. In another embodiment, X 1 is C and X 2 is N. In yet another embodiment, X 1 is C, X 2 is N and R 1 is OH. In another embodiment, X 1 is C, X 2 is N, R 1 is OH, and R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 . In another embodiment, X 1 is C, X 2 is N, R 1 is OH, R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 , and R 5 is H. In yet another embodiment, X 1 is C, X 2 is N, R 1 is OH, R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 , R 5 is H, and R 5′ is H. In another embodiment, X 1 is C, X 2 is N, R 1 is OH, R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 , R 5 is H, and R 5′ is H and R 6 is H. In yet another embodiment, X 1 is C, X 2 is N, R 1 is OH, R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 , R 5 is H, R 5′ is H, R 6 is H and R 4 is (C 1 -C 6 ) alkyl, aryl or heteroaryl optionally substituted with one or more R 12 . In another embodiment, X 1 is C, X 2 is N, R 1 is OH, R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 , R 5 is H, R 5′ is H, R 6 is H, R 4 is (C 1 -C 6 ) alkyl, aryl or heteroaryl optionally substituted with one or more R 12 , and R 12 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, halogen, —O-aryl, or —O-heteroaryl optionally substituted with one or more R 13 . In another embodiment, X 1 is C, X 2 is N, R 1 is OH, R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 , R 53 is H, R 5′ is H, R 6 is H and R 4 is (C 1 -C 6 ) alkyl, aryl or heteroaryl optionally substituted with one or more R 12 . In another embodiment, X 1 is C, X 2 is N, R 1 is OH, R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 , R 5 is H, R 5′ is H, R 6 is H, R 4 is (C 1 -C 6 ) alkyl, aryl or heteroaryl optionally substituted with one or more R 12 , R 12 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, halogen, —O-aryl, or —O-heteroaryl optionally substituted with one or more R 13 , and R 13 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, (C 1 -C 6 ) haloalkoxy, heterocyclyl, heteroaryl, aryl, —OR 14 , —C(O)R 14 , —C(O)NR 14 R 15 , —NR 14 R 15 , —S(O) q R 14 , —NR 14 S(O) q R 15 , —S(O) q NR 14 R 15 or —CN, wherein alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, —NR 14 C(O)R 15 , —OH, —CN, —C(O)R 14 , or NR 14 R 15 . In yet another embodiment, X 1 is C, X 2 is N, R 1 is OH, R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 , R 5 is H, R 5′ is H, R 6 is H, R 4 is (C 1 -C 6 ) alkyl, aryl or heteroaryl optionally substituted with one or more R 12 , R 12 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, halogen, —O-aryl, or —O-heteroaryl optionally substituted with one or more R 13 , and two R 13 together when on adjacent carbons form a heterocyclyl ring optionally substituted with one or more R 16 , two R 13 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R 16 , or two R 13 together with the carbon to which they are attached can form a spiroheterocyclyl optionally substituted with one or more R 16 .

In some embodiments of the Formulae above X 1 is C. In another embodiment, X 1 is C and X 2 is CH. In yet another embodiment, X 1 is C, X 2 is CH and R 1 is OH. In another embodiment, X 1 is C, X 2 is CH, R 1 is OH, and R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 . In another embodiment, X 1 is C, X 2 is CH, R 1 is OH, R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 , and R 5 is H. In yet another embodiment, X 1 is C, X 2 is CH, R 1 is OH, R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 , R 5 is H, and R 5′ is H. In another embodiment, X 1 is C, X 2 is CH, R 1 is OH, R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 , R 5 is H, R 5′ is H and R 6 is H. In yet another embodiment, X 1 is C, X 2 is CH, R 1 is OH, R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 , R 5 is H, R 5′ is H and R 6 is H and R 4 is (C 1 -C 6 ) alkyl, aryl or heteroaryl optionally substituted with one or more R 12 . In another embodiment, X 1 is C, X 2 is CH, R 1 is OH, R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 , R 5 is H, R 5′ is H, R 6 is H, R 4 is (C 1 -C 6 ) alkyl, aryl or heteroaryl optionally substituted with one or more R 12 , and R 12 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, halogen, —O-aryl, or —O-heteroaryl optionally substituted with one or more R 13 . In another embodiment, X 1 is C, X 2 is CH, R 1 is OH, R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 , R 5 is H, R 5′ is H, R 6 is H and R 4 is (C 1 -C 6 ) alkyl, aryl or heteroaryl optionally substituted with one or more R 12 . In another embodiment, X 1 is C, X 2 is CH, R 1 is OH, R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 , R 5 is H, R 5′ is H, R 6 , is H, R 4 is (C 1 -C 6 ) alkyl, aryl or heteroaryl optionally substituted with one or more R 12 , R 12 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, halogen, —O-aryl, or —O-heteroaryl optionally substituted with one or more R 13 , and R 13 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, (C 1 -C 6 ) haloalkoxy, heterocyclyl, heteroaryl, aryl, —OR 14 , —C(O)R 14 , —C(O)NR 14 R 15 , —NR 14 R 15 , —S(O) q R 14 , —NR 14 S(O) q R 15 , —S(O) q NR 14 R 15 , or —CN, wherein alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, —NR 14 C(O)R 15 , —OH, —CN, —C(O)R 14 , or —NR 14 R 15 . In yet another embodiment, X 1 is C, X 2 is N, R 1 is OH, R 2 is (C 1 -C 8 ) alkyl, aryl, heteroaryl, (C 3 -C 5 ) cycloalkyl, heterocyclyl, —NR 10 R 11 , or —OR 10 , wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R 8 , R 5 is H, R 5′ is H, R 6 is H, R 4 is (C 1 -C 6 ) alkyl, aryl or heteroaryl optionally substituted with one or more R 12 , R 12 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, halogen, —O-aryl, or —O-heteroaryl optionally substituted with one or more R 13 , and two R 13 together when on adjacent carbons form a heterocyclyl ring optionally substituted with one or more R 16 , two R 13 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R 16 , or two R 13 together with the carbon to which they are attached can form a spiroheterocyclyl optionally substituted with one or more R 16 .

Non-limiting illustrative compounds of the invention include:

5-{[4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1); 4-({4-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]phenyl}methoxy)benzonitrile (I-10); 1-(4-fluorophenyl)-5-((4-hydroxy-1-(4-(5-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)benzoyl)piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-1000); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4-{5-methyl-2H,4H,5H,6H-pyrrolo[3,4-c]pyrazol-2-yl}benzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1001); 2-(4-(4-(4-((1-(4-fluorophenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)-4-hydroxypiperidine-1-carbonyl)phenyl)-1H-pyrazol-1-yl)acetamide (I-1002); 5-((1-((2R,4S)-1-acryloyl-4-methylazetidine-2-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-1003); 5-{[1-(4-{2,5-diazabicyclo[2.2.1]heptan-2-yl}benzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one trifluoroacetic acid salt (I-1005); 1-(4-fluorophenyl)-5-[(4-hydroxy-1-{4-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]benzoyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1006); 5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(2-(1-methylpiperidin-2-yl)ethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-1007); 1-(3-(3-(dimethylamino)propyl)phenyl)-5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-1008); 3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-7-(3-(piperidin-1-ylmethyl)phenyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (I-1009); 3-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-7-[4-fluoro-3-(piperidin-1-ylmethyl)phenyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (I-1010); (S)-5-(1-(1-(4-Fluorobenzoyl)-4-hydroxypiperidin-4-yl)ethyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-1013); 6-{[(1r,4r)-4-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carbonyl)cyclohexyl]oxy}pyridine-3-carbonitrile (I-1014); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-[(6-methylpyrazin-2-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1015); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-[(2-methylpyrimidin-4-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1016); 5-({4-hydroxy-1-[(1r,4r)-4-[(2-fluoropyridin-3-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1017); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-{[6-azetidin-1-yl)pyridin-2-yl]oxy}cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1018); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-[(5-methoxypyridin-2-yl)oxy] cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1019); 5-({4-hydroxy-1-[(1 r,4r)-4-[(5-methoxypyridin-2-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1020); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-(pyrazin-2-yloxy)cyclohexanecarbonyl]piperidin-5-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1021); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-[(2-methylpyrimidin-5-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1022); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-[(6-fluoropyridin-2-yl)amino]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1023); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-[(6-fluoropyridin-2-yl)amino]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1024); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[1-methyl-3-(1-phenylethyl)-1H-pyrazole-4-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1025); 5-({1-[(3R)-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1028); 5-({1-[(3S)-3-(3-fluoro-1H-pyrazol-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1029); 5-({4-hydroxy-1-[2-(1,2,3,4-tetrahydronaphthalen-1-yl)acetyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-103); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,3s)-3-[(pyridin-3-yl)amino]cyclobutanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1030); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,3r)-3-[(pyridin-3-yl)amino]cyclobutanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1031); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,3s)-3-[(5-fluoropyridin-2-yl)amino]cyclobutanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1032) 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,3r)-3-[(5-fluoropyridin-2-yl)amino]cyclobutanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1033); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,3s)-3-[(pyridin-2-yl)amino]cyclobutanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1034); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,3r)-3-[(pyridin-2-yl)amino]cyclobutanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1035); 5-({1-[(3R)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1036); 5-({1-[(3S)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1037); 7-(4-fluorophenyl)-3-({4-hydroxy-1-[(1s,4s)-4-(pyridin-2-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (I-1038); Syn-5-((1-(4-((2-fluoropyridin-3-yl)amino)cyclohexane-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, isomer A (I-1039a); Anti-5-((1-(4-((2-fluoropyridin-3yl)amino)cyclohexane-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, isomer B (I-1039b); 5-({4-hydroxy-1-[4-(phenoxymethyl)benzoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-104); 7-(4-fluorophenyl)-3-({4-hydroxy-1-[(1s,4s)-4-[(1-methyl-1H-pyrazol-3-yl)amino]cyclohexanecarbonyl]piperidin-4-yl}methyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (I-1040); 7-(4-fluorophenyl)-3-({4-hydroxy-1-[(1r,4r)-4-[(1-methyl-1H-pyrazol-3-yl)amino]cyclohexanecarbonyl]piperidin-4-yl}methyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (I-1041); 1-[3-(3-fluoro-1H-pyrazol-1-yl)phenyl]-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1042); 4-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1043); 1-[4-(4-chloro-1H-pyrazol-1-yl)phenyl]-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1045); 1-(3-((3,3-difluorocyclobutyl)methoxy)phenyl)-5-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (I-1046); 1-{3-[(4,4-difluorocyclohexyl)oxy]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1047); 5-({4-hydroxy-1-[3-(1H-pyrrol-1-yl)butanoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-105); 5-({4-hydroxy-1-[(3S)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1-{4-[(3R)-3-hydroxy-3-methylpyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1052); 5-({1-[4-(difluoromethoxy)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1058); 5-[(4-hydroxy-1-{4-[(1-methylpyrrolidin-3-yl)oxy]benzoyl}piperidin-4-yl)methyl]-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1059); 4-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]-N-phenylbenzene-1-sulfonamide (I-106); 5-({1-[(3R)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1060); 5-({1-[(3S)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1061); 5-[(4-hydroxy-1-{4-[(1-methylpiperidin-4-yl)oxy]benzoyl}piperidin-4-yl)methyl]-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1062); 5-({4-hydroxy-1-[4-(pyrimidin-2-yloxy)benzoyl]piperidin-4-yl}methyl)-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1063); 5-({4-hydroxy-1-[(1s,3 s)-3-(pyridin-2-yloxy)cyclobutanecarbonyl]piperidin-4-yl}methyl-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1064); 1-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-cyclopropylurea (I-1065); 4-[(1-{5-[(cyclopropylmethyl)amino]pyridin-3-yl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-1066); 7-(4-fluorophenyl)-3-({4-hydroxy-1-[(1r,4r)-4-[(1-methyl-1H-pyrazol-3-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl)}methyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (I-1067); N-[(1r,4r)-4-[(4-[[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl]-4-hydroxypiperidin-1-yl)carbonyl]cyclohexyl]acetamide (I-1068); 5-((4-hydroxy-1-((1r,4r)-4-(pyridin-2-yloxy)cyclohexanecarbonyl) piperidin-4-yl)methyl)-1-(4-(hydroxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-1069); 4-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]-N-methyl-N-phenylbenzene-1-sulfonamide (I-107); 1-(4-bromophenyl)-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1070); 5-{[4-hydroxy-1-(6-methoxypyridine-3-carbonyl)piperidin)-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1071); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-(cyclopropylamino)cyclohexanecarbonyl] piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1072); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-[(cyclopropylmethyl)amino] cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1073); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-[(cyclopropylmethyl)amino] cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1074); N-[(1r,4r)-4-4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carbonyl)cyclohexyl]cyclopropanecarboxamide (I-1075); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)pyridine-3-carboxamide (I-1076); 7-(4-fluorophenyl)-3-{[4-hydroxy-1-(2-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (I-1077); 7-(4-fluorophenyl)-3-{[4-hydroxy-1-(1-methyl-1H-pyrazole-4-carbonyl)piperidin-4-yl]methyl}-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (I-1078); 3-{[1-(1-cyclopropyl-1H-pyrazole-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-7-(4-fluorophenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (I-1079); 4-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]-N-methyl-N-phenylbenzamide (I-108); 1-[3-(4-acetylpiperazin-1-yl)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1080); 4-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1¿6,4-thiomorpholine-1,1-dione (I-1081); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(1,2,3,4-tetrahydroquinolin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1082); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(1,2,3,4-tetrahydroquinolin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1083); 2-[1-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)piperidin-3-yl]acetonitrile (I-1084); 1-(4-chlorophenyl)-5-({4-hydroxy-1-[2-(4-methylpiperazin-1-yl)-1,3-oxazole-5-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1085); 1-(4-chlorophenyl)-5-({4-hydroxy-1-[2-(pyridin-2-yloxy)-1,3-oxazole-5-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1086); 1-(4-chlorophenyl)-5-({4-hydroxy-1-[4-(1H-1,2,3,4-tetrazol-1-yl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1087); 1-(4-chlorophenyl)-5-({4-hydroxy-1-[4-(1H-imidazol-1-yl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1088); 1-(4-chlorophenyl)-5-({4-hydroxy-1-[4-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1089); 4-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]-N-phenylbenzamide (I-109); 1-(4-chlorophenyl)-5-({4-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1090); 1-(4-chlorophenyl)-5-{[1-(5-cyclopropyl-1,3,4-oxadiazole-2-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1091); 1-(4-chlorophenyl)-5-{[1-(1-cyclopropyl-1H-imidazole-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1092); 1-(4-chlorophenyl)-5-{[1-(1-cyclopropyl-1H-pyrazole-3-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1093); 1-(4-chlorophenyl)-5-{[1-(1-cyclopropyl-1H-pyrazole-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1095); 1-(4-chlorophenyl)-5-[(4-hydroxy-1-{4-[(1-methylpiperidin-4-yl)oxy]benzoyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1096); 1-(4-chlorophenyl)-5-[[1-([3-[2-(dimethylamino)ethoxy]phenyl]carbonyl)-4-hydroxypiperidin-4-yl]methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1097); 1-(4-chlorophenyl)-5-[(1-{3-[3-(dimethylamino)propoxy]benzoyl}-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1098); 1-(4-chlorophenyl)-5-[(1-[[4-(1,5-dimethyl-1H-imidazol-2-yl)phenyl]carbonyl]-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1099); 2-(3-{5-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)acetic acid (I-11); N-{4-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]phenyl}benzamide (I-110); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-5-methylpyrazine-2-carboxamide (I-1100); 1-(4-chlorophenyl)-5-({1-[4-(1,2-dimethyl-1H-imidazol-5-yl)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1101); 5-{[1-(4,4-difluoro-3-phenylbutanoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1102); 5-({1-[(3S)-4,4-difluoro-3-phenylbutanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1103); 5-({1-[(3R)-4,4-difluoro-3-phenylbutanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1104); 5-{[1-(4-benzyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1108); N-{4-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]phenyl}benzenesulfonamide (I-111); 5-{[1-(3-benzyl-5-methyl-1,2-thiazole-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1110); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-(difluoromethoxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1112); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-(pyrazin-2-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1113); 1-(4-fluorophenyl)-4-({4-hydroxy-1-[(1r,4r)-4-[(1-methyl-1H-pyrazol-5-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1114); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-methoxycyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1115); Syn-5-((4-Hydroxy-1-methylcyclopropanecarbonyl)piperidin-4-yl)methyl)-1-(4-((4-methoxycyclohexyl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one, isomer A (I-1116a); Anti-5-((4-Hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl)methyl)-1-(4-((4-methoxycyclohexyl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one, isomer b (I-1116b); 1-{4-[(4,4-difluorocyclohexyl)oxy]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl) piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1117); 5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{4-[(3-methyloxetan-3-yl)methoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1118); 1-{4-[(1-fluorocyclobutyl)methoxy]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl) piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1119); 5-({4-hydroxy-1-[3-(1,3-thiazol-2-yl)butanoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-112); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-4-methylbenzamide (I-1120); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-methoxybenzamide (I-1121); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-fluorobenzamide (I-1122); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-fluorobenzamide (I-1123); 7-(4-fluorophenyl)-3-({4-hydroxy-1-[(1r,4r)-4-(pyridin-2-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (I-1124); 3-({1-[(3R)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-7-(4-fluorophenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (I-1125); 3-({1-[(3S)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-7-(4-fluorophenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (I-1126); 1-(4-chlorophenyl)-5-({4-hydroxy-1-[3-(pyrrolidin-1-ylmethyl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1127); 1-(4-chlorophenyl)-5-({4-hydroxy-1-[4-(1H-1,2,3-triazol-1-yl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1128); 1-(4-chlorophenyl)-5-({4-hydroxy-1-[4-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1129); 5-{[1-(2-chloro-4-phenoxybenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-113); 1-(4-chlorophenyl)-5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1130); 1-(4-chlorophenyl)-5-({1-[(3R)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1131); 1-(4-chlorophenyl)-5-({1-[(3S)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1132); 1-{4-[(3,3-difluorocyclobutyl)methoxy]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1133); 1-{4-[(4,4-difluorocyclohexyl)oxy]phenyl}-5-{[4-hydroxy-1-(2-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1134); 1-{4-[1-fluorocyclobutyl)methoxy]phenyl}-5-{[4-hydroxy-1-(2-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1135); 5-{[4-hydroxy-1-(1-methylcyclobutanecarbonyl)piperidin-4-yl]methyl}-1-{4-[(3-methyloxetan-3-yl)methoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1136); 1-{4-[(1-fluorocyclobutyl)methoxy]phenyl}-5-{[4-hydroxy-1-(1-methylcyclobutanecarbonyl) piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1137); 4-hydroxy-4-[(1-{4-[(3R)-3-methoxypyrrolidin-1-yl]phenyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-N,N-dimethylpiperidine-1-carboxamide (I-1138); 5-({4-hydroxy-1-[(3S)-3-phenylbutanoyl]piperidin-4-yl}methyl)-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1139); 5-{[1-(2-amino-4-chlorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1140); 5-((4-Hydroxy-1-(4-(4-hydroxycyclohexyloxy)benzoyl)piperidin-4-yl)methyl)-1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one (I-1141); 5-((4-hydroxy-1-(4-(1-methylazetidin-3-yloxy)benzoyl)piperidin-4-yl)methyl)-1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one (I-1142); 5-((4-Hydroxy-1-(4-(oxetan-3-yloxy)benzoyl)piperidin-4-yl)methyl)-1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one (I-1143); 5-({4-hydroxy-1-[4-(oxan-4-yloxy)benzoyl]piperidin-4-yl}methyl)-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1144); 5-((4-hydroxy-1-(4-(piperidin-4-yloxy)benzoyl)piperidin-4-yl)methyl)-1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one (I-1145); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[2-(piperidin-1-yl)ethyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1146); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[2-morpholin-4-yl)ethyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1147); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(2-ethylbutyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1148); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[2-(propan-2-yloxy)ethyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1149); 5-{[4-hydroxy-1-(2-phenyl-1,2,3,4-tetrahydroisoquinoline-6-carbonyl)piperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-115); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[cyclopropylmethyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-c]pyrimidin-4-one (I-1150); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[(1-methylpiperidin-3-yl)methyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1151); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-4-methoxybenzene-1-sulfonamide (I-1152); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(cyclopropylamino)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1153); 1-[3-(cyclohexylamino)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1154); 1-[3-(benzylamino)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H, 4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1155); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(2-phenylethyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1156); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(2,2-dimethylpropyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1157); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(pyridin-3-ylmethyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1158); 5-({1-[(3R)-4,4-difluoro-3-(4-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1159); 5-[(1-{3-[benzyl(methyl)amino]benzoyl}-4-hydroxypiperidin-4-yl)methyl]-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-116); 5-{[4-hydroxy-1-(4-{[5-(2-hydroxyethoxy)pyridin-2-yl]oxy}benzoyl)piperidin-4-yl]methyl}-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1160); 1-[4-(cyclohexylamino)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1186); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(2-phenylethyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1187); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(2,2-dimethylpropyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1188); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(pyridin-3-ylmethyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1189); 5-[(1-{4-[benzyl(methyl)amino]benzoyl}-4-hydroxypiperidin-4-yl)methyl]-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-119); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(1H-pyrazol-3-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1190); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(6-methoxypyridin-3-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1191); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(2-methoxypyridin-3-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1192); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(5-methyl-1,3,4-thiadiazol-2-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1193); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{[2-(morpholin-4-yl)ethyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1194); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(2-ethylbutyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1195); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{[2-(propan-2-yloxy)ethyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1196); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{[(1-methylpiperidin-3-yl)methyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1197); 5-{[1-(3-benzyl-1-methyl-1H-pyrazole-4-carbonyl)-4-hydroxypiperidin-4yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1161); 1-(4-fluorophenyl)-5-[(4-hydroxy-1-{1-methyl-3-[(1R)-1-phenylethyl]-1H-pyrazole-4-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1162); 1-(4-fluorophenyl)-5-[(4-hydroxy-1-{1-methyl-3-[(1S)-1-phenylethyl]-1H-pyrazole-4-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1163); 5-{[1-(3-benzyl-5-methyl-1,2-oxazole-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1164); 5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1165); 1-(4-chlorophenyl)-5-({1-[(3S)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1166); 1-(4-chlorophenyl)-5-({1-[(3R)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1167); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(3-hydroxy-3-methylpyrrolidin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1168); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{5H,6H,7H,8H-imidazol[1,2-a]pyrimidin-8-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1169); 5-({4-hydroxy-1-[3-(1,2,3,4-tetrahydroquinolin-1-yl)benzoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-117); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-{5H,6H,7H,8H-imidazo[1,2-a]pyrimidin-8-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1170); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(1,2,3,4-tetrahydroquinoxalin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1171); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(1,2,3,4-tetrahydroquinoxalin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1172); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{4H,5H,6H,7H-[1,2,4]triazol[1,5-a]pyrimidin-4-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1173); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-{4H,5H,6H,7H-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1174); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{2-methyl-5H,6H,7H,8H-[1,2,4]triazolo[1,5-a]pyrazin-7-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1175); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-{2-methyl-5H,6H,7H,8H-[1,2,4]triazolo[1,5-a]pyrazin-7-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1176); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{5H,6H,7H,8H-[1,2,4]triazolo[1,5-a]pyrazin-7-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1177); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-{5H,6H,7H,8H-[1,2,4]triazolo[1,5-a]pyrazin-7-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1178); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(4-methyl-1,2,3,4-tetrahydroquinoxalin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1179); 5-{[1-(1-acetylpiperidine-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1180); 5-[(1-{bicyclo[1.1.1]pentane-1-carbonyl}-4-hydroxypiperidin-4-yl)methyl]-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1181); 1-[4-(cyclopentylamino)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1182); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(morpholin-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1183); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(5-methoxypyridine-2-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1184); 5-[(1-{3-aminobicyclo[1.1.1]pentane-1-carbonyl}-4-hydroxypiperidin-4-yl)methyl]-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1185); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(oxan-4-ylmethyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1198); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(pyrrolidin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1199); 5-({4-hydroxy-1-[4-(1,2,3,4-tetrahydroisoquinolin-2-yl)benzoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-12); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(pyrrolidin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1200); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(piperidin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1201); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(piperidin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1202); 1-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)piperidine-4-carbonitrile (I-1203); 1-{4-[benzyl(methyl)amino]phenyl}-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1204); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(4-phenylpiperidin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1205); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(2-methoxyethyl)(methyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1206); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(2-methoxyethyl)(methyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1207); N-[1-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1yl}phenyl)piperidin-4-yl]acetamide (I-1208); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[4-(dimethylamino)piperidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1209); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4yl)methyl]-1-[3-(1,2,3,4-tetrahydroisoquinolin-2-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1210); 1-[4-(4-acetylpiperazin-1-yl)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1211); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-(pyridazin-3-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1212); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(2,4-dichlorophenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1213); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-pyridin-2-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1214); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(1H-indazol-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1215); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{8-oxa-2-azaspiro[4.5]decan-2-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1216); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{8-oxa-2-azaspiro[4.5]decan-2-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1217); 5-{[1-(1-cyclopropylpiperidine-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1218); 1-(4-fluorophenyl)-5-[(4-hydroxy-1-{3-phenylbicyclo[1.1.1]pentane-1-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1219); 5-[(1-{4-[(4aR,8aS)-decahydroisoquinolin-2-yl]benzoyl}-4-hydroxypiperidin-4-yl)methyl]-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-122); 1-(4-fluorophenyl)-5-[(4-hydroxy-1-{pyrazolo[1,5-a]pyridine-3-carbonyl}piperidine-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1221); 5-({1-[5-(difluoromethoxy)pyridine-2-carbonyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1223); 4-[1-{6-aminospiro[3.3]heptane-2-carbonyl}-4-hydroxypiperidin-4-yl)methyl]-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1224); 1-(4-fluorophenyl)-5-[(4-hydroxy-1-{2H,3H-pyrazolo[3,2-b][1,3]oxazole-6-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1225); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(3S)-piperidine-3-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1226); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(3S)-pyrrolidine-3-carbonyl]piperidin-4-yl}-methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1227); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(3R)-piperidine-3-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1228); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(3R)-pyrrolidine-3-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1229); 5-({4-hydroxy-1-[4-(1,2,3,4-tetrahydroquinolin-1-yl)benzoyl]piperidin-4-yl}methyl)-1)-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-123); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(phenylamino)phenyl]-1H,4H,5H-pyrazolo[3,4-di]pyrimidin-4-one (I-1230); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(phenylamino)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1231); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(pyridin-4-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1232); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(pyridin-2-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1233); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[4-(morpholin-4-yl)phenyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1234); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[1-(pyridin-3-ylmethyl)-1H-pyrazolo-3-yl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1235); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[1-(pyridin-2-ylmethyl)-1H-pyrazol-3-yl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1236); 1-{4-[(2,1,3-benzoxadiazol-4-yl)amino]phenyl}-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1237); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(5-cyclopropyl-1,3,4-thiadiazol-2-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1238); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(3-phenyl-1,2,4-thiadiazol-5-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1239); 5-{[4-hydroxy-1-(4-{methyl[(2-methylphenyl)methyl]amino}benzoyl)piperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-124); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(1,3-thiazol-2-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1240); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(5-methyl-1,2-oxazol-3-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1241); 1-{4-[(4-tert-butyl-1,3-thiazol-2-yl)amino]phenyl}-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1242); 1-{4-[(1,3-benzothiazol-6-yl)amino]phenyl}-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1243); 1-{4-[(5-tert-butyl-1H-pyrazol-3-yl)amino]phenyl}-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1244); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[1-4-fluorophenyl)-1H-pyrazol-3-yl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1245); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(pyridin-2-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1246); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{[4-(morpholin-4-yl)phenyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1247); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(1H-pyrazol-3-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1248); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(6-methoxypyridin-3-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1249); 5-({4-hydroxy-1-[4-(thiomorpholin-4-yl)benzoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-125); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(2-methoxypyridin-3-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1250); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(5-methyl-1,3,4-thiadiazol-2-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1251); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{[3-(morpholin-4-yl)phenyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1252); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{[2-(morpholin-4-yl)phenyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1253); 6-[(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)amino]pyridine-3-carbonitrile (I-1254); 4-({1-[4-(cyanomethoxy)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-1255); 4-hydroxy-4-({1-[4-(2-methoxyethoxy)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-N,N-dimethylpiperidine-1-carboxamide (I-1256); 1-{3-[(1,3-benzothiazol-6-yl)amino]phenyl}-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1257); 1-{3-[(5-tert-butyl-1H-pyrazol-3-yl)amino]phenyl}-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1258); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{[1-(4-fluorophenyl)-1H-pyrazol-3-yl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1259); 5-({4-hydroxy-1-[4-(1-phenoxyethyl)benzoyl]piperidin-4yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-126); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1260); 4-({1-[5-(cyclopentylamino)pyridin-3-yl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-1261); 4-hydroxy-N,N-dimethyl-4-[(4-oxo-1-{5-[(2-phenylethyl)amino]pyridin-3-yl}-1H,4H,4H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]piperidine-1-carboxamide (I-1262); 4-hydroxy-N,N dimethyl-4-{[1-(5-{[2-(morpholin-45-yl)ethyl]amino}pyridin-3-yl)-4-oxo-1H,4H,4H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}piperidine-1-carboxamide (I-1263); 4-hydroxy-N,N-dimethyl-4-({1-[5-(morpholin-4-yl)pyridin-3-yl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carboxamide (I-1264); 4-({1-[5-(4-cyanopiperidin-1-yl)pyridin-3-yl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-1265); 4-hydroxy-N,N-dimethyl-4-[(1-{5-[4-(morpholin-4-yl)piperidin-1-yl]pyridin-3-yl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]piperidine-1-carboxamide (I-1266); 4-({1-[5-(1,1-dioxo-1¿6,4-thiomorpholin-4-yl)pyridin-3-yl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-1267); 4-hydroxy-N,N-dimethyl-4-{[1-(5-{8-oxa-2-azaspiro[4.5]decan-2-yl}pyridin-3-yl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}piperidine-1-carboxamide (I-1268); 4-hydroxy-N,N-dimethyl-4-({4-oxo-1-[5-(piperazin-1-yl)pyridin-3-yl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carboxamide (I-1269); 5-[(1-{4-[1-(4-fluorophenoxy)ethyl]benzoyl}-4-hydroxypiperidin-4-yl)methyl]-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-127); 4-({1-[5-(3-fluorophenyl)pyridin-3-yl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-1270); 4-({1-[5-(4-fluorophenyl)pyridin-3-yl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-1271); 4-[(1-{5-[4-(dimethylcarbamoyl)phenyl]pyridin-3-yl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-1272); 4-hydroxy-N,N-dimethyl-4-[(4-oxo-1-{5-[4-(pyrrolidine-1-carbonyl)phenyl]pyrimidin-3-yl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]piperidine-1-carboxamide (I-1273); 4-({1-[5-(3,4-dimethoxyphenyl)pyrimidin-3-yl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-1274); 4-hydroxy-N,N-dimethyl-4-({4-oxo-1-[5-(pyridin-3-yl)pyridin-3-yl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}(methyl)piperidine-1-carboxamide (I-1275); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[3-(morpholin-4-yl)phenyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1276); 6-[(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)amino]pyridine-3-carbonitrile (I-1277); 5-[(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)amino]pyridine-2-carbonitrile (I-1278); 6-({4-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]phenyl}methoxy)pyridine-2-carbonitrile (I-128); 4-[(1-{5-[3-(dimethylcarbamoyl)phenyl]pyridin-3-yl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-1280); 4-hydroxy-N,N-dimethyl-4-[(1-{5-[3-(methylcarbamoyl)phenyl]pyridin-3-yl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]piperidine-1-carboxamide (I-1281); 4-hydroxy-4-{[1-(5-{3-[(2-hydroxyethyl)carbamoyl]phenyl}pyridin-3-yl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5yl]methyl}-N,N-dimethylpiperidine-1-carboxamide (I-1282); 4-hydroxy-N,N-dimethyl-4-({1-[5-(1-methyl-1H-indazol-5-yl)pyridin-3-yl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carboxamide (I-1283); 1-[4-(benzyloxy)phenyl]-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1284); 1-[3-(benzyloxy)phenyl]-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazole[3,4-d]pyrimidin-4-one (I-1285); 4-({1-[4-(cyclopentyloxy)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-1286); 1-[4-(cyclopentyloxy)phenyl]-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1287); 1-[3-(cyclopentyloxy)phenyl]-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1288); 4-({1-[4-(cyclopropylmethoxy)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-1289); 6-({4-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]phenyl}methoxy)pyrazine-2-carbonitrile (I-129); 1-[4-(cyclopropylmethoxy)phenyl]-5-{[1-(fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1290); 1-[3-(cyclopropylmethoxy)phenyl]-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1291); 4-({1-[4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl]-4-oxo-1H,4H,5H-pyrazole[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-1292); 4-hydroxy-4-[(1-{4-[2-(1H-imidazol-1-yl)ethoxy]phenyl}-4-oxo-1H,4H,5H-pyrazole[3,4-d]pyrimidin-5-yl)methyl]-N,N-dimethylpiperidine-1-carboxamide (I-1293); 4-({1-[4-(carbamoylmethoxy)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-1294); 4-({1-[4-(cyclobutylmethoxy)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-1295); 4-hydroxy-N,N-dimethyl-4-({1-[4-(3-methylbutoxy)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carboxamide (I-1296); 4-hydroxy-N,N-dimethyl-4-({4-oxo-1-[4-(2,2,2-trifluoroethoxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carboxamide (I-1297); 4-hydroxy-N,N-dimethyl-4-[(1-{4-[(1-methylpiperidin-2-yl)methoxy]phenyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]piperidine-1-carboxamide (I-1298); 4-[(1-{4-[(4-cyanophenyl)methoxy]phenyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-1299); 5-({4-hydroxy-1-[4-(phenylamino)benzoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-13); 4-[(1-{4-[(3-cyanophenyl)methoxy]phenyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-1300); 4-hydroxyl-N,N-dimethyl-4-({4-oxo-1-[4-(pyridin-3-ylmethoxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carboxamide (I-1301); 4-hydroxy-N,N-dimethyl-4-({4-oxo-1-[4-(pyridin-2-ylmethoxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carboxamide (I-1302); 4-hydroxy-N,N-dimethyl-4-({1-[4-(oxan-4-ylmethoxy)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carboxamide (I-1303); 4-hydroxy-N,N-dimethyl-4-[1-{4-[2-(morpholin-4-yl)-2-oxoethoxy]phenyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]piperidine-1-carboxamide (I-1304); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[2-(1H-imidazol-1-yl)ethoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1305); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{3-[2-(1H-imidazol-1-yl)ethoxy]phenyl}-1H,4H,4H-pyrazolo[3,4-d]pyrimidin-4-one (I-1306); 2-[4-(5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl)phenoxy]acetamide (I-1307); 2-[3-(5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl)phenoxy]acetamide (I-1308); 1-[4-(cyclobutylmethoxy)phenyl]-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1309); 5-[(1-{4-[4-(dimethylamino)piperidin-1-yl]benzoyl}-4-hydroxypiperidin-4-yl)methyl]-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-131); 1-[3-(cyclobutylmethoxy)phenyl]-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1310); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[3-(3-methylbutoxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1311); 1-[3-(2,2-dimethylpropoxy)phenyl]-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1312); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[(1-methylpiperidin-2-yl)methoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1313); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{3-[(1-methylpiperidin-2-yl)methoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1314); 4-[4-(5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl)phenoxymethyl]benzonitrile (I-1315); 4-[3-(5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl)phenoxymethyl]benzonitrile (I-1316); 1-{3-[(4-chlorophenyl)methoxy]phenyl}-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1317); 3-[4-(5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl)phenoxymethyl]benzonitrile (I-1318); 3-[3-(5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl)phenoxymethyl]benzonitrile (I-1319); 2-[4-(5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl)phenoxy]acetonitrile (I-1320); 2-[3-(5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4yl]methyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl)phenoxy]acetonitrile (I-1321); 4-hydroxy-N,N-dimethyl-4-[(1-{5-[4-(methylcarbamoyl)phenyl]pyridin-3-yl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]piperidine-1-carboxamide (I-1322); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(oxan-4-ylmethoxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1324); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[3-(oxan-4-ylmethoxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1325); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[2-(morpholin-4-yl)-2-oxoethoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1326); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{3-[2-(morpholin-4-yl)-2-oxoethoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1327); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{3-[(2-phenyl-1,3-thiazol-4-yl)methoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1328); 4-({1-[6-(3-cyanophenyl)pyridin-3-yl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-1329); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)benzamide (I-1330); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-phenylacetamide (I-1331); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-4]pyrimidin-1-yl}phenyl)-2-(3-methyl-1,2-oxazol-5-yl)acetamide (I-1332); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazol[3,4-d]pyrimidin-1-yl}phenyl)-4-methoxybenzamide (I-1333); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-4-fluorobenzamide (I-1334); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-methoxybenzamide (I-1335); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)pyridine-4-carboxamide (I-1336); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-methyl-1,3-thiazole-4-carboxamide (I-1337); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-(oxan-4-yl)acetamide (I-1338); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-methoxyacetamide (I-1339); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)cyclopropanecarboxamide (I-1340); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (I-1341); N-(4-{5-([1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-4-methyl-1,3-thiazole-5-carboxamide (I-1342); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-(dimethylamino)acetamide (I-1343); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-6-methylpyridine-3-carboxamide (I-1344); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-5-fluoropyridine-2-carboxamide (I-1345); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)pyridine-2-carboxamide (I-1346); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide (I-1347); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-(methylamino)benzamide (I-1348); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-4-(methylamino)benzamide (I-1349); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-methoxypyridine-3-carboxamide (I-1350); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazole[3,4-d]pyrimidin-1-yl}phenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (I-1351); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-4-methyl-1,3-thiazole-5-carboxamide (I-1352); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-(dimethylamino)acetamide (I-1353); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-6-methylpyridine-3-carboxamide (I-1354); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-5-fluoropyridine-2-carboxamide (I-1355); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-(1,1-dioxo-1¿6,4-thiomorpholin-4-yl)acetamide (I-1356); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-(morpholin-4-yl)acetamide (I-1357); (2S)—N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1-methylpyrrolidine-2-carboxamide (I-1358); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1-methylpiperidine-2-carboxamide (I-1359); 5-({4-hydroxy-1-[(3R)-3-methoxy-3-phenylpropanoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-136); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)oxane-4-carboxamide (I-1360); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-(1H-pyrazol-1-yl)acetamide (I-1361); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3,3-difluorocyclobutane-1-carboxamide (I-1362); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(2-methoxyethoxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1363); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[3-(2-methoxyethoxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1364); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[3-(pyridin-3-ylmethoxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1365); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[3-(pyrimidin-4-ylmethoxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1366); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(pyrimidin-2-ylmethoxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1367); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[3-(pyridin-2-ylmethoxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1368); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-(3-methyl-1,2-oxazol-5-yl)acetamide (I-1369); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-4-methoxybenzamide (I-1370); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-4-fluorobenzamide (I-1371); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-methoxybenzamide (I-1372); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)pyridine-4-carboxamide (I-1373); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-methyl-1,3-thiazole-4-carboxamide (I-1374); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-(oxan-4-yl)acetamide (I-1375); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-methoxyacetamide (I-1376); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)cyclopropanecarboxamide (I-1377); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-4-methylbenzamide (I-1378); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-methoxybenzamide (I-1379); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-fluorobenzamide (I-1380); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)pyridine-3-carboxamide (I-1381); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-5-methylpyrazine-2-carboxamide (I-1382); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)pyridine-2-carboxamide (I-1383); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-(methylamino)benzamide (I-1384); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-4-(methylamino)benzamide (I-1385); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-methoxypyridine-3-carboxamide (I-1386); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{[1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1387); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{[1-(pyridin-2-ylmethyl)-1H-pyrazol-3-yl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1388); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(1,3-thiazol-2-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1389); 5-{[1-(1-benzyl-1,2,3,4-tetrahydroquinoline-6-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-139); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(5-methyl-1,2-oxazol-3-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1390); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-(1,1-dioxo-1¿6,4-thiomorpholin-4-yl)acetamide (I-1391); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-(morpholin-4-yl)acetamide (I-1392); (2S)—N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1-methylpyrrolidine-2-carboxamide (I-1393); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1-methylpiperidine-2-carboxamide (I-1394); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)oxane-4-carboxamide (I-1395); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-(1H-pyrazol-1-yl)acetamide (I-1396); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3,3-difluorocyclobutane-1-carboxamide (I-1397); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-[methyl(phenyl)amino]acetamide (I-1398); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-methyl-2-(morpholin-4-yl)propanamide (I-1399); 5-{[(3S,4R)-1-benzoyl-4-hydroxy-3-methoxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-14); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-5-methyl-1,2-oxazole-4-sulfonamide (I-1400); 4-chloro-N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)benzene-1-sulfonamide (I-1401); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(oxan-4-ylmethyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1402); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-methylbenzene-1-sulfonamide (I-1403); 2-chloro-N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)benzene-1-sulfonamide (I-1404); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-methoxybenzene-1-sulfonamide (I-1405); 3-chloro-N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)benzene-1-sulfonamide (I-1406); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-fluorobenzene-1-sulfonamide (I-1407); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-methylbenzene-1-sulfonamide (I-1408); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-yl}phenyl)-2-[methyl(phenyl)amino]acetamide (I-1409); 5-({4-hydroxy-1-[(3R)-4,4,4-trifluoro-3-phenylbutanoyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-141); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-methyl-2-(morpholin-4-yl)propanamide (I-1410); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)acetamide (I-1411); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)benzamide (I-1412); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-phenylacetamide (I-1413); 3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(oxetan-3-yl)benzamide (I-1414); 3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-phenylbenzamide (I-1415); 3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(pyridin-3-yl)benzamide (I-1416); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)methanesulfonamide (I-1417); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)cyclopropanesulfonamide (I-1418); N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)oxane-4-sulfonamide (I-1419); 5-({4-hydroxy-1-[(3S)-4,4,4-trifluoro-3-phenylbutanoyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-142); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)benzenesulfonamide (I-1420); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3,5-dimethyl-1,2-oxazole-4-sulfonamide (I-1421); 4-chloro-N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)benzene-1-sulfonamide (I-1422); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-4-methoxybenzene-1-sulfonamide (I-1423); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-4-methylbenzene-1-sulfonamide (I-1424); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-yl}phenyl)-2-methylbenzene-1-sulfonamide (I-1425); 2-chloro-N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[34-d]pyrimidin-1-yl}phenyl)benzene-1-sulfonamide (I-1426); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-methoxybenzene-1-sulfonamide (I-1427); 3-chloro-N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)benzene-1-sulfonamide (I-1428); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-fluorobenzene-1-sulfonamide (I-1429); 5-({4-hydroxy-1-[(3R)-4,4,4-trifluoro-3-phenylbutanoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-143); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-methylbenzene-1-sulfonamide (I-1430); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)methanesulfonamide (I-1431); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)cyclopropanesulfonamide (I-1432); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1-(4-fluorophenyl)methanesulfonamide (I-1433); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[(3S)-3-hydroxypyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1434); 3-cyclopentyl-1-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)urea (I-1435); 5-{[1-(2-amino-4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1436); 5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1437); 3-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1-phenylurea (I-1438); 3-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1-phenylurea (I-1439); 5-({4-hydroxy-1-[(3R)-4,4,4-trifluoro-3-phenylbutanoyl]piperidin-4-yl}methyl)-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-144); 3-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1-(4-fluorophenyl)urea (I-1440); 1-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-(4-methylphenyl)urea (I-1442); 1-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-(3-methoxypropyl)urea (I-1443); 1-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-(3-methoxypropyl)urea (I-1444); 1-[4-(4-fluoropiperidin-1-yl)phenyl]-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1445); 1-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-cyclopropylurea (I-1446); 3-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1-(pyridin-3-yl)urea (I-1447); 3-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1-(pyridin-3-yl)urea (I-1448); 1-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-(thiophen-3-yl)urea (I-1449); 5-({4-hydroxy-1-[(3S)-4,4,4-trifluoro-3-phenylbutanoyl]piperidin-4-yl}methyl)-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-145); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(4-hydroxypiperidine-1-carbonyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1450); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(3-hydroxyazetidine-1-carbonyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1451); 3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-methylbenzamide (I-1452); N-benzyl-3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}benzamide (I-1453); N-cyclobutyl-3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}benzamide (I-1454); 3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-[(4-fluorophenyl)methyl]benzamide (I-1455); 3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-[2-(dimethylamino)ethyl]benzamide (I-1456); 3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-[(3-methyloxetan-3-yl)methyl]benzamide (I-1457); 4-({1-[4-fluoro-3-(3-fluoroazetidin-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-1458); 4-({1-[4-fluoro-3-(3-hydroxyazetidin-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-1459); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(1-methyl-1H-indazole-6-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1460); 4-({1-[4-(4,4-difluoropiperidin-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-1461); 4-hydroxy-N,N-dimethyl-4-{([4-oxo-1-(4-{[2-(propan-2-yloxy)ethyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}piperidine-1-carboxamide (I-1462); 3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(4-fluorophenyl)benzamide (I-1463); 3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(1,3-thiazol-2-yl)benzamide (I-1464); 3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(5-methyl-1,2-oxazol-3-yl)benzamide (I-1465); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(pyrrolidine-1-carbonyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1466); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(morpholine-4-carbonyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1467); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[4-(dimethylamino) piperidine-1-carbonyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1468); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(4-methylpiperazine-1-carbonyl)phenyl]-1H,4H,5H-pyrazol[3,4-d]pyrimidin-4-one (I-1469); 5-{[1-(4,4-difluoro-3-phenylbutanoyl)-4-hydroxypiperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-147); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(3-fluoroazetidine-1-carbonyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1470); 1-(4-fluorophenyl)-5-[(4-hydroxy-1-{imidazo[1,2-a]pyrazine-2-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1471); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(1H-indole-5-carbonyl)piperidin-4yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1472); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(1H-indole-2-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1473); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1474); 5-{[1-(2,3-dihydro-1-benzofuran-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1475); 5-{[1-(1H-1,2,3-benzotriazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1476); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(1H-indole-6-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1477) 5-{[1-(1,3-benzothiazole-6-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1478); N-tert-butyl-4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carboxamide (I-1479); 3-Cyclopentyl-1-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)urea (I-1480); 1-cyclohexyl-3-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)urea (I-1481); 1-cyclohexyl-3-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)urea (I-1482); 1-benzyl-3-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)urea (I-1483); 1-benzyl-3-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)urea (I-1484); 4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-methylbenzamide (I-1485); 4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-[(4-fluorophenyl)methyl]benzamide (I-1486); 4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-[2-(dimethylamino)ethyl]benzamide (I-1487); 4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-[(3-methyloxetan-3-yl)methyl]benzamide (I-1488); 4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(oxetan-3-yl)benzamide (11489); 4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-phenylbenzamide (I-1490); 4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(pyridin-3-yl)benzamide (I-1491); 4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(4-fluorophenyl)benzamide (I-1492); 4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(1,3-thiazol-2-yl)benzamide (I-1493); 4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(5-methyl-1,2-oxazol-3-yl)benzamide (I-1494); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(morpholine-4-carbonyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1495); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[4-(dimethylamino) piperidine-1-carbonyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1496); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(4-methylpiperazine-1-carbonyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1497); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(3,3-difluoropyrrolidine-1-carbonyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1498); N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)pyrrolidine-1-carboxamide (I-1499); 5-{[1-(1-benzyl-1H-pyrrole-2-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-150); 3-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1-(oxan-4-yl)urea, (I-1500); 1-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3,3-dimethylurea (I-1501); propan-2-yl N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)carbamate (I-1502); 4-[(1-{4-[(8aS)-octahydropyrrolo[1,2-a]piperazin-2-yl]phenyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-1503); 4-hydroxy-4-({1-[4-(4-hydroxy-4-methylpiperidin-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-N,N-dimethylpiperidine-1-carboxamide (I-1504); 5-{[1-(2,3-dihydro-1,4-benzodioxine-6-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1505); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(5-methoxy-1-methyl-1H-pyrazol-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1506); 5-{[1-(3,4-dihydro-2H-1-benzopyran-6-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1507); 5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[(1-methylcyclobutyl)methoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1508); 4-hydroxy-4-[(1-{4-[(3S)-3-methoxypyrrolidin-yl]phenyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-N,N-dimethylpiperidine-1-carboxamide (I-1509); 5-{[1-(4-fluoro-3-phenylbutanoyl)-4-hydroxypiperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-151); 5-({4-hydroxy-1-[4-(pyridin-2-yloxy)benzoyl]piperidin-4-yl}methyl)-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1510); 5-{[4-hydroxy-1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]methyl}-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1511); 5-{[1-(2,3-dihydro-1-benzofuran-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1512); 5-{[4-hydroxy-1-(1,2,3-thiadiazole-4-carbonyl)piperidin-4-yl]methyl}-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1513); 5-{[4-hydroxy-1-(2-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (i-1514); 5-[(4-hydroxy-1-{5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-2-carbonyl}piperidin-4-yl)methyl]-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1516); 5-[(4-hydroxy-1-{2H,3H-pyrazolo[3,2-b][1,3]oxazole-6-carbonyl}piperidin-4-yl)methyl]-1-(4-methylphenyl)-1H,4H,5H-pyrazol o[3,4-d]pyrimidin-4-one (I-1517); 5-{[4-hydroxy-1-(5-methyl-1,2,3-thiadiazole-4-carbonyl)piperidin-4-yl]methyl}-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1518); 1-(4-chlorophenyl)-5-({4-hydroxy-1-[4-(pyridin-2-yloxy)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1519); 1-cyclopropyl-5-{[4-hydroxy-1-(4-phenoxybenzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-152); 1-(4-chlorophenyl)-5-{[4-hydroxy-1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1520); 1-(4-chlorophenyl)-5-{[1-(2,3-dihydro-1-benzofuran-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1521); 1-(4-chlorophenyl)-5-{[4-hydroxy-1-(1,2,3-thiadiazole-4-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1522); 1-(4-chlorophenyl)-5-{[1-(3-fluoro-4-methylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1523); 1-(4-chlorophenyl)-5-{[4-hydroxy-1-(2-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1524); 4-[(1-{4-[(9aS)-octahydro-1H-pyrido[1,2-a]piperazin-2-yl]phenyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-1525); 4-hydroxy-N,N-dimethyl-4-[(4-oxo-1-{4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]piperidine-1-carboxamide (I-1526); 1-(4-chlorophenyl)-5-[(4-hydroxy-1-{2H,3H-pyrazolo[3,2-b][1,3]oxazole-6-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1527); 1-(4-chlorophenyl)-5-({4-hydroxy-1-[4-(pyrimidin-2-yloxy)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1528); 1-(4-chlorophenyl)-5-{[4-hydroxy-1-(5-methyl-1,2,3-thiadiazole-4-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1529); 5-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-153); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(1,2,3-thiadiazole-4-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1530); 5-{[1-(3-fluoro-4-methylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1531); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4,4,4-trifluoro-3-methylbutanoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1532); 5-{[1-(4,4-difluorobutanoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1533); 2-[4-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carbonyl)phenyl]-1¿6,2-thiazolidine-1,1-dione (I-1534); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[4-(1H-1,2,3-triazol-1-yl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1535); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[4-(4-hydroxypiperidin-1-yl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1536); 5-({1-[2-(difluoromethoxy)acetyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1537); 4-hydroxy-N,N-dimethyl-4-({4-oxo-1-[4-(1H-pyrazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carboxamide (I-1538); 4-hydroxy-N,N-dimethyl-4-({1-[4-(4-methyl-1H-pyrazol-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carboxamide (I-1539); 5-[(1-acetyl-4-hydroxypiperidin-4-yl)methyl]-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-154); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(4-methyl-1H-pyrazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1540); 4-[(1-{4-[(9aR)-octahydro-1H-pyrido[1,2-a]piperazin-2-yl]phenyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-1541); 5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1542); 4-hydroxy-N,N-dimethyl-4-{[4-oxo-1-(4-{[2-(piperidin-1-yl)ethyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}piperidine-1-carboxamide (I-1543); 4-[(1-{4-[(3,3-dimethylcyclobutyl)amino]phenyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-1544); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4,4,4-trifluoro-3-hydroxy-3-methylbutanoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1545); 4-[(1-{4-[(8aR)-octahydropyrrolo[1,2-a]piperazin-2-yl]phenyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-1546 5-{[4-hydroxy-1-(pyridine-4-carbonyl)piperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazol[3,4-d]pyrimidin-4 one (I-1547); 4-hydroxy-N,N-dimethyl-4-[(4-oxo-1-{4-[4-(1H-pyrazol-1-yl)piperidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]piperidine-1-carboxamide (I-1548 5-[(1-acetyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazol[3,4-d]pyrimidin-4-one (I-1549); 5-{[4-hydroxy-1-(1-methyl-1H-imidazole-4-carbonyl)piperidine-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-155); 5-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1550); 5-{[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1551); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1552) 5-{[4-hydroxy-1-(pyridine-4-carbonyl)piperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1553); 5-({4-hydroxy-1-[2-(oxan-4-yl)acetyl]piperidin-4-yl}methyl)-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1554); 5-({4-hydroxy-1-[4-(pyridin-2-yloxy)benzoyl]piperidin-4-yl}methyl)-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1555); 5-{[1-(3-ethoxypropanoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1556); 5-[(1-cyclobutanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1557); 5-{[1-(2,3-dihydro-1-benzofuran-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1558); 5-{[4-hydroxy-1-(pyridine-3-carbonyl)piperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1559); 5-{[1-(4-cyclopropylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-156); 5-{[1-(1,5-dimethyl-1H-pyrazole-3-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1560); 1-[3-(4-fluoropiperidin-1-yl)phenyl]-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1561); 5-{[1-(2-aminobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1562); 5-{[4-hydroxy-1-(5-methyl-1,2-oxazole-3-carbonyl)piperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1563); 5-{[4-hydroxy-1-(1H-indole-6-carbonyl)piperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1564); 5-{[4-hydroxy-1-(1-methylpiperidine-4-carbonyl)piperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1565); 5-{[4-hydroxy-1-(oxane-4-carbonyl)piperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1566); 5-{[1-(4,4-difluorocyclohexanecarbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1567); 5-{([1-(3,3-difluorocyclobutanecarbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1568); 1-(4-chlorophenyl)-5-[(4-hydroxy-1-{5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-2-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1569); 5-{[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-157); 5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{4-[3-(oxan-4-yl)azetidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1570); 5-[(4-hydroxy-1-{5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-2-carbonyl}piperidin-4-yl)methyl]-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1572); 5-[(4-hydroxy-1-{imidazo[1,5-a]pyridine-6-carbonyl}piperidin-4-yl)methyl]-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1573); 5-[(4-hydroxy-1-{2H,3H-pyrazolo[3,2-b][1,3]oxazole-6-carbonyl}piperidin-4-yl)methyl]-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1574); 5-({4-hydroxy-1-[4-(pyrimidin-2-yloxy)benzoyl]piperidin-4-yl}methyl)-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1575); 1-[4-(5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl]-3,3-dimethylurea (I-1576 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[);4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1577); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1578); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1579); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-158); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[4-(trifluoromethyl) pyrimidin-2-yl]oxy}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1580); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[4-(1H-pyrazol-1-yl)piperidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1581); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1582); 4-hydroxy-N,N-dimethyl-4-[(4-oxo-1-{4-[4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]piperidin-1-carboxamide (I-1583); 1-{4-[(9aR)-octahydro-1H-pyrido[1,2-a]piperazin-2-yl]phenyl}-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1584); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[4-(1H-1,2,3-triazol-1-yl)piperidine-1-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1585); 1-[3-(4-chloro-1H-pyrazol-1-yl)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1587); 1-[4-(4-chloro-1H-pyrazol-1-yl)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1588); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(oxetan-3-yloxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1589); 5-{[4-hydroxy-1-(3-hydroxybenzoyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-159); 5[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(oxan-4-ylmethoxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1590); 5-[(1-acetyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1591); 1-(4-chlorophenyl)-5-{[4-hydroxy-1-(1H-indole-6-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1593); 1-(4-chlorophenyl)-5-({4-hydroxy-1-[3-(1H-1,2,3,4-tetrazol-1-yl)propanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1594); 1-(4-chlorophenyl)-5-{[4-hydroxy-1-(oxane-4-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1595); 1-(4-chlorophenyl)-5-[(4-hydroxy-1-{pyrazolo[1,5-a]pyridine-2-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1596); 1-(4-chlorophenyl)-5-{[1-(4,4-difluorocyclohexanecarbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1597); 1-(4-chlorophenyl)-5-{[4-hydroxy-1-(3-methyloxetane-3-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1598); 1-(4-chlorophenyl)-5-{[1-(3,3-difluorocyclobutanecarbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1599); 5-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]-1,2-dihydropyridin-2-one (I-160); 1-(4-chlorophenyl)-5-{[4-hydroxy-1-(3-hydroxy-3-methylbutanoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1600); 1-(4-chlorophenyl)-5-{[4-hydroxy-1-(4-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1601); 5-{[1-(3-ethoxypropanoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1602); 5-[(1-cyclobutanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1603); 5-{[1-(2,3-dihydro-1-benzofuran-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1604); 5-{[4-hydroxy-1-(pyridine-3-carbonyl)piperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1605); 5-{[1-(1,5-dimethyl-1H-pyrazole-3-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1606); 5-{[1-(dimethyl-1,3-thiazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1607); 5-{[1-(2-aminobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1608); 5-{[4-hydroxy-1-(1H-indole-6-carbonyl)piperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1609); 5-{[4-hydroxy-1-(1H-indazole-3-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-161); 5-{[4-hydroxy-1-(oxane-4-carbonyl)piperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1610); 5-{[1-(3,3-difluorocyclobutanecarbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1611); 5-{[1-(2-amino-4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1612); 5-{[4-hydroxy-1-(2-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1613); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[1-(oxan-4-yl)-1H-pyrazol-4-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1614); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[1-(oxetan-3-yl)-1H-pyrazol-4-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1615); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1616); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1617); 1-(4-{7-azaspiro[3.5]nonan-7-yl)}phenyl)-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1618); 1-(4-{3-azaspiro[5.5]undecan-3-yl}phenyl)-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1619); 5-{[1-(3-aminobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-162); 1-(4-{3-azaspiro[5.5]undecan-3-yl}phenyl)-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1620); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-{9-methyl-3,9-diazaspiro[5.5]undecan-3-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1621); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{9-methyl-3,9-diazaspiro[5.5]undecan-3-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1622); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(4-methyl-1H-pyrazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1623); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1624); 5-[(1-acetyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-chlorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1625); 1-(4-chlorophenyl)-5-{[4-hydroxy-1-(1H-pyrazole-3-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-one (I-1626); 1-(4-chlorophenyl)-5-{[1-(5-cyclopropyl-1H-pyrazole-3-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1628); 1-(4-chlorophenyl)-5-{[4-hydroxy-1-(3-methyl-1,2-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1629); 1-(4-chlorophenyl)-5-[(4-hydroxy-1-{imidazo[1,2-a]pyridine-6-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1630); 1-(4-chlorophenyl)-5-[(1-cyclobutanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1631); 1-(4-chlorophenyl)-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1632); 1-(4-chlorophenyl)-5-{[4-hydroxy-1-(5-methyl-1,2-oxazole-3-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1633); 1-(4-chlorophenyl)-5-{[4-hydroxy-1-(5-methyl-1H-pyrazole-3-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1634); 1-(4-chlorophenyl)-5-{[1-(1,3-dimethyl-1-H-pyrazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1635); 5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{4-[3-(morpholin-4-yl)azetidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1636); 5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{3-[3-(morpholin-4-yl)azetidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1637); rel-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1638); 1-{4-[(3S)-3,4-dimethylpiperazin-1-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1639); N-{4-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]phenyl}methanesulfonamide (I-164); 1-{4-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1640); 5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-[4-(4-methylpiperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1641); 5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{4-[4-(oxetan-3-yl)piperidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1642); 5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-(4-{6-oxa-3-azabicyclo[3.1.1]heptan-3-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1643); 5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-(3-{8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1644 5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-[3-(3,4,5-trimethylpiperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1645); 1-{3-[(3S)-3,4-dimethylpiperazin-1-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1646); 1-(4-chlorophenyl)-5-{[4-hydroxy-1-(6-methoxypyridine-3-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1647); 1-(4-chlorophenyl)-5-{[1-(6-fluoropyridine-3-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1648); 1-(4-chlorophenyl)-5-[(4-hydroxy-1-{imidazol[1,5-a]pyridine-6-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1649); 1-(4-chlorophenyl)-5-({4-hydroxy-1-[4-(4-hydroxypiperidin-1-yl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1650); 1-(4-chlorophenyl)-5-{[4-hydroxy-1-(4,4,4-trifluoro-3-hydroxy-3-methylbutanoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1651); 5-{[1-(2-amino-4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-chlorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-102); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{4H,5H,6H,7H-pyrazolo[1,5-a]pyrimidin-4-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1653); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-{4H,5H,6H,7H-pyrazol[1,5-a]pyrimidin-4-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1654); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(3S)-3-hydroxypyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1655); 1-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-(propan-2-yl)urea (I-1656); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(3-hydroxy-3-methylpyrrolidin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1657); 5-{[4-hydroxy-1-(4-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1658); 5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1659); 5-({4-hydroxy-1-[3-(hydroxymethyl)benzoyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-166); 5-{[4-hydroxy-1-(5-methoxypyridine-2-carbonyl)piperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1660); 5-{[4-hydroxy-1-(6-methoxypyridine-3-carbonyl)piperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1661); 5-{[1-(6-fluoropyridine-3-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1662); 5-[(4-hydroxy-1-{5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-2-carbonyl}piperidin-4-yl)methyl]-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1663); 5-[(4-hydroxy-1-{imidazo[1,5-a]pyridine-6-carbonyl}piperidin-4-yl)methyl]-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1664); 5-({4-hydroxy-1-[4-(1H-1,2,3-triazol-1-yl)benzoyl]piperidin-4-yl}methyl)-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1665); 4-({1-[3-(4-chloro-1H-pyrazol-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-1666); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(oxan-4-yloxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1667); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(1H-pyrazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1668); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[3-(trifluoromethyl)-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyrimidin-8-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1669); 5-{[4-hydroxy-1-(2-hydroxybenzoyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-167); 5-{[1-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(pyridin-3-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1670); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(pyrimidin-5-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1671); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1672); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-3-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1673); 5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{4-[3-(2-hydroxypropan-2-yl)azetidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1674); 1-[3-(4,4-difluoropiperidin-1-yl)phenyl]-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1675); 5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{3-[3-(2-hydroxypropan-2-yl)azetidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1676); 5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-[4-(3-hydroxyazetidin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1677); 5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-[3-(3-hydroxyazetidin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1678); 1-[4-(3-fluoroazetidin-1-yl)phenyl]-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1679); 5-{[4-hydroxy-1-(1H-pyrazole-3-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-168); 1-[3-(3-fluoroazetidin-1-yl)phenyl]-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1680); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4-{3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl}benzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1681); 5-{[1-(4-{1,4-diazabicyclo[3.2.2]nonan-4-yl}benzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1682); 5-[(1-{4-[(9aS)-octahyhdro-1H-pyrazolo[1,2-a][1,4]diazepin-2-yl]benzoyl}-4-hydroxypiperidin-4-yl)methyl]-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1683); 5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[4-(hydroxymethyl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1684); 5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1685); 1-[4-(4-chloro-1H-pyrazol-1-yl)phenyl]-5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1686); 5-{[4-hydroxy-1-(2-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1-{4-[4-(hydroxymethyl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1687); 5-{[4-hydroxy-1-(2-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1-{4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1688); 1-{3-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1689); 5-{[4-hydroxy-1-(1H-indazole-6-carbonyl)piperidin-4-yl]methyl}-1-phenyl 1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-169); 5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-[3-(4-methylpiperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1690); 5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{3-[4-(oxetan-3-yl)piperidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1691); 5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-(3-{6-oxa-3-azabicyclo[3.1.1]heptan-3-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1692); 1-{4-[3-(difluoromethyl)-4-methylpiperazin-1-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1693); 1-{3-[3-(difluoromethyl)-4-methylpiperazin-1-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1694); rel-3-({1-[(3R)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-7-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (I-1695); rel-3-({1-[(3R)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-7-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (I-1696); rel-5-({1-[(3R)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1697); rel-5-({1-[(3R)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1698); 1-{3-[4-(2,2-difluoroethyl)piperazin-1-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[34-d]pyrimidin-4-one (I-1699); 5-{[1-(2-aminobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-17); N-[(2R)-2-benzyl-3-[4-hydroxy-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidin-1-yl]-3-oxopropyl]ethene-1-sulfonamido (I-170 5-{[4-hydroxy-1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{3-[4-(oxetan-3-yl)piperazin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1700); 5-{[4-hydroxy-1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1701); 1-{3-[(1S,4S)-5-acetyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1702); 4-{([1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d] pyrimidin-5-yl]methyl}-N-[(4-fluorophenyl)methyl]-4-hydroxypiperidine-1-carboxamide (I-1703); 4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxy-N-phenylpiperidine-1-carboxamide (I-1704); N-(4-fluorophenyl)-4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carboxamide (I-1705); 4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxy-N-(3-methoxypropyl)piperidine-1-carboxamide (I-1706); N-cyclopropyl-4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carboxamide (I-1707); 4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxy-N-(pyridin-3-yl)piperidine-1-carboxamide (I-1708); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(3-hydroxyazetidine-1-carbonyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1709); N-[(1r,3r)-3-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]cyclobutyl]ethene-1-sulfonamide (I-171); 5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-[4-(3-methyl-1H-pyrazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1710); 5-{[4-hydroxy-1-(3-methyloxetane-3-carbonyl)piperidin-4-yl]methyl}-1-[4-(3-methyl-1H-pyrazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1711); 1-{4-[4-(2,2-difluoroethyl)piperazin-1-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1712 5-{[4-hydroxy-1-(3-methyloxetane-3-carbonyl)piperidin-4-yl]methyl}-1-[4-(1H-pyrazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1713); 5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-(4-{3-oxa-9-azaspiro[5.5]undecan-9-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1714); 5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-(4-{1-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1715); 5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-(4-{2-oxa-7-azaspiro[3.5]nonan-7-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1716); 5-{[4-hydroxy-1-(1-methylcyclobutanecarbonyl)piperidin-4-yl]methyl}-1-{4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1717); 1-(4-{2,2-difluoro-7-azaspiro[3.5]nonan-7-yl}phenyl)-5-{[4-hydroxy-1-(1-methylcyclobutanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1718); 5-{[4-hydroxy-1-(1-methylcyclobutanecarbonyl)piperidin-4-yl]methyl}-1-{4-[1-(oxan-4-yl)-1H-pyrazol-4-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1719); 3-[4-hydroxy-4-{4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]benzamide (I-172); 1-[4-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl]-5-{[4-hydroxy-1-(1-methylcyclobutanecarbonyl) piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1720); 1-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclobutanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1721); 5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{4-[1-(oxan-4-yl)-1H-pyrazol-4-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1722); 1-[4-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl]-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1723); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4-{1-methyl-octahydro-1H-pyrazolo[3,4-b]pyridin-6-yl}benzoyl)piperidin-4yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1724); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(4-methylpyridin-2-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1725); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(5-methylpyridin-2-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1726); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1727); 1-[4-(4,4-difluoropiperidin-1-yl)phenyl]-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1728); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(1,2,3,4-tetrahydro-1,6-naphthyridin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1729); N-{4-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]phenyl}ethene-1-sulfonamide (I-173); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1730); 5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{3-[3-(oxan-4-yl)azetidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1732); 1-[4-(4-chloro-1H-pyrazol-1-yl)phenyl]-5-{[4-hydroxy-1-(2-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1733); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[4-(hydroxymethyl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1734); 5-[(1-{4-[(8aS)-octahydropyrrolo[1,2-a]piperazin-2-yl]benzoyl}-4-hydroxypiperidin-4-yl)methyl]-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1735); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{pyrazolo[1,5-a]pyridin-3-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1736); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1737); 1-[4-(1,2-benzoxazol-4-yl)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1738); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{2-hydroxy-7-azaspiro[3.5]nonan-7-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1739); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[2-(hydroxymethyl)-7-azaspiro[3.5]nonan-7-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1740); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[2-(hydroxymethyl)-7-azaspiro[3.5]nonan-7-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1741); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{2,2-difluoro-7-azaspiro[3.5]nonan-7-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1742); 1-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1743); 4-{4-[4-(5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl]-1H-pyrazol-1-yl}-1¿6-thiane-1,1-dione (I-1744); 3-{4-[4-(S-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl]-1H-pyrazol-1-yl}-1¿6-thietane-1,1-dione (I-1745); 1-[4-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl]-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1746); 1-{4-[(1S,4S)-5-acetyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1747); 1-{3-[(1R,4R)-5-acetyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1748); 1-{4-[(1R,4R)-5-acetyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1749); 5-({4-hydroxy-1-[(3R)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-175); 5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{3-[4-(2-methoxyethyl)piperazin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1750); 1-[3-(5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl]piperidine-4-carbonitrile (I-1751); 1-[4-(5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl]piperidine-4-carbonitrile (I-1752); 5-({1-[4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1753); 1-[4-(3-fluoro-1H-pyrazol-1-yl)phenyl]-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl) piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1754); 1-(4-{6-azaspiro[2.5]octan-6-yl}phenyl)-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1755); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[(3-methyloxetan-3-yl)methoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1756); 2-[2-(dimethylamino)ethoxy]ethyl 4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carboxylate (I-1757); 2-(1H-imidazol-1-yl)ethyl 4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carboxylate (I-1759); 5-({4-hydroxy-1-[(3S)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-176); 1-methylpiperidin-4-yl 4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carboxylate (I-1762); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(3-methyl-1,2-benzoxazol-5-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1763); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(1-methyl-1H-indazol-6-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1764); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-3-methyl-1H-indazol-7-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1765); 1-[4-(1,2-benzoxazol-5-yl)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1766); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyridin-3-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1767); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{1H-pyrazolo[3,2-b]pyridin-5-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1768); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[2-(trifluoromethyl)pyrimidin-4-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1769); (S)-3-((1-(4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-fluorophenyl)-6-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (I-1770); (R)-3-((1-(4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-fluorophenyl)-6-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (I-1771); 7-(4-fluorophenyl)-3-((4-hydroxy-1-((1r,4r)-4-((1-methyl-1H-pyrazol-3-yl)oxy)cyclohexane-1-carbonyl)piperidin-4-yl)methyl)-6-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (I-1772); 7-(4-fluorophenyl)-3-((4-hydroxy-1-((1s,4s)-4-((1-methyl-1H-pyrazol-3-yl)oxy)cyclohexane-1-carbonyl)piperidin-4-yl)methyl)-6-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (I-1773); (S)-3-((1-(4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-morpholinophenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (I-1774); (S)-3-((1-(4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(3-morpholinophenyl)-1,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (I-1775); (R)-3-((1-(4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-morpholinophenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (I-1776); (R)-3-((1-(4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(3-morpholinophenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (I-1777); 1-(4-((3,3-difluoro-1-methylcyclobutyl)methoxy)phenyl)-5-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (I-1778); (S)—N-(2-benzyl-3-(4-hydroxy-4-((4-oxo-1-phenyl-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)piperidin-1-yl)-3-oxopropyl)ethenesulfonamide (I-1779); 1-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-5-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (I-1800); 1-(4-(3,3-difluoroclyclobutoxy)phenyl)-5-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (I-1801); 5-({4-hydroxy-1-[(3R)-3-(1H-pyrrol-1-yl)butanoyl]piperidin-4-yl}methyl)-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-177); 5-({4-hydroxy-1-[(3S)-3-(1H-pyrrol-1-yl)butanoyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-178); 4-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]benzamide (I-179); 5-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-1-(2-hydroxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-18); 5-({4-hydroxy-1-[4-(methoxymethyl)benzoyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-180); N-{3-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]phenyl}acetamide (I-181); 4-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]-N-methylbenzene-1-sulfonamide (I-182); 4-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]-N-methylbenzamide (I-184); 5-[(1-cyclohexanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-189); 5-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-hydroxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-19); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-190); 5-{[4-hydroxy-1-(pyridine-4-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-194 5-{[4-hydroxy-1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-192); 5-{[1-(3-ethoxypropanoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-193); 5-[(1-cyclobutanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-194); 5-[(1-cyclopentanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-195); 5-{[1-(2,2-dimethylpropanoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-196); 5-{[1-(3,5-dimethylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-197); 5-{[4-hydroxy-1-(3-methylbenzoyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazol[3,4-d]pyrimidin-4-one (I-198); 5-{[4-hydroxy-1-(4-methylbenzoyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-199); 5-{[1-(2-fluoro-4-phenylbenzoyl)-4-hydroxypiperidin-4yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-2); 5-({1-[3-(aminomethyl)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-20); 5-{[1-(3,4-dimethylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-200); 5-{[1-(3-fluoro-4-methoxybenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-201); 5-{[1-(2,3-dihydro-1-benzofuran-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-202); 5-{[1-(3,5-dimethoxybenzoyl)-4-hydroxypiperidin-4yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-203); 5-{[1-(3-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-204); 5-{[1-(2-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-205); 5-{[1-(2-fluoro-3-methylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-206); 5-{[1-(3,4-difluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-207); 5-{[(1-(2,5-difluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-208); 5-{[1-(2,4-difluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-209); 5-{[1-(3-chloro-4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-210); 5-{[1-(3-chloro-4-methylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-211); 5-{[1-(4-chloro-3-methylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-212); 5-{[1-(3,4-dichlorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-213); 5-{[1-(3-chloro-4-methoxybenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-214); 5-{[4-hydroxy-1-(2-methylbenzoyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-215); 5-{[1-(2,5-dimethylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-216); 5-{[1-(2,4-dimethylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-217); 5-{[1-(5-chloro-2-methoxybenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-218); 5-{[1-(4-chloro-2-methoxybenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-219); 3-{5-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}benzoic acid (I-22); 5-{[1-(2,3-dimethoxybenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-220); 5-{[1-(2,5-dimethoxybenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-221); 5-{[1-(2,4-dimethoxybenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-222); 5-{[1-(2,5-dichlorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-223); 5-{[1-(2,4-dichlorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-224); 5-{[4-hydroxy-1-(pyridine-3-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-225); 5-{[1-(4-chloro-3-methoxybenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-226); 5-{[4-hydroxy-1-(5-methylpyrazine-2-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-227); 5-{[4-hydroxy-1-(pyridine-2-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-228); 5-{[1-(1,5-dimethyl-1H-pyrazole-3-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-229); 5-({1-[4-(cyclopropylamino)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-23); 5-{[1-(dimethyl-1,3-thiazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-230); 5-{[4-hydroxy-1-(1,2,3-thiadiazole-4-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-231); 5-{[1-(2-amino-4-chlorobenzoyl)-4-hydroxypiperidin-4-yl]meth}-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-232); 5-{[1-(2-amino-5-chlorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-233); 5-{[1-(2-amino-3-methylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-234); 5-{[4-hydroxy-1-(5-methyl-1,2-oxazole-3-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-235); 5-{[4-hydroxy-1-(5-methyl-1H-pyrazole-3-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-236); 5-{[4-hydroxy-1-(4-methyl-1,3-thiazole-5-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-237); 5-{[4-hydroxy-1-(6-methylpyridine-3-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-238); 5-({4-hydroxy-1-[2-(trifluoromethyl)pyrimidine-5-carbonyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-239); 5-{[1-(5-fluoropyridine-2-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-240); 5-{[1-(5-ethyl-1,3-oxazole-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-241); 5-{[1-(3-fluoro-4-methylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-242); 5-{[1-(3-fluoro-2-methylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-243); 5-{[1-(5-fluoro-2-methylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-244); 5-{[1-(dimethyl-1,2-oxazole-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-245); 5-{[1-(2,3-difluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-246); 5-{[4-hydroxy-1-(1H-indole-4-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-247); 5-{[1-(4,4-dimethylpentanoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-248); 5-{[4-hydroxy-1-(oxane-4-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-249); 1-(4-tert-butylphenyl)-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-25); 5-{[4-hydroxy-1-(1-methyl-1H-pyrrole-2-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-250); 5-{[1-(3,3-difluorocyclobutanecarbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-251); 5-{[4-hydroxy-1-(2-phenyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-252); N-[(1r,3r)-3-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]cyclobutyl]prop-2-ynamide (I-259); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(2,4,6-trimethylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-26); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(2,4-dichlorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-264); 5-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-266); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-267); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-268); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(propan-2-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-27); 5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-271); 4-[4-hydroxy-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]benzoic acid (I-272); 5-({4-hydroxy-1-[4-(trifluoromethoxy)benzoyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-273); 5-({1-[4-(difluoromethoxy)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-274); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-276); 5-({4-hydroxy-1-[1-(trifluoromethyl)cyclopropanecarbonyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-277); 4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-279); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-28); 5-{[1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-280); 5-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(hydroxymethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-281); 5-{[1-(4-chloroquinoline-7-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-282); 5-{[1-(4-cyclopropoxybenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-283); 4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxy-N-methylpiperidine-1-carboxamide (I-284); 5-{[1-(2-chloropyridine-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-287); 5-{[1-(2,5-dichloropyridine-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-288); 5-[(1-{bicyclo[1.1.1]pentane-1-carbonyl}-4-hydroxypiperidin-4-yl)methyl]-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-289); 1-cyclohexyl-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-29); 5-({4-hydroxy-1-[3-(trifluoromethyl)bicyclo [1.1.1]pentane-1-carbonyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-290); 5-({4-hydroxy-1-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-291); 2-cyano-N-[(1r,3r)-3-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]cyclobutyl]acetamide (I-292); 5-({1-[4-(1,1-difluoroethyl)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-4]pyrimidin-4-one (I-294); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-phenoxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-296); 5-({4-hydroxy-1-[4-(4-methylphenoxy)benzoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-3); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(pyridin-3-yl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-30); 5-((1-(2-benzylazetidine-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one, Enantiomer A (I-301a); 5-((1-(2-benzylazetidine-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one, Enantiomer B (I-301b); 5-{[1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-302); 5-{[1-(3-chlorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-303); 5-{[1-(4-cyclopropylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-one (I-304); 5-{[1-(3-chloro-1-methyl-1H-pyrazol-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-305); 5-({1-[4-(difluoromethoxy)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-306); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4-methylbenzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-one (I-307); 5-{[1-(3-fluoro-4-methoxybenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-308); 5-{[1-(3,4-difluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-309); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-methanesulfonylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-31); 5-{[1-(2,4-difluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-310); 5-{[1-(3-chloro-4-methoxybenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-311); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4-methyl-1,3-oxazole 5-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-312); 5-{[1-(dimethyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-313); 5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-314); 5-({1-[2-(dimethylamino)-1,3-oxazole-5-carbonyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-315); 5-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-phenoxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-316); 5-{[1-(2,4-dichlorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-317); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(pyridin-4-yl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-32); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3,4-dichlorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-33); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(3-fluorophenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-330); 4-(4-{5-[1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-N,N-dimethylbenzamide (I-332); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[4-(pyrrolidine-1-carbonyl)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-333); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(3,4-dimethoxyphenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-334); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(2,4-difluorophenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-335); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(3,5-difluorophenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-337); 3-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)benzonitrile (I-339); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-34); 4-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)benzonitrile (I-340); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(4-methoxyphenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-342); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(3-phenylphenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-344); 1-[3-(2-chlorophenyl)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-345); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(3-fluorophenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-346); 1-[3-(3-chlorophenyl)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-347); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(4-fluorophenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-348); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(4-methanesulfonylphenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-349); 1-(4-chlorophenyl)-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-35); 4-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-N,N-dimethylbenzamide (I-350); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[4-(pyrrolidine-1-carbonyl)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-351); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(3,4-dimethoxyphenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-352); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(2,4-difluorophenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-354); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(3,4-difluorophenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-355); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(3,5-difluorophenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-357); 3-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1 yl}phenyl)benzonitrile (I-359); 4-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)benzonitrile (I-360); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[3-(dimethylamino)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-361); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[2-methyl-4H-pyrazol-1-yl)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-363); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(dimethyl-1,2-oxazol-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-364); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(pyridin-3-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-365); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(pyrimidin-5-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-366); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(1-methyl 1H-pyrazol-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-367); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{4-[2-(morpholin-4-yl)ethoxy]phenyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-368); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{4-[2-(dimethylamino)ethoxy]phenyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-369); N-[2-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)phenyl]methanesulfonamide (I-370); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(2-methanesulfonylphenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-371); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(3-hydroxyphenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-372); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(5-fluoropyridin-3-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-373); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[3-(dimethylamino)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-374); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[4-(dimethylamino)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-375); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(dimethyl-1,2-oxazol-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-377); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(pyridin-3-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-378); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(pyrimidin-5-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-379); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-38); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-380); 4-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazol[3,4-d]pyrimidin-1-yl}phenyl)-N-methylbenzamide (I-381); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[5-hydroxy-2-(trifluoromethoxy)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-382); N-[2-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)phenyl]methanesulfonamide (I-383); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(2-methanesulfonylphenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-384); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(3-hydroxyphenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-385); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[6-(dimethylamino)pyridin-3-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-386 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(5-fluoropyridin-3-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-387); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[3-(morpholine-4-carbonyl)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-388); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-389); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[5-fluoro-2-(hydroxymethyl)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-390); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(3-fluoro-5-methoxyphenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-391); 3-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-N,N-dimethylbenzene-1-sulfonamide (I-392); 3-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-N,N-dimethylbenzamide (I-394); 3-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-N-(2-hydroxyethyl)benzamide (I-395); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(1-methyl-1H-indazol-5-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-396); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[3-(cyclopropylmethoxy)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-397); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[3-(pyrrolidin-1-yl)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-399); 4-hydroxy-N-methyl-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-N-(4-phenylphenyl)piperidine-1-carboxamide (I-4); N-[(1r,3r)-3-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]cyclobutyl]ethane-1-sulfonamide (I-40); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[2-(dimethylamino)pyrimidin-5-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-400); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[2-(morpholin-4-yl)pyrimidin-5-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-401); 1-[3-(5-chloropyridin-3-yl)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-401); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[3-morpholine-4-carbonyl)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-402); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[5-fluoro-2-(hydroxymethyl)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-403); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin)methyl]-1-[3-(3-fluoro-5-methoxyphenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-404); 3-(3-{4-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-N,N-dimethylbenzene-1-sulfonamide (I-405); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(1H-indol-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-406); 3-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-N,N-dimethylbenzamide (I-407); 3-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-N-methylbenzamide (I-408); 3-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-N-(2-hydroxyethyl)benzamide (I-409); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(1-methyl-1H-indazol-5-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-410); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[3-(cyclopropylmethoxy)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-411); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[3-(pyrrolidin-1-yl)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-413); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(morpholin-4-ylmethl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-415); 1-(4-{[cyclohexyl(ethyl)amino]methyl}phenyl)-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-416); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(morpholin-4-ylmethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-417); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(pyridine-4-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-418); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[6-(morpholin-4-yl)pyridine-3-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-419); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[6-(2,2,2-trifluoroethoxy)pyridine-3-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-420); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(pyridine-3-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-421); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[6-(trifluoromethyl)pyridine-3-carbonyl]piperidine-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-422); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-423); 4-hydroxy-N-methyl-4-{[4-oxo-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}piperidine-1-carboxamide (I-425); 5-{[(3S,4S)-1-benzoyl-3-fluoro-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-426); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-({[2-(dimethylamino)ethyl](methyl)amino}methyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-427); N-{1-[(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)methyl]piperidin-4-yl}acetamide (I-428); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(pyrrolidin-1-ylmethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-430); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(piperidin-1-ylmethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-431); 1-[(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)methyl]piperidine-4-carbonitrile (I-432); 1-(4-{[benzyl(methyl)amino]methyl}phenyl)-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-433); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[(2-methoxyethyl)(methyl)amino]methyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-434); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[4-(dimethylamino)piperidin-1-yl]methyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-435); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[methyl(2-methylpropyl)amino]methyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-436); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(1,2,3,4-tetrahydroisoquinolin-2-ylmethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-437); 1-{4-[(4-acetylpiperazin-1-yl)methyl]phenyl}-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-438); 4-[(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)methyl]-1λ 6 ,4-thiomorpholine-1,1-dione (I-439); 5-[(1R)-1-[1-(4-fluorobenzoyl)-4-hydroxypiperidin-(4-yl]ethyl]-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-44); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-({[(6-ethylpyridin-3-yl)methyl](methyl)amino}methyl)phenyl]-1H,4H,5H-pyrazole[3,4-d]pyrimidin-4-one (I-440); 2-{1-[(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)methyl]piperidin-3-yl}acetonitrile (I-441); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[cyclopropyl(oxan-4-yl)amino]methyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-442); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{8-oxa-2-azaspiro[45]decan-2-ylmethyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-443); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(pyrrolidin-1-ylmethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-444); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(piperidin-1-ylmethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-445); 1-[(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)methyl]piperidine-4-carbonitrile (I-446); 1-(3-{[benzyl(methyl)amino]methyl}phenyl)-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-447); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-({[2-(dimethylamino)ethyl] (methyl)amino}methyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-448); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{[(2-methoxyethyl)(methyl) amino]methyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-449); N-(2-{4-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]phenyl}phenyl)ethene-1-sulfonamide (I-45); N-{1-[(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)methyl]piperidin-4-yl}acetamide (I-450); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{[4-(dimethylamino)piperidin-1-yl]methyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-451); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{[methyl(2-methylpropyl)amino]methyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-452); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(1,2,3,4-tetrahydroisoquinolin-2-ylmethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-453); 1-{3-[(4-acetylpiperazin-1-yl)methyl]phenyl}-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-454); 4-[(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazol[3,4-d]pyrimidin-1-yl}phenyl)methyl]-1λ 6 ,4-thiomorpholine-1,1-dione (I-455); 2-{1-[(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)methyl]piperidin-3-yl}acetonitrile (I-456) 5[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{8-oxa-2-azaspiro[4.5]decan-2-ylmethyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-457); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[2-(oxan-4-yl)acetyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-458); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(2-methoxyacetyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-459); N-[(2R)-1-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidin-1-yl]-1-oxo-3-phenylpropan-2-yl]ethene-1-sulfonamide (I-46); 3-[1-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidin-1-yl)-1-oxopropan-2-yl]-1,3-oxazolidin-2-one (I-461); 5-{[1-(4,4-difluorocyclohexanecarbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-462); 5-{[1-(2-cyclopropylacetyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-463); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(1-(methylcyclobutanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-464); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(6-methoxypyridine-3-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-465); 1-(4-fluorophenyl)-5-{[1-(6-fluoropyridine-3-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-466) 5-({4-hydroxy-1-[4-(1-hydroxycyclopropyl)benzoyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-467) 1-(4-fluorophenyl)-5-({4-hydroxy-1-[4-(1-hydroxycyclopropyl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-468); 5-{[(3R,4S)-1-benzoyl-3-fluoro-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-469); 5-{[(1-(3-chloro-1H-pyrazole-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-47); 4-hydroxy-N-methyl-4-{[4-oxo-1-(6-phenylpyridin-3-yl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}piperidine-1-carboxamide (I-470); 1-[3-(Cyclopentylamino)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-471); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(morpholin-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-472); 1-(4-Fluorophenyl)-5-[(4-hydroxy-1-{8-oxabicyclo[3.2.1]octane-3-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-473); 4-({1-[4-(Benzyloxy)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-474); 4-((1-(4′,6-Difluoro-[1,1′-biphenyl]-3-yl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-475); N-(3-(5-((1-(Cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)acetamide (I-476); N-(3-(5-((1-(Cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-3,5-dimethylisoxazole-4-sulfonamide (I-477); 1-(3-(5-((1-(Cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-3-isopropylurea (I-478); 5-((1-(Cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(3-(3,3-difluoropyrrolidine-1-carbonyl)phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (I-479); 3-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-7-(4-fluorophenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (I-48); 1-(4-Fluorophenyl)-5-((4-hydroxy-1-(1H-pyrrolo[3,2-d]pyridine-2-carbonyl)piperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (I-480); 4-{[1-(4-Fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxy-N-(propan-2-yl)piperidine-1-carboxamide (I-481); N-(3,3 methylcyclobutyl)-4-((1-(4-fluorophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4-hydroxypiperidine-1-carboxamide (I-482); 1-(4-Chlorophenyl)-5-{[4-hydroxy-1-(1H-indole-2-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-483); (R)-5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (I-484); 5-[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{imidazo[1,2-a]pyridin-8-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-485); 3-(Pyrrolidine-1-yl)propyl 4-((1-4-fluorophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4-hydroxypiperidine-1-carboxylate (I-486); 5-[(1-{4-[(8aR)-octahydropyrrolo[1,2-a]piperazin-2-yl]benzoyl}-4-hydroxypiperidin-4-yl)methyl]-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-487); 5-{[4-Hydroxy-1-(2-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1-[4-(4-methyl-1H-pyrazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-488); 1-{4-[1-(Difluoromethyl)-1H-pyrazol-4-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (i-489); 3-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-7-(4-fluorophenyl)-6-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (I-49); 1-(4-{2,2-Difluoro-7-azaspiro[3.5]nonan-7-yl}phenyl)-5-{[4-hydroxy-1-(1 methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-490); 1-{4-[(5-Chloropyridin-2-yl)oxy]phenyl}-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-491); 1-(4-{5-[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3,3-dimethylurea (I-492); Propan-2-yl N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-4]pyrimidin-1-yl}phenyl)carbamate (I-493); 3-(4-{5-[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1-(oxan-4-yl)urea (I-494); 1-(4-{5-[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-(oxetan-3-yl)urea (I-495); 4-({1-[4-(3,3-dimethylazetidin-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-496); 5-[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(1H-pyrazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-497); 5-[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(piperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-498); 5-[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(piperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-499); 1-(3-{[cyclohexyl(ethyl)amino]methyl}phenyl)-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-5); 4-Hydroxy-N,N-dimethyl-4-{[4-oxo-1-(4-phenoxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}piperidine-1-carboxamide (I-500); 4-{[1-(4-Fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxy-N-(oxan-4-yl)piperidine-1-carboxamide (I-501); (4-{5-[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)urea (I-502); (3-{5-[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)urea (I-503); 5-[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(methylsulfamoyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-504); 5-[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(dimethylsulfamoyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-505); 1-(4-{5[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-methylurea (I-506); 1-(3-{5-[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-methylurea (I-507); 4-{[1-(4-{3,9-Diazaspiro[5.5]undecan-3-yl}phenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-508); 1-(4-Fluorophenyl)-5-[(4-hydroxy-1-{4-[(3S)-3-hydroxypyrrolidin-1-yl]benzoyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-509); 7-[3-(aminomethyl)phenyl]-3-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (I-51); 1-(4-fluorophenyl-5-({4-hydroxy-[3-(pyrrolidin-1-ylmethyl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-510); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-513); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(3S)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-514); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(3R)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-515); 5-({1-[3-(difluoromethoxy)cyclobutanecarbonyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-516); 5-({1-[(3R)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-517); 5-({1-[(3S)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-518); 5-({1-[(3S)-3-{2H,4H,5H,6H-cyclopenta[c]pyrazol-2-yl}butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-519); 3-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-7-(5-fluoropyridin-2-yl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (I-52); 5-({1-[(3R)-3-{2H,4H,5H,6H-cyclopenta[c]pyrazol-2-yl}butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-520); 5-({1-[(3S)-3-{1H,4H,5H,6H-cyclopenta[c]pyrazol-1-yl}butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-521); 5-({1-[(3R)-3-{1H,4H,5H,6H-cyclopenta[c]pyrazol-1-yl}butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-522); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(3-{octahydrocyclopenta[c]pyrrol-2-yl}butanoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-523); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(3S)-3-{octahydrocyclopenta[c]pyrrol-2-yl}butanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-524); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(3R)-3-{octahydrocyclopenta[c]pyrrol-2-yl}butanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-525); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-526); 1-(4-fluorophenyl)-5-[(4-hydroxy-1-{4-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]benzoyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-527); 1-(4-fluorophenyl)-5-[(4-hydroxy-1-{4-[(2S)-1,1,1-trifluoro-2-hydroxypropan-2-yl]benzoyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-528); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[4-(pyrrolidin-1-ylmethyl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-529); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[4-(morpholin-4-ylmethyl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-530); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(2-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-531); 1-(4-fluorophenyl)-5-[(4-hydroxy-1-{5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-2-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-532); 1-(4-fluorophenyl)-5-[(4-hydroxy-1-{4-[(1-methylpiperidin-4-yl)oxy]benzoyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-533); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[5-(piperidin-1-yl)-1,3,4-oxadiazole-2-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-534); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[4-(1H-pyrazol-1-yl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazol[3,4-d]pyrimidin-4-one (I-535); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[2-(piperidin-1-yl)-1,3-oxazole-5-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-536); 5-({1-[3-fluoro-4-(4-methylpiperazin-1-yl)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-537); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[4-(pyridin-2-yloxy)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-538); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[4-(pyrimidin-2-yloxy)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-539); 4-{3-chloro-4-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]phenyl}-N,N-dimethylbenzamide (I-54); 5-{[1-(1-benzyl-1H-indole-2-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-540); 5-{[1-(1-benzyl-1H-pyrazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-541); 5-({1-[(3s)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1 yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-542); 5-({1-[(3R)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-543); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[4-(pyridin-2-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-544); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-(pyridin-2-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-545); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-(pyridin-2-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-546); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[5-(pyridin-2-yloxy)pyridine-2-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-547); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-(1H-pyrazol-1-yl)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-548); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1 s,4s)-4-(1H-pyrazol-1-yl)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-549); 5-[(1-{2-chloro-4-[4-(piperidine-1-carbonyl)phenyl]benzoyl}-4-hydroxypiperidin-4-yl)methyl]-1-methyl-1H,4H,5H-pyrazolo[3,4-d] pyrimidin-4-one (I-55); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4-{2H,3H-pyrazolo[3,2-b][1,3]oxazol-7-yl}benzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-550); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4-{5H,6H,7H-pyrazolo[3,2-b][1,3]oxazin-3-yl}benzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-551); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4-{4H,5H,6H,7H-pyrazolo[1,5-a]pyrimidin-3-yl}benzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-552); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4-{4-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrimidin-3-yl}benzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-553); 5-{[1-(2-amino-4-chlorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-554); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[2-(morpholin-4-yl)-1,3-oxazole-5-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-555); 5-{[1-(5-cyclopropyl-1,3,4-oxadiazole-2-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-556); 5-{[1-(5-benzyl-1,3-oxazole-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-557); 1-(4-fluorophenyl)-5-[(1-{1-[4-fluorophenyl)methyl]-1H-2-carbonyl}-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-558); 5-[(1-{1-[(2,6-difluorophenyl)methyl]-1H-pyrrole-2-carbonyl}-4-hydroxypiperidin-4-yl)methyl]-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-559); 5-{[4-hydroxy-1-(4-phenoxybenzoyl)piperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-56); 1-(4-fluorophenyl)-5-[(1-{1-[(3-fluorophenyl)methyl]-1H-pyrrole-2-carbonyl}-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-560); 1-(4-fluorophenyl)-5-[(1-{1-[(2-fluorophenyl)methyl]-1H-pyrrole-2-carbonyl}-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-561); 1-(4-fluorophenyl)-5-[(4-hydroxy-1-{4-[1-methyl-1H-pyrazol-4-yl)oxy]benzoyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-562); 1-(4-fluorophenyl)-5-[(4-hydroxy-1-{4-[(5-methyl-1,2-oxazol-3-yl)oxy]benzoyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-563); 1-[4-(4-fluorophenyl)phenyl]-5-{[4-hydroxy-1-(piperazine-1-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-564); N-[(1s,3s)-3-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carbonyl)cyclobutyl]prop-2-enamide (I-568); N-[(1S,3R)-3-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidin-1-carbonyl)cyclopentyl]prop-2-enamide (I-569); 5-({4-hydroxy-1-[(3R)-3-phenylbutanoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-57); N-[(1R,3S)-3-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carbonyl)cyclopentyl]prop-2-enamide (I-570); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(2R)-1-(prop-2-enoyl)azetidine-2-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-574); N-[(1r,4r)-4-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carbonyl)cyclohexyl]prop-2-enamide (I-575); N-[(1s,4 s)-4-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidin-1-carbonyl)cyclohexyl]prop-2-enamide (I-576); N-[(1s,3s)-3-[2-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidin-1-yl)-2-oxoethyl]cyclobutyl]prop-2-ynamide (I-578); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(2S)-2-methyl-1-(prop-2-enoyl)azetidine-2-carbonyl]piperidin-4yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-579); 1-benzyl-5-({4-hydroxy-1-[(3R)-3-phenylbutanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-58); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(2R)-2-methyl-1-(prop-2-enoyl)azetidine-2-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-580); N-[1r,3 r)-3-(4-{[1-(4-fluorophenyl 1-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carbonyl)cyclobutyl]acetamide (I-582); 5-((1-(3-(aminomethyl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)-4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one (I-585); 5-((1-(4-(1-(aminomethyl)cyclopropyl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one hydrochloride (I-586); N-((1-(4-(4-((1-(4-fluorophenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5 (4H)-yl)methyl)-4-hydroxypiperidine-1-carbonyl)phenyl)cyclopropyl)methyl)acetamide (I-587); N-methyl-N-[(1r,3r)-3-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carbonyl)cyclobutyl]prop-2-ynamide (I-589); 1-tert-butyl-5-({4-hydroxy-1-[(3R)-3-phenylbutanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-59); 1-tert-butyl-5-{[4-hydroxy-1-(4-phenoxybenzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-60); N-methyl-N-[(1s,3 s)-3-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carbonyl)cyclobutyl]prop-2-ynamide (I-600); 1-(4-fluorophenyl)-5-((4-hydroxy-1-(3-((3-hydroxy-3-methyl-pyrrolidin-1-yl)methyl)benzoyl)piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one (I-601); 1-(4-fluorophenyl)-5-[(4-hydroxy-1-{3-[1-(pyrrolidin-1-yl)ethyl]benzoyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-602); 5-([1-[(5-benzyl-1H-pyrazol-4-yl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-603); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4-{5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl}benzoyl)piperidin-4-yl]methyl}-1H,4H, 5H-pyrazolo[3,4-d]pyrimidin-4-one (I-604); 1-(4-fluorophenyl)-5-((4-hydroxy-1-(4-(1-methylpiperidin-4-yl)benzoyl)piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one (I-605); 1-(4-fluorophenyl)-5-[(4-hydroxy-1-[[4-(4-methylpiperazin-1-yl)phenyl]carbonyl]piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-606); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4-{octahydro-1H-pyrido[1,2-a]piperazin-2-yl}benzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-607); 5-[(1-{4-[(9aR)-octahydro-1H-pyrido[1,2-a]piperazin-2-yl]benzoyl}-4-hydroxypiperidin-4-yl)methyl]-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-608); 5-[(1-{4-[(9a S)-octahydro-1H-pyrido[1,2-a]piperazin-2-yl]benzoyl}-4-hydroxypiperidin-4-yl)methyl]-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-609); 5-({4-hydroxy-1-[(3R)-3-phenylbutanoyl]piperidin-4-yl}methyl)-1-(propan-2-yl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-61); 1-(4-fluorophenyl)-5-[(4-hydroxy-1-[[4-(pyridin-2-yloxy)piperidin-1-yl]carbonyl]piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-610); 5-((1-(4-(5,6-dihydropyrrolo[3,4-d]pyrazol-1 (4H)-yl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one (I-611); 1-(4-fluorophenyl)-5-[(4-hydroxy-1-{4-[4-(hydroxymethyl)-1H-pyrazol-1-yl]benzoyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-612); 5-((1-(4-(4-(aminomethyl)-1H-pyrazol-1-yl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one (I-613); 1-(4-fluorophenyl)-5-(1-[4-hydroxy-1-[(4-methoxyphenyl)carbonyl]piperidin-4-yl]ethyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-614); 1-(4-fluorophenyl)-5-(1-[4-hydroxy-1-[(4-methoxyphenyl)carbonyl]piperidin-4-yl]ethyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-615); 5-(1-(1-(3-(aminomethyl)benzoyl)-4-hydroxypiperidin-4-yl)ethyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one hydrochloride (I-616); 5-[(4-hydroxypiperidin-4-yl)methyl]-1-(4-methoxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-617); 4-Hydroxy-4-[[1-(4-methoxyphenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl]-N,N-dimethylpiperidine-1-carboxamide (I-618); 4-Hydroxy-4-[[1-(4-hydroxyphenyl)-4-oxo-1H,4H,5H-pyrazolo [3,4-d]pyrimidin-5-yl]methyl]-N,N-dimethylpiperidine-1-carboxamide (I-619); 5-{[4-hydroxy-1-(4-phenoxybenzoyl)piperidin-4-yl]methyl}-1-(propan-2-yl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-62); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-methoxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-620); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-(3-methoxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-621); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-hydroxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-622); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(3-hydroxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-623); 5-(1-(1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)ethyl)-1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one (I-624); 5-{1-[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]ethyl}-1-(4-methoxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-625); 1-(3-bromo-4-fluorophenyl)-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-626); 1-(4-fluoro-3-methoxyphenyl)-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-627 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(6-fluoropyridin-3-yl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-628); 5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-cyclopropylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-629); 5-({4-hydroxy-1-[(3R)-3-phenylbutanoyl]piperidin-4-yl}methyl)-3-methyl-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-63); 1-(4-bromophenyl)-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-630); 1-(3-bromo-4-chlorophenyl)-5[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-631); 1-(4-fluoro-3-hydroxyphenyl)-5-([1-[(4-fluorophenyl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-632); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-fluoro-3-(3-methoxy-3-methylpyrrolidin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-633); 5-((1-benzoyl-4-hydroxypiperidin-4-yl)methyl)-1-(4-fluoro-3-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one (I-634); 1-(3-Amino-4-fluorophenyl)-5-([1-[(4-fluorophenyl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-635); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-fluoro-3-(3-hydroxy-3-methylpyrrolidin-1-yl)phenyl]-1H,4H,5H-pyrazol[3,4-d]pyrimidin-4-one (I-636); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-fluoro-3-[(3S)-3-hydroxy-3-methylpyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-637); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-fluoro-3-[(3R)-3-hydroxy-3-methylpyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-638); 1-[4-fluoro-3-(morpholin-4-yl)phenyl]-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-639); 5-{[4-hydroxy-1-(4-phenoxybenzoyl)piperidin-4-yl]methyl}-3-methyl-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-64); 1-(4-fluoro-3-(hydroxymethyl)phenyl)-5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one (I-640); 5-({1-[4-(difluoromethoxy)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-[4-fluoro-3-hydroxymethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-641); 1-[4-fluoro-3-(hydroxymethyl)phenyl]-({4-hydroxy-1-[4-(pyridin-2-yloxy)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-642); 1-(Biphenyl-4-yl)-5-((4-hydroxy-1-(2-morpholinooxazole-5-carbonyl)piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one (I-643); 5-({1-[4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-644); 5-({1-[(3R)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-645); 5-({1-[(3S)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-646); 5-({4-hydroxy-1-[3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-648); 5-({4-hydroxy-1-[(3S)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-649); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(3R)-3-phenylbutanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-65); 5-({4-hydroxy-1-[(3R)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-650); 1-[4-(4-fluorophenyl)phenyl]-5-({4-hydroxy-1-[3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-652); 1-[4-(4-fluorophenyl)phenyl]-5-({4-hydroxy-1-[(3R)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-653); 1-[4-(4-fluorophenyl)phenyl]-5-({4-hydroxy-1-[(3S)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-654); 4-([1-[4-(4-fluorophenyl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl)-4-hydroxy-N-methylpiperidine-1-carboxamide (I-655); 5-((1-(1-acryloylazetidine-2-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(biphenyl-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one (I-657); N-[(1r,3r)-3-(4-hydroxy-4-{[4-oxo-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}piperidine-1-carbonyl)cyclobutyl]prop-2-ynamide (I-658); 5-({4-hydroxy-1-[(2S)-2-methyl-1-(prop-2-enoyl)azetidine-2-carbonyl]piperidin-4-yl}methyl)-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-659); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4-phenoxybenzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-66); 5-({4-hydroxy-1-[(2R)-2-methyl-1-(prop-2-enoyl)azetidine-2-carbonyl]piperidin-4-yl}methyl)-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-660); pyrrolidin-3-ylmethyl 4-hydroxy-4-{[4-oxo-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}piperidine-1-carboxylate (I-661); N-(4-fluoropyrrolidin-3-yl)-4-hydroxy-4-{[4-oxo-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}piperidine-1-carboxamide (I-662); N-[(3R)-4-fluoropyrrolidin-3-yl]-4-hydroxy-4-{[4-oxo-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}piperidine-1-carboxamide (I-663); N-[(3S)-4-fluoropyrrolidin-3-yl]-4-hydroxy-4-{[4-oxo-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}piperidine-1-carboxamide (I-664); 5-((1-benzoyl-4-hydroxypiperidin-4-yl)methyl)-1-(2-(hydroxymethyl)biphenyl-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one (I-665); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(hydroxymethyl)-4-phenylphenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-666); 5-([4-hydroxy-1-[(morpholin-4-yl)carbonyl]piperidin-4-yl]methyl)-1-[3-(hydroxymethyl)-4-phenylphenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-667); 1-[3-(Aminomethyl)-4-phenylphenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-663); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(dimethylamino)methyl]-4-phenylphenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-669); 5-({4-hydroxy-1-[(3R)-3-phenylbutanoyl]piperidin-4-yl}methyl)-1-[3-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-67); 5-([1-[(4-fluorophenyl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1-(4-[[2-(propan-2-yloxy)ethyl]amino]phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-670); 5-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[2-(propan-2-yloxy)ethyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-671); 5-([4-hydroxy-1-[(4-methylphenyl)carbonyl]piperidin-4-yl]methyl)-1-[4-[4-(2-hydroxyethoxy)-1H-pyrazol-1-yl]phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-672); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-673); 5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(2′-(2-(dimethylamino)ethylamino)biphenyl-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one (I-674); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-[4-(pyrrolidin-3-yloxy)phenyl]phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-675); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{4-[2-(dimethylamino)ethoxy]-3-fluorophenyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-676); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{2-[2-(dimethylamino)ethoxy]phenyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-677); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-[4-[(1-methylpyrrolidin-3-yl)oxy]phenyl]phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-678); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(4-{[(3R)-1-methylpyrrolidin-3 yl]oxy}phenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-679); 5-({4-hydroxy-1-[(3R)-3-phenylbutanoyl]piperidin-4-yl}methyl)-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-68); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(4-{[(3S)-1-methylpyrrolidin-3-yl]oxy}phenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-680); 5-((1-cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(1-(2,2-difluoroethyl)piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one (I-681); 4-hydroxy-N,N-dimethyl-4-({1-[4-(oxan-4-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1 carboxamide (I-682); 4-[(1-{4-[1-(2,2-difluoroethyl)piperidin-4-yl]phenyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-683) 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{6-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-3-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-684); 5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(6-(3-(methylamino)pyrrolidin-1-yl)pyridin-3-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one (I-685); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{6-[3S)-3-hydroxypyrrolidin-1-yl]pyridin-3-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-686); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{6-[3R)-3-hydroxypyrrolidin-1-yl]pyridin-3-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-687); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{4-[3-(methylamino)pyrrolidin-1-yl]phenyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-688); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{4-[(3S)-3-(methylamino)pyrrolidin-1yl]phenyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-689); 5-{[4-hydroxy-1-(4-phenoxybenzoyl)piperidin-4-yl]methyl}-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-69); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{4-[(3R)-3-(methylamino) pyrrolidin-1-yl]phenyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-690); 1-[4-[3-(3-aminooxetan-3-yl)phenyl]phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-691); 5-([1-[(4-fluorophenyl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1-[4-[(1-methylazetidin-3-yl)oxy]phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-692); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[(4-fluorooxan-4-yl)methoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-693); 1-{4-[(4,4-difluorocyclohexyl)oxy]phenyl}-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-694); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-([4,4-difluorocyclohexyl)oxy]phenyl}-1H,4H,5H-pyrazole[3,4-d]pyrimidin-4-one (I-695); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[(1-fluorocyclobutyl)methoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-696); 1-(4-(4,4-difluorocyclohexyloxy)phenyl)-5-((4-hydroxy-1-(4-methylpiperazine-1-carbonyl)piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one (I-697); 5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(2-(piperazin-1-yl)biphenyl-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one (I-698); 5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(4,4-difluoropiperidin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-699); 5-({4-hydroxy-1-[(3R)-3-phenylbutanoyl]piperidin-4-yl}methyl)-1-(pyridin-2-yl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-70); 1-[4-(4,4-difluoropiperidin-1-yl)phenyl]-5-{[4-hydroxy-1-(4-methylbenzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-700); 1-[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-701); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(morpholin-4-yl)-4-phenylphenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-702); 5-([1-[(4-fluorophenyl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1-(1-methyl-1H-pyrazol-4-yl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-703); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(1-phenyl-1H-pyrazol-4-yl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-704); 1-(1-cyclopropyl-1H-pyrazol-4-yl)-5-({1-[4-(difluoromethoxy)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-705); 4-((7-(4-fluorophenyl)-4-oxo-6-phenyl-4H-pyrrolo[2,3-d]pyrimidin-3 (7H)-yl)methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-706); 1-[4-(dimethylamino)phenyl]-5-([1-[(4-fluorophenyl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-707); 5-{[4-hydroxy-1-(4-phenoxybenzoyl)piperidin-4-yl]methyl}-1-(pyridin-2-yl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-71); 1-(4-(1H-1,2,3-triazol-1-yl)phenyl)-5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-711); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-712); 5-([1-[(4-Fluorophenyl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1-[4-(1-hydroxycyclopropyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-713); 5-{[(3R,4R)-1-benzoyl-3-fluoro-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-716); 5-{[(3S,4R)-1-benzoyl-3-fluoro-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-717); 1-(4-fluorophenyl)-5-((4-hydroxy-1-(4-((1-methyl-1H-pyrazol-3-yl)oxy)benzoyl)piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one (I-719); 5-({4-hydroxy-1-[(3R)-3-phenylbutanoyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-72); 5-(1-(1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)-2-hydroxyethyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-720); 8-((1-(4-fluorophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-8-hydroxyoctahydro-4H-quinolizin-4-one (I-721); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-methoxycyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-722); 4-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carbonyl)-1Ω ω -thiane-1,1-dione (I-723); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4,5,6,7-tetrahydro-6-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-724); 1-(4-fluorophenyl)-5-{[4-hydroxy-1-(1-methyl-4,5,6,7-tetrahydro-1H-indazole-6-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-725); 5-{[1-(1-cyclopropyl-1H-pyrazole-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-726); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1 r,4r)-4-(1-methyl-1H-pyrazol-4-yl)cyclohexanecarbonyl] piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-727); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-(1-methyl-1H-pyrazol-4-yl)cyclohexanecarbonyl] piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-728); 5-{[4-hydroxy-1-(4-phenoxybenzoyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-73); 5-({1-[(3R)-3-(3-chloro-1H-pyrazol-1-yl)-4,4-difluorobutanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-731); 5-({1-[(3S)-3-(3-chloro-1H-pyrazol-1-yl)-4,4-difluorobutanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-732); 5-({1-[(3R)-3-(4-chloro-1H-pyrazol-1-yl)-4,4-difluorobutanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-733); 5-{1-[(3S)-3-(4-chloro-1H-pyrazol-1-yl)-4,4-difluorobutanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-734); 5-({1-[(3R)-4,4-difluoro-3-(4-methyl-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-735); 5-({1-[(3S)-4,4-difluoro-3-(4-methyl-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-736); 1-(4-fluorophenyl)-5-[(4-hydroxy-1-[[(1r,4r)-4-[(5-fluoropyridin-2-yl)oxy] cyclohexyl]carbonyl]piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-737); 1-(4-fluorophenyl)-5-[(4-hydroxy-1-[[1s,4s)-4-[(5-fluoropyridin-2-yl) oxy]cyclohexyl]carbonyl] piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-738); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-[(6-fluoropyridin-2-yl)oxy]cyclohexanecarbonyl] piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-739); 5-({4-hydroxy-1-[4-(1H-imidazol-1yl}methyl)benzoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-74); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-[(6-fluoropyridin-2-yl)oxy]cyclohexanecarbonyl] piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-740); 5-({4-hydroxy-1-[(1r,4r)-4-[(6-fluoropyridin-2-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-741); 5-({4-hydroxy-1-[(1s,4s)-4-[(6-fluoropyridin-2-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-742); 5-({4-hydroxy-1-[(1r,4r)-4-[(5-fluoropyridin-2-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-743); 5-({4-hydroxy-1-[(1s,4s)-4-[(5-fluoropyridin-2-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-744); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-1-methyl-4-(pyridin-2-yloxy)cyclohexanecarbonyl] piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-745); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-1-methyl-4-(pyridin-2-yloxy)cyclohexanecarbonyl] piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-746); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-(pyrimidin-2-yloxy)cyclohexanecarbonyl] piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-747); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-(pyrimidin-2-yloxy)cyclohexanecarbonyl] piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-748); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-(pyridin-3-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-749); 5-({4-hydroxy-1-[4-(1H-1,2,3,4-tetrazol-1-ylmethyl)benzoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-75); 1-(4-fluorophenyl)-5-({4-hydroxy-[(1r,4r)-4-(pyrimidin-3-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-750); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-(pyridin-4-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-751); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-(pyridin-4-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-752); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-[(1-methyl-1H-pyrazol-3-yl)oxy] cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-753); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-[(1-methyl-1H-pyrazol-3-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-7541); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-[(5-methyl-1,2-oxazol-3-yl)oxy] cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-755); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-[5-methyl-1,2-oxazol-3-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-756); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-[(1-methyl-1H-pyrazol-4-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-757); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-[(1-methyl-1H-pyrazol-4-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H, 5H-pyrazolo[3,4-d]pyrimidin-4-one (I-758); 5-((1-(2-benzylazetidine-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-759); 5-{[1-(2-benzylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-76); 5-({1-[(2R)-2-benzylazetidine-1-carbonyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-760); 1-(4-fluorophenyl)-5-[(4-hydroxy-1-{1H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-6-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-761); 1-(4-fluorophenyl)-5-[(4-hydroxy-1-{1-methyl-1H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-6-carbonyl)}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-762); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-[(1-methyl-1H-pyrazol-5-yl)amino] cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-763); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-[(1-methyl-1H-pyrazol-5-yl)amino]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-764); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-[(1-methyl-1H-pyrazol-3-yl)amino]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-765); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-[(1-methyl-1H-pyrazol-3-yl)amino]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-766); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-(phenylamino)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-767); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-(phenylamino)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-768); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-(cyclopropylamino)cyclohexanecarbonyl] piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-769); 5-({1-[3-(3-fluorophenyl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-77); 5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[(3,3-difluorocyclobutyl)methoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-770) 1-(4-chlorophenyl)-5-[(1-[[2-(cyclopropylamino)-1,3-oxazol-5-yl]carbonyl]-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-771); 1-(4-chlorophenyl)-5-{[4-hydroxy-1-(1-methyl-1H-pyrazole-4-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-772 5-((1-(3-(3-aminopropoxy)benzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-774); 5-((4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl)methyl-1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-775); 5-([1-[(2-Cyclopropyl-1,3-oxazol-5-yl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-776); (S)-1-(4-(hexahydro-1H-pyridol[1,2a]pyrazin-2(6H)-yl)phenyl)-5-((4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one (I-777); (R)-1-(4-(hexahydro-1H-pyrido [1,2-a]pyrazin-2(6H)-yl)phenyl)-5-((4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-778); 5-([1-[(2-cyclopropyl-1,3-oxazol-5-yl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1-[4-(4-methyl-1H-pyrazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-779); 5-({1-[3-(4-fluorophenyl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-78); 5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(1H-pyrazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-780); 5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-[4-(1H-pyrazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-781); 5-{[4-hydroxy-1-(1-methylcyclobutanecarbonyl)piperidin-4-yl]methyl}-1-[4-(1H-pyrazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-782); (R)-5-((1-(cyclohexanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(3-hydroxy-3-methylpyrrolidin-1-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-783); 1-(4-{3-azabicyclo[3.1.0]hexan-3-yl}phenyl-5-({1-[(3S)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-784); 1-(4-{3-azabicyclo[3.1.0]hexan-3-yl}phenyl)-5-({1-[(3R)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-785); 1-(4-(4,4-Difluorocyclohexylamino)phenyl)-5-((4-hydroxy-1-(1-methylcyclopropanecarbonyl) piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-786); N-(4′-(4-((1-(4-ethynylphenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)-4-hydroxypiperidine-1-carbonyl)biphenyl-2-yl)ethenesulfonamide (I-787); 5-([1-[(3R)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl]methyl)-1-[3-(morpholin-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-788); 5-([1-[(3S)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl]methyl)-1-[3-(morpholin-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-789); 5-{[4-hydroxy-1-(2-methyl-4-phenylbutanoyl)piperidin-4-yl]methyl}-1-methyl 1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-79); 1-(3-{3-azabicyclo[3 1.0]hexan-3-yl}phenyl)-5-({1-[(3S)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-790); 1-(3-{3-azabicyclo[3.1.0]hexan-3-yl}phenyl)-5-({1-[(3R)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-791); (R)-3-((1-(4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(3-(4-methylpiperazin-1-yl)phenyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (I-792); (S)-3-((1-(4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(3-(4-methylpiperazin-1-yl)phenyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (I-793); 7-(4-fluorophenyl)-3-((4-hydroxy-1-(trans-4-((1-methyl-1H-pyrazol-5-yl)oxy) cyclohexanecarbonyl)piperidin-4-yl)methyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (I-794); 1-(4-ethylphenyl)-5-((4-hydroxy-1-(4-(1-methylpiperidin-4-yloxy)benzoyl)piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-795); (R)-5-((1-(4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)-1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-796); (S)-5-((1-(4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)-1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-797); 5-([1-[(1-cyclopropyl-1H-pyrazol-4-yl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1-(4-cyclopropylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-798); 1-(4-cyclopropylphenyl)-5-((4-hydroxy-1-(2-methyloxazole-5-carbonyl)piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-799); 5-{[1-(2-benzylcyclopropanecarbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-80); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(2S)-1-(prop-2-ynoyl)azetidine-2-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-803); 1-(4-Fluorophenyl)-5-((4-hydroxy-1-(trans-4-(5-methylisoxazol-3-ylamino) cyclohexanecarbonyl)piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-806); 1-(4-Fluorophenyl)-5-((4-hydroxy-1-(cis-4-(5-methylisoxazol-3-ylamino)cyclohexanecarbonyl) piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-807); 5-{[4-hydroxy-1-(2-methoxy-3-phenylpropanoyl)piperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-81); 4-{[1-(3-bromo-4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-810); 4-{[1-(3-bromophenyl)-4-oxo-1H,4H,5H-pyrazol[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-811); 4-(5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-4,5-dihydropyrazolo[3,4-d]pyrimidin-1-yl)benzoic acid (I-812); N-[(2R)-1-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidin-1-yl]-1-oxo-3-phenylpropan-2-yl]ethene-1-sulfonamide (I-814); Anti-5-((4-Hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl)methyl)-1-(4-((4-methoxycyclohexyl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one, isomer A (I-815a); Syn-5-((4-Hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl)methyl)-1-(4-((4-methoxycyclohexyl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one, isomer B (I-815b); 5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-((3-hydroxy-1-methylazetidin-3-yl)methoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-816); 5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[(4,4-difluorocyclohexyl)oxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-817); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[3-(4-methylpiperazin-1-yl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-818); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[4-(morpholin-4-yl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-819); 5-{[4-hydroxy-1-(4,4,4-trifluoro-3-phenylbutanoyl)piperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-82); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-{1H,4H,6H,7H-pyrano[4,3-c]pyrazol-1-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-820); 5-([1-[(3R)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl]methyl)-1-[4-(piperidin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-821); 5-([1-[(3S)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl]methyl)-1-[4-(piperidin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-822); 1-(3-{[2-(dimethylamino)ethyl](methyl)amino}phenyl)-5-{[(1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-823); 1-[4-fluoro-3-(piperazin-1-yl)phenyl]-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-824); 5-({1-[4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-[4-(4-methylpiperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-825); 5-({1-[(3R)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-[4-(4-methylpiperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-826); 5-({1-[(3S)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-[4-(4-methylpiperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-827); 5-({1-[4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-[3-(4-methylpiperazin-1-yl)phenyl]-1H,4H,5H-pyrazol[3,4-d]pyrimidin-4-one (I-828); 5-({1-[(3R)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-[3-(4-methylpiperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-829); 2-(2-{4-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazole[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]phenyl}phenyl)acetonitrile (I-83); 5-({1-[(3S)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-[3-(4-methylpiperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-830); 5-({4-hydroxy-1-[1-(prop-2-enoyl)azetidine-2-carbonyl]piperidin-4-yl}methyl)-1-[3-(4-methylpiperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-831); 5-({4-hydroxy-1-[1-(prop-2-enoyl)azetidine-2-carbonyl]piperidin-4-yl}methyl)-1-[4-(4-methylpiperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-832); 5-({1-[(3R)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-{4-[(3S)-3-hydroxy-3-methylpyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-833); 5-({1-[(3R)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-{4-[(3R)-3-hydroxy-3-methylpyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-834); 5-({1-[(3S)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-{4-[(3S)-3-hydroxy-3-methylpyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-835); 5-({1-[(3S)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-{4-[(3R)-3-hydroxy-3-methylpyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-836) 5-({4-hydroxy-1-[(3S)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1-{4-[(3S)-3-hydroxy-3-methylpyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-837); 5-({4-hydroxy-1-[(3S)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1-{4-[(3R)-3-hydroxy-3-methylpyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-838); 5-({4-hydroxy-1-[(3R)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1-{4-[(3S)-3-hydroxy-3-methylpyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-839); 1-(2-{4-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]phenyl}phenyl)cyclopropane-1-carbonitrile (I-84); 5-({4-hydroxy-1-[(3R)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1-{4-[(3R)-3-hydroxy-3-methylpyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-840); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-[4-[(3S)-pyrrolidin-3-yloxy]phenyl]phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-841); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-[4-[(3R)-pyrrolidin-3-yloxy]phenyl]phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-842); 5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-843); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[4-(4-methylpiperazin-1-yl)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-844); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{6-[3-(methylamino) pyrrolidin-1-yl]pyridin-3-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-845); 1-(4-cyclobutylphenyl)-5-{[4-hydroxy-1-(2-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-846); 1-(4-cyclobutylphenyl)-5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-847); 3-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-7-(4-fluorophenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (I-849); 5-({1-[4-(4-chlorophenoxy)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-85); 3-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-7-(4-fluorophenyl)-6-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (I-850); 5-({1-[4-(difluoromethoxybenzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-[4-(hydroxymethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-851); 5-({4-hydroxy-1-[(1r,4r)-4-(pyridin-2-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1-[4-(hydroxymethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-852); 5-({4-hydroxy-1-[(1s,4s)-4-(pyridin-2-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1-[4-(hydroxymethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-853); 1-[4-(azetidin-1-ylmethyl)phenyl]-5-([1-[(3S)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl]methyl)-1H,4H,5H-pyrazol[3,4-d]pyrimidin-4-one (I-854); 1-[4-(azetidin-1-ylmethyl)phenyl]-5-([1-[(3R)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl]methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-855); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-[2-(dimethylamino)ethoxy]-4-phenylphenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-856); 5-({1-[4-(4-fluorophenoxy)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-86); 5-({4-hydroxy-1-[(3S)-4,4,4-trifluoro-3-phenylbutanoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-861); 5-({1-[4-(4-bromophenoxy)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-87); 5-({4-hydroxy 1-[4-(4-hydroxyphenoxy)benzoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-88); 5-({4-hydroxy-1-[4-(3-hydroxyphenoxy)benzoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-89); 5-[(4-hydroxy-1-{4-[(pyrimidin-2-yloxy)methyl]benzoyl}piperidin-4-yl)methyl]-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-9); 5-({1-[4-(3-chlorophenoxy)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-90); 5-({1-[4-(3-bromophenoxy)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-91); 1-(1-cyclopropyl-1H-pyrazol-4-yl)-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-910); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[4-(5-methyl-1,3,4-oxadiazol-2-yl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-911); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(3S)-4,4,4-trifluoro-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-912); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(3R)-4,4,4-trifluoro-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-913); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[2-(4-hydroxypiperidin-1-yl)-1,3-oxazole-5-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-915); 5-({4-hydroxy-1-[2-(4-hydroxypiperidin-1-yl)-1,3-oxazole-5-carbonyl]piperidin-4-yl}methyl)-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-916); 5-({4-hydroxy-1-[(1r,3r)-3-(pyridin-2-yloxy)cyclobutanecarbonyl]piperidin-4-yl}methyl)-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-917); 5-({1-[(3S)-4,4-difluoro-3-(4-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-915); 1-(4-chlorophenyl)-5-({4-hydroxy-1-[4-(4H-1,2,4-triazol-4-yl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-919); 5-{[4-hydroxy-1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzoyl)piperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-92); 1-(4-chlorophenyl)-5-[(4-hydroxy-1-{6-[(1-methylpyrrolidin-3-yl)oxy]pyridine-3-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-920); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[1-methyl-3-(1H-pyrazol-1-ylmethyl)-1H-pyrazole-4-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-921); 1-(4-fluorophenyl)-5-[(4-hydroxy-1-{4-[(5-methyl-1,2-oxazol-3-yl)oxy]piperidine-1-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-922); 1-(4-fluorophenyl)-5-[(4-hydroxy-1-{4-[(1-methyl-1H-pyrazol-4-yl)oxy]piperidine-1-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-923); N-[(1 r,4r)-4-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carbonyl)cyclohexyl]acetamide (I-924); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-(oxan-4-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-925); 1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-(oxan-4-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-926); 4-{[1-(4-bromophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-928); 5-({4-hydroxy-1-[4-(pyridin-3-yloxy)benzoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-93); 5-({4-hydroxy-1-[4-(4-methoxyphenoxy)benzoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-94); 5-({4-hydroxy-1-[4-(3-methylphenoxy)benzoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-95); N-[(1r,3r)-3-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carbonyl)cyclobutyl]prop-2-ynamide (I-950); N-[(1R,2S)-2-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carbonyl)cyclobutyl]prop-2-ynamide (I-952); N-[(1r,3r)-3-[2-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidin-1-yl)-2-oxoethyl]cyclobutyl]prop-2-ynamide (I-958); 4-{4-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]phenoxy}benzonitrile (I-96); 1-(3-aminophenyl)-5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-964); 1-(4-aminophenyl)-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-965); 4-((1-(4-fluoro-3-(piperazin-1-yl)phenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-966); 4-hydroxy-N,N-dimethyl-4-({4-oxo-1-[4-(piperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carboxamide (I-967); 4-[(1-{4-[(3R,4R)-3-fluoro-4-hydroxypyrrolidin-1-yl]phenyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-968); 1-[4-chloro-3-(morpholin-4-yl)phenyl]-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-969); 5-({1-[4-(3,4-dimethylphenoxy)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-97); 5-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-fluoro-4-(4-methylpiperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-970); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-fluoro-3-[(3S)-3-methoxy-3-methylpyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-971); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-fluoro-3-[(3R)-3-methoxy-3-methylpyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-972); 5-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-2-(4-methylpiperazin-1-yl)benzonitrile (I-973); 4-((1-(3-((3R,4R)-3-fluoro-4-hydroxypyrrolidin-1-yl)phenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (I-974); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[4-(4-methylpiperazin-1-yl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-975); 5-{[(1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-{2H,4H,6H,7H-pyrano[4,3-c]pyrazol-2-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-976); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[4-(2-hydroxyethoxy)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-977); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[3-(morpholin-4-yl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-978); 5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-hydroxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-980); 5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[(1-fluorocyclobutyl)methoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-981); 5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-((1-hydroxycyclobutyl)methoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-982); 5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(2-methyl-1H-imidazol-4-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-983); 1-[4-(1,5-dimethyl-1H-imidazol-2-yl)phenyl]-5-([1-[(4-fluorophenyl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-984); 5-((1-(2-Cyclopropyloxazole-5-carbonyl)-4-hydroxypiperidin-4-yl) methyl)-1-(4-(pyridin-3-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-985); 5-([1-[(4-fluorophenyl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1-[4-(4-methyl-1H-imidazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-987); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(2-methyl-1H-imidazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-988); 5-((1-(4-(difluoromethoxy)benzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(3-(hydroxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-989); 5-{[1-(3-cyclopropyl-3-phenylpropanoyl)-4-hydroxypiperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-99); 1-(4-fluoro-3-(hydroxymethyl)phenyl)-5-((4-hydroxy-1-(4-(pyrimidin-2-yloxy)benzoyl)piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-990); 4-hydroxy-4-((1-(4-(1-isopropylpiperidin-4-yl)phenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)-N,N-dimethylpiperidine-1-carboxamide (I-992); 5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[3-(piperidin-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-993); 4-hydroxy-N,N-dimethyl-4-({4-oxo-1-[4-(piperidin-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carboxamide (I-994); (R)-5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(methylsulfinyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one, enantiomer (I-995); (S)-5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(methylsulfinyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one, enantiomer B (I-996); 5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(methylsulfinyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-996a); (S)-5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(S-methylsulfonimidoyl) phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, enantiomer A (I-997); (R)-5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(S-methylsulfonimidoyl) phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, enantiomer B (I-998); 5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(S-methylsulfonimidoyl)phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (I-998a); and 1-[4-[(4-[[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl]-4-hydroxypiperidin-1-yl)carbonyl]phenyl]-1H-pyrazole-4-carboxylic acid (I-999)

In another embodiment of the invention, the compounds of Formula (I) are enantiomers. In some embodiments the compounds are the (S)-enantiomer. In other embodiments the compounds are the (R)-enantiomer. In yet other embodiments, the compounds of Formula (I) may be (+) or (−) enantiomers.

It should be understood that all isomeric forms are included within the present invention, including mixtures thereof. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans configuration. All tautomeric forms are also intended to be included.

Compounds of the invention, and pharmaceutically acceptable salts, hydrates, solvates, stereoisomers and prodrugs thereof may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.

The compounds of the invention may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of the invention incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound. The compounds may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry. The assay results may reflect the data collected for the racemic form, the enantiomerically pure form, or any other form in terms of stereochemistry.

Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by 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., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of the invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of a chiral HPLC column.

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

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.) Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”, “solvate”, “ester,” “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.

The compounds of Formula I may form salts which are also within the scope of this invention. Reference to a compound of the Formula herein is understood to include reference to salts thereof, unless otherwise indicated.

The present invention relates to compounds which are modulators of USP7. In one embodiment, the compounds of the present invention are inhibitors of USP7.

The invention is directed to compounds as described herein and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, and pharmaceutical compositions comprising one or more compounds as described herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof.

Method of Synthesizing the Compounds

The compounds of the present invention may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below.

The compounds of Formula (I) may be prepared by methods known in the art of organic synthesis as set forth 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 in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of compounds of Formula (I).

Those skilled in the art will recognize if a stereocenter exists in the compounds of Formula (I). Accordingly, the present invention includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, “Stereochemistry of Organic Compounds” by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

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

Preparation of Compounds

The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. Compounds of the present invention can be synthesized by following the steps outlined in General Schemes 1, 2, 3, and 4 which comprise different sequences of assembling intermediates IIa, IIb, IIIa, IIIb, IIIx, IVa, IVb, IVx, Va, Vb, Vx, VIIx, and VIIIx. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated.

wherein R 2 -R 6 , X 1 , m and n are defined as in Formula (I).

The general way of preparing target molecules of Formula (I) by using intermediates IIa, IIIa, IVa, and Va is outlined in General Scheme 1. Cyclization of a hydrazine hydrochloride (or the hydrazine) with a 2-(ethoxymethylidene)propanedinitrile optionally using a base, i.e., triethylamine or N,N-diisopropylethylamine (DIPEA), in solvent, i.e., ethanol, at elevated temperatures provides intermediate IIa. Intermediate IIIa is then prepared by cyclization of nitrile IIa and formic acid in the presence of a catalytic amount of water at an elevated temperature. Alternatively, intermediate IIIa can be obtained by treating IIa with a strong acid, i.e., sulfuric acid, to obtain an amide intermediate which is then cyclized to the pyrazolo pyrimidine IIIa with triethyl orthoformate and acetic anhydride at an elevated temperature. Nucleophilic addition of IIIa to a tert-butyl-1,6-[3]-dioxa-8-azaspiro[2.7]decan-7-one intermediate in a solvent, i.e., dimethylformamide (DMF) at elevated temperature provides IVa. Deprotection of intermediate IVa using a strong acid such as trifluoroacetic acid (TFA) in a solvent, i.e., dichloromethane (DCM) yields Va. Acylation of intermediate Va to produce a compound of Formula (I) where X 1 is C, can be accomplished by coupling of an acid under standard coupling conditions using a coupling reagent, i.e., [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), or O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (HBTU), and a base, i.e., triethylamine or N,N-diisopropylethylamine (DIPEA), in a solvent, e.g., dichloromethane or DMF to provide compounds of Formula (I). Alternatively, intermediate Va can be acylated with an acid chloride or carbamoyl chloride using a base, i.e., diethylamine car DIPEA, and optionally in solvent to produce a compound of Formula (I) where X 1 is C. For synthesis of a compound of Formula (I) where X 1 is S or S(O), intermediate Va is treated with a sulfonyl chloride or a sulfinic chloride and a base, i.e., triethylamine or N,N-diisopropylethylamine (DIPEA), in a solvent, i.e., dichloromethane, DMF to provide the desired product of Formula (I).

wherein R 2 -R 6 , X 1 , m, and n are defined as in Formula (I).

Alternatively, molecules of Formula (I) can be prepared using intermediates IIa, IIIx, IVx, IVa, and Va as outlined in General Scheme 2. Cyclization of a hydrazine hydrochloride (or the hydrazine) with a 2-(ethoxymethylidene)propanedinitrile optionally using a base, i.e., triethylamine or N,N-diisopropylethylamine (DIPEA), in solvent, i.e., ethanol, at elevated temperatures provides intermediate IIa. Hydrolysis of IIa using an acid (i.e., dilute hydrochloric acid) or a base (i.e., sodium hydroxide solution) in a solvent (i.e., water) provides carboxylic acid IIIx. Coupling of the acid IIIx with amine VIIx under standard coupling conditions using a coupling reagent, i.e., 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluoro-phosphate (HATU), or O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (HBTU), and a base, i.e., triethylamine or N,N-diisopropylethylamine (DIPEA), in a solvent, e.g., dichloromethane or DMF provides IVx. Intermediate IVa is then prepared by cyclization of IVx and formic acid in the presence of a catalytic amount of water at an elevated temperature. Deprotection of intermediate IVa using a strong acid such as trifluoroacetic acid (TFA) in a solvent, i.e., dichloromethane (DCM) yields Va. Acylation of intermediate Va to produce a compound of Formula (I) where X 1 is C, can be accomplished by coupling of an acid under standard coupling conditions using a coupling reagent, i.e., [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro-phosphate (HATU), or O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (HBTU), and a base, i.e., triethylamine N,N-diisopropylethylamine (DIPEA), in a solvent, e.g., dichloromethane or DMF to provide compounds of Formula (I). Alternatively, intermediate Va can be acylated with an acid chloride or carbamoyl chloride using a base, i.e., triethylamine or DIPEA, and optionally in solvent to produce a compound of Formula (I) where X 1 is C. For synthesis of a compound of Formula (I) where X 1 is S or S(O), intermediate Va is treated with a sulfonyl chloride or a sulfinic chloride and a base, i.e., triethylamine or N,N-diisopropylethylamine (DIPEA), in a solvent, i.e., dichloromethane, DMF to provide the desired product of Formula (I).

wherein R 2 -R 6 , X 1 , m, and n are defined as in Formula (I).

Molecules of Formula (I) can also be prepared using intermediates IIa, IIIx, and Vx as outlined above in General Scheme 3. Cyclization of a hydrazine hydrochloride (or the hydrazine) with a 2-(ethoxymethylidene)propanedinitrile optionally using a base, i.e., triethylamine of N,N-diisopropylethylamine (DIPEA), in solvent, i.e., ethanol, at elevated temperatures provides intermediate IIa. Hydrolysis of IIa using an acid (i.e., dilute hydrochloric acid) or a base (i.e., sodium hydroxide solution) in a solvent (i.e., water) provides carboxylic acid IIIx. Coupling of the acid IIIx with amine VIIIx under standard coupling conditions using a coupling reagent, i.e., [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro-phosphate (HATU), or O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (HBTU), and a base, i.e., triethylamine or N,N-diisopropylethylamine (DIPEA), in a solvent, e.g., dichloromethane or DMF provides Vx. Cyclization of Vx and formic acid in the presence of a catalytic amount of water at an elevated temperature provides compounds of Formula (I). Alternatively, of compounds of Formula (I) can be obtained by treating Vx with a strong acid, i.e., sulfuric acid, to obtain an amide intermediate which is then cyclized to the pyrrolo pyrimidine of Formula (I) with triethyl orthoformate and acetic anhydride at an elevated temperature.

wherein R 2 -R 6 , X 1 , m, and n are defined as in Formula (I).

The general way of preparing target molecules of Formula (I) by using intermediates IIb, IIIb, IVb, and Vb is outlined in General Scheme 4. Treatment of Intermediate IIb with 1,4-diazabicyclo[2.2.2]octane (DABCO), a solvent, i.e., dioxane and/or water, and a base, i.e., potassium carbonate or cesium carbonate, etc., at an elevated temperature provides intermediate IIIb. Nucleophilic addition of IIIb to a tert-butyl-1,6-[3]-dioxa-8-azaspiro[2.7]decan-7-one intermediate using a base, i.e., potassium carbonate or cesium carbonate, etc., in a solvent, i.e., dimethylformamide (DMF) at elevated temperature provides IVb. Deprotection of intermediate IVb using a strong acid such as trifluoroacetic acid (TFA) in a solvent, i.e., dichloromethane, (DCM) yields Vb. Acylation of intermediate Vb to produce a compound of Formula (I) where X 1 is CR 7 , can be accomplished by coupling of an acid under standard coupling conditions using a coupling reagent, i.e., [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), or O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (HBTU), and a base, i.e., triethylamine or N,N-diisopropylethylamine (DIPEA), in a solvent, e.g., dichloromethane or DMF. Alternatively, intermediate Vb can be acylated with an acid chloride or carbamoyl chloride using a base, i.e., triethylamine or DIPEA, and in a solvent, i.e., dichloromethane to produce a compound of Formula (I) where X 1 is C. For synthesis of compounds of Formula (I) where X 1 is S or S(O), Vb is treated with a sulfonyl chloride or a sulfinic chloride and a base, i.e., triethylamine or N,N-diisopropylethylamine (DIPEA), in a solvent, i.e., dichloromethane, DMF to provide the desired product of Formula (I).

A mixture of enantiomers, diastereomers, cis/trans isomers resulting from the process described above can be separated into their single components by chiral salt technique, chromatography using normal phase, reverse phase or chiral column, depending on the nature of the separation.

It should be understood that in the description and formula shown above, the various groups R 2 -R 5 , R 5′ , R 6 , X 1 , X 2 , m, n, and other variables are as defined above, except where otherwise indicated. Furthermore, for synthetic purposes, the compounds of General Schemes 1, 2, 3, and 4 are mere representative with elected radicals to illustrate the general synthetic methodology of the compounds of Formula (I) as defined herein.

Methods of Using the Disclosed Compounds

Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of USP7. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP7 an effective amount the compositions and compounds of Formula (I).

In another aspect, the present invention is directed to a method of inhibiting USP7. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (I).

Another aspect of the present invention relates to a method of treating, preventing, inhibiting or eliminating a disease or disorder in a patient associated with the inhibition of USP7, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (I). In one embodiment, the disease or disorder is selected from the group consisting of cancer and metastasis, neurodegenerative diseases, immunological disorders, diabetes, bone and joint diseases, osteoporosis, arthritis inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, viral infectivity and/or latency, and bacterial infections and diseases.

The present invention also relates to the use of an inhibitor of USP7 for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of a disease or condition mediated by USP7, wherein the medicament comprises a compound of Formula (I).

In another aspect, the present invention relates to a method for the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or condition mediated by USP7, wherein the medicament comprises a compound of Formula (I).

Another aspect of the present invention relates to a compound of Formula (I) for use in the manufacture of a medicament for treating a disease associated with inhibiting USP7.

In another aspect, the present invention relates to the use of a compound of Formula (I) in the treatment of a disease associated with inhibiting USP7.

Another aspect of the invention relates to a method of treating cancer. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I).

In another aspect, the present invention relates to a method of treating a neurodegenerative disease. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I).

Another aspect of the invention relates to a method of treating a viral infection and disease. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I).

In another aspect, the present invention relates to a method of treating an inflammatory disease or condition. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I).

Another aspect of the invention relates to a method of inducing cell cycle arrest, apoptosis in tumor cells, and/or enhanced tumor-specific T cell immunity. The method comprises contacting the cells with an effective amount of a compound of Formula (I).

In one embodiment, the present invention relates to the use of an inhibitor of USP7 for the preparation of a medicament used in treatment, prevention, inhibition or elimination of a disease or disorder associated with associated with cancer and metastasis, neurodegenerative diseases, immunological disorders, diabetes, bone and joint diseases, osteoporosis, arthritis inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, viral infectivity and/or latency, and bacterial infections and diseases.

In another embodiment, the present invention relates to a compound of Formula (I) or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier used for the treatment of cancers including, but not limited to, liposarcoma, neuroblastoma, glioblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid or vaginal cancer or Epstein-Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma or diffuse large B-cell lymphoma.

In some embodiments, the patient is selected for treatment based on gene amplification and/or elevated tumor expression of USP7, MDM2 or MDM4 relative to tissue-matched expression. In other embodiments, the patient is selected for the treatment based on tumor expression of wild type TP53 or based on the tumor immune cell composition, specifically elevated regulatory T lymphocytes, CD4+CD25+FoxP3+ T cells.

In some embodiments, administration of a compound of Formula (I) or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier induces a change in the cell cycle or cell viability.

For example, the change in the cell cycle or cell viability may be indicated by decreased tumor levels of MDM2 protein and/or increased levels of TP53, CDKN1A (p21, Cip1), PUMA or BAX or by increased expression of one or more p53 target genes. In one embodiment, the p53 target genes include, but are not limited to, CDKN1A (p21, Cip1), BBC3 (PUMA), BAX or MDM2.

In another embodiment, the present invention relates to a compound of Formula (I) or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier used for the treatment of neurodegenerative diseases including, but not limited to, Alzheimer's disease, multiple sclerosis, Huntington's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, amyotrophic lateral sclerosis, or encephalitis.

Another embodiment of the present invention relates to a compound of Formula (I) or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier used for the treatment of viral infections and diseases including but not limited to, herpes simplex-1 or -2 viral infections, hepatitis A, hepatitis C, SARS coronavirus infection and disease, Epstein-Barr virus, rhinoviral infections and diseases, adenoviral infections and diseases, or poliomyelitis.

In another embodiment, the present invention relates to a compound of Formula (I) or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carder used for the treatment of inflammatory diseases or conditions is associated with metabolic disorders including, but not limited to, Type II diabetes, insulin resistance cardiovascular disease, arrhythmia, atherosclerosis, coronary artery disease, hyperitriglyceridemia, dyslipidemia, retinopathy, nephropathy, neuropathy, or macular edema.

In another embodiment, the present invention relates to a compound of Formula (I) or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carder used for the treatment of inflammatory diseases or conditions is associated with inflammatory bowel diseases including, but not limited to, ileitis, ulcerative colitis, Barrett's syndrome, or Crohn's disease.

Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

In one embodiment, are provided methods of treating a disease or disorder associated with modulation of USP7 including, cancer and metastasis, neurodegenerative diseases, immunological disorders, diabetes, bone and joint diseases, osteoporosis, arthritis inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, viral infectivity and/or latency, and bacterial infections and diseases, comprising administering to a patient suffering from at least one of said diseases or disorder a compound of Formula (I).

One therapeutic use of the compounds of compositions of the present invention which inhibit USP7 is to provide treatment to patients or subjects suffering from cancer and metastasis, neurodegenerative diseases, immunological disorders, diabetes, bone and joint diseases, osteoporosis, arthritis inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, viral infectivity and/or latency, and bacterial infections and diseases.

The disclosed compounds of the invention can be administered in effective amounts to treat or prevent a disorder and/or prevent the development thereof in subjects.

Administration of the disclosed compounds can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes.

Depending on the intended mode of administration, the disclosed compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices. Likewise, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, and all using forms well known to those skilled in the pharmaceutical arts.

Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a Compound of the invention and a pharmaceutically acceptable carrier, such as a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene glycol; for tablets also, c) a binder, e.g., 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 acacia, tragacanth or sodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) a disintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthan gum, algic acid or its sodium salt, or effervescent mixtures; e) absorbent, colorant, flavorant and sweetener; f) an emulsifier or dispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 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, PEG200.

Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc. For example, the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.

The disclosed compounds can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions, using polyalkylene glycols such as propylene glycol, as the carrier.

The disclosed compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine phosphatidylcholines. In some embodiments, a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in U.S. Pat. No. 5,262,564 which is hereby incorporated by reference in its entirety.

Disclosed compounds can also be delivered by the use of monoclonal antibodies as individual carriers to which the disclosed compounds are coupled. The disclosed compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the Disclosed compounds can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. In one embodiment, disclosed compounds are not covalently bound to a polymer, e.g., a polycarboxylic acid polymer, or a polyacrylate.

Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.

Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound by weight or volume.

The dosage regimen utilizing the disclosed compound is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed compound employed. 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 condition.

Effective dosage amounts of the disclosed compounds, when used for the indicated effects, range from about 0.5 mg to about 5000 mg of the disclosed compound as needed to treat the condition. Compositions for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compound, or, in a range of from one amount to another amount in the list of doses. In one embodiment, the compositions are in the form of a tablet that can be scored.

The disclosure is further illustrated by the following examples and synthesis schemes, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and/or scope of the appended claims.

Analytical Methods, Materials, and Instrumentation

Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on either Broker or Varian spectrometers at 300 or 400 MHz. Spectra are given in ppm (δ) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Mass spectra were collected using a Waters ZQ Single Quad Mass Spectrometer (ion trap electrospray ionization (ESI)). Purity and low resolution mass spectral data were measured using Waters Acquity i-class ultra-performance liquid chromatography (UPLC) system with Acquity Photo Diode Array Detector, Acquity Evaporative Light Scattering Detector (ELSD) and Waters ZQ Mass Spectrometer. Data was acquired using Waters MassLynx 4.1 software and purity characterized by UV wavelength 220 nm, evaporative light scattering detection (ELSD) and electrospray positive ion (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 to 2 mins, hold 100% B to 2.2 mins and 5% B at 2.21 mins. Preparatory HPLC purifications were conducted on a Waters SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×50 mm, Waters XBridge BEH C18 OBD Prep Column, 130 Å, 5 μm, 19 mm×50 mm with UV detection (Waters 2489 UV/998 PDA), Waters SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×150 mm, Waters XBridge BEH Shield RP18 OBD Prep Column, 130 Å, 5 μm, 19 mm×150 mm, or Waters XSelect CSH C18 OBD Prep Column, 130 Å, 5 μm. 19 mm×150 mm at 254 nm or 220 nm using a standard solvent gradient program (i.e., HPLC Methods 1-8 or as designated below). The absolute configuration of the separated enantiomers of the compounds in the examples described herein were not determined. As such, the configuration of the resolved materials were arbitrarily assigned as R or S in each case.

Preparative HPLC Method 1 (ESI, 5.5 Min Method):

Instruments: HPLC: Waters 2545 Binary Gradient Module. MS: Waters 3100/ZQ Mass Detector. UV: Waters 2489 UV/998 PDA.

Conditions: Mobile phase A: water with 0.1% formic acid/Mobile phase B acetonitrile with 0.1% formic acid

Column: Waters SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×50 mm

Column temperature: Ambient

LC gradient: Hold 0% B 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.

LC Flow rate: 23 mL/min binary pump, 2 mL/min acetonitrile at column dilution.

UV wavelength: 220 nm and 254 nm

Ionization Mode: Electrospray Ionization; positive/negative; ESI+

Preparative HPLC Method 2 (ESI, 5.5 Min Method):

Instruments: HPLC: Waters 2545 Binary Gradient Module. MS: Waters 3100/ZQ Mass Detector. UV: Waters 2489 UV/998 PDA.

Conditions: Mobile phase A: water with 0.1% ammonium hydroxide/Mobile phase B acetonitrile with 0.1% ammonium hydroxide

Column: Waters XBridge BEH C18 OBD Prep Column, 130 Å, 5 μm, 19 mm×50 mm

Column temperature: Ambient

LC gradient: Hold 0% B 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.

LC Flow rate: 23 mL/min binary pump, 2 mL/min acetonitrile at column dilution

UV wavelength: 220 nm and 254 nm

Ionization Mode: Electrospray Ionization; positive negative; ESI+

Preparative HPLC Method 3 (ESI, 5.5 Min Method):

Instruments: HPLC: Waters 2545 Binary Gradient Module. MS: Waters 3100/ZQ Mass Detector. UV: Waters 2489 UV/998 PDA.

Conditions: Mobile phase A: water with 0.1% formic acid/Mobile phase B acetonitrile with 0.1% formic acid

Column: Waters SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×50 mm Column temperature: Ambient

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 074 min.

LC Flow rate: 23 mL/min binary pump, 2 mL/min acetonitrile at column dilution

UV wavelength: 220 nm and 254 nm

Ionization Mode: Electrospray Ionization; positive/negative; ESI+

Preparative HPLC Method 4 (ESI, 5.5 Min Method):

Instruments: HPLC: Waters 2545 Binary Gradient Module. MS: Waters 3100/ZQ Mass Detector. UV: Waters 2489 UV/998 PDA.

Conditions: Mobile phase A: water with 0.1% ammonium hydroxide/Mobile phase B acetonitrile with 0.1% ammonium hydroxide

Column: Waters XBridge BEH C18 OBD Prep Column, 130 Å, 5 μm, 19 mm×50 mm

Column temperature: Ambient

LC gradient: Hold 15% B for 0.9 min, then 15% to 25% in 0.01 min; then 25% to 65% in 3.84 min; then 65 to 100% to 100% in 0.01 min; hold at 100% for 0.74 min.

LC Flow rate: 23 mL/min binary pump, 2 mL/min acetonitrile at column dilution

UV wavelength: 220 nm and 254 nm

Ionization Mode: Electrospray Ionization; positive/negative; ESI+

Preparative HPLC Method 5 (ESI, 5.5 Min Method):

Instruments: HPLC: Waters 2545 Binary Gradient Module. MS: Waters 3100/ZQ Mass Detector. UV: Waters 2489 UV/998 PDA.

Conditions: Mobile phase A: water with 0.1% formic acid/Mobile phase B acetonitrile with 0.1% formic acid

Column: Waters SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×50 mm

Column temperature: Ambient

LC gradient: Hold 35% B for 0.9 min, then 35% to 45% in 0.01 min; then 45% to 85% in 3.84 min; then 85 to 100% to 100% in 0.01 min; hold at 100% for 0.74 min.

LC Flow rate: 23 mL/min binary pump, 2 mL/min acetonitrile at column dilution

UV wavelength: 220 nm and 254 nm

Ionization Mode: Electrospray Ionization; positive/negative; ESI+

Preparative HPLC Method 6 (ESI, 5.5 Min Method):

Instruments: HPLC: Waters 25.5 Binary Gradient Module. MS: Waters 3100/ZQ Mass Detector. UV: Waters 2489 UV/998 PDA.

Conditions: Mobile phase A: water with 0.1% ammonium hydroxide/Mobile phase B acetonitrile with 0.1% ammonium hydroxide

Column: Waters XBridge BEH C18 OBD Prep Column, 130 Å, 5 μm, 19 mm×50 mm

Column temperature: Ambient

LC gradient: Hold 35% B for 0.9 min, then 35% to 45% in 0.01 min, then 45% to 85% in 3.84 min; then 85 to 100% to 100% in 0.01 min; hold at 100% for 0.74 min.

LC Flow rate: 23 mL/min binary pump, 2 mL/min acetonitrile at column dilution

UV wavelength: 220 nm and 254 nm

Ionization Mode: Electrospray Ionization; positivelnentive; ESI+

Preparative HPLC Method 7 (ESI, 5.5 Min Method):

Instruments: HPLC: Waters 2545 Binary Gradient Module. MS: Waters 3100/ZQ Mass Detector. UV: Waters 2489 UV/998 PDA.

Conditions: Mobile phase A: water with 0.1% formic acid/Mobile phase B acetonitrile with 0.1% formic acid

Column: Waters SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×50 mm

Column temperature: Ambient

LC gradient: Hold 50% B for 0.9 min, then 50% to 60% in 0.01 min; then 60% to 100% in 3.84 min; then hold at 100% for 0.75 min.

LC Flow rate: 23 mL/min binary pump, 2 mL/min acetonitrile at column dilution

UV wavelength: 220 nm and 254 nm

Ionization Mode: Electrospray Ionization; positive/negative; ESI+

Preparative HPLC Method 8 (ESI, 5.5 Min Method):

Instruments: HPLC: Waters 2545 Binary Gradient Module. MS: Waters 3100/ZQ Mass Detector. UV: Waters 2489 UV/998 PDA.

Conditions: Mobile phase A: water with 0.1% ammonium hydroxide/Mobile phase B acetonitrile with 0.1% ammonium hydroxide

Column: Waters XBridge BEH C18 OBD Prep Column, 130 Å, 5 μm, 19 mm×50 mm

Column temperature: Ambient

LC gradient: Hold 50% B for 0.9 min, then 50% to 60% in 0.01 min; then 60% to 100% in 3.84 min; then hold at 100% for 0.75 min.

LC Flow rate: 23 mL/min binary pump, 2 nitimin acetonitrile at column dilution

UV wavelength: 220 nm and 254 nm

Ionization Mode: Electrospray Ionization; positive/negative; ESI+

Abbreviations used in the following examples and elsewhere herein are:

atm atmosphere br broad BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) DABCO 1,4-diazabicyclo[2.2.2]octane DBU 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine DIPEA N,N-diisopropylethylamine DMA N,N-dimethylacetamide DMF N,N-dimethylformamide DMSO dimethyl sulfoxide dppf 1,1′-bis(diphenylphosphino)ferrocene EDC N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride ESI electrospray ionization h hour(s) HATU [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC high-performance liquid chromatography LCMS liquid chromatography-mass spectrometry m multiplet MHz megahertz min minutes MPLC Medium pressure liquid chromatography MS molecular sieves MTBE 2-methoxy-2-methylpropane MW microwave NMR nuclear magnetic resonance ppm parts per million RuPhos 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl TBDMS tertbutyldimethylsilyl TFA Trifluoroacetic acid TLC thin layer chromatography X-Phos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

Example 1: Intermediate 2-1. Tert-Butyl 4-hydroxy-4-((1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)piperidine-1-carboxylate

The title compound (16.7 g, 77%) was prepared according to the procedure described for Example 21, Intermediate 2-29, Step 4, utilizing 1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (9.0 g, 59.9 mmol) as staring material 1 H NMR (400 MHz, CDCl 3 ) δ 8.08 (s, 1H), 7.99 (s, 1H), 4.24-3.98 (m, 2H), 4.00 (s, 3H), 3.97-3.78 (m, 2H), 3.21-3.09 (m, 2H), 2.96 (s, 1H), 1.66-1.56 (m, 2H), 1.56-1.48 (m, 2H), 1.45 (s, 9H) ppm. LCMS: (ESI) m/z 386 [M+Na].

Example 2: Intermediate 2-2. 5-((4-Hydroxypiperidin-4-yl)methyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one Trifluoroacetic Acid Salt

The title compound was prepared according to the procedure described for Example 21 described herein below, Intermediate 2-28, Step 5, utilizing tert-butyl 4-hydroxy-4-((1-methyl-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)piperidine-1-carboxylate from Intermediate 2-1 (7.80 g, 21.5 mmol) as starting material which was used without any further purification. LCMS: (ESI) m/z 264 [M+H].

Example 2a: Intermediate 2-2a. 5-((4-Hydroxypiperidin-4-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, Hydrochloric Acid Salt

In a ½ dram reaction vial, tert-butyl 4-hydroxy-4-((1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methyl)piperidine-1-carboxylate (Intermediate 2-1, 0.2 M 1,4-dioxane, 0.15 mL, 0.030 mmol) and hydrochloric acid (4.0 M 1,4-dioxane, 0.075 mL, 0.3 mmol) were combined. The vial was capped and agitated at 50° C. for 3 hours. The reaction was cooled and dried under a stream of nitrogen to provide 5-((4-hydroxypiperidin-4-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, hydrochloric acid salt without any further purification. LCMS: (ESI) m/z 264 [M+H].

Example 3: Intermediate 2-3. 5-((1-(4-Bromobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

A 100-mL round-bottom flask was charged with 5-((4-hydroxypiperidin-4-yl)methyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one Trifluoroacetic Acid Salt (Intermediate 2-2, 2.70 g, 7.15 mmol), 4-bromobenzoic acid (1.51 g, 7.51 mmol), and 1,2-dichloroethane (38 mL). Hydroxybenzotriazole hydrate (547 mg, 3.58 mmol), triethylamine (4.98 mL, 35.8 mmol), and EDC (1.44 g, 7.51 mmol) were then added to the slurry. The reaction mixture was stirred at 50° C. for 3 h. The resulting suspension was cooled in an ice bath and stirred for 30 min. The solids were filtered and washed with 9:1 hexanes-ethyl acetate (25 mL) to afford 5-((1-(4-bromobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Intermediate 2-3, 2.58 g, 81%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.08 (s, 1H), 7.96 (s, 1H), 7.54 (d, 2H), 7.28 (d, 2H), 4.55-4.36 (m, 1H), 4.27-4.12 (m, 1H), 4.09-3.93 (m, 1H), 4.00 (s, 3H), 3.69-3.51 (m, 1H), 3.50-3.34 (m, 1H), 3.32 (s, 1H), 1.80-1.62 (m, 2H), 1.62-1.44 (m, 2H) ppm. LCMS: (ESI) m/z 446, 448 [M+H].

The Intermediate in Table 2 was synthesized according to the procedure outlined in Example 3 above.

2-(2-Bromophenyl)acetonitrile (500 mg, 2.55 mmol) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (633 mg, 2.55 mmol), tetrakis[triphenylphosphine]palladium(0) (147 mg 0.13 mmol), tribasic potassium phosphate (1.62 g, 7.64 mmol), 1,4-dioxane (30 mL) and water (3 mL) were added to a 100-mL round-bottom flask fitted with a nitrogen inlet, magnetic stir bar and condenser. The resulting solution was stirred for 16 h at 100° C. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC with ethyl acetate/petroleum ether (1:5 v/v) to provide 2′-(cyanomethyl)-[1,1′-biphenyl]-4-carboxylic acid (Intermediate 2-5, 500 mg, 83%). LCMS: (ESI) m/z 236 [M−H].

The Intermediates in Table 3 were synthesized according to the procedure outlined in Example 4 above.

Example 5: Intermediate 2-229a. 4-(5-(tert-butoxycarbonyl)-2,5-diaza-bicyclo[2.2.1]heptan-2-yl)benzoic Acid

A 100-mL round-bottom flask was charged with ethyl 4-bromobenzoate (500 mg, 2.18 mmol), tris(dibenzylideneacetone)dipalladium-chloroform adduct (226 mg, 022 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (261 mg, 0.44 mmol), cesium carbonate (2.14 g, 6.57 mmol), toluene (20 mL) and tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (521 mg, 2.61 mmol). The resulting solution was stirred for 24 h at 110° C. The reaction was cooled to room temperature and quenched by the addition of water (20 mL). The resulting solution was extracted with of dichloromethane (4×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative thin layer chromatography eluting with ethyl acetate/petroleum ether (1:10 to 1:1, v/v). The collected fractions were combined and concentrated under vacuum to afford tert-butyl 5-(4-(ethoxycarbonyl)phenyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylate as a yellow oil (700 mg, 92%). LCMS: (ESI) 347 [M+H].

The title compound was prepared according to the procedure outlined in Example 10, Step 2 utilizing tert-butyl 5-(4-(ethoxycarbonyl)phenyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylate (600 mg, 1.73 mmol) as starting material (370 mg, 67%). LCMS: (ESI) m/z 319 [M+H].

Example 6: Intermediate 2-7. 5-((4-Hydroxy-1-(4-(hydroxymethyl)benzoyl)piperidin-4-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

In a 20 mL vial was added 5-((4-hydroxypiperidin-4-yl)methyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one trifluoroacetic acid salt (Intermediate 2-2) (0.643 g, 1.71 mmol), 4-(hydroxymethyl)benzoic acid (0.310 g, 2.04 mmol) and HATU (775 mg, 2.04 mmol) in DMF (6.8 mL) followed by triethylamine (2.13 mL, 153 mmol) to give a tan solution. The reaction was stirred for 24 h, diluted with ethyl acetate (50 mL) and poured into a separatory funnel. The organic layer was washed successively with saturated aqueous ammonium chloride (25 mL), saturated aqueous sodium bicarbonate (25 mL), and saturated aqueous sodium chloride (25 mL). The organic layer was separated, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (Biotage, 50 g silica gel column, eluting with ethyl acetate/hexanes gradient) to give 5-((4-hydroxy-1-(4-(hydroxymethyl)benzoyl)piperidin-4-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Intermediate 2-7, 300 mg, 37%). 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.23 (s, 1H), 8.06 (s, 1H), 7.37-7.30 (m, 4H), 4.96, (s, 1H) 4.50 (s, 2H), 4.2-4.0 (m, 3H), 3.89 (s, 3H), 3.5-3.2 (m, 4H), (m, 4H) ppm. LCMS: (ESI) m/z 397.95 [M+H].

The Intermediates in Table 4 were synthesized according to the procedure described for Example 6 above.

A 250-mL round-bottom flask fitted with a nitrogen balloon, magnetic stir bar, condenser and thermometer was charged with pyrrolidin-3-ol (350 mg, 4.02 mmol), 5-bromo-2-iodopyridine (1 g, 3.52 mmol), toluene (60 mL), tris(dibenzylideneacetone)dipalladium (80 mg, 0.09 mmol), (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (110 mg, 0.18 mmol) and sodium tert-butoxide (1.02 g, 10.6 mmol). The reaction mixture was stirred for 14 h at 70° C. in an oil bath. After cooling to 23° C. the reaction was quenched with water (60 mL). The product was extracted with ethyl acetate (4×60 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with dichloromethane/methanol (10:1 v/v) to afford 1-(5-bromopyridin-2-yl)pyrrolidin-3-ol as a red solid (300 mg, 35%). LCMS: (ES) m/z 243, 245 [M+H].

A mixture of methyl 1,2,3,4-tetrahydroisoquinoline-6-carboxylate hydrochloride (230 mg, 1.01 mmol), bromobenzene (230 mg, 1.47 mmol), and cesium carbonate (0.66 g, 2.02 mmol) in 1,4-dioxane (10 mL) was purged with nitrogen. RuPhos precatalyst (15 mg, 0.020 mmol) was added and the reaction mixture was heated at 80° C. for 30 min, then 120° C. for 16 h. The solvent was removed under vacuum. The residue was diluted with water (30 mL), poured into a separatory funnel, and washed with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and the solvent was removed under vacuum and the crude mixture was purified on silica gel using a gradient of 0-100% ethyl acetatelhexanes, to give methyl 2-phenyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (200 mg, 74%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.00-7.76 (m, 2H), 7.30-7.12 (m, 3H), 6.75 (d, 2H), 6.75 (t, 1H), 4.35 (s, 2H), 384 (s, 3H), 3.39 (t, 2H), 2.94 (t, 2H) ppm. LCMS: (ESI) m/z 268 [M+H].

Sodium hydroxide (1.0 M aqueous, 2.24 mL, 2.24 mmol) was stirred with methyl 2-phenyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (Step 1, 200 mg, 0.75 mmol) in tetrahydrofuran (5 mL) at 50° C. for 48 h. Hydrochloric acid (1.0 M solution in water) was added to the reaction until the pH was 4. The mixture was poured into a separatory funnel and washed with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate to afford 2-phenyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (Intermediate 2-8, 150 mg, 79%), which was used without any further purification. LCMS: (ESI) m/z 254 [M+H].

The Intermediates in Table 5 were synthesized according to the procedure described in Example 8.

Title compound (300 mg, 38%) was prepared according to procedure described in Example 8, Step 1, utilizing 4-bromobenzoate (500 mg, 2.18 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (930 mg, 4.38 mmol) as starting materials. LCMS: (ESI) m/z 361 [M+H].

Title compound was prepared according to the procedure outlined in Example 2a, utilizing ethyl-4-(3,8-diaza-bicyclo[3.2.1]octan-8-carboxylicacid, 1,1-dimethylethylester-3-yl)benzoate (Step 1, 300 mg, 083 mmol) as starting material which was used directly for next step without further purification (200 mg, 92%) LCMS: (ESI) m/z 261 [M+H].

A 100-mL round-bottom flask was charged with ethyl 4-(3,8-diaza-bicyclo[3.2.1]octan-3-yl)benzoate hydrochloride (Step 2, 200 mg, 0.67 mmol), methanol (10 mL), formaldehyde (10 mL) and sodium triacetoxyborohydride (450 mg, 2.12 mmol). The resulting mixture was stirred for 4 h at 23° C. The reaction was then quenched by the addition of water (30 mL). The resulting solution was extracted with ethyl acetate (3×40 mL) and washed with brine (40 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:5 v/v) to afford to afford ethyl 4-(8-methyl-3,8-diaza-bicyclo[3.2.1]octan-3-yl)benzoate as a colorless oil (170 mg, 92%). LCMS (ESI) m/z 275 [M+H].

The title compound was prepared according to the procedure outlined in Example 10, Step 2 utilizing ethyl 4-(8-methyl-3,8-diaza-bicyclo[3.2.1]octan-3-yl)benzoate (Step 3, 170 mg, 0.62 mmol) as starting material (130 mg, 85%) as a colorless oil which was used directly in the next step without further purification. LCMS: (ES) m/z 247 [M+H].

Ether (30 mL), titanium(IV) isopropoxide (0.5 mL, 1.69 mmol) and dimethyl terephthalate (1.00 g, 5.15 mmol) were added to a 100-mL 3-necked round-bottom flask fitted with a nitrogen inlet, magnetic stir bar and condenser. This was followed by the addition of ethylmagnesium bromide (3.0 M in ether, 2.6 mL, 7.80 mmol) dropwise with stirring at 10° C. The resulting solution was stirred for 2 h at room temperature and then quenched by the addition of sulfuric acid (15% wt, 50 mL). The resulting solution was extracted with ethyl acetate (4×30 mL). The organic layers were combined and washed with saturated aqueous sodium carbonate (50 mL) and brine (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative TLC plate with petroleum ether/ethyl acetate (15:1 v/v) to afford methyl 4-(1-hydroxycyclopropyl)benzoate (250 mg, 25%). LCMS: (ESI) m/z 193 [M+H].

Methanol (20 mL), methyl 4-(1-hydroxycyclopropyl)benzoate (Step 1, 200 mg, 1.04 mmol), and lithium hydroxide (10% aqueous, 5 mL) were added to a 100-mL round-bottom flask fitted with a nitrogen inlet, magnetic stir bar and condenser. The resulting solution was stirred for 1 h at room temperature. The pH value of the solution was adjusted to 4 with hydrogen chloride (1.0 M aqueous). The resulting solution was extracted with dichloromethane (4×20 mL) and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 4-(1-hydroxycyclopropyl)benzoic acid (Intermediate 2-9) which was used without further purification. LCMS: (ESI) m/z 177 [M−H].

Example 11: Intermediate 2-11. 5-((4-Hydroxypiperidin-4-yl)methyl)-1-(6-phenylpyridin-3-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one Trifluoroacetic Acid Salt

Title compound (500 mg, 23%) was prepared according to procedure described in procedure used for intermediate 2-28a, 6-Bromopyridin-3-amine (2.00 g, 11.6 mmol) as starting material which was purified by column chromatography eluting with dichloromethane/methanol (20:1 v/v). LCMS. (ESI) m/z 188, 190 [M+H].

Title compound (235 mg, 33%) was prepared according to procedure outlined in Example 21, Step 1 utilizing 2-(ethoxymethylidene)propanedinitrile (326 mg, 2.67 mmol) and 2-bromo-5-hydrazinylpyridine (Step 1, 500 mg, 2.66 mmol) as starting materials LCMS: (ESI) m/z 264, 266 [M+H].

Step 3. 5-Amino-1-(6-phenylpyridin-3-yl)-1H-pyrazole-4-carbonitrile Buchwald dppf, Phosphate Tribasic

Title compound (180 mg, 93%) was prepared according to procedure outlined in Example 5 utilizing 5-Amino-1-(6-bromopyridin-3-yl)-1H-pyrazole-4-carbonitrile (Step 2, 195 mg, 0.74 mmol), phenylboronic acid (136 mg, 1.11 mmol), 1,4-dioxane (15 mL), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (48 mg) followed by column chromatography purification using ethyl acetate/petroleum ether (1:1 v/v) LCMS: (ESI) m/z 262 [M+H].

5-Amino-1-(6-phenylpyridin-3-yl)-1H-pyrazole-4-carbonitrile (Step 3, 170 mg, 0.65 mmol, 1.00 equiv) and formic acid (18 mL) were added to a 100-mL round-bottom flask fitted with a magnetic stir bar and condenser. The resulting solution was heated at reflux for 16 h, then cooled to room temperature and concentrated under vacuum. The solids were washed with ethyl acetate (3×20 mL) and dried to give 1-(6-phenylpyridin-3-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (170 mg, 90%). LCMS: (ESI) m/z 290 [M+H].

Step 5. Tert-Butyl 4-hydroxy-4-((4-oxo-1-(6-phenylpyridin-3-yl)-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)piperidine-1-carboxylate

Title compound (235 mg, 33%) was prepared according to procedure outlined in Example 21, Step 4 utilizing 1-(6-phenylpyridin-3-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Step 4, 160 mg, 0.55 mmol) as starting material followed by column chromatography purification using ethyl acetate/petroleum ether (1:3 v/v) (210 mg, 76%) LCMS: (ESI) m/z 503 [M+H].

Step 6. 5-((4-Hydroxypiperidin-4-yl)methyl)-1-(6-phenylpyridin-3-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one Trifluoroacetic Acid Salt

Title compound (235 mg, 33%) was prepared according to procedure outlined in Example 21. Step 5 utilizing tert-Butyl 4-hydroxy-4-((4-oxo-1-(6-phenylpyridin-3-yl)-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)piperidine-1-carboxylate (Step 5, 210 mg, 0.42 mmol), as starting material which was used without further purification. LCMS: (ESI) m/z 402 [M+H].

The Intermediates in Table 6 were synthesized according to the procedure described for Example 11, Steps 2, 3 and Step 6.

2-Chloro-4-hydroxybenzoic acid (3.00 g, 17.4 mmol), dichloromethane (100 mL), phenylboronic acid (4.24 g, 34.8 mmol), copper (II) acetate (7.87 g, 43.3 mmol), triethylamine (5.27 g, 52.1 mmol) and 4 Å molecular sieves (MS) (3.00 g) were added to a 250-mL round-bottom flask fitted with a nitrogen inlet and magnetic stir bar. The reaction mixture was stirred for 16 h at room temperature. The solids were filtered and the filtrate was concentrated under vacuum. The residue was purified on a silica gel column with dichloromethane/methanol (10:1 v/v) to afford 2-chloro-4-phenoxybenzoic acid (Intermediate 2-13, 790 mg, 18%), LCMS: (ESI) m/z 247 [M+H].

5-Bromo-2-phenyl-1,3-oxazole (500 mg, 2.23 mmol), [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium (II), complex with dichloromethane (96 mg, 0.12 mmol), triethylamine (1.00 mL, 7.17 mmol) and methanol (20 mL) were added to a 50-mL pressure tank reactor (3 atm) fitted with a magnetic stir bar and thermometer. The reactor was evacuated and flushed three times with nitrogen. Carbon monoxide was bubbled into the reactor and the resulting mixture was stirred for 16 h at 120° C. The reaction was then quenched by the addition water (50 mL) and extracted with dichloromethane (3×50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:2 v/v) to afford methyl 2-phenyloxazole-5-carboxylate (350 mg, 77%). LCMS: (ESI) m/z 204 [M+H].

Title compound was prepared according to procedure outlined in Example 10, Step 2, utilizing methyl 2-phenyloxazole-5-carboxylate (Step 1, 350 mg, 1.72 mmol) as starting material, and was used without further purification. LCMS: (ESI) m/z 188 [M−H].

Ethyl 1-benzyl-1H-pyrrole-2-carboxylate (458 mg, 2.00 mmol), potassium hydroxide (1.12 g, 20.0 mmol), water (10 mL) and methanol (50 mL) were added to a 100-mL round-bottom flask fitted with a magnetic stir bar, thermometer and condenser. The resulting solution was stirred for 16 h at 70° C. The pH of the solution was adjusted to 2 with hydrochloric acid (6.0 M aqueous) and the resulting solution was extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 1-benzyl-1H-pyrrole-2-carboxylic acid (Intermediate 2-17), which was used in the next step without purification. LCMS: (ESI) m/z 200 [M−H].

1H-pyrazole (1.00 g, 14.7 mmol), ethyl (E)-but-2-enoate (2.50 g, 21.9 mmol), acetonitrile (30 mL) and DBU (1.20 g, 7.88 mmol) were added to a 100-mL round-bottom flask fitted with a magnetic stir bar. The resulting solution was stirred for 16 h at room temperature. The reaction was then quenched by the addition of water (50 mL) and extracted with dichloromethane 1.3×40 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give ethyl 3-(1H-pyrazol-1-yl)butanoate which was used in the next step without any further purification. LCMS: (ESI) m/z 183 [M+H].

Title compound was prepared according to a similar procedure outlined for Example 10, Step 2 utilizing ethyl 3-(1H-pyrazol-1-yl)butanoate (Step 1, 2.0 g, 11.0 mmol) as starting material which was used without further purification.

A 500-mL round-bottom flask was charged with sodium ethoxide (28.3 g, 416 mmol) and ethanol (80 mL) followed by the addition of a solution of ethyl 2,2-difluoroacetate (43 g, 347 mmol) in ethyl acetate (170 mL) added slowly with stirring at 23° C. The resulting solution was stirred for 2 h at 60° C. Upon cooling to 23° C., the reaction was quenched by the addition of hydrochloric acid (6M, 150 mL) and the pH of the solution was adjusted to 4-5. The resulting solution was extracted with ethyl acetate (3×200 mL) and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum to afford ethyl 4,4-difluoro-3-oxobutanoate as a colorless oil which was used without further purification (29 g, 42%). GCMS m/z 166.

A 500-mL round-bottom flask was charged with ethyl 4,4-difluoro-3-oxobutanoate (8 g, 48.16 mmol), toluene (250 mL) and sodium borohydride (2.38 g, 64.63 mmol). The resulting solution was stirred for 2 h at 65° C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:5 to 1:2 v/v) to afford ethyl 4,4-difluoro-3-hydroxybutanoate (6.81 g, 84%). GCMS m/z 168.

A 25-mL round-bottom flask was charged with ethyl 4,4-difluoro-3-hydroxybutanoate (5 g, 48.16 mmol) and phosphorus pentoxide (3.4 g, 23.62 mmol). The resulting solution was stirred for 2 h at 70° C. in an oil bath. The crude product was purified by distillation under reduced pressure (1 mm Hg) and the fraction was collected at 100° C. to give (E)-ethyl 4,4-difluorobut-2-enoate as a colorless oil (1.8 g, 25%). GCMS m/z 150.

A 100-mL round-bottom flask was charged with 1H-pyrazole (102 mg, 1.50 mmol) and tetrahydrofuran (20 mL) followed by the addition of sodium hydride (52 mg, 2.17 mmol) at 0° C. The resulting solution was stirred 30 min at 0° C. before adding (E)-ethyl 4,4-difluorobut-2-enoate (150 mg, 1.00 mmol). The resulting solution was stirred 16 h at 23° C. The reaction was quenched by the addition of 10 mL of water and extracted with ethyl acetate (30 mL). The pH of the aqueous layer was adjusted to 4-5 with hydrochloride (6 M) and extracted with dichloromethane (2×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give 4,4-difluoro-3-(1H-pyrazol-1-yl)butanoic acid (90 mg) as a yellow oil which was used without further purification. LCMS: (ESI) m/z 191 [M+H].

The intermediates below were synthesized according to the procedures outlined in Example 16 above

Sodium hydride (188 mg, 7.83 mmol) and tetrahydrofuran (10 mL) were added to a 3-necked 100-mL round-bottom flask fitted with a nitrogen inlet, magnetic stir bar, and thermometer. Ethyl 2-(diethoxyphosphoryl)acetate (1.05 g, 4.68 mmol) was added dropwise with stirring at 0° C. and the resulting solution was stirred for 1 h at 0° C. A solution of 2-fluoro-1-phenylethan-1-one (500 mg, 3.62 mmol) in tetrahydrofuran (10 mL) was added at 0° C. and the resulting solution was stirred for 30 min at 0° C. and then for 16 h at room temperature. The reaction was quenched by the addition of saturated aqueous ammonium chloride (30 mL) and extracted with ether (4×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography using ethyl acetate/petroleum ether (1:30 v/v) to afford ethyl (Z)-4-fluoro-3-phenylbut-2-enoate (630 mg, 84%). LCMS: (ESI) m/z 209 [M+H].

Ethyl (Z)-4-fluoro-3-phenylbut-2-enoate (Step 1, 200 mg, 0.96 mmol), palladium on carbon (10% wt, 30 mg) and ethyl acetate (30 were added to a 100-mL round-hottom flask fitted with a magnetic stir bar. The reaction mixture was purged and pressurized with hydrogen (2 atm) and then stirred for 40 min at room temperature. The reaction mixture was then filtered and concentrated under reduced pressure to afford ethyl 4-fluoro-3-phenylbutanoate which was used in next step without further purification. GCMS: n/z 210 [M+H].

Ethyl 4-fluoro-3-phenylbutanoate (200 mg, 0.96 mmol), lithium hydroxide (202 mg, 4.80 mmol), water (5 mL) and methanol (20 mL) were added to a 100-mL round-bottom flask fitted with a magnetic stir bar. The resulting solution was stirred for 2 h at room temperature. The pH was adjusted to 5 with hydrogen chloride (6.0 M aqueous) and the mixture was extracted with dichloromethane (5×20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by preparative HPLC (Waters SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×150 mm, Mobile phase A: 0.05% aqueous trifluoroacetic acid, Mobile phase B: acetonitrile, Gradient: 20% B to 60% B over 12 min; Detector: 220 and 254 nm) to give 4-fluoro-3-phenylbutanoic acid (Intermediate 2-43, 89 mg, 51%). (ESI) m/z 181 [M−H]. 1 H NMR (300 MHz, CDCl 3 ) δ 10.29-8.78 (m, 1H), 7.36-6.99 (m, 5H), 4.69-4.38 (m, 2H), 3.58-3.43 (m, 1H), 2.98-2.70 (m, 2H) ppm.

The intermediates below were synthesized according to the procedures outlined in Example 17.

1H-Pyrrole (1.00 g, 14.9 mmol), ethyl (2E)-but-2-enoate (1.70 g, 14.9 mmol) and DMF (20 mL) were added to a 100-mL round-bottom flask fitted with a nitrogen inlet, magnetic stir bar and thermometer. This was followed by the addition of sodium hydride (60% in mineral oil, 180 mg, 4.50 mmol) at −10° C. The resulting solution was allowed to warm to room temperature and stirred for 16 h. The reaction was then quenched by the addition of water (20 mL). The resulting solution was stirred for 2 h at room temperature. The pH was adjusted to ˜6 with hydrochloric acid (1.0 M aqueous). The resulting solution was extracted with dichloromethane (4×50 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 3-(1H-pyrrol-1-yl)butanoic acid (Intermediate 2-22) which was used without further purification LCMS: (ESI) m/z: 152 [M−H].

The Intermediates below were synthesized according to the procedures described in Example 18. For 2-54 and 2-55, hydrolysis was facilitated by the addition of a solution of lithium hydroxide (2.5 mmol) in water (20 mL).

Example 19: Intermediate 2-931a, 1-[4-(3-hydroxy-3-methylpyrrolidin-1-yl)phenyl]-5-[(4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one, TFA Salt

Step 1. Tert-Butyl 4-hydroxy-4-([1-[4-(3-hydroxy-3-methylpyrrolidin-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazol[3,4-d]pyrimidin-5-yl]methyl)piperidine-1-carboxylate

A 100-mL round-bottom flask fitted with a nitrogen balloon, magnetic stir bar, condenser and thermometer was charged with tert-butyl 4-[[1-(4-bromophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl]-4-hydroxypiperidine-1-carboxylate (900 mg, 1.78 mmol), 3-methylpyrrolidin-3-ol hydrochloride (990 mg, 7.19 mmol), cesium carbonate (3.82 g, 11.7 mmol), 1,4-dioxane (30 mL), tetra(dibenzylideneacetone)dipalladium (207 mg, 0.18 mmol) and Xphos (171 mg, 0.36 mmol). The resulting solution was stirred for 16 h at 100° C. After cooling to 23° C. the reaction was quenched by the addition of water (30 mL). The resulting mixture was extracted with dichloromethane (4×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with dichloromethane/methanol (50:1-20:1, v/v) to give tert-butyl 4-hydroxy-4-([1-[4-(3-hydroxy-3-methylpyrrolidin-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl)piperidine-1-carboxylate as a yellow solid (700 mg, 75%). LCMS: (ES) m/z 525 [M+H].

Step 2. 1-[4-(3-hydroxy-3-methylpyrrolidin-1-yl)phenyl]-5-[(4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one, TFA Salt

The title compound was prepared according to procedure outlined in Example 2 utilizing tert-butyl 4-hydroxy-4-([1-[4-(3-hydroxy-3-methylpyrrolidin-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl)piperidine-1-carboxylate (200 mg, 0.38 mmol) as starting material (210 mg, >95%). LCMS: (ES) m/z 425 [M+H].

Table 10: The Intermediates below were synthesized according to the procedures described in Example 19.

Example 20: N-[(2R)-2-benzyl-3-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidin-1-yl]-3-oxopropyl]prop-2-ynamide

Step 1. Tert-butyl-N-[(2S)-2-benzyl-3-[4-hydroxy-4-([4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl)piperidin-1-yl]-3-oxopropyl]carbamate

The title compound was prepared according to the procedure outlined in Example 3 utilizing 5-[(4-hydroxypiperidin-4-yl)methyl]-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one TFA salt (0.20 g, 0.46 mmol) and (2R)-2-benzyl-3-[[(tert-butoxy)carbonyl]amino] propanoic acid as starting materials followed by column chromatography purification eluting with ethyl acetate/petroleum ether (1:1 v/v) (0.190 g, 57%) LCMS: (ESI) m/z 587 [M+H].

Step 2. 5-([1-[(2S)-3-amino-2-benzylpropanoyl]-4-hydroxypiperidin-4-yl]methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one, TFA Salt

The title compound was prepared according to the procedure outlined in Example 2 utilizing tert-butyl N-[(2S)-2-benzyl-3-[4-hydroxy-4-([4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl)piperidin-1-yl]-3-oxopropyl]carbamate (0.190 g, 0.32 mmol) as starting material which was used without further purification. LCMS: (ESI) m/z 487 [M+H].

1-(4-Fluorophenyl)-5-((4-hydroxypiperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one Trifluoroacetic Acid Salt (Intermediate 2-28) and

Tert-Butyl 4-((1-(4-fluorophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4-hydroxypiperidine-1-carboxylate (Intermediate 2-29)

2-(Methoxymethylene)malononitrile (1.00 g, 8.19 mmol), (4-fluorophenyl) hydrazine hydrochloride (1.40 g, 8.61 mmol), triethylamine (1.66 g, 16.4 mmol) and ethanol (50 mL) were added to a 100-mL round-bottom flask fitted with a magnetic stir bar and condenser. The resulting solution was heated at reflux for 16 h. The resulting mixture was concentrated under vacuum. The residue was purified by column chromatography eluting with dichloromethane/methanol (10:1 v/v) to give 5-amino-1-(4-fluorophenyl)-1H-pyrazole-4-carbonitrile (1.00 g, 60%). LCMS: (ESI) m/z 203 [M+H].

5-Amino-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (Step 1, 900 mg, 4.45 mmol) was added dropwise to sulfuric acid (10 mL) at 0° C. The resulting solution was stirred for 2 h at 25° C. The pH of the solution was adjusted to 8 by the addition of sodium carbonate (10% aqueous). The resulting mixture was extracted with dichloromethane (4×50 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide 5-amino-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide which was used in Step 3 without further purification. LCMS: (ESI) m/z 221 [M+H].

5-Amino-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (Step 2, 1.00 g, 4.54 mmol), triethyl orthoformate (20 mL) and acetic anhydride (20 mL) were added to a 100-mL round-bottom flask fitted with a magnetic stir bar and condenser. The resulting solution was heated at reflux for 1 h and then concentrated under vacuum. The solids were collected and washed with hexane (3×20 mL) to afford 1-(4-fluorophenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one which was used in the next step without further purification. LCMS: (ESI) m/z 231 [M+H].

Step 4. Tert-Butyl 4-((1-(4-fluorophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4-hydroxypiperidine-1-carboxylate

1-(4-Fluorophenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Step 3, 1.00 g, 4.34 mmol), tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (926 mg, 4.34 mmol), cesium carbonate (4.30 g, 13.2 mmol) and DMF (50 mL) were added to a 100-mL round-bottom flask fitted with a magnetic stir bar and thermometer. The resulting solution was stirred for 5 h at 80° C. The resulting solution was diluted with water (50 mL). The mixture was extracted with MTBE (5×20 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with dichloromethane/methanol (50:1 v/v) to give tert-butyl 4-((1-(4-fluorophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4-hydroxypiperidine-1-carboxylate (Intermediate 2-29, 500 mg, 26%), LCMS: (ESI) m/z 444 [M+H].

Step 5. 1-(4-Fluorophenyl)-5-((4-hydroxypiperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one Trifluoroacetic Acid Salt

tert-Butyl 4-((1-(4-fluorophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4-hydroxypiperidine-1-carboxylate (Step 4, 500 mg, 1.13 mmol), dichloromethane (30 mL) and trifluoroacetic acid (3 mL) were added to a 50-mL round-bottom flask fitted with a magnetic stir bar and condenser. The resulting solution was stirred for 2 h at 25° C. The resulting mixture was concentrated under vacuum to give 1-(4-fluorophenyl)-5-((4-hydroxypiperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one Trifluoroacetic Acid Salt (Intermediate 2-28) which was used without further purification. LCMS: (ESI) m/z 344 [M+H].

Table 12: The intermediates in Table 12 were synthesized according to procedure described Example 21. All intermediates prepared according to Intermediate 2-28 were isolated as TFA salts, unless otherwise specified. Some hydrazines were prepared according to general procedure described below.

A 250-mL 3-necked round-bottom flask fitted with a magnetic stir bar and thermometer was charged with corresponding aniline or amine (89.20 mmol), hydrochloric acid (100 mL, 6N) followed by the addition of a solution of sodium nitrite (107.25 mmol) in water (20 mL) slowly added with stirring for 1 h at −20 to −10° C. To the reaction was slowly added a solution of SnCl 2 (269.2 mmol) in hydrochloric acid (50 mL, 12N) and stirring continued for 1 h. The reaction was warmed to 23° C. and the pH was adjusted to 8 with potassium hydroxide (6 N). The solids were removed by filtration. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the desired hydrazine.

Example 22: Intermediate 2-922a. 1-[3-(3-fluoro-1H-pyrazol-1-yl)phenyl]-5-[(4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one TFA Salt

Step 1. Tert-Butyl 4-([1-[3-(3-fluoro-1H-pyrazol-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl)-4-hydroxypiperidine-1-carboxylate

A 50-mL 3-necked round-bottom fitted with a nitrogen balloon, magnetic stir bar condenser and thermometer was charged with tert-butyl 4-[[1-(3-bromophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl]-4-hydroxypiperidine-1-carboxylate (Intermediate 30a, 294 mg, 0.58 mmol), 1,4-dioxane (10 mL), 3-fluoro-1H-pyrazole (100 mg, 1.16 mmol), CuI (5.7 mg, 0.03 mmol), potassium carbonate (248 mg, 1.79 mmol) and (1R,2R)-cyclohexane-1,2-diamine (17 mg, 0.15 mmol). The resulting mixture was stirred for 16 h at 100° C. under nitrogen. After cooling to 25° C., the reaction was quenched with water (10 mL). The product was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with dichloromethane/ethyl acetate (5:1-2:1, v/v) to give tert-butyl 4-([1-[3-(3-fluoro-1H-pyrazol-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl)-4-hydroxypiperidine-1-carboxylate (100 mg, 34%). LCMS: (ES) m/z 510 [M+H].

Step 2. 1-[3-(3-fluoro-1H-pyrazol-1-yl)phenyl]-5-[(4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one TFA Salt

The title compound was prepared according to procedure outlined in Example 2, utilizing tert-butyl-4-([1-[3-(3-fluoro-1H-pyrazol-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl)-4-hydroxypiperidine-1-carboxylate (Step 1, 100 mg, 0.20 mmol), as starting material (110 mg, >95%). LCMS: (ES) m/z 410 [M+H].

The intermediate below was synthesized according to the general procedure outlined above in Example 22.

Example 23: Intermediate 926a. 5-((4-Hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl)methyl)-1-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

A 50-mL 3-necked round-bottom fitted with a nitrogen balloon, magnetic stir bar and thermometer was charged with 5-([4-hydroxy-1-[(1-methylcyclopropyl)carbonyl]piperidin-4-yl]methyl)-1-(3-methoxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (prepared according to procedure outlined in Example 6, utilizing 5-[(4-hydroxypiperidin-4-yl)methyl]-1-(3-methoxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one Intermediate 926aa, and 1-methylcyclopropane-1-carboxylic acid) (800 mg, 1.74 mmol) and dichloromethane (5 mL). To the reaction was added boron tribromide in dichloromethane (8.69 mL, 3.69 mmol, 1 M) dropwise with stirring at −50° C. After addition, the resulting solution was stirred for 16 h at 25° C. The reaction was quenched with water (20 mL). The product was extracted with dichloromethane (3×30 mL) and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 5-([4-hydroxy-1-[(1-methylcyclopropyl)carbonyl]piperidin-4-yl]methyl)-1-(3-hydroxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one as a light yellow solid (620 mg, 84%). LCMS: (ESI) in m/z 424 [M+H].

Example 24: Intermediate 2-33. 1-(3-(Hydroxymethyl)phenyl)-5-((4-hydroxypiperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one Trifluoroacetic Acid Salt

1-(m-Tolyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

The title compound was prepared according to the procedure outlined in Example 21, Step 1 to Step 3, utilizing (3-methylphenyl)hydrazine hydrogen chloride as starting material (7.27 g, 64%). LCMS: (ESI) m/z 227 [M+H].

1-(m-Tolyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (500 mg, 2.2 mmol), benzoyl peroxide (268 mg, 1.05 mmol), N-bromosuccinimide (473 mg, 2.66 mmol) and carbon tetrachloride (50 mL) were added to a 100-mL round-bottom flask fitted with a nitrogen inlet, magnetic stir bar and condenser. The resulting solution was stirred for 16 h at 100° C. The resulting mixture was concentrated under vacuum to give 1-(3-(dibromomethyl)phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one which was used in next step without further purification. LCMS: (ESI) m/z 383, 385, 387 [M+H].

1-(3-(Dibromomethyl)phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Step 1, 800 mg, 2.08 mmol), calcium carbonate (10) g), 1,4-dioxane (50 mL) and water (50 mL) were added to a 250-mL round-bottom flask fitted with a nitrogen inlet, magnetic stir bar and condenser. The resulting solution was heated to reflux for 2 h. The solids were filtered and the filtrate was concentrated under vacuum to give 3-(4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzaldehyde which was used in next step without further purification. LCMS: (ESI) m/z 241 [M+H].

3-(4-Oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzaldehyde (Step 2, 500 mg, 2.08 mmol), methanol (30 mL) and sodium borohydride (70 mg, 1.85 mmol, 0.89 equiv) were added to a 100-mL round-bottom flask fitted with a nitrogen inlet, magnetic stir bar and condenser. The resulting solution was stirred for 2 h at room temperature and then concentrated under vacuum. The residue was purified by preparative TLC with dichloromethane/methanol (5:1 v/v) to provide 1-(3-(hydroxymethyl)phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (120 mg, 24%). LCMS: (ESI) m/z 243 [M+H].

Step 4. Tert-Butyl 4-hydroxy-4-((1-(3-(hydroxymethyl)phenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)piperidine-1-carboxylate

The title compound was prepared according to the procedure described in Example 21, Step 4, utilizing 1-(3-(hydroxymethyl)phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Step 3, 300 mg, 1.24 mmol) as starting material followed by purification by preparative TLC with dichloromethane/methanol (20:1 v/v) (80 mg, 14%). LCMS: (ESI) m/z 456 [M+H].

Step 5. 1-(3-(Hydroxymethyl)phenyl)-5-((4-hydroxypiperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one Trifluoroacetic Acid Salt

The title compound was prepared according to the procedure described in Example 21, Step 4, utilizing tert-Butyl 4-hydroxy-4-((1-(3-(hydroxymethyl)phenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)piperidine-1-carboxylate as starting material (Step 4, 80 mg, 0.18 mmol and was used without further purification. LCMS: (ESI) m/z 356 [M+H].

A 250-mL 3-necked round-bottom fitted with a magnetic stir bar condenser and thermometer was charged with 4-chloro-1H-pyrazole (3 g, 29 mmol), N,N-dimethylformamide (80 mL), 1-fluoro-4-nitrobenzene (4 g, 28.4 mmol) and cesium carbonate (27.8 g, 85.3 mmol) The resulting mixture was stirred for 1 h at 110° C. After cooling to 23° C., the reaction was quenched with water (150 mL). The solids were collected by filtration, washed with water (50 mL) and dried in an oven to afford 4-chloro-1-(4-nitrophenyl)-1H-pyrazole as a light yellow solid (6.2 g, 96%). LCMS: (ESI) m/z 224, 226 [M+H].

A 100-mL 3-necked round-bottom fitted with a magnetic stir bar condenser and thermometer was charged with 4-chloro-1-(4-nitrophenyl)-1H-pyrazole (Step 1, 3 g, 13.4 mmol), ethanol (10 mL), water (10 mL), iron (2.5 g, 44.8 mmol), ammonium chloride (2.1 g, 39.3 mmol) and tetrahydrofuran (10 mL). The resulting mixture was stirred for 1 h at 80° C. After cooling to 23° C., the solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was diluted with water (100 mL)) and the resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford 4-chloro-1-(4-nitrophenyl)-1H-pyrazole as a light yellow solid (2.0 g, 77%). LCMS: (ESI) m/z 194, 196 [M+H].

A 100-mL 3-necked round-bottom fitted with a magnetic stir bar and thermometer was charged with 4-(4-chloro-1H-pyrazol-1-yl)aniline (Step 2, 2.0 g, 10.33 mmol), hydrochloric acid (12N, 20 mL) and ethanol (10 mL). The resulting solution was cooled to −20 followed by sodium nitrite (1.06 g, 15.4 mmol) in water (5 mL) added dropwise with stirring at −20° C. After the mixture was stirred for 0.5 h at −10° C., tin(II) chloride (4.6 g, 20.4 mmol) was added in portions at −10° C. The resulting solution was then stirred for additional 0.5 h at −10° C. The solids were collected by filtration and dried in an oven to afford the HCl salt of 4-chloro-1-(4-hydrazinylphenyl)-1H-pyrazole (800 mg crude, 32%). LCMS: (ESI) m/z 209, 211 [M+H].

The Intermediates in Table 14 were prepared according to the procedures outlined in Example 25.

Methyl 4-acetylbenzoate (1.00 g, 5.61 mmol), tetrahydrofuran (50 mL), tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 33 mL), and trimethyl(trifluoromethyl)silane (2.40 g, 16.9 mmol) were added to a 250-mL round-bottom flask at 0° C. The resulting solution was stirred for 16 h at room temperature. Brine (10 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate petroleum ether (15:85 v/v) to give methyl 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoate (850 mg, 53%). LCMS (ESI) m/z 249 [M+H].

Methyl 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoate (Step 1, 450 mg, 1.81 mmol), methanol (30 mL), lithium hydroxide (228 mg, 5.43 mmol)) and water (10 mL) were added to a 100-mL round-bottom flask. The resulting solution was stirred for 2 h at 60° C. and then concentrated under vacuum. The pH value of the solution was adjusted to 4 with hydrogen chloride (1.0 M aqueous). The solution was then extracted with dichloromethane (3×10 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoic acid (Intermediate 2-35) which was used without further purification. LCMS: (ESI) m/z 233 [M−H].

Trimethylsulfoxonium iodide (11.2 g, 51.0 mmol), dimethyl sulfoxide, (15 mL) and sodium hydride (60% in mineral oil, 157 mg, 6.54 mmol) were added to a 50-mL round-bottom flask fitted with a magnetic stir. The resulting mixture was stirred for 30 min at room temperature. 1-benzoylpiperidin-4-one (500 mg, 2.18 mmol) was added and the resulting solution was stirred at room temperature for 4 h. The reaction was quenched by the addition of water (30 mL) and extracted with dichloromethane (3×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography using ethyl acetate to afford phenyl(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone (Intermediate 2-36, 2.00 g, 54%). LCMS: (ESI) m/z 218 [M+H].

The Intermediates in Table 15 were prepared according to a procedure similar to that outlined in Example 27.

Example 28: Intermediate 2-40. 3-(3-((1-(4-Fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)benzonitrile

3-(4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)benzonitrile (prepared from pyrrolo[2,3-d]pyrimidine and 3-cyanophenylboronic acid) (180 mg, 0.76 mmol), (4-fluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone (Intermediate 2-46, 180 mg, 0.77 mmol), cesium carbonate (745 mg, 2.29 mmol) and DMF (10 mL) were added to a 100-mL, round-bottom flask fitted with a magnetic stir bar and condenser. The resulting solution was stirred for 90 min at 80° C. and then (quenched by the addition of water (30 mL). The resulting solution was extracted with ethyl acetate (4×40 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound which was used without further purification. LCMS: (ESI) m/z 472 [M+H].

Example 29: Intermediate 2-112. 1-(4-fluorophenyl)-5-((4-hydroxypiperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one Trifluoroacetic Acid Salt

A 100-mL 3-necked round-bottom flask fitted with a nitrogen inlet, magnetic stir bar, condenser and thermometer was charged with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2 g, 13.0 mmol), 1-fluoro-4-iodobenzene (3.3 g, 14.9 mmol), potassium carbonate (3.58 g, 25.9 mmol), 1,4-dioxane (40 mL), (1R,2R)-cyclohexane-1,2-diamine (300 mg, 2.63 mmol) and cuprous iodide (493 mg, 2.59 mmol). The resulting solution was stirred 16 h at 110° C. in an oil bath under nitrogen. After cooling to 25° C., the solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:2, v/v) to afford 4-chloro-7-(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine as a light yellow solid (1.0 g, 31%). LCMS: (ESI) m/z 248, 250 [M+H].

A 100-mL 3-necked round-bottom flask fitted with a magnetic stir bar, condenser and thermometer was charged with 4-chloro-7-(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (Step 1, 800 mg, 3.23 mmol), 1,4-dioxane (10 mL, 118.0 mmol), water (50 mL), potassium carbonate (4.2 g, 30.4 mmol) and 1,4-diazabicyclo[2.2.2]octane (727 mg, 6.48 mmol). The resulting solution was stirred for 3 h at 80° C. in an oil bath. After cooling to 25° C. the reaction was quenched with water (70 mL). The product was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford 7-(4-fluorophenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one as a white solid (700 mg, 94%). LCMS: (ESI) m/z 230 [M+H].

Step 3. Tert-Butyl 4-((7-(4-4-fluorophenyl)-4-oxo-4H-pyrrolo[2,3-d]pyrimidin-3(7H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate

Title compound (500 mg, 43%) was prepared according to the procedure outline in Example 21, Step 4, utilizing 7-(4-fluorophenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (Step 2, 600 mg, 2.62 mmol) as starting material followed by column chromatography purification eluting with methanol/dichloromethane (1:20, v/v) LCMS: (ESI) m/z 443 [M+H].

Step 4. 7-(4-fluorophenyl)-3-((4-hydroxypiperidin-4-yl)methyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one Trifluoroacetic Acid Salt

Title compound (470 mg, 95%) was prepared according to the procedure outline in Example 21, Step 5, utilizing tert-butyl 4-[[7-(4-fluorophenyl)-4-oxo-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-3-yl] methyl]-4-hydroxypiperidine-1-carboxylate (Step 3, 500 mg, 1.13 mmol) as starting material LCMS: (ESI) m/z 343 [M+H].

The Intermediate in Table 16 was prepared using a procedure similar to that outlined for Example 30.

Example 31: Intermediate 2-2101. 3-((4-hydroxypiperidin-4-yl)methyl)-7-(3-(4-methylpiperazin-1-yl)phenyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one, Trifluoroacetic Acid Salt

A 250-mL round-bottom flask fitted with a magnetic stir bar was charged with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2.0 g, 13.0 mmol), (3-bromophenyl)boronic acid (3.12 g, 15.5 mmol), cupric acetate (708 mg, 3.90 mmol), dichloromethane (60 mL) and pyridine (3.08 g, 38.94 mmol). The resulting solution was stirred for 5 h at 25° C. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was diluted with water (50 mL) and the product was extracted with dichloromethane (5×40 mL). The combined organic layers were washed with hydrochloric acid (40 mL, 6N), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:2, v/v) to give 7-(3-bromophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2.0 g, 50%). LCMS: (ESI) m/z 308, 310, 312 [M+H].

A 250-mL 3-necked round-bottom flask fitted with a magnetic stir bar, condenser and thermometer was charged with 7-(3-bromophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (Step 1, 800 mg, 2.59 mmol), 1,4-diazabicyclo[2.2.2]octane (581 mg, 5.18 mmol), potassium carbonate (3.37 g, 24.4 mmol), 1,4-dioxane (20 mL) and water (40 mL). The resulting solution was stirred 16 h at 100° C. in an oil bath. After cooling to 25° C., the reaction was diluted with water (50 mL). The product was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (9:1, v/v) to give 7-(3-bromophenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (600 mg, 80%). LCMS: (ESI) m/z 290, 292 [M+H].

Step 3. Tert-Butyl 4-((7-(3-bromophenyl)-4-oxo-4H-pyrrolo[2,3-d]pyrimidin-3(7H)-yl)methyl)-4-hydroxypiperidine-4-carboxylate

A 100-mL 3-necked round-bottom flask fitted with a magnetic stir bar, condenser and thermometer was charged with 7-(3-bromophenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (300 mg, 1.03 mmol), tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (264 mg, 1.24 mmol), cesium carbonate (Step 2, 1.01 g, 3.10 mmol) and N,N-dimethylformamide (20 mL). The solution was stirred for 2 h at 80° C. in an oil bath. After cooling to 25° C., the reaction was quenched with water (50 mL). The product was extracted with ethyl acetate (5×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford tert-butyl 4-[[7-(3-bromophenyl)-4-oxo-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxypiperidine-1-carboxylate (230 mg). LCMS: (ESI) m/z 503, 505 [M+H].

Step 4. Tert-Butyl 4-hydroxy-4-((7-(3-(4-methylpiperazin-1-yl)phenyl)-4-oxo-4H-pyrrolo[2,3-d]pyrimidin-3-(7H)-yl)methyl)piperidine-1-carboxylate

A 100-mL 3-necked round-bottom flask fitted with a nitrogen balloon, magnetic stir bar, condenser and thermometer was charged with tert-butyl 4-[[7-(3-bromophenyl)-4-oxo-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxypiperidine-1-carboxylate (Step 3, 170 mg, 0.34 mmol), 1-methylpiperazine (44.3 mg, 0.44 mmol), cesium carbonate (332.5 mg, 1.02 mmol), 1,4-dioxane (20 mL), tris(dibenzylideneacetone)dipalladium-chloroform adduct (35.2 mg, 0.03 mmol) and (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (21 mg, 0.03 mmol). The resulting solution was stirred for 16 h at 110° C. in an oil bath under nitrogen. After cooling to 25° C., the solids were removed by filtration and the filtrate was diluted with water (100 mL). The product was extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting with dichloromethane/methanol (10:1, v/v) to give tert-butyl 4-hydroxy-4-([7-[3-(4-methylpiperazin-1-yl)phenyl]-4-oxo-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-3-yl]methyl)piperidine-1-carboxylate (100 mg, 57%). LCMS: (ESI) m/z 523 [M+H].

Step 5. 3-((4-hydroxypiperidin-4-yl)methyl)-7-(3-(4-methylpiperazin-1-yl)phenyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one, TFA Salt

A 50-mL round-bottom flask fitted with a magnetic stir bar was charged with tert-butyl 4-hydroxy-4-([7-[3-(4-methylpiperazin-1-yl)phenyl]-4-oxo-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-3-yl]methyl)piperidine-1-carboxylate (Step 4, 100 mg, 0.19 mmol), dichloromethane (10 mL) and trifluoroacetic acid (1 mL). The resulting solution was stirred for 3 h at 25° C. The resulting mixture was concentrated under vacuum to give the TFA salt of 3-[(4-hydroxypiperidin-4-yl)methyl]-7-[3-(4-methylpiperazin-1-yl)phenyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (130 mg, >95%), LCMS. (ESI) m/z 423[M+H].

The Intermediates in Table 17 were prepared using a procedure similar to that outlined for Example 31 and isolated as TFA salts.

Example 32: Intermediate 2-47. 3-((1-(4-Fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(piperidin-4-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one Trifluoroacetic Acid Salt

4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (2.00 g, 13.0 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (7.80 g, 38.8 mmol), triphenylphosphine (4.52 g, 17.2 mmol) and tetrahydrofuran (120 mL) were added to a 500-mL 3-necked round-bottom flask fitted with a nitrogen inlet and magnetic stir bar. A solution of diethyl azodicarboxylate (6.80 g, 39.1 mmol) in toluene (30 mL) was then added dropwise with stirring at room temperature. The resulting solution was stirred for 4 h at room temperature, quenched by the addition of water (100 mL) and extracted with dichloromethane (3×100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using ethyl acetate/petroleum ether (1:1 v/v) to afford tert-butyl 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (2.50 g, 57%). LCMS: (ESI) m/z 337 [M+H].

tert-Butyl 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (Step 1, 2.50 g, 7.42 mmol), DABCO (1.70 g, 15.2 mmol), potassium carbonate (10.2 g, 73.8 mmol), 1,4-dioxane (80 mL) and water (40 mL) were added to a 250-mL round-bottom flask fitted with a magnetic stir bar and condenser. The resulting solution was stirred for 4 h at 60° C., diluted with water (50 mL) and extracted with ethyl acetate (5×50 mL). The organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography using dichloromethane/methanol (10/1 v/v) to afford tert-butyl 4-(4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (1.30 g, 55%). LCMS: (ESI) m/z 319 [M+H].

Step 3. Tert-Butyl 4-(3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxa-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate

tert-butyl 4-(4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (Step 2, 600 mg, 1.88 mmol), (4-fluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone (Intermediate 2-46, 300 mg, 1.28 mmol), cesium carbonate (1.25 g, 3.83 mmol) and DMF (50 mL) were added to a 100-mL round-bottom flask fitted with a magnetic stir bar and condenser. The resulting solution was stirred for 2 h at 80° C. and then quenched by the addition of water (30 mL). The resulting solution was extracted with ethyl acetate (4×50 mL) and the organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC with methanol/dichloromethane (1:20 v/v) to afford tert-butyl 4-(3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (600 mg, 58%). LCMS: (ESI) m/z 554 [M+H].

Step 4, 3-((1-(4-Fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(piperidin-4-yl)-3,7-dihydro-4H-pyrrolo[3,4-d]pyrimidin-4-one Trifluoroacetic Acid Salt

tert-Butyl 4-(3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (Step 3, 600 mg, 1.08 mmol), dichloromethane (30 mL) and trifluoroacetic acid (6 mL) were added to a 100-mL round-bottom flask fitted with a magnetic stir bar. The resulting solution was stirred for 2 h at room temperature and then concentrated under reduced pressure to give 3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(piperidin-4-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one trifluoroacetic acid salt (Intermediate 2-47) which was used in next step without further purification. LCMS: (ESI) m/z 454 [M+H].

A 250-mL round-bottom flask was charged with methyl 3-formylbenzoate (1 g, 6.09 mmol) pyrrolidine (433 mg, 6.09 mmol) and chloroform (100 mL). The resulting solution was stirred at 0° C. for 1 h. Sodium borohydride (70 mg, 1.85 mmol) and acetic acid (5 mL) were added to the mixture at 0° C. The resulting solution was stirred 16 h at 23° C. The pH of the solution was adjusted to 8 with saturated sodium bicarbonate solution (30 mL) and extracted with dichloromethane (3×100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:4 v/v) to afford methyl 4-(pyrrolidin-1-ylmethyl)benzoate (500 mg, 37%) as a colorless oil. LCMS: (ESI) m/z 220 [M+H].

A 100-mL round-bottom flask was charged with methyl 3-(pyrrolidin-1-ylmethyl) benzoate (500 mg, 2.28 mmol), methanol (20 mL), lithium hydroxide (274 mg, 11.44 mmol) and water (5 mL). The resulting solution was stirred for 1 h at 40° C. The pH of the solution was adjusted to 6 with hydrochloric acid (6.0 M). The solids were collected by filtration, washed with ethyl acetate (3×20 mL) and dried in an oven to afford 4-(pyrrolidin-1-ylmethyl)benzoic acid as a white solid which was used without further purification (Intermediate 2-57, 650 mg, >95%). LCMS (ESI) m/z 206 [M+H].

The intermediates in Table 18 were synthesized according to the procedures above.

A 25-mL round-bottom flask was charged with piperidine-1-carbonyl chloride (178 mg, 1.21 mmol), ethyl (hydrazinecarbonyl)formate (132 mg, 1.00 mmol), triethylamine (152 mg, 1.50 mmol) and tetrahydrofuran (10 mL). The resulting solution was stirred 16 h at 60° C. The reaction was then quenched by the addition of 20 mL of water and extracted with dichloromethane (2×10 mL). The organic layers were combined and washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (5:1 to 20.1 v/v) to afford ethyl 2-oxo-2-(2-(piperidine-1-carbonyl hydrazinyl)acetate (200 mg, 82%) as a white solid. LCMS (ESI) m/z 244 [M+H].

A 25-mL round-bottom flask was charged with 2-oxo-2-(2-(piperidine-1-carbonyl hydrazinyl)acetate (Step 1, 100 mg, 0.41 mmol), 4-methylbenzene-1-sulfonyl chloride (78 mg, 0.41 mmol), triethylamine (50 mg, 0.49 mmol) and dichloromethane (15 mL). The resulting solution was stirred 16 h at 23° C. The reaction was then quenched by the addition of water (10 mL) and the resulting mixture was extracted with dichloromethane (3×10 mL). The organic layers were combined and washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (2:1 to 10:1 v/v) to afford ethyl 5-(piperidin-1-yl)-1,3,4-oxadiazole-2-carboxylate as an off-white solid (80 mg, 87%). LCMS: (ESI) m/z 226 [M+H].

A 25-mL round-bottom flask was charged with ethyl 5-(piperidin-1-yl)-1,3,4-oxadiazole-2-carboxylate (Step 2, 80 mg, 0.35 mmol), lithium hydroxide (17 mg, 0.70 mmol), water (5 mL) and tetrahydrofuran (5 mL). The resulting solution was stirred for 3 h at 23° C. The pH of the solution was adjusted to 5-6 with hydrochloric acid (6.0 M). The resulting solution was extracted with dichloromethane (2×30 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford 5-(piperidin-1-yl)-1,3,4-oxadiazole-2-carboxylic acid (Intermediate 2-59, 60 mg, 87%) as an off-white solid which was used directly in the next step without further purification. LCMS (ESI) m/z 198 [M+H].

The Intermediate in Table 19 below was synthesized according to the procedures above, starting with the chloride described in Table 19.

A 100-mL round-bottom flask was charged with 4-fluorobenzonitrile (2 g, 16.51 mmol), cesium carbonate (16 g, 49.11 mmol), N,N-dimethylformamide (20 mL) and 1H-pyrazole (2.24 g, 32.90 mmol). The resulting solution was refluxed for 2 h. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:10 to 1:4 v/v) to afford 4-(1H-pyrazol-1-yl)benzonitrile as a yellow oil (1.3 g, 47%). LCMS: (ESI) 170 [M+H].

A 250-mL round-bottom flask was charged with 4-(1H-pyrazol-1-yl)benzonitrile (Step 1, 2 g, 11.82 mmol), ethanol (40 mL), water (40 mL) and sodium hydroxide (705 mg, 17.63 mmol). The resulting solution was stirred at 105° C. 16 h and then concentrated under vacuum. The residue was diluted with water (30 mL) and extracted with ethyl acetate (50 mL). The pH of the aqueous phase was adjusted to 5 with hydrochloric acid (6.0 M). The solids were collected by filtration, washed with water (10 mL) and dried in an oven to afford 4-(1H-pyrazol-1-yl)benzoic acid as a light yellow solid (Intermediate 2-60, 1 g, 45%). LCMS: (ESI) m/z 189 [M+H].

The intermediates in Table 20 were prepared according to the procedure outlined in Example 35.

Example 36: Intermediate 2-336aa. 4-(1H-1,2,3-triazol-1-yl)benzenamine and 4-(1H-1,2,3-triazol-2-yl)benzenamine

A 250-mL 3-necked round-bottom flask was charged with 2H-1,2,3-triazole (1.061 g, 15.4 mmol), N,N-dimethylformamide (60 mL), 1-fluoro-4-nitrobenzene (2 g, 14.2 mmol) and K 2 CO 3 (5.87 g, 42.2 mmol). The resulting solution was stirred for 16 h at 110° C. in an oil bath and cooled to 25° C. The reaction was diluted with water (50 mL). The product was extracted with ethyl acetate (5×30 mL). The combined organic layers were concentrated under vacuum. The residue was purified by preparative HPLC* to afford the mixture of 1-(4-nitrophenyl)-1H-1,2,3-triazole and 2-(4-nitrophenyl)-2H-1,2,3-triazole (1:3) (1.6 g, 59%) as a yellow solid. LCMS: (ESI) m/z 191 [M+H]. *Column: silica gel. Mobile phase A: ethyl acetate/Mobile phase B: petroleum ether. Gradient: 10% B to 50% B over 35 min Detector: 254 nm.

A 250-mL 3-necked round-bottom flask fitted with a magnetic stir bar, condenser and thermometer was charged with the mixture of 1-(4-nitrophenyl)-1H-1,2,3-triazole and 2-(4-nitrophenyl)-2H-1,2,3-triazole (Step 1, 1 g, 5.26 mmol), ethanol (30 mL), water (30 mL), Fe (1.5 g, 26.8 mmol), ammonium chloride (832 mg, 15.6 mmol). The resulting solution was stirred for 3 h at 80° C. in an oil bath. The reaction was cooled to 23° C. and the solids were removed by filtration. The filtrate was concentrated under vacuum and the residue was diluted with water (30 mL). The product was extracted with ethyl acetate (5×30 mL). The combined organic layers were concentrated under vacuum to afford a mixture of 4-(1H-1,2,3-triazol-1-yl)benzenamine and 4-(1H-1,2,3-triazol-2-yl)benzenamine (800 mg, 94%) as a yellow solid. LCMS: (ESI) m/z 161 [M+H].

A 5-ml, microwave tube was charged with ethyl 2-bromo-1,3-oxazole-5-carboxylate (500 mg, 227 mmol), piperidine (219 mg, 2.57 mmol) and (trifluoromethyl)benzene (2 mL). The final reaction mixture was irradiated with microwave radiation for 30 min at 150° C. The resulting solution was cooled to 23° C. and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:1 v/v) to afford ethyl 2-(piperidin-1-yl)-1,3-oxazole-5-carboxylate as a white solid (400 mg, 78%). LCMS: (ESI) m/z 225 [M+H].

A 100-ml round-bottom flask was charged with ethyl 2-(piperidin-1-yl)-1,3-oxazole-5-carboxylate (Step 1, 400 mg, 1.78 mmol), lithium hydroxide (129 mg, 5.39 mmol), methanol (15 mL) and water (2 mL). The resulting solution was stirred for 3 h at 55° C. The resulting solution was diluted with 30 mL of water and the pH was adjusted to 5-6 with hydrochloric acid (6.0 M). The mixture was extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford 2-(piperidin-1-yl)-1,3-oxazole-5-carboxylic acid (Intermediate 2-61, 350 mg, 99%) as a light yellow oil which was used directly in the next step without further purification. LCMS: (ESI) m/z 197 [M+H].

The Intermediates in Table 21 below were synthesized according to the procedures outlined above.

A 250-mL round-bottom flask was charged with 1H-pyrazole (1 g, 14.69 mmol), potassium hydroxide (1.2 g, 21.39 mmol), potassium carbonate (3 g, 21.71 mmol), tetrabutylammonium bromide (7 g, 21.71 mmol), xylene (50 mL) and (bromomethyl)benzene (2.5 g, 14.62 mmol). The resulting mixture was stirred 16 h at 23° C. The reaction was then quenched by the addition of 150 mL of water. The resulting mixture was extracted with ethyl acetate (3×80 mL) and washed with 200 mL of water. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:3 v/v) to afford 1-benzyl-1H-pyrazole as a light yellow solid (1.3 g, 56%). LCMS: (ESI) m/z 159 [M+H].

A 100-mL 3-necked round-bottom flask equipped with a nitrogen balloon and thermometer was charged with 1-benzyl-1H-pyrazole (Step 1, 400 mg, 2.53 mmol) and tetrahydrofuran (25 mL). To the reaction was added n-butyl lithium (2.5 mL, 1.0 mmol) at −78° C. The resulting mixture was stirred for 1 hour at −78° C. in a dry ice bath before carbon dioxide was bubbled into the mixture. The resulting solution was stirred for additional 1 hour at −78° C. in a dry ice bath and then quenched by, the addition of 30 mL, of water and extracted with ethyl acetate (3×40 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford 1-benzyl-1H-pyrazole-5-carboxylic acid (including by product: 2-phenyl-2-(1H-pyrazol-1-yl)acetic acid) as a white oil which was used directly in the next step without further purification (Intermediate 2-64, 150 mg, 29%). LCMS: (ESI) m/z 203 [M+H].

Example 38: Intermediate 2-71. 4-(1H-pyrazol-1-yl)cyclohexanecarboxylic acid yl)cyclohexanecarboxylic Acid

A 250-mL round-bottom flask was charged with ethyl 4-hydroxycyclohexane-1-carboxylate (3 g, 17.42 mmol), 4-methylbenzene-1-sulfonyl chloride (5 g, 26.23 mmol), dichloromethane (50 mL) and triethylamine (5.28 g, 52.18 mmol). The resulting solution was stirred for 4 h at 23° C. The reaction was then quenched with water (50 mL) The mixture was extracted with dichloromethane (2×50 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:10 v/v) to afford ethyl 4-(tosyloxy)cyclohexanecarboxylate as a yellow solid (2.7 g, 47%). LCMS: (ESI) m/z 327 [M+H].

A 100-mL round-bottom flask was charged with ethyl 4-(tosyloxy) cyclohexanecarboxylate (Step 1, 2 g, 6.13 mmol), 1H-pyrazole (626 mg, 920 mmol), N,N-dimethylformamide (60 mL) and cesium carbonate (6 g, 18.42 mmol). The resulting solution was stirred 16 h at 80° C. After cooling to room temperature, the reaction was then quenched by the addition of water (60 mL) and extracted with ethyl acetate (3×60 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:1 v/v) to afford ethyl 4-(1H-pyrazol-1-yl)cyclohexanecarboxylate as a yellow solid (400 mg, 29%). LCMS: (ESI) m/z 223 [M+H].

The title compound was prepared according to procedure outlined in Example 8, Step 2, utilizing ethyl 4-(1H-pyrazol-1-yl) cyclohexanecarboxylate (100 mg, 0.45 mmol) as starting material (Intermediate 2-71, 40 mg, 46%) which was used without further purification. LCMS: (ESI)) m/z 195 [M+H].

A 50-mL round-bottom flask was charged with methyl 4-(2-methoxy-2-oxoethyl) benzoate (1 g, 4.80 mmol), (dimethoxymethyl)dimethylamine (571 mg, 4.79 mmol) and N,N-dimethylformamide (15 mL). The resulting solution was stirred for 4 h at 60° C. After cooling to 23° C., the reaction was quenched with water (30 mL) and the product was extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:1 v/v) to afford methyl 4-(1-(dimethylamino)-3-methoxy-3-oxoprop-1-en-2-yl)benzoate as a yellow solid (800 mg, 63%). LCMS. (ESI) m/z 264 [M+H].

A 50-mL round-bottom flask was charged with methyl 4-(1-(dimethylamino)-3-methoxy-3-oxoprop-1-en-2-yl)benzoate (Step 1, 800 mg, 3.04 mmol), hydrazine hydrochloride (310 mg, 4.56 mmol), triethylamine (921 mg, 9.10 mmol) and ethanol (20 mL). The resulting solution was stirred for 2 h at 90 and cooled to 23° C. before concentrating the solution under vacuum. The residue was purified by preparative thin layer chromatography eluting with dichloromethane/methanol (10:1 v/v) to afford methyl 4-(5-oxo-2,5-dihydro-1H-pyrazol-4-yl)benzoate as a yellow solid (520 mg, 78%). LCMS: (ESI) m/z 219 [M+H].

A 50-mL round-bottom flask was charged with methyl 4-(5-oxo-2,5-dihydro-1H-pyrazol-4-yl)benzoate (Step 2, 250 mg, 1.15 mmol), 1,3-dibromopropane (232 mg, 1.15 mmol), cesium carbonate (1.12 g, 3.44 mmol) and DMF (15 mL). The resulting solution was stirred 16 h at 80° C. The mixture was allowed to cool to 23° C. and then quenched with water (1.5 mL) and extracted with ethyl acetate (3×20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative thin layer chromatography eluting with dichloromethane/methanol (20:1 v/v) to afford methyl 4-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)benzoate as a yellow solid (100 mg, 34%). LCMS: (ESI) m/z 259 [M+H].

The title compound was prepared according to procedure outlined in Example 8, Step 2, utilizing methyl 4-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)benzoate (Step 3, 100 mg, 0.39 mmol) as starting material (Intermediate 2-72, 80 mg, 85%). LCMS: (ESI) m/z 245 [M+H].

The Intermediate in Table 22 below was synthesized according to the procedures outlined above.

A 100-mL round-bottom flask equipped with a nitrogen balloon was charged with [4-(methoxycarbonyl)phenyl] boronic acid (400 mg, 2.22 mmol), 3-bromo-4H,5H,6H,7H-pyrazolo[1,5-a]pyrimidine (300 mg, 1.48 mmol), potassium carbonate (946.7 mg, 4.46 mmol), toluene (20 mL), tris(dibenzylideneacetone)dipalladium-chloroform adduct (136 mg, 0.15 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl) phosphine (61 mg, 0.15 mmol) and cesium fluoride (22.6 mg, 0.15 mmol). The resulting solution was stirred 16 h at 120° C. in an oil bath. The reaction mixture was allowed to cool to 23° C. and the solids were filtered. The filtrate was concentrated under vacuum and the residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (3:2 v/v) to afford methyl 4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)benzoate as a yellow solid (160 mg, 42%). LCMS: (ESI) m/z 258 [M+H].

The title compound was prepared according to procedure outlined in Example 10, Step 2, utilizing methyl 4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)benzoate (Step 1, 120 mg, 0.47 mmol), as starting material purified by column chromatography eluting with dichloromethane/methanol (20:1 v/v) (Intermediate 2-74, 80 mg, 71%). LCMS: (ESI) m/z 244 [M+H].

The Intermediate in Table 23 below was synthesized according to the procedures outlined above. 3-bromo-4H,5H,6H,7H-pyrazolo[1,5-a]pyrimidine (40 mg, 0.20 mmol) was alkylated prior to following the procedures above with iodomethane (28 mg, 0.20 mmol) inn DMF (10 mL) in the presence of (9 mg, 0.23 mmol).

A 100-mL round-bottom flask was charged with 2-phenylacetyl chloride (0.500 g, 3.23 mmol), ethyl 2-(methylideneamino)acetate (0.366 g, 3.18 mmol), 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.492 g, 3.23 mmol), tetrahydrofuran (30 mL). The resulting solution was stirred for 16 h at 23° C. and then diluted with water (30 mL). The product was extracted with of ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtrated and concentrated under vacuum to afford ethyl 5-benzyloxazole-4-carboxylate (0.070 g, 9%) as a white solid which was directly used in the next step without purification. LCMS: (ESI) m/z 232 [M+H].

The title compound was prepared according to procedure outlined in Example 10, Step 2, utilizing 5-benzyloxazole-4-carboxylate (Step 1, 0.070 g, 0.30 mmol) as starting material which was directly used in the next step without purification (Intermediate 2-77, 0.060 g, 49%). LCMS: (ESI) m/z 204 [M+H].

A 100-mL round-bottom flask was charged with ethyl-1H-pyrrole-2-carboxylate (617 mg, 4.43 mmol), 1-(bromomethyl)-4-fluorobenzene (1.0 g, 5.29 mmol), cesium carbonate (4.3 g, 13.20 mmol) and N,N-dimethylformamide (20 mL). The resulting solution was stirred for 16 h at 60° C. in an oil bath. After cooling to 23 the reaction was quenched with water (30 mL). The resulting solution was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtrated and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:10 v/v) to afford ethyl 1-[(4-fluorophenyl)methyl]-1H-pyrrole-2-carboxylate (1.04 g, 95%). LCMS: (ESI) m/z 248 [M+H].

The title compound was prepared according to procedure outlined in Example 8, Step 2, utilizing ethyl 1-[(4-fluorophenyl)methyl]-1H-pyrrole-2-carboxylate (Step 1, 1.04 g, 421 mmol) as starting material (Intermediate 2-78, 300 mg, 33%) which was used without further purification. LCMS (ESI) m/z 220 [M+H].

Table 23a: The Intermediates in Table 23a below were also synthesized according to the procedures outlined above.

Example 43: Intermediate 2-85. tert-butyl 4-hydroxy-4-[1S)-1-[1-(4-methoxyphenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]ethyl]piperidine-1-carboxylate

A 250-mL 3-necked round-bottom flask equipped with a balloon filled with nitrogen was charged with bromo(ethyl)triphenyl-5-phosphane (9.3 g, 25.05 mmol), and tetrahydrofuran (100 mL). To the reaction was added n-butyl lithium (2.5M in hexane, 11 mL, 27.5 mmol) dropwise with stirring at −78° C. for 1 h before adding tert-butyl 4-oxopiperidine-1-carboxylate (5 g, 25.09 mmol) as a solution in tetrahydrofuran (20 mL) at −20° C. Stirring was continued for 1 h at −20° C. before quenching with water (30 mL). The product was extracted with ethyl acetate (5×50 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:9 v/v) to afford tert-butyl 4-ethylidenepiperidine-1-carboxylate (4.2 g, 79%) as a light yellow solid. LCMS (ESI) m/z 212 [M+H].

A 250-mL round-bottom flask was charged with tert-butyl 4-ethylidenepiperidine-1-carboxylate (Step 1, 4.2 g, 19.88 mmol), 3-chloroperoxybenzoic acid (5.16 g, 29.9 mmol) and dichloromethane (100 mL). The resulting solution was stirred for 3 h at worn temperature and quenched with aqueous saturated sodium sulfite solution (10 mL). The pH was adjusted to 7 with sodium bicarbonate (6 M) and the product was extracted with dichloromethane (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:10 to 1:5 v/v) to afford tert-butyl 2-methyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate (3.8 g, 84%)b as a colorless liqu d. LCMS (ESI) m/z 228 [M+H].

Step 3. Tert-Butyl 4-hydroxy-4-(1-(1-(4-methoxyphenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)ethyl)piperidine-1-carboxylate

The title compound was prepared according to the procedure outlines in Example 28 utilizing 1-(4-methoxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (prepared according to the procedure outline in Example 21, Step 3, using p-methoxy hydrazine hydrochloride as the starting material, 2.3 g, 9.49 mmol) and tert-butyl 2-methyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate (Step 2, 2.6 g, 11.44 mmol), followed by column chromatography purification eluting with ethyl acetate/petroleum ether (1:1 v/v) (3.8 g, 81%) LCMS (ESI) m/z 470 [M+H]. The racemic product (tert-butyl 4-hydroxy-4-(1-(1-(4-methoxyphenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5 (4H)-yl)ethyl)piperidine-1-carboxylate) (2.25 g) was further purified by prep-SFC* to afford 1-tert-butyl 4-hydroxy-4-[(1S)-1-[1-(4-methoxyphenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]ethyl]piperidine-1-carboxylate (Intermediate 2-85, 629.1 mg, retention time: 2.02 min, 14.3%, stereochemistry unconfirmed) as a white solid. 1H NMR (300 MHz, DMSO-d 6 ) δ 0.95-1.19 (m, 1H), 1.20-1.44 (m, 13H), 1.45-1.71 (m, 2H), 2.79-3.15 (m, 2H), 3.50-3.81 (m, 2H), 3.83 (s, 3H), 4.85-5.10 (d, J=7.5 Hz, 1H), 5.11 (s, 1H), 7.00-7.18 (m, 2H), 7.81-8.00 (m, 2H), 8.32 (s, 1H), 8.39 (s, 1H). LCMS (ESI) m/z 470 [M+H].

1-tert-butyl-4-hydroxy-4-[(1S)-1-[1-(4-methoxyphenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]ethyl]-1-[3],3-oxazocan-2-one (Intermediate 2-85, 614 mg, 14%) as a white solid, Retention time: 1.46 min, stereochemistry unconfirmed). 1 H NMR (300 MHz, DMSO-d 6 ) δ 0.92-1.11 (m, 1H), 1.17-1.44 (m, 13H), 1.50-1.75 (m, 2H), 2.80-3.18 (m, 2H), 3.45-3.80 (m, 2H), 3.82 (s, 3H), 4.85-5.02 (m, 1H), 5.11 (brs, 1H), 6.92-7.22 (m, 2H), 7.75-8.05 (m, 2H), 8.32 (s, 1H), 8.39 (s, 1H). MS (ESI, m/z) 470 [M+H]+. *SFC column: CHIRALCEL OJ-3, 4.6×50 mm, 3 um. Mobile Phase A 0.1% aqueous DEA/Mobile phase B: methanol, Flow rate: 4 ml/min. Detector: 220 and 254 nm.

The Intermediate in Table 24 below was synthesized according to the procedures outlined in Example 43.

The title compound was prepared according to procedure described in Example 7 utilizing the piperidin-4-one, TFA salt (1 g, 4.69 mmol) and 4-fluorobenzoic acid (1.44 g, 10.3 mmol followed by purification by column chromatography eluting with ethyl acetate/petroleum ether (1:1, v/v) (800 mg, 77%). LCMS: (ESI) m/z 222 [M+H].

The title compound was prepared according to the procedure outlined in Example 43, Step 1, utilizing 1-(4-fluorobenzoyl)piperidin-4-one (Step 1, 800 mg, 3.62 mmol) as starting material which was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:3, v/v) (250 mg, 30%). LCMS: (ESI) m/z 234 [M+H].

The title compound was prepared according to the procedure outlined in Example 43, Step 2, utilizing (4-ethylidenepiperidin-1-yl)(4-fluorophenyl)methanone (Step 2, 250 mg, 1.07 mmol) as starting material (250 mg, 93%). LCMS: (ESI) m/z 250 [M+H].

Example 45. Intermediate 2-88. 4-((1-(4-Fluorophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4-hydroxypiperidine-1-carbonyl Chloride

Triphosgene, (0.078 g, 0.263 mmol), triethylamine (0.092 mL, 0.658 mmol), and THF (1.0 mL) were added to a 10-mL round bottom flask fitted with a nitrogen inlet and magnetic stir bar. The mixture was cooled to −45° C., and a solution of 1-(4-fluorophenyl)-5-((4-hydroxypiperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one hydrochloride (Intermediate 2-86, 0.05 g, 0.132 mmol) in THF (1.0 mL) was added slowly while maintaining the temperature below −35° C. The mixture was stirred for 1 h cold, warmed to room temperature, and then concentrated under reduced pressure to dryness. The residue was purified by column chromatography using dichloromethane-ethyl acetate (1:1 v/v) to give 4-((1-(4-fluorophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4-hydroxypiperidine-1-carbonyl chloride (Intermediate 2-88, 40 mg, 75%). LCMS: (ESI) m/z 406.09 [M+H].

A 50-mL round-bottom flask fitted with a magnetic stir bar was charged with 4,5,6,7-tetrahydro-1H-indazole-6-carboxylic acid (640 mg, 3.96 mmol), methanol (10 mL) and thionyl chloride (1.43 g, 12.0 mmol). The resulting solution was stirred for 2 h at 23° C. The reaction mixture was concentrated under vacuum to afford methyl 4,5,6,7-tetrahydro-1H-indazole-6-carboxylate as a yellow oil (645 mg, 90%). LCMS: (ESI) m/z 181 [M+H].

A 50-mL round-bottom flask fitted with a magnetic stir bar was charged with methyl 4,5,6,7-tetrahydro-1H-indazole-6-carboxylate (Step 1, 360 mg, 2.00 mmol) and tetrahydrofuran (5 mL, 61.7 mmol). Sodium hydride (120 mg, 3.00 mmol, 60% wt) was added in one portion. The reaction mixture was stirred for 2 h at 23° C. before adding iodomethane (340 mg, 2.40 mmol) dropwise. The resulting solution was stirred for 2 h at 23° C. and quenched with water (20 mL). The product was extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:10, v/v) so afford methyl 1-methyl-4,5,6,7-tetrahydro-1H-indazole-6-carboxylate as a yellow oil (340 mg, 88%). LCMS: (ESI) m/z 195 [M+H].

The title compound was prepared according to the procedure outline in Example 10, Step 2 utilizing methyl 1-methyl-4,5,6,7-tetrahydro-1H-indazole-6-carboxylate (Step 2, 194 mg, 1.00 mmol), as starting material (Intermediate 2-96, 180 mg, >95%). LCMS: (ESI) m/z 181 [M+H].

A 100-mL 3-necked round-bottom flask fitted with a nitrogen inlet, magnetic stir bar, condenser and thermometer was charged with ethyl 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (500 mg, 1.78 mmol), Pd(PPh 3 ) 4 (206 mg, 0.18 mmol), potassium phosphate (1.13 g, 5.34 mmol), water (4 mL), 4-bromo-1-methyl-1H-pyrazole (431 mg, 2.68 mmol) and 1.4-dioxane (40 mL). The solution was stirred 12 h at 100° C. under nitrogen. The reaction mixture was cooled to 25° C. and diluted with water (40 mL). The product was extracted with dichloromethane (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:10, v/v) to afford ethyl 4-(1-methyl-1H-pyrazol-4-yl)cyclohex-3-ene-1-carboxylate (0.35 g, 84%). LCMS: (ESI) m/z 235 [M+H].

A 100-mL round-bottom flask fitted with a hydrogen balloon, magnetic stir bar was charged with methyl 4-(1-methyl-1H-pyrazol-4-yl)cyclohex-3-ene-1-carboxylate (Step 1, 300 mg, 1.36 mmol), palladium on carbon (50 mg, 10% wt) and methanol (20 mL). The mixture was stirred 12 h at 25° C. under hydrogen. The solids were removed by filtration and the filtrate was concentrated under vacuum to afford methyl 4-(1-methyl-1H-pyrazol-4-yl)cyclohexane-1-carboxylate (0.21 g, 74%), LCMS: (ESI) m/z 237 [M+H].

The title compound was prepared according to the procedure outlined in Example 10, Step 2, utilizing methyl 4-(1-methyl-1H-pyrazol-4-yl)cyclohexane-1-carboxylate (Step 2, 200 mg, 0.90 mmol) as starting material (Intermediate 2-97, 150 mg, 80%). LCMS: (ESI) m/z 209 [M+H].

Example 48: Intermediate 2-114. 1-(4-Fluorophenyl)-5-((4-hydroxy-1-(4-oxocyclohexanecarbonyl)piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

The title compound was prepared according to procedure outlined in Example 6 utilizing 1-(4-fluorophenyl)-5-[(4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one TFA salt (Intermediate 2-28, 1.0 g, 2.19 mmol) and 4-oxocyclohexane-1-carboxylic acid (prepared according to procedure outline in Example 8, Step 2, utilizing ethyl 4-oxocyclohexane-1-carboxylate as starting material, 625 mg, 4.40 mmol), 1.0 g, 49%). LCMS: (ESI) m/z 468 [M+H].

The Intermediates in Table 26 were synthesized according to the procedure for Example 48 above.

A 100-mL round-bottom flask purged and maintained with an inert atmosphere, of nitrogen was charged with ethyl 2-bromo-1,3-oxazole-5-carboxylate (600 mg, 2.73 mmol), cyclopropylboronic acid (377 mg, 4.39 mmol), toluene (30 mL, 282 mmol), potassium phosphate (1.59 g, 7.49 mmol) in water (4 mL) and 1,1′-(diphenyl phosphine) ferrocene methylene chloride palladium dichloride (12 mg, 0.06 mmol). The solution was stirred for 16 h at 120° C. in an oil bath. The reaction quenched with water (10 mL) and the product was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtrated and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:20 to 1:5 v/v) to give ethyl 2-cyclopropyl-1,3-oxazole-5-carboxylate (70 mg, 61%). LCMS (ES) m/z 182 [M+H].

Title compound (400 mg, 86%) was prepared according to the procedure described in Example 10, Step 2, utilizing ethyl 2-cyclopropyl-1,3-oxazole-5-carboxylate (Step 1, 550 mg, 3.04 mmol) as starting material (400 mg, 86%). LCMS: (ES) m/z 154 [M+H].

A 250-mL round-bottom flask was charged with ethyl 1H-imidazole-4-carboxylate (500 mg, 3.57 mmol), cyclopropylboronic acid (614.7 mg, 7.16 mmol), sodium carbonate (757 mg, 7.14 mmol), 1,2-dichloroethane (30 mL), 4,4′-bipyridine (558 mg, 3.58 mmol) and cupric acetate (646 mg, 3.56 mmol). The resulting mixture was stirred for 16 h at 70 and cooled to 23° C. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1.1 v/v) to afford ethyl 1-cyclopropyl-1H-imidazole-4-carboxylate (300 mg, 47%). LCMS: (ESI) m/z 181 [M+H].

Title compound (60 mg, 89%) was prepared according to the procedure described in Example 37, Step 2, utilizing ethyl 1-cyclopropyl-1H-imidazole-4-carboxylate (Step 1, 80 mg, 0.44 mmol) as starting material and used next without further purification. LCMS (ESI) m/z 153 [M+H].

The Intermediate in Table 27 below was also synthesized according to the procedures outlined for Example 50.

A 250-mL round-bottom flask was charged with methyl 3-oxo-4-phenylbutanoate (1.92 g, 9.99 mmol), sulfuryl dichloride (1.62 g, 12.0 mmol) and dichloromethane (50 mL). The resulting solution was stirred for 1 h at 23° C. and then quenched with water (50 mL). The product was extracted with dichloromethane (2×100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:100 to 1:30 v/v) to afford methyl 2-chloro-3-oxo-4-phenylbutanoate (1.65 g, 73%) as a yellow solid, LCMS: (ESI) m/z 227 [M+H].

A 250-mL round-bottom flask was charged with methyl 2-chloro-3-oxo-4-phenylbutanoate (Step 1, 2.26 g, 9.97 mmol), formic acid (30 mL) and ammonium formate (2.31 g, 30.00 mmol). The resulting solution was stirred for 3 h at 100° C. The reaction was cooled to 23° C. and quenched with saturated sodium bicarbonate (50 mL). The product was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:50 to 1:8 v/v) to afford methyl 4-benzyloxazole-5-carboxylate (300 mg, 14%) as a yellow solid. LCMS: (ESI) m/z 218 [M+H].

The title compound was prepared according to the procedure outlined in Example 8, Step 2, utilizing methyl 4-benzyloxazole-5-carboxylate (Step 2, 300 mg, 1.38 mmol) as starting material (Intermediate 2-124, 245 mg, 87%). LCMS: (ESI) m/z 204 [M+H].

A 100-mL round-bottom flask with a nitrogen ball was charged with piperidin-4-ol (1 g, 9.89 mmol), triphenylphosphine (3.5 g, 13.34 mmol), ethyl 4-hydroxybenzoate (2.25 g, 13.5 mmol), tetrahydrofuran (50 mL) and diethyl azodicarboxylate (3.45 g, 19.8 mmol). The resulting solution was stirred 16 h at 23° C. and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:1 v/v) to afford ethyl 4-(1-methylpyrrolidin-3-yloxy)benzoate (0.5 g, 20%). (ESI) m/z 250 [M+H].

The title compound was prepared according to the procedure outlined in Example 10, Step 2, utilizing ethyl 4-(1-methylpyrrolidin-3-yloxy)benzoate (Step 1, 200 mg, 0.80 mmol) as starting material (Intermediate 2-125, 0.15 g, 84%) as a yellow oil used without further purification. LCMS: (ESI) m/z 222 [M+H].

The Intermediates in Table 28 below were synthesized according to the procedures outlined for Example 52.

A 100-mL round-bottom flask fitted with a magnetic stir bar was charged with triethylamine (1 mL), dichloromethane (10 mL) and methanamine hydrochloride (362 mg, 5.40 mmol) and 4-(chlorosulfonyl)benzoic acid (400 mg, 1.81 mmol) in dichloromethane (5 mL) added in portions at 25° C. The resulting solution was stirred for 4 h at 25° C. The reaction mixture was quenched with water (20 mL). The product was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative thin layer chromatography eluting with dichloromethane/methanol (20:1, v/v) to afford 4-(methylsulfamoyl)benzoic acid as a light yellow solid (Intermediate 2-136, 214 mg, 55%). LCMS: (ESI) m/z 216 [M+H].

A 100-mL round-bottom flask flushed with nitrogen was charged with methyl 3-(bromomethyl)-1-methyl-1H-pyrazole-4-carboxylate (600 mg, 2.60 mmol), Pd(dppf) 2 Cl 2 CH 2 Cl 2 (200 mg, 0.27 mmol), potassium carbonate (674 mg, 4.88 mmol), 1,4-dioxane (40 mL), water (4 mL) and phenylboronic acid (600 mg, 4.88 mmol). The resulting solution was stirred for 16 h at 100° C. under nitrogen. After cooling to 25° C., the reaction was quenched with water (20 mL) and the product was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (3×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:1, v/v) to afford methyl 3-benzyl-1-methyl-1H-pyrazole-4-carboxylate (150 mg, 26%). LCMS: (ES) m/z 231 [M+H].

The title compound was prepared according to the procedure outlined in Example 10, Step 2, utilizing—methyl 3-benzyl-1-methyl-1H-pyrazole-4-carboxylate (Step 1, 150 mg, 0.65 mmol),—as starting material (Intermediate 2-140, 160 mg, >95%). LCMS: (ES) m/z 217 [M+H].

A 500-mL round-bottom flask fitted with a magnetic stir bar was charged with 2-phenylpropanoic acid (15 g, 100 mmol), acetonitrile (200 mL) and 1-[(1H-imidazol-1-yl)carbonyl]-1H-imidazole (16.2 g, 99.9 mmol). The resulting solution was stirred for 2 h at 25° C. The mixture was concentrated under vacuum and the residue was diluted with water (50 mL). The product was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 1-(1H-imidazol-1-yl)-2-phenylpropan-1-one (28 g, >95%). LCMS: (ES) m/z 201 [M+H].

A 1-L round-bottom flask fitted with a magnetic stir bar was charged with 1-ethyl 3-potassium propanedioate (35 g, 206 mmol), acetonitrile (500 mL), triethylamine (31 g, 306 mmol), magnesium chloride (24 g, 252 mmol) and 1-(1H-imidazol-1-yl)-2-phenylpropan-1-one (Step 1, 20 g, 100 mmol). The resulting solution was stirred for 10 h at 25° C. The mixture was concentrated under vacuum. The residue was diluted with water (100 mL) and the product was extracted with dichloromethane (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:1, v/v) to give ethyl 3-oxo-4-phenylpentanoate (20 g, 91%). LCMS: (ES) m/z 221 [M+H].

A 50-mL 3-necked round-bottom flask fitted with a magnetic stir bar, condenser and thermometer was charged with ethyl 3-oxo-4-phenylpentanoate (Step 2, 1 g, 4.54 mmol) and N,N-dimethylformamide dimethyl acetal (30 mL). The resulting solution was stirred for 1 h at 110° C. Alter cooling to 25° C., the mixture was concentrated under vacuum to give ethyl-2-[(dimethylamino)methylidene]-3-oxo-4-phenylpentanoate as a yellow oil (1 g, 80%), LCMS: (ES) m/z 276 [M+H].

A 100-mL round-bottom flask fitted with a magnetic stir bar was charged with ethyl-2-[(dimethylamino)methylidene]-3-oxo-4-phenylpentanoate (Step 3, 550 mg, 2.00 mmol), ethanol (20 mL), a solution of methylhydrazine in water (10 mL, 40%) and tiiethylamine (606 mg, 5.99 mmol). The resulting solution was stirred for 3 h at 25° C. The solvent was removed under vacuum and the residue was diluted with water (20 mL). The product was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:1, v/v) to give ethyl 1-methyl-3-(1-phenylethyl)-1H-pyrazole-4-carboxylate (340 mg, 66%). LCMS: (ES) m/z 259 [M+H].

The title compound was prepared according to the procedure outline din Example 10, Step 2, utilizing ethyl 1-methyl-3-(1-phenylethyl)-1H-pyrazole-4-carboxylate (Step 4, 340 mg, 1.32 mmol) as starting material (Intermediate 2-141, 300 mg, >95%). LCMS: (ES) m/z 231 [M+H].

A 100-mL 3-necked round-bottom flask fitted with a magnetic stir bar, condenser and thermometer was charged with methyl 3-oxobutanoate (3.24 mL, 27.9 mmol), SnCl 4 in dichloromethane (3.5 mL, 3.50 mmol, 1M), toluene (40 mL) and 2-phenylacetonitrile (3.46 mL). The resulting solution was stirred for 2 h at 110° C. After cooling to 25° C., the solids were removed by filtration. The filtrate was diluted with water (20 mL). The resulting mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with saturated ammonium bicarbonate (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:10, v/v) to afford methyl (2E)-2-acetyl-3-amino-4-phenylbut-2-enoate as a yellow oil (3.2 g, 49%). LCMS: (ES) m/z 234 [M+H].

A 100-mL 3-necked round-bottom flask fitted with a magnetic stir bar, condenser and thermometer was charged with triethylamine (0.75 mL), ethanol (15 mL) and hydroxylamine (375 mg, 11.35 mmol). The mixture was stirred for 1 h at 25° C. before adding methyl (2E)-2-acetyl-3-amino-4-phenylbut-2-enoate (Step 1, 1.05 g, 4.50 mmol). The reaction was heated to 100° C. and stirred for 5 h. After cooling to 25° C., the resulting mixture was concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:5, v/v) to afford methyl 3-benzyl-5-methyl-1,2-oxazole-4-carboxylate as a yellow oil (800 mg, 77%). LCMS: (ES) m/z 232 [M+H].

The title compound was prepared according to the procedure outlined in Example 14, utilizing methyl 3-benzyl-5-methyl-1,2-oxazole-4-carboxylate (Step 2, 300 mg, 1.30 mmol) as starting material, (Intermediate 2-144, 0.15 g, 53%). LCMS: (ES) m/z 218 [M+H].

A 100-mL 3-necked round-bottom flask fitted with a nitrogen balloon, magnetic stir bar, condenser and thermometer was charged with 4-bromo-1-(triphenylmethyl)-1H-pyrazole (1 g, 2.57 mmol), 1-methylpiperazine (516 mg, 5.15 mmol), sodium tert-butoxide (743 mg, 7.73 mmol), toluene (30 mL), tris(dibenzylideneacetone)dipalladium-chloroform adduct (207 mg, 0.20 mmol) and X-Phos (123 mg, 0.26 mmol). The solution was stirred for 16 h at 120° C. in an oil bath. After cooling to 25° C., the reaction was quenched with water (30 mL). The product was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with dichloromethane/methanol (10:1, v/v) to afford 1-methyl-4-[1-(triphenylmethyl)-1H-pyrazol-4-yl]piperazine as a brown solid (200 mg, 19%). LCMS: (ESI) m/z 409 [M+H].

A 100-mL round-bottom flask fitted with a magnetic stir bar was charged with 1-methyl-4-[1-(triphenylmethyl)-1H-pyrazol-4-yl]piperazine (Step 1, 200 mg, 0.49 mmol) and hydrogen chloride in 1,4-dioxane (15 mL, 3M). The solution was stirred for 2 h at 25° C. and concentrated under vacuum. The residue was diluted with ethyl acetate (20 mL). The solids were collected by filtration, washed with ethyl acetate (10 mL) and dried in an oven to afford the 1-methyl-4-(1H-pyrazol-4-yl)piperazine, HCl salt (Intermediate 2-147, 250 mg). LCMS: (ESI) m/z 167 [M+H].

A 100-mL 3-necked round-bottom flask fitted with