EP4747253A1

EP4747253A1 - Spirocyclic wrn helicase inhibitors

Info

Publication number: EP4747253A1
Application number: EP24840358.6A
Authority: EP
Inventors: Joey L. Methot; Shuhei Kawamura; Joanna L. Chen; Jenny Lorena RICO DUQUE; Kaitlyn Marie LOGAN; Erin F. Dimauro; Peter H. Fuller; Anmol Gulati; Indu T. Bharathan; Abhisek Banerjee
Original assignee: MSD Pharmaceuticals Pvt Ltd; Merck Sharp & Dohme LLC
Current assignee: MSD Pharmaceuticals Pvt Ltd; Merck Sharp & Dohme LLC
Priority date: 2023-07-11
Filing date: 2024-07-08
Publication date: 2026-05-27
Also published as: WO2025014846A1

Abstract

The present disclosure is directed to compounds of Formula I: wherein Z¹, Z², R¹, R², R³, and R⁴ are described herein, which are spirocyclic compounds for inhibiting Werner Syndrome dsDNA helicase (WRN) and methods of treating disease using these compounds. This disclosure further provides compounds and their use for the treatment of cancers characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), including colorectal, gastric, endometrial and ovarian cancer.

Description

SPIROCYCLIC WRN HELICASE INHIBITORS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of priority to U.S. Provisional Application No. 63/519,724, filed August 15, 2023, and U.S. Provisional Application No.63/513,000, filed July 11, 2023, the disclosure of which is incorporated herein by their entirety. REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY [0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. The XML file, created on August 11, 2023, is named 25728_WO_PCT_SL.XML and is 3,812 bytes in size. FIELD [0003] The present disclosure relates to compounds of Formula I, or pharmaceutically acceptable salts thereof, and their use for inhibiting Werner Syndrome dsDNA helicase (WRN). Another aspect of the disclosure are compounds of Formula I and their use for treating cancer, for example in the treatment of cancer characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). Still another aspect of the disclosure provides methods of treating cancers, including colorectal, gastric and endometrial cancer using the compounds disclosed herein. BACKGROUND [0004] Werner syndrome dsDNA helicase (WRN) is one of five RecQ family ATP-dependent motors involved in DNA unwinding for repair. WRN can uniquely process hypermutated DNA structures (e.g., G-quadruplexes, bubble DNA, Holliday junctions, forked DNA). WRN helicase activity is dispensable in WT/MSS cells, but essential when mismatch repair (MMR) genes are mutated (MSI cells). [0005] A common initial event in cancer development is the loss of DNA mismatch repair (MMR) of colorectal (CRC), endometrial, ovarian and gastric cancers (Aaltonen, L. A. et al., Clues to the pathogenesis of familial colorectal cancer, Science 260, 812-816 (1993), Bonneville R et al., Landscape of Microsatellite Instability Across 39 Cancer Types. JCO Precis Oncol.1: PO.17.00073 (2017)). A high mutational burden and frequent deletion and insertion events in repetitive DNA tracts (known as microsatellite instability (MSI)) occurs in cancers that have lost competence in mismatch repair (MMR). While progress has been made in the treatment of microsatellite instability high (MSI-H) cancers, there is still a significant unmet medical need in CRC and other MSI-H indications (André T., et al. Pembrolizumab in Microsatellite-Instability- High Advanced Colorectal Cancer. N Engl J Med 383(23):2207-2218 (2020)). Through large- scale functional genomics screens across large panels of cell lines, Werner Syndrome RecQ helicase (WRN) has been identified as being selectively required for the survival of cell lines with defective mismatch repair that have become MSI-H (Behan, F. M. et al., Nature 568, 511- 516 (2019); and Chan, E. M. et al., Nature 568, 551-556 (2019). Kategaya, L., Perumal, et al., iScience 13, 488-497 (2019), and Lieb, S. et al., eLife 8, e43333 (2019)). See also US20230046859. Depletion of WRN leads to anti-proliferative effects resulting in activation of multiple DNA damage signaling markers, induction of cell cycle arrest and apoptosis in MMR cancer models but not cancer cells with an intact MMR pathway. This indicates that WRN provides a DNA repair and maintenance function that is essential for cell survival in MSI cancers. Thus, inhibiting the WRN helicase is an attractive strategy for the treatment of mismatch repair defective cancers. There remains a need for new treatments and therapies for the treatment of cancer, particularly in cancers characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), including colorectal, gastric, ovarian, or endometrial cancer. SUMMARY [0006] The present disclosure is directed to compounds of Formula I: wherein Q, Q¹, X, Y, Z¹, Z², R¹, R², R³, and R⁴ are described below. [0007] This disclosure provides spirocyclic compounds for inhibiting Werner Syndrome dsDNA helicase (WRN) and methods of treating disease using these compounds. This disclosure further provides compounds and their use for the treatment of cancers characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), including colorectal, gastric, endometrial and ovarian cancer. [0008] Another aspect of the disclosure provides substituted spirocyclic compounds, analogues and derivatives thereof and their use for inhibiting Werner Syndrome RecQ DNA helicase (WRN). Another aspect of the disclosure provides methods of treating disease using the compounds described herein, including the use in treating cancer, including treatment of cancers characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). Still another aspect of the disclosure provides methods of treating cancers, including colorectal, gastric and endometrial cancer using the compounds disclosed herein. Yet another aspect of the disclosure provides the use of the compounds of this disclosure as research chemicals, intermediate compounds, combinations, processes and formulations. [0009] Another aspect of the disclosure provides orally bioavailable WRN inhibitor compounds with context-selective gH2AX induction activity. [0010] Another aspect of the disclosure provides compounds of Formula I, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof and/or combinations thereof, said compounds being inhibitors of Werner Syndrome RecQ DNA Helicase (WRN). Another aspect of the disclosure provides methods of treating, preventing, or ameliorating a disease or condition, comprising administering to a subject in need thereof an effective amount of a WRN inhibitor. Another aspect of the disclosure provides compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof and combinations thereof useful for the treatment of cancer, wherein the cancers are characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). Also provided in this disclosure are compounds that bind to, and/or inhibit WRN, and are therefore useful as research chemicals, e.g., as a chemical probe, and as tool compounds. Various embodiments of the disclosure are described herein. [0011] The summary of the technology described above is non-limiting and other features and advantages of the technology will be apparent from the following detailed description, and from the claims. DETAILED DESCRIPTION [0012] The present disclosure is directed to compounds of Formula I:

or a pharmaceutically acceptable salt thereof wherein Q and Q¹ are independently absent or -CHR-; Z¹ is selected from -O-, -CH2-, -OCH2-, -CH2O-, -NR⁵-, and -CH2CH2-; Z² is selected from -C(R¹)₂-, -CH₂CHR-, OCH₂-, and -O-; X and Y are independently is CH, or N; each R¹ is is independently selected from hydrogen, C_1-6 alkyl, halogen; R² is (CR2)nheteroaryl, or (CR2)nheterocycloalkyl, said heteroaryl and heterocycloalkyl optionally substituted with 1 to 3 groups selected from R^a; each R is independently hydrogen, halogen, or C1-6 alkyl; R⁵ is hydrogen or C_1-6 alkyl; R³ is aryl, heterocycloalkyl, or heteroaryl, said aryl, heterocycloalkyl, and heteroaryl optionally substituted with 1 to 3 groups selected from R^a; R⁴ is selected from C3-10 cycloalkyl, aryl, heteroaryl, said cycloalkyl, aryl, heteroaryl optionally substituted with 1 to 3 groups selected from R^a; n is 0 to 4; and each R^a is independently selected from hydroxyl, C_1-6 alkyl, halogen, C_1-3 haloalkyl, -O-, -OC_1-6 alkyl, C(O)C1-6 alkyl, -NH2, C3-6 cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, said alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl optionally substituted with 1 to 3 groups of OH, C_1-6 alkyl and halogen. [0013] An embodiment of structural Formula I is realized when Q is absent. Another embodiment of structural Formula I is realized when Q or Q1 is absent. Still another embodiment of structural Formula I is realized when both Q and Q1 are -CHR-. Still another embodiment of structural Formula I is realized when both Q and Q1 are -CH₂-. Still another embodiment of structural Formula I is realized when both Q and Q1 are absent. [0014] Another embodiment of Formula I is realized when Z¹ is -O-. Another embodiment of Formula I is realized when Z¹ is -CH2-. Another embodiment of Formula I is realized when Z¹ is -OCH2-. Another embodiment of Formula I is realized when Z¹ is -CH2O-. Still another embodiment of Formula I is realized when Z¹ is and -CH₂CH₂-. Yet another embodiment of Formula I is realized when Z¹ is and NR⁵-. In another embodiment of Formula I, Z¹ is -N(CH3)-. Another embodiment of Formula I is realized when Z² is -C(R¹)₂-. A subembodiment is realized when the two R¹s are halogen. Another subembodiment is realized when the two R¹s are C1-6 alkyl. Another subembodiment is realized when one of the two R¹s is halogen and the other is selected from C1-6 alkyl and halogen. [0015] Another embodiment of Formula I is realized when Z² is -CH₂-. Still another embodiment of Formula I is realized when Z² is -O- and R¹ is absent. Still another embodiment of Formula I is realized when Z² is -CH₂CHR-. Still another embodiment of Formula I is realized when Z² is -OCH2-. [0016] Another embodiment of Formula I is realized when X is -CH-. [0017] Another embodiment of Formula I is realized when X is N. [0018] Another embodiment of Formula I is realized when Y is -CH-. [0019] Another embodiment of Formula I is realized when Y is N. [0020] Another embodiment of Formula I is realized when X and Y are both N. [0021] Another embodiment of Formula I is realized when each R¹ is independently selected from hydrogen, C1-6 alkyl, halogen. Another embodiment of Formula I is realized when each R¹ is hydrogen. Another embodiment of Formula I is realized when one or both of the R¹ substituents are C1-6 alkyl, independently selected from methyl, ethyl, propyl, isopropyl, butyl, pentyl, and hexyl. A further subembodiment of this aspect of the disclosure is realized one or both R¹s are independently selected from methyl, ethyl, propyl or isopropyl. Another embodiment of Formula I is realized when one or both R¹s are halogen. Another embodiment of Formula I is realized when each R¹ isindependently selected from hydrogen, fluorine, bromine and chlorine, or C_1-6 alkyl. [0022] Another embodiment of Formula I is realized when R² is (CH2)npyridyl, (CH₂)_npyrimidinyl, (CH₂)_npyrazolyl, (CH₂)_noxazolyl, (CH₂)_nbenzoxazolyl, and (CH₂)_nisoxazolyl said pyridyl, pyrimidinyl, pyrazolyl, oxazolyl, isoxazolyl optionally substituted with 1 to 3 groups selected from R^a; A subembodiment is realized when R² is optionally substituted (CH₂)_npyridyl. A subembodiment is realized when R² is optionally substituted (CH2)npyrimidinyl. A subembodiment is realized when R² is optionally substituted (CH₂)_npyrazolyl. A subembodiment is realized when R² is optionally substituted (CH₂)_noxazolyl. A subembodiment is realized when R² is optionally substituted (CH2)nbenzoxazolyl. A subembodiment is realized when R² is optionally substituted (CH2)nisoxazolyl. [0023] Another embodiment of Formula I is realized when R² is optionally substituted (CR2)npyrrolidinyl. [0024] Another embodiment of Formula I is realized when R³ is selected from morpholinyl, piperidinyl, dihydropyranyl, pyranyl, pyridyl, pyrazolyl, oxazolyl, and isoxazolyl, said morpholinyl, piperidinyl, dihydropyranyl, pyranyl, pyridyl, pyrazolyl, oxazolyl, isoxazolyl, and phenyl optionally substituted with 1 to 3 groups selected from R^a. A subembodiment is realized when R³ is unsubstituted or substituted morpholinyl. An aspect of when R³ is morpholinyl is realized when the morpholinyl is attached at its nitrogen atom. A subembodiment is realized when R³ is unsubstituted or substituted piperidinyl. An aspect of when R³ is piperidinyl is realized when the piperidinyl is attached at a nitrogen atom. A subembodiment is realized when R³ is unsubstituted or substituted dihydropyranyl. A subembodiment is realized when R³ is unsubstituted or substituted pyranyl. A subembodiment is realized when R³ is unsubstituted or substituted pyridyl. A subembodiment is realized when R³ is unsubstituted or substituted pyrazolyl. A subembodiment is realized when R³ is unsubstituted or substituted oxazolyl. A subembodiment is realized when R³ is unsubstituted or substituted isoxazolyl. A subembodiment is realized when R³ is unsubstituted or substituted phenyl. [0025] Another embodiment of Formula I is realized when R⁴ is optionally substituted C3-10 cycloalkyl, said C3-10 cycloalkyl selected from cyclopropyl, cyclobutyl, bicyclobutanyl, cyclopentyl, bicyclopentanyl, cyclohexyl, and bicyclohexyl. A subembodiment of this aspect is realized when R⁴ is optionally substituted cyclopropyl. Another subembodiment of this aspect is realized when R⁴ is optionally substituted cyclobutyl. Another subembodiment of this aspect is realized when R⁴ is optionally substituted bicyclobutanyl. Another subembodiment of this aspect is realized when R⁴ is optionally substituted cyclopentyl. Another subembodiment of this aspect is realized when R⁴ is optionally substituted bicyclopentanyl. Another subembodiment of this aspect is realized when R⁴ is optionally substituted cyclohexyl. Another subembodiment of this aspect is realized when R⁴ is optionally substituted bicyclocyclohexyl. [0026] Another embodiment of Formula I is realized when R⁴ is optionally substituted phenyl. [0027] Another embodiment of Formula I is realized when R⁴ is optionally substituted heteroaryl. An aspect of when R⁴ is realized when the heteroaryl is selected from pyridyl, pyrazolyl, pyrimidinyl, pyrrolyl, thiazolyl and the like. A subembodiment of this aspect is realized when R⁴ is optionally substituted pyridyl. Another subembodiment of this aspect is realized when R⁴ is optionally substituted pyrazolyl. Another subembodiment of this aspect is realized when R⁴ is optionally substituted pyrimidinyl. Another subembodiment of this aspect is realized when R⁴ is optionally substituted pyrrrolyl. Another subembodiment of this aspect is realized when R⁴ is optionally substituted thiazolyl. [0028] Another embodiment of Formula I is realized when each R^a is independently selected from OH, OCH₃, OCH₂CH₃, C(O)CH₃, C(O)CH₂CH₃, methyl, ethyl, propyl, butyl, hexyl, phenyl, oxetanyl, cyclopropyl, NH2, -O-, fluorine, bromo, chloro, CH2F, CHF2, and CF3. In a class of this embodiment, each R^a is independently selected from OH, methyl, fluoro, chloro, CH2F, CHF2 and CF3. In a subclass of this class, each R^a is independently selected from OH, methyl, chloro, and CF₃. [0029] Another embodiment of Formula I is realized by structural Formula II: or a pharmaceutically acceptable R², R³ and R⁴ are as described herein. Another embodiment of Formula II is realized when each R¹ is independently selected from hydrogen, methyl, ethyl, propyl, butyl, hexyl, and halogen. Another embodiment of Formula II is realized when R² is unsubstituted or substituted pyridyl. Another embodiment of Formula II is realized when R² is unsubstituted or substituted pyrimidinyl. Another embodiment of Formula II is realized when R² is optionally substituted pyrazolyl. Another embodiment of Formula II is realized when R² is optionally substituted oxazolyl. Another embodiment of Formula II is realized when R² is optionally substituted isoxazolyl. Another embodiment of Formula II is realized when R³ is unsubstituted or substituted morpholinyl. Another embodiment of Formula II is realized when R³ is unsubstituted or substituted dihydropyranyl. Another embodiment of Formula II is realized when R³ is unsubstituted or substituted pyranyl. Another embodiment of Formula II is realized when R³ is unsubstituted or substituted piperidinyl. Another embodiment of Formula II is realized when R³ is unsubstituted or substituted pyridyl. Another embodiment of Formula II is realized when R³ is unsubstituted or substituted pyrazolyl. Another embodiment of Formula II is realized when R³ is unsubstituted or substituted oxazolyl. Another embodiment of Formula II is realized when R³ is unsubstituted or substituted benzoxazolyl. Another embodiment of Formula II is realized when R³ is unsubstituted or substituted isoxazolyl. [0030] Another embodiment of Formula II is realized when R⁴ is unsubstituted or substituted phenyl. Another embodiment of Formula II is realized when R⁴ is unsubstituted or substituted pyridyl. Another embodiment of Formula II is realized when R⁴ is unsubstituted or substituted pyrazolyl. Another embodiment of Formula II is realized when R⁴ is unsubstituted or substituted bicyclopentyl. Another embodiment of Formula II is realized when R⁴ is unsubstituted or substituted thiazolyl. [0031] An embodiment of Formula II is realized when Z¹ is -O-. Another embodiment of Formula II is realized when Z¹ is -O-, R¹ is selected from hydrogen, methyl, ethyl, propyl, butyl, hexyl, and halogen, R² is selected from unsubstituted or substituted pyridyl and unsubstituted or substituted pyrimidinyl, and R³ is unsubstituted or substituted morpholinyl or unsubstituted or substituted dihydropyranyl. [0032] Another embodiment of Formula II is realized when Z¹ is -CH2-. Another embodiment of Formula II is realized when Z¹ is -CH₂-, R¹ is selected from hydrogen, methyl, ethyl, propyl, butyl, hexyl, and halogen, R² is selected from unsubstituted or substituted pyridyl and unsubstituted or substituted pyrimidinyl, and R³ is unsubstituted or substituted morpholinyl or unsubstituted or substituted dihydropyranyl. [0033] Another embodiment of Formula II is realized when Z¹ is -OCH₂-. Another embodiment of Formula II is realized when Z¹ is -OCH2-, R¹ is selected from hydrogen, methyl, ethyl, propyl, butyl, hexyl, and halogen, R² is selected from unsubstituted or substituted pyridyl and unsubstituted or substituted pyrimidinyl, and R³ is unsubstituted or substituted morpholinyl or unsubstituted or substituted dihydropyranyl. [0034] Another embodiment of Formula II is realized when Z¹ is -CH₂O-. Another embodiment of Formula II is realized when Z¹ is -CH2O-, R¹ is selected from hydrogen, methyl, ethyl, propyl, butyl, hexyl, and halogen, R² is selected from unsubstituted or substituted pyridyl and unsubstituted or substituted pyrimidinyl, and R³ is unsubstituted or substituted morpholinyl or unsubstituted or substituted dihydropyranyl. [0035] Another embodiment of Formula II is realized when Z¹ is -CH₂CH₂-. Another embodiment of Formula II is realized when Z¹ is -CH2CH2-, R¹ is selected from hydrogen, methyl, ethyl, propyl, butyl, hexyl, and halogen, R² is selected from unsubstituted or substituted pyridyl and unsubstituted or substituted pyrimidinyl, and R³ is unsubstituted or substituted morpholinyl or unsubstituted or substituted dihydropyranyl. [0036] Another embodiment of Formula II is realized when Z¹ is NR⁵-. Another embodiment of Formula II is realized when Z¹ is NR⁵-, R¹ is selected from hydrogen, methyl, ethyl, propyl, butyl, hexyl, and halogen, R² is selected from unsubstituted or substituted pyridyl and unsubstituted or substituted pyrimidinyl, and R³ is unsubstituted or substituted morpholinyl or unsubstituted or substituted dihydropyranyl. An aspect of this embodiment is realized when R⁵ of -NR⁵- is H or CH₃ [0037] Another embodiment of Formula II is realized when Z¹ is -O-, -CH2-, -OCH2-, -CH2O-,- CH₂CH₂-, or NR⁵-, R⁵ is H or CH₃, and R⁴ is unsubstituted or substituted phenyl. Another embodiment of Formula II is realized when Z¹ is -O-, -CH2-, -OCH2-, -CH2O-, -CH2CH2-, or NR⁵-, R⁵ is H or CH₃, and R⁴ is unsubstituted or substituted pyrazolyl. Another embodiment of Formula II is realized when Z¹ is -O-, -CH2-, -OCH2-, -CH2O-, -CH2CH2-, or -NR⁵-, R⁵ is H or CH3, and R⁴ is unsubstituted or substituted pyridyl. Another embodiment of Formula II is realized when Z¹ is -O-, -CH2-, -OCH2-, -CH2O-, -CH2CH2-, -NR⁵-, wherein R⁵ is H or CH3, and R⁴ is unsubstituted or substituted bicyclopentyl. [0038] Another embodiment of Formula I is realized by structural Formula III:

or a pharmaceutically acceptable R², R³ and R⁴ are as described herein. [0039] Another embodiment of Formula I is realized by structural Formula IV: or a pharmaceutically acceptable ^{2 3 4} R , R and R are as described herein. [0040] Non-limiting examples of compounds of the disclosure are listed in Table 1 below. Table 1 MS I) /z xxxx

e n t ons [0041] The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof. That notwithstanding and except where stated otherwise, the following definitions apply throughout the specification and claims. Chemical names, common names and chemical structures may be used interchangeably to describe that same structure. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence the definition of “alkyl” applies to “alkyl” as well as the “alkyl” portion of “hydroxyalkyl”, “haloalkyl”, arylalkyl, alkylaryl, “alkoxy” etc. [0042] Listed below are definitions of various terms used herein. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group. [0043] 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. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well-known and commonly employed in the art. [0044] As used herein, the articles “a” and “an” refer to one or to 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. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting. [0045] As used herein, the term “about” in quantitative terms refers to plus or minus 10% of the value it modifies (rounded up to the nearest whole number if the value is not sub-dividable, such as a number of molecules or nucleotides). [0046] All ranges disclosed herein are inclusive of the recited endpoint and independently combinable (for example, the range of “from 50 mg to 500 mg” is inclusive of the endpoints, 50 mg and 500 mg, and all the intermediate values). The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value; they are sufficiently imprecise to include values approximating these ranges and/or values. [0047] As used herein, the term “comprising” may include the embodiments “consisting of” and “consisting essentially of.” The terms “comprise(s),” “include(s),” “having,” “has,” “may,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients/steps and permit the presence of other ingredients/steps. However, such description should be construed as also describing compositions or processes as “consisting of” and “consisting essentially of” the enumerated components, which allows the presence of only the named components or compounds, along with any acceptable carriers or fluids, and excludes other components or compounds. [0048] In each of the various embodiments of the disclosure, in the compounds used in the methods herein, each variable (including those in each of Formulae I- IV, and the various embodiments thereof) it shall be understood that each variable is to be selected independently of the others unless otherwise indicated. [0049] In each of the various embodiments of the disclosure, the compounds described herein, including those in each of Formulae I-IV and the various embodiments thereof, may exit in different forms of the compounds such as, for example, any solvates, hydrates, stereoisomers, and tautomers of said compounds and of any pharmaceutically acceptable salts thereof. [0050] It shall be understood that, in the various embodiments of the disclosure described herein, any variable not explicitly defined in the context of the embodiment is as defined in Formula I. [0051] In the various embodiments described herein, each variable is selected independently of the others unless otherwise indicated. [0052] "Patient" includes both human and non-human animals. Non-human animals include those research animals and companion animals such as mice, rats, primates, monkeys, chimpanzees, great apes, dogs, and house cats. [0053] "Pharmaceutical composition" (or “pharmaceutically acceptable composition”) means a composition suitable for administration to a patient. Such compositions may contain the neat compound (or compounds) of the disclosure or mixtures thereof, or salts, solvates, prodrugs, isomers, or tautomers thereof, and one or more pharmaceutically acceptable carriers or diluents. The term “pharmaceutical composition” is also intended to encompass both the bulk composition and individual dosage units comprised of one or more (e.g., two) pharmaceutically active agents such as, for example, a compound of the present disclosure and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients. The bulk composition and each individual dosage unit can contain fixed amounts of the afore-said "more than one pharmaceutically active agents". The bulk composition is material that has not yet been formed into individual dosage units. An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like. Similarly, the herein-described method of treating a patient by administering a pharmaceutical composition of the present disclosure is also intended to encompass the administration of the afore-said bulk composition and individual dosage units. [0054] “Pharmaceutically acceptable carrier” refers to a substance useful in the preparation or use of a pharmaceutical composition and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffering agents, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegration agents, lubricants, wetting agents, sweetening agents, flavoring agents, dyes, and combinations thereof, as would be known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22nd Ed. Pharmaceutical Press, 2013, pp.1049-1070). [0055] The term “effective amount” or “therapeutically effective amount” of a compound of the present disclosure refers to an amount of the compound of the present disclosure that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. [0056] In one embodiment, the term “a therapeutically effective amount” refers to the amount of the compound of the present disclosure that, when administered to a subject, is effective to (1) at least partially alleviate, prevent and/or ameliorate a condition, or a disorder or a disease (i) mediated by WRN, or (ii) associated with WRN activity, or (II) characterized by activity (normal or abnormal) of WRN; or (2) reduce or inhibit the activity of WRN. [0057] In another embodiment, the term “a therapeutically effective amount” refers to the amount of the compound of the present disclosure that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of WRN, or reducing WRN protein levels. [0058] The term “cancer” refers to a disease characterized by the rapid and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of various cancers are described herein and include but are not limited to colorectal, gastric, endometrial, prostate, adrenocortical, uterine, cervical, esophageal, breast, kidney, ovarian cancer and the like. [0059] The terms “tumor” and “cancer” are used interchangeably herein, e.g., both terms encompass solid and liquid, e.g., diffuse or circulating, tumors. As used herein, the term “cancer” or “tumor” includes premalignant, as well as malignant cancers and tumors. [0060] ‘WRN inhibitor’ or ‘WRN helicase inhibitor’ as used herein means a compound that inhibits Werner Syndrome RecQ DNA helicase (WRN). The term “WRN” as used herein refers to the protein of Werner Syndrome RecQ DNA helicase. The term “WRN” includes mutants, fragments, variants, isoforms, and homologs of full-length wild-type WRN. [0061] ‘Disease or condition mediated by WRN’ includes a disease or condition, such as cancer, which is treated by WRN inhibition. In particular this can include cancers characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). [0062] ‘Microsatellite unstable cancer’, microsatellite instability-high cancer’, ‘microsatellite high cancer’ and ‘MSI-high cancer’ ‘MSI^hi’ and ‘MSI-H’ when used herein, are used interchangeably, and describe cancers that have a high number of alterations in the length of simple repetitive genomic sequences within microsatellites. [0063] The determination of MSI-H or dMMR tumor status for patients can be performed using, e.g., polymerase chain reaction (PCR) tests for MSI-H status or immunohistochemistry (IHC) tests for dMMR. Methods for identification of MSI-H or dMMR tumor status are described, e.g., in Ryan et al. Crit Rev Oncol Hematol.2017; 116:38-57; Dietmaier and Hofstadter. Lab Invest 2001, 81:1453-1456; and Kawakami et al. Curr Treat Options Oncol. 2015; 16(7): 30). [0064] Microsatellite instability can be found in colorectal cancer, gastric cancer and endometrial cancer in particular, but also in adrenocortical, uterine, cervical, esophageal, breast, kidney, prostate and ovarian cancers. Examples of microsatellite high cancers include uterine corpus endometrial carcinoma, colon adenocarcinoma, stomach adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, esophageal carcinoma, breast carcinoma, kidney renal clear cell carcinoma and ovarian serous cystadenocarcinoma. [0065] A cancer that has “defective mismatch repair” (dMMR) or “dMMR character” includes cancer types associated with documented MLH1, PMS2, MSH2, MSH3, MSH6, MLH3, and PMS1 mutations or epigenetic silencing, microsatellite fragile sites, or other gene inactivation mechanisms, including but not limited to cancers of the lung, breast, kidney, large intestine, ovary, prostate, upper aerodigestive tract, stomach, endometrium, liver, pancreas, haematopoietic and lymphoid tissue, skin, thyroid, pleura, autonomic ganglia, central nervous system, soft tissue, pediatric rhabdoid sarcomas, melanomas and other cancers. A cell or cancer with “defective” mismatch repair has a significantly reduced (e.g., at least about 25%, 30%, 40%, 50%, 60%, 70%, 80% or 90% decrease) amount of mismatch repair. In some cases, a cell or cancer which is defective in mismatch repair will perform no mismatch repair. [0066] The term “subject” refers to primates (e.g., humans, male or female), dogs, rabbits, guinea pigs, pigs, rats and mice. In certain embodiments, the subject is a primate, a rat or a mouse. In yet other embodiments, the subject is a human. [0067] “Inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process. [0068] The term “treat”, “treating” or “treatment” of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient. [0069] “Halogen” and "halo" mean fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine. [0070] “Alkylene," by itself or as part of another substituent means a divalent hydrocarbon chain radical having the stated number of carbon atoms. For example, -(C1-C5)alkylene, would include, e.g., -CH₂-, -CH₂CH₂-, -CH₂CH₂CH₂-, -CH₂CH₂CH₂CH₂-, -CH₂CH(CH₃)CH2- or - CH₂CH₂CH₂CH₂CH₂-. A straight alkylene means a divalent straight hydrocarbon chain radical having the stated number of carbon atoms. A branched alkylene means a divalent branched hydrocarbon chain radical having the stated number of carbon atoms. A saturated alkylene means a divalent saturated hydrocarbon chain radical having the stated number of carbon atoms. An unsaturated alkylene means a divalent hydrocarbon chain radical having the stated number of carbon atoms and one or more double or triple covalent bonds within the chain. A cycloalkylene means a divalent hydrocarbon chain radical having the stated number of carbon atoms and a cycloalkyl moiety within the chain. [0071] "Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl. [0072] “Haloalkyl” means an alkyl as defined above wherein one or more hydrogen atoms on the alkyl is replaced by a halo group defined above, for example CHF2, CH2F and CF3. [0073] "Aryl" means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. "Monocyclic aryl" means phenyl. [0074] Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 12 carbon atoms, preferably about 3 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 10 ring atoms. The cycloalkyl can be optionally substituted with one or more substituents, which may be the same or different, as described herein. Monocyclic cycloalkyl refers to monocyclic versions of the cycloalkyl moieties described herein. Non- limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. The term "C₃-C₁₀cycloalkyl" encompasses bridged, saturated or unsaturated cycloalkyl groups having 3 to 10 carbons. "Cycloalkyl" also includes non-aromatic rings as well as monocyclic, non-aromatic rings fused to a saturated cycloalkyl group and aromatic rings fused to a saturated cycloalkyl group. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and the like. Examples described by structure include: , , , and . [0075] “Heterocycloalkyl” (or "heterocyclyl") means a non-aromatic, saturated or partially saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any –NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), -N(Tos) group and the like; such protections are also considered part of this disclosure. The heterocyclyl can be optionally substituted by one or more substituents, which may be the same or different, as described herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Thus, the term “oxide,” when it appears in a definition of a variable in a general structure described herein, refers to the corresponding N-oxide, S-oxide, or S,S-dioxide. “Heterocyclyl” also includes rings wherein =O replaces two available hydrogens on the same carbon atom (i.e., heterocyclyl includes rings having a carbonyl group in the ring). Such =O groups may be referred to herein as “oxo.” An example of such a moiety is pyrrolidinone (or pyrrolidone): . As used herein, the term “monocyclic heterocycloalkyl” refers monocyclic versions of the heterocycloalkyl moieties described herein and include a 4- to 7-membered monocyclic heterocycloalkyl groups comprising from 1 to 4 ring heteroatoms, said ring heteroatoms being independently selected from the group consisting of N, N-oxide, O, S, S-oxide, S(O), and S(O)2. The point of attachment to the parent moiety is to any available ring carbon or ring heteroatom. Non-limiting examples of monocyclic heterocycloalkyl groups include piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, beta lactam, gamma lactam, delta lactam, beta lactone, gamma lactone, delta lactone, and pyrrolidinone, and oxides thereof. A non-limiting example of a monocyclic heterocycloalkyl group include the moiety: . Non-limiting examples of multicyclic heterocycloalkyl groups include, bicyclic heterocycloalkyl groups. Specific examples include, but are not limited to, and . [0076] "Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen. [0077] The term “substituted” means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom’s normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By “stable compound’ or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. [0078] The term “optionally substituted” means optional substitution with the specified groups, radicals or moieties. [0079] “Combination” refers to either a fixed combination in one dosage unit form, or a combined administration where a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a combination partner (e.g., another drug as explained below, also referred to as “therapeutic agent” or “co-agent”) may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative. The single components may be packaged in a kit or separately. One or both of the components (e.g., powders or liquids) may be reconstituted or diluted to a desired dose prior to administration. The terms “co-administration” or “combined administration” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g., a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term “pharmaceutical combination” as used herein means a product that results from the mixing or combining of more than one therapeutic agent and includes both fixed and non-fixed combinations of the therapeutic agents. The term “fixed combination” means that the therapeutic agents, e.g., a compound of the present disclosure and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non- fixed combination” means that the therapeutic agents, e.g., a compound of the present disclosure and a combination partner, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g., the administration of three or more therapeutic agents. [0080] When a variable appears more than once in a group, e.g., R¹ in -C(R¹)2-, or a variable appears more than once in a structure presented herein, the variables can be the same or different at each occurrence. [0081] A solid line , as a bond generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R)- and (S)-stereochemistry. For example: . [0082] Systems, such as, for example indicates that the indicated line (bond) may be attached to any of the substitutable ring atoms. [0083] As well known in the art, a bond drawn from a particular atom wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom, unless stated otherwise. For example:

[0084] In another embodiment, the compounds useful in the methods of the disclosure, and/or compositions comprising them useful in said methods, are present in isolated and/or purified form. The term "purified", "in purified form" or “in isolated and purified form” for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g., from a reaction mixture), or natural source or combination thereof. Thus, the term "purified", "in purified form" or “in isolated and purified form” for a compound refers to the physical state of said compound (or a tautomer or stereoisomer thereof, or pharmaceutically acceptable salt or solvate of said compound, said stereoisomer, or said tautomer) after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be suitable for in vivo or medicinal use and/or characterizable by standard analytical techniques described herein or well known to the skilled artisan. [0085] When a functional group in a compound is termed “protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al., Protective Groups in Organic Synthesis (1991), Wiley, New York. [0086] Another embodiment provides prodrugs and/or solvates of the compounds of the disclosure. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term “prodrug” means a compound (e.g., a drug precursor) that is transformed in vivo to yield a compound of the disclosure or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol.14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. [0087] One or more compounds used in the methods of the disclosure may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms. "Solvate" means a physical association of a compound of the disclosure with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non- limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H2O. [0088] One or more compounds used in the methods of the disclosure may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example M. Caira et al., J. Pharmaceutical Sci., 1993, 3, 601-611, describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al., AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et al., Chem. Commun., 603-604 (2001). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate). [0089] Another embodiment provides pharmaceutically acceptable salts of the compounds to be used in the methods of the disclosure. Thus, reference to a compound used in the methods of the disclosure herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of the disclosure contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds used in the methods of the disclosure may be formed, for example, by reacting a compound of the disclosure with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. [0090] Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. [0091] Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto. [0092] Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. [0093] All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the disclosure and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the disclosure. [0094] Another embodiment provides pharmaceutically acceptable esters of the compounds used in the methods of the disclosure. Such esters include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, C1-4alkyl, or C1-4alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C1-20 alcohol or reactive derivative thereof, or by a 2,3-di (C6-24)acyl glycerol. [0095] As mentioned herein, another embodiment provides tautomers of the compounds of the disclosure to be used in the methods herein, and salts, solvates, esters and prodrugs of said tautomers. It shall be understood that all tautomeric forms of such compounds are within the scope of the compounds used in the methods of the disclosure. For example, all keto-enol and imine-enamine forms of the compounds, when present, are included in the disclosure. [0096] The compounds used in the methods of the disclosure may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds used in the methods of the disclosure as well as mixtures thereof, including racemic mixtures, form part of the present disclosure. In addition, the present disclosure embraces use of all geometric and positional isomers. For example, if a compound used in the methods of the disclosure incorporates a double bond or a fused ring, both the cis- and trans-forms, (E) and (Z) forms, as well as mixtures, are embraced within the scope of the disclosure. [0097] Another embodiment provides for diastereomeric mixtures and individual enantiomers of the compounds used in the methods of the disclosure. Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as, for example, 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 used in the methods of the disclosure may be atropisomers (e.g., substituted biaryls) and are considered as part of this disclosure. Enantiomers can also be separated by use of chiral HPLC column. [0098] All stereoisomers (for example, geometric isomers, optical isomers and the like) of the compounds used in the methods of the disclosure (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 as embodiments within the scope of this disclosure, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of the disclosure 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 disclosure. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the methods of the disclosure). [0099] Individual stereoisomers of the compounds of the disclosure 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 disclosure 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. [0100] In the compounds used in the methods of the disclosure, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present disclosure is meant to include all suitable isotopic variations of the compounds of the disclosure. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H). The presence of deuterium in the compounds of the disclosure is indicated by "D". Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds of the disclosure can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the schemes and examples herein using appropriate isotopically-enriched reagents and/or intermediates. Such isotopic compounds are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. [0101] In another embodiment, the compounds useful in the methods of the disclosure, and/or compositions comprising them useful in said methods, are present in isolated and/or purified form. The term "purified", "in purified form" or “in isolated and purified form” for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g., from a reaction mixture), or natural source or combination thereof. Thus, the term "purified", "in purified form" or “in isolated and purified form” for a compound refers to the physical state of said compound (or a tautomer or stereoisomer thereof, or pharmaceutically acceptable salt or solvate of said compound, said stereoisomer, or said tautomer) after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be suitable for in vivo or medicinal use and/or characterizable by standard analytical techniques described herein or well known to the skilled artisan. [0102] It shall be understood that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences. [0103] Compounds described herein may be administered to a patient orally or parenterally. As formulated into a dosage form suitable for administration, the compounds described herein can be used as a pharmaceutical composition for the prevention, treatment, or remedy of the above diseases. [0104] In clinical use of the compounds described herein, usually, the compound is formulated into various preparations together with pharmaceutically acceptable additives according to the dosage form and may then be administered. By "pharmaceutically acceptable" it is meant the additive, carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. As such, various additives ordinarily used in the field of pharmaceutical preparations are usable. Specific examples thereof include gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, corn starch, microcrystalline wax, white petrolatum, magnesium metasilicate aluminate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene, hardened castor oil, polyvinylpyrrolidone, magnesium stearate, light silicic acid anhydride, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin, hydroxypropyl cyclodextrin, and the like. [0105] Preparations to be formed with those additives include, for example, solid preparations such as tablets, capsules, granules, powders and suppositories; and liquid preparations such as syrups, elixirs and injections. These may be formulated according to conventional methods known in the field of pharmaceutical preparations. The liquid preparations may also be in such a form that may be dissolved or suspended in water or in any other suitable medium in their use. [0106] Especially for injections, if desired, the preparations may be dissolved or suspended in physiological saline or glucose liquid, and a buffer or a preservative may be optionally added thereto. [0107] The pharmaceutical compositions may contain the compound of the disclosure in an amount of from 1 to 99.9 % by weight, preferably from 1 to 60 % by weight of the composition. The compositions may further contain any other therapeutically-effective compounds. [0108] In case where the compounds of the disclosure are used for prevention or treatment for the above-mentioned diseases, the dose and the dosing frequency may be varied, depending on the sex, the age, the body weight and the disease condition of the patient and on the type and the range of the intended remedial effect. In general, when orally administered, the dose may be from 0.001 to 50 mg/kg of body weight/day, and it may be administered at a time or in several times. In specific embodiments, the dose is from about 0.01 to about 25 mg/kg/day, in particular embodiments, from about 0.05 to about 10 mg/kg/day, or from about 0.001 to about 50 mg/kg/day. For oral administration, the compositions are preferably provided in the form of tablets or capsules containing from 0.01 mg to 1,000 mg. In specific embodiments, the dose is 0.01, 0.05, 0.1, 0.2, 0.5, 1.0, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 225, 250, 500, 750, 850 or 1,000 milligrams of a compound described herein. This dosage regimen may be adjusted to provide the optimal therapeutic response. [0109] The compounds of the disclosure may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which compounds described herein or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered in an amount commonly used therefore, contemporaneously or sequentially with a compound described herein or a pharmaceutically acceptable salt thereof. When a compound described herein is used contemporaneously with one or more other drugs, the pharmaceutical composition may in specific embodiments contain such other drugs and the compound described herein or its pharmaceutically acceptable salt in unit dosage form. However, the combination therapy may also include therapies in which the compound described herein, or its pharmaceutically acceptable salt and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the disclosure and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the disclosure include those that contain one or more other active ingredients, in addition to a compound described herein or a pharmaceutically acceptable salt thereof. [0110] Examples of other active ingredients that may be administered in combination with a compound of any of the Formulas described herein or a pharmaceutically acceptable salt thereof and either administered separately or in the same pharmaceutical composition, include, but are not limited to pain relieving agents, anti-angiogenic agents, anti-neoplastic agents, anti-diabetic agents, anti-infective agents, or gastrointestinal agents, or combinations thereof. [0111] Suitable compounds that may be used in combination with a compound according to the disclosure include without limitation sildenafil, vardenafil, tadalafil and alprostadil, epoprostenol, iloprost, bosentan, amlodipine, diltiazem, nifedipine, ambrisentan and warfarin, fluticasone, budesonide, mometasone, flunisolide, beclomethasone, montelukast, zafirlukast, zileuton, salmeterol, formoterol, theophylline, albuterol, levalbuterol, pirbuterol, ipratropium, prednisone, methylprednisolone, omalizumab, corticosteroid and cromolyn, atorvastatin, lovastatin, simvastatin, pravastatin, fluvastatin, rosuvastatin, gemfibrozil, fenofibrate, nicotinic acid, clopidogrel and pharmaceutically acceptable salts thereof. [0112] Accordingly, the combinations described herein can include compounds of any of the Formulas herein and one or more additional therapeutic agents, e.g., one or more anti-cancer agents, cytotoxic or cytostatic agents, hormone treatment, vaccines, and/or other immunotherapies. In other embodiments, the combination is further administered or used in combination with other therapeutic treatment modalities, including surgery, radiation, cryosurgery, and/or thermotherapy. Such combination therapies may advantageously utilize lower dosages of the administered therapeutic agents, thus avoiding possible toxicities or complications associated with the treatment. [0113] Additionally, a compound of any of the Formulas disclosed herein may be used in combination with one or more other active agents, including but not limited to, other anti-cancer agents that are used in the prevention, treatment, control, amelioration, or reduction of risk of a particular disease or condition (e.g., cell proliferation disorders). In one embodiment, a compound disclosed herein is combined with one or more other anti-cancer agents for use in the prevention, treatment, control amelioration, or reduction of risk of a particular disease or condition for which the compounds disclosed herein are useful. Such other active agents may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the disclosure. [0114] In one embodiment, the other active agent is selected from the group consisting of vascular endothelial growth factor (VEGF) receptor inhibitors, topoisomerase II inhibitors, smoothen inhibitors, alkylating agents, anti-tumor antibiotics, anti-metabolites, retinoids, immunomodulatory agents including but not limited to anti-cancer vaccines, CTLA-4, LAG-3 and PD-1 antagonists. [0115] The additional therapeutic agent also can be, for example, chemotherapy, a chemical compound such as an anti-cancer agent, peptide, antibody, antibody fragment or nucleic acid, which is therapeutically active or enhances the therapeutic activity when administered to a patient in combination with a compound of the present disclosure. [0116] Additional therapeutic agents such PD-1 antagonists that are useful in any of the treatment methods, medicaments and uses of the disclosure include a monoclonal antibody (mAb), or antigen binding fragment thereof, which specifically binds to PD-1 or PD-Ll, and preferably specifically binds to human PD-1 or human PD-Ll. The mAb may be a human antibody, a humanized antibody or a chimeric antibody, and may include a human constant region. In some embodiments the human constant region is selected from the group consisting of IgGl, IgG2, IgG3 and IgG4 constant regions, and in some embodiments, the human constant region is an IgGl or IgG4 constant region. In some embodiments, the antigen binding fragment is selected from the group consisting of Fab, Fab'-SH, F(ab')2, scFv and Fv fragments. Examples of PD-1 antagonists include, but are not limited to, pembrolizumab (KEYTRUDA®, Merck and Co., Inc., Rahway, NJ, USA). “Pembrolizumab” (formerly known as MK-3475, SCH 900475 and lambrolizumab and sometimes referred to as “pembro”) is a humanized IgG4 mAb with the structure described in WHO Drug Information, Vol.27, No.2, pages 161-162 (2013). Additional examples of PD-1 antagonists include nivolumab (OPDIVO®, Bristol-Myers Squibb Company, Princeton, NJ, USA), atezolizumab (MPDL3280A; TECENTRIQ®, Genentech, San Francisco, CA, USA), durvalumab (IMFINZI®, Astra Zeneca Pharmaceuticals, LP, Wilmington, DE), avelumab (BAVENCIO®, Merck KGaA, Darmstadt, Germany and Pfizer, Inc., New York, NY), cemiplimab (LIBTAYO®, Regeneron Pharmaceuticals, Inc., Tarrytown, NY, and Sanofi-Aventis LLC, Bridgewater, NJ, U.S.), and dostarlimab (JEMPERLI®, GlaxoSmithKline LLC, Philadelphia, PA). [0117] Examples of monoclonal antibodies (mAbs) that bind to human PD-1, and useful in the treatment methods, medicaments and uses of the disclosure, are described in US7488802, US7521051, US8008449, US8354509, US8168757, WO2004/004771, WO2004/072286, WO2004/056875, and US2011/0271358. [0118] Examples of mAbs that bind to human PD-Ll, and useful in the treatment methods, medicaments and uses of the disclosure, are described in WO2013/019906, W02010/077634 Al and US8383796. Specific anti-human PD-Ll mAbs useful as the PD-1 antagonist in the treatment methods, medicaments and uses of the disclosure include MPDL3280A, BMS-936559, MEDI4736, MSB0010718C and an antibody which comprises the heavy chain and light chain variable regions of SEQ ID NO:24 and SEQ ID NO:21, respectively, of WO2013/019906. [0119] Other PD-1 antagonists useful in any of the treatment methods, medicaments and uses of the disclosure include an immunoadhesin that specifically binds to PD-1 or PD- L1, and preferably specifically binds to human PD-1 or human PD-Ll, e.g., a fusion protein containing the extracellular or PD-1 binding portion of PD-Ll or PD-L2 fused to a constant region such as an Fc region of an immunoglobulin molecule. Examples of immunoadhesin molecules that specifically bind to PD-1 are described in WO2010/027827 and WO2011/066342. Specific fusion proteins useful as the PD-1 antagonist in the treatment methods, medicaments and uses of the disclosure include AMP-224 (also known as B7-DCIg), which is a PD-L2-FC fusion protein that binds to human PD-1. [0120] Thus, one embodiment provides a method of treating cancer comprising administering an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in combination with a PD-1 antagonist to a subject in need thereof. In such embodiments, the compounds of the disclosure, or a pharmaceutically acceptable salt thereof, and the PD-1 antagonist are administered concurrently or sequentially. [0121] Specific non-limiting examples of such cancers in accordance with this embodiment include melanoma (including unresectable or metastatic melanoma), head & neck cancer (including recurrent or metastatic head and neck squamous cell cancer (HNSCC)), classical Hodgkin lymphoma (cHL), urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large-B-cell lymphoma, microsatellite instability-high (MSI-H) cancer, non-small cell lung cancer, hepatocellular carcinoma, clear cell kidney cancer, colorectal cancer, breast cancer, squamous cell lung cancer, basal carcinoma, sarcoma, bladder cancer, endometrial cancer, pancreatic cancer, liver cancer, gastrointestinal cancer, multiple myeloma, renal cancer, mesothelioma, ovarian cancer, anal cancer, biliary tract cancer, esophageal cancer, and salivary cancer. [0122] In one embodiment, there is provided a method of treating cancer comprising administering an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist, wherein said cancer is selected from unresectable or metastatic melanoma, melanoma following complete resection, recurrent, metastatic, or unresectable head and neck squamous cell cancer (HNSCC), classical Hodgkin lymphoma (cHL), urothelial carcinoma, gastric cancer, Merkel cell carcinoma, renal cell carcinoma, endometrial carcinoma, tumor mutational burden-high (TMB- H) cancer, cervical cancer, primary mediastinal large-B-cell lymphoma, microsatellite instability- high (MSI-H) or mismatch repair deficient cancer, non-small cell lung cancer, esophageal cancer, cutaneous squamous cell carcinoma, triple negative breast cancer, and hepatocellular carcinoma. In one such embodiment, the agent is a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In other such embodiments, the agent is durvalumab or avelumab. In one embodiment, the agent is cemiplimab. In one embodiment, the agent is dostarlimab. [0123] Pembrolizumab is approved by the U.S. FDA for the treatment of patients with unresectable or metastatic melanoma and for the adjuvant treatment of melanoma following complete resection, and for the treatment of certain patients with recurrent, metastatic, or unresectable head and neck squamous cell cancer (HNSCC), classical Hodgkin lymphoma (cHL), urothelial carcinoma, gastric cancer, Merkel cell carcinoma, renal cell cancer, endometrial cancer, tumor mutational burden-high (TMB-H) cancer, cervical cancer, primary mediastinal large-B-cell lymphoma, microsatellite instability-high (MSI-H) or mismatch repair deficient cancer, non-small cell lung cancer, esophageal cancer, cutaneous squamous cell carcinoma, triple negative breast cancer, and hepatocellular carcinoma, as described in the Prescribing Information for KEYTRUDA™ (Merck & Co., Inc., Rahway, NJ USA; initial U.S. approval 2014, updated January 2023). In another embodiment, there is provided a method of treating cancer comprising administering an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in combination with pembrolizumab to a person in need thereof, wherein said cancer is selected from unresectable or metastatic melanoma, adjuvant melanoma, recurrent, unresectable or metastatic head and neck squamous cell cancer (HNSCC), classical Hodgkin lymphoma (cHL), urothelial carcinoma, gastric cancer, Merkel cell carcinoma, renal cell cancer, endometrial cancer, tumor mutational burden-high (TMB-H) cancer, cervical cancer, primary mediastinal large-B-cell lymphoma, microsatellite instability-high (MSI-H) or mismatch repair deficient cancer, non-small cell lung cancer, esophageal cancer, cutaneous squamous cell carcinoma, triple negative breast cancer, and hepatocellular carcinoma. [0124] In another embodiment, there is provided a method of treating cancer comprising administering an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in combination with a PD-1 antagonist to a person in need thereof, wherein said cancer is selected from melanoma, non-small cell lung cancer, head and neck squamous cell cancer (HNSCC), Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, microsatellite instability-high cancer, gastric cancer, Merkel cell carcinoma, hepatocellular carcinoma, esophageal cancer and cervical cancer. In one such embodiment, the agent is a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In another such embodiment, the agent is durvalumab. In another such embodiment, the agent is avelumab. In other such embodiment, the agent is durvalumab or avelumab. [0125] In another embodiment, there is provided a method of treating cancer comprising administering an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist, wherein said cancer is selected from melanoma, non-small cell lung cancer, small cell lung cancer, head and neck cancer, bladder cancer, breast cancer, gastrointestinal cancer, multiple myeloma, hepatocellular cancer, lymphoma, renal cancer, mesothelioma, ovarian cancer, esophageal cancer, anal cancer, biliary tract cancer, colorectal cancer, cervical cancer, thyroid cancer, and salivary cancer. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In another such embodiment, the agent is durvalumab. In another such embodiment, the agent is avelumab. In other such embodiment, the agent is durvalumab or avelumab. [0126] In one embodiment, there is provided a method of treating unresectable or metastatic melanoma comprising administering an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In other such embodiment, the agent is durvalumab or avelumab. [0127] In one embodiment, there is provided a method of treating recurrent or metastatic head and neck squamous cell cancer (HNSCC) comprising administering an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In other such embodiment, the agent is durvalumab or avelumab. [0128] In one embodiment, there is provided a method of treating classical Hodgkin lymphoma (cHL) comprising administering an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In other such embodiment, the agent is durvalumab or avelumab. [0129] In one embodiment, there is provided a method of treating urothelial carcinoma comprising administering an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In other such embodiment, the agent is durvalumab or avelumab. [0130] In one embodiment, there is provided a method of treating gastric cancer comprising administering an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In other such embodiment, the agent is durvalumab or avelumab. [0131] In one embodiment, there is provided a method of treating cervical cancer comprising administering an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In other such embodiment, the agent is durvalumab or avelumab. [0132] In one embodiment, there is provided a method of treating primary mediastinal large-B- cell lymphoma comprising administering an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD- 1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In other such embodiment, the agent is durvalumab or avelumab. [0133] In one embodiment, there is provided a method of treating microsatellite instability-high (MSI-H) cancer comprising administering an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In other such embodiment, the agent is durvalumab or avelumab. [0134] In one embodiment, there is provided a method of treating non-small cell lung cancer comprising administering an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In other such embodiment, the agent is durvalumab or avelumab. [0135] In one embodiment, there is provided a method of treating hepatocellular carcinoma comprising administering an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In other such embodiment, the agent is durvalumab or avelumab. [0136] In another embodiment, there is provided a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a chemotherapy, and a PD-1 inhibitor. In particular, the chemotherapy and PD-1 inhibitor are selected from those described above. More particularly, the chemotherapy is irinotecan (Camptosar®) and the PD-1 inhibitor is pembrolizumab. [0137] Examples of vascular endothelial growth factor (VEGF) receptor inhibitors include, but are not limited to, bevacizumab (sold under the trademark AVASTIN by Genentech/Roche), axitinib, (N-methyl-2-[[3-[([pound])-2-pyridin-2-ylethenyl]-l H-indazol-6-yl]sulfanyl]benzamide, also known as AG013736, and described in PCT Publication No. WO01/002369), Brivanib Alaninate ((S)-((R)-l-(4-(4-Fluoro-2-methyl-lH-indol-5-yloxy)-5-methylpyrrolo[2,l- f][l,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate, also known as BMS-582664), motesanib (N-(2,3-dihydro-3,3-dimethyl-l H-indoi-6-yl)-2-[(4-pyridinyimethy)amino]-3- pyridinecarboxamide. and described in PCT Publication No. WO 02/068470), pasireotide (also known as SO 230, and described in PCT Publication No. WO02/010192), and sorafenib (sold under the tradename NEXAVAR). [0138] Examples of topoisomerase II inhibitors include but are not limited to, etoposide (also known as VP-16 and Etoposide phosphate, sold under the tradenames TOPOSAR, VEPESID and ETOPOPHOS), and teniposide (also known as VM-26, sold under the tradename VUMON). [0139] Examples of alkylating agents include but are not limited to, 5-azacytidine (sold under the trade name VIDAZA), decitabine (sold under the trade name of DECOGEN), temozolomide (sold under the trade names TEMODAR and TEMODAL by Schering-Plough/Merck), dactinomycin (also known as actinomycin-D and sold under the tradename COSMEGEN), melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under the tradename ALKERAN), altretamine (also known as hexamethylmelamine (HMM), sold under the tradename HEXALEN), carmustine (sold under the tradename BCNU), bendamustine (sold under the tradename TREANDA), busulfan (sold under the tradenames BUSULFEX and MYLERAN), carboplatin (sold under the tradename PARAPLATIN), lomustine (also known as CCNU, sold under the tradename CeeNU), cisplatin (also known as CDDP, sold under the tradenames PLATINOL and PLATINOL-AQ), chlorambucil (sold under the tradename LEUKERAN), cyclophosphamide (sold under the tradenames CYTOXAN and NEOSAR), dacarbazine (also known as DTIC, DIC and imidazole carboxamide, sold under the tradename DTIC-DOME), altretamine (also known as hexamethylmelamine (HMM) sold under the tradename HEXALEN), ifosfamide (sold under the tradename IFEX), procarbazine (sold under the tradename MATULANE), mechlorethamine (also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, sold under the tradename MUSTARGEN), streptozocin (sold under the tradename ZANOSAR), thiotepa (also known as thiophosphoamide, TESPA and TSPA, and sold under the tradename THIOPLEX). [0140] Examples of anti-tumor antibiotics include, but are not limited to, doxorubicin (sold under the tradenames ADRIAMYCIN and RUB EX), bleomycin (sold under the tradename LENOXANE), daunorubicin (also known as dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, sold under the tradename CERUBIDINE), daunorubicin liposomal (daunorubicin citrate liposome, sold under the tradename DAUNOXOME), mitoxantrone (also known as DHAD, sold under the tradename NOVANTRONE), epirubicin (sold under the tradename ELLENCE), idarubicin (sold under the tradenames IDAMYCIN, IDAMYCIN PFS), and mitomycin C (sold under the tradename MUTAMYCIN). [0141] Examples of anti-metabolites include, but are not limited to, claribine (2- chlorodeoxyadenosine, sold under the tradename LEUSTATIN), 5-fluorouracil (sold under the tradename ADRUCIL), 6-thioguanine (sold under the tradename PURINETHOL), pemetrexed (sold under the tradename ALIMTA), cytarabine (also known as arabinosylcytosine (Ara-C), sold under the tradename CYTOSAR-U), cytarabine liposomal (also known as Liposomal Ara-C, sold under the tradename DEPOCYT), decitabine (sold under the tradename DACOGEN), hydroxyurea (sold under the tradenames HYDREA, DROXIA and MYLOCEL), fludarabine (sold under the tradename FLUDARA), floxuridine (sold under the tradename FUDR), cladribine (also known as 2-chlorodeoxyadenosine (2-CdA) sold under the tradename LEUSTATIN), methotrexate (also known as amethopterin, methotrexate sodium (MTX), sold under the tradenames RHEUMATREX and TREXALL), and pentostatin (sold under the tradename NIPENT). [0142] Examples of retinoids include, but are not limited to, alitretinoin (sold under the tradename PANRETIN), tretinoin (all-trans retinoic acid, also known as ATRA, sold under the tradename VESANOID), Isotretinoin (13-c/s-retinoic acid, sold under the tradenames ACCUTANE, AMNESTEEM, CLARAVIS, CLARUS, DECUTAN, ISOTANE, IZOTECH, ORATANE, ISOTRET, and SOTRET), and bexarotene (sold under the tradename TARGRETIN). [0143] In such combinations a compound of the invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s). [0144] In certain embodiments of the methods, kits and uses provided herein, the anti-human compounds of Formula I, II, III, or IV and the anti-human PD-1 monoclonal antibody are administered on the same day. In some embodiments, the compounds of Formula I, II, III, or IV and the anti-human PD-1 monoclonal antibody are administered sequentially. In some embodiments, the compounds of Formula I, II, III, or IV and the anti-human PD-1 monoclonal antibody are administered concurrently. In some embodiments, the compounds of Formula I, II, III, or IV and the anti-human PD-1 monoclonal antibody are co-formulated. [0145] In one embodiment, the disclosure provides a product comprising a compound of the present disclosure and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of a disease or condition mediated by WRN. Products provided as a combined preparation include a composition comprising the compound of formula (I) and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound of the present disclosure and the other therapeutic agent(s) in separate form, e.g., in the form of a kit. [0146] In one embodiment, the disclosure provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the present disclosure. In one embodiment, the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like. [0147] The kit of the disclosure may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit of the disclosure typically comprises directions for administration. [0148] In the combination therapies of the disclosure, the compound of the present disclosure and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compound of the present disclosure and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g., in the case of a kit comprising the compound of the present disclosure and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (II) in the patient themselves, e.g., during sequential administration of the compound of the present disclosure and the other therapeutic agent. [0149] Accordingly, the disclosure provides the use of a compound of the present disclosure for treating a disease or condition mediated by WRN, wherein the medicament is prepared for administration with another therapeutic agent. The disclosure also provides the use of another therapeutic agent for treating a disease or condition mediated by WRN, wherein the medicament is administered with a compound of the present disclosure. [0150] The disclosure also provides a compound of the present disclosure for use in treating a disease or condition mediated by WRN, wherein the compound of the present disclosure is prepared for administration with another therapeutic agent. The disclosure also provides another therapeutic agent for use in treating a disease or condition mediated by WRN, wherein the other therapeutic agent is prepared for administration with a compound of the present disclosure. The disclosure also provides a compound of the present disclosure for use in treating a disease or condition mediated by WRN, wherein the compound of the present disclosure is administered with another therapeutic agent. The disclosure also provides another therapeutic agent for use in a method of treating a disease or condition mediated by WRN, wherein the other therapeutic agent is administered with a compound of the present disclosure. [0151] The disclosure also provides the use of a compound of the present disclosure for treating a disease or condition mediated by WRN, wherein the patient has previously (e.g., within 24 hours) been treated with another therapeutic agent. The disclosure also provides the use of another therapeutic agent for treating a disease or condition mediated by WRN, wherein the patient has previously (e.g., within 24 hours) been treated with compound of the present disclosure. [0152] The following examples are intended to illustrate the disclosure and are not to be construed as being limitations thereon. Temperatures are given in degrees Celsius. If not mentioned otherwise, all evaporations are performed under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (=20-133 mbar). Abbreviations used are those conventional in the art. [0153] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesize the compounds of the present disclosure are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art. Further, the compounds of the present disclosure can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples. [0154] The structures of all final products, intermediates and starting materials are confirmed by standard analytical spectroscopic characteristics, e.g., MS, IR or NMR. The absolute stereochemistry of certain isomers has been determined by analyses of X-ray crystal structures of complexes in which the respective compounds are bound to WRN or by small molecule X-ray crystal structures of a precursor of the final compound. [0155] The meanings of the abbreviations in Examples are shown below. Boc/BOC Tert-butyloxycarbonyl B B l

Standard atmosp ere [atm] = 101325 pasca [Pa] = 14.6959488 ps The meanings of the abbreviations in the nuclear magnetic resonance spectra are shown below: s = singlet, d = doublet, dd = double doublet, dt = double triplet, ddd = double double doublet, Sept = septet, t = triplet, m = multiplet, br = broad, brs = broad singlet, q = quartet J = coupling constant and Hz = hertz. [0156] Compounds of this invention can be prepared using the intermediates and processes outlined below. The following exemplified compounds of the invention may contain one or more asymmetric centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. The invention is meant to comprehend all such isomeric forms of these compounds. In the examples, where a compound has one or more stereocenters, the stereocenters are indicated with an asterisk, as shown below: [0157] Typically, the compounds of Formula (I) can be prepared according to the Schemes provided infra. The examples which outline specific synthetic routes, and the generic schemes below provide guidance to the synthetic chemist of ordinary skill in the art, who will readily appreciate that the solvent, concentration, reagent, protecting group, order of synthetic steps, time, temperature, and the like can be modified as necessary. [0158] The examples are meant to be illustrative and should not be construed as further limiting. The contents of the figures and all references, patents, and published patent applications cited throughout this application are expressly incorporated herein by reference. GENERAL SYNTHETIC SCHEMES [0159] The WRN inhibitors described in this invention were prepared via several general schemes. One general scheme (see General Scheme I) begins with the formation of the spirocyclic triazolopyrimidinone core through cyclocondensation of a spirocyclic ketoester with a suitably R³-substituted aminotriazole, typically catalyzed by an acid such as phosphoric acid at elevated temperature (step 1). In some case a dehydrating agent such as phosphorous pentoxide was used. In step 2, the spirocyclic triazolopyrimidinone core is alkylated with a suitably R⁴- substituted iodoacetamide precursor, typically catalyzed by a base such as DIEA. In step 3, the piperidine protective group is removed (such as HCl-catalyzed deprotection of a Boc group). Finally in step 4, the piperidine is acylated through amide bond formation with a suitable R²- substituted carboxylic acid to provide the desired spirocyclic WRN inhibitor. [0160] The WRN inhibitors described in this invention were prepared via several general schemes. General Scheme I

[0161] A second general synthetic approach is outlined in General Scheme II. Here the cyclocondensation step 1 is performed with a spirocyclic ketoester and 3-bromo-1H-1,2,4-triazol- 5-amine, in the presence of an acid or dehydrating agent, giving the spirocyclic triazolopyrimidinone core with a handle to later introduce the R³ group. Step 2 is the alkylation with a suitable R⁴-substituted iodoacetamide reagent catalyzed by a base such as DIEA. The protective group is removed in step 3, and an acyl group is installed in step 4 with an R²- substituted carboxylic acid using amide coupling methods. Finally in step 5, the desired spirocyclic WRN inhibitors were obtained by introduction of the R³ substitutent either through carbon-carbon or carbon-nitrogen bond formation step. General Scheme II [0162] Described in General Scheme III, the R³ substituent is introduced earlier in the synthetic sequence. Specifically, the cyclocondensation step 1 to form the spirocyclic triazolopyrimidinone core is performed with 3-bromo-1H-1,2,4-triazol-5-amine as described in General Scheme 2. Next, the core is alkylated with a suitable R⁴-substituted iodoacetamide. At this point, step 3 is either a carbon-carbon or carbon-nitrogen bond forming reaction to introduce the R³ substituent. The sequence is concluded by deprotection (step 4) and amide bond formation (step 5) to provide the desired spirocyclic WRN inhibitor. General Scheme III Step 1 Step 2 PG ^H ₂ ^N P N _N G H N H^N Br N R⁴ I O O _{N O} N Z¹ Acid or Dehydration ¹ N Z Br DIEA Z² O Agent, Heat Z² N N (^R1) _0-2 O _(R ¹ _)0-2 H PG ^PG _O R² N N O O N Step 4 O Z¹ N N Step 3 Br Z¹ N N R³ Deprotection N 1 N Z² N ² Z R³ N Install R³ Z N N Step 5 ² (R¹) ¹ C-C or C-N ² Z N N 0_-2 O (R )_0-2 O R OH (R¹)_0-2 O HN ⁴ coupling HN O R R⁴ Amide Coupling HN R⁴ [0163] An alternative core is the spirocyclic pyrazolopyrimidinone, prepared in a fashion analogous to the preparation of spirocyclic triazolopyrimidine core. As shown in General Scheme IV, the spirocyclic ketoester is cyclocondensed with a suitably R³-substituted aminopyrazole to construct the core of the inhibitor. The remainder of the synthesis would include alkylation with an R⁴-substituted iodoacetamide, deprotection, and amide bond formation to install the R²-substituted amide. General Scheme IV Step 1 Step 2 PG H₂N PG H N N H^N R³ N R⁴ I O O _{N O} N Z¹ Acid or Dehydration Z¹ N R³ DIEA Z² O Agent, Heat ² ^R1 Z N (⁾ _0-2 O _(R ¹ _)0-2 H R² PG H Step O N N 4 O O ² N R OH O N N Step 3 N N Z¹ R³ Z¹ R³ O N N Z¹ R³ Z² N Deprotection Z² N Amide ² (R¹)_0-2 O (R¹ Z )_0-2 O Coupling N (R¹)_0-2 O HN ⁴ HN R R⁴ HN R⁴ [0164] As shown in General Scheme V, an alternative core is a spirocyclic imidazopyrimidinone. The spirocyclic ketoester can be condensed with guanidine using either an acid or dehydration agent. The resulting spirocyclic aminohydroxypyrimidine was alkylated with a suitably R³-substituted alpha haloketone. The remainder of the synthesis would include alkylation with an R⁴-substituted iodoacetamide, deprotection, and amide bond formation to install the R²-substituted amide. General Scheme V Step 1 Step 2 PG PG PG H₂N NH₂ R³ N N Br N N OH O O H O Z¹ N Acid or Dehydration Z¹ DIEA Z¹ N R³ ² O A^{gent, Heat} Z² Z² N 1 Z N _NH2 _{0-2 (R )0-2} ¹ N (^{R )} O ¹ (R )_0-2 H Step 3 PG R² O H N O N R⁴N I Step 4 O O ¹ N ³ Deprotection Z 2 R Z¹ N R³ DIEA Z N N Step 5 (R¹)_0-2 Z² R² O N N O H (R¹)_0-2 O HN O R⁴ Amide Coupling HN R⁴ [0165] The general synthetic schemes outlined in this invention can be utilized for the preparation of pyrrolidinyl-spirocyclic inhibitors such as those described in General Scheme VI, in which a spirocyclic pyrrolidinyl ketoester is used as a precursor. [0166] The general synthetic schemes outlined in this invention can be utilized for the preparation of azetidinyl-spirocyclic inhibitors such as those described in General Scheme VII, in which a spirocyclic azetidinyl ketoester is used as a precursor. General Scheme VI

General Scheme VII PREPARATION OF SYNTHETIC INTERMEDIATES [0167] Preparation of 8-(tert-Butyl) 1-Ethyl 2-oxo-8-azaspiro[4.5]decane-1,8-dicarboxylate (Intermediate I).

Step 1. In one reaction vessel, a stirred solution of magnesium chloride (3.22 g, 33.8 mmol) and TEA (6.14 mL, 44.1 mmol) in MeCN (250 mL) was treated with potassium 3-ethoxy- 3-oxopropanoate (5.0 g, 29 mmol) at room temperature, then stirred for 2 h. In a separate reaction vessel, a stirred solution of 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid (3.78 g, 14.7 mmol) in DMF (100 mL) was treated with CDI (2.48 g, 15.3 mmol) at room temperature, then stirred for 2 h. Next, the contents of the first reaction vessel was added to the contents of the second reaction vessel, and the combined mixture stirred for 16 h. The reaction mixture was quenched with water (150 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layer was washed with brine (200 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to afford tert-butyl 4-(5-ethoxy-3,5-dioxopentyl)piperidine-1-carboxylate (10.0 g, 21.4 mmol). MS (EI) calc’d for C₁₂H₂₂NO₃ [M-Boc+H]⁺ 228, found 228. Step 2. A stirred solution of tert-butyl 4-(5-ethoxy-3,5-dioxopentyl)piperidine-1- carboxylate (10 g, 31 mmol) and TEA (4.68 mL, 33.6 mmol) in MeCN (100 mL) was treated with 4-acetamidobenzenesulfonyl azide (7.34 g, 30.5 mmol) at room temperature. The reaction mixture was stirred at 25 °C for 16 h. Diethyl ether was added to the reaction and stirred for 15 min. Reaction mixture was filtered and filtrate was washed with ethyl acetate (250 mL), diluted with ice water (500 mL) and extracted with EtOAc (2 x 500 mL). Combined organic layer was washed with cold brine (2 x 450 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 (20% EtOAc/Pet ether) silica column and compound eluted with a gradient of 20% EtOAc in pet ether to afford tert-butyl 4-(4-diazo-5-ethoxy-3,5-dioxopentyl)piperidine-1-carboxylate (3.50 g, 9.71 mmol). MS (EI) calc’d for C17H28N3O5 [M+H]⁺ 354, found 354. Step 3. To a stirred solution of tert-butyl 4-(4-diazo-5-ethoxy-3,5- dioxopentyl)piperidine-1-carboxylate (3.5 g, 9.90 mmol) in DCM (70 mL) was added 4 M HCl (7.4 mL, 30 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h, and concentrated under reduced pressure to afford ethyl 2-diazo-3-oxo-5-(piperidin-4-yl)pentanoate (2.50 g, 8.46 mmol). MS (EI) calc’d for C₁₂H₂₀N₃O₃ [M+H]⁺ 254, found 254. Step 4. A stirred solution of ethyl 2-diazo-3-oxo-5-(piperidin-4-yl)pentanoate (2.5 g, 9.9 mmol) in DCM (5 mL) was treated with TEA (4.1 mL, 30 mmol) followed by benzyl bromide (1.40 mL, 11.8 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. Reaction mixture was concentrated under reduced pressure and purified by chromatography on SiO₂ (30% EtOAc/Pet. Ether) to afford ethyl 5-(1-benzylpiperidin-4-yl)-2-diazo-3-oxopentanoate (2.70 g, 7.63 mmol). MS (EI) calc’d for C19H26N3O3 [M+H]⁺ 344, found 344. Step 5. A round bottom flask containing DCM (25 mL) was treated with rhodium(II) acetate dimer (0.080 g, 0.18 mmol) in a glove box. A solution of ethyl 5-(1-benzylpiperidin-4- yl)-2-diazo-3-oxopentanoate (1.25 g, 3.64 mmol) in DCM (25 mL) was added, and the reaction mixture stirred at 25 °C for 2 h. Reaction mixture was concentrated under reduced pressure and purified by chromatography on SiO2 (5% MeOH/DCM) to afford ethyl 8-benzyl-2-oxo-8- azaspiro[4.5]decane-1-carboxylate (700 mg, 2.18 mmol). MS (EI) calc’d for C19H26NO3 [M+H]⁺ 316, found 316. Steps 6 and 7. A stirred solution of ethyl 8-benzyl-2-oxo-8-azaspiro[4.5]decane-1- carboxylate (1.0 g, 3.2 mmol) in EtOH (25 mL) was treated with 10% Pd/C (0.439 g, 4.12 mmol) at room temperature. The reaction mixture was stirred under H₂ atmosphere at 25 °C for 4 h. Next, Boc-anhydride (1.24 mL, 5.33 mmol) and TEA (1.49 mL, 10.7 mmol) were added, and the reaction mixture was stirred at 25 °C for 16 h. Reaction mixture was filtered through a pad of celite and the Celite washed with ethyl acetate (250 mL). Organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Chromatography on SiO₂ (30% EtOAc/Pet ether) afforded 8-(tert-butyl) 1-ethyl 2-oxo-8-azaspiro[4.5]decane-1,8- dicarboxylate (800 mg, 2.16 mmol). MS (EI) calc’d for C₁₇H₂₈NO₅ [M+H]⁺ 326, found 326. [0168] Preparation of 8-(tert-Butyl) 4-Ethyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-4,8- dicarboxylate (Intermediate II). Steps 1 and 2. Ethyl 8-benzyl-3-oxo-1-oxa-8-azaspiro[4.5]decane-4-carboxylate (4.00 g, 12.6 mmol) was dissolved in EtOH (90 mL) with gentle warming, then cooled to RT. Added 10% Pd/C (140 mg, 1.32 mmol). Flushed with hydrogen gas, applied hydrogen balloon with stirring at RT for 24 h. Recharged with more 10% Pd/C (140 mg, 1.32 mmol) and stirred with a hydrogen balloon for another 24 h. A white suspension had formed, added BOC2O (4.00 g, 18.3 mmol), followed by TEA (2.00 mL, 14.4 mmol). Added 90 mL of DCM and stirred for 1 h. Filtered, concentrated to a yellow oil. Chromatography on SiO2 (ELSD detector, 0-100% 3:1 EtOAc:EtOH/hexanes) gave 8-(tert-Butyl) 4-Ethyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-4,8- dicarboxylate (4.36 g) (Intermediate II). MS (EI) calc’d for C16H26NO6 [M+H]⁺, 328; found, 328. [0169] Preparation of Racemic 8-(tert-Butyl) 1-Ethyl 3-methyl-2-oxo-8-azaspiro[4.5]decane- 1,8-dicarboxylate (Intermediate III). [0170] A solution of 8-(tert-butyl) 1-ethyl 2-oxo-8-azaspiro[4.5]decane-1,8-dicarboxylate (8.00 g, 24.6 mmol) in THF (100 mL) was treated with 2 M LDA (36.9 ml, 73.8 mmol) at 0 °C under N2 atmosphere. The mixture was stirred at 0 °C for 1 h. Then MeI (1.85 ml, 29.5 mmol) was added to the reaction solution dropwise at 0 °C. The reaction solution was stirred at 0 °C for 1 h, then quenched with sat. NH4Cl (50 mL), extracted with EtOAc (3 x 80 mL), washed with brine (50 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (80 g silica gel, 0~10% ethyl acetate in petroleum ether) to give racemic 8-(tert-butyl) 1-ethyl 3- methyl-2-oxo-8-azaspiro[4.5]decane-1,8-dicarboxylate (6.00 g, 17.7 mmol). ¹H NMR (CDCl3) δ 4.11-4.30 (m, 2H), 3.75-4.08 (m, 1H), 3.46-3.65 (m, 1H), 3.27-3.37 (m, 1H), 3.09-3.20 (m, 1H), 3.01 (s, 1H), 2.75-2.89 (m, 1H), 2.39-2.56 (m, 1H), 2.13-2.32 (m, 1H), 1.81-2.05 (m, 1H), 1.53- 1.73 (m, 4H), 1.45-1.48 (m, 9H), 1.26-1.31 (m, 3H), 1.16-1.23 (m, 3H). MS (EI) calc’d for C₁₄H₂₂NO₅ (M+H-tBu)⁺, 284; found, 284. [0171] Preparation of Racemic 8-(tert-Butyl) 4-Ethyl 2-methyl-3-oxo-1-oxa-8- azaspiro[4.5]decane-4,8-dicarboxylate (Intermediate IV). [0172] A solution of 8-(tert-butyl) 4-ethyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-4,8- dicarboxylate (600 mg, 1.83 mmol) in THF (6 mL) was purged with N2. The solution was cooled to 0 °C and 2 M LDA (2.75 mL, 5.50 mmol) was added dropwise. The mixture was allowed to stir at 0 °C for 30 min. Then MeI (0.126 mL, 2.02 mmol) was added and the subsequent mixture was allowed to stir at 0 °C for 1 h. The reaction was quenched with saturated ammonium chloride (10 mL), extracted with EtOAc (10 mL x 2). The combined organic layer was washed with brine, dried over Na₂SO₄, and then concentrated to dryness. The residue was purified by silica gel chromatography (4 g silica gel, 5% ethyl acetate/pet. Ether) to give racemic 8-(tert-butyl) 4-ethyl 2-methyl-3-oxo-1-oxa-8-azaspiro[4.5]decane-4,8-dicarboxylate (360 mg). ¹H NMR (400 MHz, CDCl3) δ 4.82-4.06 (m, 3H), 4.03-3.64 (m, 2H), 3.50-2.88 (m, 3H), 2.24- 1.68 (m, 3H), 1.58-1.52 (m, 1H), 1.50-1.48 (m, 9H), 1.44-1.28 (m, 6H). MS (EI) calc’d for C13H20NO6 (M+H-tBu)⁺, 242; found, 242. [0173] Preparation of 3-(tert-Butyl) 7-Methyl 8-Oxo-3-azaspiro[5.5]undecane-3,7- dicarboxylate (Intermediate V).

Step 1. A solution of tert-butyl 4-(4-ethoxy-4-oxobutylidene)piperidine-1-carboxylate (6.7 g, 22.5 mmol) in EtOH (60 mL) and water (12 mL) was treated with LiOH ^H2O (2.84 g, 67.6 mmol). The reaction was stirred at 25 °C for 12 h. The reaction was concentrated and the residue was diluted with water (40 mL) and extracted with EtOAc (20 mL). The aqueous phase was acidified with 2 N HCl to pH ~ 6, and extracted with EtOAc (20 ml x 2). The combined organic layers were washed with sat. NaCl solution (15 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give 4-(1-(tert-butoxycarbonyl)piperidin-4-ylidene)butanoic acid (6.0 g, 22 mmol). ¹H NMR (400 MHz, CDCl3) δ 5.25-5.15 (m, 1H), 3.46-3.31 (m, 4H), 2.45-2.31 (m, 4H), 2.25 -2.18 (m, 2H), 2.16-2.11 (m, 2H), 1.47 (s, 9H). MS (EI) m/z 270. Step 2. Prepare Solution 1: A stirred solution of magnesium chloride (2.10 g, 22.1 mmol) and TEA (3.90 mL, 28.8 mmol) in MeCN (50 mL) was treated with potassium 3- methoxy-3-oxopropanoate (3.0 g, 19 mmol). The reaction mixture was stirred at 25 °C for 2 h. Prepare Solution 2: A stirred solution of 4-(1-(tert-butoxycarbonyl)piperidin-4-ylidene)butanoic acid (2.59 g, crude) in DMF (20 mL) was treated with CDI (1.56 g, 9.60 mmol). The reaction mixture was stirred at 25 °C for 2 h. Solution 1 was then added to the Solution 2. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with water (150 mL) and extracted with EtOAc (2 x 50 mL). Combined organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (40 g silica gel, 15% ethyl acetate/pet. Ether) to give tert-butyl 4-(6- methoxy-4,6-dioxohexylidene)piperidine-1-carboxylate (2 g).¹H NMR (400 MHz, CDCl3) δ 5.16 (t, J = 7.2 Hz, 1H), 3.76-3.73 (m, 3H), 3.45 (s, 2H), 3.40-3.35 (m, 4H), 2.63-2.53 (m, 2H), 2.31 (q, J = 7.2 Hz, 2H), 2.25-2.17 (m, 2H), 2.15-2.07 (m, 2H), 1.47 (s, 9H). MS (EI) m/z 326. Step 3. A mixture of tert-butyl 4-(6-methoxy-4,6-dioxohexylidene)piperidine-1- carboxylate (500 mg, 1.54 mmol), bis(acetonitrile)dichloropalladium(II) (80 mg, 0.31 mmol), CuCl₂ (207 mg, 1.54 mmol) and Yb(Otf)₃ (953 mg, 1.54 mmol) in THF (50 mL) was degassed and backfilled with N2 (three times). The mixture was heated to 60 °C for 16 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in EtOH (10 mL) was treated with DIEA (0.805 mL, 4.61 mmol) and Boc2O (0.535 ml, 2.31 mmol). The mixture was stirred for another 2 h. The reaction was concentrated to remove EtOH. The mixture was diluted with EtOAc (20 mL), filtered the solid and the filtrate was washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (4 g silica gel, 20% ethyl acetate/pet. Ether) to give 3- (tert-butyl) 7-methyl 8-oxo-3-azaspiro[5.5]undec-9-ene-3,7-dicarboxylate (220 mg). ¹H NMR (400 MHz, CDCl3) δ 7.00-6.92 (m, 1H), 6.11 (dd, J = 1.6, 10.0 Hz, 1H), 3.71 (s, 3H), 3.61-3.45 (m, 2H), 3.42 (s, 1H), 3.38-3.27 (m, 2H), 2.80-2.70 (m, 1H), 2.33 (dd, J = 5.6, 19.2 Hz, 1H), 1.73-1.63 (m, 2H), 1.56-1.53 (m, 2H), 1.46 (s, 9H). MS (EI) m/z 268. Step 4. A solution of 3-(tert-butyl) 7-methyl 8-oxo-3-azaspiro[5.5]undec-10-ene-3,7- dicarboxylate (230 mg, 0.711 mmol) in MeOH (5 mL) was treated with Pd/C (20 mg) (10% in activated carbon) at 25 °C and backfilled with H2 (three times, 15 psi). The reaction mixture was stirred at 25 °C for 12 h. The suspension was filtered through a pad of Celite and filter cake was washed with MeOH (3 x 10 mL). The combined filtrates were concentrated to dryness. The residue was purified by silica gel chromatography (4g silica gel, 9% ethyl acetate/pet. Ether) to give 3-(tert-butyl) 7-methyl 8-oxo-3-azaspiro[5.5]undecane-3,7-dicarboxylate (160 mg). MS (EI) m/z 284. [0174] Preparation of 9-(tert-Butyl) 5-Ethyl 4-Oxo-1-oxa-9-azaspiro[5.5]undecane-5,9- dicarboxylate (Intermediate VI). Step 1. NaH (1.69 g, 42.3 mmol, 60% in mineral oil) was added to THF (50 mL) at 0 °C under nitrogen atmosphere. Ethyl 3-oxobutanoate (5.0 g, 38.4 mmol) was then slowly added at 0 °C and stirred for 10 minutes. Next, nBuLi (16.9 mL, 42.3 mmol) (2.5 M in hexane) was added slowly at this temperature and the stirring continued for 10 minutes. Next, ((chloromethoxy) methyl)benzene (5.61 mL, 40.3 mmol) was slowly added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for another 1 h. The reaction was quenched with ice cold water at 0°C followed by 6N HCl to pH = 2-3. The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine solution (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (80 g of silica gel, 30% EtOAc/pet. Ether) to give ethyl 5-(benzyloxy)-3- oxopentanoate (2.0 g). ¹H NMR (400 MHz, DMSO-d6) δ 7.38-7.32 (m, 3H), 7.31-7.22 (m, 2H), 4.54-4.47 (m, 2H), 4.15-4.02 (m, 2H), 3.67-3.64 (m, 2H), 3.35 (s, 2H), 3.01-2.62 (m, 2H), 1.23- 1.13 (m, 3H). Step 2. A solution of ethyl 5-(benzyloxy)-3-oxopentanoate (2.0 g, 7.99 mmol) in DCM (30 mL) was treated with boron trichloride (24.0 mL, 24.0 mmol) (1 M in DCM) under N₂ at -78 °C. The mixture was slowly warmed to room temperature and stirred at 25 °C for 2 h. The reaction was quenched with ice cold water (20 mL) at 0 °C, and extracted with DCM (3 x 20 mL). The combined organic layer was washed with brine solution (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (20 g of silica gel, 30% EtOAc/pet. Ether) to give ethyl 5-hydroxy-3- oxopentanoate (800 mg).¹H NMR (400 MHz, CDCl3) δ 4.28-4.18 (m, 2H), 3.92-3.89 (m, 2H), 3.51 (s, 2H), 2.85-2.82 (m, 2H), 1.35-1.25 (m, 3H). Step 3. A solution of ethyl 5-hydroxy-3-oxopentanoate (320 mg, 2.00 mmol) and benzyl 4-oxopiperidine-1-carboxylate (466 mg, 2.00 mmol) in MeCN (3 mL) was treated with BF₃-Oet₂ (1.52 mL, 12.0 mmol) at 0 °C under N₂. The reaction was stirred at 25 °C for 12 h. The reaction was treated with DIEA (1.05 mL, 5.99 mmol), Boc2O (630 mg, 3.00 mmol) and EtOH (3 mL). The reaction was stirred at 25 °C for 12 h, concentrated under reduced pressure, then purified by silica gel chromatography (12 g silica gel, 30% EtOAc/pet. Ether) to give 9- (tert-butyl) 5-ethyl 4-oxo-1-oxa-9-azaspiro[5.5]undecane-5,9-dicarboxylate (300 mg). ¹H NMR (400 MHz, CDCl₃) δ 4.34-4.17 (m, 2H), 4.15-3.75 (m, 4H), 3.40-2.90 (m, 3H), 2.55-2.25 (m, 3H), 2.02-1.71 (m, 2H), 1.59-1.53 (m, 1H), 1.49-1.47 (m, 9H), 1.38-1.24 (m, 3H). MS (EI) m/z 242. EXAMPLES Example 1 [0175] Preparation of N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(1’-(3-hydroxypicolinoyl)-2- morpholino-8-oxo-5,8-dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’- piperidin]-4(6H)-yl)acetamide (Compound 1). Step 2 H Step 1 N I Boc ^H2^N _N Boc O F C Cl N H^N N O N ₃ _N O DIEA, DMF, 50 ^oC, 16 h O O H₃PO₄, EtOH, 80 ^o N N C, 16 h N O Step 3 N N 4M HCl, DCM O H HO H Step 4 N ^N OH _O O N N N OH O N O N O N N N N N O O TCFH, NMI N N HN MeCN, 25 ^oC, 4 h O HN Cl CF₃ Compound 1 Cl CF₃ Step 1. A stirred solution of 8-(tert-butyl) 1-ethyl 2-oxo-8-azaspiro[4.5]decane-1,8- dicarboxylate (900 mg, 2.77 mmol) in EtOH (10 mL) was treated with 3-morpholino-1H-1,2,4- triazol-5-amine (312 mg, 1.84 mmol) and phosphoric acid (190 mg, 1.94 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 16 h, then concentrated under reduced pressure. The residue was purified by triturating with ether and 50% MeOH/DCM to afford tert- butyl 2-morpholino-8-oxo-4,5,6,8-tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine- 7,4’-piperidine]-1’-carboxylate (100 mg, 0.193 mmol). MS (EI) calc’d for C21H31N6O4 [M+H]⁺ 431, found 431. Step 2. A stirred solution of tert-butyl 2-morpholino-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (100 mg, 0.232 mmol) and N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide (84 mg, 0.23 mmol) in DMF (1 mL) was treated with DIEA (0.12 mL, 0.70 mmol). The reaction mixture was stirred at 50 °C for 16 h. Reaction mixture was quenched with water (100 mL) and extracted with EtOAc (2 x 100 mL). Combined organic layer was washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SiO₂ (10% MeOH/DCM) to afford tert-butyl 4-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-morpholino-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (70 mg, 0.077 mmol). MS (EI) calc’d for C30H36ClF3N7O5 [M+H]⁺ 666, found 666. Step 3. A stirred solution of tert-butyl 4-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-morpholino-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (70 mg, 0.11 mmol) in DCM (3 mL) was treated with 4 M HCl (0.13 mL, 0.53 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h, then concentrated under reduced pressure to afford N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-morpholino-8-oxo-5,8- dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4(6H)-yl)acetamide (65 mg, 0.078 mmol). MS (EI) calc’d for C25H28ClF3N7O3 [M+H]⁺ 566, found 566. Step 4. A stirred solution of 3-hydroxypicolinic acid (18 mg, 0.13 mmol) and N-(2- chloro-4-(trifluoromethyl)phenyl)-2-(2-morpholino-8-oxo-5,8- dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4(6H)-yl)acetamide (60 mg, 0.11 mmol) in MeCN (5 mL) was treated with bis(dimethylamino)-chlorocarbenium hexafluorophosphate (45 mg, 0.16 mmol) and 1-methylimidazole (26 mg, 0.32 mmol) at room temperature. The reaction mixture was stirred at 25 °C for 4 h, quenched with water (50 mL) and extracted with 10% MeOH in DCM (2 x 50 mL). Combined organic layer was washed with brine (70 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (10 mM ammonium bicarbonate/MeCN; betasil phenyl hexyl (21.2x250) mm column) to afford N-(2-chloro-4-(trifluoromethyl)phenyl)-2- (1’-(3-hydroxypicolinoyl)-2-morpholino-8-oxo-5,8- dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4(6H)-yl)acetamide (7.5 mg, 10.81 µmol) (Compound 1).¹H NMR (400 MHz, DMSO-d6) at 90 °C δ 10.09 (br d, J = 3.2 Hz, 2 H), 7.99-8.09 (m, 2 H), 7.83 (s, 1 H), 7.65 (dd, J = 8.6 Hz, 1.8 Hz, 1 H), 7.20-7.31 (m, 2 H), 5.07 (s, 2 H), 4.29 (br s, 2 H), 3.61-3.70 (m, 4 H), 3.36-3.45 (m, 4 H), 3.01-3.14 (m, 4 H), 2.35-2.47 (m, 2 H), 2.15 (t, J = 7.6 Hz, 2 H), 1.45 (d, J = 12.0 Hz, 2 H). MS (EI) calc’d for C31H31ClF3N8O5 [M+H]⁺ 687, found 687. Example 2 [0176] Preparation of N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(1’-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2-morpholino-8-oxo-5,8- dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4(6H)-yl)acetamide (Compound 2). Step 1 H H₂ ^N Step 3 N N I Boc Boc N ^HN N O N O o N F₃C Cl H PO , O _{3 4} EtOH, 80 C, 16 h O DIEA, DMF, 16 h N N O Step 2 N O Step 4 Boc₂O, NaHCO₃, 4M N N HCl, DCM O water, THF H Intermediate I Step 5 ^N H _HO N O OH ^N N _O N N OH N N O N O N N O N N O TCFH, NMI N O N N HN MeCN, 25 ^oC, 16 h O Cl CF₃ HN Compound 2 Cl CF₃ Steps 1 and 2. A stirred solution of 8-(tert-butyl) 1-ethyl 2-oxo-8-azaspiro[4.5]decane- 1,8-dicarboxylate Intermediate I (700 mg, 2.15 mmol) in EtOH (10 mL) was treated with 3- morpholino-1H-1,2,4-triazol-5-amine (364 mg, 2.15 mmol) and H3PO4 (211 mg, 2.15 mmol). The mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was cooled and concentrated giving 300 mg, 0.900 mmol of intermediate. The residue was then dissolved in water (1 mL), treated with NaHCO₃ (763 mg, 9.08 mmol), Boc₂O (238 mg, 1.09 mmol) and THF (0.1 mL). Stirred for 1 h. The product was extracted with 10% MeOH/DCM (3 x 50 mL), combined organic layer dried over sodium sulphate, filtered and concentrated. The residue was triturated with MTBE (50 mL), filtered and dried on high vacuum to obtain tert-butyl 2- morpholino-8-oxo-4,5,6,8-tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’- piperidine]-1’-carboxylate (170 mg, 0.339 mmol). MS (EI) calc’d for C₂₁H₃₁N₆O₄ [M+H]⁺ 431, found 431. Step 3. A stirred solution of tert-butyl 2-morpholino-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (170 mg, 0.339 mmol) and N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide (144 mg, 0.395 mmol) in DMF (2 mL) was treated with DIEA (0.14 mL, 0.79 mmol). The reaction mixture was stirred at RT for 16 h. Reaction mixture was quenched with water (10 mL) and extracted with 10% MeOH/DCM (3 x 15 mL). Combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SiO₂ (0-5% MeOH/DCM) to afford tert-butyl 4-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-morpholino-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (120 mg, 0.144 mmol). MS (EI) calc’d for C30H36ClF3N7O5 [M+H]⁺ 666, found 666. Step 4. A stirred solution of tert-butyl 4-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-morpholino-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (120 mg, 0.180 mmol) in DCM (5 mL) was treated with 4 M HCl in dioxane (0.90 mL, 3.60 mmol) at 0 °C, then stirred at RT for 16 h. Concentrated to dryness and used as is for the next step (obtained 92 mg, 0.133 mmol). MS (EI) calc’d for C25H28ClF3N7O3 [M+H]⁺ 566, found 566. Step 5. A stirred solution of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-morpholino-8- oxo-5,8-dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4(6H)- yl)acetamide (80 mg, 0.13 mmol) in MeCN (5 mL) was treated with TCFH (56 mg, 0.20 mmol) and NMI (0.053 mL, 0.66 mmol) followed by 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (20 mg, 0.13 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h, then diluted with EtOAc (50 mL), washed with water (2 x 5 mL), the aqueous layer was again extracted with EtOAc (3 x 20 mL), the combined organic layers were dried over sodium sulphate, filtered and concentrated. The residue was purified by reverse phase chromatography (0:30 to 19:30 MeCN/10 mM NH₄CO₃) to provide N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(1’-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2-morpholino-8-oxo-5,8- dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4(6H)-yl)acetamide (32 mg, 0.045 mmol) (Compound 2). ¹H NMR (400 MHz, DMSO-d₆): δ 10.3 (br, 1 H), 8.55 (s, 1 H), 8.05 (d, J = 8.4 Hz, 1 H), 7.96 (d, J = 1.6 Hz, 1 H), 7.72 (dd, J = 8,8, 1.6 Hz, 1 H), 5.12 (br s, 2 H), 4.52 (br d, J = 3.2 Hz, 1 H), 3.64-3.68 (m, 4 H), 3.49 (br d, 13 Hz), 3.37-3.39 (m, 4 H), 3.17 (t, J = 13 Hz, 1 H), 2.94-3.01 (m, 2 H), 2.90 (m, 1 H), 2.43 (s, 3 H), 2.31-2.39 (m, 2 H), 2.10-2.18 (m, 2 H), 1.53 (br d, J = 13 Hz, 1 H), 1.36 (br d, J = 12 Hz, 1 H); MS (EI) calc’d for C31H32ClF3N9O5 [M+H]⁺ 702, found 702. Example 3 [0177] Preparation of N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(1’-(3-hydroxypicolinoyl)-2- morpholino-8-oxo-5,8-dihydro-4H-spiro[furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’- piperidin]-4-yl)acetamide (Compound 3). Step 1 H2^N _N Step 3 H Boc N O Bo N H^N c N I N 3 O₄, EtOH, 90 ^o N H P C, 16 h O O F C Cl O ₃ O _O Step 2 N N O N O DIEA, DMF Boc N Step 4 2O, DCM, N O H HCl, dioxane DCM Intermediate II HO H N Step 5 ^N O OH _O N N N OH O O N O N N N N O N O N O O TCFH, NMI N N MeCN HN O HN Cl CF₃ Compound 3 Cl CF₃ Steps 1 and 2. A solution of 8-(tert-butyl) 4-ethyl 3-oxo-1-oxa-8-azaspiro[4.5]decane- 4,8-dicarboxylate, Intermediate II (350 mg, 1.07 mmol) in EtOH (3.5 mL) was treated with 3- morpholino-1H-1,2,4-triazol-5-amine (174 mg, 1.07 mmol) and phosphoric acid (15 mg, 0.15 mmol). The heterogeneous mixture was heated to 90 °C and stirred for 16 h. Concentrated to dryness. Suspended in DCM (0.93 mL), treated with DIPEA (0.93 mL, 5.35 mmol) and Boc₂O (233 mg, 1.07 mmol). The heterogeneous mixture was stirred for 16 h and concentrated to dryness to provide crude tert-butyl 2-morpholino-8-oxo-5,8-dihydro-4H-spiro[furo[3,4- d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (455 mg, 1.07 mmol). MS (EI) calc’d for C20H29N6O5 [M+H]⁺, 433; found, 432. Step 3. A solution of tert-butyl 2-morpholino-8-oxo-5,8-dihydro-4H-spiro[furo[3,4- d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (83 mg, 0.19 mmol) in DMF (1.9 mL) was treated with N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide (209 mg, 0.576 mmol) and DIEA (0.13 mL, 0.77 mmol). The reaction was stirred overnight, concentrated to dryness, and purified by chromatography on SiO2 (ELSD detector, 0-100% EtOAc:EtOH/hexane) to afford tert-butyl 4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-2-morpholino-8-oxo-5,8-dihydro-4H-spiro[furo[3,4-d]-[1,2,4]triazolo[1,5- a]pyrimidine-7,4’-piperidine]-1’-carboxylate (20 mg, 0.030 mmol). MS (EI) calc’d for C29H34ClF3N7O6 [M+H]⁺ 669; found, 669. Step 4. A solution of tert-butyl 4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-2-morpholino-8-oxo-5,8-dihydro-4H-spiro[furo[3,4-d][1,2,4]triazolo[1,5- a]pyrimidine-7,4’-piperidine]-1’-carboxylate (20 mg, 0.030 mmol) in dioxane (0.75 mL) was treated with 4M HCl in dioxane (1.0 mL, 25 mmol). The resulting mixture was allowed to stir at 23 °C overnight. The reaction was concentrated to afford N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(2-morpholino-8-oxo-5,8-dihydro-4H-spiro[furo[3,4- d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4-yl)acetamide (17 mg, 0.030 mmol). Step 5. A vial was charged with N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2- morpholino-8-oxo-5,8-dihydro-4H-spiro[furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’- piperidin]-4-yl)acetamide (43 mg, 0.075 mmol) dissolved in MeCN (0.75 mL). This was treated with 3-hydroxypicolinic acid (21 mg, 0.15 mmol), N,N,N‘,N‘- TetraMethylchloroformamidinium-hexafluorophosphate (32 mg, 0.11 mmol), and 1- methylimidazole (19 mg, 0.23 mmol). The mixture was stirred overnight, then purified by reverse phase chromatography (20-50% MeCN/water with 0.1% TFA modifier) to afford 4-(2- ((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-1’-(3-hydroxypicolinoyl)-2- morpholino-8-oxo-5,8-dihydro-4H-spiro[furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’- piperidin]-1-ium 2,2,2-trifluoroacetate (3.5 mg, 0.0044 mmol). MS (EI) calc’d for C30H30ClF3N8O6 [M+H]⁺, 689; found, 689. Example 4 [0178] Preparation of 2-(1’-(3-Hydroxypicolinoyl)-2-morpholino-8-oxo-5,8-dihydro-4H- spiro[furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4-yl)-N-(2-methyl-4- (trifluoromethyl)phenyl)acetamide (Compound 4). H H Step 1 N N I O Boc O N F₃C N N O O N O DIEA, DMF N N N N O N O Step 2 O N N TFA, DCM H HN CF HO ₃ Step 3 O ^N OH N OH N O O N N O N O EDC, HOBt, N N DMF O Compound 4 HN CF₃ Steps 1 and 2. A solution of tert-butyl 2-morpholino-8-oxo-5,8-dihydro-4H- spiro[furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (132 mg, 0.305 mmol) in DMF (0.65 mL) was treated with 2-iodo-N-(2-methyl-4- (trifluoromethyl)phenyl)acetamide (126 mg, 0.366 mmol) and DIEA (0.11 mL, 0.61 mmol) and the reaction stirred at room temperature for 4 hours. The reaction mixture was directly purified on a silica gel column using 0-10% MeOH/DCM. The intermediate (141 mg, 0.211 mmol) was dissolved in 1 mL of DCM, treated with TFA (0.24 mL, 3.1 mmol) and stirred for 3 h. The mixture was concentrated to collect the product, N-(2-methyl-4-(trifluoromethyl)phenyl)-2-(2- morpholino-8-oxo-5,8-dihydro-4H-spiro[furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’- piperidin]-4-yl)acetamide (120 mg, 0.211 mmol). MS (EI) calc’d for C₂₅H₂₉F₃N₇O₄ [M+H]⁺, 548; found, 548. Step 3. To a solution of N-(2-methyl-4-(trifluoromethyl)phenyl)-2-(2-morpholino-8- oxo-5,8-dihydro-4H-spiro[furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4- yl)acetamide (25 mg, 0.46 mmol), 3-hydroxypicolinic acid (10 mg, 0.69 mmol), 1H- benzo[d][1,2,3]triazol-1-ol (9 mg, 0.69 mmol) in DMF (1 mL), 3- (((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (22 mg, 0.11 mmol) and DIEA (0.020 mL, 0.11 mmol) were added. The reaction was stirred at RT overnight, diluted with EtOAc, washed with water, dried (MgSO₄) and concentrated. Chromatography on SiO2 (0-15% MeOH/DCM) provided 2-(1’-(3-hydroxypicolinoyl)-2-morpholino-8-oxo-5,8- dihydro-4H-spiro[furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4-yl)-N-(2-methyl- 4-(trifluoromethyl)phenyl)acetamide (5.3 mg, 0.0079 mmol) (Compound 4). ¹H NMR (500 MHz, DMSO-d₆) δ 10.08 (s, 1 H), 8.05 (s, 1 H), 7.72 (d, J = 8.3 Hz, 1 H), 7.63 (s, 1 H), 7.55 (s, 1 H), 7.30 (s, 2 H), 5.02-5.18 (m, 2 H), 5.00 (s, 2 H), 4.57 (d, J = 10.0 Hz, 1 H), 3.68 (s, 6 H), 3.11- 3.21 (m, 1 H), 2.91-3.08 (m, 1 H), 2.33 (s, 3 H), 2.08-2.25 (m, 2 H), 1.68-1.83 (m, 1 H), 1.54- 1.68 (m, 1 H), 1.14-1.35 (m, 4 H); MS (EI) calc’d for C31H32F3N8O6 [M+H]⁺ 669; found 669. Example 5 [0179] Preparation of 2-(1’-(2-(Benzo[d]oxazol-2-yl)acetyl)-2-morpholino-8-oxo-5,8-dihydro- 4H-spiro[furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide (Compound 5).

Steps 1 and 2. A solution of 8-(tert-butyl) 4-ethyl 3-oxo-1-oxa-8-azaspiro[4.5]decane- 4,8-dicarboxylate, Intermediate II (200 mg, 0.611 mmol) and 5-morpholino-4H-1,2,4-triazol-3- amine (103 mg, 0.611 mmol) in EtOH (2.5 mL) was treated with phosphoric acid (60 mg, 0.611 mmol) and the reaction mixture was stirred at 90°C for 2 days. Concentrated to dryness, suspended in 1 mL of EtOH. To the reaction mixture, Boc₂O (200 mg, 0.916 mmol) and TEA (0.170 mL, 1.22 mmol) were added and the mixture stirred for 24 h. Concentrated to dryness and tert-butyl 2-morpholino-8-oxo-5,8-dihydro-4H-spiro[furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine- 7,4’-piperidine]-1’-carboxylate was carried forward as is (264 mg, 0.610 mmol). MS (EI) calc’d for C₁₅H₂₀N₆O₃ [M-Boc+H]⁺ 333; found, 333. Steps 3 and 4. To tert-butyl 2-morpholino-8-oxo-5,8-dihydro-4H-spiro[furo[3,4- d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (50 mg, 0.116 mmol) in DMF (0.25 mL), N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide (50 mg, 0.14 mmol) and DIEA (30 mg, 0.23 mmol) were added and the reaction stirred for 4 hours. The reaction was filtered and purified by chromatography on SiO2 (0-10% MeOH/DCM) to provide tert-butyl 4-(2- ((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-morpholino-8-oxo-5,8-dihydro-4H- spiro[furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate. The residue was dissolved in DCM (0.5 mL) and TFA (0.090 mL) and the mixture stirred for 2 h. The mixture was concentrated to provide N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-morpholino-8- oxo-5,8-dihydro-4H-spiro[furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4- yl)acetamide (61 mg, 0.107 mmol). MS (EI) calc’d for C₂₄H₂₆ClF₃N₇O₄ [M+H]⁺, 568; found, 568. Step 5. A solution of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-morpholino-8-oxo- 5,8-dihydro-4H-spiro[furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4-yl)acetamide (25 mg, 0.044 mmol) in DMF (0.5 mL) was treated with 2-(benzo[d]oxazol-2-yl)acetic acid (8.0 mg, 0.044 mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (21 mg, 0.11 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (15 mg, 0.11 mmol) and N- ethyl-N-isopropylpropan-2-amine (0.040 mL, 0.22 mmol). The mixture was stirred overnight, diluted with EtOAc, washed with water, dried (MgSO₄), conc. Chromatgraphy on SiO₂ (0-10% MeOH/DCM) followed by HPLC (Arginine column, 21x250 mm, 1:1 MeOH/MeCN with 0.1% NH₄OH) provided 2-(1’-(2-(benzo[d]oxazol-2-yl)acetyl)-2-morpholino-8-oxo-5,8-dihydro-4H- spiro[furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide (7.2 mg, 0.0099 mmol). ¹H-NMR (500 MHz, DMSO-d₆) δ 10.40 (s, 1 H), 8.07 (d, J = 8.6 Hz, 1 H), 7.97 (s, 1 H), 7.64-7.82 (m, 3 H), 7.37 (d, J = 14.2 Hz, 2 H), 5.10 (d, J = 11.2 Hz, 4 H), 4.32-4.44 (m, 2 H), 4.27 (d, J = 16.5 Hz, 1 H), 3.90-4.01 (m, 1 H), 3.68 (d, J = 4.5 Hz, 4 H), 3.40-3.42 (m, 3 H), 2.84-3.02 (m, 1 H), 2.24-2.35 (m, 1 H), 2.12 (s, 1 H), 1.69-1.80 (m, 2 H), 1.23-1.40 (m, 1 H); MS (EI) calc’d for C₃₃H₃₁ClF₃₈O₆ [M+H]⁺ 727; found, 727. Example 6 [0180] Preparation of (N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(1’-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2-morpholino-8-oxo-5,8-dihydro-4H-spiro[furo[3,4- d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4-yl)acetamide) (Compound 6). Step 1 H _HO ^N N O OBn N O ^N N N OH O N O N N N N O O O N N EDC, HOBt, O N O HN DIEA, DMF N N Step 2 O Cl CF₃ BCl₃, DCM HN Compound 6 Cl CF₃ Step 1. A solution of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-morpholino-8-oxo- 5,8-dihydro-4H-spiro[furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4-yl)acetamide (25 mg, 0.44 mmol) , 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (21 mg, 0.11 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (9.0 mg, 0.066 mmol) in DMF (0.45 mL) was treated with DIEA (0.023 mL, 0.13 mmol) and 5-(benzyloxy)-6- methylpyrimidine-4-carboxylic acid (22 mg, 0.88 mmol), and the reaction stirred at room temp overnight. The mixture was purified on a silica gel column using 0-10% MeOH/DCM to provide 2-(1’-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)-2-morpholino-8-oxo-5,8-dihydro-4H- spiro[furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide (21 mg, 0.027 mmol). MS (EI) calc’d for C₃₇H₃₆ClF₃N₉O₆ [M+H]⁺ 794; found, 794. Step 2. A solution of 2-(1’-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)-2- morpholino-8-oxo-5,8-dihydro-4H-spiro[furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’- piperidin]-4-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (42 mg, 53 mmol) in DCM (0.95 mL) was treated at 0 °C with BCl₃ (0.50 mL, 0.50 mmol) and the reaction stirred for 3 hours. The reaction was quenched with excess MeOH, concentrated, and purifed by chromatography on SiO₂ (0-15% MeOH/DCM) to provide (N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(1’-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2-morpholino-8- oxo-5,8-dihydro-4H-spiro[furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4- yl)acetamide) (19 mg, 0.026 mmol).¹H NMR (500 MHz, DMSO-d6) δ 10.48 (s, 1 H), 8.60 (s, 1 H), 8.05 (d, J = 8.5 Hz, 1 H), 7.96 (s, 1 H), 7.73 (d, J = 8.6 Hz, 1 H), 5.07-5.14 (m, 3 H), 4.48- 4.59 (m, 1 H), 3.84-3.86 (m, 2 H), 3.66-3.69 (m, 4 H), 3.47-3.53 (m, 1 H), 3.32-3.41 (m, 4 H), 3.17 (s, 1 H), 3.06 (t, J = 11.9 Hz, 1 H), 2.48 (s, 3 H), 2.16-2.30 (m, 2 H), 1.80 (d, J = 12.4 Hz, 1 H), 1.64 (d, J = 12.0 Hz, 1 H); MS (EI) calc’d for C₃₀H₃₀ClF₃N₉O₆ [M+H]⁺ 704, found 704. Example 7 [0181] Preparation of N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4- yl)-1’-(3-hydroxypicolinoyl)-8-oxo-5,8-dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5- a]pyrimidine-7,4’-piperidin]-4(6H)-yl)acetamide (Compound 7).

Step 1. A stirred solution of Intermediate I (1.30 g, 4.00 mmol) in EtOH (5 mL) was treated with 3-bromo-1H-1,2,4-triazol-5-amine (0.651 g, 4.00 mmol), phosphorus (V) pentoxide (2.29 g, 7.99 mmol) at 0 °C. The reaction mixture was stirred at 80 °C for 16 h under argon. Reaction mixture was cooled, then to this reaction mixture were added di-tert-butyl dicarbonate (0.872 g, 4.00 mmol) and N, N-diisopropylethylamine (2.09 mL, 12.0 mmol). The reaction mixture was stirred for 3 h, then concentrated under reduced pressure. The residue was purified by chromatography on SiO₂ (30% EtOAc in hexane) to afford tert-butyl 2-bromo-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (1.2 g, 2.38 mmol). MS (EI) calc’d for C₁₇H₂₂BrN₅O₃ [M+H]⁺ 424; found, 424. Step 2. A mixture of tert-butyl 2-bromo-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (200 mg, 0.471 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (120 mg, 0.571 mmol), Pd(dtbpf)Cl₂ (16 mg, 0.025 mmol) and K₂CO₃ (130 mg, 0.943 mmol) in Dioxane (4 ml) and H2O (0.4 ml) was degassed and backfilled with N2 (three times). The mixture was heated to 100 °C for 16 h. After cooling to rt, the reaction was dissolved in EtOAc (25 mL), dried over Na2SO4, the solid was filtered off and the filtrate was concentrated and the residue was purified by chromatography on silica gel (DCM/MeOH = 20/1 to 10/1) to give tert- butyl 2-(3,6-dihydro-2H-pyran-4-yl)-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine -7,4’-piperidine]-1’-carboxylate (180 mg). MS (EI) calc’d for C₂₂H₂₉N₅O₄ [M+H]⁺ 428; found, 428. Step 3. A stirred solution of tert-butyl 2-(3,6-dihydro-2H-pyran-4-yl)-8-oxo-4,5,6,8- tetrahydrospiro [cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (80 mg, 0.19 mmol) and N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide (61 mg, 0.17 mmol) in DMF (2 mL) was treated with DIEA (0.098 mL, 0.56 mmol). The reaction mixture was stirred at 30 °C for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). Combined organic layer were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (SiO₂, Pet. Ether/EtOAc = 1: 2) to give tert-butyl 4-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d][1,2,4]triazolo [1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (35 mg). ¹H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H), 8.49 (d, J = 8.8 Hz, 1H), 7.65 (s, 1H), 7.54 (d, J = 10.0 Hz, 1H), 6.96 (s, 1H), 4.97 (s, 2H), 4.40-4.34 (m, 2H), 4.23-4.06 (m, 2H), 3.93 (t, J = 5.6 Hz, 2H), 3.13 (t, J = 7.6 Hz, 2H), 2.90-2.78 (m, 2H), 2.76-2.70 (m, 2H), 2.60-2.49 (m, 2H), 2.29-2.12 (m, 2H), 1.49 (s, 9H), 1.45-1.38 (m, 2H). Step 4. Tert-butyl 4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6- dihydro-2H-pyran-4-yl)-8-oxo-4,5,6,8-tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5- a]pyrimidine-7,4’-piperidine]-1’-carboxylate (150 mg, 0.23 mmol) was dissolved in MeOH (1 mL) was treated with 2 M HCl/Dioxane (3 mL). The reaction mixture was stirred for 2 h. The reaction was concentrated to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H- pyran-4-yl)-8-oxo-5,8-dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’- piperidin]-4(6H)-yl)acetamide (120 mg, 0.21 mmol). MS (EI) calc’d for C26H26ClF3N6O3 [M+H]⁺ 563, found 563. Step 5. A stirred solution of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro- 2H-pyran-4-yl)-8-oxo-5,8-dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’- piperidin]-4(6H)-yl)acetamide (100 mg, 0.18 mmol) in DMF (2 mL) was treated with HATU (102 mg, 0.268 mmol), N,N-diisopropylethylamine (69 mg, 0.54 mmol), 3-hydroxypicolinic acid (25 mg, 0.18 mmol). The reaction mixture was stirred for 16 h under argon. Reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 x 30 mL). Combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated. Crude compound was purified by reverse phase chromatography to afford Compound 7 (70 mg, 0.082 mmol). ¹H NMR (400 MHz, DMSO-d6) VT at 90 °C: δ 8.06 (dd, J = 4.0 Hz, 2.0 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 1.6 Hz, 1H), 7.66 (dd, J = 8.6 Hz, 1.4 Hz, 1H), 7.24-7.33 (m, 2H), 6.82 (s, 1H), 5.17 (s, 2H), 3.50-4.90 (m, 6H), 3.05 (t, J = 7.4 Hz, 4H), 2.54-2.57 (m, 2H), 2.36-2.47 (m, 2H), 2.20 (t, J = 7.4 Hz, 2H), 1.50 (d, J = 9.6 Hz, 2H); MS (EI) calc’d for C32H29ClF3N7O5 [M+H]⁺ 684, found 684. Example 8 [0182] Preparation of N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4- yl)-1’-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-8-oxo-5,8- dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4(6H)-yl)acetamide (Compound 8). Step 1. To a solution of 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (26 mg, 0.11 mmol), DIEA (0.13 mL, 0.74 mmol) and HATU (135 mg, 0.355 mmol) in DMF (2 mL) was added N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-8-oxo-5,8- dihydrospiro[cyclopenta[d] [1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4(6H)-yl)acetamide (60 mg, 0.10 mmol) at 30 °C. The reaction mixture was stirred at 30 °C for 8.5 h. The reaction was diluted with water (8 mL), extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and the filtrate was evaporated under reduced pressure to give the crude product. The crude product was purified by preparative TLC (SiO2, ethyl acetate 100%) to give 2-(1’-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)-2-(3,6- dihydro-2H-pyran-4-yl)-8-oxo-5,8-dihydrospiro[cyclopenta[d] [1,2,4]triazolo[1,5-a]pyrimidine- 7,4’-piperidin]-4(6H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl) acetamide (35 mg, 0.044 mmol). MS (EI) 789 (M+H)⁺. Step 2. A solution of 2-(1’-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)-2-(3,6- dihydro-2H-pyran-4-yl)-8-oxo-5,8-dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine- 7,4’-piperidin]-4(6H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (35 mg, 0.044 mmol) in THF (1 mL) was treated with trichloroborane (0.760 mL, 0.760 mmol) (1 M in DCM) at -78 °C under N2 atmosphere. The reaction mixture was stirred at 30 °C for 2 h. The mixture was quenched with MeOH (1 mL) and concentrated. The residue was purified by reverse phase chromatography (50-100% MeCN/water with 0.04% HCl) to give N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-1’-(5-hydroxy-6-methylpyrimidine- 4-carbonyl)-8-oxo-5,8-dihydrospiro[cyclopenta[d][1, 2,4] triazolo[1,5-a]pyrimidine-7,4’- piperidin]-4(6H)-yl)acetamide (3.7 mg, 0.0053 mmol). ¹H NMR (400 MHz, CD3OD) δ 8.72 (s, 1H), 8.17 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 1.6 Hz, 1H), 7.65-7.59 (m, 1H), 6.94 (s, 1H), 5.27 (d, J = 2.4 Hz, 2H), 4.75-4.68 (m, 1H), 4.35-4.29 (m, 2H), 4.01-3.93 (m, 1H), 3.90 (t, J = 5.6 Hz, 2H), 3.41-3.35 (m, 1H), 3.18-3.11 (m, 2H), 3.11-3.02 (m, 1H), 2.67-2.61 (m, 4H), 2.60 (s, 3H), 2.39- 2.26 (m, 2H), 1.75-1.67 (m, 1H), 1.61-1.53 (m, 1H). MS (EI) calc’d for C32H31ClF3N8O5 [M+H]⁺ 699, found 699. Example 9 [0183] Compound 9 was prepared analogously to Compound 7, substituting Intermediate I for Intermediate II. Example 10 [0184] Preparation of N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(1’-(3-hydroxypicolinoyl)-2- (1-methyl-1H-pyrazol-4-yl)-8-oxo-5,8-dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5- a]pyrimidine-7,4’-piperidin]-4(6H)-yl)acetamide (Compound 10).

Step 1. A stirred solution of tert-butyl 2-bromo-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (700 mg, 1.65 mmol) in THF (20 mL) was treated with N-(2-chloro-4-(trifluoromethyl)phenyl)- 2-iodoacetamide (600 mg, 1.65 mmol). The reaction mixture was stirred for 16 h under argon. The reaction mixture was concentrated, the crude compound was purified by chromatography on SiO2 (2% MeOH/DCM) to provide tert-butyl 2-bromo-4-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (400 mg, 0.497 mmol). MS (EI) calcd for C₂₆H₂₈BrClF₃N₆O₄ [M+H]⁺ 659. Step 2. A stirred solution of tert-butyl 2-bromo-4-(2-((2-chloro-4- (trifluoromethyl)phenyl)-amino)-2-oxoethyl)-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (50 mg, 0.076 mmol) in DCM (5 mL) was treated with 4 M HCl in dioxane (9.0 µL, 0.076 mmol). The reaction mixture was stirred at 25 °C for 2 h, then concentrated under reduced pressure. Crude compound was washed with diethyl ether and dried under reduced pressure to afford 2-(2-bromo-8-oxo-5,8-dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’- piperidin]-4(6H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (42 mg, 0.074 mmol). Step 3. A stirred solution of 3-hydroxypicolinic acid (25 mg, 0.18 mmol) in DMF (2 mL) was treated with HATU (102 mg, 0.268 mmol), N,N-diisopropylethylamine (69 mg, 0.54 mmol), 2-(2-bromo-8-oxo-5,8-dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’- piperidin]-4(6H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (100 mg, 0.179 mmol). The reaction mixture was stirred for 16 h under argon atmosphere. Reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 x 30 mL). Combined organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated. Crude compound was triturated with n-pentane and the obtained solid was washed with n-pentane, dried under reduced pressure to afford 2-(2-bromo-1’-(3-hydroxypicolinoyl)-8-oxo-5,8- dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4(6H)-yl)-N-(2- chloro-4-(trifluoromethyl)phenyl)acetamide (70 mg, 0.082 mmol). MS (EI) calc’d for C27H23BrClF3N7O4 [M+H]⁺ 680, found 680. Step 4. A stirred solution of 2-(2-bromo-1’-(3-hydroxypicolinoyl)-8-oxo-5,8- dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4(6H)-yl)-N-(2- chloro-4-(trifluoromethyl)phenyl)acetamide (30 mg, 0.044 mmol) in toluene (2 mL), EtOH (2 mL) and water (0.5 mL) was treated with potassium phosphate tribasic (28 mg, 0.13 mmol), 1- methyl-4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1h-pyrazole (9.2 mg, 0.044 mmol). The reaction mixture was purged with argon gas for 15 min. Then to this reaction mixture was added Xphos-Pd-G2 (3.8 mg, 0.0044 mmol). The reaction mixture was stirred at 80 °C for 2 h under argon atmosphere. Reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure. Crude compound was purified by reverse phase chromatography (MeCN/water with 10 mM NH4HCO3) compound 10, N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(1’-(3-hydroxypicolinoyl)-2-(1-methyl-1H-pyrazol-4-yl)-8-oxo-5,8- dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4(6H)-yl)acetamide (14 mg, 0.020 mmol).¹H NMR (400 MHz, DMSO-d₆) δ 10.04 (br s, 2H), 8.30 (s, 1H), 8.02-8.13 (m, 2H), 7.97 (d, J = 1.6 Hz, 1H), 7.90 (d, J = 0.4 Hz, 1H), 7.71 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.23-7.32 (m, 2H), 5.24 (s, 2H), 4.57 (d, J = 12.4 Hz, 1H), 3.90 (s, 3H), 3.42 (d, J = 12.4 Hz, 1H), 2.96-3.22 (m, 3H), 2.89 (t, J = 13.2 Hz, 1H), 2.32-2.43 (m, 2H), 2.10-2.27 (m, 2H), 1.56 (d, J = 12.0 Hz, 1H), 1.38 (d, J = 12.0 Hz, 1H). MS (EI) calcd for C₃₁H₂₈ClF₃N₉O₄ [M+H]⁺ 682, found 682. Example 11 [0185] Compound 11 was prepared analogously to Compound 10, substituting 1-methyl-4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1h-pyrazole for pyridine-3-boronic acid. Example 12 [0186] Preparation of 2-(2-(3,6-Dihydro-2H-pyran-4-yl)-1’-(5-hydroxy-6-methylpyrimidine-4- carbonyl)-8-oxo-5,8-dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]- 4(6H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide (Compound 12). Step 1. A stirred solution of tert-butyl 2-bromo-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d][1,2,4] triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (500 mg, 1.18 mmol) and 2-iodo-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide (404 mg, 1.18 mmol) in DMF (5 mL) was treated with DIEA (0.617 ml, 3.54 mmol). The reaction mixture was stirred for 16 h. Reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 20 mL). Combined organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by silica gel chromatography (12 g silica gel, 70% ethyl acetate/pet. Ether) to give tert-butyl 2-bromo-4-(2- ((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d][1,2,4] triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (700 mg). ¹H NMR (400 MHz, CD₃OD) δ 7.73 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.49 (d, J = 8.8 Hz, 1H), 5.17 (s, 2H), 4.15-4.00 (m, 2H), 3.12 (t, J = 7.6 Hz, 2H), 2.99-2.87 (m, 2H), 2.47- 2.36 (m, 5H), 2.25 (t, J = 7.6 Hz, 2H), 1.53-1.46 (m, 11H). MS (EI) 539. Step 2. A mixture of tert-butyl 2-bromo-4-(2-((2-methyl-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (200 mg, 0.313 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (79 mg, 0.38 mmol), K2CO3 (86 mg, 0.63 mmol) and Pd(dtbpf)Cl2 (20 mg, 0.031 mmol) in Dioxane (3 mL) and H₂O (0.2 mL) was degassed and backfilled with N2 (three times). The mixture was heated to 100 °C for 15 h. The reaction was quenched by water (10 mL), extracted by EtOAc (10 mL x 2), dried over Na₂SO₄, filtered and concentrated. The residue was purified by Prep-TLC (SiO2, 100% EtOAc) to give tert-butyl 2-(3,6-dihydro-2H-pyran-4-yl)-4-(2-((2- methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d][1,2,4] triazolo[1,5-a]pyrimidine-7,4’ -piperidine]-1’-carboxylate (180 mg). ¹H NMR (400 MHz, CD₃OD) δ 7.72 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 6.93 (s, 1H), 5.19 (s, 2H), 4.39-4.28 (m, 2H), 4.09 (d, J = 11.6 Hz, 2H), 3.90 (t, J = 5.6 Hz, 2H), 3.11 (t, J = 7.6 Hz, 2H), 2.99-2.87 (m, 2H), 2.64 (d, J = 2.0 Hz, 2H), 2.50-2.41 (m, 2H), 2.39 (s, 3H), 2.25 (t, J = 7.6 Hz, 2H), 1.53-1.46 (m, 11H). MS (EI) 587.2 Step 3. A solution of tert-butyl 2-(3,6-dihydro-2H-pyran-4-yl)-4-(2-((2-methyl-4- (trifluoromethyl)phenyl) amino)-2-oxoethyl)-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’ -piperidine]-1’-carboxylate (180 mg, 0.280 mmol) in 2 M HCl/Dioxane (3 mL) was stirred at 25 °C for 2 hours. The reaction was filtered and concentrated to give 2-(2-(3,6-dihydro-2H-pyran-4-yl)-8-oxo-5,8- dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4(6H)-yl)-N-(2- methyl-4-(trifluoromethyl)phenyl)acetamide (150 mg). MS (EI) 543. Step 4. A solution of 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (68 mg, 0.28 mmol), DIEA (0.15 mL, 0.83 mmol) and HATU (158 mg, 0.415 mmol) in DMF (2 mL) was treated with 2-(2-(3,6-dihydro-2H-pyran-4-yl)-8-oxo-5,8-dihydrospiro[cyclopenta[d][1,2,4]- triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4(6H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)- acetamide (150 mg). The reaction mixture was stirred for 16 h. The reaction was diluted was EtOAc (2 mL), washed with water (5 mL), and the aqueous layer was re-extracted with EtOAc (2 x 2 mL). The organic layer was washed with brine (2 mL), dried over Na2SO4, filtered and the solvent was evaporated to give the crude product. The crude product was purified by preparative TLC (SiO2, Ethyl acetate 100%) to give 2-(1’-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)-2- (3,6-dihydro-2H-pyran-4-yl)-8-oxo-5,8-dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5- a]pyrimidine-7,4’-piperidin]-4(6H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide (180 mg). ¹H NMR (400 MHz, CD3OD) δ 8.81-8.77 (m, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.50-7.47 (m, 2H), 7.46-7.35 (m, 3H), 6.94 (4,1H), 5.24-5.18 (m, 1H), 5.20 (s, 2H), 5.14-5.10 (m, 1H), 4.76-4.67 (m, 2H), 4.33 (d, J = 2.8 Hz, 2H), 3.90 (t, J = 5.6 Hz, 2H), 3.43 (d, J = 13.2 Hz, 1H), 3.35 (s, 3H), 3.25 (d, J = 2.8 Hz, 1H), 3.13 (d, J = 7.6 Hz, 2H), 2.69-2.55 (m, 4H), 2.41 (s, 3H), 2.35-2.23 (m, 2H), 1.78-1.67 (m, 1H), 1.59-1.47 (m, 1H). MS (EI) 769.2. Step 5. A solution of 2-(1’-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)-2-(3,6- dihydro-2H-pyran-4-yl)-8-oxo-5,8-dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine- 7,4’-piperidin]-4(6H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide (175 mg, 0.228 mmol) in TFA (2 mL) was stirred at 40 °C for 2 h. The reaction was evaporated under reduced pressure. The residue was purified by reverse phase chromatography (34-54% MeCN/water with 0.1% TFA) to give 2-(2-(3,6-dihydro-2H-pyran-4-yl)-1’-(5-hydroxy-6-methylpyrimidine-4- carbonyl)-8-oxo-5,8-dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]- 4(6H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide (50 mg). ¹H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H), 6.94 (s, 1H), 5.21 (s, 2H), 4.81-4.62 (m, 1H), 4.33 (d, J = 2.8 Hz, 2H), 4.17-4.01 (m, 1H), 3.90 (t, J = 5.6 Hz, 2H), 3.35 (s, 1H), 3.19-3.10 (m, 2H), 3.06 (t, J = 12.8 Hz, 1H), 2.69-2.57 (m, 4H), 2.53 (s, 3H), 2.39 (s, 3H), 2.37-2.26 (m, 2H), 1.82-1.64 (m, 1H), 1.62-1.50 (m, 1H). MS (EI) calc’d for C₃₃H₃₄F₃N₈O₅ [M+H]⁺ 679, found, 679. Examples 12-15 [0187] Compounds 13-15 were prepared in a fashion analogous to the preparation of compound 12, substituting for the appropriate iodoacetamide intermediate. Example 16 [0188] Preparation of (R or S)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H- pyran-4-yl)-1’-(3-hydroxypicolinoyl)-5-methyl-8-oxo-5,8- dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4(6H)-yl)acetamide (Compound 16). Step 1. A solution of 8-(tert-butyl) 1-ethyl 3-methyl-2-oxo-8-azaspiro[4.5]decane-1,8- dicarboxylate (1.00 g, 2.95 mmol) in EtOH (8 mL) was treated with 3-bromo-1H-1,2,4-triazol-5- amine (0.408 g, 2.50 mmol), phosphorus(V) oxide (0.836 g, 5.89 mmol) and the resulting mixture was stirred at 90 °C for 12 h. After cooling to room temperature, then the mixture was added DIEA (1.54 mL, 8.84 mmol), Boc2O (0.821 mL, 3.54 mmol) and stirred for 2 h. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (20 g silica gel, 8% MeOH/DCM) to give tert-butyl 2-bromo-5-methyl-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine -7,4’-piperidine]-1’-carboxylate (450 mg). MS (EI) 440. Step 2. A solution of tert-butyl 2-bromo-5-methyl-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta-[d][1,2,4] triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (450 mg, 1.03 mmol) in Dioxane (6 mL) and H₂O (1 mL) was treated with 2-(3,6-dihydro-2H- pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (259 mg, 1.23 mmol), K2CO3 (284 mg, 2.05 mmol), Pd(dtbpf)Cl2 (67 mg, 0.10 mmol). The resulting mixture was stirred at 100 °C for 12 h under N2. Filtered the mixture and the filtrate was concentrated. The residue was purified by silica gel chromatography (4 g silica gel, 8% MeOH/DCM) to give tert-butyl 2-(3,6-dihydro-2H- pyran-4-yl)-5-methyl-8-oxo-4,5,6,8-tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5- a]pyrimidine-7,4’-piperidine]-1’-carboxylate (380 mg). MS (EI) 442. Step 3. A solution of tert-butyl 2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8-oxo-4,5,6,8- tetrahydrospiro [cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (350 mg, 0.793 mmol) in DMF (5 mL) was treated with DIEA (0.415 mL, 2.38 mmol), N-(2- chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide (274 mg, 0.753 mmol) and the resulting mixture was stirred for 12 h. The mixture was quenched with water (20 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (12 g silica gel, 50% ethyl acetate/pet. Ether) to give tert-butyl 4-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8-oxo- 4,5,6,8-tetrahydrospiro[cyclopenta[d] [1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’- carboxylate (100 mg). MS (EI) 677. Step 4. Tert-Butyl 4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2- (3,6-dihydro-2H-pyran-4-yl)-5-methyl-8-oxo-4,5,6,8-tetrahydrospiro[cyclopenta[d][1,2,4]- triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (200 mg, 0.295 mmol) was resolved by Chiral-SFC (Condition: SFC-22 (Column: DAICEL CHIRALPAK IC(250mmx30mm, 10um)), Mobile phase: A: CO₂, B: CO₂-ETOH (0.1% NH₄OH), Gradient: 60% B, Flow Rate: 80 mL/min) to give tert-butyl 4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro- 2H-pyran-4-yl)-5-methyl-8-oxo-4,5,6,8-tetrahydrospiro[cyclopenta[d][1,2,4]-triazolo[1,5- a]pyrimidine-7,4’-piperidine]-1’-carboxylate (80 mg) (Rt = 1.219 min, ee = 100.00%) as colorless oil and tert-butyl 4-(2-((2-chloro-4-(trifluoromethyl)phenyl)-amino)-2-oxoethyl)-2-(3,6- dihydro-2H-pyran-4-yl)-5-methyl-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (80 mg) (Rt = 2.401 min, ee = 99.88%). P1: ¹H NMR (400 MHz, CD₃OD) δ 8.15 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 1.2 Hz, 1H), 7.65-7.58 (m, 1H), 6.92 (s, 1H), 5.41-5.14 (m, 2H), 4.31 (d, J = 2.8 Hz, 2H), 4.12-4.06 (m, 2H), 3.89 (t, J = 5.4 Hz, 2H), 3.52-3.46 (m, 1H), 3.35 (s, 1H), 3.11-2.79 (m, 2H), 2.68-2.55 (m, 3H), 2.49-2.32 (m, 2H), 2.13-2.07 (m, 1H), 1.62-1.54 (m, 1H), 1.49 (s, 9H), 1.43 (d, J = 7.2 Hz, 3H). P2: ¹H NMR (400 MHz, CD3OD) δ 8.15 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 1.2 Hz, 1H), 7.65-7.59 (m, 1H), 6.92 (s, 1H), 5.40-5.15 (m, 2H), 4.31 (d, J = 2.8 Hz, 2H), 4.12-4.06 (m, 2H), 3.89 (t, J = 5.2 Hz, 2H), 3.52-3.46 (m, 1H), 3.35 (s, 1H), 3.10-2.78 (m, 2H), 2.69-2.55 (m, 3H), 2.49-2.30 (m, 2H), 2.14-2.06 (m, 1H), 1.62-1.54 (m, 1H), 1.49 (s, 9H), 1.43 (d, J = 7.2 Hz, 3H). Step 5. To a solution of enantiomer P2 of tert-butyl 4-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8-oxo- 4,5,6,8-tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’- carboxylate (40 mg, 0.059 mmol) in MeOH (0.5 mL) was added HCl/Dioxane (2 M) (1 mL) and the mixture was stirred at 25 °C for 3 h. The mixture was directly concentrated to give N-(2- chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8-oxo-5,8- dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4(6H)-yl)acetamide (34 mg, 0.059 mmol). MS (EI) 577. Step 6. To a solution of 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (17 mg, 0.071 mmol) in DMF (1 mL) was added DIEA (0.031 ml, 0.18 mmol), HATU (34 mg, 0.088 mmol) and stirred for 3 min. Then N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro- 2H-pyran-4-yl)-5-methyl-8-oxo-5,8-dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine- 7,4’-piperidin]-4(6H)-yl)acetamide (34 mg) was added and the resulting mixture was stirred for 12 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The residue was purified by Prep-TLC (silica gel, ethyl acetate/pet. Ether = 3/1) to give 2-(1’-(5-(benzyloxy)- 6-methylpyrimidine-4-carbonyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8-oxo-5,8- dihydrospiro[cyclopenta[d][1,2,4] triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4(6H)-yl)-N-(2- chloro-4-(trifluoromethyl)phenyl)acetamide (40 mg). MS (EI) 803. Step 7. A mixture of (P2 derived) 2-(1’-(5-(benzyloxy)-6-methylpyrimidine-4- carbonyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8-oxo-5,8- dihydrospiro[cyclopenta[d][1,2,4]triazolo-[1,5-a]pyrimidine-7,4’-piperidin]-4(6H)-yl)-N-(2- chloro-4-(trifluoromethyl)phenyl)acetamide from P2 (35 mg, 0.044 mmol) in TFA (1 mL) was stirred at 40 °C for 5 h. The reaction mixture was concentrated and the residue was purified by reverse phase chromatography (50-70% MeCN/water with 0.1% TFA) to give S- or R-N-(2- chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-1’-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-5-methyl-8-oxo-5,8- dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4(6H)-yl)acetamide (19 mg, 0.027 mmol).¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 8.14 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 1.6 Hz, 1H), 7.65-7.57 (m, 1H), 6.92 (s, 1H), 5.42-5.30 (m, 1H), 5.24-5.15 (m, 1H), 4.75- 4.69 (m, 1H), 4.35-4.27 (m, 2H), 4.16-3.99 (m, 1H), 3.88 (t, J=5.2 Hz, 2H), 3.56-3.48 (m, 1H), 3.45-3.25 (m, 1H), 3.20-2.91 (m, 1H), 2.82-2.73 (m, 1H), 2.65-2.55 (m, 3H), 2.53 (s, 3H), 2.50- 2.34 (m, 1H), 2.21-2.13 (m, 1H), 1.82-1.60 (m, 1H), 1.60-1.40 (m, 4H). MS (EI) calc’d for C33H34ClF3N8O5 [M+H]⁺, 713; found, 713. Example 17 [0189] Preparation of (R or S)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H- pyran-4-yl)-1’-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-5-methyl-8-oxo-5,8-dihydro-4H- spiro[furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4-yl)acetamide (Compound 17)

Step 1. A solution of 8-(tert-butyl) 4-ethyl 2-methyl-3-oxo-1-oxa-8- azaspiro[4.5]decane-4,8-dicarboxylate (360 mg, 1.05 mmol) in EtOH (5 mL) at 0 °C was treated with phosphorus(V) oxide (150 mg, 1.05 mmol) and 3-bromo-1H-1,2,4-triazol-5-amine (172 mg, 1.05 mmol). The reaction mixture was stirred at 90 °C for 16 h. DIEA (0.553 mL, 3.16 mmol) and Boc2O (0.367 mL, 1.58 mmol) were added to the mixture. The reaction mixture was stirred for 2 h. The mixture was concentrated and the residue was purified by Prep-TLC using DCM/MeOH = 10:1 to give tert-butyl 2-bromo-5-methyl-8-oxo-5,8-dihydro-4H-spiro[furo[3,4- d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (180 mg). MS (EI) 440. Step 2. A mixture of tert-butyl 2-bromo-5-methyl-8-oxo-5,8-dihydro-4H-spiro[furo[3,4- d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (160 mg, 0.363 mmol), 2-(3,6- dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (92 mg, 0.44 mmol), K₂CO₃ (100 mg, 0.727 mmol) and Pd(dtbpf)Cl₂ (24 mg, 0.036 mmol) in Dioxane (3 mL) and H₂O (0.3 mL) was degassed and backfilled with N2 (three times). The mixture was heated to 100 °C for 12 h. The mixture was concentrated and the residue was purified by Prep-TLC using DCM/MeOH = 10:1 to give tert-butyl 2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8-oxo-5,8- dihydro-4H-spiro[furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (100 mg). MS (EI) 444. Step 3. A mixture of tert-butyl 2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8-oxo-5,8- dihydro-4H-spiro[furo [3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidine]-1’-carboxylate (100 mg, 0.225 mmol) in DMF (3 mL) was treated with DIEA (0.118 mL, 0.676 mmol) and N- (2-chloro-4-(trifluoromethyl) phenyl)-2-iodoacetamide (90 mg, 0.25 mmol). The mixture was stirred for 12 h and concentrated, then the residue was purified by Prep-TLC using DCM/MeOH = 10:1 to give tert-butyl 4-(2-((2-chloro-4-(trifluoromethyl) phenyl)amino)-2-oxoethyl)-2-(3,6- dihydro-2H-pyran-4-yl)-5-methyl-8-oxo-5,8-dihydro-4H-spiro [furo[3,4-d][1,2,4]triazolo[1,5- a]pyrimidine-7,4’-piperidine]-1’-carboxylate (80 mg). MS (EI) 623. Step 4. A stirred solution of tert-butyl 4-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8-oxo-5,8- dihydro-4H-spiro[furo[3,4-d][1,2,4]triazolo[1,5-a] pyrimidine-7,4’-piperidine]-1’-carboxylate (80 mg, 0.118 mmol) in DCM (2 mL) was added 2 M HCl/Dioxane (0.2 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5- methyl-8-oxo-5,8-dihydro-4H-spiro [furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]- 4-yl)acetamide which was used directly in next step without further purification (60 mg, 0.104 mmol). MS (EI) 579. Step 5. A mixture of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H- pyran-4-yl)-5-methyl-8-oxo-5,8-dihydro-4H-spiro[furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine- 7,4’-piperidin]-4-yl) acetamide (40 mg), 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (19 mg, 0.076 mmol) and NMI (11 mg, 0.14 mmol) in DCM (2 mL) was treated with TCFH (29 mg, 0.10 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. The mixture was concentrated. The crude product was purified by Prep-TLC using DCM/MeOH = 10:1 to give 2- (1’-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8- oxo-5,8-dihydro-4H-spiro[furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4-yl)-N-(2- chloro-4-(trifluoromethyl)phenyl)acetamide (30 mg). MS (EI) 805. Step 6. A solution of 2-(1’-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)-2-(3,6- dihydro-2H-pyran-4-yl)-5-methyl-8-oxo-5,8-dihydro-4H-spiro[furo[3,4-d][1,2,4]triazolo[1,5- a]pyrimidine-7,4’-piperidin]-4-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (30 mg, 0.037 mmol) in TFA (1 mL) was stirred at 40 °C for 2 h. The mixture was concentrated and the residue was purified by reverse phase chromatography (55-100% MeCN/water with 0.1% TFA) to give racemic N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-1’-(5- hydroxy-6-methylpyrimidine-4-carbonyl)-5-methyl-8-oxo-5,8-dihydro-4H-spiro[furo[3,4- d][1,2,4]triazolo[1,5-a]pyrimidine-7,4’-piperidin]-4-yl)acetamide (20 mg). MS (EI) 715. Step 7. The racemic product N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro- 2H-pyran-4-yl)-1’-(5-hydroxy -6-methylpyrimidine-4-carbonyl)-5-methyl-8-oxo-5,8-dihydro- 4H-spiro[furo[3,4-d][1,2,4]triazolo [1,5-a]pyrimidine-7,4’-piperidin]-4-yl)acetamide (20 mg, 0.028 mmol) was resolved by chiral SFC. Column: DAICEL CHIRALCEL OD (250mm x 30mm, 10um), 40% ETOH (0.1% NH4OH) in CO2 to give the first eluted isomer N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-1’-(5-hydroxy-6-methyl pyrimidine- 4-carbonyl)-5-methyl-8-oxo-5,8-dihydro-4H-spiro[furo[3,4-d][1,2,4]triazolo[1,5-a] pyrimidine- 7,4’-piperidin]-4-yl)acetamide. Peak 1 (7.9 mg) [Chiralcel OD-3_ethanol(DEA)_Rt = 1.869 min] ; Peak 2 (8.3 mg) [Chiralcel OD-3_ethanol(DEA)_Rt = 2.162 min]. Peak 2 characterization: ¹H NMR (400 MHz, CD3OD) δ 8.54 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.82 (s, 1H), 7.62 (d, J = 8.8 Hz, 1H), 6.95 (s, 1H), 5.54-5.50 (m, 1H), 5.31-5.18 (m, 2H), 4.71 (s, 1H), 4.32 (s, 2H), 4.01 (s, 1H), 3.90-3.88 (m, 2H), 3.65-3.49 (m, 1H), 3.30-3.13 (m, 1H), 2.66-2.55 (m, 3H), 2.55-2.30 (m, 4H), 1.95-1.70 (m, 2H), 1.67-1.61 (m, 3H). MS (EI) calc’d for C32H31ClF3N8O6 [M+H]⁺, 715; found, 715. Example 18 [0190] Preparation of N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2’-(3,6-dihydro-2H-pyran-4- yl)-1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-9’-oxo-5’,6’,7’,9’-tetrahydro-4’H- spiro[piperidine-4,8’-[1,2,4]triazolo[5,1-b]quinazolin]-4’-yl)acetamide (Compound 18).

.5]undecane-3,7- dicarboxylate Intermediate V (160 mg, 0.471 mmol), 3-bromo-1H-1,2,4-triazol-5-amine (85 mg, 0.52 mmol) in EtOH (1.5 mL) was treated with phosphorus(V) oxide (134 mg, 0.943 mmol) at 0 ºC and the resulting mixture was stirred at 80 °C for 12 h. The reaction mixture was treated with DIEA (183 mg, 1.41 mmol), Boc₂O (206 mg, 0.943 mmol) and stirred at 25 ºC for 3 h. The mixture was concentrated and the residue was purified by silica gel chromatography (4 g silica gel, 5% MeOH/DCM) to give tert-butyl 2’-bromo-9’-oxo-5’, 6’, 7’, 9’-tetrahydro-4’H- spiro[piperidine-4,8’-[1,2,4]triazolo[5,1-b]quinazoline]-1-carboxylate (140 mg).¹H NMR (400 MHz, CDCl₃) δ 12.49 (s, 1H), 4.14-3.90 (m, 2H), 3.12-2.78 (m, 6H), 2.05-1.79 (m, 4H), 1.50 (s, 9H), 1.31-1.22 (m, 2H). MS (EI) [M-tBu+H]⁺ 340. Step 2. A mixture of tert-butyl 2’-bromo-9’-oxo-5’,6’,7’,9’-tetrahydro-4’H- spiro[piperidine-4,8’-[1,2,4]triazolo [5,1-b]quinazoline]-1-carboxylate (140 mg, 0.319 mmol), 2- (3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (101 mg, 0.479 mmol) and K2CO3 (88 mg, 0.64 mmol) in Dioxane (3 mL) and H2O (0.3 mL) was treated with Pd(dtbpf)Cl2 (42 mg, 0.064 mmol). The mixture was degassed and backfilled with N2 (three times). The mixture was heated to 100 °C for 24 h. After cooling to rt, the reaction was dissolved in EtOAc (25 mL), dried over Na2SO4, the solid was filtered and the filtrate was concentrated and the residue was purified by Prep-TLC (silica gel, DCM/MeOH = 10/1) to give the tert-butyl 2’-(3,6- dihydro-2H-pyran-4-yl)-9’-oxo-5’,6’,7’,9’-tetrahydro-4’H-spiro[piperidine-4,8’- [1,2,4]triazolo[5,1-b] quinazoline]-1-carboxylate (94 mg). MS (EI) [M-tBu+H]⁺ 386. Step 3. A solution of tert-butyl 2’-(3,6-dihydro-2H-pyran-4-yl)-9’-oxo-5’, 6’, 7’, 9’- tetrahydro-4’H-spiro [piperidine-4,8’-[1,2,4]triazolo[5,1-b]quinazoline]-1-carboxylate (94 mg, 0.21 mmol) in MeOH (1 mL) was treated with 2 N HCl/Dioxane (1 mL). The reaction mixture was stirred at for 12 h. The reaction was concentrated to give 2’-(3,6-dihydro-2H-pyran-4-yl)-6’, 7’-dihydro-4’H-spiro[piperidine-4,8’-[1,2,4]triazolo[5,1-b]quinazolin]-9’(5’H)-one (70 mg, 0.20 mmol). MS (EI) m/z [M+H]⁺ 342. Step 4. A mixture of 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (47 mg, 0.19 mmol), 2’-(3,6-dihydro-2H-pyran-4-yl)-6’, 7’-dihydro-4’H-spiro[piperidine-4,8’- [1,2,4]triazolo[5,1-b]quinazolin]-9’(5’H)-one (60 mg, 0.17 mmol) and NMI (29 mg, 0.35 mmol) in DCM (5 mL) was treated with TCFH (74 mg, 0.26 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 h. The crude product was purified by Prep-TLC (silica gel, ethyl acetate/ethyl alcohol = 5/1) to give 1-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)-2’-(3,6-dihydro-2H- pyran-4-yl)-6’, 7’-dihydro-4’H-spiro[piperidine-4,8’-[1,2,4]triazolo[5,1-b]quinazolin]-9’(5’H)- one (90 mg). MS (EI) m/z [M+H]⁺ 568. Step 5. A stirred solution of 1-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)-2’-(3,6- dihydro-2H-pyran-4-yl)-6’, 7’-dihydro-4’H-spiro[piperidine-4,8’-[1,2,4]triazolo[5,1- b]quinazolin]-9’(5’H)-one (30 mg, 0.053 mmol) and N-(2-chloro-4-(trifluoromethyl)phenyl)-2- iodoacetamide (38 mg, 0.11 mmol) in DMF (1 mL) was treated with DIEA (20 mg, 0.16 mmol). The reaction mixture was stirred at 25 °C for 10 h. The reaction mixture was quenched with water (6 mL) and extracted with EtOAc (3 x 2 mL). Combined organic layer was washed with brine (3 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 2-(1-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)-2’-(3,6-dihydro-2H-pyran-4-yl)-9’- oxo-5’, 6’, 7’, 9’-tetrahydro-4’H-spiro [piperidine-4,8’-[1,2,4]triazolo[5,1-b]quinazolin]-4’-yl)- N-(2-chloro-4-(trifluoromethyl)phenyl) acetamide (30 mg, crude) which was used to the next step without purification. MS (EI) m/z 803. Step 6. A solution of 2-(1-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)-2’-(3,6- dihydro-2H-pyran-4-yl)-9’-oxo-5’, 6’, 7’, 9’-tetrahydro-4’H-spiro[piperidine-4,8’- [1,2,4]triazolo[5,1-b]quinazolin]-4’-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (30 mg, crude) was dissolved in TFA (0.5 mL). The reaction mixture was stirred at 40 °C for 12 h. The reaction was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (50-100% MeCN/water with 0.1% TFA) to give N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(2’-(3,6-dihydro-2H-pyran-4-yl)-1-(5-hydroxy-6-methylpyrimidine- 4-carbonyl)-9’-oxo-5’, 6’, 7’, 9’-tetrahydro-4’H-spiro [piperidine-4,8’-[1,2,4]triazolo[5,1- b]quinazolin]-4’-yl)acetamide (9.5 mg).1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.81 (s, 1H), 7.65-7.59 (m, 1H), 6.95 (s, 1H), 5.37 (s, 2H), 4.60-4.50 (m, 1H), 4.38-4.29 (m, 2H), 4.14-4.00 (m, 1H), 3.89 (t, J = 5.6 Hz, 2H), 3.57-3.45 (m, 1H), 3.28-3.17 (m, 1H), 3.16-2.98 (m, 2H), 2.88-2.75 (m, 2H), 2.69-2.60 (m, 2H), 2.53 (s, 3H), 2.10-2.00 (m, 2H), 1.94-1.85 (m, 2H), 1.61-1.50 (m, 1H), 1.50-1.39 (m, 1H). MS (EI) calc’d for C33H33ClF3N8O5 [M+H]⁺ 713, found 713. Example 19 [0191] Preparation of N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2’-(3,6-dihydro-2H-pyran-4- yl)-1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-9’-oxo-5’,9’-dihydrospiro[piperidine-4,8’- pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidin]-4’(6’H)-yl)acetamide (Compound 19).

Step 1 Boc Step 2 Boc ^H ₂ ^N _N B N N r PinB O 3, oC Step 1. A solution of 9-(tert-butyl) 5-ethyl 4-oxo-1-oxa-9-azaspiro[5.5]undecane-5,9- dicarboxylate (430 mg, 1.26 mmol), 3-bromo-1H-1,2,4-triazol-5-amine (226 mg, 1.39 mmol) in EtOH (4 mL) was treated with phosphorus(V) oxide (358 mg, 2.52 mmol) and the resulting mixture was stirred at 80 °C for 12 h. The reaction mixture was treated with N-ethyl-N- isopropylpropan-2-amine (163 mg, 1.26 mmol), di-tert-butyl 118ecarbonate (550 mg, 2.52 mmol) and stirred for 3 h. The mixture was concentrated and the residue was purified by silica gel chromatography (4 g silica gel, 5% methyl alcohol/dichloromethane) to give tert-butyl 2’- bromo-9’-oxo-4’,5’,6’,9’-tetrahydrospiro[piperidine-4,8’-pyrano[4,3-d][1,2,4]triazolo[1,5- a]pyrimidine]-1-carboxylate (400 mg, 0.727 mmol). ¹H NMR (400 MHz, CDCl3) δ 4.01 (br t, J = 5.6 Hz, 4H), 3.14 (br s, 2H), 2.96 (br t, J = 5.2 Hz, 2H), 2.84 – 2.64 (m, 2H), 1.60 (br d, J = 12.8 Hz, 2H), 1.50 (s, 9H). MS (EI) [M+H-Boc]⁺ m/z 340. Step 2. A mixture of tert-butyl 2’-bromo-9’-oxo-4’,5’,6’,9’-tetrahydrospiro[piperidine- 4,8’-pyrano[4,3-d][1,2,4] triazolo[1,5-a]pyrimidine]-1-carboxylate (160 mg, 0.363 mmol), 2- (3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (76 mg, 0.36 mmol), K2CO3 (100 mg, 0.727 mmol) and Pd(dtbpf)Cl2 (24 mg, 0.036 mmol) in Dioxane (3 mL) and H2O (0.3 mL) was degassed and backfilled with N2 (three times). The mixture was heated to 100 °C for 16 h. The reaction was concentrated under reduced pressure. The crude product was purified by Prep-TLC (SiO2, DCM/MeOH = 10:1) to give tert-butyl 2’-(3,6-dihydro-2H-pyran-4- yl)-9’-oxo-4’,5’,6’,9’-tetrahydrospiro[piperidine-4,8’-pyrano[4,3-d][1,2,4]triazolo[1,5- a]pyrimidine]-1-carboxylate (150 mg). MS (EI) [M+H-Boc]⁺ m/z 344. Step 3. A mixture of N-(2-chloro-4-(trifluoromethyl) phenyl)-2-iodoacetamide (148 mg, 0.406 mmol) and tert-butyl 2’-(3,6-dihydro-2H-pyran-4-yl)-9’-oxo-4’,5’,6’,9’- tetrahydrospiro[piperidine-4,8’-pyrano[4,3 -d][1,2,4]triazolo[1,5-a]pyrimidine]-1-carboxylate (150 mg, 0.338 mmol) in DMF (3 mL) was treated with DIEA (0.177 mL, 1.02 mmol). The mixture was stirred at 25 °C for 1 h, quenched by addition of H2O (5 mL). Then the mixture was extracted with EtOAc (5 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (4 g, 50% EtOAc/pet. Ether) to give tert-butyl 4’-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-2’-(3,6-dihydro-2H-pyran-4-yl)-9’-oxo-4’,5’,6’,9’- tetrahydrospiro[piperidine-4,8’-pyrano[4,3 -d][1,2,4]triazolo[1,5-a]pyrimidine]-1-carboxylate (130 mg). MS (EI) [M+H-tBu]⁺ m/z 623. Step 4. A stirred solution of tert-butyl 4’-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-2’-(3,6-dihydro-2H-pyran-4-yl)-9’-oxo-4’,5’,6’,9’- tetrahydrospiro[piperidine-4,8’-pyrano[4,3-d][1,2,4] triazolo[1,5-a]pyrimidine]-1-carboxylate (130 mg, 0.191 mmol) in DCM (3 mL) was treated with HCl in Dioxane (0.3 mL, 4.0 M) at 0 °C. The reaction mixture was stirred for 12 h. The mixture was concentrated under reduced pressure to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2’-(3,6-dihydro-2H-pyran-4-yl)-9’-oxo-5’,9’- dihydrospiro[piperidine-4,8’-pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidin]-4’(6’H)-yl)acetamide (100 mg, 0.17 mmol). MS (EI) [M+H]⁺ m/z 579. Step 5. A mixture of 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (23 mg, 0.095 mmol), N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2’-(3,6-dihydro-2H-pyran-4-yl)-9’-oxo- 5’,9’-dihydrospiro [piperidine-4,8’-pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidin]-4’(6’H)- yl)acetamide (50 mg, 0.086 mmol) and NMI (14 mg, 0.17 mmol) in DCM (1.5 mL) was treated with TCFH (29 mg, 0.10 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. The mixture was concentrated and filtered. The crude product was purified by reverse phase chromatography (gradient of MeCN/water with 0.1% TFA) to give 2-(1-(5-(benzyloxy)-6-methylpyrimidine-4- carbonyl)-2’-(3,6-dihydro-2H-pyran-4-yl)-9’-oxo-5’,9’-dihydrospiro[piperidine-4,8’-pyrano[4,3- d][1,2,4]triazolo[1,5-a]pyrimidin]-4’(6’H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (50 mg). MS (EI) [M+H]⁺ m/z 805. Step 6. A mixture of 2-(1-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)-2’-(3,6- dihydro-2H-pyran-4-yl)-9’-oxo-5’,9’-dihydrospiro[piperidine-4,8’-pyrano[4,3- d][1,2,4]triazolo[1,5-a]pyrimidin]-4’(6’H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (50 mg, 0.062 mmol) in TFA (1 mL) was stirred at 40 °C for 2 h. The mixture was concentrated and filtered. The crude product was purified by reverse phase chromatography (gradient of MeCN/water with 0.1% TFA) to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2’-(3,6-dihydro- 2H-pyran-4-yl)-1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-9’-oxo-5’,9’- dihydrospiro[piperidine-4,8’-pyrano [4,3-d][1,2,4]triazolo[1,5-a]pyrimidin]-4’(6’H)-yl)acetamide (31 mg).¹H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 10.25 (s, 1H), 8.58 (s, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 1.6 Hz, 1H), 7.80-7.65 (m, 1H), 6.86 (s, 1H), 5.33 (s, 2H), 4.45 (d, J = 10.4 Hz, 1H), 4.27 (d, J = 2.4 Hz, 2H), 3.95 (s, 2H), 3.83-3.80 (m, 2H), 3.37-3.32 (m, 2H), 3.14- 3.03 (m, 1H), 2.87-2.77 (m, 2H), 2.74-2.64 (m, 2H), 2.54-2.52 (m, 2H), 2.45 (s, 3H), 1.81-1.78 (m, 1H), 1.62-1.58 (m, 1H). MS (EI) calc’d for C32H31ClF3N8O6 [M+H]⁺, 715, found 715. Examples 20-25 [0192] Compounds 20-25 were prepared in a fashion analogous to the preparation of compound 10, substituting for the appropriate boronic ester. Examples 26-30 [0193] Compounds 26-30 were prepared in a fashion analogous to the preparation of compound 12, substituting for the appropriate iodoacetamide intermediate. Examples 31-76 [0194] Compounds 31-36 were prepared in a fashion analogous to the preparation of compound 7, substituting for the appropriate carboxylic acid. Example 37 [0195] Compound 37 was prepared in a fashion analogous to the preparation of compound 8, substituting Intermediate I for Intermediate II. Example 38 [0196] Compound 38 was prepared in a fashion analogous to the preparation of compound 7, utilizing phenyl boronic acid. Examples 39-45 [0197] Compounds 39-45 were prepared in a fashion analogous to the preparation of compound 19. Example 46 [0198] Preparation of N-(2-Chloro-4-cyclopropylphenyl)-2-(2’-(3,6-dihydro-2H-pyran-4- yl)-1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-9’-oxo-5’,9’-dihydrospiro[piperidine-4,8’- pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidin]-4’(6’H)-yl)acetamide (Compound 46).

BnO Boc N N Step 1 O N O Step 1. A solution of tert-butyl 2’-(3,6-dihydro-2H-pyran-4-yl)-9’-oxo-4’,5’,6’,9’- tetrahydrospiro[piperidine-4,8’-pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine]-1-carboxylate (160 mg, 0.361 mmol) in DCM (10 ml) was treated with 2M HCl/Dioxane (1 mL). The reaction mixture was stirred at 25 °C for 12 h. The mixture was concentrated to give 2’-(3,6-dihydro-2H- pyran-4-yl)-5’,6’-dihydrospiro[piperidine-4,8’-pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidin]- 9’(4’H)-one (120 mg, 0.350 mmol). MS (EI) m/z 344. Step 2. A mixture of 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (94 mg, 0.38 mmol), 2’-(3,6-dihydro-2H-pyran-4-yl)-5’,6’-dihydrospiro[piperidine-4,8’-pyrano[4,3- d][1,2,4]triazolo[1,5-a]pyrimidin]-9’(4’H)-one (120 mg, 0.350 mmol) and NMI (57 mg, 0.70 mmol) in DCM (5 mL) was treated with TCFH (147 mg, 0.524 mmol) at 0 °C. The mixture was stirred at 25 °C for 24 h. The mixture was concentrated, the crude product was purified by Prep- TLC (silica gel, DCM/MeOH = 10/1) to give 1-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)- 2’-(3,6-dihydro-2H-pyran-4-yl)-5’,6’-dihydrospiro[piperidine-4,8’-pyrano[4,3-d][1,2,4] triazolo[1,5-a]pyrimidin]-9’(4’H)-one (160 mg). MS (EI) m/z 570. Step 3. A solution of 1-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)-2’-(3,6- dihydro-2H-pyran-4-yl)-5’, 6’-dihydrospiro[piperidine-4,8’-pyrano[4,3-d][1,2,4]triazolo[1,5- a]pyrimidin]-9’(4’H)-one (24 mg, 0.042 mmol) in DMF (0.5 mL) was treated with N-(2-chloro- 4-cyclopropylphenyl)-2-iodoacetamide (14 mg, 0.042 mmol) and DIEA (0.022 mL, 0.126 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction was diluted with EtOAc (2 mL), washed with water (5 mL), and the aqueous layer was re-extracted with EtOAc (2 x 2 mL). The organic layer was washed with brine (5 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give 2-(1-(5-(benzyloxy)-6-methylpyrimidine- 4-carbonyl)-2’-(3,6-dihydro-2H-pyran-4-yl)-9’-oxo-5’,9’-dihydrospiro[piperidine -4,8’- pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidin]-4’(6’H)-yl)-N-(2-chloro-4-cyclopropylphenyl) acetamide (22 mg, 0.028 mmol). MS (EI) m/z 777. Step 4. A solution of 2-(1-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)-2’-(3,6- dihydro-2H-pyran-4-yl)-9’-oxo-5’,9’-dihydrospiro[piperidine-4,8’-pyrano[4,3- d][1,2,4]triazolo[1,5-a]pyrimidin]-4’(6’H)-yl)-N-(2-chloro-4-cyclopropylphenyl)acetamide (22 mg, 0.028 mmol) in TFA (2 mL) was stirred at 40 °C for 2 hours. The reaction mixture was evaporated under reduced pressure. The residue was purified by reverse phase chromatography (MeCN/water with 0.1% TFA) to give N-(2-chloro-4-cyclopropylphenyl)-2-(2’-(3,6-dihydro-2H- pyran-4-yl)-1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-9’-oxo-5’,9’-dihydrospiro[piperidine- 4,8’-pyrano[4,3-d][1,2,4]triazolo [1,5-a]pyrimidin]-4’(6’H)-yl)acetamide (5.9 mg). ¹H NMR (400 MHz, CD3OD) δ 8.56 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 1.6 Hz, 1H), 7.04-6.94 (m, 2H), 5.30 (s, 2H), 4.67-4.51 (m, 1H), 4.33 (d, J = 2.4 Hz, 2H), 4.03 (d, J = 3.2 Hz, 2H), 3.99- 3.93 (m, 1H), 3.90 (t, J = 5.6 Hz, 2H), 3.63-3.50 (m, 1H), 3.29-3.17 (m, 1H), 2.97-2.80 (m, 4H), 2.63 (d, J = 1.6 Hz, 2H), 2.52 (s, 3H), 2.00-1.78 (m, 2H), 1.73 (d, J=13.2 Hz, 1H), 1.10-0.92 (m, 2H), 0.75-0.55 (m, 2H). MS (EI) calc’d for C₃₄H₃₆ClN₈O₆ [M+H]⁺ 688; found 688. Examples 47-53 [0199] Compound 47-53 were prepared in a fashion analogous to the preparation of compound 46, substituting for the appropriate iodoacetamide intermediate. Examples 54-57 [0200] Compound 54-57 were prepared in a fashion analogous to the preparation of compound 19, substituting for the appropriate iodoacetamide intermediate and acid precursors. Example 58 [0201] Preparation of N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2’-(3-fluorophenyl)-1-(5- hydroxy-6-methylpyrimidine-4-carbonyl)-9’-oxo-5’,9’-dihydrospiro[piperidine-4,8’-pyrano[4,3- d][1,2,4]triazolo[1,5-a]pyrimidin]-4’(6’H)-yl)acetamide (Compound 58). Step 1 Step 2 B H Boc ^H ₂ ^N oc N N N I N ^HN Br O O F C Cl Step 1. A solution of 9-(tert-butyl) 5-ethyl 4-oxo-1-oxa-9-azaspiro[5.5]undecane-5,9- dicarboxylate (2.0 g, 5.86 mmol) in EtOH (30 mL) was treated with 3-bromo-1H-1,2,4-triazol-5- amine (0.955 g, 5.86 mmol), phosphorus(V) oxide (1.663 g, 11.72 mmol) and the resulting mixture was stirred at 80 °C for 12 h and then cooled. To the reaction mixture were added DIEA (3.07 mL, 17.6 mmol), Boc₂O (1.92 g, 8.79 mmol) and the mixture was stirred at 25 ºC for 3 h. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (20 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to give tert-butyl 2’- bromo-9’-oxo-4’,5’,6’,9’-tetrahydrospiro[piperidine-4,8’-pyrano[4,3-d][1,2,4]triazolo[1,5- a]pyrimidine]-1-carboxylate (2.58 g, 5.86 mmol, crude). MS (EI) [M+H-tBu]⁺ 744. Step 2. A solution of tert-butyl 2’-bromo-9’-oxo-4’,5’,6’,9’-tetrahydrospiro[piperidine- 4,8’-pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine]-1-carboxylate (2.58 g, 3.23 mmol) in DMF (20 mL) was treated with N-ethyl-N-isopropylpropan-2-amine (2.00 g, 11.4 mmol), N-(2-chloro- 4-(trifluoromethyl)phenyl)-2-iodoacetamide (2.48 g, 6.81 mmol) and the mixture was stirred at 20 °C for 14 h. The mixture was diluted with water (20 mL), extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (20 mL x 4), dried over anhydrous Na2SO4, filtered and concentrated. The concentrate was purified by silica gel chromatography (40 g silica gel, 50% EtOAc/pet. Ether) to give tert-butyl 2’-bromo-4’-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-9’-oxo-4’,5’,6’,9’-tetrahydrospiro[piperidine-4,8’- pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine]-1-carboxylate (3.0 g, 4.43 mmol). ¹H NMR (400 MHz, CDCl₃) δ 8.96 (s, 1H), 8.47 (d, J = 8.8 Hz, 1H), 7.68 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 5.08 (s, 2H), 4.05-3.93 (m, 4H), 3.12 (d, J = 14.8 Hz, 2H), 2.93 (t, J = 5.2 Hz, 2H), 2.73 (s, 2H), 1.58- 1.51 (m, 2H), 1.49 (s, 9H). MS (EI) calc’d for C₂₂H₂₀BrClF₃N₆O₅ [M+H-tBu]⁺, 619, 621. Step 3. A mixture of tert-butyl 2’-bromo-4’-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-9’-oxo-4’,5’,6’,9’-tetrahydrospiro[piperidine-4,8’- pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine]-1-carboxylate (1.20 g, 1.78 mmol) in 2 M HCl/Dioxane (20 mL) was stirred at 25° C for 12 h. The mixture was concentrated under reduce pressure to give 2-(2’-bromo-9’-oxo-5’,9’-dihydrospiro[piperidine-4,8’-pyrano[4,3- d][1,2,4]triazolo[1,5-a]pyrimidin]-4’(6’H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (1.0 g, 1.74 mmol). MS (EI) m/z 575, 577. Step 4. A solution of 2-(2’-bromo-9’-oxo-5’,9’-dihydrospiro[piperidine-4,8’- pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidin]-4’(6’H)-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)-acetamide (1.0 g, 1.74 mmol), 5-(benzyloxy)-6-methylpyrimidine-4- carboxylic acid (0.424 g, 1.74 mmol) and NMI (0.285 g, 3.47 mmol) in DMF (0.5 mL) was treated with TCFH (0.731 g, 2.61 mmol) at 30 °C. The reaction mixture was stirred at 25 °C for 12 h. The mixture was diluted with water (20 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (20 g silica gel, 80% EtOAc/pet. Ether) to give 2-(1-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)-2’-bromo- 9’-oxo-5’,6’,7’,9’-tetrahydro-4’H-spiro[piperidine-4,8’-[1,2,4]triazolo[5,1-b]quinazolin]-4’-yl)- N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (0.90 g, 1.12 mmol).¹H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.86-8.79 (m, 1H), 8.40 (d, J = 8.8 Hz, 1H), 7.67 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.45-7.33 (m, 5H), 5.29-5.22 (m, 1H), 5.19-5.09 (m, 3H), 4.72 (d, J = 11.2 Hz, 1H), 4.07-3.95 (m, 2H), 3.53-3.43 (m, 1H), 3.32-3.14 (m, 2H), 2.95-2.83 (m, 4H), 2.34 (s, 3H), 1.91- 1.78 (m, 1H), 1.63-1.57 (m, 1H). MS (EI) [M+H]⁺, 802. Step 5. A mixture of 2-(1-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)-2’-bromo- 9’-oxo-5’,9’-dihydrospiro[piperidine-4,8’-pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidin]-4’(6’H)- yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (40 mg, 0.050 mmol), (3-fluorophenyl) boronic acid (7.0 mg, 0.050 mmol), K₃PO₄ (21 mg, 0.10 mmol) and PPh₃-Pd-G2 (2.9 mg, 0.005 mmol) in Dioxane (2 mL) and H2O (0.2 mL) was degassed and backfilled with N2 (three times). The mixture was heated to 80 °C for 12 h. The mixture was concentrated. The crude product was purified by Prep-TLC using (DCM/MeOH 10:1 as eluent) to give 2-(1-(5-(benzyloxy)-6- methylpyrimidine-4-carbonyl)-2’-(3-fluorophenyl)-9’-oxo-5’,9’-dihydrospiro[piperidine-4,8’- pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidin]-4’(6’H)-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide (20 mg). MS (EI) m/z 817. Step 6. A solution of 2-(1-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)-2’-(1,3- dimethyl-1H-pyrazol-4-yl)-9’-oxo-5’,9’-dihydrospiro[piperidine-4,8’-pyrano[4,3- d][1,2,4]triazolo[1,5-a]pyrimidin]-4’(6’H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (45 mg, 0.055 mmol) in TFA (0.5 mL) was stirred at 40 °C for 12 h. The crude product was purified by reverse preparative HPLC (MeCN/water, 0.1% TFA) to give N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(2’-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-9’-oxo-5’,9’-dihydrospiro[piperidine-4,8’-pyrano[4,3- d][1,2,4]triazolo[1,5-a]pyrimidin]-4’(6’H)-yl)acetamide (21 mg). ¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.09 (s, 1H), 7.80 (s, 1H), 7.60 (d, J = 7.6 Hz, 1H), 5.40 (s, 2H), 4.60 (d, J = 11.6 Hz, 1H), 4.04 (d, J = 2.4 Hz, 2H), 3.96 (d, J = 12.4 Hz, 1H), 3.86 (s, 3H), 3.58 (t, J = 12.4 Hz, 1H), 3.30-3.22 (m, 1H), 2.97-2.86 (m, 4H), 2.53 (s, 6H), 1.90 (d, J=13.2 Hz, 1H), 1.75 (d, J=15.2 Hz, 1H). MS (EI) calc’d for C₃₃H₂₈ClF₄N₈O₅ [M+H]⁺, 727; found 727. Examples 59-63 [0202] Compounds 59 to 63 were prepared in a fashion analogous to the preparation of compound 58, substituting for the appropriate boronic acid or boronic ester. Example 64 [0203] Preparation of 2-(2’-(4-Aminophenyl)-1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)- 9’-oxo-5’,9’-dihydrospiro[piperidine-4,8’-pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidin]-4’(6’H)- yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (Compound 64). Step 1. A mixture of 2-(1-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)-2’-bromo- 9’-oxo-5’,9’-dihydrospiro[piperidine-4,8’-pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidin]-4’(6’H)- yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (50 mg, 0.062 mmol), 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (16 mg, 0.075 mmol), Cs2CO3 (61 mg, 0.19 mmol) and Pd(dtbpf)Cl2 (8.1 mg, 0.012 mmol) in Dioxane (1 mL) and H2O (0.1 mL) was degassed and backfilled with N2 (three times). The mixture was heated to 60 °C for 12 h. The mixture was filtered and concentrated. The crude product was purified by Prep-HPLC (gradient of MeCN/water with 0.1% TFA) to give 2-(2’-(4-aminophenyl)-1-(5-(benzyloxy)-6- methylpyrimidine-4-carbonyl)-9’-oxo-5’,9’-dihydrospiro[piperidine-4,8’-pyrano[4,3- d][1,2,4]triazolo[1,5-a]pyrimidin]-4’(6’H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (30 mg). MS (EI) m/z 814. Step 2. A mixture of 2-(2’-(4-aminophenyl)-1-(5-(benzyloxy)-6-methylpyrimidine-4- carbonyl)-9’-oxo-5’,9’-dihydrospiro[piperidine-4,8’-pyrano[4,3-d][1,2,4]triazolo[1,5- a]pyrimidin]-4’(6’H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (30 mg, 0.037 mmol) in TFA (1 mL) was stirred at 40 °C for 2 h. The mixture was filtered and concentrated. The crude product was purified by Prep-HPLC (gradient of MeCN/water with 0.1% TFA) to give 2- (2’-(4-aminophenyl)-1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-9’-oxo-5’,9’- dihydrospiro[piperidine-4,8’-pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidin]-4’(6’H)-yl)-N-(2- chloro-4-(trifluoromethyl)phenyl)acetamide (12.6 mg).¹H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.22-8.15 (m, 3H), 7.81 ( s, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.25-7.18 (m, 2H), 5.44 (s, 2H), 4.62 (d, J = 12.0 Hz, 1H), 4.08-3.96 (m, 3H), 3.62-3.56 (m, 1H), 3.28 (s, 1H), 2.89 (s, 4H), 2.56- 2.49 (m, 3H), 1.91 (d, J=13.2 Hz, 1H), 1.76 (d, J = 12.8 Hz, 1H). MS (EI) calc’d for C₃₃H₃₀ClF₃N₉O₅ [M+H]⁺, 724; found 724. Examples 65 to 68 [0204] Compounds 65 to 68 were prepared in a fashion analogous to the preparation of compound 64, substituting for the appropriate boronic acid or boronic ester. Example 69 [0205] Preparation of N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(1-(3-hydroxypicolinoyl)-2’- (1-methyl-1H-pyrazol-4-yl)-9’-oxo-5’,9’-dihydrospiro[piperidine-4,8’-pyrano[4,3- d][1,2,4]triazolo[1,5-a]pyrimidin]-4’(6’H)-yl)acetamide (Compound 69) Step 1. A solution of tert-butyl 2’-bromo-4’-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-9’-oxo-4’,5’,6’,9’-tetrahydrospiro[piperidine-4,8’- pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine]-1-carboxylate (60 mg, 0.089 mmol), 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (22 mg, 0.11 mmol), Cs2CO3 (87 mg, 0.27 mmol) in Dioxane (1 mL) and Water (0.1 mL) was treated with PdCl₂(dtbpf) (5.8 mg, 0.0089 mmol) at 25 °C under N2 atmosphere. The reaction mixture was stirred at 60 °C for 12 h. The reaction mixture was diluted with EtOAc (1 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by preparative TLC (SiO2, Petroleum ether:Ethyl acetate = 1:2) to give tert-butyl 4’-(2- ((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2’-(1-methyl-1H-pyrazol-4-yl)-9’-oxo- 4’,5’,6’,9’-tetrahydrospiro[piperidine-4,8’-pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine]-1- carboxylate (50 mg). MS (EI) [M+H-tBu]⁺ 621. Step 2. A solution of tert-butyl 4’-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-2’-(1-methyl-1H-pyrazol-4-yl)-9’-oxo-4’,5’,6’,9’-tetrahydrospiro[piperidine-4,8’- pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine]-1-carboxylate (50 mg, 0.074 mmol) in 2 M HCl/Dioxane (1 mL) was stirred at 25 °C for 4 h. The reaction solution was evaporated under reduced pressure to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2’-(1-methyl-1H-pyrazol-4- yl)-9’-oxo-5’,9’-dihydrospiro[piperidine-4,8’-pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidin]- 4’(6’H)-yl)acetamide (42.6 mg, 0.0738 mmol). MS (EI) [M+H]⁺ 577. Step 3. A solution of 3-hydroxypicolinic acid (10 mg, 0.073 mmol) and CDI (9.8 mg, 0.061 mmol) in DMF (0.5 mL) was stirred at 25 °C for 30 min. Then a solution of N-(2-chloro- 4-(trifluoromethyl)phenyl)-2-(2’-(1-methyl-1H-pyrazol-4-yl)-9’-oxo-5’,9’- dihydrospiro[piperidine-4,8’-pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidin]-4’(6’H)-yl)acetamide (35 mg, 0.061 mmol) and DIEA (0.053 mL, 0.30 mmol) dissolved in DMF (0.5 mL) was added to the reaction. The reaction mixture was stirred at 25 °C for another 1 h. The reaction was purified by prep-HPLC (gradient of MeCN/water with 0.1% TFA) to give N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(1-(3-hydroxypicolinoyl)-2’-(1-methyl-1H-pyrazol-4-yl)-9’-oxo- 5’,9’-dihydrospiro[piperidine-4,8’-pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidin]-4’(6’H)- yl)acetamide (18 mg). ¹H NMR (400 MHz, CD₃OD) δ 8.27-8.16 (m, 3H), 8.04 (s, 1H), 7.82 (d, J = 1.6 Hz, 1H), 7.68-7.59 (m, 3H), 5.43 (s, 2H), 4.63 (d, J = 10.0 Hz, 1H), 4.05 (d, J = 3.6 Hz, 2H), 3.96 (s, 3H), 3.68-3.58 (m, 1H), 3.52 (d, J = 11.6 Hz, 1H), 3.35-3.29 (m, 1H), 2.99-2.87 (m, 4H), 1.92 (d, J = 13.6 Hz, 1H), 1.75 (d, J = 13.6 Hz, 1H). MS (EI) calc’d for C31H28ClF3N9O5 [M+H]⁺, 698; found 698. Examples 70 to 74 [0206] Compounds 70 to 74 were prepared in a fashion analogous to the preparation of compound 69, substituting for the appropriate boronic acid or boronic ester. Examples 75 and 76 [0207] Compounds 75 and 76 were prepared as a racemate in a fashion analogous to the preparation of compound 69, substituting for the appropriate boronic acid or boronic ester. The racemate was then resolved using chiral SFC separation [Column: DAICEL CHIRALCEL OD (250mm x 30mm,10um), Mobile phase: A: CO2, B: CO2-EtOH (0.1% NH4OH), Gradient: 35% B, FlowRate: 150 mL/min]. Compound 75, Rt = 2.273 min and Compound 76, Rt = 2.658 min. Examples 77 and 78 [0208] Compounds 77 and 78 were prepared in a fashion analogous to the preparation of compound 41, substituting for the appropriate iodoacetamide. Example 79 [0209] Compound 79 was prepared in a fashion analogous to the preparation of Compound 3, substituting Intermediate II for Intermediate VI. Example 80 [0210] Compound 80 was prepared in a fashion analogous to the preparation of Compound 6, substituting Intermediate II for Intermediate VI. Example 81 [0211] Compound 81 was prepared in a fashion analogous to the preparation of Compound 3, substituting Intermediate II for Intermediate VI. Example 82 [0212] Compound 82 was prepared in a fashion analogous to the preparation of Compound 3, substituting Intermediate II for Intermediate VI. Example 83 [0213] Compound 83 was prepared in a fashion analogous to the preparation of Compound 3, substituting Intermediate II for Intermediate VI. Example 84 [0214] Compound 84 was prepared in a fashion analogous to the preparation of Compound 3, substituting Intermediate II for Intermediate VI. Example 85 [0215] Compound 85 was prepared in a fashion analogous to the preparation of Compound 2, substituting Intermediate I for Intermediate V. Example 86 [0216] Compound 86 was prepared in a fashion analogous to the preparation of Compound 45, substituting for the appropriate carboxylic acid. Example 87 [0217] Compound 87 was prepared in a fashion analogous to the preparation of Compound 77, substituting for the appropriate carboxylic acid. Example 88 [0218] Compound 88 was prepared in a fashion analogous to the preparation of Compound 67, substituting for the appropriate carboxylic acid. Example 89 [0219] Compound 89 was prepared in a fashion analogous to the preparation of Compound 58, substituting for the appropriate boronic ester. Examples 90-92 [0220] Compounds 90-92 was prepared in a fashion analogous to the preparation of Compound 69, substituting for the appropriate boronic ester. Example 93 [0221] Compound 93 was prepared in a fashion analogous to the preparation of Compound 69, substituting for the appropriate boronic ester and carboxylic acid. Example 94 [0222] Compound 94 was prepared in a fashion analogous to the preparation of Compound 79. Example 95 [0223] Preparation of (R or S)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2'-(3,6-dihydro-2H- pyran-4-yl)-1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-5'-methyl-9'-oxo-5',9'- dihydrospiro[piperidine-4,8'-pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidin]-4'(6'H)-yl)acetamide (Compound 95) Step 1. A solution of 9-(tert-butyl) 5-ethyl 4-oxo-1-oxa-9-azaspiro[5.5]undecane-5,9- dicarboxylate (500 mg, 1.47 mmol) in THF (5 mL) was purged with nitrogen. The solution was cooled to 0 °C and a 2 M THF solution of LDA (2.20 mL, 4.39 mmol) was added dropwise. The mixture was stirred at 0 °C for 30 min. MeI (0.10 mL, 1.61 mmol) was added and the mixture stirred at 0 °C for 1 h. The reaction was quenched with saturated ammonium chloride (10 mL). Extracted with EtOAc (10 mL x 2). The combined organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (5% ethyl acetate/pet. ether) to 9-(tert-butyl) 5-ethyl 3-methyl-4-oxo-1-oxa-9- azaspiro[5.5]undecane-5,9-dicarboxylate (200 mg).¹H NMR (400 MHz, CDCl3) δ 4.22-4.07 (m, 2H), 4.05-3.79 (m, 2H), 3.77-3.62 (m, 1H), 3.55-3.40 (m, 1H), 3.39-3.33 (m, 1H), 3.25-3.12 (m, 1H), 3.07-2.95 (m, 1H), 2.83-2.62 (m, 1H), 2.55-2.34 (m, 1H), 2.29-2.15 (m, 1H), 1.79-1.58 (m, 1H), 1.50-1.45 (m, 1H), 1.41-1.37 (m, 9H), 1.27-1.19 (m, 3H), 1.15-0.89 (m, 3H). MS (EI) [M+H]⁺ m/z 356. Step 2. A solution of 9-(tert-butyl) 5-ethyl 3-methyl-4-oxo-1-oxa-9- azaspiro[5.5]undecane-5,9-dicarboxylate (180 mg, 0.506 mmol) in EtOH (2 mL) at 0 °C was added phosphorus(V) oxide (72 mg, 0.506 mmol) and 3-bromo-1H-1,2,4-triazol-5-amine (83 mg, 0.506 mmol). The reaction mixture was stirred at 90 °C for 16 h. DIEA (0.26 mL, 1.52 mmol) and Boc2O (0.177 mL, 0.759 mmol) was to the mixture. The reaction mixture was stirred at 30 °C for 2 h. The mixture was concentrated. The crude product was purified by Prep-TLC (SiO₂, DCM/MeOH = 10:1) to give tert-butyl 2'-bromo-5'-methyl-9'-oxo-4',5',6',9'- tetrahydrospiro[piperidine-4,8'-pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine]-1-carboxylate (70 mg). ¹H NMR (400 MHz, CDCl3) δ 4.08-3.84 (m, 3H), 3.68 (dd, J = 2.8, 11.2 Hz, 1H), 3.29- 3.24 (m, 1H), 3.15 (s, 1H), 2.98-2.90 (m, 1H), 2.85-2.78 (m, 1H), 2.63-2.55 (m, 1H), 1.69-1.64 (m, 2H), 1.50 -1.46 (m, 12H). MS (EI) [M+H]⁺ m/z 398. Step 3. A mixture of tert-butyl 2'-bromo-5'-methyl-9'-oxo-4',5',6',9'-tetrahydrospiro- [piperidine-4,8'-pyrano [4,3-d][1,2,4]triazolo[1,5-a]pyrimidine]-1-carboxylate (70 mg, 0.154 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (39 mg, 0.185 mmol), K2CO3 (43 mg, 0.308 mmol) and Pd(dtbpf)Cl2 (10.0 mg, 0.015 mmol) in Dioxane (2 mL) and water (0.2 mL) was degassed and backfilled with nitrogen (three times). The mixture was heated to 100 °C for 12 h. The mixture was concentrated. The crude product was purified by Prep-TLC (SiO₂, DCM/MeOH = 10:1) to give tert-butyl 2'-(3,6-dihydro-2H-pyran-4-yl)-5'- methyl-9'-oxo-4', 5', 6', 9'-tetrahydrospiro[piperidine-4,8'-pyrano[4,3-d][1,2,4]triazolo[1,5-a] pyrimidine]-1-carboxylate (40 mg). MS (EI) [M+H]⁺ 402. Step 4. A mixture of tert-butyl 2'-(3,6-dihydro-2H-pyran-4-yl)-5'-methyl-9'-oxo-4', 5', 6', 9'-tetrahydrospiro [piperidine-4,8'-pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine]-1- carboxylate (40 mg, 0.087 mmol) in DMF (1 mL) was treated with DIEA (0.046 mL, 0.26 mmol) and N-(2-chloro-4-(trifluoromethyl) phenyl)-2-iodoacetamide (35 mg, 0.096 mmol) at 25 °C. The mixture was stirred at 25 °C for 12 h. The mixture was concentrated and the residue was purified by reverse phase chromatography (gradient of MeCN/water with 0.1% TFA) to give tert- butyl 4'-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2'-(3,6-dihydro-2H-pyran-4- yl)-5'-methyl-9'-oxo-4', 5', 6', 9'-tetrahydrospiro[piperidine-4,8'-pyrano[4,3-d][1,2,4]triazolo[1,5- a]pyrimidine]-1-carboxylate (20 mg). MS (EI) [M+H-tBu]⁺ m/z 637. Step 5. A stirred solution of tert-butyl 4'-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-2'-(3,6-dihydro-2H-pyran-4-yl)-5'-methyl-9'-oxo- 4',5',6',9'-tetrahydrospiro[piperidine-4,8'-pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine]-1- carboxylate (20 mg, 0.029 mmol) in DCM (1 mL) was treated with 2N HCl/Dioxane (0.1 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2'-(3,6-dihydro-2H-pyran-4- yl)-5'-methyl-9'-oxo-5',9'-dihydrospiro [piperidine-4,8'-pyrano[4,3-d][1,2,4]triazolo[1,5- a]pyrimidin]-4'(6'H)-yl)acetamide (15 mg, 0.025 mmol). MS (EI) [M+H]⁺ m/z 593. Step 6. A mixture of 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (7.4 mg, 0.030 mmol), N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2'-(3,6-dihydro-2H-pyran-4-yl)-5'- methyl-9'-oxo-5',9'-dihydrospiro[piperidine-4,8'-pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidin]- 4'(6'H)-yl)acetamide (15 mg, 0.025 mmol) and NMI (4.2 mg, 0.051 mmol) in DCM (2 mL) was treated with TCFH (10.7 mg, 0.038 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 h. The mixture was concentrated. The crude product was purified by Prep-TLC (SiO2, DCM/MeOH = 10:1) to give 2-(1-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)-2'-(3,6- dihydro-2H-pyran-4-yl)-5'-methyl-9'-oxo-5', 9'-dihydrospiro[piperidine-4,8'-pyrano[4,3- d][1,2,4]triazolo[1,5-a] pyrimidin]-4'(6'H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (18 mg, 0.022 mmol). MS (EI) [M+H]⁺ m/z 819. Step 7. A solution of 2-(1-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)-2'-(3,6- dihydro-2H-pyran-4-yl)-5'-methyl-9'-oxo-5',9'-dihydrospiro[piperidine-4,8'-pyrano[4,3- d][1,2,4]triazolo[1,5-a]pyrimidin]-4'(6'H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (18 mg, 0.022 mmol) in TFA (1 mL) was stirred at 40 °C for 2 h. The mixture was concentrated and filtered. The crude product was purified by reverse phase chromatography (gradient of MeCN/water with 0.1% TFA) to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2'-(3,6-dihydro- 2H-pyran-4-yl)-1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-5'-methyl-9'-oxo-5', 9'- dihydrospiro[piperidine-4,8'-pyrano [4,3-d][1,2,4]triazolo[1,5-a]pyrimidin]-4'(6'H)-yl)acetamide (11 mg). MS (EI) [M+H]⁺ 729. Step 8. The N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2'-(3,6-dihydro-2H-pyran-4-yl)- 1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-5'-methyl-9'-oxo-5',9'-dihydrospiro[piperidine- 4,8'-pyrano[4,3-d] [1,2,4]triazolo[1,5-a]pyrimidin]-4'(6'H)-yl)acetamide (11 mg, 0.015 mmol) was resolved by chiral SFC. Condition: SFC-27 (Column: DAICEL CHIRALPAK AD (250mm*30mm, 10um)), Mobile phase: A: CO2, B: CO2-i-PrOH (0.1% NH4OH), Gradient: 40% B, FlowRate: 150 mL/min). Compound 95 was the second eluted enantiomer. [0224] First eluted isomer (less active enantiomer) N-(2-chloro-4-(trifluoromethyl)phenyl)-2- (2'-(3,6-dihydro-2H-pyran-4-yl)-1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-5'-methyl-9'-oxo- 5', 9'-dihydrospiro[piperidine-4,8'-pyrano[4,3-d] [1,2,4]triazolo[1,5-a]pyrimidin]-4'(6'H)- yl)acetamide (3.5 mg) (Chiralpak AD-3_ethanol (DEA)_5_40_25ML, Rt = 1.159 min) was repurified by reverse phase chromatography (gradient of MeCN/water with 0.1% TFA). ¹H NMR (400 MHz, CD3OD) δ 8.59 (s, 1H), 8.17 (d, J = 7.6 Hz, 1H), 7.83 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 6.97 (s, 1H), 5.68-5.08 (m, 2H), 4.68-4.61 (m, 1H), 4.33 (d, J=2.4 Hz, 2H), 4.08-3.98 (m, 2H), 3.93-3.90 (m, 2H), 3.86 (d, J = 8.0 Hz, 1H), 3.74-3.57 (m, 1H), 3.29-3.07 (m, 2H), 2.92 (s, 1H), 2.79-2.72 (m, 1H), 2.65 (s, 2H), 2.55 (s, 3H), 2.06-1.90 (m, 1H), 1.73-1.59 (m, 1H), 1.53-1.48 (m, 3H). MS (EI) calc'd for C₃₃H₃₃ClF₃N₈O₆ [M+H]⁺ 729; found 729. [0225] Second eluted isomer (Compound 95) N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2'- (3,6-dihydro-2H-pyran-4-yl)-1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-5'-methyl-9'-oxo- 5',9'-dihydrospiro [piperidine-4,8'-pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidin]-4'(6'H)- yl)acetamide (3.5 mg) (Chiralpak AD-3_ethanol(DEA)_5_40_25ML, Rt = 1.790 min) was repurified by reverse phase chromatography (gradient of MeCN/water with 0.1% TFA). ¹H NMR (400 MHz, CD₃OD) δ 8.59 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.83 (s, 1H), 7.63 (d, J = 8.8 Hz, 1H), 6.97 (s, 1H), 5.61-5.56 (m, 1H), 5.26-5.22 (m, 1H), 4.71-4.56 (m, 1H), 4.33 (d, J = 2.4 Hz, 2H), 4.09-3.95 (m, 2H), 3.93-3.84 (m, 3H), 3.73-3.50 (m, 1H), 3.43-3.24 (m, 1H), 3.14 (d, J=12.8 Hz, 1H), 2.92 (s, 1H), 2.79-2.72 (m, 1H), 2.65 (s, 2H), 2.55 (s, 3H), 2.09-1.92 (m, 1H), 1.73-1.57 (m, 1H), 1.53-1.48 (m, 3H). MS (EI) calc'd for C33H33ClF3N8O6 [M+H]⁺ 729; found 729. Example 96 [0226] Compound 96 was prepared in a fashion analogous to the preparation of Compound 95. Example 97 [0227] Preparation of N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-((2R, 4R or 2R, 4S)-2'-(3,6- dihydro-2H-pyran-4-yl)-1-(3-hydroxypicolinoyl)-2-methyl-9'-oxo-5',9'-dihydrospiro[piperidine- 4,8'-pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidin]-4'(6'H)-yl)acetamide (Compound 97) Step 1. A solution of ethyl 5-hydroxy-3-oxopentanoate (550 mg, 3.43 mmol) and benzyl (R)-2-methyl-4-oxopiperidine-1-carboxylate (849 mg, 3.43 mmol) in MeCN (20 mL) was treated with BF₃-OEt₂ (2.61 mL, 20.6 mmol) at 0 °C. The reaction was stirred at 25 °C for 2 h. The reaction was quenched with DIEA (1.80 mL, 10.3 mmol). The mixture was concentrated under reduced pressure. The mixture dissolved in EtOH (20 mL) was added Pd/C (365 mg, 10% in activated carbon) and Boc₂O (1.30 mL, 5.15 mmol). The reaction was stirred at 25 °C for 12 h under H2 condition (15 psi). The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent of 15% ethyl acetate/pet. ether) to give 9-(tert-butyl) 5-ethyl (8R)-8-methyl-4-oxo-1-oxa-9-azaspiro[5.5]undecane-5,9- dicarboxylate (680 mg). ¹H NMR (400 MHz, CD3Cl) δ 4.51-4.00 (m, 3H), 3.97-3.70 (m, 2H), 3.55-2.85 (m, 2H), 2.73-2.15 (m, 4H), 2.00-1.60 (m, 3H), 1.51-1.44 (m, 9H), 1.38-1.19 (m, 6H). MS (EI) m/z 356. Step 2. A solution of 9-(tert-butyl) 5-ethyl (8R)-8-methyl-4-oxo-1-oxa-9-azaspiro[5.5]- undecane-5,9-dicarboxylate (680 mg, 1.91 mmol) in EtOH (10 mL) was treated with 3-bromo- 1H-1,2,4-triazol-5-amine (312 mg, 1.91 mmol), phosphorus(V) oxide (543 mg, 3.83 mmol) at 25 ºC and the resulting mixture was stirred at 80 °C for 12 h. The mixture was cooled to 25 °C. The mixture was added DIEA (1.00 mL, 5.74 mmol) and Boc2O (0.666 mL, 2.87 mmol) at 25 °C and the resulting mixture was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent of ethyl acetate/pet ether) to give tert-butyl (2R)-2'-bromo-2-methyl-9'-oxo-4',5',6',9'-tetrahydrospiro[piperidine-4,8'- pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine]-1-carboxylate (650 mg). MS (EI) m/z [M+H- Boc]⁺ 354. Step 3. A solution of tert-butyl (2R)-2'-bromo-2-methyl-9'-oxo-4',5',6',9'- tetrahydrospiro-[piperidine-4,8'-pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine]-1-carboxylate (200 mg, 0.440 mmol), DIEA (0.23 mL, 1.32 mmol) and N-(2-chloro-4-(trifluoromethyl)phenyl)- 2-iodoacetamide (192 mg, 0.528 mmol) in DMF (3 mL) was stirred at 25 °C for 12 hours. The reaction was added H2O (5 mL). The mixture was extracted with EtOAc (5 mL × 2). The combined organic layer was washed with brine and then dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent of 30% ethyl acetate/pet. ether) to give tert-butyl (2R)-2'-bromo-4'-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-methyl-9'-oxo-4',5',6',9'- tetrahydrospiro[piperidine-4,8'-pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine]-1-carboxylate (160 mg). Step 4. A mixture of tert-butyl (2R)-2'-bromo-4'-(2-((2-chloro-4- (trifluoromethyl)phenyl)-amino)-2-oxoethyl)-2-methyl-9'-oxo-4',5',6',9'- tetrahydrospiro[piperidine-4,8'-pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine]-1-carboxylate (160 mg, 0.232 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (53.6 mg, 0.255 mmol), Cs₂CO₃ (227 mg, 0.696 mmol) and Pd(dtbpf)Cl₂ (30 mg, 0.046 mmol) in Dioxane (3 mL) and H2O (0.3 mL) was degassed and backfilled with N2 (three times). The mixture was heated to 60 °C for 12 h. LCMS showed that the reaction was completed. The mixture was concentrated and filtered. The crude product was purified by reverse phase chromatography (gradient of MeCN/water with 0.1% TFA) to give tert-butyl (2R)-4'-(2-((2- chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2'-(3,6-dihydro-2H-pyran-4-yl)-2-methyl- 9'-oxo-4',5',6',9'-tetrahydrospiro[piperidine-4,8'-pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine]-1- carboxylate (40 mg). MS (EI) [M+H-tBu]⁺ 637. Step 5. The tert-butyl 4'-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2'- (3,6-dihydro-2H-pyran-4-yl)-2-methyl-9'-oxo-4',5',6',9'-tetrahydrospiro[piperidine-4,8'- pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine]-1-carboxylate (40 mg, 0.058 mmol) was resolved by Chiral SFC (Condition: Condition: SFC-17 (Column: DAICEL CHIRALPAK IG (250mm*30mm, 10um)), Mobile phase: A: CO₂, B: CO₂-ETOH (0.1%NH₄OH), Gradient: 50% B, FlowRate: 80 mL/min) to give tert-butyl 4'-(2-((2-chloro-4-(trifluoromethyl)phenyl)-amino)- 2-oxoethyl)-2'-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-9'-oxo-4',5',6',9'- tetrahydrospiro[piperidine-4,8'-pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine]-1-carboxylate (6 mg) (Chiralpak IG-3_ethanol(DEA)_5_40_25ML, Rt = 0.442 min, ee = 99.8%) and tert-butyl 4'- (2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2'-(3,6-dihydro-2H-pyran-4-yl)-2- methyl-9'-oxo-4',5',6',9'-tetrahydrospiro[piperidine-4,8'-pyrano[4,3-d][1,2,4]triazolo[1,5- a]pyrimidine]-1-carboxylate (18 mg) (Chiralpak IG-3_ethanol(DEA)_5_40_25ML, Rt = 0.884 min, ee = 99.8%). [0228] The second eluted enantiomer was carried forward to prepare the more active enantiomer. Characterization for resolved diastereomer: ¹H NMR (400 MHz, CD₃Cl) δ 9.13 (s, 1H), 8.48 (d, J = 8.8 Hz, 1H), 7.66 (s, 1H), 7.55 (d, J = 8.8 Hz, 1H), 6.98 (s, 1H), 5.23-4.98 (m, 2H), 4.58-4.34 (m, 3H), 4.04-3.84 (m, 5H), 3.36-3.20 (m, 1H), 3.02-2.89 (m, 2H), 2.87-2.68 (m, 4H), 1.70-1.65 (m, 1H), 1.62-1.56 (m, 1H), 1.49 (s, 9H), 1.28-1.26 (m, 3H). Step 6. A stirred solution of tert-butyl 4'-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-2'-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-9'-oxo- 4',5',6',9'-tetrahydrospiro[piperidine-4,8'-pyrano[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine]-1- carboxylate (18 mg, 0.026 mmol) in DCM (1 mL) was added 2 M HCl/Dioxane (0.5 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2'-(3,6-dihydro-2H-pyran-4- yl)-2-methyl-9'-oxo-5',9'-dihydrospiro[piperidine-4,8'-pyrano[4,3-d][1,2,4]triazolo[1,5- a]pyrimidin]-4'(6'H)-yl)acetamide (14 mg, 0.024 mmol). MS (EI) m/z 593. Step 7. A stirred solution of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2'-(3,6-dihydro- 2H-pyran-4-yl)-2-methyl-9'-oxo-5',9'-dihydrospiro[piperidine-4,8'-pyrano[4,3- d][1,2,4]triazolo[1,5-a]pyrimidin]-4'(6'H)-yl)acetamide (14 mg, 0.026 mmol) in DMF (1 mL) was treated with Et3N (9.9 µL, 0.071 mmol) and perfluorophenyl 3-hydroxypicolinate (3 mg, 9.8 µmol) at 25 °C. The reaction mixture was stirred at 25 °C for 2 h. The mixture was filtered. The crude product was purified by reverse phase chromatography (MeCN/water with 0.1% TFA) to give N-(2-Cl-4-(Trifluoromethyl)phenyl)-2-((2R, 4R or 2R, 4S)-2'-(3,6-dihydro-2H-pyran-4- yl)-1-(3-hydroxypicolinoyl)-2-methyl-9'-oxo-5',9'-dihydrospiro[piperidine-4,8'-pyrano[4,3- d][1,2,4]triazolo[1,5-a]pyrimidin]-4'(6'H)-yl)acetamide (7.7 mg). ¹H NMR (400 MHz, CD₃OD) δ 8.24-8.13 (m, 2H), 7.87-7.77 (m, 1H), 7.65-7.49 (m, 3H), 7.00- 690 (m, 1H), 5.43-5.31 (m, 2H), 4.83-4.50 (m, 1H), 4.36-4.26 (m, 2H), 4.09-3.98 (m, 2H), 3.94-3.73 (m, 3H), 3.52-3.33 (m, 1H), 3.05-2.81 (m, 4H), 2.67-2.58 (m, 2H), 1.95-1.76 (m, 1H), 1.73-1.53 (m, 1H), 1.53-1.39 (m, 3H). MS (EI) calc'd for C₃₃H₃₂ClF₃N₇O₆ [M+H]⁺ 714, found 714. Example 98 [0229] Compound 98 was prepared in a fashion analogous to the preparation of Compound 97, substituting benzyl (R)-2-methyl-4-oxopiperidine-1-carboxylate for benzyl (S)-2-methyl-4- oxopiperidine-1-carboxylate. Example 99 [0230] Compound 99 was prepared in a fashion analogous to the preparation of Compound 3, substituting for the appropriate carboxylic acid. Example 100 [0231] Compound 100 was prepared in a fashion analogous to the preparation of Compound 9, substituting for the appropriate boronic ester. Example 101 [0232] Compound 101 was prepared in a fashion analogous to the preparation of Compound 8, substituting for the appropriate boronic ester. Examples 102 to 106 [0233] Compounds 102 to 106 were prepared in a fashion analogous to the preparation of Compound 16, substituting in the last step with the appropriate carboxylic acid. Example 107 [0234] Preparation of (R or S)-N-(2-Chloro-6-(trifluoromethyl)pyridin-3-yl)-2-(2-(3,6-dihydro- 2H-pyran-4-yl)-1'-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-5-methyl-8-oxo-5,8- dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidin]-4(6H)-yl)acetamide (Compound 107). Step 1 Boc Chiral SFC N Step 2 H N O B O F₃ O F₃ Step 1. The racemic tert-butyl 2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d] [1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidine]-1'-carboxylate (1.70 g, 3.20 mmol) was resolved by Chiral-SFC [Condition: SFC-28 (Column: DAICEL CHIRALPAK IG(250mm*50mm, 10um)), Mobile phase: A: CO2, B: CO2-i-PrOH (0.1% NH4OH), Gradient: 50% B, FlowRate: 200 mL/min] to give (R or S)-tert-butyl 2-(3,6-dihydro- 2H-pyran-4-yl)-5-methyl-8-oxo-4,5,6,8-tetrahydrospiro[cyclopenta[d] [1,2,4]triazolo[1,5- a]pyrimidine-7,4'-piperidine]-1'-carboxylate (400 mg, 24% yield) (Rt = 1.349 min, ee = 100.00%) and (R or S)-tert-butyl 2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidine]-1'-carboxylate (420 mg) (Rt = 2.417 min, ee = 98.05%). Peak 2 (Rt = 2.417 min) was carried forward. ¹H NMR (400 MHz, CD₃OD) δ 6.90 (s, 1H), 4.34 (q, J = 2.8 Hz, 2H), 4.12-4.04 (m, 2H), 3.90 (t, J = 5.6 Hz, 2H), 3.40-3.32 (m, 2H), 2.94 (s, 2H), 2.67-2.55 (m, 4H), 2.28-2.24 (m, 1H), 1.77-1.65 (m, 1H), 1.49 (s, 9H), 1.50-1.42 (m, 1H), 1.40 (d, J = 7.2 Hz, 3H). Step 2. A solution of R or S-tert-butyl 2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8-oxo- 4,5,6,8-tetrahydrospiro [cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidine]-1'- carboxylate enantiomer 2 (Rt = 2.417 above) (80 mg, 0.181 mmol) in DMF (1 mL) was added DIEA (0.095 mL, 0.54 mmol), N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-iodoacetamide (63 mg, 0.172 mmol) and the resulting mixture was stirred at 25 °C for 12 h. The mixture was treated with water (8 mL) and extracted with EtOAc (2 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by Prep-TLC (silica gel, ethyl acetate/pet. ether = 2/1) to give (R or S)-tert-butyl 4-(2-((2-chloro-6- (trifluoromethyl)pyridin-3-yl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8- oxo-4,5,6,8-tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a] pyrimidine-7,4'-piperidine]-1'- carboxylate (70 mg, 0.10 mmol). MS (EI) [M+H]⁺, 678. Step 3. A solution of (R or S)-tert-butyl 4-(2-((2-chloro-6-(trifluoromethyl)pyridin-3- yl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidine]-1'-carboxylate (70 mg, 0.103 mmol) in MeOH (0.5 mL) was treated with HCl/Dioxane (2 M) (1 mL) and the mixture was stirred at 25 °C for 3 h. The mixture was directly concentrated to give (R or S)-N- (2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8-oxo- 5,8-dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidin]-4(6H)- yl)acetamide (55 mg, 0.095 mmol), which was used to next step without further purification. MS (EI) [M+H]⁺ 578. Step 4. A solution of 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (36 mg, 0.15 mmol) in DMF (1 mL) was treated with DIEA (0.063 mL, 0.36 mmol), HATU (69 mg, 0.18 mmol) and stirred at 25 °C for 1 min. Then (R or S)-N-(2-chloro-6-(trifluoromethyl)pyridin-3- yl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8-oxo-5,8-dihydrospiro[cyclopenta- [d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidin]-4(6H) -yl)acetamide (55 mg, 0.095 mmol) was added and the resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (2 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The residue was purified by Prep-TLC (silica gel, ethyl acetate/MeOH = 20/1) to give (R or S)-2-(1'-(5-(benzyloxy)-6-methylpyrimidine-4- carbonyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8-oxo-5,8- dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a] pyrimidine-7,4'-piperidin]-4(6H)-yl)-N-(2- chloro-6-(trifluoromethyl)pyridin-3-yl)acetamide (40 mg). MS (EI) [M+H]⁺ 804. Step 5. A mixture of (R or S)-2-(1'-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)-2- (3,6-dihydro-2H-pyran-4-yl)-5-methyl-8-oxo-5,8-dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5- a]pyrimidine-7,4'-piperidin]-4(6H)-yl)-N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)acetamide (40 mg, 0.050 mmol) in TFA (1 mL) was stirred at 40 °C for 5 h. The reaction mixture was concentrated and the residue was purified by reverse phase chromatography (gradient of MeCN/water with 0.1% TFA) to give (R or S)-N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-(2- (3,6-dihydro-2H-pyran-4-yl)-1'-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-5-methyl-8-oxo- 5,8-dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidin]-4(6H)- yl)acetamide (16 mg, 0.022 mmol). ¹H NMR (400 MHz, CD3OD) δ 8.65 (d, J = 8.4 Hz, 1H), 8.59 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 6.93-6.59 (m, 1H), 5.44-5.20 (m, 2H), 4.75-4.71 (m, 1H), 4.35-4.27 (m, 2H), 4.09-4.05 (m, 1H), 3.88 (t, J = 5.6 Hz, 2H), 3.56-3.48 (m, 1H), 3.46-3.40 (m, 1H), 3.28-3.24 (m, 1H), 3.19-2.94 (m, 1H), 2.80-2.76 (m, 1H), 2.66-2.55 (m, 3H), 2.53 (s, 3H), 2.50-2.35 (m, 1H), 2.25-2.11 (m, 1H), 1.81-1.47 (m, 2H), 1.48-1.40 (m, 3H). MS (EI) calc'd for C₃₂H₃₂ClF₃N₉O₅ [M+H]⁺, 714; found 714. Examples 108-114 [0235] Compounds 108-114 were prepared in a fashion analogous to the preparation of 107, substituting for the appropriate iodoacetamide reagent. Example 115 [0236] Preparation of (R or S)-2-(2-(3,6-Dihydro-2H-pyran-4-yl)-1'-(3-hydroxypicolinoyl)-5- methyl-8-oxo-5,8-dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidin]- 4(6H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide (Compound 115). -yl)-5-methyl-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d] [1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidine]-1'-carboxylate (1.70 g, 3.20 mmol) was resolved by Chiral-SFC [Condition: SFC-28 (Column: DAICEL CHIRALPAK IG(250mm*50mm, 10um)), Mobile phase: A: CO₂, B: CO₂-i-PrOH (0.1% NH4OH), Gradient: 50% B, FlowRate: 200 mL/min] to give (R or S)-tert-butyl 2-(3,6-dihydro- 2H-pyran-4-yl)-5-methyl-8-oxo-4,5,6,8-tetrahydrospiro[cyclopenta[d] [1,2,4]triazolo[1,5- a]pyrimidine-7,4'-piperidine]-1'-carboxylate (400 mg) (Rt = 1.349 min, ee = 100.00%) and (R or S)-tert-butyl 2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidine]-1'-carboxylate (420 mg) (Rt = 2.417 min, ee = 98.05%). Peak 2 (Rt = 2.417 min) was carried forward. ¹H NMR (400 MHz, CD3OD) δ 6.90 (s, 1H), 4.34 (q, J = 2.8 Hz, 2H), 4.12-4.04 (m, 2H), 3.90 (t, J = 5.6 Hz, 2H), 3.40-3.32 (m, 2H), 2.94 (s, 2H), 2.67-2.55 (m, 4H), 2.28-2.24 (m, 1H), 1.77-1.65 (m, 1H), 1.49 (s, 9H), 1.50-1.42 (m, 1H), 1.40 (d, J = 7.2 Hz, 3H). Step 2. A solution of resolved enantiomer 2 above (R or S)-tert-butyl 2-(3,6-dihydro- 2H-pyran-4-yl)-5-methyl-8-oxo-4,5,6,8-tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5- a]pyrimidine-7,4'-piperidine]-1'-carboxylate (40 mg, 0.091 mmol) in DMF (0.5 mL) was treated with 2-iodo-N-(4-(trifluoromethyl)phenyl)acetamide (45 mg, 0.14 mmol), DIEA (0.016 mL, 0.091 mmol) at 25 °C. The reaction mixture was stirred at 50 °C for 1 h. The reaction solution was diluted with EtOAc (1 mL), washed with water (3 mL) and the aqueous layer was re- extracted with EtOAc (2 x 1 mL). The organic layer was washed with brine (1 mL), dried over Na₂SO₄, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by preparative TLC (SiO2, Petroleum ether:Ethyl acetate = 1:2) to give (R or S)-tert-butyl 2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8-oxo-4-(2- oxo-2-((4-(trifluoromethyl)phenyl)amino)ethyl)-4,5,6,8- tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidine]-1'-carboxylate (40 mg). MS (EI) [M+H-tBu]⁺ 578. Step 3. A solution of (R or S)-tert-butyl 2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8- oxo-3-(2-oxo-2-((4-(trifluoromethyl)phenyl)amino)ethyl)-3,5,6,8-tetrahydrospiro[cyclopenta[d]- [1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidine]-1'-carboxylate (40 mg, 0.062 mmol) in 2 M HCl/Dioxane (1 mL) was stirred at 25 °C for 12 h. The reaction solution was evaporated under reduced pressure to give (R or S)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8-oxo-5,8- dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidin]-3(6H)-yl)-N-(4- (trifluoromethyl)phenyl)acetamide (34 mg, 0.063 mmol). The crude product was used to the next step without further purification. MS (EI) [M+H]⁺ 543. Step 4. A stirred solution of (R or S)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8- oxo-5,8-dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidin]-4(6H)-yl)-N- (4-(trifluoromethyl)phenyl)acetamide (34 mg, 0.063 mmol) and TEA (8.7 µL, 0.062 mmol) in THF (1 mL) was treated with perfluorophenyl 3-hydroxypicolinate (19 mg, 0.062 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 1 h. The reaction solution was evaporated under reduced pressure to give the crude product. The crude product was purified by reverse preparative HPLC (gradient of MeCN/water with 0.1% TFA) to give (R or S)-2-(2-(3,6-dihydro- 2H-pyran-4-yl)-1'-(3-hydroxypicolinoyl)-5-methyl-8-oxo-5,8- dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidin]-4(6H)-yl)-N-(4- (trifluoromethyl)phenyl)acetamide (5.7 mg). ¹H NMR (400 MHz, CD₃OD) δ 8.18 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.8 Hz, 2H), 7.58-7.53 (m, 2H), 6.88 (s, 1H), 5.30-5.19 (m, 1H), 5.11-5.04 (m, 1H), 4.77-4.70 (m, 1H), 4.29 (d, J=2.8 Hz, 2H), 3.87 (t, J = 5.6 Hz, 2H), 3.70-3.59 (m, 1H), 3.54-3.33 (m, 2H), 3.17-3.01 (m, 1H), 2.84-2.75 (m, 1H), 2.65-2.59 (m, 3H), 2.48-2.36 (m, 1H), 2.22-2.11 (m, 1H), 1.81-1.52 (m, 2H), 1.46-1.39 (m, 3H). MS (EI) calc'd for C33H33F3N7O5 [M+H]⁺, 664; found 664. Examples 116-120 [0237] Compounds 116-120 were prepared in a fashion analogous to the preparation of Compound 115, substituting for the appropriate carboxylic acid. Example 121 [0238] Preparation of (R or S)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(1'-(3- hydroxypicolinoyl)-5-methyl-2-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-8-oxo-5,8- dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidin]-4(6H)-yl)acetamide (Compound 121) Step 3 Step 1 H Boc HCl, dioxane N I N Step 4 6F₅ Step 1. A stirred solution of tert-butyl 2-bromo-5-methyl-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidine]-1'-carboxylate (1.30 g, 2.22 mmol) and N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide (0.970 g, 2.67 mmol) in DMF (15 mL) was treated N-ethyl-N-isopropylpropan-2-amine (1.16 mL, 6.67 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched with water (60 mL) and extracted with EtOAc (2 x 30 mL). Combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with 60% ethyl acetate/pet. ether) to give tert-butyl 2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)- 2-oxoethyl)-5-methyl-8-oxo-4,5,6,8-tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5- a]pyrimidine-7,4'-piperidine]-1'-carboxylate (600 mg, 0.889 mmol). MS (EI) [M+H-tBu]⁺ 619. Step 2. The racemic tert-butyl 2-bromo-4-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-methyl-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidine]-1'-carboxylate (1.80 g, 2.67 mmol) was resolved with chiral SFC [Condition: SFC-28 (Column: DAICEL CHIRALPAK IC(250mm*50mm,10um)), Mobile phase: A: CO₂, B: CO₂-ETOH (0.1% NH4OH), Gradient: 40% B, FlowRate: 200 mL/min] to give resolved (R or S)-tert-butyl 2- bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-methyl-8-oxo-4,5,6,8- tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidine]-1'-carboxylate; P1 (620 mg) (Rt = 1.448 min, ee = 100%) and P2 (720 mg, 39% yield) (Rt = 2.022 min, ee = 99.86%). P2 (2.022 min) was carried forward: ¹H NMR (400 MHz, CDCl₃) δ 8.89 (s, 1H), 8.47 (d, J = 8.8 Hz, 1H), 7.68 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 5.10 (d, J = 15.6 Hz, 1H), 4.91 (d, J = 15.6 Hz, 1H), 4.25-4.00 (m, 2H), 3.55-3.40 (m, 1H), 3.00-2.75 (m, 2H), 2.72-2.63 (m, 1H), 2.56-2.42 (m, 1H), 2.38-2.24 (m, 1H), 2.15-2.00 (m, 1H), 1.77-1.67 (m, 1H), 1.49 (s, 9H), 1.47 (s, 3H), 1.35- 1.28 (m, 1H). MS (EI) [M+H-tBu]⁺ 619. Step 3. A solution of Enantiomer 2 above (R or S)-tert-butyl 2-bromo-4-(2-((2-chloro- 4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-methyl-8-oxo-4,5,6,8-tetrahydrospiro- [cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidine]-1'-carboxylate (150 mg, 0.223 mmol) in MeOH (2 mL) was treated with 2 M HCl/Dioxane (2 mL) at 20 °C. The reaction mixture was stirred at 20 °C for 1 h. The reaction was concentrated in vacuo to give (R or S)-2- (2-bromo-5-methyl-8-oxo-5,8-dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'- piperidin]-4(6H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (125 mg, 0.218 mmol), which was used to the next step without purification. MS (EI) [M+H]⁺ 575. Step 4. A stirred solution of (R or S)-2-(2-bromo-5-methyl-8-oxo-5,8-dihydrospiro- [cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidin]-4(6H)-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide (125 mg, 0.218 mmol) in THF (2 mL) was treated with TEA (66 mg, 0.654 mmol) and perfluorophenyl 3-hydroxypicolinate (66.5 mg, 0.218 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 1 h. The reaction was purified by Prep-TLC (silica gel, DCM/MeOH = 20/1) to give (R or S)-2-(2-bromo-1'-(3-hydroxypicolinoyl)-5-methyl-8-oxo- 5,8-dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidin]-4(6H)-yl)-N-(2- chloro-4-(trifluoromethyl)phenyl)acetamide (120 mg). MS (EI) [M+H]⁺ 696. Step 5. A mixture of (R or S)-2-(2-bromo-1'-(3-hydroxypicolinoyl)-5-methyl-8-oxo- 5,8-dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidin]-4(6H)-yl)-N-(2- chloro-4-(trifluoromethyl)phenyl)acetamide (20 mg, 0.029 mmol), Cs₂CO₃ (28 mg, 0.086 mmol), 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.2 mg, 0.029 mmol) and Pd(dtbpf)Cl₂ (5.6 mg, 8.63 µmol) in Dioxane (1 mL) and H₂O (0.1 mL) was degassed and backfilled with nitrogen (three times). The mixture was heated to 60 °C for 3 h. The mixture was diluted with EtOAc (10 mL), dried over Na₂SO₄, filtered and the filtrate was evaporated under reduced pressure. The residue was purified by reverse phase chromatography (gradient of MeCN/water with 0.1% TFA) to give (R or S)-N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(1'-(3-hydroxypicolinoyl)-5-methyl-2-(1-(oxetan-3-yl)-1H-pyrazol-4- yl)-8-oxo-5,8-dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidin]-4(6H)- yl)acetamide (9.9 mg).¹H NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 8.22-8.10 (m, 3H), 7.82 (d, J = 1.6 Hz, 1H), 7.61 (d, J = 9.2 Hz, 1H), 7.54-7.45 (m, 2H), 5.63 (q, J = 6.8 Hz, 1H), 5.45-5.33 (m, 1H), 5.28-5.19 (m, 1H), 5.05 (d, J = 6.8 Hz, 4H), 4.81-4.67 (m, 1H), 3.74-3.59 (m, 1H), 3.58- 3.36 (m, 2H), 3.21-2.95 (m, 1H), 2.88-2.74 (m, 1H), 2.69-2.56 (m, 1H), 2.53-2.35 (m, 1H), 2.27- 2.12 (m, 1H), 1.81-1.41 (m, 5H). MS (EI) calc'd for C₃₄H₃₂ClF₃N₉O₅ [M+H]⁺ 738, found 738. Examples 122-124 [0239] Compounds 122-124 were prepared in a fashion analogous to the preparation of Compound 121. Example 125 [0240] Preparation of (R or S)-2-(2-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)-1'-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-5-methyl-8-oxo-5,8-dihydrospiro[cyclopenta[d]- [1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidin]-4(6H)-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide (Compound 125). Step 1 ^N H _HO N ^N CF₃ Step 1. A solution of (R or S)-2-(2-bromo-5-methyl-8-oxo-5,8- dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidin]-4(6H)-yl)-N-(2- chloro-4-(trifluoromethyl)phenyl)acetamide (120 mg, 0.21 mmol) and TEA (0.15 mL, 1.05 mmol) in THF (2 mL) was treated with perfluorophenyl 5-(benzyloxy)-6-methylpyrimidine-4- carboxylate (77 mg, 0.19 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 1 h. The reaction was evaporated under reduced pressure to give the crude product. The crude product was purified by preparative TLC (SiO2, 100% Ethyl acetate) to give (R or S)-2-(1'-(5- (benzyloxy)-6-methylpyrimidine-4-carbonyl)-2-bromo-5-methyl-8-oxo-5,8- dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidin]-4(6H)-yl)-N-(2- chloro-4-(trifluoromethyl)phenyl)acetamide (110 mg). MS (EI) [M+H]⁺ 799. Step 2. A solution of (R or S)-2-(1'-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)-2- bromo-5-methyl-8-oxo-5,8-dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'- piperidin]-4(6H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (110 mg, 0.137 mmol) in TFA (2.0 mL, 26 mmol) was stirred at 40 °C for 4 h. The reaction solution was removed by nitrogen flow to give (R or S)-2-(2-bromo-1'-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-5- methyl-8-oxo-5,8-dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidin]- 4(6H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (98 mg, 0.14 mmol). The crude product was used to the next step without further purification. MS (EI) [M+H]⁺ 709. Step 3. A solution of (R or S)-2-(2-bromo-1'-(5-hydroxy-6-methylpyrimidine-4- carbonyl)-5-methyl-8-oxo-5,8-dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'- piperidin]-4(6H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (34 mg, 0.048 mmol), 1- (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (14 mg, 0.057 mmol), Cs₂CO₃ (47 mg, 0.144 mmol) in Dioxane/H₂O (1 mL, v/v = 10:1) was treated with PdCl2(dtbpf) (3.1 mg, 4.8 µmol) at 25 °C under N2 atmosphere. The reaction mixture was stirred at 60 °C for 12 h. The reaction solution was diluted with EtOAc (1 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by reverse preparative HPLC (gradient of MeCN/water with 0.1% TFA) to give (R or S)-2-(2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-1'-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-5-methyl-8-oxo-5,8- dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidin]-4(6H)-yl)-N-(2- chloro-4-(trifluoromethyl)phenyl)acetamide (12 mg). ¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 8.20-8.09 (m, 1H), 7.81 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 6.90 (s, 1H), 5.45-5.29 (m, 1H), 5.26-5.16 (m, 1H), 4.75-4.68 (m, 1H), 4.22 (s, 2H), 4.10-4.3 (m, 1H), 3.79-3.67 (m, 2H), 3.52 (d, J = 4.0 Hz, 1H), 3.46-3.23 (m, 1H), 3.16-2.95 (m, 1H), 2.82-2.71 (m, 2H), 2.69-2.56 (m, 2H), 2.53 (s, 3H), 2.46-2.34 (m, 1H), 2.15 (d, J=17.2 Hz, 4H), 1.79-1.52 (m, 2H), 1.48-1.39 (m, 3H). MS (EI) calc'd for C35H36ClF3N9O5 [M+H]⁺ 754; found 754. Example 126 [0241] Compound 126 was prepared in a fashion analogous to the preparation of Compound 125, substituting for the appropriate boronic ester. Example 127 [0242] Compound 127 was prepared in a fashion analogous to the preparation of Compound 121, substituting for the appropriate iodoacetamide and boronic ester. Example 128 [0243] Preparation of (R or S)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-hydroxy-4- methylpiperidin-1-yl)-1'-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-5-methyl-8-oxo-5,8- dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidin]-4(6H)-yl)acetamide (Compound 128). [0244] A solution of (R or S)-2-(2-bromo-1'-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-5- methyl-8-oxo-5,8-dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidin]- 4(6H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (20 mg, 0.028 mmol) in Dioxane (1 mL) was treated with 4-methylpiperidin-4-ol (6.5 mg, 0.056 mmol) at 25 °C under nitrogen atmosphere. The reaction mixture was stirred at 90 °C for 12 h. The reaction solution was evaporated under reduced pressure to give the crude product. The crude product was purified by reverse preparative HPLC (gradient of MeCN/water with 0.1% TFA) to give (R or S)-N-(2- chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-hydroxy-4-methylpiperidin-1-yl)-1'-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-5-methyl-8-oxo-5,8- dihydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidin]-4(6H)-yl)acetamide (13 mg). ¹H NMR (400MHz, CD3OD) δ 8.56 (s, 1H), 8.41 (d, J = 8.8 Hz, 1H), 7.64 (s, 1H), 7.52 (d, J = 8.4 Hz, 1H), 5.46-5.23 (m, 1H), 5.07-4.83 (m, 2H), 4.82-4.65 (m, 1H), 3.88-3.81 (m, 2H), 3.48-3.25 (m, 4H), 3.04-2.78 (m, 2H), 2.68-2.58 (m, 1H), 2.55 (s, 3H), 2.41-2.30 (m, 1H), 2.15 – 2.02 (m, 1H), 1.66-1.56 (m, 5H), 1.49-1.38 (m, 4H), 1.26 (s, 3H). MS (EI) calc'd for C34H38ClF3N9O5 [M+H]⁺ 744, found 744. Example 129 [0245] Compound 129 was prepared in a fashion analogous to the preparation of Compound 128, substituting for the appropriate carboxylic acid. Example 130 [0246] Compound 130 was prepared in a fashion analogous to the preparation of Compound 121, substituting readily available 3-morpholino-1H-1,2,4-triazol-5-amine for 3-bromo.1H-1,2,4- triazol-5-amine. Example 131 [0247] Compound 131 was prepared in a fashion analogous to the preparation of Compound 105, substituting methyl iodide for ethyl iodide in the first step. Example 132 [0248] Preparation of (R or S)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H- pyran-4-yl)-1'-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-5-methyl-8-oxo-5,8-dihydro-4H- spiro[furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidin]-4-yl)acetamide (Compound 132). Step 1. A solution of 8-(tert-butyl) 4-ethyl 2-methyl-3-oxo-1-oxa-8- azaspiro[4.5]decane-4,8-dicarboxylate (360 mg, 1.05 mmol) in EtOH (5 mL) at 0 °C was treated with phosphorus(V) oxide (150 mg, 1.05 mmol) and 3-bromo-1H-1,2,4-triazol-5-amine (172 mg, 1.05 mmol). The reaction mixture was stirred at 90 °C for 16 h. DIEA (0.553 mL, 3.16 mmol) and Boc2O (0.367 mL, 1.58 mmol) were added to the mixture. The reaction mixture was stirred at 30 °C for 2 h. The mixture was concentrated and the residue was purified by Prep-TLC using (DCM/MeOH = 10:1) to give tert-butyl 2-bromo-5-methyl-8-oxo-5,8-dihydro-4H-spiro[furo[3,4- d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidine]-1'-carboxylate (180 mg). MS (EI) m/z 440. Step 2. A mixture of tert-butyl 2-bromo-5-methyl-8-oxo-5,8-dihydro-4H-spiro[furo[3,4- d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidine]-1'-carboxylate (160 mg, 0.363 mmol), 2-(3,6- dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (92 mg, 0.44 mmol), K₂CO₃ (100 mg, 0.727 mmol) and Pd(dtbpf)Cl2 (23 mg, 0.036 mmol) in Dioxane (3 mL) and H2O (0.3 mL) was degassed and backfilled with N₂ (three times). The mixture was heated to 100 °C for 12 h. The mixture was concentrated and the residue was purified by Prep-TLC using (DCM/MeOH = 10:1) to give tert-butyl 2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8-oxo-5,8-dihydro-4H- spiro[furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidine]-1'-carboxylate (100 mg). MS (EI) [M+H]⁺ 444. Step 3. A mixture of tert-butyl 2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8-oxo-5,8- dihydro-4H-spiro[furo [3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidine]-1'-carboxylate (100 mg, 0.225 mmol) in DMF (3 mL) was treated with DIEA (0.12 mL, 0.676 mmol) and N-(2- chloro-4-(trifluoromethyl) phenyl)-2-iodoacetamide (90 mg, 0.248 mmol) at 25 °C. The mixture was stirred at 25 °C for 12 h. The mixture was concentrated and the residue was purified by Prep-TLC using (DCM/MeOH = 10:1) to give tert-butyl 4-(2-((2-chloro-4-(trifluoromethyl) phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8-oxo-5,8-dihydro-4H-spiro [furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidine]-1'-carboxylate (80 mg). MS (EI) m/z 623. Step 4. A stirred solution of tert-butyl 4-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8-oxo-5,8- dihydro-4H-spiro[furo[3,4-d][1,2,4]triazolo[1,5-a] pyrimidine-7,4'-piperidine]-1'-carboxylate (80 mg, 0.12 mmol) in DCM (2 mL) was added 2 M HCl/Dioxane (0.2 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-8-oxo- 5,8-dihydro-4H-spiro [furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidin]-4-yl)acetamide (60 mg, 0.10 mmol) which was used directly in next step without further purification. MS (EI) m/z 579. Step 5. A mixture of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H- pyran-4-yl)-5-methyl-8-oxo-5,8-dihydro-4H-spiro[furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine- 7,4'-piperidin]-4-yl) acetamide (40 mg, 0.67 mmol), 5-(benzyloxy)-6-methylpyrimidine-4- carboxylic acid (19 mg, 0.076 mmol) and NMI (11 mg, 0.14 mmol) in DCM (2 mL) was treated with TCFH (29 mg, 0.10 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. The mixture was concentrated. The crude product was purified by Prep-TLC using (DCM/MeOH = 10:1) to give 2-(1'-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5- methyl-8-oxo-5,8-dihydro-4H-spiro[furo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidin]- 4-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (30 mg). MS (EI) m/z 805. Step 6. A solution of 2-(1'-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)-2-(3,6- dihydro-2H-pyran-4-yl)-5-methyl-8-oxo-5,8-dihydro-4H-spiro[furo[3,4-d][1,2,4]triazolo[1,5- a]pyrimidine-7,4'-piperidin]-4-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (30 mg, 0.037 mmol) in TFA (1 mL) was stirred at 40 °C for 2 h. The mixture was concentrated and the residue was purified by reverse phase chromatography (gradient of MeCN/water with 0.1% TFA) to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-1'-(5-hydroxy- 6-methylpyrimidine-4-carbonyl)-5-methyl-8-oxo-5,8-dihydro-4H-spiro[furo[3,4- d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidin]-4-yl)acetamide (20 mg). MS (EI) m/z 715. Step 7. The racemic product N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro- 2H-pyran-4-yl)-1'-(5-hydroxy -6-methylpyrimidine-4-carbonyl)-5-methyl-8-oxo-5,8-dihydro-4H- spiro[furo[3,4-d][1,2,4]triazolo [1,5-a]pyrimidine-7,4'-piperidin]-4-yl)acetamide (20 mg, 0.028 mmol) was resolved by Chiral SFC. Condition: SFC-27 (Column: DAICEL CHIRALCEL OD (250mm*30mm, 10um)), Mobile phase: A: CO2, B: CO2-ETOH (0.1% NH4OH), Gradient: 40% B, FlowRate: 150 mL/min) to give the first eluted isomer (R or S)-N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-1'-(5-hydroxy-6-methyl pyrimidine- 4-carbonyl)-5-methyl-8-oxo-5,8-dihydro-4H-spiro[furo[3,4-d][1,2,4]triazolo[1,5-a] pyrimidine- 7,4'-piperidin]-4-yl)acetamide (7.9 mg) (Chiralcel OD-3_ethanol(DEA)_5_40_25ML, Rt = 1.869 min) and the second eluted isomer that was more active and identified as Compound 132 (R or S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-1'-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-5-methyl-8-oxo-5,8-dihydro-4H-spiro[furo[3,4- d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidin]-4-yl)acetamide (8.3 mg) (Chiralcel OD- 3_ethanol(DEA)_5_40_25ML, Rt = 2.162 min). ¹H NMR (400 MHz, CD₃OD) δ 8.54 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.82 (s, 1H), 7.62 (d, J = 8.8 Hz, 1H), 6.95 (s, 1H), 5.54-5.50 (m, 1H), 5.31-5.18 (m, 2H), 4.71 (s, 1H), 4.32 (s, 2H), 4.01 (s, 1H), 3.90-3.88 (m, 2H), 3.65-3.49 (m, 1H), 3.30-3.13 (m, 1H), 2.66-2.55 (m, 3H), 2.55-2.30 (m, 4H), 1.95-1.70 (m, 2H), 1.67-1.61 (m, 3H). MS (EI) calc'd for C₃₂H₃₁ClF₃N₈O₆ [M+H]⁺ 715, found 715. Example 133 [0249] Compound 133 was prepared in a fashion analogous to the preparation of Compound 132, and the racemic material resolved using chiral SFC [Condition: SFC-27 (Column: DAICEL CHIRALCEL OD (250mm*30mm, 10um)), Mobile phase: A: CO2, B: CO2-ETOH (0.1% NH₄OH), Gradient: 35% B, Flow Rate: 150 mL/min) to give the resolved enantiomers at 1.898 min and 2.077 min. The first enantiomer was discarded while the second enantiomer bioactive. Example 134 [0250] Compound 134 was prepared in a fashion analogous to the preparation of Compound 132, and the racemic material resolved by chiral SFC. Conditions: Column IB-N, 21X250mm, 5um; 35% MeOH w/0.1%NH4OH in CO2. First eluted enantiomer 3.60 min was discarded, second eluted enantiomer 5.00 min was the bioactive enantiomer. Example 135 [0251] Compound 135 was prepared in a fashion analogous to the preparation of Compound 6, from Intermediate IV. The racemic material was resolved by chiral SFC. Conditions: Column IB-N, 21X250mm, 5um; 30% MeOH w/0.1% NH4OH in CO2. First eluted enantiomer 3.30 min was discarded, second eluted enantiomer 5.20 min was the bioactive enantiomer. Example 136 [0252] Compound 136 was prepared in a fashion analogous to the preparation of Compound 3, from Intermediate IV. The racemic material was resolved by chiral SFC. Conditions: Column IB-N, 21X250mm, 5um; 30% MeOH w/0.1% NH₄OH in CO₂. First eluted enantiomer 4.30 min was discarded, second eluted enantiomer 6.50 min was the bioactive enantiomer. [0253] The disclosed subject matter is not to be limited in scope by the specific embodiments and examples described herein. Indeed, various modifications of the disclosure in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims. [0254] All references (e.g., publications or patents or patent applications) cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual reference (e.g., publication or patent or patent application) was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Other embodiments are within the following claims. Biological Assays and Data WRN INHIBITOR ACTIVITY EVALUATION WRN Helicase Assay Procedure [0255] Compounds were and will be evaluated in a double-stranded DNA unwinding assay to demonstrate inhibition of WRN helicase. To measure WRN helicase unwinding activity, we utilized a 384 well fluorescent plate-based assay following the separation of a fluor/quencher labeled forked double stranded DNA substrate. For construction of assay ready plates, 200 nL compounds were dispensed in DMSO via 3-fold serial dilution, into 384 well NBS low volume all black assay plates (Corning 3820) using an Echo acoustic dispenser. All assay reaction solutions were prepared in 1X Assay Buffer (25 mM HEPES pH 7.3, 50 mM NaCl, 2 mM MgCl₂, 0.01% Tween-20, 0.5 mM TCEP, 0.5% DMSO). Solution preparation: a 2X Enzyme Mix was generated containing 500 pM of recombinant WRN helicase core (500-942) and 60 nM annealed fluor/quencher labeled double stranded DNA oligo (IDT Custom synthesis (sequence 1) TAMRA-5’-GAACGAACACATCGGGTACGTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT-‘3 (sequence 2): 5’-TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTCGTACCCGATGTGTTCGTTC- BHQ2-‘3. and a 2X Substrate Mix was made consisting of 4 mM ATP (Fisher #R1441) Reactions were assembled first by dispensing 10 µL of 60 nM annealed fluorescent quenched labeled double stranded DNA oligo in 1X assay buffer to a single column to serve as the min control. Following this, 10 µL of 2X Enzyme Mix was added to all remaining wells. The reaction plate was covered and incubated at room temperature for 1 hour. After preincubation, the unwinding reaction was initiated by the addition of 10 uL of 2X Substrate Mix across all wells of the assay plate. The plate was gently mixed and incubated at room temperature for 1 hour, prior to quenching by the addition of 2 µL of 10% SDS. Fluorescence intensity was measured using excitation and emission wavelengths of 544 nm and 590 nm, respectively. High fluorescence intensity (enzyme + substrates + DMSO) represents the signal from max unwinding (no helicase inhibition), while low florescence intensity (substrates + DMSO) represents no helicase unwinding activity/complete inhibition. Assay data was normalized to max and min signals and reported as % inhibition. Compound concentration response curves were fit by a 4P inhibition model to extract IC₅₀, hill slope, and % maximum inhibition. SW48 and SW620 Cell Viability Assay [0256] WRN inhibitors with good potency in the ouble-stranded DNA unwinding assay will then be evaluated in a cell viability assay using both MSI-H and MSS cells, specifically, the SW48 and SW620 cells, respectively. A large batch of SW48 and SW620 cells will be frozen down to ensure ROP assays using the same passage of cells to reduce variation. Cells will be thawed and cultured in T175 flasks six days before assay. SW48 (MSI) cells will be cultured in DMEM supplemented with 10% FBS and SW620 cells (MSS) will be cultured in Leibovitz’s L- 15 medium supplemented with 10% FBS. On day 0, cells will be trypsinized and seeded at the density of 3000 cells per well on collagen-coated 384-well clear bottom plates in media supplemented with 2% FBS. The plates will be shaken for 30 seconds and followed by a brief spin to ensure even seeding. Plates were put into 37°C incubator with 5% CO2 for overnight incubation. On day 1, old media will be removed and cells were treated with 30 µl of fresh media containing compounds for 96 h with top concentration at 10 µM and a ten-point 3 fold serial dilution. On day 5, 30 µl of cell titer glo reagents will be added to the plates, shaken for 10 minutes at room temperature to lyse cells, and followed by reading on envision plate reader using the ultra-sensitive luminescence method. Raw data will be imported to Spotfire for curve fitting. Assay data will be normalized to max and min signals and reported as % inhibition. Compound concentration response curves will be fit by a 4P inhibition model to extract IC₅₀, hill slope, and % maximum inhibition. Biological Assay Data Table Compound WRN Helicase DNA SW48 Cell Viability SW620 Cell Viability Unwinding IC₅₀ (nM) GI₅₀ (nM) GI₅₀ (nM) 31 4.7 218 >49,750 32 2.5 78 >49,750 63 4.6 912 >49,750 64 3.5 49 22,410 95 9.6 364 30,100 96 8.9 403 20,180 127 2.5 289 20,210 128 6.1 217 >49,750

Claims

WHAT IS CLAIMED IS: 1. A compound of Formula I: or a pharmaceutically acceptable salt thereof wherein Q and Q¹ are independently absent or -CHR-; Z¹ is selected from -O-, -CH2-, -OCH2-, -CH2O-, -NR⁵-, and -CH2CH2-; Z² is selected from -C(R¹)₂-, -CH₂CHR-, OCH₂-, and -O-; X and Y are independently is CH, or N; each R¹ is is independently selected from hydrogen, C_1-6 alkyl, halogen; R² is (CR2)nheteroaryl, or (CR2)nheterocycloalkyl, said heteroaryl and heterocycloalkyl optionally substituted with 1 to 3 groups selected from R^a; each R is independently hydrogen, halogen, or C1-6 alkyl; R⁵ is hydrogen or C_1-6 alkyl; R³ is aryl, heterocycloalkyl, or heteroaryl, said aryl, heterocycloalkyl, and heteroaryl optionally substituted with 1 to 3 groups selected from R^a; R⁴ is selected from C3-10 cycloalkyl, aryl, heteroaryl, said cycloalkyl, aryl, heteroaryl optionally substituted with 1 to 3 groups selected from R^a; n is 0 to 4; and each R^a is independently selected from hydroxyl, C1-6 alkyl, halogen, C1-3 haloalkyl, -O-, -OC1-6 alkyl, C(O)C_1-6 alkyl, -NH₂, C_3-6 cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, said alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl optionally substituted with 1 to 3 groups of OH, C_1-6 alkyl and halogen.

2. The compound according to claim 1, wherein Q and Q¹ are both -CH₂-.

3. The compound according to claim 1 wherein one of Q and Q¹ is present and the other is absent, or both Q and Q¹ are absent.

4. The compound according to claim 1, wherein Z¹ is O.

5. The compound according to claim 1, wherein Z¹ is CH2.

6. The compound according to claim 1, wherein Z¹ is -OCH2- or -CH2O-.

7. The compound according to claim 1, wherein Z¹ is -CH2CH2-.

8. The compound according to any one of claims 1 through 7, wherein Z² is -CH-.

9. The compound according to any one of claims 1 through 3, 5 and 7 wherein Z² is - O-.

10. The compound according to any one of claims 5 and 6, wherein Z² is -C(R¹)₂-, and least one R¹ is not hydrogen.

11. The compound according to any one of claims 5 and 7, wherein Z² is -O- .

12. The compound according to any one of claims 1 through 11, wherein X is -CH-.

13. The compound according to any one of claims 1 through 11, wherein X is -N-.

14. The compound according to any one of claims 1 through 12, wherein Y is -CH-.

15. The compound according to any one of claims 1 through 12, wherein Y is -N-.

16. The compound according to any one of claims 1 through 11, wherein X and Y are -N-.

17. The compound according to any one of claims 1 through 11, wherein one of X and Y is -N- and the other is -CH-.

18. The compound according to any one of claims 1 through 7 and 10 through 17, wherein each R¹ is independently selected from hydrogen, halogen methyl, ethyl, propyl, isopropyl, butyl, pentyl, and hexyl.

19. The compound according to any one of claims 1 through 18, wherein R² is selected from (CH2)npyridyl, (CH2)npyrimidinyl, (CH2)npyrazolyl, (CH2)noxazolyl, (CH₂)_nbenzoxazolyl, and (CH₂)_nisoxazolyl, said pyridyl, pyrimidinyl, pyrazolyl, oxazolyl, isoxazolyl optionally substituted with 1 to 3 groups selected from R^a.

20. The compound according to any one of claims 1 through 19 wherein R² is selected from pyridyl, and pyrimidinyl, said pyridyl and pyrimidinyl optionally substituted with 1 to 3 groups selected from R^a.

21. The compound according to any one of claims 1 through 20, wherein R³ is selected from morpholinyl, piperidinyl, dihydropyranyl, pyranyl, pyridyl, pyrazolyl, oxazolyl, and isoxazolyl, said morpholinyl, piperidinyl, dihydropyranyl, pyranyl, pyridyl, pyrazolyl, oxazolyl, and isoxazolyl, optionally substituted with 1 to 3 groups selected from R^a.

22. The compound according to anyone of claims 1 through 21, wherein R³ is selected from morpholinyl and dihydropyranyl, said morpholinyl and dihydropyranyl optionally substituted with 1 to 3 groups selected from R^a.

23. The compound according to anyone of claims 1 through 22, wherein R⁴ is selected from optionally substituted cyclopropyl, cyclobutyl, bicyclobutanyl, cyclopentyl, bicyclopentanyl, cyclohexyl, bicyclohexyl, phenyl, pyridyl, pyrazolyl, pyrimidinyl, thiazolyl and pyrrolyl.

24. The compound according to anyone of claims 1 through 23, wherein R⁴ is selected from optionally substituted cyclopentyl, bicyclopentanyl, pyridyl, thiazolyl, pyrazolyl, and phenyl.

25. The compound according to claim 1 of structural Formula II: or a pharmaceutically acceptable salt thereof. 26. The compound according to claim 25, wherein Z¹ is selected from -O-, -CH₂-, - OCH2-, -CH2O-, -NH, NCH3, and -CH2CH2-, R¹ is selected from hydrogen, methyl, ethyl, propyl, butyl, hexyl, and halogen, R² is selected from unsubstituted or substituted pyridyl and unsubstituted or substituted pyrimidinyl, R³ is unsubstituted or substituted morpholinyl or unsubstituted or substituted dihydropyranyl and R⁴ is selected from phenyl, pyrazolyl, pyridyl, and bicyclopentyl, said phenyl, pyrazolyl, pyridyl, and bicyclopentyl optionally substituted with 1 to 3 groups of R^a. 27. The compound according to claim 1 of structural Formula III:

III or a pharmaceutically acceptable salt thereof. 28. The compound according to claim 1 of structural formula IV: IV or a pharmaceutically acceptable salt thereof. 29. A compound according to claim 1 selected from:

HO HO O ^N _O ^N O F₃ , , ,

, , ,

F₃C N N O N O N N O N N O HN , , , Cl CF₃ , ,

O N O 3 , , , ,

,

, ,

_O ^N , ,

_HO ^N HO N^N , , , ,

HO HO _O ^N _O ^N HO _HO ^N , O 3 ,

_HO ^N ^N O F₃ , 30. A pharmaceutical composition comprising a compound of any one of claims 1 through 29 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

31. A method of modulating or inhibiting WRN activity in a subject, comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 through 29, or a pharmaceutically acceptable salt thereof.

32. A method of treating a disorder or disease which can be treated by WRN inhibition in a subject, comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 through 29, or a pharmaceutically acceptable salt thereof.

33. A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 through 29, or a pharmaceutically acceptable salt thereof.

34. The method according to claim 33 wherein the cancer is selected from cervical, adrenocortical, kidney, breast, esophageal, colorectal, gastric, prostate, ovarian, endometrial and uterine. 35 The compound of any one of claims 1 through 29, or a pharmaceutically acceptable salt thereof, for use as a medicament. 36. The compound according to claim 35, or a pharmaceutically acceptable salt thereof, wherein the use is for the treatment of a disease that is treated by WRN inhibition. 37. The compound according to claim 35, or a pharmaceutically acceptable salt thereof, wherein the use is for the treatment of cancer.