Spirocyclic WRN inhibitors

Abstract

The present disclosure is directed to spirocyclic WRN inhibitors and pharmaceutically acceptable salts thereof, and compositions thereof, as well as methods of treatment of cancers such as those involving WRN protein. Such spirocyclic WRN inhibitors include compounds of Formula I-a: and pharmaceutically acceptable salts thereof.

Description

SPIROCYCLIC WRN INHIBITORS FIELD OF INVENTION

[0001] The invention provides bicyclic compounds and compositions, the use thereof and methods using the compounds, for inhibiting Werner Syndrome RecQ DNA helicase (WRN) and methods of treating disease using said compounds, in particular the use in treating cancer, and in particular the treatment of cancer characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), including colorectal, gastric and endometrial cancer. The invention also provides the use of said compounds as research chemicals, intermediate compounds, in combinations, and in formulations. CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of United States Provisional Patent Application nos. 63 / 783,584, filed April 4, 2025; and 63 / 670,429, filed July 12, 2024; the entire contents of which are incorporated herein by reference. SEQUENCE LISTING

[0003] This application contains a Sequence Listing which has been submitted in .xml format and is hereby incorporated by reference. The ST.26 copy, created on July 9, 2025, is named 407274-95WRWO_217205_SL.xml and is 8,124 bytes in size. BACKGROUND

[0004] Loss of DNA mismatch repair is a common initiating event in cancer development occurring in 10-30% of colorectal, 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)). Cancers that are deficient in mismatch repair (dMMR) have a high mutational burden, and frequent deletion and insertion events in repetitive DNA tracts, a phenotype known as microsatellite instability (MSI). While progress has been made in the treatment of microsatellite instability high (MSI-H) cancers, and the demonstration that pembrolizumab (anti- PD1) treatment led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for MSI-H-dMMR metastatic colorectal cancer (CRC) which resulted 1 BUSINESS.33169534.1 407274-95WRWO (217205)in the recent approval of pembrolizumab as first-line treatment of these 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):22072218 (2020)). Several large-scale functional genomics screens across large panels of cell lines, including Novartis with 398 cell lines from the Cancer Cell Line Encyclopedia (CCLE) (McDonald E.R. et al., Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening. Cell 170(3):577-592 (2017)), have identified the Werner Syndrome RecQ helicase (WRN) as being selectively required for the survival of cell lines with defective mismatch repair that have become MSI-H (Behan, F. M. et al. Prioritization of cancer therapeutic targets using CRISPR—Cas9 screens. Nature 568, 511-516 (2019), Chan, E. M. et al. WRN helicase is a synthetic lethal target in microsatellite unstable cancers. Nature 568, 551-556 (2019). Kategaya, L., Perumal, S. K., Hager, J. H. & Belmont, L. D. Werner syndrome helicase is required for the survival of cancer cells with microsatellite instability. iScience 13, 488-497 (2019), Lieb, S. et al. Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells. eLife 8, e43333 (2019)). WRN is synthetically lethal with MSI cancers. Depletion of WRN leads to anti-proliferative effects and results in activation of multiple DNA damage signaling markers, induction of cell cycle arrest and apoptosis in MSI-H cancer models but not cancer cells with an intact MMR pathway (otherwise known as microsatellite stable or MSS). The anti-proliferative effects of WRN depletion could not be rescued with a helicase deficient WRN construct, demonstrating that helicase activity of WRN is required for MSI-H viability. These findings indicate that WRN helicase provides a DNA repair and maintenance function that is essential for cell survival in MSI cancers. Recently, the mechanism of WRN dependence has been elucidated. It has been shown that dinucleotide TA repeats are selectively unstable in MSI cells and undergo large scale expansions. These expanded TA repeats form secondary DNA structures that require the WRN helicase for unwinding (van Wietmarschen, N. et al. Repeat expansions confer WRN dependence in microsatellite-unstable cancers. Nature 586, 292-298, 2020). In the absence of WRN (or upon WRN helicase inhibition), expanded TA repeats in MSI cells are subject to nuclease cleavage and chromosome breakage. Thus, inhibiting the WRN helicase is an attractive strategy for the treatment of MSI-H cancers. 2 BUSINESS.33169534.1 407274-95WRWO (217205)SUMMARY

[0005] There remains a need for new treatments and therapies for the treatment of cancer, and in particular cancers characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), including colorectal, gastric or endometrial cancer. The invention provides compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof and combinations thereof, said compounds being inhibitors of Werner Syndrome RecQ DNA Helicase (WRN). The invention further 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. The invention also provides compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof and combinations thereof, said compounds being useful for the treatment of cancer, in particular cancers characterized as microsatellite instability-high (MSI- H) or mismatch repair deficient (dMMR). Also provided are compounds that bind to, and / or inhibit WRN, and are therefore useful as research chemicals, e.g., as chemical probes, and as tool compounds. Various embodiments of the invention are described herein.

[0006] In one aspect, the disclosure provides a compound of any one of Formulas I-a to I-x, or a pharmaceutically acceptable salt thereof: , , , BUSINESSRWO (217205), ,;wherein

[0007] In another aspect, the invention provides a pharmaceutical composition comprising a compound of the present invention and one or more pharmaceutically acceptable carriers.

[0008] In another aspect, the invention provides a combination, in particular a pharmaceutical combination, comprising a compound of the present invention and one or more therapeutically active agents. 4 BUSINESS.33169534.1 407274-95WRWO (217205)

[0009] In another aspect, the invention provides a compound of the present invention for use as a medicament, in particular for the treatment of a disorder or disease which can be treated by WRN inhibition.

[0010] In another aspect, the invention provides a compound of the present invention for use in the treatment of cancer, particularly wherein the cancer is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

[0011] In another aspect, the invention provides 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 a compound of the present invention.

[0012] In another aspect, the invention provides a method of treating cancer in a subject, more particularly wherein the cancer is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), comprising administering to the subject a therapeutically effective amount of a compound of the present invention.

[0013] In another aspect, the invention provides the use of a compound of the present invention in the manufacture of a medicament for the treatment of a disorder or disease which can be treated by WRN inhibition.

[0014] In another aspect, the invention provides a compound of the present invention for use as a research chemical, for example as a chemical probe or as a tool compound.

[0015] In another aspect, the invention provides a solid form, process or intermediate as described herein. DETAILED DESCRIPTION 1. General Description of Certain Embodiments of the Invention:

[0016] In one aspect, the disclosure provides a compound of any one of Formulas I-a to I-x, or a pharmaceutically acceptable salt thereof: 5 BUSINESS.33169534.1 407274-95WRWO (217205), , , , BUSINESRWO (217205),;w )2, O, andNR3; provided that only one of Q and Y is O or NR3; wherein Ring B is a fused ring selected from a 5-6 membered heteroaryl, phenyl, and 5-6 membered partially unsaturated heterocyclyl, said heteroaryl or heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from O, S, N, and NR18; wherein Ring B is substituted with R1aand z instances of R1b; R18is H or optionally substituted C1-C6aliphatic; z is 0, 1, or 2; each R1bgroup is independently selected from H, halogen, CN, OH, oxo, C1-C6aliphatic, C1-C6alkoxy, C3-C6cycloalkyl, C1-C6alkylene-O-C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and C3-C6cycloalkoxy, wherein said C1-C6aliphatic, C1-C6alkoxy, C3-C6cycloalkyl, C1- C6alkylene-O-C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and C3-C6cycloalkoxy are each independently and optionally substituted with 1-5 halogen, OH, CN, C1-C6alkyl, or C3- C6cycloalkyl groups; provided that when Ring B is a 5 membered ring then z is 0 or 1; R19and R20, along with the carbon atom to which they are both attached, together form Ring A selected from: a) a 4-7 membered saturated or partially unsaturated monocyclic carbocyclyl or 4-7membered saturated or partially unsaturated monocyclic heterocyclyl (having 1-4 7 BUSINESS.33169534.1 407274-95WRWO (217205)heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 nitrogen atoms in addition to the 1-4 heteroatoms); and b) a 4-12 membered saturated or partially unsaturated bicyclic ring system that isfused, bridged, or spirocyclic selected from carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein Ring A is substituted with 0-4 independently selected RBsubstituents; and wherein Ring A is substituted with a linking group -L-R4, wherein -L-R4is selected from 44 4;a) a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur) optionally substituted with 1-3 groups independently selected from halogen, C1-C6aliphatic, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkoxy, and C3- C6cycloalkoxy, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RB; b) a 4-7 membered saturated or partially unsaturated monocyclic heterocyclyl(having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6aliphatic, C3- C6cycloalkyl, C1-C6alkoxy, C3-C6cycloalkoxy, and -OR, wherein said 4-7 membered saturated or partially unsaturated heterocyclyl is further substituted with 0-3 independently selected RB; c) a 4-12 membered saturated or partially unsaturated bicyclic ring system that isfused, bridged, or spirocyclic selected from carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected RB; and d) H, halogen, C1-C6aliphatic, C3-C7cycloalkyl, C1-C6alkylene-O-C1-C6alkyl, CN, -OR, -OR10, -NR10R11, -C(O)NR10R11,-CH2NR10R11, or -SO2R12, wherein said C1- C6aliphatic, C3-C7cycloalkyl, or C1-C6alkylene-O-C1-C6alkyl is substituted with 0-5 independently selected RB; 8 BUSINESS.33169534.1 407274-95WRWO (217205)R2is selected from C(RC)2C(O)N(R)R2A, C(RC)2C(RC)2C(O)N(R)R2A, C(RC)2C(RC)2N(R)C(O) N(R)R2A, and C(RC)2C(RC)2N(R)C(O)R2A; R2Ais selected from: a) phenyl or pyridyl, each of which is optionally substituted with 1, 2, or 3substituents independently selected from halogen, C1-C4aliphatic, haloC1-C4alkyl, C3-C6- cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, and –SF5, and wherein two substituents on adjacent atoms of the phenyl or pyridyl, together with said adjacent atoms, optionally form a 4-7 membered carbocyclyl fused to the phenyl or pyridyl, or wherein two substituents on adjacent atoms of the phenyl or pyridyl together with said adjacent atoms optionally form a 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused to the phenyl or pyridyl, wherein said fused 4-7 membered carbocyclyl or fused 4-7 membered heterocyclyl is substituted with 0-5 independently selected halogen; or b) R2A is 2-benzimidazolyl, 2-naphthyl, or 3-quinolinyl, each of which is optionallysubstituted with 1, 2, or 3 substituents independently selected from halogen, C1-4alkyl, and - OH; or c) R2A is cubanyl, a saturated or partially unsaturated 4-8 membered monocyclicring, a saturated or partially unsaturated bridged, fused or spirocyclic 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, wherein said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring comprises 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said cubanyl, saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4aliphatic, haloC1-C4alkyl, C3-C6-cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, C3-C6- cycloalkoxy, haloC4-C6cyclalkoxy and –SF5, and wherein two optional substituents on the same atom of said saturated or partially unsaturated monocyclic ring, or said saturated or partially unsaturated bridged, fused or spirocyclic ring form a cyclic group selected from: ^an optionally substituted 3-7 membered saturated or partially unsaturatedcarbocyclyl, and 9 BUSINESS.33169534.1 407274-95WRWO (217205)^ an optionally substituted 4-7 membered saturated or partially unsaturatedheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R3is independently selected from hydrogen, C1-C4aliphatic, oxo, C3-C5cycloalkyl, and C1-C4alkoxy, each of which, besides hydrogen or oxo, is optionally substituted with -OH, 1- 5 independently selected halogen, or OR; d is 0, 1, or 2; d-1 is 0 or 1; R4is selected from: a) phenyl or a first 5-6 membered heteroaryl (having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur) wherein said phenyl or first 5-6 membered heteroaryl is substituted with 0-5 RB; and optionally two adjacent atoms of said phenyl or first 5-6 membered heteroaryl have two substituents that together with said adjacent atoms form a cyclic group fused to the phenyl or first 5-6 membered heteroaryl selected from a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or a second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said fused cyclic group is substituted with 0-3 independently selected RB; or b) R4 is a C1-C4aliphatic, C1-C4alkoxy, or C3-C6cycloalkyl, each of which issubstituted with 0-3 groups independently selected from halogen, -CN, -OH, C1-C4alkyl, C1-C4alkoxy, optionally substituted 5-6 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 5-6 membered heterocyclyloxy having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R10is H, C1-C6aliphatic, haloC1-C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, –C(O)C1-C6alkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur); each R10except H being optionally substituted with 1 or 2 independently selected RB; 10 BUSINESS.33169534.1 407274-95WRWO (217205)R11is H, C1-C6aliphatic, or C3-C6cycloalkyl, or R10and R11are taken together with the nitrogen atom to which they are attached to form a 5-6 membered ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, -OH, -CN, C1-C4alkoxy, and haloC1-C4alkoxy; R12is C1-C6aliphatic, C3-C6cycloalkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R12optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1- C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, and C3-C6cycloalkoxy; RBis independently selected at each occurrence from the group consisting of optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogen, optionally substituted C1-C6aliphatic, haloC1- C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, C1-C6alkoxy, haloC1-C6alkoxy, C3- C6cycloalkoxy, haloC3-C6cycloalkoxy, C1-C6alkylene-O-C1-C6alkyl, –CN, –NO2, oxo, –OR, – SR, NR2, S(O)2R, S(O)2NR2, S(O)R, S(O)NR2, C(O)R, C(O)OR, –C(O)NR2, C(O)N(R)OR, OC(O)R, OC(O)NR2, -N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR2, N(R)C(NR)NR2, N(R)S(O)2NR2, and –N(R)S(O)2R; or two RBgroups on the same atom are taken together with the same atom together to form a 3-7 membered carbocyclic ring; RCis independently selected at each occurrence from hydrogen, -CH3, or -CH2CH3, or two RCtaken together with the carbon to which they are attached form a cyclopropyl ring; each R is independently hydrogen, or an optionally substituted C1-6aliphatic group, an optionally substituted phenyl, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or two R groups on the same atom are taken together with the same atom to form a cyclic group selected from an optionally substituted 4-7 membered saturated ring, a 4-7 membered partially unsaturated ring, or a 5-6 membered heteroaryl ring (having 1-4 heteroatoms 11 BUSINESS.33169534.1 407274-95WRWO (217205)independently selected from nitrogen, oxygen, and sulfur); wherein said cyclic group has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0017] In one embodiment, the disclosure provides a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of I-a’ to I-dd’: , ,,,BUSINEWO (217205),,,, ,13 BUSINESS.33169534.1 407274-95WRWO (217205),,,,BUSINEO (217205),wherein R19and R20combine to form Ring A; wherein each R1bgroup is independently selected from H, halogen, CN, OH, C1- C6aliphatic, C1-C6alkoxy, C3-C6cycloalkyl, C1-C6alkylene-O-C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and C3-C6cycloalkoxy, wherein said C1-C6aliphatic, C1-C6alkoxy, C3- C6cycloalkyl, C1-C6alkylene-O-C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and C3- C6cycloalkoxy are each independently and optionally substituted with 1-5 halogen, OH, CN, C1- C6alkyl, or C3-C6cycloalkyl groups; wherein z is 0, 1, or 2; Ring A is: a) a 4-7 membered saturated or partially unsaturated monocyclic carbocyclyl or 4-7membered saturated or partially unsaturated heterocyclyl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 nitrogen atoms in addition to the 1-4 heteroatoms); or b)a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein Ring A is substituted with 0-4 independently selected RBsubstituents; and Ring A is substituted with a linking group -L-R4, wherein linker -L-R4is selected from - ;R1ais selected from: a) a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur) optionally substituted with 1-3 groups independently 15 BUSINESS.33169534.1 407274-95WRWO (217205)selected from halogen, C1-C6aliphatic, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkoxy, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RB; b) a 4-7 membered saturated or partially unsaturated monocyclic heterocyclyl(having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6aliphatic, C3- C6cycloalkyl, C1-C6alkoxy, C3-C6cycloalkoxy, and -OR, wherein said 4-7 membered saturated or partially unsaturated heterocyclyl is further substituted with 0-3 independently selected RB; c) a 4-12 membered saturated or partially unsaturated bicyclic ring system thatis fused, bridged, or spirocyclic selected from carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected RB; and d) H, halogen, C1-C6aliphatic, C3-C7cycloalkyl, C1-C6alkylene-O-C1-C6alkyl,CN, -OR, -OR10, -NR10R11, -C(O)NR10R11, -CH2NR10R11, or -SO2R12, wherein said C1- C6aliphatic, C3-C7cycloalkyl, or C1-C6alkylene-O-C1-C6alkyl is substituted with 0-5 independently selected RB; R2is selected from C(RC)2C(O)N(R)R2A, C(RC)2C(RC)2C(O)N(R)R2A, C(RC)2C(RC)2N(R)C(O) N(R)R2A, and C(RC)2C(RC)2N(R)C(O)R2A; R2Ais selected from: a) phenyl or pyridyl, each of which is optionally substituted with 1, 2, or 3substituents independently selected from halogen, C1-C4aliphatic, haloC1-C4alkyl, C3-C6- cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, and –SF5, and wherein two substituents on adjacent atoms of the phenyl or pyridyl, together with said adjacent atoms, optionally form a 4-7 membered carbocyclyl fused to the phenyl or pyridyl, and wherein two substituents on adjacent atoms of the phenyl or pyridyl together with said adjacent atoms optionally form a 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused to the phenyl or pyridyl, 16 BUSINESS.33169534.1 407274-95WRWO (217205)wherein said fused 4-7 membered carbocyclyl or fused 4-7 membered heterocyclyl is substituted with 0-5 independently selected halogen; or b) R2A is 2-benzimidazolyl, 2-naphthyl, or 3-quinolinyl, each of which isoptionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1- 4alkyl, and -OH; or c) R2A is cubanyl, a saturated or partially unsaturated 4-8 memberedmonocyclic ring, a saturated or partially unsaturated bridged, fused or spirocyclic 5-, 6-, 7- , 8-, 9-, 10-, 11-, or 12-membered ring, wherein said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring comprises 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said cubanyl, saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring are each optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1- C4aliphatic, haloC1-C4alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1- C4alkoxy, haloC1-C4alkoxy, C3-C6cycloalkoxy, haloC4-C6cyclalkoxy and –SF5, and wherein two optional substituents on the same atom of said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring form a cyclic group selected from: ^an optionally substituted 3-7 membered saturated or partially unsaturatedcarbocyclyl, and ^an optionally substituted 4-7 membered saturated or partially unsaturatedheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R3is independently selected from hydrogen, C1-C4aliphatic, oxo, C3-C5cycloalkyl, or C1- C4alkoxy, each of which, besides hydrogen or oxo, is optionally substituted with -OH, 1-5 independently selected halogen, or OR; d is 0, 1, or 2; and wherein “d – 1” is 0 or 1; R4is selected from: 17 BUSINESS.33169534.1 407274-95WRWO (217205)a) phenyl or a first 5-6 membered heteroaryl (having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur) wherein said phenyl or first 5-6 membered heteroaryl is substituted with 0-5 RB; and optionally two adjacent atoms of said phenyl or first 5-6 membered heteroaryl have two substituents that together with said adjacent atoms form a cyclic group fused to the phenyl or first 5-6 membered heteroaryl selected from a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or a second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said fused cyclic group is substituted with 0-3 independently selected RB; or b) R4 is a C1-C4aliphatic, C1-C4alkoxy, or C3-C6cycloalkyl, each of which issubstituted with 0-3 groups independently selected from halogen, -CN, -OH, C1-C4alkyl, C1-C4alkoxy, optionally substituted 5-6 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 5-6 membered heterocyclyloxy having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R10is H, C1-C6aliphatic, haloC1-C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, –C(O)C1-C6alkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur); each R10except H being optionally substituted with 1 or 2 independently selected RB; R11is H, C1-C6aliphatic, or C3-C6cycloalkyl, or R10and R11are taken together with the nitrogen atom to which they are attached to form a 5-6 membered ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, -OH, -CN, C1-C4alkoxy, and haloC1-C4alkoxy; R12is C1-C6aliphatic, C3-C6cycloalkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R12optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1- C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, and C3-C6cycloalkoxy; 18 BUSINESS.33169534.1 407274-95WRWO (217205)RBis independently selected at each occurrence from the group consisting of optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogen, optionally substituted C1-C6aliphatic, haloC1-C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, C1-C6alkoxy, haloC1-C6alkoxy, C3-C6cycloalkoxy, haloC3-C6cycloalkoxy, C1-C6alkylene-O-C1-C6alkyl, –CN, –NO2, oxo, –OR, –SR, NR2, S(O)2R, S(O)2NR2, S(O)R, S(O)NR2, C(O)R, C(O)OR, –C(O)NR2, C(O)N(R)OR, OC(O)R, OC(O)NR2, - N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR2, N(R)C(NR)NR2, N(R)S(O)2NR2, and –N(R)S(O)2R; RCis independently selected at each occurrence from hydrogen, -CH3, or -CH2CH3, or two RCtaken together with the carbon to which they are attached form a cyclopropyl ring; each R is independently hydrogen, or an optionally substituted C1-6aliphatic group, an optionally substituted phenyl, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or two R groups on the same atom are taken together with the same atom to form a cyclic group selected from an optionally substituted 4-7 membered saturated ring, a 4-7 membered partially unsaturated ring, or a 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said cyclic group has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0018] In another aspect, the invention provides 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 a compound of the present invention. 2. Compounds and Definitions:

[0019] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the 19 BUSINESS.33169534.1 407274-95WRWO (217205)chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry,” 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001. Compound structures shown throughout the present specification and in the examples or claims contain designations at certain stereocenters. Stereocenters marked with “abs” intend to cover material wherein the marked stereocenter is of the stereochemistry shown in the diagram. Stereocenters marked with “&1” or “and1” indicate that the compound material has a mixture of R and S-configured stereoisomers with respect to the marked stereocenter and is in the same relative configuration to each other if they share the same label such as “and1” or “&1.”

[0020] The term “aliphatic” or “aliphatic group,” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0021] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which 20 BUSINESS.33169534.1 407274-95WRWO (217205)is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 5-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. The term “alkyl” refers to a C1-12 straight or branched saturated aliphatic group. In certain instances, alkyl refers to a C1-8 straight or branched saturated aliphatic group or a C1-6straight or branched saturated aliphatic group. The term “lower alkyl” refers to a C1-4 straight or branched alkyl group.

[0022] Exemplary lower alkyl groups are methyl (-CH3), ethyl (-CH2CH3), propyl, isopropyl (also referred to interchangeably herein as 2-propyl, iPr,iPr and i-Pr), butyl, isobutyl (also referred to interchangeably herein as 2-butyl, iBu,iBu and i-Bu) and tert-butyl (also referred to interchangeably herein as 2-methyl-2-butyl, tBu,tBu and t-Bu).

[0023] The term “alkenyl” refers to a C2-12 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon double bond. In certain instances, alkenyl refers to a C2-8 or a C2-6 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon double bond. The term “lower alkenyl” refers to a C2-4 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon double bond. Alkenyl groups include both cis (Z) and trans (E) regioisomers. Exemplary lower alkenyl groups are vinyl, allyl, 2-propenyl, and butenyl isomers (-CH2CH2CH=CH2, - CH2CH=CHCH3and -CH=CHCH2CH3).

[0024] The term “alkynyl” refers to a C2-12straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon triple bond. In certain instances, alkynyl refers to a C2-8 or a C2-6 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon triple bond. The term “lower alkynyl” refers to a C2-4straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon triple bond. Exemplary lower alkynyl groups are ethynyl, 1-propynyl, 2-propynyl, 1- butynyl, 2-butynyl, and 3-butynyl.

[0025] The term “haloalkyl” refers to a straight or branched alkyl group that is substituted with one or more halogen atoms. The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms. 21 BUSINESS.33169534.1 407274-95WRWO (217205)

[0026] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl).

[0027] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.

[0028] The term “cubanyl” refers to a substituent of cubane as shown below.

[0029] The substituent -Me, as used hs to a methyl group, -CH3.

[0030] As used herein, the term “bivalent C1-8 (or C1-6 i.e., C1-C6) saturated or unsaturated, straight or branched, hydrocarbon chain,” refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0031] As used herein, the term “bivalent,” to describe a cyclic (and noncyclic) group refers to, for example, bivalent carbocyclylene, phenylene, heterocyclylene, and heteroarylene that are bivalent moieties of carbocycles, phenyls, heterocycles, and heteroaryls described herein. Non- limiting examples include .

[0032] “Carbocyclylene” as used herein refers to a carbocyclic or cycloalkyl moiety that is bivalent as described above (i.e., attached at two different points to the rest of the compound). Non-limiting examples include cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene as shown below. 22 BUSINESS.33169534.1 407274-95WRWO (217205)

[0033] e or partially unsaturated as in the examples shown below.

[0034] A carbocycyene may e mut-cyc c, or exampe, cyc c or tricyclic. Such multi- cyclic carbocyclylene systems may be saturated or partially unsaturated (while one ring of the bicyclic system may be aromatic it is to be understood that multi-cyclic ring systems that are not in their entirety aromatic may also fall under the definition of carbocyclylene). The rings may form bridged, fused, or spiro systems. Non-limiting examples are shown below. 23 BUSINESS.33169534.1 407274-95WRWO (217205)

[0035] “Heterocyclylene” as used herein refers to a heterocyclic or heterocyclyl moiety that is bivalent as described above (i.e., attached at two different points to the rest of the compound) and may also be saturated or partially unsaturated. Non-limiting examples include those shown below. Heterocyclylene is understood to include bicyclic heterocyclylene systems. Non-limiting examples of bicyclic heterocyclylene moieties are also shown below and said bicyclic systems may be spirocyclic, fused, or bridged and may be saturated or partially unsaturated.

[0036] “Phenylene” as used herein refers to a phenyl moiety that is bivalent as described above (i.e., attached at two different points to the rest of the compound). Examples are shown below. 24 BUSINESS.33169534.1 407274-95WRWO (217205)

[0037] “Arylene” as usedclic aryl (i.e., phenyl or a multi- cyclic aryl) moiety that is bivalent as described above (i.e., attached at two different points to the rest of the compound), wherein the arylene group contains no heteroatoms. Examples are shown below.

[0038] “Hete, ryl ring system that contains at least one heteroatom wherein the ring system is bivalent as described above (i.e., attached at two different points to the rest of the compound). Examples are shown below.

[0039] Theterm alkylene refers to a bivalent alkyl group. An alkylene chain” is a polymethylene group, i.e., –(CH2)n–, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0040] “Carbocyclyl (or heterocyclyl, aryl, phenyl, or heteroaryl) fused to” another phenyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, for example, a “phenyl or pyridyl” as used herein, may be referred to as “partially unsaturated” without said “carbocyclyl (or heterocyclyl, aryl, phenyl, or heteroaryl) fused to” the other ring requiring further unsaturation besides the carbon 25 BUSINESS.33169534.1 407274-95WRWO (217205)carbon bond which it shares with the ring to which it is fused (i.e., the “phenyl or pyridyl”). This is illustrated below.

[0041] A further example below shows a carbocyclyl moiety fused to a Ring E as defined in the embodiments herein. Said carbocyclyl does not explicitly require a descriptor of “partially unsaturated” to describe said carbocyclyl because it shares two carbons with the aromatic pyridine to which it is fused. Such language is used herein to describe such systems, for example, “R4Aand R4B, along with their intervening atoms, join to form 4-7 membered carbocyclyl that is fused to Ring E” as shown in the image below. As such, “Ring E” may refer to a monocyclic ring (i.e., the pyridine shown below and its substituents which do not form a fused ring), without any further fused rings created by its substituents (i.e., R4Aand R4B). Any further fused ring created by thesubstituents of Ring E is described as being “fused to Ring E.” Likewise, R4A and R4B, along withtheir intervening atoms, join to form 4-7 membered carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring E (not pictured), is subject to the same interpretation.

[0042] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0043] The term “halogen” means F, Cl, Br, or I. 26 BUSINESS.33169534.1 407274-95WRWO (217205)

[0044] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system comprises 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0045] The terms “heteroaryl” and “heteroar–,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, 9 or 10 ring atoms; having 6, 10, or 14 ^ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, triazinyl, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl (i.e., 1,2,3-triazolyl), 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar–,” as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, indolizinyl, isoindolin-1-only, 1,2-dihydro-3H- pyrrolo[3,4-c]pyridin-3-onyl, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-onyl, imidazo[1,2- a]pyridyl, imidazo[1,5-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrrolo[1,2-b]pyridazinyl, pyrrolo[1,2- a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H– quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. A heteroaryl group may be mono– or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl 27 BUSINESS.33169534.1 407274-95WRWO (217205)group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0046] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. Said 7–10–membered bicyclic heterocyclic moiety that is partially unsaturated may include an aryl or heteroaryl ring fused to a non-aromatic ring. For example, said 7–10–membered bicyclic heterocyclic moiety may include a bicyclic heterocyclyl as shown below: . When used in reerence o a r ng a om o a e erocyc e, e erm n rogen ncludes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4–dihydro–2H–pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in N–substituted pyrrolidinyl).

[0047] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6- azaspiro[3.3]heptane, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono– or bicyclic. The 28 BUSINESS.33169534.1 407274-95WRWO (217205)term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0048] “Arylene” or “heteroarylene,” as used herein (i.e., phenylene), refers to any bivalent aryl or heterocyclyl described herein, that is a bisradical substituted at each of two substitutable positions of the ring system as described in detail supra.

[0049] “Heterocyclyloxy,” as used herein, refers to an -OR group wherein the R is a heterocyclyl. Nonlimiting examples are shown below.

[0050] Ay that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0051] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasiblecompounds. The term “stable,” as used herein, refers to compounds that are not substantiallyaltered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0052] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4B(OR^)2; –(CH2)0–4R^; –(CH2)0–4OR^; - O(CH2)0-4Ro; –O–(CH2)0–4C(O)OR°; –(CH2)0–4CH(OR^)2; –(CH2)0–4SR^; –(CH2)0–4Ph, which 29 BUSINESS.33169534.1 407274-95WRWO (217205)may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; – CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R^)2; –(CH2)0–4N(R^)C(O)R^; –N(R^)C(S)R^; –(CH2)0–4N(R^)C(O)NR^2; –N(R^)C(S)NR^2; –(CH2)0–4N(R^)C(O)OR^; –N(R^)N(R^)C(O)R^; – N(R^)N(R^)C(O)NR^2; –N(R^)N(R^)C(O)OR^; –N(R^)C(NR^)N(R^)2; –(CH2)0–4C(O)R^; – C(S)R^; –(CH2)0–4C(O)OR^; –(CH2)0–4C(O)SR^; –(CH2)0–4C(O)OSiR^3; –(CH2)0–4OC(O)R^; – OC(O)(CH2)0–4SR°; –(CH2)0–4SC(O)R^; –(CH2)0–4C(O)NR^2; –C(S)NR^2; –C(S)SR°; – SC(S)SR°; –(CH2)0–4OC(O)NR^2; –C(O)N(OR^)R^; –C(O)C(O)R^; –C(O)CH2C(O)R^; –C(NOR^)R^; –(CH2)0–4SSR^; –(CH2)0–4S(O)2R^; –(CH2)0–4S(O)2OR^; –(CH2)0–4OS(O)2R^; –S(O)2NR^2; –(CH2)0–4S(O)R^; –N(R^)S(O)2NR^2; –N(R^)S(O)2R^; –N(OR^)R^; –C(NH)NR^2; – (CH2)0–4P(O)2R^; –(CH2)0–4P(O)R^2; –(CH2)0–4OP(O)R^2; –(CH2)0–4OP(O)(OR^)2; –SiR^3; –(C1– 4 straight or branched alkylene)O–N(R^)2; or –(C1–4 straight or branched alkylene)C(O)O–N(R^)2, wherein each R^ may be substituted as defined below and is independently hydrogen, C1–6aliphatic, -SO2-C1–4aliphatic (i.e., -SO2CH3) –CH2Ph, –O(CH2)0–1Ph, -CH2-(5-6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0– 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0053] Suitable monovalent substituents on R^ (or the ring formed by taking two independent occurrences of R^ together with their intervening atoms), are independently halogen, –(CH2)0–2R^, –(haloR^), –(CH2)0–2OH, –(CH2)0–2OR^, –(CH2)0–2CH(OR^)2; –O(haloR^), –CN, –N3, –(CH2)0–2C(O)R^, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR^, –(CH2)0–2SR^, –(CH2)0–2SH, –(CH2)0–2NH2, – (CH2)0–2NHR^, –(CH2)0–2NR^2, –NO2, –SiR^3, –OSiR^3, -C(O)SR^, –(C1–4 straight or branched alkylene)C(O)OR^, or –SSR^wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–6aliphatic, – CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0– 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R^ include =O and =S. 30 BUSINESS.33169534.1 407274-95WRWO (217205)

[0054] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group, which includes instances of R^ (or the ring formed by taking two independent occurrences of R^ together with their intervening atoms), include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or – S(C(R*2))2–3S–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0– 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0055] Suitable substituents on the aliphatic group of R*include halogen, –R^, -(haloR^), -OH, –OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or –NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0056] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, -S(O)2R†,†; wherein each R†is independeined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0057] Suitable substituents on the aliphatic group of R†are independently halogen, –R^, -(haloR^), –OH, –OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or –NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one 31 BUSINESS.33169534.1 407274-95WRWO (217205)or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0058] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2– hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like.

[0059] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0060] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the 32 BUSINESS.33169534.1 407274-95WRWO (217205)structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, Z and E conformational isomers and Ra (or M) and Sa (or P) atropisomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. In certain embodiments, Ring A of a provided compound may be substituted with one or more deuterium atoms.

[0061] The structures as drawn represent relative configurations, unless labeled as absolute configurations. The invention contemplates individual enantiomers and racemic mixtures. 3. Description of Exemplary Embodiments:

[0062] In one aspect, the disclosure provides a compound of Formula I-a to I-x, or a pharmaceutically acceptable salt thereof: , , BUSINESSRWO (217205), , ,;w, , , )2, O, and NR3; provided that only one of Q and Y is O or NR3; 34 BUSINESS.33169534.1 407274-95WRWO (217205)wherein Ring B is a fused ring selected from a 5-6 membered heteroaryl, phenyl, and 5-6 membered partially unsaturated heterocyclyl, said heteroaryl or heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from O, S, N, and NR18; wherein Ring B is substituted with R1aand z instances of R1b; R18is H or optionally substituted C1-C6aliphatic; z is 0, 1, or 2; each R1bgroup is independently selected from H, halogen, CN, OH, oxo, C1-C6aliphatic, C1-C6alkoxy, C3-C6cycloalkyl, C1-C6alkylene-O-C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and C3-C6cycloalkoxy, wherein said C1-C6aliphatic, C1-C6alkoxy, C3-C6cycloalkyl, C1- C6alkylene-O-C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and C3-C6cycloalkoxy are each independently and optionally substituted with 1-5 halogen, OH, CN, C1-C6alkyl, or C3- C6cycloalkyl groups; provided that when Ring B is a 5 membered ring then z is 0 or 1; R19and R20, along with the carbon atom to which they are both attached, together form Ring A selected from: a) a 4-7 membered saturated or partially unsaturated monocyclic carbocyclylor 4-7 membered saturated or partially unsaturated monocyclic heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 nitrogen atoms in addition to the 1-4 heteroatoms); and b) a 4-12 membered saturated or partially unsaturated bicyclic ring systemthat is fused, bridged, or spirocyclic selected from carbocyclyl or heterocyclyl (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein Ring A is substituted with 0-4 independently selected RBsubstituents; and wherein Ring A is substituted with a linking group -L-R4, wherein -L-R4is selected from ; 35407274-95WRWO (217205)a) a 5-6 membered heteroaryl (having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur) optionally substituted with 1-3 groups independently selected from halogen, C1-C6aliphatic, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkoxy, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RB; b) a 4-7 membered saturated or partially unsaturated monocyclic heterocyclyl(having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6aliphatic, C3- C6cycloalkyl, C1-C6alkoxy, C3-C6cycloalkoxy, and -OR, wherein said 4-7 membered saturated or partially unsaturated heterocyclyl is further substituted with 0-3 independently selected RB; c) a 4-12 membered saturated or partially unsaturated bicyclic ring systemthat is fused, bridged, or spirocyclic selected from carbocyclyl or heterocyclyl (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected RB; and d) H, halogen, C1-C6aliphatic, C3-C7cycloalkyl, C1-C6alkylene-O-C1-C6alkyl,CN, -OR, -OR10, -NR10R11, -C(O)NR10R11,-CH2NR10R11, or -SO2R12, wherein said C1- C6aliphatic, C3-C7cycloalkyl, or C1-C6alkylene-O-C1-C6alkyl is substituted with 0-5 independently selected RB; R2is selected from C(RC)2C(O)N(R)R2A, C(RC)2C(RC)2C(O)N(R)R2A, C(RC)2C(RC)2N(R)C(O) N(R)R2A, and C(RC)2C(RC)2N(R)C(O)R2A; R2Ais selected from: a) phenyl or pyridyl, each of which is optionally substituted with 1, 2, or 3 substituentsindependently selected from halogen, C1-C4aliphatic, haloC1-C4alkyl, C3-C6-cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, and – SF5, and wherein two substituents on adjacent atoms of the phenyl or pyridyl, together with said adjacent atoms, optionally form a 4-7 membered carbocyclyl fused to the phenyl or pyridyl, or wherein two substituents on adjacent atoms of the phenyl or pyridyl together with said adjacent atoms optionally form a 4-7 membered 36 BUSINESS.33169534.1 407274-95WRWO (217205)heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused to the phenyl or pyridyl, wherein said fused 4-7 membered carbocyclyl or fused 4-7 membered heterocyclyl is substituted with 0-5 independently selected halogen; or b) R2A is 2-benzimidazolyl, 2-naphthyl, or 3-quinolinyl, each of which is optionallysubstituted with 1, 2, or 3 substituents independently selected from halogen, C1- 4alkyl, and -OH; or c) R2A is cubanyl, a saturated or partially unsaturated 4-8 membered monocyclic ring, asaturated or partially unsaturated bridged, fused or spirocyclic 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, wherein said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring comprises 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said cubanyl, saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1- C4aliphatic, haloC1-C4alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1- C4alkoxy, haloC1-C4alkoxy, C3-C6cycloalkoxy, haloC4-C6cyclalkoxy and –SF5, and wherein two optional substituents on the same atom of said saturated or partially unsaturated monocyclic ring, or said saturated or partially unsaturated bridged, fused or spirocyclic ring form a cyclic group selected from: ^an optionally substituted 3-7 membered saturated or partially unsaturatedcarbocyclyl, and ^an optionally substituted 4-7 membered saturated or partially unsaturatedheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R3is independently selected from hydrogen, C1-C4aliphatic, oxo, C3-C5cycloalkyl, and C1-C4alkoxy, each of which, besides hydrogen or oxo, is optionally substituted with -OH, 1- 5 independently selected halogen, or OR; d is 0, 1, or 2; 37 BUSINESS.33169534.1 407274-95WRWO (217205)d – 1 is 0 or 1; R4is selected from: a) phenyl or a first 5-6 membered heteroaryl (having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur) wherein said phenyl or first 5- 6 membered heteroaryl is substituted with 0-5 RB; and optionally two adjacent atoms of said phenyl or first 5-6 membered heteroaryl have two substituents that together with said adjacent atoms form a cyclic group fused to the phenyl or first 5-6 membered heteroaryl selected from a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or a second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said fused cyclic group is substituted with 0-3 independently selected RB; or b) C1-C4aliphatic, C1-C4alkoxy, or C3-C6cycloalkyl, each of which is substituted with 0-3 groups independently selected from halogen, -CN, -OH, C1-C4alkyl, C1-C4alkoxy, optionally substituted 5-6 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 5-6 membered heterocyclyloxy having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R10is H, C1-C6aliphatic, haloC1-C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, –C(O)C1-C6alkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur); each R10except H being optionally substituted with 1 or 2 independently selected RB; R11is H, C1-C6aliphatic, or C3-C6cycloalkyl, or R10and R11are taken together with the nitrogen atom to which they are attached to form a 5-6 membered ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, -OH, -CN, C1-C4alkoxy, and haloC1-C4alkoxy; R12is C1-C6aliphatic, C3-C6cycloalkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R12optionally 38 BUSINESS.33169534.1 407274-95WRWO (217205)substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1- C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, and C3-C6cycloalkoxy; RBis independently selected at each occurrence from the group consisting of optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogen, optionally substituted C1-C6aliphatic, haloC1- C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, C1-C6alkoxy, haloC1-C6alkoxy, C3- C6cycloalkoxy, haloC3-C6cycloalkoxy, C1-C6alkylene-O-C1-C6alkyl, –CN, –NO2, oxo, –OR, – SR, NR2, S(O)2R, S(O)2NR2, S(O)R, S(O)NR2, C(O)R, C(O)OR, –C(O)NR2, C(O)N(R)OR, OC(O)R, OC(O)NR2, -N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR2, N(R)C(NR)NR2, N(R)S(O)2NR2, and –N(R)S(O)2R; or two RBgroups on the same atom are taken together with the same atom together to form a 3-7 membered carbocyclic ring; RCis independently selected at each occurrence from hydrogen, -CH3, or -CH2CH3, or two RCtaken together with the carbon to which they are attached form a cyclopropyl ring; each R is independently hydrogen, or an optionally substituted C1-6aliphatic group, an optionally substituted phenyl, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or two R groups on the same atom are taken together with the same atom to form a cyclic group selected from an optionally substituted 4-7 membered saturated ring, a 4-7 membered partially unsaturated ring, or a 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said cyclic group has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0063] As described generally above, Y is selected from C(R3)2, O, and NR3. In some embodiments, Y is C(R3)2. In some embodiments, Y is O. In some embodiments, Y is NR3. 39 BUSINESS.33169534.1 407274-95WRWO (217205)

[0064] As described generally above, Q is selected from C(R3)2, O, and NR3. In some embodiments, Q is C(R3)2. In some embodiments, Q is O. In some embodiments, Q is NR3. In some embodiments, only one of Q and Y is O or NR3.

[0065] As described generally above, Ring B is a fused ring selected from 5-6 membered heteroaryl, phenyl, and 5-6 membered partially unsaturated heterocyclyl, said heteroaryl or heterocyclyl containing 1, 2, or 3, heteroatoms independently selected from O, S, N, and NR18; wherein Ring B is substituted with R1aand z instances of R1b. In some embodiments, Ring B is a 5-6 membered heteroaryl containing 1 nitrogen atom. In some embodiments, Ring B is a 5-6 membered heteroaryl containing 2 nitrogen atoms. In some embodiments, Ring B is a 5-6 membered heteroaryl containing 3 nitrogen atoms. In some embodiments, Ring B is pyrazinyl or triazoyl. In some embodiments, Ring B is as selected from one of the substituents of Table 1 or Table 1a.

[0066] As described generally above, R18is H or optionally substituted C1-C6aliphatic. In some embodiments, R18is H. In some embodiments, R18is C1-C6aliphatic. In some embodiments, R18is as selected from one of the substituents of Table 1 or Table 1a.

[0067] In some embodiments, Ring A is a 4-7 membered saturated or partially unsaturated monocyclic carbocyclyl or 4-7 membered saturated or partially unsaturated heterocyclyl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 nitrogen atoms in addition to the 1-4 heteroatoms). In some embodiments, Ring A is a 4-7 membered saturated or partially unsaturated monocyclic carbocyclyl, wherein Ring A is substituted with 0-4 independently selected RBsubstituents. In some embodiments, Ring A is a 4- 7 membered saturated or partially unsaturated monocyclic heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 nitrogen atoms in addition to the 1-4 heteroatoms), wherein Ring A is substituted with 0-4 independently selected RBsubstituents.

[0068] In some embodiments, Ring A is a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Ring A is a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic and is a carbocyclyl, wherein Ring A is substituted with 0-4 40 BUSINESS.33169534.1 407274-95WRWO (217205)independently selected RBsubstituents. In some embodiments, Ring A is a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic and is a heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein Ring A is substituted with 0-4 independently selected RBsubstituents.

[0069] In some embodiments, Ring A is a 4-12 membered saturated or partially unsaturated bicyclic ring system comprising 2 fused rings. In some embodiments, Ring A is a 4-12 membered saturated or partially unsaturated bicyclic ring system comprising a spirocyclic ring system. In some embodiments, Ring A is a 4-12 membered saturated or partially unsaturated bicyclic ring system comprising a bridged ring system. , , ,[ ] n some em o ments, ng , toget er w t an , s .

[0072] In some embodiments, Ring A, together with L and R4, is 41 BUSINESS.33169534.1 407274-95WRWO (217205).

[0073] In some embodiments, Ring4ith L and R , is .

[0074] In some embodiments, Ring, ith L and R4, is .

[0075] In some embodiments, Ring, g ith L and R4, is .

[0076] In some embodiments, RingA, together with L and R4, is .

[0077] In some embodiments, Ring A is as selected from one of the substituents of Table 1 or Table 1a.

[0078] As described generally above, L-R4is selected from -C(O)-R4, -S(O)-R4, -S(O)2-R4, 4. 4.407274-95WRWO (217205)

[0081] In some embodiments, L-R4is -S(O)2-R4.

[0082] In some embodiments L-R4is .

[0083] In some embodimentscted from one of the substituents of Table 1 or Table 1a.

[0084] As described generally above, R1ais selected from: a) a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur) optionally substituted with 1-3 groups independently selected from halogen, C1-C6aliphatic, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkoxy, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RB; b) a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6aliphatic, C3-C6cycloalkyl, C1- C6alkoxy, C3-C6cycloalkoxy, and -OR, wherein said 4-7 membered saturated or partially unsaturated heterocyclyl is further substituted with 0-3 independently selected RB; c) a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused,bridged, or spirocyclic selected from carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected RB; and d) H, halogen, C1-C6aliphatic, C3-C7cycloalkyl, C1-C6alkylene-O-C1-C6alkyl, CN, -OR, -OR10, -NR10R11, -C(O)NR10R11, -CH2NR10R11, -SO2R12, wherein said C1-C6aliphatic, C3-C7cycloalkyl, or C1-C6alkylene-O-C1-C6alkyl is substituted with 0-5 independently selected RB;or R1a and one R1b on adjacent atoms of Ring B, taken together with the adjacent Ring B atoms towhich they are attached, form a cyclic group fused to Ring B selected from phenyl, a 5-6 membered heteroaryl (having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), a 4- 7 membered saturated or partially unsaturated carbocyclyl, or a 4-7 membered saturated or 43 BUSINESS.33169534.1 407274-95WRWO (217205)partially unsaturated heterocyclyl (having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), wherein said cyclic group fused to Ring B is substituted with 0-3 independently selected RB.

[0085] In some embodiments, R1ais a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1 or 2 groups independently selected from C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, and C3-C6cycloalkoxy, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RB. In some embodiments, R1ais a 4-6 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), said heterocyclyl substituted with 0-2 RBgroups independently selected from halogen, oxo, -NR2, optionally substituted C1-4aliphatic, -OR, azetidinyl optionally substituted with 1 or 2 independently selected halogen, and pyrrolidinyl optionally substituted with 1 or 2 independently selected halogen. In some embodiments, R1ais a 6-8 membered saturated or partially unsaturated bridged bicyclic heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), said heterocyclyl substituted with 0-2 RBgroups independently selected from halogen, oxo, -NR2, optionally substituted C1-4aliphatic, -OR, azetidinyl optionally substituted with 1 or 2 independently selected halogen, and pyrrolidinyl optionally substituted with 1 or 2 independently selected halogen. In some embodiments, R1ais a 3-7 membered optionally substituted carbocyclyl. In some embodiments, R1ais an optionally substituted C2-C4alkenyl. In some embodiments, R1ais cyclopropyl substituted C2-C4alkenyl. In some embodiments, R1ais methyl substituted C2-C4alkenyl.

[0086] In some embodiments, R1ais a 6-membered partially unsaturated heterocyclyl (having 1 oxygen atom). In some embodiments, R1ais a 4-8 membered saturated heterocyclyl (having 1 oxygen atom). In some embodiments, R1ais a 6-membered heteroaryl (having 1 nitrogen atom), said heteroaryl may be optionally substituted with 1 or 2 groups independently selected from C1- C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, and C3-C6cycloalkoxy, wherein said heteroaryl is further substituted with 0-1 RB, wherein RBis an optionally substituted C1-6aliphatic group. In some embodiments, R1ais a 6-membered heteroaryl (having 2 nitrogen atoms), said heteroaryl may be optionally substituted with 1 or 2 groups independently selected from C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, and C3-C6cycloalkoxy, wherein said heteroaryl is further substituted with 0-1 RB, wherein RBis an optionally substituted C1-6aliphatic group. In some embodiments, R1ais –NR10R1144 BUSINESS.33169534.1 407274-95WRWO (217205)wherein R10is a 5-6 membered heteroaryl (having 1 or 2 nitrogen atoms) optionally substituted with 1 or 2 groups independently selected from halogen, CH3, OCH3, C3-C6cycloalkyl, and C3- C6cycloalkoxy and wherein R11is H or CH3. In some embodiments, R1ais –CH2NR10R11wherein R10is a 5-6 membered heteroaryl (having 1 or 2 nitrogen atoms) optionally substituted with 1 or 2 groups independently selected from halogen, CH3, OCH3, C3-C6cycloalkyl, and C3-C6cycloalkoxy and wherein R11is H or CH3. In some embodiments, R1ais C2-C4alkene wherein said alkene is optionally substituted with OCH3or 1, 2, or 3 fluorine. In some embodiments, R1ais C2-C4alkyne wherein said alkyne is optionally substituted with OCH3 or 1, 2, or 3 fluorine. In some embodiments, R1ais –SO2R12wherein R12is selected from CH3 or a 5-6 membered heteroaryl having 1-2 nitrogen heteroatoms optionally substituted with 1 or 2 groups independently selected from halogen and CH3. In some embodiments, R1ais cyclopropyl optionally substituted with 1-2 fluorine. In some embodiments, R1ais C1-C6alkyl optionally substituted with OH or 1-2 fluorine. In some embodiments, R1ais –C(O)NR10R11wherein R10is H or CH3 and wherein R11is H or CH3.

[0087] In some embodiments, R1ais a 5-membered heteroaryl (having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1 or 2 groups independently selected from C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, and C3-C6cycloalkoxy, wherein said 5-membered heteroaryl is optionally further substituted with 0-3 independently selected RB. In some embodiments, R1ais a 5-membered heteroaryl (having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1 or 2 groups independently selected from C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, and C3-C6cycloalkoxy. In some embodiments, R1ais a 5-membered heteroaryl (having 2 nitrogen atoms) optionally substituted with 1 or 2 groups independently selected from C1-C6alkyl, C1-C6alkoxy, C3- C6cycloalkyl, and C3-C6cycloalkoxy, wherein said 5-membered heteroaryl is optionally further substituted with 0-1 RB, wherein RBis hydroxyl substituted C1-C4alkyl.

[0088] In some embodiments, R1ais a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with one group of C1-C6alkoxy or C3-C6cycloalkyl, wherein said 5-6 membered heteroaryl is optionally further substituted with 0-3 independently selected RB.

[0089] In some embodiments, R1ais pyridyl substituted with C1-C4alkoxy and further substituted with 0-2 RB. 45 BUSINESS.33169534.1 407274-95WRWO (217205)

[0090] In some embodiments, R1ais 5-membered heteroaryl (having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 additional ring nitrogen atoms), wherein said 5-membered heteroaryl is optionally substituted with C1-C6alkyl, or C3- C5cycloalkyl and further substituted with 0-2 RB.

[0091] In some embodiments, R1ais selected from groups a)-d): a) a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur) optionally substituted with 1 or 2 groups independently selected from C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, and C3-C6cycloalkoxy, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RB; b) a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, C3-C6cycloalkoxy, and -OR, wherein said 4-7 membered saturated or partially unsaturated heterocyclyl is further substituted with 0-3 independently selected RB; c) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that isfused, bridged, or spirocyclic selected from carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), said carbocyclyl or heterocyclyle is substituted with 0-3 independently selected RB; and d) H, halogen, C1-C6alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C7cycloalkyl, C1-C6alkyl-O-C1-C6alkyl, CN, -OR, -NR10R11, -C(O)NR10R11,-CH2NR10R11, -SO2R12, wherein C1- C6alkyl, C2-C4 alkenyl, C2-C4alkynyl, C3-C7cycloalkyl, or C1-C6alkylene-O-C1-C6alkyl may be substituted with 0-5 independently selected RB.

[0092] In some embodiments, R1ais a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, and C3-C6cycloalkoxy, and -OR, wherein said 4-7 membered saturated or partially unsaturated heterocyclyl is further substituted with 0-3 independently selected RB. 46 BUSINESS.33169534.1 407274-95WRWO (217205)

[0093] In some embodiments, R1ais a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1 or 2 groups independently selected from C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, and C3-C6cycloalkoxy, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RB.

[0094] In some embodiments, R1ais selected from the group consisting of: where.

[0095] In some embodiments, R1ais ,7205), , , , ,05),or[ ] n some emo ments, s 49 BUSINESS.33169534.1 407274-95WRWO (217205), , , ,

[0101] In some embodiments, Rais 50 BUSINESS.33169534.1 407274-95WRWO (217205)

[0103] In some embodiments R1ais

[0104] In some embodiments

[0105] In some embodiments R1ai

[0106] In some embodiments, s se ected from one of the substituents of Table 1 or Table 1a.

[0107] As described generally above, each R1bis independently selected from H, halogen, CN, OH, C1-C6aliphatic, C1-C6alkoxy, C3-C6cycloalkyl, C1-C6alkylene-O-C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and C3-C6cycloalkoxy, wherein said C1-C6aliphatic, C1-C6alkoxy, C3- C6cycloalkyl, C1-C6alkylene-O-C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and C3- C6cycloalkoxy are each independently and optionally substituted with 1-5 halogen, OH, CN, C1- C6alkyl, or C3-C6cycloalkyl groups.

[0108] In some embodiments, R1a and one R1b on adjacent atoms of Ring B, taken togetherwith the adjacent Ring B atoms to which they are attached, form a cyclic group fused to Ring B selected from phenyl, a 5-6 membered heteroaryl (having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), a 4-7 membered saturated or partially unsaturated carbocyclyl, or a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-3 heteroatoms 51 BUSINESS.33169534.1 407274-95WRWO (217205)independently selected from nitrogen, oxygen and sulfur), wherein said cyclic group fused to Ring B is substituted with 0-3 independently selected RB. In some embodiments, R1bis selected from one of the substituents of Table 1 or Table 1a.

[0109] As described generally above, R2is is selected from C(RC)2C(O)N(R)R2A, C(RC)2C(RC)2C(O)N(R)R2A, C(RC)2C(RC)2N(R)C(O) N(R)R2A, and C(RC)2C(RC)2N(R)C(O)R2A. In some embodiments, R2is C(RC)2C(O)N(R)R2A. In some embodiments, R2is C(RC)2C(RC)2C(O)N(R)R2A. In some embodiments, R2is C(RC)2C(RC)2N(R)C(O)N(R)R2A. In some embodiments, R2is C(RC)2C(RC)2N(R)C(O)R2A. In some embodiments, R2is CH2C(O)N(H)R2A. In some embodiments, R2is CH2CH2C(O)N(H)R2A. In some embodiments, R2is CH2CH2N(R)C(O)N(R)R2A. In some embodiments, R2is CH2CH2N(H)C(O)R2A. In someembodiments, R2 is C(RC)2C(O)N(H)R2A, wherein R2A is phenyl or is bicyclo[1.1.1]pentyloptionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4alkyl, or haloC1-C4alkyl. In some embodiments, R2is C(RC)2C(O)N(H)R2A, wherein R2Ais bicyclo[1.1.1]pentyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4alkyl, or haloC1-C4alkyl.

[0110] In some embodiments, R2is205),205)

[0113] In some embodiment .

[0114] In some embodiment .

[0115] In some embodiment .

[0116] In some embodimentone of the substituents of Table 1 or Table 1a.

[0117] As described generally above, R2Ais phenyl, pyridyl, cubanyl, a saturated or partially unsaturated 4-8 membered monocyclic ring, a saturated or partially unsaturated bridged, fused or spirocyclic 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, wherein said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring comprises 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said phenyl, pyridyl, cubanyl, saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring are each optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4aliphatic, haloC1-C4alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, C3-C6-cycloalkoxy, haloC4-C6cyclalkoxy and –SF5, and wherein two optional substituents on the same atom of said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring form a cyclic group selected from: ^an optionally substituted 3-7 membered saturated or partially unsaturatedcarbocyclyl, and ^an optionally substituted 4-7 membered saturated or partially unsaturatedheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 54 BUSINESS.33169534.1 407274-95WRWO (217205)

[0118] In some embodiments, there are 1-6 respective instances of wherein 2 substituents on the same 1st, 2nd, 3rd, 4th, 5th, or 6thatom of said saturated or partially unsaturated monocyclic ring, or said saturated or partially unsaturated bridged, fused, or spirocyclic ring form 1-6 of said cyclic groups. In some embodiments, there is one instance wherein 2 substituents on the same atom of said saturated or partially unsaturated monocyclic ring, or said saturated or partially unsaturated bridged, fused, or spirocyclic ring form one of said cyclic groups. In some embodiments, there 2 respective instances of wherein 2 substituents on the same 1stand 2ndatoms of said saturated or partially unsaturated monocyclic ring, or said saturated or partially unsaturated bridged, fused, or spirocyclic ring form both of said cyclic groups. In some embodiments, there are 3 respective instances of wherein 2 substituents on the same 1st, 2nd, and 3rd, atoms of said saturated or partially unsaturated monocyclic ring, or said saturated or partially unsaturated bridged, fused, or spirocyclic ring form the three of said cyclic groups. In some embodiments, there are 4 respective instances of wherein 2 substituents on the same 1st, 2nd, 3rd, and 4thatoms of said saturated or partially unsaturated monocyclic ring, or said saturated or partially unsaturated bridged, fused, or spirocyclic ring form the four of said cyclic groups. In some embodiments, there are 5 respective instances of wherein 2 substituents on the same 1st, 2nd, 3rd, 4thand 5thatoms of said saturated or partially unsaturated monocyclic ring, or said saturated or partially unsaturated bridged, fused, or spirocyclic ring form the five of said cyclic groups. In some embodiments, there 6 respective instances of wherein 2 substituents on the same 1st, 2nd, 3rd, 4th5th, and 6thatoms of said saturated or partially unsaturated monocyclic ring, or said saturated or partially unsaturated bridged, fused, or spirocyclic ring form the six of said cyclic groups.

[0119] In some embodiments, R2Ais phenyl, pyridyl, cubanyl, a saturated or partially unsaturated 4-8 membered monocyclic ring, a saturated or partially unsaturated bridged, fused or spirocyclic 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, wherein said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring which comprises 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring are each optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4alkyl, haloC1-C4alkyl, C3-C6cycloalkyl, haloC3-C6- cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, C3-C6cycloalkoxy, haloC4-C6cyclalkoxy 55 BUSINESS.33169534.1 407274-95WRWO (217205)and –SF5. In some embodiments, R2Ais bicyclo[1.1.1]pentyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4alkyl, and haloC1-C4alkyl.

[0120] In some embodiments, R2Ais a saturated or partially unsaturated bridged 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, which comprises 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said bridged ring is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4alkyl, haloC1-C4alkyl, C3- C6cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, C3-C6cycloalkoxy, haloC4-C6cyclalkoxy and –SF5.

[0121] In some embodiments, R2Ais a saturated or partially unsaturated fused 5-, 6-, 7-, 8-, 9, 10-, 11-, or 12-membered ring, which comprises 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said fused ring is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4alkyl, haloC1-C4alkyl, C3-C6- cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, C3-C6cycloalkoxy, haloC4-C6cyclalkoxy and –SF5.

[0122] In some embodiments, R2Ais a saturated or partially unsaturated spirocyclic 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, which comprises 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said spirocyclic ring is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4alkyl, haloC1- C4alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, C3-C6- cycloalkoxy, haloC4-C6cyclalkoxy and –SF5.

[0123] In some embodiments, R2Ais bicyclo[1.1.1]pentyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4alkyl, haloC1-C4alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, C3-C6cycloalkoxy, haloC4-C6- cyclalkoxy and –SF5. In some embodiments, R2Ais bicyclo[1.1.1]pentyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4alkyl, and haloC1-C4alkyl. In some embodiments, R2Ais bicyclo[1.1.1]pentyl optionally substituted with a halogen, C1- C4alkyl, or haloC1-C4alkyl. In some embodiments, R2Ais bicyclo[1.1.1]pentyl optionally substituted with 2 substituents independently selected from halogen, C1-C4alkyl, and haloC1- C4alkyl. In some embodiments, R2Ais bicyclo[1.1.1]pentyl optionally substituted with 3 substituents independently selected from halogen, C1-C4alkyl, and haloC1-C4alkyl. 56 BUSINESS.33169534.1 407274-95WRWO (217205)

[0124] In some embodiments, R2Ais Ring F selected from the group consisting of: , wherein x, y, and q are independently selected from O, N15 15 15 15 2AR , CHR or CR R , wherein R comprises 0, 1, 2, or 3, instances of R15independently selected from H, halogen, C1-C4aliphatic, haloC1-C4alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, C3-C6cycloalkoxy, haloC4-C6cyclalkoxy and –SF5.

[0125] In some embodiments, R2Ais Ring F of the following structu , wherein R15is selected from halogen, C1-C4aliphatic, haloC1-C4alkyl, C3-CoC3- C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, C3-C6cycloalkoxy, haloC4-C6cyclalkoxy and –SF5.

[0126] In some embodiments, R2Ais bicyclo[1.1.1]pentyl comprising a -CF3 substituent or bicyclo[1.1.1]pentyl comprising a -CHF2 substituent.

[0127] In some embodiments, R2Ais as selected from one of the substituents of Table 1 or Table 1a.

[0128] As described generally above, R3is independently selected from hydrogen, oxo C1- C4alkyl, C3-C5cycloalkyl, C1-C4alkoxy, each of which, besides hydrogen, is optionally substituted with -OH, 1-5 independently selected halogen, -OR

[0129] In some embodiments, R3is hydrogen. In some embodiments, R3is oxo. In some embodiments, R3is C1-C4alkyl optionally substituted with -OH, 1-5 independently selected halogen, or C1-C4alkoxy. In some embodiments, R3is C1-C4alkyl. In some embodiments, R3is - CH2CH3. In some embodiments, R3is -CH3. In some embodiments, R3is C3-C5cycloalkyl, C1- 57 BUSINESS.33169534.1 407274-95WRWO (217205)C4alkoxy optionally substituted with -OH, 1-5 independently selected halogen, or C1-C4alkoxy. In some embodiments, R3is C3-C5cycloalkyl optionally substituted with -OH, 1-5 independently selected halogen, or C1-C4alkoxy. In some embodiments, R3is C1-C4alkoxy optionally substituted with -OH, 1-5 independently selected halogen, or C1-C4alkoxy. In some embodiments, R3is selected from the group consisting of C1-C4alkyl and C3-C5cycloalkyl.

[0130] In some embodiments, R3is as selected from one of the substituents of Table 1 or Table 1a.

[0131] In some embodiments, R4is selected from one of a), b), and c): a) R4 is a Ring E that is selected from the group consisting of:and wherein is a point of attachment to L; and any substituents that are present on Ring E selected from R4A, R4B, R4C, R4D, R4E, and R4Fare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; C1-C4alkoxy; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3- C6cycloalkoxy; and NR13R14; or R4Aand R4B, along with their intervening atoms, join to form 4-7 membered carbocyclyl substituted with 0-3 independently selected RB, a 4-7 membered heterocyclyl substituted with 0-3 independently selected RB, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; 58 BUSINESS.33169534.1 407274-95WRWO (217205)and any substituents that are present on Ring E selected from R4C, R4D, R4E, and R4Fare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2- C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; or R4Band R4C, along with their intervening atoms, join to form a 4-7 membered carbocyclyl substituted with 0-3 independently selected RB, a 4-7 membered heterocyclyl substituted with 0-3 independently selected RB, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and any substituents that are present on Ring E selected from R4A, R4D, R4E, and R4Fare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2- C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; or R4C and R4D, along with their intervening atoms, join to form a 4-7 memberedcarbocyclyl substituted with 0-3 independently selected RB, a 4-7 membered heterocyclyl substituted with 0-3 independently selected RB, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and any substituents that are present on Ring E selected from R4A, R4B, R4Eand R4Fare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2- C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; or R4Eis halogen or -OH, and R4A, R4B, R4C, and R4Dare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1- C4alkyl; C1-C3alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; or 59 BUSINESS.33169534.1 407274-95WRWO (217205)R4Eand R4A, along with their intervening atoms, join to form a 5-6 membered optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and R4B, R4C, and R4Dare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3- C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; or R4Fand R4A, along with their intervening atoms, join to form a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and R4Band R4Care each independently selected from hydrogen; halogen; -CN; C1- C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3- C6cycloalkoxy; and NR13R14; R13is independently selected at each occurrence from hydrogen and C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; and R14is hydrogen, or R13and R14combine with the nitrogen atom to which they are attached to form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl, said heterocyclic ring optionally substituted with -CH3; or b) R4 is a 5-membered heteroaryl (having 1 heteroatom independently selected fromnitrogen, oxygen, and sulfur and 0, 1, 2, or 3 additional ring nitrogen atoms), wherein said heteroaryl is substituted with 0-4 groups independently selected from halogen, - OH, -CN, C1-C4alkyl, haloC1-C4alkyl, C3-C6cycloalkyl, and C1-C4alkoxy; and c) R4 is a C1-C4alkyl, C1-C4alkoxy, or C3-C6cycloalkyl, each of which is substituted with0-3 groups independently selected from halogen, -CN, -OH, C1-C4alkyl, C1-C4alkoxy, optionally substituted 5-6 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 5- 6 membered heterocyclyloxy having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 60 BUSINESS.33169534.1 407274-95WRWO (217205)

[0132] In some embodiments, R4is Ring E of the following structure: wherein * is a point of attachment to linded to Ring A; and wherein: R4A, R4C, and R4Dare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3- C6cycloalkoxy; and NR13R14; or R4Cand R4D, along with their intervening atoms, join to form 4-7 membered carbocyclyl ) substituted with 0-3 independently selected RB, a 4-7 membered heterocyclyl substituted with 0-3 independently selected RB, or 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB, that is fused to Ring E; and R4Ais hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1- C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; and R13is independently selected at each occurrence from hydrogen and C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; and NR13R14, taken in combination form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, said heterocyclic ring optionally substituted with -CH3. R14is hydrogen, or R13and R14combine with the nitrogen atom to which they are attached to form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, said heterocyclic ring optionally substituted with -CH3.

[0133] In some embodiments, R4is Ring E of the following structure: 61 BUSINESS.33169534.1 407274-95WRWO (217205)wherein * is a point of attachment to linnded to Ring A; and wherein: R4Ais -OCH3, -OCH2CH3, or -OCHF2; R4Cand R4Dare each independently selected from hydrogen; -CN; C1-C4alkyl; C2- C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, -OCH3, or - OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; and R13is independently selected at each occurrence from hydrogen or C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; or NR13R14, taken in combination form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, said heterocyclic ring optionally substituted with -CH3; R14is hydrogen, or R13and R14combine with the nitrogen atom to which they are attached to form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, said heterocyclic ring optionally substituted with -CH3. or R4is a 5-membered heteroaryl (having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur and 0, 1, 2, or 3 additional ring nitrogen atoms), wherein said heteroaryl is substituted with 0-4 substituents independently selected from halogen, -OH, -CN, C1-C4alkyl, haloC1-C4alkyl, C3-C6cycloalkyl, and C1-C4alkoxy.

[0134] In some embodiments, R4is Ring E of the following structure:wherein * is a point of attachment to linker L that is bonded to Ring A; 62 BUSINESS.33169534.1 407274-95WRWO (217205)and wherein: R4Ais -OCH3, -OCH2CH3, or -OCHF2; R4Cand R4Dare each independently selected from hydrogen; -CN; C1-C4alkyl; C2- C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, -OCH3, or - OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; and R13is independently selected at each occurrence from hydrogen or C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; or NR13R14, taken in combination form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, said heterocyclic ring optionally substituted with -CH3; and R14is hydrogen.

[0135] In some embodiments, R4is Ring E of the following structure: wherein * is a point of attachment to linnded to Ring A; and wherein: R4A, R4C, and R4Dare each independently selected from hydrogen; halogen; and C1- C4alkyl.

[0136] In some embodiments, R4is Ring E of the following structure:wherein * is a point of attachment to linker L that is bonded to Ring A; and wherein: 63 BUSINESS.33169534.1 407274-95WRWO (217205)R4A, R4B, and R4Care each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; C1-C4alkoxy; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, - OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; or R4Aand R4B, along with their intervening atoms, join to form 4-7 membered carbocyclyl or heterocyclyl or 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring E; and R4Cis hydrogen; halogen; -CN; C1- C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, - OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; or NR13R14; or R4Band R4C, along with their intervening atoms, join to form a 4-7 membered carbocyclyl substituted with 0-3 independently selected RB, a 4-7 membered heterocyclyl substituted with 0-3 independently selected RB, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and R4Ais selected from hydrogen; halogen; -CN; C1- C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, - OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; and R13is independently selected at each occurrence from hydrogen or C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; or NR13R14, taken in combination form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, said heterocyclic ring optionally substituted with -CH3; and R14is hydrogen.

[0137] In some embodiments, R4is Ring E of the following structure:wherein * is a point of attachment to linker L that is bonded to Ring A; and wherein: 64 BUSINESS.33169534.1 407274-95WRWO (217205)R4A and R4B, along with their intervening atoms, join to form 4-7 membered carbocyclyl, 4-7membered heterocyclyl, or 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring E; and R4Cis hydrogen.

[0138] In some embodiments, R4is Ring E of the following structure: wherein * is a point of attachment to linnded to Ring A; and wherein: R4Aand R4B, along with their intervening atoms, join to form 5-membered heterocyclyl (having 1 oxygen atom) that is fused to Ring E; and R4Cis hydrogen.

[0139] In some embodiments, R4is Ring E of the following structure: wherein * is a point of attachment linker L that is bonded to Ring A; and wherein: R4A, R4B, and R4Dare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; C1-C4alkoxy; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, - OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; or R4Aand R4B, along with their intervening atoms, join to form a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl, a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring E; and R4Dis hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C3alkyl 65 BUSINESS.33169534.1 407274-95WRWO (217205)substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3- C6cycloalkoxy; or NR13R14; and R13is independently selected at each occurrence from hydrogen or C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; or NR13R14, taken in combination form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, said heterocyclic ring optionally substituted with -CH3; and R14is H.

[0140] In some embodiments, R4is Ring E of the following structure: wherein * is a point of attachment to linded to Ring A; and wherein: R4Aand R4Dare each hydrogen; and R4Bis C1-C4alkyl.

[0141] In some embodiments, R4is Ring E of the following structure: wherein * is a point of attachment linker L that is bonded to Ring A; and wherein: R4Aand R4Care each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2- C4alkenyl; C2-C4alkynyl; C1-C4alkoxy; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, - OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; and 66 BUSINESS.33169534.1 407274-95WRWO (217205)R13is independently selected at each occurrence from hydrogen or C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; or NR13R14, taken in combination form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, said heterocyclic ring optionally substituted with -CH3; and R14is H.

[0142] In some embodiments, R4is Ring E of the following structure: wherein * is a point of attachment to linnded to Ring A; and wherein: R4Aand R4Care each independently selected from hydrogen and C1-C4alkyl.

[0143] In some embodiments, R4is Ring E of the following structure: wherein * is a point of attachment to liner t at s bonded to Ring A; and wherein: R4A, R4B, R4C, R4D, and R4Eare each independently selected from hydrogen; halogen; -CN; C1- C4alkyl; C2-C4alkenyl; C2-C4alkynyl; C1-C4alkoxy; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; or R4Aand R4B, along with their intervening atoms, join to form 4-7 membered carbocyclyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring E; and R4C, R4D, and R4Eare 67 BUSINESS.33169534.1 407274-95WRWO (217205)each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2- C4alkynyl; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1- C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; or R4Cand R4D, along with their intervening atoms, join to form 4-7 membered carbocyclyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring E; and R4A, R4B, and R4Eare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2- C4alkynyl; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1- C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; or R4Eis halogen or -OH, and R4A, R4B, R4C, and R4Dare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3- C6cycloalkoxy; and NR13R14; or R4Eand R4A, along with their intervening atoms, join to form 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused to Ring E; and R4B, R4C, and R4Dare each independently selected from hydrogen; halogen; -CN; C1- C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, - OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; and R13is independently selected at each occurrence from hydrogen or C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; or NR13R14, taken in combination form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, said heterocyclic ring optionally substituted with -CH3; and R14is H.

[0144] In some embodiments, R4is Ring E of the following structure: BUSINESS.33169534.1407274-95WRWO (217205)wherein * is a point of attachment to linker L that is bonded to Ring A; and wherein: R4A, R4B, R4C, R4D, and R4Eare each independently selected from hydrogen; halogen; C1- C4alkyl; and C1-C4alkoxy; or R4C and R4D, along with their intervening atoms, join to form a 4-7 membered heterocyclyl(having 1-3 nitrogen atoms) fused to Ring E; and R4A, R4B, and R4Eare each hydrogen.

[0145] In some embodiments, R4is Ring E of the following structure: wherein * is a point of attachment to linded to Ring A; and wherein: R4Fand R4A, along with their intervening atoms, join to form 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused to Ring E; and R4Band R4Care each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, -OCH3, or - OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; R13is independently selected at each occurrence from hydrogen or C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; or NR13R14, taken in combination form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, said heterocyclic ring optionally substituted with -CH3; and R14is H.

[0146] In some embodiments, R4is Ring E of the following structure: 69 BUSINESS.33169534.1 407274-95WRWO (217205)wherein * is a point of attachment to linnded to Ring A; and wherein: R4Fand R4A, along with their intervening atoms, join to form 5-6 membered heteroaryl (having 1-2 nitrogen atoms) fused to Ring E; and R4Band R4Care each hydrogen.

[0147] In some embodiments, R4is a 5-membered heteroaryl (having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur and 0, 1, 2, or 3 additional ring nitrogen atoms), wherein said heteroaryl is substituted with 0-4 groups independently selected from halogen, -OH, -CN, C1-C4alkyl, haloC1-C4alkyl, C3-C6cycloalkyl, and C1-C4alkoxy.

[0148] In some embodiments, R4is a 5-membered heteroaryl (having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur and 0, 1, 2, or 3 additional ring nitrogen atoms), wherein said heteroaryl is substituted with 0-4 groups independently selected from OH, - CH3, -CHF2, cyclopropyl, and -OCH3.

[0149] In some embodiments, R4is a C1-C4alkyl, C1-C4alkoxy, or C3-C6cycloalkyl, each of which is substituted with 0-3 groups independently selected from halogen, -CN, -OH, C1-C4alkyl, C1-C4alkoxy, optionally substituted 5-6 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 5-6 membered heterocyclyloxy having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R4is a C1-C4alkyl, substituted with 0-3 independently selected halogen, -CN, -OH, C1-C4alkyl, and C1-C4alkoxy. In some embodiments, R4is a C1-C4alkoxy, substituted with 0-3 independently selected halogen, -CN, -OH, C1-C4alkyl, and C1-C4alkoxy. In some embodiments, R4is a C3-C6cycloalkyl, substituted with 0-3 independently selected halogen, -CN, -OH, C1-C4alkyl, and C1-C4alkoxy.

[0150] In some embodiments, R4is an isoxazolyl substituted with -OH or C1-C4alkoxy.

[0151] In some embodiments, R4is a 5-membered heteroaryl (having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur and 0, 1, 2, or 3 additional ring nitrogen 70 BUSINESS.33169534.1 407274-95WRWO (217205)atoms) selected from the group consisting of thiophenyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, oxazolyl, isoxazolyl, 1,2,4- oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, wherein said heteroaryl is optionally substituted with 0-4 groups independently selected from halogen, -OH, -CN, C1-C4alkyl, haloC1-C4alkyl, C3- C6cycloalkyl, and C1-C4alkoxy.

[0152] In some embodiments, R4is selected from the group consisting of: wherein *X is CH, CR7, or N; R5is -OH or halogen; R6is halogen, C1-4alkyl, or C1-4alkoxy; each R7is independently hydrogen, halogen, C1-4alkyl, or C1-4alkoxy; R8is C1-4alkyl; each of the 0-2 instances of R9is independently a hydrogen or C1-4alkyl. In some embodiments: X is CH or N; R5is -OH or fluoro; R6is fluoro, -CH3, or -OCH3; each R7is independently hydrogen, fluoro, -CH3, or -OCH3; R8is -CH3; each instance of R9is independently a hydrogen or -CH3.

[0153] In some embodiments, R4is 71 BUSINESS.33169534.1 407274-95WRWO (217205), , , , , , , , , , , , , , , , , , ,72 BUSINESS.33169534.1 407274-95WRWO (217205)oror73 BUSINESS.33169534.1 407274-95WRWO (217205)or,

[0157] As described generally above, R10is H, C1-C6aliphatic, haloC1-C6alkyl, C3- C6cycloalkyl, haloC3-C6cycloalkyl, –C(O)C1-C6alkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R10except H being optionally substituted with 1 or 2 independently selected RB.

[0158] In some embodiments, R10is H. In some embodiments, R10is C1-C6aliphatic, haloC1- C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, –C(O)C1-C6alkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R10being optionally substituted with 1 or 2 independently selected RB. In some embodiments, R10is C1- C6aliphatic, haloC1-C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, or –C(O)C1-C6alkyl; each R10being optionally substituted with 1 or 2 independently selected RB. In some embodiments, R10is a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); R10being optionally substituted with 1 or 2 independently selected RB.

[0159] In some embodiments, R10is as shown in a substituent of Table 1 or Table 1a.

[0160] As described generally above, R11is H, C1-C6aliphatic, or C3-C6cycloalkyl, or R10and R11are taken together with the nitrogen atom to which they are attached to form a 5-6 membered ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, -OH, -CN, C1-C4alkoxy, and haloC1-C4alkoxy.

[0161] In some embodiments, R11is H, C1-C6aliphatic, or C3-C6cycloalkyl. In some embodiments, R11is H. In some embodiments, R11is C1-C6aliphatic. In some embodiments, R11is C3-C6cycloalkyl. In some embodiments, R10and R11are taken together with the nitrogen atom to 74 BUSINESS.33169534.1 407274-95WRWO (217205)which they are attached to form a 5-6 membered ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, -OH, -CN, C1-C4alkoxy, and haloC1-C4alkoxy.

[0162] In some embodiments, R11is as shown in a substituent of Table 1 or Table 1a.

[0163] As described generally above, R12is C1-C6aliphatic, C3-C6cycloalkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R12optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, and C3-C6cycloalkoxy.

[0164] In some embodiments, R12is C1-C6aliphatic optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1-C6alkyl, C1-C6alkoxy, C3- C6cycloalkyl, and C3-C6cycloalkoxy. In some embodiments, R12is C1-C6aliphatic optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1- C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, and C3-C6cycloalkoxy. In some embodiments, R12is C3- C6cycloalkyl optionally substituted with 1 or 2 groups independently selected from halogen, C1- C6aliphatic, haloC1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, and C3-C6cycloalkoxy. In some embodiments, R12is a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, and C3- C6cycloalkoxy.

[0165] In some embodiments, R12is as shown in a substituent of Table 1 or Table 1a.

[0166] As described generally above, RBis independently selected at each occurrence from the group consisting of optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogen, optionally substituted C1-C6aliphatic, haloC1-C6alkyl, C3-C6cycloalkyl, halo-C3-C6cycloalkyl, C1-C6alkoxy, halo-C1-C6alkoxy, C3-C6cycloalkoxy, halo-C3-C6cycloalkoxy, C1-C6alkylene-O-C1-C6alkyl, – CN, –NO2, oxo, –OR, –SR, NR2, S(O)2R, S(O)2NR2, S(O)R, S(O)NR2, C(O)R, C(O)OR, – C(O)NR2, C(O)N(R)OR, OC(O)R, OC(O)NR2, -N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR2, N(R)C(NR)NR2, N(R)S(O)2NR2, and –N(R)S(O)2R. 75 BUSINESS.33169534.1 407274-95WRWO (217205)

[0167] In some embodiments, RBis independently selected at each occurrence from the group consisting of halogen, -OR, or an optionally substituted C1-6aliphatic group. In some embodiments, RBis independently selected at each occurrence from a halogen. In some embodiments, RBis independently selected at each occurrence from -OR. In some embodiments, RBis independently selected at each occurrence from an optionally substituted C1-6aliphatic group.

[0168] In some embodiments, RBis as selected from one of the substituents of Table 1 or Table 1a.

[0169] As described generally above, RCis independently selected at each occurrence from hydrogen, -CH3, and -CH2CH3, or two RCtaken together with the carbon to which they are attached form a cyclopropyl ring. In some embodiments, RCis independently selected at each occurrence from hydrogen, -CH3, and -CH2CH3. In some embodiments, RCis hydrogen. In some embodiments, one RCis -CH3, and the other RCis hydrogen. In some embodiments, two RCtaken together with the carbon to which they are attached form a cyclopropyl ring.

[0170] In some embodiments, RCis as selected from one of the substituents of Table 1 or Table 1a.

[0171] As described generally above, each R is independently hydrogen, or an optionally substituted C1-6aliphatic group, an optionally substituted phenyl, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or two R groups on the same atom are taken together with the same atom to form a cyclic group selected from an optionally substituted 4-7 membered saturated ring, a 4-7 membered partially unsaturated ring, or a 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said cyclic group has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0172] In some embodiments, each R is hydrogen. In some embodiments, each R is independently an optionally substituted C1-6aliphatic group, an optionally substituted phenyl, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 76 BUSINESS.33169534.1 407274-95WRWO (217205)1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0173] In some embodiments, two R groups on the same atom are taken together with the same atom to form a cyclic group selected from an optionally substituted 4-7 membered saturated ring, a 4-7 membered partially unsaturated ring, or a 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said cyclic group has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, each R is independently hydrogen or a C1-6 alkyl.

[0174] In some embodiments, each R is as selected from one or more of the substituents of a compound of Table 1 or Table 1a.

[0175] As described generally above, z is 0, 1, or 2. In some embodiments, z is 0. In some embodiments, z is 1. In some embodiments, z is 2.

[0176] As described generally above, d is 0, 1, or 2. In some embodiments, d is 0. In some embodiments, d is 1. In some embodiments, d is 2. As used herein “d – 1” is 0 or 1. In some embodiments, “d – 1” is 0. In some embodiments, “d – 1” is 1.

[0177] In some embodiments, the compound is of any one of Formula II-a to Formula II-y:77 BUSINESS.33169534.1 407274-95WRWO (217205)BUSINESS.35WRWO (217205)O R4N to 4BUSINESS.35WRWO (217205); or a pharmaceutically acceptable salt thereof.

[0178] In some embodiments, the compound is a compound of Formula II-a’ to Formula II- y’: 80 BUSINESS.33169534.1 407274-95WRWO (217205), , ,81 BUSINESS.33169534.1 407274-95WRWO (217205), , ,82 BUSINESS.33169534.1 407274-95WRWO (217205),,or a pharmaceutically acceptable salt thereof; wherein R1a, R1b, R2, R3, d, z, and R4, are as defined herein, both singly and in combination.

[0179] In some embodiments, the compound is a compound of Formula II-a to Formula II-y; or a pharmaceutically acceptable salt thereof. 83 BUSINESS.33169534.1 407274-95WRWO (217205)wherein R1a, R1b, R2, R3, d, z, and R4, are as defined herein, both singly and in combination, and 2,or a pharmaceutically acceptable salt thereof; wherein R1a, R1b, R2, R3, d, z, and R4, are as defined herein, both singly and in combination and and

[0181] In some embodiments, the compound is a compound of Formula II-b: 84 BUSINESS.33169534.1 407274-95WRWO (217205),y le salt thereof; wherein R1a, R1b, R2, R3, d, z, and R4, are as defined herein, both singly and in combination and R2ais selected from and. -c:or a pharmaceutically acceptable salt thereof; wherein R1a, R1b, R2, R3, d, z, and R4, are as defined herein, both singly and in combination and and05)

[0183] In some embodiments, the compound is a compound of Formula II-d:, or a pharmaceutically acceptable salt thereof; wherein R1a, R1b, R2, R3, d, z, and R4, are as defined herein, both singly and in combination and and-e:or a pharmaceutically acceptable salt thereof; 86 BUSINESS.33169534.1 407274-95WRWO (217205)wherein R1a, R1b, R2, R3, d, z, and R4, are as defined herein, both singly and in combination and R2ais selected from and .I-f:or a pharmaceutically acceptable salt thereof; wherein R1a, R1b, R2, R3, d, z, and R4, are as defined herein, both singly and in combination and and-g:or a pharmaceutically acceptable salt thereof; 87 BUSINESS.33169534.1 407274-95WRWO (217205)wherein R1a, R1b, R2, R3, d, z, and R4, are as defined herein, both singly and in combination and R2ais selected from and .-h:or a pharmaceutically acceptable salt thereof; wherein R1a, R1b, R2, R3, d, z, and R4, are as defined herein, both singly and in combination and andI-i:88 BUSINESS.33169534.1 407274-95WRWO (217205)or a pharmaceutically acceptable salt thereof; wherein R1a, R1b, R2, R3, d, z, and R4, are as defined herein, both singly and in combination and R2ais selected from and .I-j:or a p armaceutca y acceptab e sa t t ereo ; wherein R1a, R1b, R2, R3, d, z, and R4, are as defined herein, both singly and in combination and and

[0190] In some embodiments, the compound is a compound of Formula II-k: 89 BUSINESS.33169534.1 407274-95WRWO (217205),ble salt thereof; wherein R1a, R1b, R2, R3, d, z, and R4, are as defined herein, both singly and in combination and andI-l:or a pharmaceutically acceptable salt thereof; wherein R1a, R1b, R2, R3, d, z, and R4, are as defined herein, both singly and in combination and and

[0192] In some embodiments, the compound is a compound of Formula II-m: 90 BUSINESS.33169534.1 407274-95WRWO (217205),or a pharmaceutically acceptable salt thereof; wherein R1a, R1b, R2, R3, d, z, and R4, are as defined herein, both singly and in combination and and-n:or a pharmaceutically acceptable salt thereof; wherein R1a, R2, R3, d, and R4, are as defined herein, both singly and in combination and R2ais and

[0194] In some embodiments, the compound is a compound of Formula II-o: 91 BUSINESS.33169534.1 407274-95WRWO (217205),le salt thereof; wherein R1a, R1b, R2, R3, d, z, and R4, are as defined herein, both singly and in combination and and-p:or a pharmaceutically acceptable salt thereof; wherein R1a, R2, R3, d, and R4, are as defined herein, both singly and in combination and R2ais and05)

[0196] In some embodiments, the compound is a compound of Formula II-q: ,ptable salt thereof; wherein R1a, R2, R3, d, and R4, are as defined herein, both singly and in combination and R2ais andI-r:or a pharmaceutically acceptable salt thereof; wherein R1a, R2, R3, d, and R4, are as defined herein, both singly and in combination and R2ais and

[0198] In some embodiments, the compound is a compound of Formula II-s: 93 BUSINESS.33169534.1 407274-95WRWO (217205),table salt thereof; wherein R1a, R2, R3, d, and R4, are as defined herein, both singly and in combination and R2ais andI-t:or a pharmaceutically acceptable salt thereof; wherein R1a, R2, R3, d, and R4, are as defined herein, both singly and in combination and R2ais and

[0200] In some embodiments, the compound is a compound of Formula II-u: 94 BUSINESS.33169534.1 407274-95WRWO (217205),ptable salt thereof; wherein R1a, R2, R3, d, and R4, are as defined herein, both singly and in combination and R2ais and-v:or a pharmaceutically acceptable salt thereof; wherein R1a, R2, R3, d, and R4, are as defined herein, both singly and in combination and R2ais and

[0202] In some embodiments, the compound is a compound of Formula II-w: 95 BUSINESS.33169534.1 407274-95WRWO (217205),y le salt thereof; wherein R1a, R2, R3, d, and R4, are as defined herein, both singly and in combination and R2ais and-x:or a pharmaceutically acceptable salt thereof; wherein R1a, R1b, R2, R3, d, and R4, are as defined herein, both singly and in combination and R2aand05)

[0204] In some embodiments, the compound is a compound of Formula II-y: ,ptable salt thereof; wherein R1a, R2, R3, d, and R4, are as defined herein, both singly and in combination and R2ais and

[0005] n some embod ments, t e compound s se ected rom one o t ose dep cted n able 1 and Table 1a, or a pharmaceutically acceptable salt thereof. Table 1 and Table 1a identify compounds by their IUPAC name and Table 2 or Table 2a lists the same compounds and show their chemical structure. In the event of any discrepancy or ambiguity between Table 1’s and Table 1a’s name for a compound and Table 2’s or Table 2a’s structure for that same compound, Table 2’s or Table 2a’s compound structures will dominate and identify the compound corresponding to each respective compound number (I-#) in Table 1 or Table 1a. Table 1 No. IUPAC Name97 BUSINESS.33169534.1 407274-95WRWO (217205)N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[12'-(dimethylamino)-1-(5-hydroxy-6- I-2 methylpyrimidine-4-carbonyl)-6'-methyl-2'-oxo-8'10'13'-triazaspiro[piperidine- 3-98 BUSINESS.33169534.1 407274-95WRWO (217205)N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[12'-(dimethylamino)-1-(4-hydroxy-2- methoxypyridine-3-carbonyl)-6'-methyl-2'-oxo-8'10'13'-triazaspiro[piperidine- - e99 BUSINESS.33169534.1 407274-95WRWO (217205)2-[12'-(dimethylamino)-1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-6'-methyl- 2'-oxo-8'10'13'-triazaspiro[piperidine-44'-tricyclo[7.4.0.0^{37}]tridecane]- '-100 BUSINESS.33169534.1 407274-95WRWO (217205)N-{3-cyclopropylbicyclo[1.1.1]pentan-1-yl}-2-[1-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-11'-(2-methoxypyridin-4-yl)-6'-methyl-2'-oxo- - '- - '-101 BUSINESS.33169534.1 407274-95WRWO (217205)N-{3-cyclopropylbicyclo[1.1.1]pentan-1-yl}-2-[11'-(3,6-dihydro-2H-pyran-4-yl)- 1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-6'-methyl-2'-oxo-1'8'10'12'- '- '- - - - -102 BUSINESS.33169534.1 407274-95WRWO (217205)N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[11'-(3,6-dihydro-2H-pyran-4-yl)-1-(5- hydroxy-6-methylpyrimidine-4-carbonyl)-2'-oxo-1'8'10'12'- '- '- '- - -103 BUSINESS.33169534.1 407274-95WRWO (217205)N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[(4R*,6'R**)-11'-(3,6-dihydro-2H- pyran-4-yl)-1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-336'-trimethyl-2'- - '- '-104 BUSINESS.33169534.1 407274-95WRWO (217205)N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[(2R*,4R**,6'R***)-11'-(3,6-dihydro- 2H-pyran-4-yl)-1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-26'-dimethyl-2'- '-105 BUSINESS.33169534.1 407274-95WRWO (217205)rel-N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[(6'R)-1-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-6'11'12'-trimethyl-2'-oxo-8'10'13'- - '- - '- - -106 BUSINESS.33169534.1 407274-95WRWO (217205)rel-N-[4-(difluoromethyl)-2-fluorophenyl]-2-[(6'R)-1-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-11'-(2-methoxypyridin-4-yl)-6'-methyl-2'-oxo- '- '- '-107 BUSINESS.33169534.1 407274-95WRWO (217205)N-{3-cyclopropylbicyclo[1.1.1]pentan-1-yl}-2-[11'-(3,6-dihydro-2H-pyran-4-yl)- 1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-6'-methyl-2'-oxo-8'10'11'12'- '- '-Table 1a No. IUPAC Name - '-108 BUSINESS.33169534.1 407274-95WRWO (217205)N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[(4S,6'S)-11'-(3,6-dihydro-2H-pyran- 4-yl)-1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-336'-trimethyl-2'-oxo- - - - -109 BUSINESS.33169534.1 407274-95WRWO (217205)N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[(4S,6'S)-11'-(3,6-dihydro-2H-pyran- 4-yl)-1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-336'-trimethyl-2'-oxo- - -

[0206] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration (e.g. by injection, infusion, transdermal or topical administration), and rectal administration, in particular oral administration. Topical administration may also pertain to inhalation or intranasal application. The pharmaceutical compositions of the present invention can be made up in a solid form (including, without limitation, capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including, without limitation, solutions, suspensions or emulsions). Tablets may be either film coated or enteric coated according to methods known in the art. Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with one or more of: 110 BUSINESS.33169534.1 407274-95WRWO (217205)a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and / orpolyethylene glycol; for tablets alsoc) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth,methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desiredd) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures;ande) absorbents, colorants, flavors and sweeteners.

[0207] Typical approaches to solubilize compounds for parenteral administration are the optimization of the pH or the use of co-solvents (e.g. PEG300, PEG400, propylene glycol, or ethanol). If these approaches are, for any reason, not feasible, the use of surfactants may be considered (e.g. Tween® 80 or Cremophor EL®). Cyclodextrins are established as safe solubilizing agents. Compounds with a high solubility in natural oils may be solubilized in parenteral fat emulsions.

[0208] There is also provided a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. Uses

[0209] The compounds of the present invention in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, e.g. WRN inhibiting properties, e.g. as indicated in vitro tests as provided in the next sections, and are therefore indicated for therapy, or for use as research chemicals, e.g. as a chemical probe, and as tool compounds.

[0210] Also provided is a compound as described herein. Said compound can be used as a research chemical, a compound herein comprising an added biotin moiety, for example a tool compound or chemical probe, in particular for research on WRN. In another embodiment there is provided the use of a compound as described herein, as a research chemical, for example tool compound or chemical probe, in particular for research on WRN. 111 BUSINESS.33169534.1 407274-95WRWO (217205)

[0211] There is also provided a compound described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer. Cancers that may be treated by WRN inhibition include cancers that are characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). In particular, a compound described herein, or a pharmaceutically acceptable salt thereof, may be useful in the treatment of a cancer that is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

[0212] There is also provided a compound as described herein, or a pharmaceutically acceptable salt thereof, for use as a medicament. In particular, said use is: ^for the treatment of a disease that is treated by WRN inhibition,^ for the treatment of cancer,^ for the treatment of cancer that is characterized as microsatellite instability-high(MSI-H) or mismatch repair deficient (dMMR), ^for the treatment of cancer that is characterized as microsatellite instability-high(MSI-H) or mismatch repair deficient (dMMR), such as colorectal, gastric, prostate, endometrial, adrenocortical, uterine, cervical, esophageal, breast, kidney and ovarian cancer, ^for the treatment of cancer that is characterized as microsatellite instability-high(MSI-H) or mismatch repair deficient (dMMR) is selected from colorectal, gastric, prostate and endometrial cancer, or ^for the treatment of cancer wherein the cancer characterized as microsatelliteinstability-high (MSI-H) or mismatch repair deficient (dMMR) is selected from 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, prostate cancer and ovarian serous cystadenocarcinoma.

[0213] There is also provided a method of: 112 BUSINESS.33169534.1 407274-95WRWO (217205)^ modulating WRN activity in a subject, wherein the method comprisesadministering to the subject a therapeutically effective amount of the compound as described herein, or a pharmaceutically acceptable salt thereof, ^inhibiting WRN in a subject, wherein the method comprises administering to thesubject a therapeutically effective amount of the compound as described herein, or a pharmaceutically acceptable salt thereof, ^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 as described herein, or a pharmaceutically acceptable salt thereof, ^treating cancer in a subject, comprising administering to the subject atherapeutically effective amount of the compound as described herein, or a pharmaceutically acceptable salt thereof, ^treating cancer in a subject, comprising administering a compound as describedherein, wherein the cancer is characterized as microsatellite instability-high (MSI- H) or mismatch repair deficient (dMMR). In particular, the cancer characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) is selected from colorectal, gastric, prostate, endometrial, adrenocortical, uterine, cervical, esophageal, breast, kidney and ovarian cancer. More particularly, the cancer characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) is selected from colorectal, gastric, prostate and endometrial cancer. Examples 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, prostate cancer and ovarian serous cystadenocarcinoma.

[0214] There is also provided the use of a compound as described herein, or a pharmaceutically acceptable salt thereof: ^in therapy,^ in the manufacture of a medicament,113 BUSINESS.33169534.1 407274-95WRWO (217205)^ in the manufacture of a medicament for the treatment of cancer. In particular, saidcancer is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), ^in the manufacture of a medicament for treatment of a disease which may be treatedby WRN inhibition, wherein in particular, the cancer is characterized by microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), for example colorectal, gastric, prostate, endometrial, adrenocortical, uterine, cervical, esophageal, breast, kidney and ovarian cancer, in particular, colorectal, gastric, prostate or endometrial cancer, or 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.

[0215] In some embodiments, the subject has or is identified as having a microsatellite instable (MSI-H) cancer, e.g., in reference to a control, e.g., a normal, subject. In one embodiment, the subject has MSI-H advanced solid tumors, a colorectal cancer (CRC), endometrial, uterine, stomach or other MSI-H cancer. In some embodiments, the subject has a colorectal (CRC), endometrial or stomach cancer, which cancer has or is identified as having a microsatellite instability (MSI-H), e.g., in reference to a control, e.g., a normal, subject. Such identification techniques are known in the art. Forms

[0216] Depending on the choice of the starting materials and procedures, the compounds can be present in the form of one of the possible stereoisomers or as mixtures thereof, for example as pure optical isomers, or as stereoisomer mixtures, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms. The present invention is meant to include all such possible stereoisomers, including racemic mixtures, diasteriomeric mixtures and optically pure forms. Optically active (R)- and (S)-stereoisomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted 114 BUSINESS.33169534.1 407274-95WRWO (217205)cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.

[0217] Any formula given herein is intended to represent unlabeled forms as well as isotopically labeled forms of the compounds, in addition to the deuteration specifically disclosed herein. Isotopically labeled compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Isotopes that can be incorporated into compounds of the invention include, for example, isotopes of hydrogen.

[0218] Further, incorporation of certain isotopes, particularly deuterium (i.e., 2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index or tolerability. It is understood that deuterium in this context is regarded as a substituent of a compound of the present invention. The concentration of deuterium, may be defined by the isotopic enrichment factor. The term “isotopic enrichment factor” as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this invention is denoted as being deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). It should be understood that the term “isotopic enrichment factor” can be applied to any isotope in the same manner as described for deuterium.

[0219] Other examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 3H, 11C, 13C, 14C, 15N, 18F 31P, 32P, 35S, 36CI, 123I, 124I, and 125I, respectively. Accordingly it should be understood that the invention includes compounds that incorporate one or more of any of the aforementioned isotopes, including for example, radioactive isotopes, such as 3H and 14C, or those into which non-radioactive isotopes, such as 2H and 13C are present. Such 115 BUSINESS.33169534.1 407274-95WRWO (217205)isotopically labelled compounds are useful in metabolic studies (with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an 18F or labeled compound may be particularly desirable for PET or SPECT studies. Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non- labeled reagent previously employed.

[0220] A “compound of the present invention” or a “compound of Formula I” includes a zwitterion thereof, a non-zwitterion thereof (non-charged form), or a pharmaceutically acceptable salt of said zwitterionic or non-zwitterionic form thereof. “Zwitterion” or “zwitterionic form” means a compound containing both positive and negatively charged functional groups.

[0221] 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.

[0222] 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.

[0223] “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. In one embodiment, the protein is encoded by the WRN gene (Entrez gene ID 7486; Ensembl ID ENSG00000165392). Exemplary WRN sequences are available at the Uniprot database under accession number Q14191.

[0224] “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). 116 BUSINESS.33169534.1 407274-95WRWO (217205)

[0225] “Microsatellite unstable cancer,” “microsatellite instability-high cancer,” “microsatellite high cancer” and “MSI-high cancer,” “MSIhi” 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.

[0226] 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).

[0227] 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.

[0228] 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.

[0229] As used herein, the term “pharmaceutical composition” refers to a compound of the invention, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration. 117 BUSINESS.33169534.1 407274-95WRWO (217205)

[0230] As used herein, the term “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).

[0231] The terms “synthetic lethality,” and “synthetically lethal” are used to refer to reduced cell viability and / or a reduced rate of cell proliferation caused by a combination of mutations or approaches to cause loss of function (e.g., RNA interference or protein function inhibition) in two or more genes but not by the loss of function of only one of these genes.

[0232] The term “a therapeutically effective amount” of a compound of the present invention refers to an amount of the compound of the present invention 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. In some embodiments, the methods of the invention comprise administration of a therapeutically effective amount of a compound herein.

[0233] In one embodiment, the term “a therapeutically effective amount” refers to the amount of the compound of the present invention 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 (iii) characterized by activity (normal or abnormal) of WRN; or (2) reduce or inhibit the activity of WRN.

[0234] In another embodiment, the term “a therapeutically effective amount” refers to the amount of the compound of the present invention 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.

[0235] As used herein, 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. 118 BUSINESS.33169534.1 407274-95WRWO (217205)

[0236] As used herein, the term “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.

[0237] As used herein, 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.

[0238] As used herein, the term “prevent,” “preventing” or “prevention” of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

[0239] As used herein, a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.

[0240] As used herein, the term “a,” “an,” “the” and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.

[0241] “May join” means joins or does not join.

[0242] “May be replaced by deuterium” means is replaced by deuterium, or is not replaced by deuterium.

[0243] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. Isomeric forms 119 BUSINESS.33169534.1 407274-95WRWO (217205)

[0244] Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R, S)-configuration. In certain embodiments, each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (R)- or (S)- configuration. Substituents at atoms with unsaturated double bonds may, if possible, be present in cis-(Z)- or trans-(E)- form.

[0245] Accordingly, as used herein a compound of the present invention can be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.

[0246] Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0247] Any resulting racemates of compounds of the present invention or of intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O’-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic compounds of the present invention or racemic intermediates can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.

[0248] Compounds of the invention, that contain groups capable of acting as donors and / or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals may be prepared from compounds disclosed herein by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds disclosed herein with the co-crystal former under crystallization 120 BUSINESS.33169534.1 407274-95WRWO (217205)conditions and isolating co-crystals thereby formed. Suitable co-crystal formers include those described in WO 2004 / 078163. Hence the invention further provides co-crystals comprising a compound of the disclosure.

[0249] Furthermore, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.

[0250] The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the invention embrace both solvated and unsolvated forms. The term “solvate” refers to a molecular complex of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like. The term “hydrate” refers to the complex where the solvent molecule is water. Dosage Forms

[0251] The pharmaceutical composition or combination of the present invention may, for example, be in unit dosage of about 1-1000 mg of active ingredient(s) for a subject of about 50-70 kg. Combinations

[0252] “Combination” refers to either a fixed combination in one dosage unit form, or a combined administration where a compound of the disclosure, 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, e.g. synergistic effect. 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 121 BUSINESS.33169534.1 407274-95WRWO (217205)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 invention and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage.

[0253] The term “non-fixed combination” means that the therapeutic agents, e.g. a compound of the present invention 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.

[0254] The combinations described herein can include a compound disclosed 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.

[0255] There is also provided a combination comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, as described herein, and one or more additional therapeutically active agents. The additional therapeutic agent is, for example, a chemical compound, 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. In particular, an additional therapeutically active agent is: ^an anti-cancer agent,^ a chemotherapy,^ chemotherapy selected from anastrozole (Arimidex®), bicalutamide (Casodex®),bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5- 122 BUSINESS.33169534.1 407274-95WRWO (217205)fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate, ^liposome injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®),doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine (difluorodeoxycitidine), hydroxyurea (Hydrea®), Idarubicin (Idamycin®), ifosfamide (IFEX0), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), phoenix (Yttrium90 / MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®), in particular fluorouracil (5-FU) and irinotecan (Camptosar®). ^a PD-1 inhibitor,^ an anti-PD-1 antibody molecule,^ a PD-1 inhibitor selected from spartalizumab (Novartis), nivolumab (Bristol-MyersSquibb), pembrolizumab (Merck & Co), pidilizumab (CureTech), MED10680 (Medimmune), cemiplimab (REGN2810, Regeneron), dostarlimab (TSR-042, Tesaro), PF-06801591 (Pfizer), tislelizumab (BGB-A317, Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), balstilimab (AGEN2035, Agenus), sintilimab (InnoVent), toripalimab (Shanghai Junshi Bioscience), camrelizumab (Jiangsu Hengrui Medicine Co.), AMP-224 (Amplimmune), penpulimab (Akeso Biopharma Inc), zimberelimab (Arcus Biosciences Inc), and prolgolimab (Biocad Ltd), 123 BUSINESS.33169534.1 407274-95WRWO (217205)^ spartalizumab, or^ tislelizumab (BGB-A317, Beigene).

[0256] In a further embodiment, the additional therapeutically active agent is the chemotherapy irinotecan (Camptosar®).

[0257] In another embodiment, the additional therapeutically active agent is an inhibitor of PD-1, e.g., human PD-1. In another embodiment, the immunomodulator is an inhibitor of PD-L1, e.g., human PD-L1. In one embodiment, the inhibitor of PD-1 or PD-L1 is an antibody molecule to PD-1 or PD-L1. In another embodiment, the additional therapeutically active agent is an anti- PD-1 antibody molecule.

[0258] In a further embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule as described in US 2015 / 0210769, published on July 30, 2015, entitled “Antibody Molecules to PD- 1 and Uses Thereof.”

[0259] In another embodiment, there is provided a combination of a compound disclosed herein 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. In some embodiments, the PD-1 inhibitor is pembrolizumab, nivolumab, cemiplimab, dostarlimab, or retifanlimab.

[0260] The above-mentioned compounds, which can be used in combination with a compound of the present invention, can be prepared and administered as described in the art, such as in the documents cited above.

[0261] In one embodiment, the invention provides a product comprising a compound of the present invention 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 disclosed herein and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound of the present invention and the other therapeutic agent(s) in separate form, e.g. in the form of a kit.

[0262] In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the present invention. 124 BUSINESS.33169534.1 407274-95WRWO (217205)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.

[0263] The kit of the invention 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 invention typically comprises directions for administration.

[0264] In the combination therapies of the invention, the compound of the present invention and the other therapeutic agent may be manufactured and / or formulated by the same or different manufacturers. Moreover, the compound of the present invention 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 invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of the present invention and the other therapeutic agent.

[0265] Accordingly, the invention provides the use of a compound of the present invention for treating a disease or condition mediated by WRN, wherein the medicament is prepared for administration with another therapeutic agent. The invention 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 invention.

[0266] The invention also provides a compound of the present invention for use in treating a disease or condition mediated by WRN, wherein the compound of the present invention is prepared for administration with another therapeutic agent. The invention 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 invention. The invention also provides a compound of the present invention for use in treating a disease or condition mediated by WRN, wherein the compound of the present invention is administered with another therapeutic agent. The invention 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 invention. 125 BUSINESS.33169534.1 407274-95WRWO (217205)

[0267] The invention also provides the use of a compound of the present invention 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 invention 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 invention. 5. General synthetic methods of producing compounds of the disclosure

[0268] Compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying synthetic schemes. Scheme 1126 BUSINESS.33169534.1 407274-95WRWO (217205)[0p , p p onate F (Rz= alkyl, allows for the preparation of enone 2. The latter can be reacted with α-deprotonated phenyl vinyl sulfide to yield the tertiary alcohol 3. A bismuth salt-induced cyclization reaction yields then spirocyclic enone 4, which can be saturated by hydrogenation, giving access to spirocyclic ketone 5. Condensation with secondary amine, such as pyrrolidine, yields enamine 6, which is reacted with acyl chloride A in the presence of base such as TEA allowing for the preparation of amino enone 7. Hydrolysis of 7 under acidic conditions yields 1,3-dicarbonyl 8. TFA-induced cyclative condensation of 8 leads to polycyclic intermediate 9. Functionalization of the secondary amine with a Boc group yields protected intermediate 10. Scheme 2 127 BUSINESS.33169534.1 407274-95WRWO (217205)

[00270] As depicted in Scheme 2, treatment of intermediate 10 with α-iodo amide B in the presence of base such as DIEA allows for the preparation of N-functionalized pyridinone 11. The latter can be subjected to C-C or C-N coupling, for example Suzuki cross-coupling, Ullmann reaction, Buchwald-Hartwig cross-coupling or nucleophilic aromatic substitution, to yield intermediate 12 Conditions for such C-C and C-N coupling reactions are well known to the person skilled in the art. Then, the secondary amine hydrochloride 13 is prepared by treatment of 12 with HCl in a non-aqueous solvent, followed by amide or sulfonamide coupling under literature known conditions with carboxylic acid derivative C or sulfonic acid derivative Z (X1= OH, halogen; to form derivative 14 or 14a respectively. Scheme 3 128 BUSINESS.33169534.1 407274-95WRWO (217205)

[0271] As depicted in Scheme 3, alternatively to the procedure described in Scheme 2, intermediate 10 is subject to C-C or C-N coupling followed by alkylation with α-bromo ester D (Rz= alkyl), in the presence of base such as DIEA to allow for the preparation of N-functionalized pyrazinone 15. Then, acid treatment leads to secondary amine hydrochloride 16, which is further functionalized by amide coupling under literature known conditions with carboxylic acid derivative C, to yield derivative 17. Base- or acid-catalyzed hydrolysis of ester 17 to carboxylic acid 18 followed by amide coupling under literature known conditions with amine E, yields derivative 14. The latter, prepared as a mixture of stereoisomers, can be separated into its 129 BUSINESS.33169534.1 407274-95WRWO (217205)respective single enantiomers by means of chiral stationary phase HPLC or SFC methods. Alternatively, sulfonamides 14a can be prepared by analogy to scheme 3 using coupling with sulfonic acid derivative Z instead of carboxylic acid derivative C in step 3. Scheme 4

[0272] As depicted in Scheme 4, compound 4 of Scheme 1 is furthermore used to prepare β- keto ester 19 by deprotonation, followed by reaction with acyl cyanide J (RE= alkyl). The latter is hydrogenated, leading to the saturated β-keto ester 20, which is then condensed with aminotriazole H to allow for the preparation of triazolo pyrimidinone 21. Functionalization of the secondary amine with a Boc group leads to triazolo pyrimidinone 22. Scheme 5 130 BUSINESS.33169534.1 407274-95WRWO (217205)de B in the presence of base such as DIEA allows for the preparation of N-functionalized triazolo pyrimidinone 23. The latter is subjected to literature known conditions for C-C or C-N coupling, for example Suzuki cross-coupling or Buchwald coupling, to yield derivative 24. Acid-catalyzed Boc cleavage leads to secondary amine 25, which is subjected to amide or sulfonamide coupling with carboxylic acid derivative C or sulfonic acid derivative Z under literature known conditions, to yield compound 26 or 26a respectively. The latter, prepared as a mixtures of stereoisomers, can be separated into respective single enantiomers by means of chiral stationary phase HPLC or SFC methods. Scheme 6 131 BUSINESS.33169534.1 407274-95WRWO (217205)[00, heteroaryl, optionally substituted) is treated with sodium nitrite in the presence of acid followed by reaction with α-cyano ester K (RF= alkyl), leading to addition product 28. Copper-mediated cyclization of the latter in the presence of HN(PMB)2 allows for the preparation of triazole 29. Base- or acid-catalyzed hydrolysis of ester 29 leads to carboxylic acid 30, which is converted into acyl chloride 31, and further transformed into acyl cyanide 32. Addition of the latter to an enolate, generated from spirocyclic ketone 5, leads to 1,3-diketone 33, which is cyclized under acidic conditions to triazolo pyridone 34 and further treated with Boc2O to yield N-protected intermediate 35. Scheme 7(217205)the presence of base such as DIEA allows for the preparation of N-functionalized triazolo pyridone 36. Acidic cleavage of the Boc group, followed by salt exchange leads to secondary amine hydrochloride 37, which is subjected to amide coupling or sulfonamide coupling with carboxylic acid derivative C or sulfonic acid derivative Z under literature known conditions to yield amide 38 or sulfonamide 38a respectively. The latter, prepared as a mixtures of stereoisomers, can be separated into respective single enantiomers by means of chiral stationary phase HPLC or SFC methods. Scheme 8205)

[0276] As dee 7, treatment of triazolo pyridone 35 with α-bromo ester D in the presence of base such as DIEA allows for the preparation of N-functionalized triazolo pyridone 39. Acid-catalyzed cleavage of the Boc group and salt exchange leads to secondary amine hydrochloride 40, which is subjected to amide coupling with carboxylic acid derivative C under literature known conditions to yield amide 41. Base- or acid-catalyzed hydrolysis of ester 41 leads to carboxylic acid, which is subjected to an amide coupling under literature known conditions with amine E, to yield amide 38. The latter, prepared as a mixture of stereoisomers, can be separated into its respective single enantiomers by means of chiral stationary phase HPLC or SFC methods. Alternatively, sulfonamides 38a can be prepared by analogy to scheme 8 using coupling with sulfonic acid derivative Z instead of carboxylic acid derivative C in step 4.

[0277] Those having ordinary skill in the art will be able to adapt such synthetic procedures to afford variably substituted compounds disclosed herein for synthesis of the compounds of the disclosure. EXAMPLES

[0278] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the procedures provided herein. It will be appreciated that, although the methods depict the synthesis of certain compounds of the present disclosure, the methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein. List of abbreviations: AIBN: Azobisisobutyronitrile 134 BUSINESS.33169534.1 407274-95WRWO (217205)NCS: N-chlorosuccinimide THF: tetrahydrofuran LiOH-H2O: Lithium hydroxide monohydrate (COCl)2: Oxalyl chloride DIEA: N,N-diisopropylethylamine NBS: N-bromosuccinimide TsOH-H2O: 4-methylbenzenesulfonic acid monohydrate TsOH: 4-Methylbenzenesulfonic acid H3PO4: phosphoric acid EtOH: ethanol TFA: trifluoroacetic acid Boc2O: di-tert-butyl dicarbonate POCl3: Phosphoryl chloride HCl: hydrochloric acid EDCI: N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride ppm: parts per million LCMS: liquid chromatography–mass spectrometry HPLC: high-performance liquid chromatography NMR: nuclear magnetic resonance CDCl3: deuterated chloroform H2O: water DCM: dichloromethane MeOH: methanol DMF: N,N-dimethyl formamide EtOAc: ethyl acetate PE: petroleum ether Na2SO4: sodium sulfate br: broad s: singlet d: doublet dq: doublet of quartets 135 BUSINESS.33169534.1 407274-95WRWO (217205)t: triplet m: multiplet q: quartet PPh3: triphenyl phosphine LDA: Lithium diisopropylamide ACN: acetonitrile NH4HCO3: ammonium bicarbonate eq: equivalent N: normality aq.: aqueous M: molar concentration Boc: tert-butyloxycarbonyl FA: formic acid Et3N: triethylamine NaOH: sodium hydroxide N2: nitrogen Pd(dppf)Cl2:bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex K3PO4: tripotassium phosphate NH4Cl: ammonium chloride pH: potential of hydrogen TLC: thin layer chromatography CuCN: Copper(I) cyanide DMA: Dimethylacetamide NaIO4: sodium periodate NaHCO3: Sodium hydrogen carbonate NaBH4: sodium borohydride K3PO4: Tripotassium phosphate anhydrous Cs2CO3: dicesium carbonate CuI: Copper(I) iodide Pd(PPh3)2Cl2: dichloropalladium triphenylphosphane 136 BUSINESS.33169534.1 407274-95WRWO (217205)Rose Bengal: dipotassium 4,5,6,7-tetrachloro-2',4',5',7'-tetraiodo-3-oxospiro[2-benzofuran-1,9'- xanthene]-3',6'-diolate Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium(0) NaH: Sodium Hydride K2OsO4-2H2O: dipotassium dioxido(dioxo)osmium dihydrate DAST: Diethylaminosulfur trifluoride LiOH: Lithium Hydroxide LHMDS: Lithium bis(trimethylsilyl)amide K2CO3: Potassium carbonate, anhydrous Pd(dppf)Cl2-CH2Cl2: [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane O2: Oxygen DMSO: Dimethyl sulfoxide LED: light emitting diode h: hour N2: nitrogen pH: potential of hydrogen Co(acac)2: Cobalt(II) acetylacetonate Na2S: sodium sulfide NH3: ammonia CO: carbon monoxide t-BuOK: potassium t-butoxide NaBH(OAc)3: Sodium triacetoxyborohydride SFC: Supercritical fluid chromatography PMB: 4-methoxybenzyl CD3OD: deuterated methanol MeMgBr: methylmagnesium bromide HBr: hydrobromic acid HI: Hydriodic acid DMSO-d6: deuterated dimethyl sulfoxide P2S5: phosphorus pentasulfide 137 BUSINESS.33169534.1 407274-95WRWO (217205)DMAP: 4-dimethylaminopyridine NMP: N-methylpyrrolidone DEA: Diethylamine Example 1: Synthesis of Compounds of the disclosure Synthesis of N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[12'-(dimethylamino)-1-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-6'-methyl-2'-oxo-8',10',13'-triazaspiro[piperidine-4,4'- tricyclo[7.4.0.0^{3,7}]tridecane]-1'(9'),3'(7'),10',12'-tetraen-8'-yl]acetamide (racemic mixture, I-1), N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[12'-(dimethylamino)-1-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-6'-methyl-2'-oxo-8',10',13'-triazaspiro[piperidine-4,4'- tricyclo[7.4.0.0^{3,7}]tridecane]-1'(9'),3'(7'),10',12'-tetraen-8'-yl]acetamide (single isomer, first eluting isomer as isomer 1, I-2), and N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[12'- (dimethylamino)-1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-6'-methyl-2'-oxo-8',10',13'- triazaspiro[piperidine-4,4'-tricyclo[7.4.0.0^{3,7}]tridecane]-1'(9'),3'(7'),10',12'-tetraen-8'- yl]acetamide (single isomer, second eluting isomer as isomer 2, I-3)138 BUSINESS.33169534.1 407274-95WRWO (217205)N N N N O O

[0279] Step 1.midine-4-carboxylate (25 mg, 142 µmol, 2.73 eq, Intermediate-16) and pyridine hydrochloride (19 mg, 165 µmol, 3.00 eq) in DCM (1 mL) was added N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(dimethylamino)-6- methyl-9-oxo-6,9-dihydrospiro[cyclopenta[5,6]pyrido[2,3-b]pyrazine-8,4'-piperidin]-5(7H)- yl)acetamide hydrochloride (30 mg, 51.6 µmol, 1.00 eq, racemic mixture, Intermediate-8), DIEA (21 mg, 165 µmol, 3.20 eq) and EDCI (63 mg, 330 µmol, 6.40 eq) at room temperature. The resulting mixture was stirred for 4 h at 40 °C. The resulting mixture was concentrated under reduced pressure and the residue was dissolved in THF (1.00 mL). A 1 M aq. NaOH solution (0.50 mL, 0.50 mmol, 9.69 eq) was added, and the resulting mixture was stirred for 1 h at room temperature. The mixture was diluted with H2O, and then acidified to pH ~6 with FA (formic acid). The reaction mixture was extracted with EtOAc (3 x 5 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (C18 column, water (0.1% FA)-ACN) to afford the title compound. LCMS: 685.3[M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 10.25 (br s, 1H), 8.56 (s, 1H), 8.42 (s, 1H), 8.06 (d, 1H), 7.95 (d, 1H), 7.70 (dd, 1H), 5.44 – 5.18 (m, 2H), 4.60 – 4.49 (m, 1H), 3.60 – 3.46 (m, 2H), 3.32 – 2.81 (m, 9H), 2.59 - 2.50 (m, 1H), 2.45 (s, 3H), 2.22 - 1.96 (m, 2H), 1.63 – 1.08 (m, 5H).

[0280] Step 2. N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[12'-(dimethylamino)-1-(5-hydroxy- 6-methylpyrimidine-4-carbonyl)-6'-methyl-2'-oxo-8',10',13'-triazaspiro[piperidine-4,4'- tricyclo[7.4.0.0^{3,7}]tridecane]-1'(9'),3'(7'),10',12'-tetraen-8'-yl]acetamide (racemic mixture, I- 1) was separated by preparative chiral HPLC with the following conditions, to afford the title compounds. Preparative chiral HPLC method: Column: JW-CHIRAL ART Cellulose-SB, 20 x 250 mm, 5 µm; mobile phase A: EtOH:DCM = 1:1, mobile phase B: Hex (0.1% FA); flow rate: 139 BUSINESS.33169534.1 407274-95WRWO (217205)20 mL / min; isocratic 50% B in 12 min; wavelength: 220 / 254 nm. Peak 1 retention time 3.52 min, peak 2 retention time 10.63 min. Analytical chiral HPLC method: Column JW-CHIRAL ART Cellulose-SB, 4.6 x 100 mm, 3 µm M bil Ph A H x (01% FA) B EtOHDCM = 11 -tricyclo[7.4.0.0^{3,7}]tridecane]-1'(9'),3'(7'),10',12'-tetraen-8'-yl]acetamide (single isomer, first eluting isomer as isomer 1, I-2, preparative chiral HPLC retention time: 3.52 min, analytical chiralHPLC retention time 1.69 min). LCMS: 685.2[M+H]+. 1H NMR (400 MHz, DMSO-d6): δ ppm10.25 (s, 1H), 8.56 (s, 1H), 8.42 (s, 1H), 8.06 (d, 1H), 7.95 (d, 1H), 7.70 (dd, 1H), 5.44 – 5.18 (m, 2H), 4.60 – 4.49 (m, 1H), 3.60 – 3.46 (m, 2H), 3.32 – 2.81 (m, 9H), 2.59 - 2.50 (m, 1H), 2.45 (s, 3H), 2.22 - 1.96 (m, 2H), 1.63 – 1.08 (m, 5H).

[0282] N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[12'-(dimethylamino)-1-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-6'-methyl-2'-oxo-8',10',13'-triazaspiro[piperidine-4,4'- tricyclo[7.4.0.0^{3,7}]tridecane]-1'(9'),3'(7'),10',12'-tetraen-8'-yl]acetamide (single isomer, second eluting isomer as isomer 2, I-3, preparative chiral HPLC retention time: 10.63 min, analytical chiral HPLC retention time 5.11 min). LCMS: 685.2[M+H]+.1H NMR (400 MHz,DMSO-d6) δ ppm 10.25 (s, 1H), 8.56 (s, 1H), 8.42 (s, 1H), 8.06 (d, 1H), 7.95 (d, 1H), 7.70 (dd,1H), 5.44 – 5.18 (m, 2H), 4.60 – 4.49 (m, 1H), 3.60 – 3.46 (m, 2H), 3.32 – 2.81 (m, 9H), 2.59 - 2.50 (m, 1H), 2.45 (s, 3H), 2.22 - 1.96 (m, 2H), 1.63 – 1.08 (m, 5H). 140 BUSINESS.33169534.1 407274-95WRWO (217205)Synthesis of N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[12'-cyclopropyl-1-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-6'-methyl-2'-oxo-8',10',13'-triazaspiro[piperidine-4,4'- tricyclo[7.4.0.0^{3,7}]tridecane]-1'(13'),3'(7'),9',11'-tetraen-8'-yl]acetamide (racemic mixture, I-13). [002yl)-2-(2- cyclopropyl-6-methyl-9-oxo-6,9-dihydrospiro[cyclopenta[5,6]pyrido[2,3-b]pyrazine-8,4'- piperidin]-5(7H)-yl)acetamide hydrochloride (80 mg, 147 µmol, 1.00 eq, racemic mixture, Intermediate-9) in DCM (1.60 mL) were added DIEA (152 mg, 1.18 mmol, 8.00 eq) and 5- hydroxy-6-methylpyrimidine-4-carbonyl chloride (126 mg, 735 µmol, 5.00 eq, Intermediate-11) at room temperature. The resulting mixture was stirred at room temperature for 1 h, followed by dilution with water (5 mL), and extraction with DCM (2 x 4 mL). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in THF (0.80 mL), and then a solution of NaOH (6.00 mg, 150 µmol, 1.00 eq) in H2O (0.80 mL) was added at room temperature. The resulting mixture was stirred at room temperature for additional 10 min, and then was acidified to pH~5 with 1 N aq. HCl. The resulting mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (C18 Column, water (10% NH4HCO3)-ACN) to afford the title compound. LCMS: 682.1[M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 8.76 (s, 1H), 8.56 (br s, 1H), 8.04 – 7.94 (m, 2H), 7.72 – 7.67 (m, 1H), 5.45 – 5.24 (m, 2H), 4.60 – 4.49 (m, 1H), 3.62 – 3.20 (m, 2H), 3.19 – 2.98 (m, 1H), 2.83 – 2.77 (m, 1H), 2.51 – 2.33 (m, 6H), 2.23 – 2.01 (m, 2H), 141 BUSINESS.33169534.1 407274-95WRWO (217205)1.57 – 1.28 (m, 5H), 1.21 – 1.07 (m, 4H). Signal of one non-exchangeable1H not detected, due to signal overlap with H2O. Synthesis of N-{3-cyclopropylbicyclo[1.1.1]pentan-1-yl}-2-[12'-(dimethylamino)-1-(5-hydroxy- 6-methylpyrimidine-4-carbonyl)-6'-methyl-2'-oxo-8',10',13'-triazaspiro[piperidine-4,4'- tricyclo[7.4.0.0^{3,7}]tridecane]-1'(9'),3'(7'),10',12'-tetraen-8'-yl]acetamide (racemic mixture, I-19). [00284hydroxy-6- methylpyrimidine-4-carbonyl)-6-methyl-9-oxo-6,9-dihydrospiro[cyclopenta[5,6]pyrido[2,3- b]pyrazine-8,4'-piperidin]-5(7H)-yl)acetic acid (40 mg, 79 μmol, 1.00 eq, racemic mixture, Intermediate-17) and 3-cyclopropylbicyclo[1.1.1]pentan-1-amine hydrochloride (13 mg, 79 μmol, 1.00 eq) in THF (0.2 mL) and DMF (0.2 mL) were added DIEA (41 mg, 316 μmol, 4.00 eq) and HATU (60 mg, 158 μmol, 2.00 eq). The resulting mixture was stirred at room temperature for 30 min. Then, 1 N aq. NaOH solution (0.4 mL) was added and the resulting mixture was stirred at room temperature for 30 min. The mixture was acidified to pH~4 with FA., followed by extraction with EtOAc (4 x 2 mL). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (C18 column, water (10 mmol / L NH4HCO3)-ACN) to afford the title compound. LCMS: 613.5[M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 8.72 (s, 1H), 8.49 (br s, 1H), 8.39 (s, 1H), 4.95 – 4.77 (m, 2H), 4.57 – 4.51 (m, 1H), 3.57 – 3.46 (m, 1H), 3.15 (br s, 6H), 3.09 – 2.78 (m, 3H), 2.61 – 2.55 (m, 1H), 2.42 (s, 3H), 2.20 – 1.97 (m, 3H), 1.76 (s, 6H), 1.52 – 1.05 (m, 5H), 0.90 – 0.85 (m, 1H), 0.38 – 0.33 (m, 2H), 0.08 – 0.05 (m, 2H). 142 BUSINESS.33169534.1 407274-95WRWO (217205)Synthesis of N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[11'-(3,6-dihydro-2H-pyran-4-yl)-1-(5- hydroxy-6-methylpyrimidine-4-carbonyl)-6'-methyl-2'-oxo-1',8',10',12'- tetraazaspiro[piperidine-4,4'-tricyclo[7.3.0.0^{3,7}]dodecane]-3'(7'),9',11'-trien-8'- yl]acetamide (racemic mixture, I-20). [(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 hydrochloride (100 mg, 0.16 mmol, 1.00 eq, racemic mixture, Intermediate-22) and sodium 5-hydroxy-6-methylpyrimidine-4-carboxylate (57 mg, 0.32 mmol, 2.00 eq, Intermediate-16) in THF (3.00 mL) were added DIEA (63 mg, 0.48 mmol, 3.00 eq) and HATU (124 mg, 0.32 mmol, 2.00 eq) at room temperature. The resulting mixture was stirred for 1 h at room temperature, followed by dilution with water (10 mL), and extraction with EtOAc (2 x 10 mL). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in THF (3.00 mL), followed by addition of a 1 N aq. NaOH solution (3.0 mL) at room temperature. The resulting mixture was stirred at room temperature for additional 10 min, and then was acidified to pH~5 with 1 N aq. HCl solution. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in MeOH and purified by reverse phase HPLC (C18 Column, water (0.1% FA)-ACN) to afford the title compound. LCMS: 713.4[M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 10.36 (s, 1H), 10.23 (br s, 1H), 8.58 (s, 1H), 8.03 – 7.96 (m, 2H), 7.75 – 7.70 (m, 1H), 6.83 – 6.79 (m, 1H), 5.30 – 5.07 (m, 2H), 4.60 – 4.50 (m, 1H), 4.29 – 4.22 143 BUSINESS.33169534.1 407274-95WRWO (217205)(m, 2H), 3.81 (t, 2H), 3.57 – 3.48 (m, 5H), 3.33 – 2.81 (m, 2H), 2.61 – 2.18 (m, 5H), 2.14 – 2.00 (m, 1H), 1.69 – 1.25 (m, 5H). Synthesis of N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[1-(5-hydroxy-6-methylpyrimidine-4- carbonyl)-11'-(2-methoxypyridin-4-yl)-6'-methyl-2'-oxo-8',10',11',12'- tetraazaspiro[piperidine-4,4'-tricyclo[7.3.0.0^{3,7}]dodecane]-1'(12'),3'(7'),9'-trien-8'- yl]acetamide (racemic mixture, I-21), N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[1-(5-hydroxy- 6-methylpyrimidine-4-carbonyl)-11'-(2-methoxypyridin-4-yl)-6'-methyl-2'-oxo-8',10',11',12'- tetraazaspiro[piperidine-4,4'-tricyclo[7.3.0.0^{3,7}]dodecane]-1'(12'),3'(7'),9'-trien-8'- yl]acetamide (single stereoisomer, first eluting compound as stereoisomer 1, I-28), and N-[2- chloro-4-(trifluoromethyl)phenyl]-2-[1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-11'-(2- methoxypyridin-4-yl)-6'-methyl-2'-oxo-8',10',11',12'-tetraazaspiro[piperidine-4,4'- tricyclo[7.3.0.0^{3,7}]dodecane]-1'(12'),3'(7'),9'-trien-8'-yl]acetamide (single stereoisomer, second eluting compound as stereoisomer 2, I-29)144 BUSINESS.33169534.1 407274-95WRWO (217205)[00 -(2-(2-methoxypyridin-4-yl)-5-methyl-8-oxo-2,5,6,8-tetrahydro-4H- spiro[cyclopenta[b][1,2,3]triazolo[4,5-e]pyridine-7,4'-piperidin]-4-yl)acetamide HCl salt (Intermediate-26) (500 mg, 0.78 mmol, 1.00 eq) and sodium 5-hydroxy-6-methylpyrimidine-4- carboxylate (Intermediate-16) (414 mg, 2.34 mmol, 3.00 eq) in pyridine (10.0 mL) was added HATU (447 mg, 1.17 mmol, 1.50 eq) in portions at room temperature. After stirring at room temperature for 2 h, the resulting mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with EA (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (C18 column, water (0.1%FA)-ACN) to afford the title compound.

[0287] Step-2. N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[1-(5-hydroxy-6-methylpyrimidine- 4-carbonyl)-11'-(2-methoxypyridin-4-yl)-6'-methyl-2'-oxo-8',10',11',12'-tetraazaspiro[piperidine- 4,4'-tricyclo[7.3.0.0^{3,7}]dodecane]-1'(12'),3'(7'),9'-trien-8'-yl]acetamide (racemic mixture, I- 21) was separated by preparative chiral HPLC using the following conditions, to afford the title compounds. Preparative chiral HPLC method: Column: JW-CHIRAL ART Cellulose-SB, 20*250mm, 5^m; mobile phase A: EtOH: DCM=1:1 (0.3%DEA+0.2%FA), mobile phase B: Hex; isocratic elution: 60% phase B; flow rate: 20 mL / min; wavelength: 220 / 254 nm. Peak 1 retention time: 4.57 min, peak 2 retention time 6.68 min. Analytical chiral HPLC method: column CHIRAL Cellulose‐SB, 4.6*100 mm, 3 μm145 BUSINESS.33169534.1 407274-95WRWO (217205)Mobile Phase Phase A: (EtOH: DCM=1: 1)(0.3%DEA+0.2%FA) Phase B: Hexaneca o y - - - e o ypy - -y - - e y - -o o- , , , -e a y o- - spiro[cyclopenta[b][1,2,3]triazolo[4,5-e]pyridine-7,4'-piperidin]-4-yl)acetamide (single stereoisomer, first eluting compound as stereoisomer 1, I-28, preparative chiral HPLC retention time: 4.57 min, analytical chiral HPLC retention time 1.99 min). LCMS: 738[M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.53 (s, 1H), 8.41 – 8.39 (m, 1H), 8.03 – 7.98 (m, 2H), 7.72 – 7.71 (m, 2H), 7.42 (s, 1H), 5.38 – 5.18 (m, 2H), 4.54 (t, 1H), 3.94 (s, 3H), 3.54 – 3.46 (m, 2H), 3.34 – 3.25 (m, 0.5H), 3.20 –3.00 (m, 1H), 2.86 – 2.73 (m, 1.5H), 2.51 – 2.44 (m, 4H), 2.27 – 2.01 (m, 2H), 1.61 – 1.16 (m, 5H).

[0289] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(1'-(5-hydroxy-6-methylpyrimidine-4- carbonyl)-2-(2-methoxypyridin-4-yl)-5-methyl-8-oxo-2,5,6,8-tetrahydro-4H- spiro[cyclopenta[b][1,2,3]triazolo[4,5-e]pyridine-7,4'-piperidin]-4-yl)acetamide (single stereoisomer, second eluting compound as stereoisomer 2, I-29, preparative chiral HPLC retention time: 6.68 min, analytical chiral HPLC retention time 2.483 min). LCMS: 738[M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.54 (s, 1H), 8.40 – 8.39 (m, 1H), 8.03 – 7.98 (m, 2H), 7.72 – 7.70 (m, 2H), 7.42 (s, 1H), 5.38 – 5.19 (m, 2H), 4.54 (t, 1H), 3.94 (s, 3H), 3.54 – 3.46 (m, 2H), 3.34 – 3.25 (m, 0.5H), 3.20 –3.00 (m, 1H), 2.86 – 2.73 (m, 1.5H), 2.51 – 2.44 (m, 4H), 2.27 – 2.01 (m, 2H), 1.61 – 1.16 (m, 5H). Intermediates Synthesis of 6-bromo-3-((4-methoxybenzyl)amino)pyrazine-2-carbonyl chloride (Intermediate- 1) 146 BUSINESS.33169534.1 407274-95WRWO (217205).00 g, 31.8 mmol, 1.00 eq) and (4-methoxyphenyl)methanamine (3.93 g, 28.6 mmol, 0.90 eq) in 1,4- dioxane (80.0 mL) was added DIEA (6.17 g, 47.7 mmol, 1.50 eq) at 0 °C. The resulting mixture was stirred overnight at 90 °C. The resulting mixture was concentrated under reduced pressure and the residue was purified by flash silica gel chromatography (eluent of EtOAc / PE) to afford methyl 6-bromo-3-((4-methoxybenzyl)amino)pyrazine-2-carboxylate. LCMS: 352 / 354 [M+H]+.

[0291] Step 2. To a stirred solution of methyl 6-bromo-3-((4-methoxybenzyl)amino)pyrazine- 2-carboxylate (2.00 g, 5.70 mmol, 1.00 eq) in THF (20.0 mL) was added the solution of LiOH (408 mg, 17.1 mmol, 3.00 eq) in H2O (20.0 mL) at room temperature. The resulting mixture was stirred for 2 h at 60 °C. The mixture was acidified to pH~5 with 1 N aq. HCl. The resulting mixture was extracted with EtOAc (3 x 40 mL). The combined organic layer was dried with anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 6-bromo- 3-((4-methoxybenzyl)amino)pyrazine-2-carboxylic acid, which was used in the next step without further purification. LCMS: 338 / 340 [M+H]+.

[0292] Step 3. To a stirred solution of 6-bromo-3-((4-methoxybenzyl)amino)pyrazine-2- carboxylic acid (2.00 g, 5.91 mmol, 1.00 eq) in DCM (40.0 mL) were added (COCl)2 (1.13 g, 8.87 mmol, 1.50 eq) and DMF (43 mg, 591 µmol, 0.10 eq) at 0 °C. The resulting mixture was stirred for 1 h at room temperature under N2atmosphere. The resulting mixture was concentrated under reduced pressure to afford 6-bromo-3-((4-methoxybenzyl)amino)pyrazine-2-carbonyl chloride (Intermediate-1), which was used in the next step without further purification. 147 BUSINESS.33169534.1 407274-95WRWO (217205)Synthesis of tert-butyl 2-methyl-3-oxo-8-azaspiro[4.5]dec-1-ene-8-carboxylate (Intermediate- 2), tert-butyl 2-methyl-3-oxo-8-azaspiro[4.5]decane-8-carboxylate (racemic mixture, Intermediate-3), and tert-butyl 3-methyl-2-(pyrrolidin-1-yl)-8-azaspiro[4.5]dec-1-ene-8- carboxylate (racemic mixture, Intermediate-4)

[0293] Step 1. Diethyl (2-oxopropyl)phosphonate (46.8 g, 241 mmol, 1.50 eq) was added to a solution of KOH (13.5 g, 241 mmol, 1.50 eq) in EtOH / H2O (300 mL, 4:1) at 0 °C. The mixture was stirred at 0 °C for 30 minutes, then the ice bath was removed and tert-butyl 4-oxopiperidine- 1-carboxylate (32.0 g, 161 mmol, 1.00 eq) was added in portions over 10 min. After stirring for 1 h at room temperature, all volatiles were removed under reduced pressure. The residue was diluted with water and the aqueous phase was extracted with EtOAc (3 × 300 mL). The combined organic layer was washed with brine (50 mL), dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography 148 BUSINESS.33169534.1 407274-95WRWO (217205)(eluent of EtOAc / PE) to afford tert-butyl 4-(2-oxopropylidene)piperidine-1-carboxylate. LCMS: 140[M+H,-Boc]+.

[0294] Step 2. To a solution of phenyl(vinyl)sulfane (9.56 g, 70.2 mmol, 1.20 eq) and TMEDA (8.16 g, 70.2 mmol, 1.20 eq) in THF (200 mL) was added dropwise n-BuLi (2.5 M in THF, 32.7 mL, 81.9 mmol, 1.40 eq) at -78 °C under N2 atmosphere. The reaction mixture was stirred at -5 °C for 30 min. The reaction mixture was cooled down to -78 °C. Then, a solution of tert-butyl 4-(2- oxopropylidene)piperidine-1-carboxylate (14.0 g, 58.5 mmol, 1.00 eq) in THF (40 mL) was added dropwise and the mixture was stirred for another 1 h. The reaction mixture was treated with sat. aq. NH4Cl solution (300 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layer was washed with brine (50 mL), dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of EtOAc / PE) to afford tert-butyl 4-(2-hydroxy-2-methyl-3-(phenylthio)but-3-en-1- ylidene)piperidine-1-carboxylate (racemic mixture). LCMS: 376[M+H]+.

[0295] Step 3. To a stirred solution of tert-butyl 4-(2-hydroxy-2-methyl-3-(phenylthio)but-3- en-1-ylidene)piperidine-1-carboxylate (78.0 g, 208 mmol, 1.00 eq, racemic mixture) in ACN (1.56 L) was added Bi(OTf)3 (6.81 g, 10.4 mmol, 0.05 eq) at room temperature, and then stirred for 30min at 60 °C. Then, an additional batch of Bi(OTf)3 (6.81 g, 10.4 mmol, 0.05 eq) was added at 60°C, and the resulting mixture was stirred for 2 h at 60 °C. Next, H2O (312 mL) was added and the mixture was stirred for 1 h at 60 °C. The resulting mixture was allowed to cool down to room temperature, followed by addition of sat. aq. NaHCO3solution (1.5 L). The mixture was extracted with EtOAc (3 x 2 L). The combined organic layer was washed with brine (1L), dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (C18 column, water (0.1% FA)-ACN) to get a crude product. The crude product was further purified by flash silica gel chromatography (eluent of EtOAc / PE) to afford tert-butyl 2-methyl-3-oxo-8-azaspiro[4.5]dec-1-ene-8-carboxylate (Intermediate-2). LCMS: 210[M+H-t-Bu]+.

[0296] Step 4. To a stirred solution of tert-butyl 2-methyl-3-oxo-8-azaspiro[4.5]dec-1-ene-8- carboxylate (2.30 g, 8.67 mmol, 1.00 eq, Intermediate-2) in MeOH (50 mL) was added Pd / C (461 mg, 5 wt% Pd) at room temperature. The resulting mixture was stirred overnight at room temperature under H2(30 atm) atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH. The combined filtrate was concentrated under reduced pressure to afford 149 BUSINESS.33169534.1 407274-95WRWO (217205)the tert-butyl 2-methyl-3-oxo-8-azaspiro[4.5]decane-8-carboxylate (racemic mixture, Intermediate-3), which was used in the next step without further purification. LCMS: 268[M+H]+.

[0297] Step 5. To a stirred mixture of molecular sieves 4 Å (10.0 g), pTsOH-H2O (370 mg, 1.95 mmol, 0.10 eq) and tert-butyl 2-methyl-3-oxo-8-azaspiro[4.5]decane-8-carboxylate (5.20 g, 19.5 mmol, 1.00 eq, racemic mixture, Intermediate-3) in toluene (100 mL) was added pyrrolidine (6.92 g, 97.3 mmol, 5.00 eq) at room temperature. The resulting mixture was stirred overnight at 120 °C under N2atmosphere. The resulting mixture was filtered, and the filter cake was washed with toluene. The combined filtrate was concentrated under reduced pressure to afford the tert- butyl 3-methyl-2-(pyrrolidin-1-yl)-8-azaspiro[4.5]dec-1-ene-8-carboxylate (racemic mixture, Intermediate-4), which was used in the next step without further purification. GCMS: 320[M]+. Synthesis of tert-butyl 2-bromo-6-methyl-9-oxo-5,6,7,9- tetrahydrospiro[cyclopenta[5,6]pyrido[2,3-b]pyrazine-8,4'-piperidine]-1'-carboxylate (racemic mixture, Intermediate 5) and tert-butyl 2-bromo-5-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-6-methyl-9-oxo-5,6,7,9- tetrahydrospiro[cyclopenta[5,6]pyrido[2,3-b]pyrazine-8,4'-piperidine]-1'-carboxylate (racemic mixture, Intermediate 7) BUSINEWO (217205)

[0298] Step 1. To the stirred solution of tert-butyl 3-methyl-2-(pyrrolidin-1-yl)-8- azaspiro[4.5]dec-1-ene-8-carboxylate (6.40 g, 20.0 mmol, 1.00 eq, Intermediate-4) in THF (100 mL) were added 6-bromo-3-((4-methoxybenzyl)amino)pyrazine-2-carbonyl chloride (5.70 g, 16.0 mmol, 0.80 eq, Intermediate-1) in portions at 0 °C, and then TEA (2.02 g, 20.0 mmol, 1.00 eq) was added dropwise at 0 °C. The resulting mixture was stirred for 2 h at room temperature under N2 atmosphere. The reaction was treated with water and extracted with EtOAc (3 x 100 mL). The combined organic layer was dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and then purified by reverse phase HPLC (C18 column, water (10 mmol / L NH4HCO3)-ACN) to afford tert-butyl 1-(6-bromo-3-((4- methoxybenzyl)amino)pyrazine-2-carbonyl)-3-methyl-2-(pyrrolidin-1-yl)-8-azaspiro[4.5]dec-1- ene-8-carboxylate (racemic mixture). LCMS:640 / 642[M+H]+.

[0299] Step 2. To a stirred solution of tert-butyl 1-(6-bromo-3-((4- methoxybenzyl)amino)pyrazine-2-carbonyl)-3-methyl-2-(pyrrolidin-1-yl)-8-azaspiro[4.5]dec-1- ene-8-carboxylate (500 mg, 0.78 mmol, 1.00 eq) in AcOH (10 mL) was added water (1 mL) at room temperature. The resulting mixture was stirred for 2 days at room temperature. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl 1-(6-bromo-3-((4- methoxybenzyl)amino)pyrazine-2-carbonyl)-3-methyl-2-oxo-8-azaspiro[4.5]decane-8- carboxylate (racemic mixture), which was used in the next step without further purification. LCMS:587 / 589[M+H]+. 151 BUSINESS.33169534.1 407274-95WRWO (217205)

[0300] Step 3. A mixture of tert-butyl 1-(6-bromo-3-((4-methoxybenzyl)amino)pyrazine-2- carbonyl)-3-methyl-2-oxo-8-azaspiro[4.5]decane-8-carboxylate (400 mg, 0.68 mmol, 1.00 eq) and TFA (10.0 mL) was stirred for 1h at 60 °C. The resulting mixture was concentrated under reduced pressure to afford 2-bromo-6-methyl-6,7-dihydrospiro[cyclopenta[5,6]pyrido[2,3-b]pyrazine- 8,4'-piperidin]-9(5H)-one 2,2,2-trifluoroacetate (racemic mixture), which was used in the next step without further purification. LCMS:349 / 351[M+H]+(M corresponds to free base).

[0301] Step 4. To a stirred solution of 2-bromo-6-methyl-6,7- dihydrospiro[cyclopenta[5,6]pyrido[2,3-b]pyrazine-8,4'-piperidin]-9(5H)-one 2,2,2- trifluoroacetate (400 mg, 1.15 mmol, 1.00 eq) in THF (10 mL) was added saturated aq. NaHCO3 (10 mL) at room temperature, and then Boc2O (500 mg, 2.30 mmol, 2.00 eq) was added at room temperature. The resulting mixture was stirred for 2 h at room temperature, followed by extraction with EtOAc (3 x 20 mL). The combined organic layer was dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (C18 column, water (10 mmol / L NH4HCO3)-ACN) to afford tert-butyl 2- bromo-6-methyl-9-oxo-5,6,7,9-tetrahydrospiro[cyclopenta[5,6]pyrido[2,3-b]pyrazine-8,4'- piperidine]-1'-carboxylate (racemic mixture, Intermediate-5). LCMS: 449 / 451[M+H]+.

[0302] Step 5. To a stirred solution of tert-butyl 2-bromo-6-methyl-9-oxo-5,6,7,9- tetrahydrospiro[cyclopenta[5,6]pyrido[2,3-b]pyrazine-8,4'-piperidine]-1'-carboxylate (230 mg, 0.51 mmol, 1.00 eq) and N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide (223 mg, 0.61 mmol, 1.20 eq, Intermediate-6) in ACN (3 mL) was added DIEA (198 mg, 1.53 mmol, 3.00 eq) at room temperature. The resulting mixture was stirred for 2 h at 60 °C. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was concentrated under reduced pressure. The residue was purified by trituration with EtOAc (2 mL) to afford tert-butyl 2-bromo-5-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)- 6-methyl-9-oxo-5,6,7,9-tetrahydrospiro[cyclopenta[5,6]pyrido[2,3-b]pyrazine-8,4'-piperidine]- 1'-carboxylate (racemic mixture, Intermediate-7). LCMS: 684 / 686[M+H]+. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(dimethylamino)-6-methyl-9-oxo-6,9- dihydrospiro[cyclopenta[5,6]pyrido[2,3-b]pyrazine-8,4'-piperidin]-5(7H)-yl)acetamide hydrochloride (racemic mixture, Intermediate-8) 152 BUSINESS.33169534.1 407274-95WRWO (217205)[00303-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-6-methyl-9-oxo-5,6,7,9- tetrahydrospiro[cyclopenta[5,6]pyrido[2,3-b]pyrazine-8,4'-piperidine]-1'-carboxylate (200 mg, 0.29 mmol, 1.00 eq, racemic mixture, Intermediate-7) and dimethylamine hydrochloride (119 mg, 1.45 mmol, 5.00 eq) in 1,4-dioxane (4 mL) was added DIEA (226 mg, 1.74 mmol, 6.00 eq) at room temperature. The resulting mixture was stirred for 8 h at 100 °C. The reaction mixture was cooled down to room temperature, and then was diluted with H2O (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified by trituration with EtOAc (2 mL) to afford tert-butyl 5-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(dimethylamino)-6-methyl-9-oxo-5,6,7,9- tetrahydrospiro[cyclopenta[5,6]pyrido[2,3-b]pyrazine-8,4'-piperidine]-1'-carboxylate (racemic mixture). LCMS:649[M+H]+.

[0304] Step 2. To a stirred solution of tert-butyl 5-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(dimethylamino)-6-methyl-9-oxo-5,6,7,9- tetrahydrospiro[cyclopenta[5,6]pyrido[2,3-b]pyrazine-8,4'-piperidine]-1'-carboxylate (100 mg, 153 BUSINESS.33169534.1 407274-95WRWO (217205)0.15 mmol, 1.00 eq) in 1,4-dioxane (1 mL) was added 4 M HCl solution in 1,4-dioxane (1 mL, 4.00 mmol, 26.7 eq) at room temperature. The resulting mixture was stirred for 2 h at room temperature and then concentrated under reduced pressure to afford N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(2-(dimethylamino)-6-methyl-9-oxo-6,9- dihydrospiro[cyclopenta[5,6]pyrido[2,3-b]pyrazine-8,4'-piperidin]-5(7H)-yl)acetamide hydrochloride (racemic mixture, Intermediate-8), which was used in the next step without further purification. LCMS: 549[M+H]+(M corresponds to free base). Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-cyclopropyl-6-methyl-9-oxo-6,9- dihydrospiro[cyclopenta[5,6]pyrido[2,3-b]pyrazine-8,4'-piperidin]-5(7H)-yl)acetamide hydrochloride (racemic mixture, Intermediate-9) Boc Boc N B(OH)2N d1

[0305] Step 1. To a mixture of tert-butyl 2-bromo-5-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-6-methyl-9-oxo-5,6,7,9- tetrahydrospiro[cyclopenta[5,6]pyrido[2,3-b]pyrazine-8,4'-piperidine]-1'-carboxylate (290 mg, 423 µmol, 1.00 eq, racemic mixture, Intermediate-7), cyclopropylboronic acid (73 mg, 846 µmol, 154 BUSINESS.33169534.1 407274-95WRWO (217205)2.00 eq) and K3PO4(539 mg, 2.54 mmol, 6.00 eq) in toluene (5.80 mL) and H2O (0.58 mL) was added Pd(dppf)Cl2 (62 mg, 85 µmol, 0.20 eq) at room temperature. The mixture was degassed three times with N2, followed by stirring for 30 min at 110 °C under N2 atmosphere. The resulting mixture was filtered and the filter cake was washed with ACN. The combined filtrate was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (C18 Column, water (10% NH4HCO3)-ACN) to afford tert-butyl 5-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-cyclopropyl-6-methyl-9-oxo-5,6,7,9- tetrahydrospiro[cyclopenta[5,6]pyrido[2,3-b]pyrazine-8,4'-piperidine]-1'-carboxylate (racemic mixture). LCMS: 646[M+H]+.

[0306] Step 2. To a mixture of tert-butyl 5-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-2-cyclopropyl-6-methyl-9-oxo-5,6,7,9-tetrahydrospiro[cyclopenta[5,6]pyrido[2,3- b]pyrazine-8,4'-piperidine]-1'-carboxylate (130 mg, 201 µmol, 1.00 eq, racemic mixture) in DCM (0.65 mL) was added 4 M HCl in 1,4-dioxane (0.65 mL, 2.60 mmol, 12.9 eq). The resulting solution was stirred at room temperature for 1 h, followed by concentration under reduced pressure to afford N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-cyclopropyl-6-methyl-9-oxo-6,9- dihydrospiro[cyclopenta[5,6]pyrido[2,3-b]pyrazine-8,4'-piperidin]-5(7H)-yl)acetamide hydrochloride (racemic mixture, Intermediate-9), which was used in the next step without further purification. LCMS: 546[M+H]+(M corresponds to free base). Synthesis of 5-hydroxy-6-methylpyrimidine-4-carbonyl chloride (Intermediate-11)

[0307] Step 1.o a so u o o so u - y o y- - e y py e- -carboxylate (180 mg, 1.02 mmol, 1.00 eq, Intermediate-16) in DCM (2.00 mL) was added (COCl)2(259 mg, 2.04 mmol, 2.00 eq) and two drops of DMF at 0oC. The resulting mixture was stirred at room temperature for 30 min and then concentrated under reduced pressure to afford 5-hydroxy-6-methylpyrimidine-4- carbonyl chloride, which was used in the next step without further purification. LCMS: 169[M+H]+. 155 BUSINESS.33169534.1 407274-95WRWO (217205)Synthesis of methyl 5-methoxy-6-methylpyrimidine-4-carboxylate (Intermediate-18) and 5- hydroxy-6-methylpyrimidine-4-carboxylic acid (Intermediate-10)

[0308] Step 1: To a mixture of 4,6-dichloro-5-methoxypyrimidine (30.00 g, 167.6 mmol, 1.0 eq) in THF (300 mL) was added a 3 M solution of MeMgBr (61.45 mL, 184.4 mmol, 1.1 eq) in diethyl ether dropwise at 0 °C and then the mixture was stirred at 5 °C for 1 h. The resulting mixture was poured into H2O (200 mL) and extracted with EtOAc (100 mL*3). The combined organic layer was washed with brine (100 mL), dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuum. The residue was purified by flash silica gel chromatography (eluent of EtOAc / PE) to afford 4-chloro-5-methoxy-6-methylpyrimidine. LCMS: 159.1 [M+H]+.

[0309] Step 2: To a mixture of 4-chloro-5-methoxy-6-methylpyrimidine (22.00 g, 138.7 mmol, 1.0 eq) in MeOH (250 mL) was added Pd(dppf)Cl2-CH2Cl2 (6.80 g, 8.32 mmol, 0.06 eq) and TEA (28.1 g, 278 mmol, 2.0 eq). The reaction was purged with CO (50 psi) and stirred at 50 °C overnight. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of EtOAc / PE) to afford methyl 5-methoxy-6-methylpyrimidine-4-carboxylate (Intermediate-18). LCMS: 183.1 [M+H]+.

[0310] Step 3: A mixture of methyl 5-methoxy-6-methylpyrimidine-4-carboxylate (16.00 g, 87.83 mmol, 1.0 eq) in 68wt% aq. HBr solution (68.5 mL) was stirred at 50 °C overnight. Then 56wt% aq. HI solution (67.2 mL) was added and the mixture was stirred at 50 °C for 6 h. The reaction mixture was cooled to room temperature and basified with 50wt% aq. NaOH solution to pH ~9 at 0 °C, then adjusted to pH ~7 with 2 M aq. HCl solution at 0 °C. The mixture was filtered, the filter cake was dried in vacuum to afford 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (Intermediate-10), which was used in the next step without further purification. LCMS: 155.1 [M+H]+. Synthesis of 6-hydroxybenzo[d]oxazole-7-carboxylic acid (Intermediate-12). 156 BUSINESS.33169534.1 407274-95WRWO (217205)

[0311] Step 1. To a stirred solution of methyl 6-hydroxybenzo[d]oxazole-7-carboxylate (45 mg, 0.23 mmol, 1.00 eq) in H2O (0.10 mL) and MeOH (0.40 mL) was added NaOH (94 mg, 2.33 mmol, 10.0 eq) at room temperature. The resulting mixture was stirred for 3 h at 60 °C and then allowed to cool down to room temperature, followed by dilution with H2O (1 mL). The pH value was adjusted to 5~6 with 1 N aq. HCl while being cooled in an ice-water bath. The mixture was extracted with EtOAc (3 x 5 mL). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 6- hydroxybenzo[d]oxazole-7-carboxylic acid (Intermediate-12), which was used for next stepwithout further purification. LCMS: 180[M+H]+.Synthesis of 4-hydroxy-2-methoxynicotinic acid (Intermediate-13).

[0312] Step 1. To a stirred solution of methyl 4-hydroxy-2-methoxynicotinate (Intermediate- 29) (1.00 g, 5.46 mmol, 1.00 eq) in H2O (2.00 mL) and MeOH (8.00 mL) was added NaOH (2.18 g, 54.5 mmol, 10.0 eq) at room temperature. The resulting mixture was stirred for 16 h at 60 °C and then allowed to cool down to room temperature. The mixture was diluted with H2O (10 mL) and the pH value was adjusted to ~2 with 1 N aq. HCl while cooled in an ice-water bath. The mixture was extracted with DCM / MeOH (10 / 1) (3 x 20 mL). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 4-hydroxy-2-methoxynicotinic acid (Intermediate-13), which was used for next step without further purification. LCMS: 170[M+H]+. Synthesis of 3-hydroxy-2-methoxyisonicotinic acid (Intermediate-14). 157 BUSINESS.33169534.1 407274-95WRWO (217205)

[0313] Step 1. To a stirred mixture of 3-amino-2-methoxyisonicotinic acid (3.00 g, 17.8 mmol, 1 eq) in H2O (42.0 mL) was added H2SO4 (1.80 mL, 169 mmol, 9.50 eq) dropwise at 0 °C. To the above mixture was added a solution of NaNO2 (1.23 g, 17.8 mmol, 1.00 eq) in H2O (12.0 mL) dropwise at 0 °C. The resulting mixture was stirred at 80 °C for additional 1 h. The mixture was allowed to cool down to room temperature, followed by adjustment of the pH value to ~7 with 1 N aq. NaOH. The resulting mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (C18 column, water (0.1% FA)-ACN) to afford 3-hydroxy- 2-methoxyisonicotinic acid (Intermediate-14). LCMS: 170[M+H]+. Synthesis of ethyl 2-(2-(dimethylamino)-6-methyl-9-oxo-6,9- dihydrospiro[cyclopenta[5,6]pyrido[2,3-b]pyrazine-8,4'-piperidin]-5(7H)-yl)acetate hydrochloride (racemic mixture, Intermediate-15) and 2-(2-(dimethylamino)-1'-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-6-methyl-9-oxo-6,9-dihydrospiro[cyclopenta[5,6]pyrido[2,3- b]pyrazine-8,4'-piperidin]-5(7H)-yl)acetic acid (racemic mixture, Intermediate-17). BUSINESS.35WRWO (217205)

[0314] Step 1. To a stirred mixture of tert-butyl 2-bromo-6-methyl-9-oxo-5,6,7,9- tetrahydrospiro[cyclopenta[5,6]pyrido[2,3-b]pyrazine-8,4'-piperidine]-1'-carboxylate (500 mg, 1.11 mmol, 1.00 eq, racemic mixture, Intermediate-5) and dimethylamine hydrochloride (450 mg, 5.52 mmol, 4.96 eq) in 1,4-dioxane (5.00 mL) was added DIEA (850 mg, 6.58 mmol, 5.91 eq) at room temperature. The resulting mixture was stirred at 100 °C for 16 h and then cooled down to room temperature. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (4 x 20 mL). The combined organic layer was dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash silica gel chromatography (eluent of DCM / MeOH) to afford tert-butyl 2-(dimethylamino)-6-methyl-9-oxo- 5,6,7,9-tetrahydrospiro[cyclopenta[5,6]pyrido[2,3-b]pyrazine-8,4'-piperidine]-1'-carboxylate (racemic mixture). LCMS: 414[M+H]+.

[0315] Step 2. To a solution of tert-butyl 2-(dimethylamino)-6-methyl-9-oxo-5,6,7,9- tetrahydrospiro[cyclopenta[5,6]pyrido[2,3-b]pyrazine-8,4'-piperidine]-1'-carboxylate (400 mg, 0.97 mmol, 1.00 eq, racemic mixture) in THF (4.00 mL) was added NaH (193 mg, 4.83 mmol, 5.00 eq, 60% dispersion in mineral oil) at 0 °C. The mixture was stirred for 30 min at 0 °C. Then, ethyl bromoacetate (485 mg, 2.90 mmol, 3.00 eq) was added and the mixture was warmed to 60 °C and stirred for 2 h. The mixture was then cooled down to room temperature and treated with sat. aq. NH4Cl solution (20 mL), followed by extraction with EtOAc (3 x 20 mL). The combined organic layer was dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (C18 column, water (6 mmol / L NH4HCO3)-ACN) to afford tert-butyl 2-(dimethylamino)-5-(2-ethoxy-2-oxoethyl)-6-methyl-9- 159 BUSINESS.33169534.1 407274-95WRWO (217205)oxo-5,6,7,9-tetrahydrospiro[cyclopenta[5,6]pyrido[2,3-b]pyrazine-8,4'-piperidine]-1'-carboxylate (racemic mixture). LCMS: 500[M+H]+.

[0316] Step 3. To a solution of tert-butyl 2-(dimethylamino)-5-(2-ethoxy-2-oxoethyl)-6- methyl-9-oxo-5,6,7,9-tetrahydrospiro[cyclopenta[5,6]pyrido[2,3-b]pyrazine-8,4'-piperidine]-1'- carboxylate (300 mg, 0.60 mmol, 1.00 eq, racemic mixture) in DCM (3.00 mL) was added 4 M HCl in 1,4-dioxane (0.60 mL, 2.40 mmol, 4.00 eq). The resulting solution was stirred at room temperature for 1 h, followed by concentration under reduced pressure to afford ethyl 2-(2- (dimethylamino)-6-methyl-9-oxo-6,9-dihydrospiro[cyclopenta[5,6]pyrido[2,3-b]pyrazine-8,4'- piperidin]-5(7H)-yl)acetate hydrochloride (racemic mixture, Intermediate-15), which was used in the next step without further purification. LCMS: 400[M-H]+. (M corresponds to free base).

[0317] Step 4. To a stirred solution of ethyl 2-(2-(dimethylamino)-6-methyl-9-oxo-6,9- dihydrospiro[cyclopenta[5,6]pyrido[2,3-b]pyrazine-8,4'-piperidin]-5(7H)-yl)acetate hydrochloride (300 mg, 0.69 mmol, 1.00 eq, racemic mixture, Intermediate-15) and sodium 5- hydroxy-6-methylpyrimidine-4-carboxylate (243 mg, 1.38 mmol, 2.00 eq, Intermediate- 16) in THF (3.00 mL) and DMF (3.00 mL) were added DIEA (356 mg, 2.76 mmol, 4.00 eq) and HATU (524 mg, 1.38 mmol, 2.00 eq). The resulting mixture was stirred at room temperature for 30 min. Next, the mixture was poured into 1 N aq. NaOH solution (6 mL) and the resulting mixture was stirred at 40 °C for 30 min, followed by cooled down to room temperature. The mixture was acidified to pH~3 with 1 N aq. HCl and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (C18 column, water (0.05% FA)-ACN) to afford 2-(2-(dimethylamino)-1'-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-6-methyl-9-oxo- 6,9-dihydrospiro[cyclopenta[5,6]pyrido[2,3-b]pyrazine-8,4'-piperidin]-5(7H)-yl)acetic acid (racemic mixture, Intermediate-17). LCMS: 508[M+H]+. Synthesis of sodium 5-hydroxy-6-methylpyrimidine-4-carboxylate (Intermediate-16)160 BUSINESS.33169534.1 407274-95WRWO (217205)

[0318] Step 1. To a solution of methyl 5-methoxy-6-methylpyrimidine-4-carboxylate (Intermediate-18) (10.0 g, 41.1 mmol, 1.00 eq) in DMF (100 mL) was added NaSEt (17.3 g, 205 mmol, 5.00 eq) under N2 atmosphere. The reaction mixture was stirred at 50 °C for 3 hours, then cooled to 20 °C, diluted with water (30 mL) and stirred for 1 hour. Then MTBE (200 mL) was added and the resulting mixture was stirred for 30 min. The aqueous layer was separated and adjusted to pH = 7.0~8.0 with 12M HCl (aq.) at 0 °C. The resulting mixture was stirred for 1 hour at 0 °C and filtered to give the crude product. The crude product was triturated with EtOH (70 mL) at 20 °C for 4 hours, filtered and dried under reduced pressure to afford sodium 5-hydroxy-6- methylpyrimidine-4-carboxylate (Intermediate-16). LCMS: 155.1 [M-Na+2H]+. Synthesis of 8-(tert-butyl) 1-ethyl 3-methyl-2-oxo-8-azaspiro[4.5]decane-1,8-dicarboxylate (racemic mixture, Intermediate-19), and 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 (racemic mixture, Intermediate-20), 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 (racemic mixture, Intermediate-21), and 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 hydrochloride (racemic mixture, Intermediate-22).161 BUSINESS.33169534.1 407274-95WRWO (217205)

[0319] Step 1. To a solution of tert-butyl 2-methyl-3-oxo-e-8- carboxylate (5.00 g, 18.8 mmol, 1.00 eq, Intermediate-2) in THF (90.0 mL) was added dropwise LDA (19.0 mL, 37.6 mmol, 2.00 eq, 2 M in THF) at -78 °C under N2 atmosphere. The reaction mixture was stirred at 0 °C for 1 h. Then, a solution of ethyl cyanoformate (3.73 g, 37.6 mmol, 2.00 eq) in THF (10.0 mL) was added to the reaction mixture dropwise at -78 °C. The resulting solution was stirred for additional 1 h, during which time the temperature was allowed to increase to -40 °C. The reaction was then terminated at this temperature by the addition of sat. aq. NH4Cl solution (50.0 mL) and then the mixture was extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in MeOH and purified by reverse phase HPLC (C18 Column, water (0.1% FA)-ACN) to afford 8-(tert-butyl) 1-ethyl 3-methyl-2-oxo-8- azaspiro[4.5]dec-3-ene-1,8-dicarboxylate (racemic mixture). LCMS: 282.0[M+H-t-Bu]+.

[0320] Step 2. To a stirred solution of 8-tert-butyl 1-ethyl 3-methyl-2-oxo-8-azaspiro[4.5]dec- 3-ene-1,8-dicarboxylate (2.50 g, 7.41 mmol, 1.00 eq, racemic mixture) in EtOAc (25.0 mL) was added Pd / C (250 mg, 5% Pd basis) at room temperature under N2 atmosphere. The resulting 162 BUSINESS.33169534.1 407274-95WRWO (217205)mixture was purged three times with H2and stirred for 1 h at room temperature under H2atmosphere (2 atm). The resulting mixture was filtered, and the filter cake was washed with MeOH. All the filtrates were combined and concentrated under reduced pressure, to give a residue of 8- (tert-butyl) 1-ethyl 3-methyl-2-oxo-8-azaspiro[4.5]decane-1,8-dicarboxylate (racemic mixture, Intermediate-19), which was used in the next step directly without further purification. LCMS: 284.0[M+H-t-Bu]+.

[0321] Step 3. A solution of 8-(tert-butyl) 1-ethyl 3-methyl-2-oxo-8-azaspiro[4.5]decane-1,8- dicarboxylate (2.40 g, 7.07 mmol, 1.00 eq, racemic mixture, Intermediate-19), 5-bromo-2H-1,2,4- triazol-3-amine (1.15 g, 7.07 mmol, 1.00 eq) and H3PO4 (4.88 g, 42.4 mmol, 6.00 eq, 85%wt in water) in EtOH (24.0 mL) was stirred at 100 °C overnight. The resulting mixture was allowed to cool down to room temperature and all volatiles were removed under reduced pressure. The residue was dissolved in DCM (30 mL), cooled in an ice-water bath, and DIEA was added to the solution until the pH reached ~9. Next, di-tert-butyl dicarbonate (2.00 g, 9.17 mmol, 1.30 eq) was added at room temperature and the resulting mixture was stirred for 0.5 h at room temperature. The resulting suspension was filtered, and the filtrate was concentrated under vacuum. The residue 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 (racemic mixture, Intermediate-20) was dissolved in MeOH and purified by reverse phase HPLC (C18 column, water (0.1% FA)-ACN) to afford the title compound. LCMS: 438.0 / 440.0[M+H]+.

[0322] Step 4. A mixture 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, 1.00 eq, racemic mixture, Intermediate-20), N-[2-chloro-4- (trifluoromethyl)phenyl]-2-iodoacetamide (373 mg, 1.03 mmol, 1.00 eq, Intermediate-6), and DIEA (398 mg, 3.09 mmol, 3.00 eq) in THF (10.0 mL) was stirred overnight at 60 °C. The resulting mixture was allowed to cool down to room temperature and was then concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of EtOAc / PE) to afford 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 (racemic mixture, Intermediate-21). LCMS: 673.0 / 675.0[M+H]+.

[0323] Step 5. To a stirred mixture of tert-butyl 2-bromo-4-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-methyl-8-oxo-4,5,6,8- 163 BUSINESS.33169534.1 407274-95WRWO (217205)tetrahydrospiro[cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-7,4'-piperidine]-1'-carboxylate (350 mg, 0.52 mmol, 1.00 eq, racemic mixture, Intermediate-21) and 2-(3,6-dihydro-2H-pyran-4- yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (218 mg, 1.04 mmol, 2.00 eq) in 1,4-dioxane (7.00 mL) and H2O (0.70 mL) were added Na2CO3(165 mg, 1.56 mmol, 3.00 equiv) and Pd(dppf)Cl2- CH2Cl2 (43 mg, 0.05 mmol, 0.10 eq) at room temperature under N2 atmosphere. The mixture was stirred for 2 h at 90 °C. The resulting mixture was allowed to cool down to room temperature and was then concentrated under reduced pressure. The residue was dissolved in DCM, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of EtOAc / PE) to afford 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 (racemic mixture). LCMS: 677.0[M+H]+.

[0324] Step 6. To a mixture 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 (270 mg, 0.40 mmol, 1.00 eq, racemic mixture) in DCM (2.00 mL) was added a solution of 4 M HCl solution in 1,4-dioxane (2.00 mL, 8.00 mmol, 20.0 eq) at room temperature. The resulting solution was stirred for 0.5 h at room temperature, and was then concentrated under reduced pressure. The resulting residue of 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 hydrochloride (racemic mixture, Intermediate-22) was used in the next step directly without further purification. LCMS: 577.0[M+H]+(M corresponds to free base). Synthesis of 5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)-2H-1,2,3-triazole-4- carboxylic acid (Intermediate-23) and 5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4- yl)-2H-1,2,3-triazole-4-carbonyl cyanide (Intermediate-24). 164 BUSINESS.33169534.1 407274-95WRWO (217205)

[0325] Step 1. To a stirred solution of HBF4(230 mL, 40% wt% in H2O) was added 2- methoxypyridin-4-amine (50.0 g, 403 mmol, 1.00 eq) at -10°C, and then was added NaNO2(30.6 g, 443 mmol, 1.10 eq) in portions over 15 min at -10°C. The resulting mixture was stirred at -10°C for additional 1h. To the above mixture was added a mixture of NaOAc (198 g, 2.42 mol, 6.00 eq) and ethyl 2-cyanoacetate (50.1 g, 443 mmol, 1.10 eq) in H2O (1.00 L) over 30 min at -10°C. The resulting mixture was stirred at room temperature for additional 1h. The precipitated solids were collected by filtration and washed with H2O. The resulting solid was air-dried to afford ethyl-2- cyano-2-(2-(2-methoxypyridin-4-yl)hydrazineylidene)acetate. LCMS: 249[M+H]+.

[0326] Step 2. To a stirred solution of ethyl-2-cyano-2-(2-(2-methoxypyridin-4- yl)hydrazineylidene)acetate (20.0 g, 80.6 mmol, 1.00 eq) in ACN (800 mL) was added bis(4- methoxybenzyl)amine (31.1 g, 121 mmol, 1.50 eq) at room temperature. The resulting mixture was stirred for 30 min at 80°C. To the above mixture was added Cu(OAc)2(14.6 g, 80.6 mmol, 1.00 eq) at 80 °C, after stirring for 2h at 80oC, an additional portion of Cu(OAc)2 (14.6 g, 80.6 mmol, 1.00 eq) was added to the mixture at 80 °C. The resulting mixture was stirred at 80 °C for overnight. The mixture was allowed to cool down to room temperature. The resulting mixture was 165 BUSINESS.33169534.1 407274-95WRWO (217205)filtered, the filter cake was washed with EtOAc. The filtrates were combined and concentrated under reduced pressure. The residue was dissolved in EtOAc, and was washed with FA (1wt% solution in water). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of EtOAc / PE) to afford ethyl 5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)-2H-1,2,3- triazole-4-carboxylate. LCMS: 504[M+H]+.

[0327] Step 3. To a stirred solution of ethyl 5-(bis(4-methoxybenzyl)amino)-2-(2- methoxypyridin-4-yl)-2H-1,2,3-triazole-4-carboxylate (10.0 g, 19.9 mmol, 1.00 eq) in MeOH (100 mL) was added a solution of NaOH (3.18 g, 79.6 mmol, 4.00 eq) in H2O (100 mL) at room temperature. After stirring for overnight at 60 °C, the reaction mixture was cooled down to room temperature and concentrated under reduced pressure to remove most of the MeOH. The mixture was acidified to pH=4 with 1N HCl (aq.). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 5-(bis(4- methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)-2H-1,2,3-triazole-4-carboxylic acid (Intermediate-23), which was used for next step without further purification. LCMS: 476 [M+H]+.

[0328] Step 4. To a stirred mixture of 5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin- 4-yl)-2H-1,2,3-triazole-4-carboxylic acid (Intermediate-23) (3.00 g, 6.31 mmol, 1.00 eq) in DCM (60.0 mL) was added oxalyl dichloride (1.20 g, 9.46 mmol, 1.50 eq) dropwise at 0 °C under N2 atmosphere. The resulting mixture was stirred for 1 h at room temperature under N2atmosphere, and then was concentrated under reduced pressure to afford 5-(bis(4-methoxybenzyl)amino)-2-(2- methoxypyridin-4-yl)-2H-1,2,3-triazole-4-carbonyl chloride, which was used in the next step without further purification.

[0329] Step 5. To a stirred mixture of 5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin- 4-yl)-2H-1,2,3-triazole-4-carbonyl chloride (8.60 g, 17.4 mmol, 1.00 eq) in ACN (150 mL) was added CuCN (3.10 g, 34.8 mmol, 2.00 eq) at room temperature. The resulting mixture was stirred for 1h at 80 °C under N2atmosphere. The resulting mixture was allowed to cool down to room temperature, and then was concentrated under reduced pressure to afford 5-(bis(4- methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)-2H-1,2,3-triazole-4-carbonyl cyanide (Intermediate-24), which was used in the next step without further purification. LCMS: 485[M+H]+. 166 BUSINESS.33169534.1 407274-95WRWO (217205)Synthesis of tert-butyl-2-(2-methoxypyridin-4-yl)-5-methyl-8-oxo-4,5,6,8-tetrahydro-2H- spiro[cyclopenta[b][1,2,3]triazolo[4,5-e]pyridine-7,4'-piperidine]-1'-carboxylate (racemic mixture, Intermediate-25)

[0330] Step 1. To a solution of tert-butyl 2-methyl-3-oxo-8-azaspiro[4.5]decane-8- carboxylate (racemic mixture, Intermediate-3) (2.68 g, 10.0 mmol, 1.00 eq) in THF (60.0 mL) was added dropwise LDA (7.50 mL, 15.0 mmol, 1.50 eq, 2.0 M in THF) at -78 °C under N2atmosphere. After stirred for 1 h at 0 °C, the reaction mixture was cooled down to -78 °C again. To the mixture was added a solution of 5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)-2H-1,2,3- triazole-4-carbonyl cyanide (Intermediate-24) (4.37 g, 9.02 mmol, 0.90 eq) in THF (20.0 mL) dropwise maintaining the temperature at approximately -78 °C. The resulting mixture was stirred for another 30 min at -78 °C. The reaction was quenched with saturated NH4Cl aqueous solution (100 mL). The mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in MeOH and purified by reverse Phase HPLC (C18 column, water (0.1% FA)-ACN) to afford tert-butyl 1-(5-(bis(4- methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)-2H-1,2,3-triazole-4-carbonyl)-3-methyl-2- oxo-8-azaspiro[4.5]decane-8-carboxylate (racemic mixture). LCMS: 725[M+H]+. 167 BUSINESS.33169534.1 407274-95WRWO (217205)

[0331] Step 2. A mixture of tert-butyl 1-(5-(bis(4-methoxybenzyl)amino)-2-(2- methoxypyridin-4-yl)-2H-1,2,3-triazole-4-carbonyl)-3-methyl-2-oxo-8-azaspiro[4.5]decane-8- carboxylate (racemic mixture) (4.00 g, 5.52 mmol, 1.00 eq) and TFA (40.0 mL) was stirred for 30 min at 60 °C. The reaction mixture was cooled down to room temperature, and then was concentrated under reduced pressure to afford 2-(2-methoxypyridin-4-yl)-5-methyl-2,4,5,6- tetrahydro-8H-spiro[cyclopenta[b][1,2,3]triazolo[4,5-e]pyridine-7,4'-piperidin]-8-one, TFA salt (racemic mixture), which was used in the next step without further purification. LCMS: 367 [M+H]+(M corresponds to free base).

[0332] Step 3. To a stirred solution of 2-(2-methoxypyridin-4-yl)-5-methyl-2,4,5,6-tetrahydro- 8H-spiro[cyclopenta[b][1,2,3]triazolo[4,5-e]pyridine-7,4'-piperidin]-8-one, TFA salt (racemic mixture) (3.00 g, 5.52 mmol, 1.00 eq) in THF (30.0 mL) were added saturated NaHCO3aqueous solution (30.0 mL) and Boc2O (3.58 g, 16.4 mmol, 2.00 eq) at room temperature. After stirred for 3 h at room temperature, the resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in MeOH and purified by reverse Phase HPLC (C18 column, water (0.1% FA)-ACN) to afford tert- butyl 2-(2-methoxypyridin-4-yl)-5-methyl-8-oxo-4,5,6,8-tetrahydro-2H- spiro[cyclopenta[b][1,2,3]triazolo[4,5-e]pyridine-7,4'-piperidine]-1'-carboxylate (racemic mixture, Intermediate-25). LCMS: 467 [M+H]+. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(2-methoxypyridin-4-yl)-5-methyl-8- oxo-2,5,6,8-tetrahydro-4H-spiro[cyclopenta[b][1,2,3]triazolo[4,5-e]pyridine-7,4'-piperidin]-4- yl)acetamide (racemic mixture, Intermediate-26) 168 BUSINESS.33169534.1 407274-95WRWO (217205)-8-oxo- 4,5,6,8-tetrahydro-2H-spiro[cyclopenta[b][1,2,3]triazolo[4,5-e]pyridine-7,4'-piperidine]-1'- carboxylate (racemic mixture, Intermediate-25) (70 mg, 150 µmol, 1.00 eq) and N-(2-chloro-4- (trifluoromethyl)phenyl)-2-iodoacetamide (Intermediate-6) (65 mg, 180 µmol, 1.20 eq) in THF (1.00 mL) was added DIEA (58 mg, 450 µmol, 3.00 eq) at room temperature. The resulting mixture was stirred for overnight at room temperature. The resulting mixture was purified directly by reverse phase HPLC (C18 column, water (0.1% FA)-ACN) to afford tert-butyl 4-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(2-methoxypyridin-4-yl)-5-methyl-8-oxo-4,5,6,8- tetrahydro-2H-spiro[cyclopenta[b][1,2,3]triazolo[4,5-e]pyridine-7,4'-piperidine]-1'-carboxylate (racemic mixture). LCMS:702[M+H]+.

[0334] Step 2. To a stirred solution of tert-butyl 4-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(2-methoxypyridin-4-yl)-5-methyl-8-oxo-4,5,6,8- tetrahydro-2H-spiro[cyclopenta[b][1,2,3]triazolo[4,5-e]pyridine-7,4'-piperidine]-1'-carboxylate (racemic mixture) (30 mg, 43 µmol, 1.00 eq) in DCM (0.40 mL) was added TFA (0.20 mL) at room temperature. The resulting mixture was stirred for 1 h at room temperature, and then was 169 BUSINESS.33169534.1 407274-95WRWO (217205)concentrated under reduced pressure. The residue was dissolved in ACN and H2O (with 0.1% HCl) and then was lyophilized to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(2-methoxypyridin- 4-yl)-5-methyl-8-oxo-2,5,6,8-tetrahydro-4H-spiro[cyclopenta[b][1,2,3]triazolo[4,5-e]pyridine- 7,4'-piperidin]-4-yl)acetamide, HCl salt (racemic mixture, Intermediate-26), which was used in the next step directly without further purification. LCMS:602[M+H]+(M corresponds to free base). Synthesis of 7-hydroxy-2,3-dihydrofuro[3,2-c]pyridine-6-carboxylic acid (Intermediate-27)

[0335] Step 1. To a solution of methyl 3-methylfuran-2-carboxylate (5.00 g, 35.7 mmol, 1.00 eq) in CCl4(50.0 mL) were added NBS (6.68 g, 37.5 mmol, 1.05 eq) and AIBN (2.35 g, 14.3 mmol, 0.40 eq) at room temperature. The mixture was degassed three times with N2and stirred at 50 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of EtOAc / PE) to afford methyl 3- (bromomethyl)furan-2-carboxylate. LCMS: 219 / 221 [M+H]+.

[0336] Step 2. To a solution of methyl 3-(bromomethyl)furan-2-carboxylate (4.70 g, 21.5 mmol, 1.00 eq) and K2CO3 (5.93 g, 43.0 mmol, 2.00 eq) in ACN (47.0 mL) was added methyl 2- (4-methylbenzenesulfonamido)acetate (5.23 g, 21.5 mmol, 1.00 eq) and the mixture was stirred at room temperature for 16 h. The reaction was filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica (Eluent of EtOAc / PE) to afford methyl 3-(((N-(2-methoxy-2-oxoethyl)-4-methylphenyl)sulfonamido)methyl)furan-2- carboxylate. LCMS: 382 [M+H]+.

[0337] Step 3. To a solution of methyl 3-(((N-(2-methoxy-2-oxoethyl)-4- methylphenyl)sulfonamido)methyl)furan-2-carboxylate (1.80 g, 4.72 mmol, 1.00 eq) in THF (18.0 170 BUSINESS.33169534.1 407274-95WRWO (217205)mL) was added a 1 M solution of LHMDS (14.2 mL, 14.2 mmol, 3.00 eq) in THF dropwise at -78 °C under N2 atmosphere. After addition, the reaction mixture was allowed to warm to 0 °C and stirred for 5 h under N2 atmosphere. A saturated NH4Cl (aq.) solution was added to the reaction mixture and the aq. phase was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of EtOAc / PE) to afford methyl 7-hydroxyfuro[3,2-c]pyridine-6- carboxylate. LCMS: 194 [M+H]+.

[0338] Step 4. To a mixture of methyl 7-hydroxyfuro[3,2-c]pyridine-6-carboxylate (760 mg, 3.93 mmol, 1.00 eq) in MeOH (10.0 mL) was added Pd / C (152 mg, 20%). The mixture was degassed and purged with H2gas (40 psi). Then it was stirred at 50 °C for 16 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of DCM / MeOH) to afford methyl 7-hydroxy-2,3- dihydrofuro[3,2-c]pyridine-6-carboxylate. LCMS: 196 [M+H]+.

[0339] Step 5. To a mixture of methyl 7-hydroxy-2,3-dihydrofuro[3,2-c]pyridine-6- carboxylate (680 mg, 3.48 mmol, 1.00 eq) in H2O (3.00 mL) and MeOH (3.00 mL) was added NaOH (557 mg, 13.9 mmol, 4.00 eq) at room temperature and the resulting mixture was stirred at 60 °C for 16 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O and acidified by 3 N HCl. The precipitated solids were collected by filtration and dried to afford 7-hydroxy-2,3-dihydrofuro[3,2-c]pyridine-6-carboxylic acid (Intermediate-27), which was used in the next step directly without further purification. LCMS: 182 [M+H]+. Synthesis of 4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carboxylic acid (Intermediate-28)205)

[0340] Step 1. To a stirred solution of methyl 2-methylfuran-3-carboxylate (10.0 g, 71.4 mmol, 1.00 eq) in CCl4 (55.0 mL) was added NBS (15.2 g, 85.6 mmol, 1.20 eq) and AIBN (586 mg, 3.57 mmol, 0.05 eq) at room temperature. The resulting mixture was degassed three times with N2 and stirred overnight at 50oC under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of EtOAc / PE) to afford methyl2-(bromomethyl)furan-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.86 (d, 1H), 6.80(d, 1H), 4.95 (s, 2H), 3.82 (s, 3H).

[0341] Step 2. To a stirred solution of methyl 2-(bromomethyl)furan-3-carboxylate (12.0 g, 54.8 mmol, 1.00 eq) and methyl 2-(4-methylbenzenesulfonamido)acetate (13.3 g, 54.8 mmol, 1.00 eq) in ACN (100 mL) was added K2CO3(15.1 g, 110 mmol, 2.00 eq) at room temperature. The resulting mixture was degassed three times with N2and then stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of EtOAc / PE) to afford methyl 2- (((N-(2-methoxy-2-oxoethyl)-4-methylphenyl)sulfonamido)methyl)furan-3-carboxylate. LCMS: 382.1 [M+H]+.

[0342] Step 3. To a stirred solution of methyl 2-([N-(2-methoxy-2-oxoethyl)4- methylbenzenesulfonamido]methylfuran-3-carboxylate (9.00 g, 23.6 mmol, 1.00 eq) in THF (50.0 mL) was added a 1 M solution of LHMDS (70.0 mL, 70.0 mmol, 3.00 eq) in THF at -78oC under N2. The resulting mixture was stirred for 1h at room temperature under N2. The reaction mixture was quenched with saturated NH4Cl solution at 0 ℃ and diluted with H2O (200 mL). The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of EtOAc / PE) to afford a crude product, which was purified by trituration with PE (250 mL) to afford methyl 4-hydroxyfuro[2,3-c]pyridine-5-carboxylate. LCMS: 194.0 [M+H]+.

[0343] Step 4. To a solution of methyl 4-hydroxyfuro[2,3-c]pyridine-5-carboxylate (1.00 g, 5.18 mmol, 1.00 eq) in AcOH (1.00 mL) and MeOH (10.0 mL) was added Pd / C (1.65 g, 10%). 172 BUSINESS.33169534.1 407274-95WRWO (217205)The mixture was degassed three times with H2, and then stirred at room temperature for 1 h under H2. The reaction mixture was filtered, and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (C18 column, H2O (10mmol / L NH4HCO3)-ACN) to afford methyl 4-hydroxy-2,3-dihydrofuro[2,3- c]pyridine-5-carboxylate. LCMS: 195.9 [M+H]+.

[0344] Step 5. To a stirred solution of methyl 4-hydroxy-2H,3H-furo[2,3-c]pyridine-5- carboxylate (300 mg, 1.54 mmol, 1.00 eq) in MeOH (3.00 mL) were added NaOH (246 mg, 6.15 mmol, 4.00 eq) and H2O (3.00 mL) at room temperature. The reaction mixture was stirred overnight at 60oC. The mixture was acidified to pH = 3 with 1 N HCl. The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carboxylic acid (Intermediate-28), which was used in the next step directly without further purification. LCMS: 181.9 [M+H]+. Synthesis of methyl 4-hydroxy-2-methoxynicotinate (Intermediate-29) and 4-hydroxy-2- methoxy-5-methylnicotinic acid (Intermediate-30)

[0345] Step 1: To a solution of 2-methoxypyridin-4-ol (5.00 g, 39.96 mmol, 1.0 eq) in ACN (80 mL) was added NBS (7.11 g, 39.96 mmol, 1.0 eq) at 0 °C, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with H2O (100 mL), and then extracted with EtOAc (100 mL * 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was 173 BUSINESS.33169534.1 407274-95WRWO (217205)purified by flash silica gel chromatography (eluent of EtOAc / PE) to afford 3-bromo-2- methoxypyridin-4-ol. LCMS: 203.9 [M+H]+.

[0346] Step 2: To a mixture of 3-bromo-2-methoxypyridin-4-ol (3.84 g, 18.82 mmol, 1.0 eq) i n MeOH (20 mL) and DMF (20 mL) was added Pd(dppf)Cl2.CH2Cl2(1.54 g, 1.88 mmol, 0.1 e q) and TEA (5.71 g, 56.46 mmol, 3.0 eq), and the resulting mixture was stirred at 80 °C overnigh t under CO (50 psi) atmosphere. The reaction mixture was filtered and the filtrate was concentrat ed under reduced pressure. The residue was dissolved into DCM (100 mL), washed with saturate d NH4Cl (70 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to giv e a residue. The residue was purified by flash silica gel chromatography (eluent of EtOAc / PE) to afford methyl 4-hydroxy-2-methoxynicotinate (Intermediate-29).1H NMR (400 MHz, CDCl3) δ 12.26 (s, 1H), 8.05 (d, 1H), 6.57 (d, 1H), 4.01 (d, 6H).

[0347] Step 3: To a solution of methyl 4-hydroxy-2-methoxynicotinate (Intermediate-29) (1.40 g, 7.64 mmol, 1.0 eq) in ACN (14 mL) was added NBS (1.36 g, 7.64 mmol, 1.0 eq), and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was filtered, the filter cake was washed with cold ACN (5 mL) and then dried in vacuo to afford methyl 5-bromo- 4-hydroxy-2-methoxynicotinate, which was used in the next step without further purification. LCMS: 262.1 [M+H]+.

[0348] Step 4: To a mixture of methyl 5-bromo-4-hydroxy-2-methoxynicotinate (300 mg, 1.14 mmol, 1.0 eq) and tetramethylstannane (409 mg, 2.29 mmol, 2.0 eq) in DMF (2 mL) was added Pd2(dba)3(105 mg, 114 μmol, 0.1 eq) and XPhos (109 mg, 229 μmol, 0.2 eq), and the resulting mixture was stirred at 120 °C overnight under N2atmosphere. The reaction mixture was diluted with H2O (20 mL), extracted with EtOAc (10 mL *3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (C18 column, water (0.1% FA)-ACN) to afford methyl 4-hydroxy-2-methoxy-5-methylnicotinate. LCMS: 198.3 [M+H]+.

[0349] Step 5: To a solution of methyl 4-hydroxy-2-methoxy-5-methylnicotinate (30 mg, 152 μmol, 1.0 eq) in H2O (0.2 mL), THF (0.2 mL) and MeOH (0.2 mL) was added aqueous LiOH solution (1 M, 608 μL, 4.0 eq) and it was stirred at 40 °C overnight. The reaction mixture was acidified by addition of aqueous HCl solution (1 M) to pH 5~6, and then extracted with EtOAc (5 mL * 10). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 4-hydroxy-2-methoxy-5-methylnicotinic acid 174 BUSINESS.33169534.1 407274-95WRWO (217205)(Intermediate-30), which was used in the next step without further purification. LCMS: 184.1 [M+H]+.

[0350] The compounds of the disclosure are shown below in Table 2 or Table 2a’s along with the LCMS method (see below table for method conditions), mass observed, and retention time of compound. Table 2 Mass No. Compound Structure MethodObserved Retention Time [min]175 BUSINESS.33169534.1 407274-95WRWO (217205)Mass No. Compound Structure MethodObserved Retention / l Time [min]176 BUSINESS.33169534.1 407274-95WRWO (217205)Mass No. Compound Structure MethodObserved Retention / l Time [min]177 BUSINESS.33169534.1 407274-95WRWO (217205)Mass No. Compound Structure MethodObserved Retention / l Time [min]178 BUSINESS.33169534.1 407274-95WRWO (217205)Mass No. Compound Structure MethodObserved Retention / l Time [min]179 BUSINESS.33169534.1 407274-95WRWO (217205)Mass No. Compound Structure MethodObserved Retention / l Time [min]180 BUSINESS.33169534.1 407274-95WRWO (217205)Mass No. Compound Structure MethodObserved Retention / l Time [min]181 BUSINESS.33169534.1 407274-95WRWO (217205)Mass No. Compound Structure MethodObserved Retention / l Time [min]182 BUSINESS.33169534.1 407274-95WRWO (217205)Mass No. Compound Structure MethodObserved Retention / l Time [min]183 BUSINESS.33169534.1 407274-95WRWO (217205)Mass No. Compound Structure MethodObserved Retention / l Time [min]184 BUSINESS.33169534.1 407274-95WRWO (217205)Mass No. Compound Structure MethodObserved Retention / l Time [min]185 BUSINESS.33169534.1 407274-95WRWO (217205)Mass No. Compound Structure MethodObserved Retention / l Time [min]186 BUSINESS.33169534.1 407274-95WRWO (217205)Mass No. Compound Structure MethodObserved Retention / l Time [min]187 BUSINESS.33169534.1 407274-95WRWO (217205)Mass No. Compound Structure MethodObserved Retention / l Time [min]188 BUSINESS.33169534.1 407274-95WRWO (217205)Mass No. Compound Structure MethodObserved Retention / l Time [min]189 BUSINESS.33169534.1 407274-95WRWO (217205)Mass No. Compound Structure MethodObserved Retention / l Time [min]190 BUSINESS.33169534.1 407274-95WRWO (217205)Mass No. Compound Structure MethodObserved Retention / l Time [min]191 BUSINESS.33169534.1 407274-95WRWO (217205)Mass No. Compound Structure MethodObserved Retention / l Time [min]192 BUSINESS.33169534.1 407274-95WRWO (217205)Mass No. Compound Structure MethodObserved Retention / l Time [min]193 BUSINESS.33169534.1 407274-95WRWO (217205)Mass No. Compound Structure MethodObserved Retention / l Time [min]194 BUSINESS.33169534.1 407274-95WRWO (217205)Mass No. Compound Structure MethodObserved Retention / l Time [min]195 BUSINESS.33169534.1 407274-95WRWO (217205)Mass No. Compound Structure MethodObserved Retention / l Time [min]196 BUSINESS.33169534.1 407274-95WRWO (217205)Mass No. Compound Structure MethodObserved Retention / l Time [min]197 BUSINESS.33169534.1 407274-95WRWO (217205)Mass No. Compound Structure MethodObserved Retention / l Time [min]198 BUSINESS.33169534.1 407274-95WRWO (217205)Mass No. Compound Structure MethodObserved Retention / l Time [min]199 BUSINESS.33169534.1 407274-95WRWO (217205)Table 2a No. Compound Structure200 BUSINESS.33169534.1 407274-95WRWO (217205)No. Compound Structure BUSINESWO (217205)No. Compound Structure BUSINESWO (217205)No. Compound Structure BUSINESWO (217205)No. Compound StructureLCMS methods 204 BUSINESS.33169534.1 407274-95WRWO (217205)LCMS 1 Instrument Shimadzu LCMS-2020 Stationary Phase HALO C183.0X30mm, 5.0µm Mode Binary Gradient Mobile Phase A 0.0375% TFA in water (v / v) Mobile Phase B 0.01875% TFA in Acetonitrile (v / v) Gradient 5 to 95% B in 0.5min, 95% B for 0.3min, 95 to 5% B in 0.25min Flow Rate 1.5 mL / min Column Temperature 50 °C Column 3.0X30mm, 5.0µm LCMS 2 Instrument Agilent HPLC-1290 Stationary Phase HALO C18 Mode Binary Gradient Mobile Phase A water / 0.05%TFA Mobile Phase B ACN / 0.05%TFA Gradient 10% to 95% B in 6 min, hold 95% B in 2 min Flow Rate (mL / min) 1.5 Column Temperature (°C) 40 Column Dimensions 100x4.6mm, 2.7µm LCMS 3 Instrument Shimadzu LCMS‐2020 Stationary Phase HALO C18 Mode Binary Gradient Mobile Phase A water / 0.05%TFA 205 BUSINESS.33169534.1 407274-95WRWO (217205)Mobile Phase B ACN / 0.05%TFA Gradient 5% to 100% B in 1.2 min, hold 100% B in 0.6 min Flow Rate (mL / min) 1.5 Column Temperature (°C) 40 Column Dimensions 30x3.0mm, 2.0µm LCMS 4 Instrument Shimadzu LCMS‐2020 Stationary Phase Shim‐pack Scepter C18 Mode Binary Gradient Mobile Phase A water / 5mM NH4HCO3 Mobile Phase B ACN Gradient 10% to 95% B in 1.2 min, hold 95% B in 0.6 min Flow Rate (mL / min) 1.5 Column Temperature (°C) 40 Column Dimensions 33x3.0mm, 3.0µm LCMS 5 Instrument Shimadzu LCMS-2020 Stationary Phase Luna Omega PS C18 Mode Binary Gradient Mobile Phase A water / 0.1%FA Mobile Phase B ACN / 0.1%FA Gradient 5% to 100% B in 1.2 min, hold 100% B in 0.6 min Flow Rate 1.2 mL / min 206 BUSINESS.33169534.1 407274-95WRWO (217205)Column Temperature 40 °C Column 30x2.1mm, 3.0µm LCMS 6 Instrument Shimadzu LCMS-2020 Stationary Phase HALO C18 Mode Binary Gradient Mobile Phase A water / 0.05%TFA Mobile Phase B ACN / 0.05%TFA Gradient 5% to 40% B in 1.7 min, 40% to 100% B in 0.6 min, hold 100% B in 0.5 min Flow Rate 1.5 mL / min Column Temperature 40 °C Column 33x3.0mm, 2.0µm LCMS 7 Instrument Shimadzu LCMS-2020 Stationary Phase Kinetex XB‐C18100A Mode Binary Gradient Mobile Phase A water / 0.05%TFA Mobile Phase B ACN / 0.05%TFA Gradient 5% to 60% B in 1.7 min, 60% to 100% B in 0.6 min, hold 100% B in 0.5 min Flow Rate 1.5 mL / min Column Temperature 40 °C Column 30x2.1mm, 1.7µm 207 BUSINESS.33169534.1 407274-95WRWO (217205)LCMS 8 Instrument Shimadzu LCMS-2020 Stationary Phase HALO PCS C18 Mode Binary Gradient Mobile Phase A water / 0.1%FA Mobile Phase B ACN / 0.07%FA Gradient 5% to 60% B in 1.7 min, 60% to 100% B in 0.6 min, hold 100% B in 0.5 min Flow Rate 1.2 mL / min Column Temperature 40 °C Column 30x2.1mm, 2.7µm LCMS 9 Instrument Shimadzu LCMS-2020 Stationary Phase HALO C18 Mode Binary Gradient Mobile Phase A water / 0.05%TFA Mobile Phase B ACN / 0.05%TFA Gradient 5% to 50% B in 1.7 min, 50% to 100% B in 0.8 min, hold 100% B in 0.5 min Flow Rate 1.5 mL / min Column Temperature 40 °C Column 30x3.0mm, 2.0µm LCMS 10 Instrument Shimadzu LCMS‐2021 208 BUSINESS.33169534.1 407274-95WRWO (217205)Stationary Phase Shim‐pack Scepter C18 Mode Binary Gradient Mobile Phase A 5mM NH4HCO3 / 10% ACN, 90% water Mobile Phase B ACN Gradient 20% to 60% B in 1.6 min, 60% to 90% B in 0.6 min, hold 90% B in 0.5 min Flow Rate 1.5 mL / min Column Temperature 40 °C Column 33x3.0mm, 3.1^m LCMS 11 Instrument Shimadzu LCMS‐2020 Stationary Phase Shim‐pack Scepter C18 Mode Binary Gradient Mobile Phase A water / 5mM NH4HCO3Mobile Phase B ACN Gradient 0% to 90% B in 1.2 min, hold 90% B in 0.6 min Flow Rate 1.5 mL / min Column Temperature 40 °C Column 33x3.0mm, 3.0µm LCMS 12 Instrument Shimadzu LCMS‐2020 Stationary Phase Shim‐pack Scepter C18 Mode Binary Gradient 209 BUSINESS.33169534.1 407274-95WRWO (217205)Mobile Phase A water / 5mM NH4HCO3Mobile Phase B ACN Gradient 10% to 95% B in 1.2 min, hold 95% B in 0.6 min Flow Rate 1.5 mL / min Column Temperature 40 °C Column 33x3.0mm, 3.0µm LCMS 13 Instrument Shimadzu LCMS‐2020 Stationary Phase Shim‐pack Scepter C18 Mode Binary Gradient Mobile Phase A water / 5mM NH4HCO3Mobile Phase B ACN Gradient 10% to 95% B in 1.2 min, hold 95% B in 0.6 min Flow Rate 1.5 mL / min Column Temperature 40 °C Column 33x3.0mm, 3.0µm LCMS 14 Instrument Shimadzu LCMS‐2020 Stationary Phase Shim‐pack Scepter C18 Mode Binary Gradient Mobile Phase A 5mM NH4HCO3 / 10% ACN, 90% water Mobile Phase B ACN 210 BUSINESS.33169534.1 407274-95WRWO (217205)Gradient 20% to 60% B in 1.7 min, 60% to 90% B in 0.6 min, hold 90% B in 0.5 min Flow Rate 1.5 mL / min Column Temperature 40 °C Column 33x3.0mm, 3.0µm LCMS 15 Instrument Shimadzu LCMS‐2021 Stationary Phase HALO C18 Mode Binary Gradient Mobile Phase A water / 0.05%TFA Mobile Phase B ACN / 0.05%TFA Gradient 30% to 60% B in 1.7 min, 60% to 100% B in 0.6 min, hold 100% B in 0.5 min Flow Rate 1.5 mL / min Column Temperature 40 °C Column 30x3.0mm, 2.0µm LCMS 16 Instrument Shimadzu LCMS‐2020 Stationary Phase HALO C18 Mode Binary Gradient Mobile Phase A water / 0.05%TFA Mobile Phase B ACN / 0.05%TFA Gradient 20% to 60% B in 1.7 min, 60% to 100% B in 0.6 min, hold 100% B in 0.5 min 211 BUSINESS.33169534.1 407274-95WRWO (217205)Flow Rate 1.5 mL / min Column Temperature 40 °C Column 30x3.0mm, 2.0µm LCMS 17 Instrument Shimadzu LCMS‐2020 Stationary Phase HALO C18 Mode Binary Gradient Mobile Phase A water / 0.05%TFA Mobile Phase B ACN / 0.05%TFA Gradient 30% to 60% B in 1.7 min, 60% to 100% B in 0.6 min, hold 100% B in 0.5 min Flow Rate 1.5 mL / min Column Temperature 40 °C Column 30x3.0mm, 2.0µm LCMS 18 Instrument Shimadzu LCMS‐2020 Stationary Phase Luna Omega PS C18 Mode Binary Gradient Mobile Phase A water / 0.1%FA Mobile Phase B ACN / 0.07%FA Gradient 5% to 100% B in 1.2 min, hold 100% B in 0.6 min Flow Rate 1.2 mL / min Column Temperature 40 °C 212 BUSINESS.33169534.1 407274-95WRWO (217205)Column 30x2.1mm, 3.0µm LCMS 19 Instrument Shimadzu LCMS‐2020 Stationary Phase Luna Omega PS C18 Mode Binary Gradient Mobile Phase A water / 0.1%FA Mobile Phase B ACN / 0.07%FA Gradient 20% to 50% B in 1.7 min, 50% to 100% B in 0.6 min, hold 100% B in 0.5 min Flow Rate 1.5 mL / min Column Temperature 40 °C Column 30x2.1mm, 3.0µm LCMS 20 Instrument Shimadzu LCMS‐2020 Stationary Phase HALO C18 Mode Binary Gradient Mobile Phase A water / 0.05%TFA Mobile Phase B ACN / 0.05%TFA Gradient 30% to 50% B in 1.7 min, 50% to 100% B in 0.6 min, hold 100% B in 0.5 min Flow Rate 1.5 mL / min Column Temperature 40 °C Column 30x3.0mm, 2.0µm 213 BUSINESS.33169534.1 407274-95WRWO (217205)LCMS methods LCMS 21 Instrument Shimadzu LCMS‐2020 Mode Binary gradient Stationary Phase Shimpack Scepter C18 Mobile Phase A water / 5mM NH4HCO3 Mobile Phase B ACN Column Dimensions 33x3.0mm, 3.0um Flow Rate (mL / min) 1.5 Column Temperature (°C) 40 Gradient 20% to 50% B in 1.7 min, 50% to 90% B in 0.6 min, hold 90% B in 0.5 min LCMS 22 Instrument Shimadzu LCMS‐2020 Mode Binary gradient Stationary Phase Shimpack Scepter C18 Mobile Phase A 5mM NH4HCO3 in H2O / Acetonitrile(95:5,V / V) Mobile Phase B ACN Column Dimensions 33x3.0mm, 3.0um Flow Rate (mL / min) 1.5 Column Temperature (°C) 40 Gradient 5% to 90% B in 1.2 min, hold 90% B in 0.6 min LCMS 23 Instrument Shimadzu LCMS‐2020 Mode Binary gradient Stationary Phase HALO C18 Mobile Phase A water / 0.05%TFA Mobile Phase B ACN / 0.05%TFA Column Dimensions 30x3.0mm, 2.0um 214 BUSINESS.33169534.1 407274-95WRWO (217205)Flow Rate (mL / min) 1.5 Column Temperature (°C) 40 Gradient 5% to 100% B in 2.0 min, hold 100% B in 0.7 min LCMS 24 Instrument Shimadzu LCMS‐2020 Mode Binary gradient Stationary Phase Shimpack Scepter C18 Mobile Phase A water / 5mM NH4HCO3 Mobile Phase B ACN Column Dimensions 33x3.0mm, 3.0um Flow Rate (mL / min) 1.5 Column Temperature (°C) 40 Gradient 40% to 80% B in 1.7 min, 80% to 95% B in 0.6 min, hold 95% B in 0.5 min LCMS 25 Instrument Shimadzu LCMS‐2020 Mode Binary gradient Stationary Phase HALO C18 Mobile Phase A water / 0.05%TFA Mobile Phase B ACN / 0.05%TFA Column Dimensions 30x3.0mm, 2.0um Flow Rate (mL / min) 1.5 Column Temperature (°C) 40 Gradient 20% to 40% B in 1.7 min, 40% to 100% B in 0.6 min, hold 100% B in 0.5 min Example 2: WRN (BV08) ADP-Glo assay protocol 215 BUSINESS.33169534.1 407274-95WRWO (217205)

[0351] Bovine skin gelatin (BSG), dimethyl sulfoxide (DMSO), Pluronic F-127 and tris(2- carboxyethyl)phosphine hydrochloride solution (TCEP) were purchased from Sigma-Aldrich (St. Louis, MO) at the highest level of purity possible. Bicine buffer solution was purchased from Alfa Aesar (Tewksbury, MA) and compound NSC-617145 was purchased from Tocris (Minneapolis, MN). DNA duplex was synthesized at BGI (Shenzhen, China) and was composed of strand 1 with the sequence 5’-GCACTGGCCGTCGTTTTACGGTCG-3’ (SEQ ID NO.: 1) and strand 2 with the sequence 5’-TCCAAGTAAAACGACGGCCAGTGC-3’ (SEQ ID NO.: 2). DNA strands were annealed by heating to 95oC for 5 minutes followed by slow cooling to room temperature. Compounds in 100% DMSO (0.1 ^l) were spotted into a 384-well white polystyrene Optiplate- 384 (Perkin Elmer; Waltham, MA) assay plate using a LabCyte Echo 550 (Agilent; Santa Clara, CA). DMSO (0.1 ^l) was added to columns 12, rows A-H and column 24, rows I-P for the maximum signal control. Compound NSC-617145 (0.1 ^l) was added to columns 12, rows I-P and 24, rows A-H for the minimum signal control (100% inhibition). Compounds / DMSO were preincubated for 15 minutes at 25°C with 5 ^l 2X WRN (BV08), prepared as described below, in assay buffer containing 20 mM Bicine (pH = 7.5), 1 mM MgCl2, 10 mM KCl, 0.1% Pluronic F- 127, 0.005% BSG, 1 mM TCEP. The reaction was initiated by the addition of 5 ^l 2X substrate mixture in assay buffer and incubated for 60 minutes at 25°C. The final concentrations of the assay components were 0.15 nM WRN, 5 ^M ATP, and 0.1 nM DNA duplex. The final DMSO concentration was 1% and the reference compound concentration (NSC-617145) used for the minimal signal control was 20 ^M. The reaction was stopped by the addition of the ADP-Glo Kit components (Promega; Madison, WI) as directed and the relative luminescence units (RLU) were read on an Envision 2104 (Perkin Elmer; Waltham, MA). % inhibition calculation: %INH = (RLU MAX- RLU sample) / (RLU MAX – RLU MIN)) × 100 Where RLU = relative luminescence units, sample = signal in sample well, and MIN and MAX are the respective minimum and maximum signal controls. Four-parameter IC50 fit equation: Y = Bottom + (Top - Bottom) / (1 + (IC50 / X)^Hill Slope) Where top and bottom are normally allowed to float but may be fixed at 100 or 0 respectively in a 3-parameter fit. Y is the % inhibition and X is the compound concentration. 216 BUSINESS.33169534.1 407274-95WRWO (217205)WRN protein production

[0352] Molecular Biology and virus production. The DNA encoding human Werner helicase (Uniprot Q14191, amino acids 517-1235 with L1074F point mutation) was generated with codon- optimization for E.coli expression and subcloned into the pFastBac vector with a TEV cleavable 8xHis tag (SEQ ID NO: 5) (WRN-BV08). The baculovirus from the expression plasmid WRN- BV08 was generated from transfection and amplification following the manufacturer’s instructions.

[0353] Gene sequence of WRN-BV08 [pFastBac1-WRN-(517-1235 L1074F)-TEV-8His] (SEQ ID NO.: 3) ATGAACGAGGGCGAAGAAGACGACGACAAGGACTTCCTGTGGCCTGCCCCTAACGA AGAACAAGTGACATGCCTGAAGATGTACTTCGGACACAGTAGCTTCAAGCCTGTGC AATGGAAGGTCATCCACTCCGTGCTGGAAGAAAGAAGGGACAACGTGGCTGTGATG GCTACCGGATACGGTAAGTCCCTGTGCTTCCAGTACCCTCCCGTGTACGTGGGCAAG ATCGGTCTGGTGATCTCCCCTCTGATCTCTCTGATGGAGGACCAGGTGCTGCAATTG AAGATGTCCAACATCCCCGCTTGCTTCCTGGGTTCCGCTCAAAGTGAGAACGTGCTG ACAGACATCAAGCTGGGCAAGTACCGCATCGTGTACGTGACCCCTGAGTACTGCTCC GGTAACATGGGTCTGCTGCAACAGCTGGAGGCTGACATCGGAATCACCCTGATCGCT GTGGACGAGGCTCACTGCATCTCCGAGTGGGGACACGACTTCCGCGACTCCTTCCGT AAGCTGGGATCCTTGAAGACCGCTCTCCCTATGGTGCCTATCGTGGCCCTGACCGCC ACTGCTTCCTCCTCCATCCGCGAGGACATCGTGCGTTGCCTGAACCTGCGCAACCCT CAGATCACTTGCACCGGTTTCGACCGCCCTAACTTGTACCTCGAGGTGCGTCGCAAG ACCGGTAACATCCTCCAGGACCTGCAGCCTTTCCTGGTCAAGACCTCCTCCCACTGG GAATTTGAGGGCCCTACCATCATCTACTGCCCTTCCCGCAAGATGACCCAGCAAGTC ACCGGCGAGCTGCGCAAGCTCAACCTCTCCTGCGGTACCTACCACGCTGGTATGTCC TTCTCCACCCGCAAGGACATCCACCACCGCTTCGTCCGTGACGAAATCCAATGCGTC ATCGCTACCATCGCTTTCGGAATGGGCATCAACAAGGCTGACATCCGCCAGGTGATC CACTACGGCGCCCCCAAGGACATGGAATCCTACTACCAGGAAATCGGTCGCGCCGG TCGCGACGGTCTGCAGTCTTCCTGTCACGTGCTGTGGGCCCCCGCTGACATCAACCT GAACCGCCACCTGCTGACCGAAATCCGCAACGAGAAGTTCCGCCTGTACAAGCTCA AGATGATGGCTAAGATGGAGAAGTACCTGCACTCCTCCCGCTGTCGCCGTCAGATCA TCCTCTCCCACTTCGAGGACAAGCAAGTGCAAAAGGCTAGCCTGGGTATCATGGGC 217 BUSINESS.33169534.1 407274-95WRWO (217205)ACCGAAAAGTGTTGTGACAACTGCCGCTCCCGCCTCGACCACTGCTACTCCATGGAC GACAGCGAGGACACCTCCTGGGACTTCGGTCCTCAAGCTTTCAAGCTCTTGTCCGCT GTGGACATCCTGGGCGAGAAGTTCGGTATCGGTCTCCCCATCCTCTTCCTGCGTGGT AGCAACTCCCAACGCCTGGCTGACCAGTACCGCCGCCACTCCCTCTTCGGTACCGGT AAGGACCAGACCGAGTCCTGGTGGAAGGCTTTCTCTCGCCAACTGATCACCGAAGG TTTCCTGGTGGAGGTGTCCCGCTACAACAAGTTCATGAAGATCTGCGCTCTCACTAA GAAGGGAAGGAACTGGCTGCACAAGGCTAACACTGAGTCCCAATCCCTCATCCTGC AGGCTAACGAGGAGCTGTGCCCTAAGAAGTTCCTGCTGCCTTCCTCCAAGACCGTGT CCTCCGGAACAAAGGAACACTGCTACAACCAAGTCCCTGTGGAGCTCTCCACCGAG AAGAAGTCCAACCTGGAGAAGCTGTACAGCTACAAGCCTTGCGACAAGATCAGCTC CGGTTCCAACATCAGCAAGAAGTCCATCATGGTGCAATCCCCTGAAAAGGCCTACTC CAGCTCCCAACCTGTCATCTCCGCTCAAGAGCAAGAGACCCAGATCGTGCTGTACGG TAAGCTGGTCGAAGCCCGCCAAAAGCACGCTAACAAGATGGACGTCCCTCCCGCTA TCCTCGCCACCAACAAGATCCTCGTGGATATGGCTAAGATGCGCCCCACCACCGTCG AGAACGTGAAGCGCATCGACGGTGTCTCCGAGGGTAAGGCCGCTATGCTGGCTCCT CTGCTGGAAGTGATCAAGCACTTCTGCCAGACCAACTCCGTGCAGACCGACCTGTTC AGTAGTGAGAACCTGTACTTCCAAGGCCACCATCATCATCATCATCACCACTAA

[0354] Protein sequence of WRN-BV08 [pFastBac1-WRN-(517-1235 L1074F)-TEV-8His] (SEQ ID NO.: 4) MNEGEEDDDKDFLWPAPNEEQVTCLKMYFGHSSFKPVQWKVIHSVLEERRDNVAVMA TGYGKSLCFQYPPVYVGKIGLVISPLISLMEDQVLQLKMSNIPACFLGSAQSENVLTDIKL GKYRIVYVTPEYCSGNMGLLQQLEADIGITLIAVDEAHCISEWGHDFRDSFRKLGSLKTA LPMVPIVALTATASSSIREDIVRCLNLRNPQITCTGFDRPNLYLEVRRKTGNILQDLQPFL VKTSSHWEFEGPTIIYCPSRKMTQQVTGELRKLNLSCGTYHAGMSFSTRKDIHHRFVRD EIQCVIATIAFGMGINKADIRQVIHYGAPKDMESYYQEIGRAGRDGLQSSCHVLWAPADI NLNRHLLTEIRNEKFRLYKLKMMAKMEKYLHSSRCRRQIILSHFEDKQVQKASLGIMGT EKCCDNCRSRLDHCYSMDDSEDTSWDFGPQAFKLLSAVDILGEKFGIGLPILFLRGSNSQ RLADQYRRHSLFGTGKDQTESWWKAFSRQLITEGFLVEVSRYNKFMKICALTKKGRNW LHKANTESQSLILQANEELCPKKFLLPSSKTVSSGTKEHCYNQVPVELSTEKKSNLEKLY SYKPCDKISSGSNISKKSIMVQSPEKAYSSSQPVISAQEQETQIVLYGKLVEARQKHANK 218 BUSINESS.33169534.1 407274-95WRWO (217205)MDVPPAILATNKILVDMAKMRPTTVENVKRIDGVSEGKAAMLAPLLEVIKHFCQTNSV QTDLFSSENLYFQGHHHHHHHH

[0355] Sf9 cells grown in SF900II media were infected with 1:200 WRN-BV08 P2 virus and incubated for protein expression for 72 h at 27°C. The WRN protein was purified using the following protocol. The cell pellets were thawed and resuspended in buffer A (50 mM Tris, pH 7.5, 500 mM NaCl, 1 mM TCEP, 10% Glycerol) supplemented with 0.5% CHAPS, 1mM PMSF, 1µg / ml Leupeptin, 1µg / ml Pepstatin, and the Pierce Universal Nuclease and cocktail tablet. Cleared lysates were loaded onto a Ni SepharoseTMexcel column and washed with buffer A and bound protein was eluted with buffer A supplemented with 300 mM imidazole. The eluted protein was dialyzed against buffer A and digested by His-tagged TEV (1:5 ratio) overnight at 4°C. ZnCl2was added into the sample at final 15^M before loading onto a second Ni SepharoseTMexcel column. Untagged WRN protein was eluted from the column with buffer A supplemented with 20 mM imidazole, dialyzed overnight into buffer B (50 mM Tris, pH 7.5, 1 mM TCEP, 10% Glycerol) supplemented with 150 mM NaCl and loaded onto a Heparin column. Proteins were eluted with a step gradient of buffer B supplemented with 150 mM, 200 mM, 300 mM and 500 mM NaCl. WRN containing fractions were pooled and concentrated prior to loading on to size exclusion chromatography using a HiLoad 16 / 600 Superdex TM 200 pg column (GE Healthcare) in buffer C (20 mM HEPES, pH 7.5, 250 mM NaCl, 0.25 mM TCEP, 2.5% Glycerol).

[0356] The resultant IC50results obtained for the tested compounds are shown below in Table 3. Compounds with an IC50 less than or equal to 0.005 µM are designated as “A.” Compounds with an IC50greater than 0.005 µM and less than or equal to 0.05 µM are designated as “B.” Compounds with an IC50greater than 0.05 µM and less than or equal to 0.1 µM are designated as “C.” Compounds with an IC50 greater than 0.1 µM or equal to 0.5 µM are designated as “D.” Compounds with an IC50 greater than 0.5 µM are designated as “E.” Table 3 Cmpd. No. ADP-Glo_hWRN_IC50 [^M]219 BUSINESS.33169534.1 407274-95WRWO (217205)Cmpd. No.ADP-Glo_hWRN_IC50 [^M] I-8 B220 BUSINESS.33169534.1 407274-95WRWO (217205)Cmpd. No.ADP-Glo_hWRN_IC50 [^M] I-37 B221 BUSINESS.33169534.1 407274-95WRWO (217205)Cmpd. No.ADP-Glo_hWRN_IC50 [^M] I-66 BExample 3: Method for determining effect on p21 induction in cells.

[0357] The colon carcinoma cell line HCT116 was obtained from ATCC and cultured in growth medium consisting of Mccoy's 5A Medium (Gibco 16600108) supplemented with 10% FBS (Transgene FS201-02) and 100 units / mL penicillin-streptomycin (Gibco 15140122) and maintained at 37 °C under 5% CO2.On the day of seeding, 2,000 cells in 30µL of culture media were plated per well to Poly-D-Lysine 384 Well Black Clear Plates (Biocoat 356663) and incubated overnight at 37 °C under 5% CO2. The following day, compounds were serially diluted in DMSO for a total of 11 test concentrations. The typical starting concentration of compounds was 10^M with 2-fold dilutions. Next, 150nL of diluted compound was added in duplicate to the assay plate, using an Echo 655 (Labcyte). The plate was centrifuged at 500 RPM for 1 min and then incubated at 37 °C under 5% CO2 for 24h. After 24h, medium was removed, and cells were fixed by adding 40µL of 4% paraformaldehyde solution to each well and incubated for 20 min at room temperature. The plate was then washed 4 times with 100µL per well of wash buffer (PBS with 0.1% Tween-20) using a microplate washer. Next, 30µL of ice-cold methanol was added to each well and the plate was incubated at -20 °C for 10 min. The plate was washed 4 times with 100µL per well of wash buffer by a microplate washer, then 30µL per well of blocking buffer (Intercept PBS blocking buffer (LI-COR 927-70001) with 0.05% Tween-20) was added and the 222 BUSINESS.33169534.1 407274-95WRWO (217205)plate was incubated at room temperature with shaking for 2h. Next, to each test well, 20µL of primary antibody solution (p21 Waf1 / CIP (12D1) Rabbit mAb (Cell Signaling Technologies 2947) diluted 1:1000 and GAPDH (D4C6R) Mouse mAb (Cell Signaling Technologies 97166) diluted 1:2000 in blocking buffer) was added and the plate was placed at 4 °C, overnight. The following day, the plate was washed 5 times with 100µL per well of wash buffer using a microplate washer for 5 min.20µL per well of secondary antibody (IRDye 680CW Goat anti-Mouse IgG (H+L) (LI- COR 926-68070) diluted 1: 2000 in Blocking Buffer and IRDye 800CW Goat anti-Rabbit IgG (H+L) (LI-COR 926-32211) diluted 1: 2000 in Blocking Buffer) was then added and the plate was stored for 2h in the dark at room temperature with shaking. The plate was then washed 4 times with 100µL per well of wash buffer again using a microplate washer. Finally, the p21 signal and the GAPDH signal were quantified using a LI-COR Odyssey CLx Imager machine reading at 800nm and 700nm, respectively. Each plate contained DMSO control (low control) and an internal reference WRN inhibitor (high control) respectively. For quantitation, the 800nm / 700nm ratio was calculated for each well to give fold p21 induction and then percent activation for each compound well was calculated as follows (100 x (ratio cpd well-ratio low control) / (ratio high control – ratio low control)). EC50 values for each compound were generated after non-linear regression curve fitting using commercially available software. The resultant EC50results obtained for the tested compounds are shown below in Table 4. Compounds with an EC50 less than or equal to 0.50 µM are designated as “A.” Compounds with an EC50 greater than 0.50 µM and less than or equal to 2.00 µM are designated as “B.” Compounds with an EC50greater than 2.00 µM and less than or equal to 5.00 µM are designated as “C.” Compounds with an EC50greater than 5.00 µM are designated as “D.” Table 4 Cmpd. No.P21_EC50 [^M]223 BUSINESS.33169534.1 407274-95WRWO (217205)Cmpd. No.P21_EC50 [^M]I-10 A224 BUSINESS.33169534.1 407274-95WRWO (217205)Cmpd. No.P21_EC50 [^M]I-39 B225 BUSINESS.33169534.1 407274-95WRWO (217205)Cmpd. No.P21_EC50 [^M]I-68 Anot ava a e. 226 BUSINESS.33169534.1 407274-95WRWO (217205)

Claims

CLAIMS We claim:

1. A compound of any one of Formulas I-a to I-x, or a pharmaceutically acceptable saltthereof: , , ,227 BUSINESS.33169534.1 407274-95WRWO (217205), ,;w)2, O, and NR3; provided that only one of Q and Y is O or NR3; wherein Ring B is a fused ring selected from a 5-6 membered heteroaryl, phenyl, and 5-6 membered partially unsaturated heterocyclyl, said heteroaryl or heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from O, S, N, and NR18; wherein Ring B is substituted with R1aand z instances of R1b; R18is H or optionally substituted C1-C6aliphatic; z is 0, 1, or 2; each R1bgroup is independently selected from H, halogen, CN, OH, oxo, C1-C6aliphatic, C1-C6alkoxy, C3-C6cycloalkyl, C1-C6alkylene-O-C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and C3-C6cycloalkoxy, wherein said C1-C6aliphatic, C1-C6alkoxy, C3-C6cycloalkyl, C1- C6alkylene-O-C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and C3-C6cycloalkoxy are each 228 BUSINESS.33169534.1 407274-95WRWO (217205)independently and optionally substituted with 1-5 halogen, OH, CN, C1-C6alkyl, or C3- C6cycloalkyl groups; provided that when Ring B is a 5 membered ring then z is 0 or 1; R19and R20, along with the carbon atom to which they are both attached, together form Ring A selected from: a) a 4-7 membered saturated or partially unsaturated monocyclic carbocyclyl or 4-7membered saturated or partially unsaturated monocyclic heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 nitrogen atoms in addition to the 1-4 heteroatoms); and b) a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused,bridged, or spirocyclic selected from carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein Ring A is substituted with 0-4 independently selected RBsubstituents; and wherein Ring A is substituted with a linking group -L-R4, wherein -L-R4is selected from ;a) a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur) optionally substituted with 1-3 groups independently selected from halogen, C1-C6aliphatic, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkoxy, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RB; b) a 4-7 membered saturated or partially unsaturated monocyclic heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6aliphatic, C3- C6cycloalkyl, C1-C6alkoxy, C3-C6cycloalkoxy, and -OR, wherein said 4-7 membered saturated or partially unsaturated heterocyclyl is further substituted with 0-3 independently selected RB; c) a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused,bridged, or spirocyclic selected from carbocyclyl or heterocyclyl (having 1-4 229 BUSINESS.33169534.1 407274-95WRWO (217205)heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected RB; and d) H, halogen, C1-C6aliphatic, C3-C7cycloalkyl, C1-C6alkylene-O-C1-C6alkyl, CN, -OR,-OR10, -NR10R11, -C(O)NR10R11,-CH2NR10R11, or -SO2R12, wherein said C1- C6aliphatic, C3-C7cycloalkyl, or C1-C6alkylene-O-C1-C6alkyl is substituted with 0-5 independently selected RB; R2is selected from C(RC)2C(O)N(R)R2A, C(RC)2C(RC)2C(O)N(R)R2A, C(RC)2C(RC)2N(R)C(O) N(R)R2A, and C(RC)2C(RC)2N(R)C(O)R2A; R2Ais phenyl or pyridyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4aliphatic, haloC1-C4alkyl, C3-C6-cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, and –SF5, and wherein two substituents on adjacent atoms of the phenyl or pyridyl, together with said adjacent atoms, optionally form a 4-7 membered carbocyclyl fused to the phenyl or pyridyl, or wherein two substituents on adjacent atoms of the phenyl or pyridyl together with said adjacent atoms optionally form a 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused to the phenyl or pyridyl, wherein said fused 4-7 membered carbocyclyl or fused 4-7 membered heterocyclyl is substituted with 0-5 independently selected halogen; or R2Ais 2-benzimidazolyl, 2-naphthyl, or 3-quinolinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-4alkyl, and -OH; or R2Ais cubanyl, a saturated or partially unsaturated 4-8 membered monocyclic ring, a saturated or partially unsaturated bridged, fused or spirocyclic 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered ring, wherein said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring comprises 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said cubanyl, saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4aliphatic, haloC1-C4alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1- C4alkoxy, haloC1-C4alkoxy, C3-C6cycloalkoxy, haloC4-C6cyclalkoxy and –SF5, and wherein two optional substituents on the same atom of said saturated or partially unsaturated monocyclic ring, 230 BUSINESS.33169534.1 407274-95WRWO (217205)or said saturated or partially unsaturated bridged, fused or spirocyclic ring form a cyclic group selected from: ^an optionally substituted 3-7 membered saturated or partially unsaturatedcarbocyclyl, and ^an optionally substituted 4-7 membered saturated or partially unsaturatedheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R3is independently selected from hydrogen, C1-C4aliphatic, oxo, C3-C5cycloalkyl, and C1-C4alkoxy, each of which, besides hydrogen or oxo, is optionally substituted with -OH, 1- 5 independently selected halogen, or OR; d is 0, 1, or 2; d – 1 is 0 or 1; R4is phenyl or a first 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) wherein said phenyl or first 5-6 membered heteroaryl is substituted with 0-5 RB; and optionally two adjacent atoms of said phenyl or first 5-6 membered heteroaryl have two substituents that together with said adjacent atoms form a cyclic group fused to the phenyl or first 5-6 membered heteroaryl selected from a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or a second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said fused cyclic group is substituted with 0-3 independently selected RB; or R4is a C1-C4aliphatic, C1-C4alkoxy, or C3-C6cycloalkyl, each of which is substituted with 0-3 groups independently selected from halogen, -CN, -OH, C1-C4alkyl, C1-C4alkoxy, optionally substituted 5-6 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 5-6 membered heterocyclyloxy having 1- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R10is H, C1-C6aliphatic, haloC1-C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, –C(O)C1-C6alkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur); each R10except H being optionally substituted with 1 or 2 independently selected RB; 231 BUSINESS.33169534.1 407274-95WRWO (217205)R11is H, C1-C6aliphatic, or C3-C6cycloalkyl, or R10and R11are taken together with the nitrogen atom to which they are attached to form a 5-6 membered ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, -OH, -CN, C1-C4alkoxy, and haloC1-C4alkoxy; R12is C1-C6aliphatic, C3-C6cycloalkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R12optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1- C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, and C3-C6cycloalkoxy; RBis independently selected at each occurrence from the group consisting of optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogen, optionally substituted C1-C6aliphatic, haloC1- C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, C1-C6alkoxy, haloC1-C6alkoxy, C3- C6cycloalkoxy, haloC3-C6cycloalkoxy, C1-C6alkylene-O-C1-C6alkyl, –CN, –NO2, oxo, –OR, – SR, NR2, S(O)2R, S(O)2NR2, S(O)R, S(O)NR2, C(O)R, C(O)OR, –C(O)NR2, C(O)N(R)OR, OC(O)R, OC(O)NR2, -N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR2, N(R)C(NR)NR2, N(R)S(O)2NR2, and –N(R)S(O)2R; or two RBgroups on the same atom are taken together with the same atom together to form a 3-7 membered carbocyclic ring; RCis independently selected at each occurrence from hydrogen, -CH3, or -CH2CH3, or two RCtaken together with the carbon to which they are attached form a cyclopropyl ring; each R is independently hydrogen, or an optionally substituted C1-6aliphatic group, an optionally substituted phenyl, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or two R groups on the same atom are taken together with the same atom to form a cyclic group selected from an optionally substituted 4-7 membered saturated ring, a 4-7 membered partially unsaturated ring, or a 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently 232 BUSINESS.33169534.1 407274-95WRWO (217205)selected from nitrogen, oxygen, and sulfur); wherein said cyclic group has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, of a formulaselected from the group consisting of II-a to II-y:233 BUSINESS.33169534.1 407274-95WRWO (217205)BUSINESS.WRWO (217205)235 BUSINESS.33169534.1 407274-95WRWO (217205); or a pharmaceutically acceptable salt thereof; wherein d – 1 is 0 or 1; and wherein R1ais selected from groups a)-d): a) a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur) optionally substituted with 1 or 2 groups independently selected from C3-C6cycloalkyl and C3-C6cycloalkoxy, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RB; b) a 4-6 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), said heterocyclyl substituted with 0-2 RBgroups independently selected from halogen, oxo, NR2, optionally substituted C1-C4aliphatic, -OR, azetidinyl optionally substituted with 1 or 2 independently selected halogen, and pyrrolidinyl optionally substituted with 1 or 2 independently selected halogen; c) a 6-8 membered saturated or partially unsaturated bridged bicyclic heterocyclyl (having1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), said heterocyclyl substituted with 0-2 RBgroups independently selected from halogen, oxo, NR2, optionally substituted C1-C4aliphatic, -OR, azetidinyl optionally substituted with 236 BUSINESS.33169534.1 407274-95WRWO (217205)1 or 2 independently selected halogen, and pyrrolidinyl optionally substituted with 1 or 2 independently selected halogen; and d) H, halogen, C1-C6alkyl, C2-C4alkene, C2-C4alkyne, CN, -OR10, -NR10R11, –C(O)NR10R11,–CH2NR10R11, –SO2R12, a 3-7 membered carbocyclyl, wherein said C1- C6alkyl, C2-C4alkene, C2-C4alkyne, or 3-7 membered carbocyclyl may be optionally substituted with 0-3 independently selected RB.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, whereinR4is selected from one of a), b), and c): a) R4 is a Ring E that is selected from the group consisting of:and wand: any substituents that are present on Ring E selected from R4A, R4B, R4C, R4D, R4E, and R4Fare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; C1-C4alkoxy; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, -OCH3, or - OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; or R4Aand R4B, along with their intervening atoms, join to form 4-7 membered carbocyclyl substituted with 0-3 independently selected RB, a 4-7 membered heterocyclyl substituted with 0-3 independently selected RB, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and any substituents that are present on Ring E selected from R4C, R4D, R4E, and R4F are each independently selected from237 BUSINESS.33169534.1 407274-95WRWO (217205)hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1- C3alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; or R4Band R4C, along with their intervening atoms, join to form a 4-7 membered carbocyclyl substituted with 0-3 independently selected RB, a 4-7 membered heterocyclyl substituted with 0-3 independently selected RB, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and any substituents that are present on Ring E selected from R4A, R4D, R4E, and R4Fare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1- C3alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; or R4C and R4D, along with their intervening atoms, join to form a 4-7 membered carbocyclylsubstituted with 0-3 independently selected RB, a 4-7 membered heterocyclyl substituted with 0-3 independently selected RB, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and any substituents that are present on Ring E selected from R4A, R4B, R4Eand R4Fare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3- C6cycloalkoxy; and NR13R14; or R4Eis halogen or -OH, and R4A, R4B, R4C, and R4Dare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1- C3alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; or R4Eand R4A, along with their intervening atoms, join to form a 5-6 membered optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and R4B, R4C, and R4Dare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, 238 BUSINESS.33169534.1 407274-95WRWO (217205)-OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; or R4Fand R4A, along with their intervening atoms, join to form a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and R4Band R4Care each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; R13is independently selected at each occurrence from hydrogen and C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; and R14is hydrogen, or R13and R14combine with the nitrogen atom to which they are attached to form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, said heterocyclic ring optionally substituted with -CH3; b) R4 is a 5-membered heteroaryl (having 1 heteroatom independently selected fromnitrogen, oxygen, and sulfur and 0, 1, 2, or 3 additional ring nitrogen atoms), wherein said heteroaryl is substituted with 0-4 groups independently selected from halogen, - OH, -CN, C1-C4alkyl, haloC1-C4alkyl, C3-C6cycloalkyl, and C1-C4alkoxy; and c) R4 is a C1-C4alkyl, C1-C4alkoxy, or C3-C6cycloalkyl, each of which is substituted with0-3 groups independently selected from halogen, -CN, -OH, C1-C4alkyl, C1-C4alkoxy, optionally substituted 5-6 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 5- 6 membered heterocyclyloxy having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. wherein Ring A is substituted with 0-4 independently selected RBsubstituents.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, whereinR4is selected from one of a), b), and c): a) R4 is a Ring E that is selected from the group consisting of:239 BUSINESS.33169534.1 407274-95WRWO (217205)and wany substituents that are present on Ring E selected from R4A, R4B, R4C, R4D, R4E, and R4Fare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; C1-C4alkoxy; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3- C6cycloalkoxy; and NR13R14; or R4Aand R4B, along with their intervening atoms, join to form 4-7 membered carbocyclyl substituted with 0-3 independently selected RB, a 4-7 membered heterocyclyl substituted with 0-3 independently selected RB, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and any substituents that are present on Ring E selected from R4C, R4D, R4E, and R4Fare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2- C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; or R4Band R4C, along with their intervening atoms, join to form a 4-7 membered carbocyclyl substituted with 0-3 independently selected RB, a 4-7 membered heterocyclyl substituted with 0-3 independently selected RB, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and any substituents that are present on Ring E selected from R4A, R4D, R4E, and 240 BUSINESS.33169534.1 407274-95WRWO (217205)R4Fare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2- C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; or R4C and R4D, along with their intervening atoms, join to form a 4-7 memberedcarbocyclyl substituted with 0-3 independently selected RB, a 4-7 membered heterocyclyl substituted with 0-3 independently selected RB, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and any substituents that are present on Ring E selected from R4A, R4B, R4Eand R4Fare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2- C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; or R4Eis halogen or -OH, and R4A, R4B, R4C, and R4Dare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1- C4alkyl; C1-C3alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; or R4Eand R4A, along with their intervening atoms, join to form a 5-6 membered optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and R4B, R4C, and R4Dare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3- C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; or R4Fand R4A, along with their intervening atoms, join to form a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and R4Band R4Care each independently selected from hydrogen; halogen; -CN; C1- C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C3alkyl substituted with 241 BUSINESS.33169534.1 407274-95WRWO (217205)-OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3- C6cycloalkoxy; and NR13R14; and R13is independently selected at each occurrence from hydrogen and C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; and R14is hydrogen, or R13and R14combine with the nitrogen atom to which they are attached to form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, wherein said heterocyclic ring is optionally substituted with -CH3; b) R4 is a 5-membered heteroaryl (having 1 heteroatom independently selected fromnitrogen, oxygen, and sulfur and 0, 1, 2, or 3 additional ring nitrogen atoms), wherein said heteroaryl is substituted with 0-4 groups independently selected from halogen, - OH, -CN, C1-C4alkyl, haloC1-C4alkyl, C3-C6cycloalkyl, and C1-C4alkoxy; and c) R4 is a C1-C4alkyl, C1-C4alkoxy, or C3-C6cycloalkyl, each of which is substituted with0-3 groups independently selected from halogen, -CN, -OH, C1-C4alkyl, C1-C4alkoxy, optionally substituted 5-6 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 5- 6 membered heterocyclyloxy having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

5. The compound of claim 4, wherein R1a is a 5-6 membered heteroaryl (having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1-3 groups selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkyl, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RBand R1bis selected from H, halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, and haloC1- C6alkoxy.

6. The compound of claim 4, wherein R1a is a 4-6 membered saturated or partially unsaturatedheterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and said heterocyclyl is substituted with 0-2 RBgroups independently selected from halogen, oxo, NR2, optionally substituted C1-C4aliphatic, -OR, azetidinyl optionally substituted with 1 or 2 independently selected halogen, and pyrrolidinyl optionally substituted with 1 or 2 independently 242 BUSINESS.33169534.1 407274-95WRWO (217205)selected halogen; and each R1bis independently selected from H, halogen, C1-C6alkyl, haloC1- C6alkyl, C1-C6alkoxy, and haloC1-C6alkoxy.

7. The compound of claim 4, wherein R1a is halogen, C1-C6alkyl, C2-C4alkene, C2-C4alkyne,CN, -OR10, -NR10R11, –C(O)NR10R11, –CH2NR10R11, –SO2R12, or a C3-C7cycloalkyl, wherein said C1-C6alkyl, C2-C4alkene, C2-C4alkyne, and C3-C7cycloalkyl is substituted with 0-3 RBindependently selected from halogen, C3-C6cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1- C4alkoxy, and haloC1-C4alkoxy; and R1bis selected from H, halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, and haloC1-C6alkoxy.

8. The compound of claim 4, wherein R1a is pyridyl optionally substituted with C1-C4alkoxyand further substituted with 0-2 RB; and R1bis selected from H, halogen, C1-C6alkyl, haloC1- C6alkyl, C1-C6alkoxy, and haloC1-C6alkoxy.

9. The compound of claim 4, wherein R1a is 5-membered heteroaryl (having 1 heteroatomindependently selected from nitrogen, oxygen, and sulfur, and 0 or 1 additional ring nitrogen atoms), wherein said 5-membered heteroaryl is optionally substituted with a C3-C5cycloalkyl and further substituted with 0-2 independently selected RB; and R1bis selected from H, halogen, C1- C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, and haloC1-C6alkoxy.

10. The compound of claim 1, wherein R1a is a 5-6 membered saturated or partially unsaturatedheterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), said heterocyclyl substituted with 0-2 RBindependently selected from halogen, oxo, NR2, optionally substituted C1-4aliphatic, -OR, azetidinyl optionally substituted with 1 or 2 independently selected halogen, and pyrrolidinyl optionally substituted with 1 or 2 independently selected halogen; and R1bis selected from H, halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, and haloC1-C6alkoxy.

11. The compound of claim 1, wherein R1a is selected from the group consisting of:243 BUSINESS.33169534.1 407274-95WRWO (217205),12. The compound of any one of claims 1-11, wherein R4 is Ring E of the following structure:wherein * iR4Ais hydrogen, -CH3, -CH2CH3, -F, -CF2H, -CF3, -OCH3, -OCF3, -OCH2CH3, or -OCHF2; R4B, R4Cand R4Dare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2- C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; and R13is independently selected at each occurrence from hydrogen or C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3, and R14is H; or NR13R14, taken in combination form 244 BUSINESS.33169534.1 407274-95WRWO (217205)a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, said heterocyclic ring optionally substituted with -CH3; or R4is a 5-membered heteroaryl (having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur and 0, 1, 2, or 3 additional ring nitrogen atoms), wherein said heteroaryl is substituted with 0-4 RBindependently selected from halogen, -OH, -CN, C1-C4alkyl, haloC1- C4alkyl, C3-C6cycloalkyl, and C1-C4alkoxy.

13. The compound of any one of claims 1-11, wherein R4 is:, wherein * is a point of attachR4Ais hydrogen, halogen, -CH3, -CH2CH3, -F, -CF2H, -CF3, -OCH3, -OCF3, -OCH2CH3, or -OCHF2; R4Band R4Care each independently selected from hydrogen; -CN; C1-C4alkyl; C2- C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C3alkyl substituted with -OH, -OCH3, or - OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; and R13is independently selected at each occurrence from hydrogen or C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3, and R14is H; or NR13R14, taken in combination, form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, and said heterocyclic ring is optionally substituted with -CH3.

14. The compound of any one of claims 1-11, wherein R4 is a 5-membered heteroaryl (having1 heteroatom independently selected from nitrogen, oxygen, and sulfur and 0, 1, 2, or 3 additional ring nitrogen atoms), wherein said heteroaryl is substituted with 0-4 RBindependently selected from halogen, -OH, -CN, C1-C4alkyl, haloC1-C4alkyl, C3-C6cycloalkyl, and C1-C4alkoxy.

15. The compound of any one of claims 1-11, wherein R4 is a 5-membered heteroaryl (having1 heteroatom independently selected from nitrogen, oxygen, and sulfur and 0, 1, 2, or 3 additional 245 BUSINESS.33169534.1 407274-95WRWO (217205)ring nitrogen atoms) selected from the group consisting of thiophenyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, oxazolyl, isoxazolyl, 1,2,4- oxadiazolyl, 1,2,3-triazolyl, and 1,2,4-triazolyl, wherein said heteroaryl is optionally substituted with 0-4 RBindependently selected from halogen, -OH, -CN, C1-C4alkyl, haloC1-C4alkyl, C3- C6cycloalkyl, and C1-C4alkoxy.

16. The compound of claim 15, wherein R4 is an isoxazolyl substituted with -OH or C1-C4alkoxy.

17. The compound of any one of claims 1-11, wherein R4 is, , , , , ,205), , ,18. The compound of any one of claims 1-17, wherein R2A comprises a -CF3 substituent.

19. The compound of any one of claims 1-18, wherein R2 is.

20. The compound of claim 1-17, wherein R2 is.

21. The compound of any one of claims 1-20, wherein R3 is C1-C4alkyl or C3-C5cycloalkyl.

22. A compound described in Table 1, Table 1a, Table 2, or Table 2a; or a pharmaceuticallyacceptable salt thereof. 247 BUSINESS.33169534.1 407274-95WRWO (217205)23. A pharmaceutical composition comprising a compound or pharmaceutically acceptable saltthereof according to any one of claims 1-22, and one or more pharmaceutically acceptable carriers.

24. A method of treating cancer in a subject, wherein the cancer is characterized asmicrosatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-22, or a pharmaceutically acceptable salt thereof.

25. A method of modulating WRN activity in a subject, wherein the method comprisesadministering to the subject an effective amount of the compound according to any one of claims 1-22, or a pharmaceutically acceptable salt thereof.

26. A method of treating a disorder or disease which can be treated by WRN inhibition in asubject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound according to any one of claims 1-22, or a pharmaceutically acceptable salt thereof.

27. A method of inhibiting WRN in a subject, wherein the method comprises administering tothe subject an effective amount of the compound according to any one of claims 1-22, or a pharmaceutically acceptable salt thereof.

28. The method of claim 26, wherein the disorder or disease is a cancer characterized asmicrosatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

29. The method of claim 28, wherein the cancer characterized as microsatellite instability-high(MSI-H) or mismatch repair deficient (dMMR) is selected from colorectal, gastric, prostate, endometrial, adrenocortical, uterine, cervical, esophageal, breast, kidney and ovarian cancer. 248 BUSINESS.33169534.1 407274-95WRWO (217205)

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