Oxazolopyridin-7(4H)-one wrn inhibitors

Abstract

The present disclosure is directed to oxazolopyridin-7(4H)-one based compounds, including compounds of Formula (I): (Formula (I)) and pharmaceutically acceptable salts thereof, and compositions thereof, as well as methods of treatment of cancers such as those involving WRN protein.

Description

OXAZOLOPYRIDIN-7(4H)-ONE WRN INHIBITORS RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 507,362 filed June 9, 2023; U.S. Provisional Application No.63 / 518,298 filed August 8, 2023; and U.S. Provisional Application No.63 / 613,651 filed December 21, 2023; the contents of each of which are incorporated by reference in their entireties. FIELD OF INVENTION

[0002] 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, combinations, processes and formulations. SEQUENCE LISTING

[0003] This application contains a Sequence Listing which has been submitted in .xml format via EFS and is hereby incorporated by reference. The ST.26 copy, created on June 8, 2023, is named 407274-80WRP3_ST26.xml and is 8,751 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 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 (Andre 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 andchromosome breakage. Thus, inhibiting the WRN helicase is an attractive strategy for the treatment of MSI-H cancers.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 a chemical probe, and as tool compounds. Various embodiments of the invention are described herein.

[0006] In one aspect, the disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof:R2N wherein R1, R2, R3, R4, Y, Z, -L-, and Ring A are as described and defined herein.

[0007] In another aspect, the invention provides a pharmaceutical composition comprising a compound of Formula I 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 Formula I of the present invention and one or more therapeutically active agents.

[0009] In another aspect, the invention provides a compound of Formula I 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 Formula I 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 Formula I 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 Formula I of the present invention.

[0013] In another aspect, the invention provides the use of a compound of Formula I 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 Formula I 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 DESCRIPTION1. General Description of Certain Embodiments o f the Invention:

[0016] In one aspect, the disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereofwherein Ring A represents:a) a 4-7 membered saturated or partially unsaturated bivalent monocyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or b) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene and heterocyclylene (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein Ring A is substituted with 0-4 independently selected RAsubstituents; each of Y and Z is selected from N and O, wherein Y is N and Z is O or Y is O and Z is N, wherein ----- denotes a single or double bond and the 5-membered ring comprising Z and Y is aromatic; L is a linker selected from -C(O)-, -S(O)-, -S(O)2-, an R1is selected from one of groups a) to e):a) a 5-6 membered monocyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1-3 groups independently selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, and C3- C6cycloalkoxy, wherein said 5-6 membered monocyclic heteroaryl is further substituted with 0-3 independently selected RA; b) a 9-10 membered bicyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1 or 2 groups independently selected from C1-C6aliphatic, C3-C6cycloalkyl, C1-C6alkoxy, and C3-C6cycloalkoxy, wherein said 9-10 membered bicyclic heteroaryl is further substituted with 0-3 independently selected RA;c) 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-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, and C3-C6cycloalkoxy, and -OR, wherein said 4-7 membered saturated or partially unsaturated monocyclic heterocyclyl is further substituted with 0-3 independently selected RA; d) a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl and heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected RA; and e) H, halogen, C1-C6aliphatic, C3-C7cycloalkyl, C1-C6alkylene-O-C1-C6alkyl, -CN, -OR, - NR10R11, -C(O)NR10R11, -CH2NR10R11, -SO2R12, wherein the C1-C6aliphatic, C3- C7cycloalkyl, or C1-C6alkylene-O-C1-C6alkyl is substituted with 0-5 independently selected RA; R10is H, C1-C6aliphatic, haloC1-C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, –C(O)C3- C6cycloalkyl, –C(O)C1-C6alkyl, or 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 RA; R11is H, C1-C6aliphatic, or C3-C6cycloalkyl, or R10and R11may combine 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) optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1-C6alkyl, C1-C6alkoxy, C3- C6cycloalkyl, and C3-C6cycloalkoxy; RAis 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, hydroxy-C1-C6alkyl, haloC1- C6alkyl, an optionally substituted 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; R2is C(RB)2C(O)N(R)R2A; RBis independently selected at each occurrence from hydrogen, -CH3, and -CH2CH3, or two RBtaken together with the carbon to which they are attached form a cyclopropyl ring; 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-C6cycloalkyl, haloC3- C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, and –SF5; or two substituents on adjacent atoms of the phenyl or pyridyl together with said adjacent atoms form a 4-7 membered carbocyclyl fused to the phenyl or pyridyl; or two substituents on adjacent atoms of the phenyl or pyridyl together with said adjacent atoms 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 4-7 membered carbocyclyl or 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-C4aliphatic, haloC1-C4alkyl, and - OH; R3is hydrogen, C1-C4aliphatic, C3-C5cycloalkyl, C1-C4alkoxy, -NHR3A, -N(R3A)2, or C1- C4alkylthio, each of which, besides hydrogen, is optionally substituted with -OH, 1-5 independently selected halogen, -OR, -C(O)NR10R11, or N(R)C(O)R; each R3Ais independently selected at each occurrence from C1-C4alkyl; R4is phenyl or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) wherein said phenyl or 5-6 membered heteroaryl are substituted with 0-5 RAor two substituents on adjacent atoms of said phenyl or 5-6 membered heteroaryl togetherwith said adjacent atoms form a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl, or a 5- 6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to the phenyl or 5-6 membered heteroaryl wherein said 4-7 membered carbocyclyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl are substituted with 0-3 RA; or R4is a C1-C4alkyl, C1-C4alkoxy, or C3-C6cycloalkyl, each of which is substituted with 0-3 groups independently selected from halogen, -CN, -OH, oxo, NH2, C1-C4alkyl, C1-C4alkoxy, optionally substituted 5-6 membered heterocyclyl, and optionally substituted 5-6 membered heterocyclyloxy; 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 an optionally substituted 4-7 membered saturated ring, 4-7 membered partially unsaturated ring, or 5-6 membered heteroaryl ring (wherein said 4-7 membered saturated ring and 4-7 membered partially unsaturated ring has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and wherein said 5-6 membered heteroaryl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0017] For clarity, it is understood that ----- above denotes a single or double bond and that if, g which can be treated by WRN inhibition in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula I of the present invention, or a pharmaceutically acceptable salt thereof.

[0019] In another aspect, the disclosure provides a compound of Formula I’, or a pharmaceutically acceptable salt thereof: I’ wherein R4is selected from one of a), b), and c): a) R4is a Ring B that is selected from the group consisting of: and ; wherein * is a point of attachment to L in Formula I; and wherein: any substituents that are present on Ring E selected from R4A, R4B, R4C, R4D, R4E, and R4Fare each independently selected from hydrogen; halogen; -OH; -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 optionally substituted carbocyclyl, 4-7 membered optionally substituted heterocyclyl, or 5-6 membered optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring E; and any substituentsthat are present on Ring E selected from R4C, R4D, R4E, and R4Fare each independently selected from hydrogen; halogen; -OH; -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 4-7 membered optionally substituted carbocyclyl, 4-7 membered optionally substituted heterocyclyl, or 5-6 membered optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) 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; -OH; -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 optionally substituted carbocyclyl, 4-7 membered optionally substituted heterocyclyl, or 5-6 membered optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) 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; -OH; -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 optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring E; and R4B, R4C, and R4Dare each independently selected from hydrogen; halogen; -OH; -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; orR4Fand R4A, along with their intervening atoms, join to form optionally substituted 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring E; and R4Band R4Care each independently selected from hydrogen; halogen; -OH; -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 NR13R14forms a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl, said heterocyclic ring optionally substituted with -CH3; or b) 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; or c) 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, and optionally substituted 5-6 membered heterocyclyloxy.

[0020] 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 Formula I’ of the present invention, or a pharmaceutically acceptable salt thereof.

[0021] In one aspect, the disclosure provides a compound of Formula I’’, or a pharmaceutically acceptable salt thereof:wherein Ring A represents: a) a 4-7 membered saturated or partially unsaturated bivalent monocyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or b) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene and heterocyclylene (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein Ring A is substituted with 0-4 independently selected RAsubstituents; each of Y and Z is selected from N and O, wherein Y is N and Z is O or Y is O and Z is N, wherein ----- denotes a single or double bond and the 5-membered ring comprising Z and Y is aromatic; L is a linker selected from -C(O)-, -S(O)-, -S(O)2-, and ; R1is selected from one of groups a) to e): a) a 5-6 membered monocyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1-3 groups independently selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, and C3- C6cycloalkoxy, wherein said 5-6 membered monocyclic heteroaryl is further substituted with 0-3 independently selected RA; b) a 9-10 membered bicyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1 or 2 groups independently selected from C1-C6aliphatic, C3-C6cycloalkyl, C1-C6alkoxy, and C3-C6cycloalkoxy, wherein said 9-10 membered bicyclic heteroaryl is further substituted with 0-3 independently selected RA; c) 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-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, and C3-C6cycloalkoxy, and -OR, wherein said 4-7 membered saturated orpartially unsaturated monocyclic heterocyclyl is further substituted with 0-3 independently selected RA; d) a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl and heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected RA; and e) H, halogen, C1-C6aliphatic, C3-C7cycloalkyl, C1-C6alkylene-O-C1-C6alkyl, -CN, -OR, - NR10R11, -C(O)NR10R11, -CH2NR10R11, -SO2R12, wherein the C1-C6aliphatic, C3- C7cycloalkyl, or C1-C6alkylene-O-C1-C6alkyl is substituted with 0-5 independently selected RA; R10is H, C1-C6aliphatic, haloC1-C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, –C(O)C3- C6cycloalkyl, –C(O)C1-C6alkyl, or 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 RA; R11is H, C1-C6aliphatic, or C3-C6cycloalkyl, or R10and R11may combine 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) optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1-C6alkyl, C1-C6alkoxy, C3- C6cycloalkyl, and C3-C6cycloalkoxy; RAis 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, hydroxy-C1-C6alkyl, haloC1- C6alkyl, an optionally substituted 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; R2is selected from C(RB)2C(O)N(R)R2A, C(RB)2C(RB)2C(O)N(R)R2A, C(RB)2C(RB)2N(R)C(O) N(R)R2A, and C(RB)2C(RB)2N(R)C(O)R2A; RBis independently selected at each occurrence from hydrogen, -CH3, and -CH2CH3, or two RBtaken together with the carbon to which they are attached form a cyclopropyl ring; 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 contains 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-C6cycloalkoxy, haloC3-C6- cycloalkoxy and –SF5; or two substituents on adjacent atoms of the phenyl or pyridyl together with said adjacent atoms form a 4-7 membered carbocyclyl fused to the phenyl or pyridyl; or two substituents on adjacent atoms of the phenyl or pyridyl together with said adjacent atoms 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 4-7 membered carbocyclyl or 4-7 membered heterocyclyl is substituted with 0-5 independently selected halogen, and wherein 2 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 unsaturated carbocyclyl, and ● an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orR2Ais 2-benzimidazolyl, 2-naphthyl, or 3-quinolinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4aliphatic, haloC1-C4alkyl, and - OH; R3is hydrogen, C1-C4aliphatic, C3-C5cycloalkyl, C1-C4alkoxy, -NHR3A, -N(R3A)2, or C1- C4alkylthio, each of which, besides hydrogen, is optionally substituted with -OH, 1-5 independently selected halogen, -OR, -C(O)NR10R11, or N(R)C(O)R; each R3Ais independently selected at each occurrence from C1-C4alkyl; R4is phenyl or a first 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) wherein said phenyl or said first 5-6 membered heteroaryl are substituted with 0-5 RAor two substituents on adjacent atoms of said phenyl or said first 5-6 membered heteroaryl together with said adjacent atoms form a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl, or a second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to the phenyl or first 5-6 membered heteroaryl wherein said 4-7 membered carbocyclyl, 4-7 membered heterocyclyl, or second 5-6 membered heteroaryl are substituted with 0-3 RA; or R4is a C1-C4alkyl, C1-C4alkoxy, or C3-C6cycloalkyl, each of which is substituted with 0-3 groups independently selected from halogen, -CN, -OH, oxo, NH2, C1-C4alkyl, C1-C4alkoxy, optionally substituted 5-6 membered heterocyclyl, and optionally substituted 5-6 membered heterocyclyloxy; 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 an optionally substituted 4-7 membered saturated ring, 4-7 membered partially unsaturated ring, or 5-6 membered heteroaryl ring (wherein said 4-7 membered saturated ring and 4-7 membered partially unsaturated ring has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfurand wherein said 5-6 membered heteroaryl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0022] 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 Formula I” of the present invention, or a pharmaceutically acceptable salt thereof.2. Compounds and Definitions:

[0023] 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 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.

[0024] 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 unsubstitutedalkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0025] 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 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 abridged bicyclic group is optionally substituted. The term “alkyl” refers to a Ci-12 straight or branched saturated aliphatic group. In certain instances, alkyl refers to a Ci-s straight or branched saturated aliphatic group or a Ci-6 straight or branched saturated aliphatic group. The term “lower alkyl” refers to a Ci-4 straight or branched alkyl group.

[0026] Exemplary lower alkyl groups are methyl (-CH3), ethyl (-CH2CH3), propyl, isopropyl (also referred to interchangeably herein as 2-propyl, iPr, *Pr and i-Pr), butyl, isobutyl (also referred to interchangeably herein as 2-butyl, iBu, ‘Bu and i-Bu) and tert-butyl (also referred to interchangeably herein as 2-methyl-2 -butyl, tBu, ’Bu and t-Bu).

[0027] 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=CHCH3, and -CH=CHCH2CH3).

[0028] The term “alkynyl” refers to a C2-12 straight 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 C2-4 straightor 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.

[0029] 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.

[0030] 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).

[0031] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.

[0032] 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.

[0033] 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 , , , , and .

[0034] “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.cyclopropylene

[0035] A carbocyclylene may be saturated as in the examples shown above or partially unsaturated as in the examples shown below.

[0036] A carbocyclylene may be multi-cyclic, for example, bicyclic 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.spirocyclic bicyclic carbocyclylenes fused bicyclic carbocyclylenes bridged bicyclic carbocyclylenes

[0037] “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. spirocyclic bicyclic heterocyclylenes fused bicyclic heterocyclylenes bridged bicyclic heterocyclylenes

[0038] “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.

[0039] “Arylene” as used herein refers to an mono or multi-cyclic 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.

[0040] “Heteroarylene,” as used herein refers to a mono or multi-cyclic aryl 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.

[0041] The term “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.

[0042] “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 carbon bond which it shares with the ring to which it is fused (i.e., the “phenyl or pyridyl”). This is illustrated below. partially unsaturated cyclopentyl fused to phenyl, i.e., "cyclopentyl fused to phenyl"5 -membered partially unsaturated heterocyclyl fused to the phenyl, i.e."heterocyclyl fused to phenyl"

[0043] A further example below shows a carbocyclyl moiety fused to a Ring B 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 B” as shown in the image below. As such, “Ring B” 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 the substituents of Ring B is described as being “fused to Ring B.” Likewise, R4Aand R4B, along with their 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 B (not pictured), is subject to the same interpretation.V carbocyclyl that isRing B fused to Ring B

[0044] 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.

[0045] The term “cubanyl” refers to a substituent of cubane as shown below.

[0046] The term “halogen” means F, Cl, Br, or I.

[0047] 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 contains 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.

[0048] 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 n 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 quatemized 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-l-only, l,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-onyl, 2,3-dihydro-lH-pyrrolo[3,4-c]pyridin-l-onyl, imidazo[l ,2- a]pyridyl, imidazo[l,5-a]pyridyl, pyrazolo[l,5-a]pyridyl, pyrrolo[l,2-b]pyridazinyl, pyrrolo[l,2- a]pyrimidinyl, imidazo[l,2-b]pyridazinyl, imidazo[l,2-a]pyrimidinyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 47 / 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 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.

[0049] 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. When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes 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- 277 pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in A substituted pyrrolidinyl).

[0050] 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. Theterm “heterocyclyl alkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0051] “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.

[0052] “Heterocyclyloxy,” as used herein, refers to an -OR group wherein the R is a heterocyclyl. Nonlimiting examples are shown below.

[0053] As used herein, the term “partially unsaturated” refers to a ring moiety 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.

[0054] 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 feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered 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.

[0055] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)o 4B(OR°)2; -(CH2)o 4R0; -(CH2)o 4OR0; - 0(CH2)o-4R°; -0-(CH2)O4C(O)ORO; -(CH2)O-ICH(OR0)2; -(CH2)O 4SRO; -(CH2)O4Ph. whichmay be substituted with R°; -(CH2)o-40(CH2)o-iPh which may be substituted with R°; - CH=CHPh, which may be substituted with R°; -(CH2)o40(CH2)o i -pyridyl which may be substituted with R°; -N02; -CN; -N3; -(CH2)0-4N(R°)2; -(CH2)0 4N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2)O4N(RO)C(O)NR°2; -N(RO)C(S)NR°2; -(CH2)O4N(RO)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(RO)C(NR°)N(RO)2;-(CH2)O4C(O)RO; - C(S)R°; -(CH2)0 4C(O)ORO; -(CH2)O 4C(O)SRO: -(CH2)O 4C(O)OSiR°3; -(CH2)0 4OC(O)R°; - OC(0)(CH2)O4SRO; -(CH2)O4SC(0)RO; -(CH2)O4C(0)NRO2; -C(S)NRO2; -C(S)SR°; - SC(S)SR°; -(CH2)O4OC(O)NRO2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)RO; - C(NOR°)R°; -(CH2)0 4SSRO; -(CH2)O4S(O)2RO; -(CH2)O4S(O)2ORO; -(CH2)O4OS(O)2RO; - S(O)2NR°2; -(CH2)O 4S(O)RO; -N(RO)S(O)2NR°2; -N(RO)S(O)2R°; -N(OR°)R°; -C(NH)NRO2; - (CH2)O4P(O)2R°; -(CH2)O 4P(O)RO2; -(CH2)O4OP(O)RO2; -(CH2)O4OP(O)(ORO)2; -SiR°3; -(Ci 4 straight or branched alkylene)O-N(R°)2; or -(Ci-4straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, Ci 6 aliphatic, -SO2-Ci4aliphatic (i.e., -SO2CH3) -CH2Ph, -0(CH2)o iPh, -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.

[0056] 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)o-2R*, -(haloR*), -(CH2)O2OH, -(CH2)O2OR*, -(CH2)O2CH(OR’)2; -O(haloR’), -CN, -N3, -(CH2)o2C(O)R’, (CH2)O2C(O)OH, (CH2)O2C(O)OR*, (CH2)O2SR’, (CH2)O2SH, (CH2)O 2NH2, (CH2)O-2NHR*, -(CH2)O-2NR’2, -NO2, -SiR*3, -OSiR\ -C(O)SR* -(Ci~4straight 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 C1-6 aliphatic, - CH2Ph, -0(CH2)o-iPh, 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 =0 and =S.

[0057] 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: =0, =S, =NNR*2, =NNHC(0)R*, =NNHC(0)0R*, =NNHS(0)2R*, =NR*, =N0R*, -O(C(R*2))2 3O-, or - S(C(R*2))2-3S-, wherein each independent occurrence of R* is selected from hydrogen, Ci- 6 aliphatic 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, C1-6 aliphatic 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.

[0058] 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 C 1-4 aliphatic, -CH2Ph, -0(CH2)o iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0059] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R\ -NR‘;'2, -C(O)Rf, -C(O)ORt, -C(O)C(O)Rf, -C(O)CH2C(O)Rt, -S(O)2RT, -S(O)2NR^2, -C(S)NRt2, -C(NH)NRt2, or -N(Rt)S(O)2Rt; wherein each R:is independently hydrogen, C1-6 aliphatic which may be substituted as defined 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 Ft , 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.

[0060] 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 oneor more halogens, and is independently C1-4 aliphatic, -CFhPh, -0(CH2)o-iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0061] 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, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemi sulfate, 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.

[0062] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (Ci 4alkyl)4 salts. 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.

[0063] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of thestructure; 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.

[0064] 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:

[0065] In one aspect, the disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof wherein Ring A represents: a) a 4-7 membered saturated or partially unsaturated bivalent monocyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or b) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene and heterocyclylene (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur);wherein Ring A is substituted with 0-4 independently selected RAsubstituents; each of Y and Z is selected from N and O, wherein Y is N and Z is O or Y is O and Z is N, - denotes a single or double bond, and the 5-membered ring comprising Z and Y is aromatic;HNS ZOL is a linker selected from -C(O)-, -S(O)-, -S(O)2-, and * ;R1is selected from one of groups a) to e): a) a 5-6 membered monocyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1-3 groups independently selected from halogen, Ci-Cealkyl, haloCi-Cealkyl, Ca-Cecycloalkyl, Ci-Cealkoxy, and C3- CLcycloalkoxy, wherein said 5-6 membered monocyclic heteroaryl is further substituted with 0-3 independently selected RA; b) a 9-10 membered bicyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1 or 2 groups independently selected from Ci-Cealiphatic, Cs-Cecycloalkyl, Ci-Cealkoxy, and Ca-Cecycloalkoxy, wherein said 9-10 membered bicyclic heteroaryl is further substituted with 0-3 independently selected RA; c) 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 Ci-Cealkyl, Cs-Cficycloalkyl, Ci-Cealkoxy, and Ca-Cecycloalkoxy, and -OR, wherein said 4-7 membered saturated or partially unsaturated monocyclic heterocyclyl is further substituted with 0-3 independently selected RA; d) a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl and heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected RA; and e) H, halogen, Ci-Cealiphatic, Ca-Cvcycloalkyl, Ci-Cealkylene-O-Ci-Cealkyl, -CN, -OR, - NR10Rn, -C(O)NR10Ru-CH2NR10Rn, -SO2R12, wherein the Ci-C6aliphatic, C3-C7cycloalkyl, or C1-C6alkylene-O-C1-C6alkyl is substituted with 0-5 independently selected RA; R10is H, C1-C6aliphatic, haloC1-C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, –C(O)C3- C6cycloalkyl, –C(O)C1-C6alkyl, or 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 RA; R11is H, C1-C6aliphatic, or C3-C6cycloalkyl, or R10and R11may combine 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) optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1-C6alkyl, C1-C6alkoxy, C3- C6cycloalkyl, and C3-C6cycloalkoxy; RAis 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, hydroxy-C1-C6alkyl, haloC1- C6alkyl, an optionally substituted 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; R2is C(RB)2C(O)N(R)R2A; RBis independently selected at each occurrence from hydrogen, -CH3, and -CH2CH3, or two RBtaken together with the carbon to which they are attached form a cyclopropyl ring;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-C6cycloalkyl, haloC3- C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, and –SF5; or two substituents on adjacent atoms of the phenyl or pyridyl together with said adjacent atoms form a 4-7 membered carbocyclyl fused to the phenyl or pyridyl; or two substituents on adjacent atoms of the phenyl or pyridyl together with said adjacent atoms 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 4-7 membered carbocyclyl or 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-C4aliphatic, haloC1-C4alkyl, and - OH; R3is hydrogen, C1-C4aliphatic, C3-C5cycloalkyl, C1-C4alkoxy, -NHR3A, -N(R3A)2, or C1- C4alkylthio, each of which, besides hydrogen, is optionally substituted with -OH, 1-5 independently selected halogen, -OR, -C(O)NR10R11, or N(R)C(O)R; each R3Ais independently selected at each occurrence from C1-C4alkyl; R4is phenyl or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) wherein said phenyl or 5-6 membered heteroaryl are substituted with 0-5 RAor two substituents on adjacent atoms of said phenyl or 5-6 membered heteroaryl together with said adjacent atoms form a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl, or a 5- 6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to the phenyl or 5-6 membered heteroaryl wherein said 4-7 membered carbocyclyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl are substituted with 0-3 RA; or R4is a C1-C4alkyl, C1-C4alkoxy, or C3-C6cycloalkyl, each of which is substituted with 0-3 groups independently selected from halogen, -CN, -OH, oxo, NH2, C1-C4alkyl, C1-C4alkoxy, optionally substituted 5-6 membered heterocyclyl, and optionally substituted 5-6 membered heterocyclyloxy; 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 unsaturatedcarbocyclic 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 an optionally substituted 4-7 membered saturated ring, 4-7 membered partially unsaturated ring, or 5-6 membered heteroaryl ring (wherein said 4-7 membered saturated ring and 4-7 membered partially unsaturated ring has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and wherein said 5-6 membered heteroaryl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0066] In one aspect, the disclosure provides a compound of Formula Ix, or a pharmaceutically acceptable salt thereof:R2wherein Ring A represents: a) a 4-7 membered saturated or partially unsaturated bivalent monocyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or b) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene and heterocyclylene (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein Ring A is substituted with 0-4 independently selected RAsubstituents; each of Y and Z is selected from N and O, wherein Y is N and Z is O or Y is O and Z is N, - denotes a single or double bond, and the 5-membered ring comprising Z and Y is aromatic;R1is selected from one of groups a) to e):a) a 5-6 membered monocyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1-3 groups independently selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, and C3- C6cycloalkoxy, wherein said 5-6 membered monocyclic heteroaryl is further substituted with 0-3 independently selected RA; b) a 9-10 membered bicyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1 or 2 groups independently selected from C1-C6aliphatic, C3-C6cycloalkyl, C1-C6alkoxy, and C3-C6cycloalkoxy, wherein said 9-10 membered bicyclic heteroaryl is further substituted with 0-3 independently selected RA; c) 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-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, and C3-C6cycloalkoxy, and -OR, wherein said 4-7 membered saturated or partially unsaturated monocyclic heterocyclyl is further substituted with 0-3 independently selected RA; d) a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl and heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected RA; and e) H, halogen, C1-C6aliphatic, C3-C7cycloalkyl, C1-C6alkylene-O-C1-C6alkyl, -CN, -OR, - NR10R11, -C(O)NR10R11, -CH2NR10R11, -SO2R12, wherein the C1-C6aliphatic, C3- C7cycloalkyl, or C1-C6alkylene-O-C1-C6alkyl is substituted with 0-5 independently selected RA; R10is H, C1-C6aliphatic, haloC1-C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, –C(O)C3- C6cycloalkyl, –C(O)C1-C6alkyl, or 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 RA;R11is H, C1-C6aliphatic, or C3-C6cycloalkyl, or R10and R11may combine 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) optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1-C6alkyl, C1-C6alkoxy, C3- C6cycloalkyl, and C3-C6cycloalkoxy; RAis 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, hydroxy-C1-C6alkyl, haloC1- C6alkyl, an optionally substituted 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; R2is C(RB)2C(O)N(R)R2A; RBis independently selected at each occurrence from hydrogen, -CH3, and -CH2CH3, or two RBtaken together with the carbon to which they are attached form a cyclopropyl ring; 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-C6cycloalkyl, haloC3- C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, and –SF5; or two substituents on adjacent atoms of the phenyl or pyridyl together with said adjacent atoms form a 4-7 membered carbocyclyl fused to the phenyl or pyridyl; or two substituents on adjacent atoms of the phenyl or pyridyl together with said adjacent atoms form a 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused to the phenyl or pyridyl, whereinsaid 4-7 membered carbocyclyl or 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-C4aliphatic, haloC1-C4alkyl, and - OH; R3is hydrogen, C1-C4aliphatic, C3-C5cycloalkyl, C1-C4alkoxy, -NHR3A, -N(R3A)2, or C1- C4alkylthio, each of which, besides hydrogen, is optionally substituted with -OH, 1-5 independently selected halogen, -OR, -C(O)NR10R11, or N(R)C(O)R; each R3Ais independently selected at each occurrence from C1-C4alkyl; R4is phenyl or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) wherein said phenyl or 5-6 membered heteroaryl are substituted with 0-5 RAor two substituents on adjacent atoms of said phenyl or 5-6 membered heteroaryl together with said adjacent atoms form a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl, or a 5- 6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to the phenyl or 5-6 membered heteroaryl wherein said 4-7 membered carbocyclyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl are substituted with 0-3 RA; or R4is a C1-C4alkyl, C1-C4alkoxy, or C3-C6cycloalkyl, each of which is substituted with 0-3 groups independently selected from halogen, -CN, -OH, oxo, NH2, C1-C4alkyl, C1-C4alkoxy, optionally substituted 5-6 membered heterocyclyl, and optionally substituted 5-6 membered heterocyclyloxy; 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 an optionally substituted 4-7 membered saturated ring, 4-7 membered partially unsaturated ring, or 5-6 membered heteroaryl ring (wherein said 4-7 membered saturated ring and 4-7 membered partiallyunsaturated ring has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and wherein said 5-6 membered heteroaryl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0067] In one aspect, the disclosure provides a compound of Formula Iy, or a pharmaceutically acceptable salt thereof: Iywherein Ring A represents: a) a 4-7 membered saturated or partially unsaturated bivalent monocyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or b) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene and heterocyclylene (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein Ring A is substituted with 0-4 independently selected RAsubstituents; each of Y and Z is selected from N and O, wherein Y is N and Z is O or Y is O and Z is N, ----- denotes a single or double bond, and the 5-membered ring comprising Z and Y is aromatic; R1is selected from one of groups a) to e): a) a 5-6 membered monocyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1-3 groups independently selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, and C3- C6cycloalkoxy, wherein said 5-6 membered monocyclic heteroaryl is further substituted with 0-3 independently selected RA; b) a 9-10 membered bicyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1 or 2 groups independentlyselected from C1-C6aliphatic, C3-C6cycloalkyl, C1-C6alkoxy, and C3-C6cycloalkoxy, wherein said 9-10 membered bicyclic heteroaryl is further substituted with 0-3 independently selected RA; c) 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-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, and C3-C6cycloalkoxy, and -OR, wherein said 4-7 membered saturated or partially unsaturated monocyclic heterocyclyl is further substituted with 0-3 independently selected RA; d) a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl and heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected RA; and e) H, halogen, C1-C6aliphatic, C3-C7cycloalkyl, C1-C6alkylene-O-C1-C6alkyl, -CN, -OR, - NR10R11, -C(O)NR10R11, -CH2NR10R11, -SO2R12, wherein the C1-C6aliphatic, C3- C7cycloalkyl, or C1-C6alkylene-O-C1-C6alkyl is substituted with 0-5 independently selected RA; R10is H, C1-C6aliphatic, haloC1-C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, –C(O)C3- C6cycloalkyl, –C(O)C1-C6alkyl, or 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 RA; R11is H, C1-C6aliphatic, or C3-C6cycloalkyl, or R10and R11may combine 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) optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1-C6alkyl, C1-C6alkoxy, C3- C6cycloalkyl, and C3-C6cycloalkoxy;RAis 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, hydroxy-C1-C6alkyl, haloC1- C6alkyl, an optionally substituted 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; R2is selected from C(RB)2C(O)N(R)R2A, C(RB)2C(RB)2C(O)N(R)R2A, C(RB)2C(RB)2N(R)C(O) N(R)R2A, and C(RB)2C(RB)2N(R)C(O)R2A; RBis independently selected at each occurrence from hydrogen, -CH3, and -CH2CH3, or two RBtaken together with the carbon to which they are attached form a cyclopropyl ring; 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 contains 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-C6cycloalkoxy, haloC3-C6-cycloalkoxy and –SF5; or two substituents on adjacent atoms of the phenyl or pyridyl together with said adjacent atoms form a 4-7 membered carbocyclyl fused to the phenyl or pyridyl; or two substituents on adjacent atoms of the phenyl or pyridyl together with said adjacent atoms 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 4-7 membered carbocyclyl or 4-7 membered heterocyclyl is substituted with 0-5 independently selected halogen, and wherein 2substituents 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 unsaturated carbocyclyl, and ^ an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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-C4aliphatic, haloC1-C4alkyl, and - OH; R3is hydrogen, C1-C4aliphatic, C3-C5cycloalkyl, C1-C4alkoxy, -NHR3A, -N(R3A)2, or C1- C4alkylthio, each of which, besides hydrogen, is optionally substituted with -OH, 1-5 independently selected halogen, -OR, -C(O)NR10R11, or N(R)C(O)R; each R3Ais independently selected at each occurrence from C1-C4alkyl; R4is phenyl or a first 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) wherein said phenyl or said first 5-6 membered heteroaryl are substituted with 0-5 RAor two substituents on adjacent atoms of said phenyl or said first 5-6 membered heteroaryl together with said adjacent atoms form a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl, or a second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to the phenyl or first 5-6 membered heteroaryl wherein said 4-7 membered carbocyclyl, 4-7 membered heterocyclyl, or second 5-6 membered heteroaryl are substituted with 0-3 RA; or R4is a C1-C4alkyl, C1-C4alkoxy, or C3-C6cycloalkyl, each of which is substituted with 0-3 groups independently selected from halogen, -CN, -OH, oxo, NH2, C1-C4alkyl, C1-C4alkoxy, optionally substituted 5-6 membered heterocyclyl, and optionally substituted 5-6 membered heterocyclyloxy; 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 unsaturatedheterocyclic 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 an optionally substituted 4-7 membered saturated ring, 4-7 membered partially unsaturated ring, or 5-6 membered heteroaryl ring (wherein said 4-7 membered saturated ring and 4-7 membered partially unsaturated ring has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and wherein said 5-6 membered heteroaryl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0068] In one aspect, the disclosure provides a compound of Formula I”, or a pharmaceutically acceptable salt thereofR2R2N wherein Ring A represents: a) a 4-7 membered saturated or partially unsaturated bivalent monocyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or b) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene and heterocyclylene (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein Ring A is substituted with 0-4 independently selected RAsubstituents; each of Y and Z is selected from N and O, wherein Y is N and Z is O or Y is O and Z is N, - denotes a single or double bond, and the 5-membered ring comprising Z and Y is aromatic;L is a linker selected from -C(O)-, -S(O)-, -S(O)2-, andR1is selected from one of groups a) to e): a) a 5-6 membered monocyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1-3 groups independently selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, and C3- C6cycloalkoxy, wherein said 5-6 membered monocyclic heteroaryl is further substituted with 0-3 independently selected RA; b) a 9-10 membered bicyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1 or 2 groups independently selected from C1-C6aliphatic, C3-C6cycloalkyl, C1-C6alkoxy, and C3-C6cycloalkoxy, wherein said 9-10 membered bicyclic heteroaryl is further substituted with 0-3 independently selected RA; c) 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-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, and C3-C6cycloalkoxy, and -OR, wherein said 4-7 membered saturated or partially unsaturated monocyclic heterocyclyl is further substituted with 0-3 independently selected RA; d) a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl and heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected RA; and e) H, halogen, C1-C6aliphatic, C3-C7cycloalkyl, C1-C6alkylene-O-C1-C6alkyl, -CN, -OR, - NR10R11, -C(O)NR10R11, -CH2NR10R11, -SO2R12, wherein the C1-C6aliphatic, C3- C7cycloalkyl, or C1-C6alkylene-O-C1-C6alkyl is substituted with 0-5 independently selected RA; R10is H, C1-C6aliphatic, haloC1-C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, –C(O)C3- C6cycloalkyl, –C(O)C1-C6alkyl, or 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 RA;R11is H, C1-C6aliphatic, or C3-C6cycloalkyl, or R10and R11may combine 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) optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1-C6alkyl, C1-C6alkoxy, C3- C6cycloalkyl, and C3-C6cycloalkoxy; RAis 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, hydroxy-C1-C6alkyl, haloC1- C6alkyl, an optionally substituted 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; R2is selected from C(RB)2C(O)N(R)R2A, C(RB)2C(RB)2C(O)N(R)R2A, C(RB)2C(RB)2N(R)C(O) N(R)R2A, and C(RB)2C(RB)2N(R)C(O)R2A; RBis independently selected at each occurrence from hydrogen, -CH3, and -CH2CH3, or two RBtaken together with the carbon to which they are attached form a cyclopropyl ring; 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 contains 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 substituentsindependently selected from halogen, C1-C4aliphatic, haloC1-C4alkyl, C3-C6cycloalkyl, haloC3- C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, C3-C6cycloalkoxy, haloC3-C6- cycloalkoxy and –SF5; or two substituents on adjacent atoms of the phenyl or pyridyl together with said adjacent atoms form a 4-7 membered carbocyclyl fused to the phenyl or pyridyl; or two substituents on adjacent atoms of the phenyl or pyridyl together with said adjacent atoms 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 4-7 membered carbocyclyl or 4-7 membered heterocyclyl is substituted with 0-5 independently selected halogen, and wherein 2 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 unsaturated carbocyclyl, and ^ an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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-C4aliphatic, haloC1-C4alkyl, and - OH; R3is hydrogen, C1-C4aliphatic, C3-C5cycloalkyl, C1-C4alkoxy, -NHR3A, -N(R3A)2, or C1- C4alkylthio, each of which, besides hydrogen, is optionally substituted with -OH, 1-5 independently selected halogen, -OR, -C(O)NR10R11, or N(R)C(O)R; each R3Ais independently selected at each occurrence from C1-C4alkyl; R4is phenyl or a first 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) wherein said phenyl or said first 5-6 membered heteroaryl are substituted with 0-5 RAor two substituents on adjacent atoms of said phenyl or said first 5-6 membered heteroaryl together with said adjacent atoms form a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl, or a second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to the phenyl or first 5-6membered heteroaryl wherein said 4-7 membered carbocyclyl, 4-7 membered heterocyclyl, or second 5-6 membered heteroaryl are substituted with 0-3 RA; or R4is a C1-C4alkyl, C1-C4alkoxy, or C3-C6cycloalkyl, each of which is substituted with 0-3 groups independently selected from halogen, -CN, -OH, oxo, NH2, C1-C4alkyl, C1-C4alkoxy, optionally substituted 5-6 membered heterocyclyl, and optionally substituted 5-6 membered heterocyclyloxy; 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 an optionally substituted 4-7 membered saturated ring, 4-7 membered partially unsaturated ring, or 5-6 membered heteroaryl ring (wherein said 4-7 membered saturated ring and 4-7 membered partially unsaturated ring has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and wherein said 5-6 membered heteroaryl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0069] In one aspect, the present invention provides a compound of Formula I, I’, Ix, Iy, or I’’, wherein R4is selected from one of a), b), and c): a) R4is a Ring B that is selected from the group consisting of: and ;wherein * is a point of attachment to L in Formula I, I’, Ix, Iy, or I’’; and wherein: any substituents that are present on Ring B selected from R4A, R4B, R4C, R4D, R4E, and R4Fare each independently selected from hydrogen; halogen; -OH; -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 optionally substituted carbocyclyl, 4-7 membered optionally substituted heterocyclyl, or 5-6 membered optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring B; and any substituents that are present on Ring B selected from R4C, R4D, R4E, and R4Fare each independently selected from hydrogen; halogen; -OH; -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 4-7 membered optionally substituted carbocyclyl, 4-7 membered optionally substituted heterocyclyl, or 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring B; and any substituents that are present on Ring B selected from R4A, R4D, R4E, and R4Fare each independently selected from hydrogen; halogen; -OH; -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 optionally substituted carbocyclyl, 4-7 membered optionally substituted heterocyclyl, or 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring B; and any substituents that are present on Ring B selected from R4A, R4B, R4Eand R4Fare each independently selected from hydrogen; halogen; -OH; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C3alkylsubstituted 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 optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring B; and R4B, R4C, and R4Dare each independently selected from hydrogen; halogen; -OH; -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 optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring B; and any substituents that are present on Ring B selected from R4B, R4C, and R4Dare each independently selected from hydrogen; halogen; -OH; -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 R14is hydrogen; or NR13R14forms a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl, said heterocyclic ring optionally substituted with -CH3; or b) 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; or c) 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, and optionally substituted 5-6 membered heterocyclyl oxy.

[0070] As described generally above, Ring A represents: a) a 4-7 membered saturated or partially unsaturated bivalent monocyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or b) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene and heterocyclylene (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein Ring A is substituted with 0-4 independently selected RAsubstituents.

[0071] In some embodiments, Ring A is a 4-7 membered saturated or partially unsaturated bivalent monocyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein Ring A is substituted with 0-4 independently selected RAsubstituents. In some embodiments, Ring A is a 4- 7 membered saturated or partially unsaturated bivalent monocyclic carbocyclylene, wherein Ring A is substituted with 0-4 independently selected RAsubstituents. In some embodiments, Ring A is a 4-7 membered saturated or partially unsaturated bivalent monocyclic heterocyclylene (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein Ring A is substituted with 0-4 independently selected RAsubstituents.

[0072] In some embodiments, Ring A is a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein Ring A is substituted with 0-4 independently selected RAsubstituents. In some embodiments, Ring A is a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic and is a carbocyclylene, wherein Ring A is substituted with 0-4 independently selected RAsubstituents. In some embodiments, Ring A is a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic and is a heterocyclylene (having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur), wherein Ring A is substituted with 0-4 independently selected RAsubstituents.

[0073] In some embodiments, Ring A is a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system comprising 2 fused rings. In some embodiments, Ring A is a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system comprising a spirocyclic ring system. In some embodiments, Ring A is a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system comprising a bridged ring system.

[0074] In some embodiments, Ring A is selected from and wherein Ring A is substituted with 0-4 independently selected RAsubstituents.

[0075] In some embodiments, Ring A is(RA)0-4 .

[0076] In some embodiments, Ring A is

[0077] In some embodiments, Ring A is

[0078] In some embodiments, Ring A is as selected from one of the substituents of Table 1,Table la, or Table lb.

[0079] As described generally above, R1is selected from groups a)-e): a) a 5-6 membered monocyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1-3 groups independently selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, and C3- C6cycloalkoxy, wherein said 5-6 membered monocyclic heteroaryl is further substituted with 0-3 independently selected RA; b) a 9-10 membered bicyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1 or 2 groups independently selected from C1-C6aliphatic, C3-C6cycloalkyl, C1-C6alkoxy, and C3-C6cycloalkoxy, wherein said 9-10 membered bicyclic heteroaryl is further substituted with 0-3 independently selected RA; c) 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-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, and C3-C6cycloalkoxy, and -OR, wherein said 4-7 membered saturated or partially unsaturated monocyclic heterocyclyl is further substituted with 0-3 independently selected RA; d) a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl and heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected RA; and e) H, halogen, C1-C6aliphatic, C3-C7cycloalkyl, C1-C6alkylene-O-C1-C6alkyl, -CN, -OR, - NR10R11, -C(O)NR10R11, -CH2NR10R11, -SO2R12, wherein the C1-C6aliphatic, C3- C7cycloalkyl, or C1-C6alkylene-O-C1-C6alkyl is substituted with 0-5 independently selected RA.

[0080] In some embodiments, R1is a 5-6 membered monocyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1-3 groups independently selected from C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, and C3- C6cycloalkoxy, wherein said 5-6 membered monocyclic heteroaryl is further substituted with 0-2independently selected RA. In some embodiments, R1is a 4- or 6-membered saturated or partially unsaturated monocyclic heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), said heterocyclyl substituted with 0-2 groups 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, R1is 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 groups independently selected from halogen, oxo, -NR2, optionally substituted C1-4 aliphatic, -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, R1is a 3-7 membered optionally substituted carbocyclyl. In some embodiments, R1is an optionally substituted C2-C4alkenyl. In some embodiments, R1is cyclopropyl substituted C2-C4alkenyl. In some embodiments, R1is methyl substituted C2alkenyl.

[0081] In some embodiments, R1is a 6-membered partially unsaturated heterocyclyl (having 1 oxygen atom). In some embodiments, R1is 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 RA, wherein RAis an optionally substituted C1-6 aliphatic group. In some embodiments, R1is 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 RA, wherein RAis an optionally substituted C1-6 aliphatic group.

[0082] In some embodiments, R1is a bicyclic 9-10 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 bicyclic 9-10 membered heteroaryl is further substituted with 0-3 independently selected RA.

[0083] In some embodiments, R1is a 5-membered heteroaryl (having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1 or 2 groupsindependently selected from C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, and C3-C6cycloalkoxy, wherein said 5-membered heteroaryl is optionally further substituted with 0-2 independently selected RA. In some embodiments, R1is 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, R1is a 5-membered heteroaryl (having 2 nitrogen atoms) substituted with 1 or 2 groups independently selected from C1-C6alkoxy, C3-C6cycloalkyl, and C3-C6cycloalkoxy, wherein said 5-membered heteroaryl is optionally further substituted with 0-1 RA, wherein RAis hydroxyl substituted C1-C4alkyl.

[0084] In some embodiments, R1is 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 RA.

[0085] In some embodiments, R1is pyridyl substituted with C1-C4alkoxy and further substituted with 0-2 RAsubstituents.

[0086] In some embodiments, R1is 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 RAsubstituents.

[0087] In some embodiments, R1is c) a 5-6 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), said heterocyclyl substituted with 0-2 groups 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; or d) 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 groups independently selected from halogen, oxo, -NR2, optionallysubstituted C1-4aliphatic, -OR, azetidinyl optionally substituted with 1 or 2 independently selected halogen, and pyrrolidinyl optionally substituted with 1 or 2 independently selected halogen.

[0088] In some embodiments, R1is a 5-6 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), said heterocyclyl substituted with 0-2 groups 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.

[0089] In some embodiments, R1is a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 1 group selected from C1-C6alkoxy and C3-C6cycloalkyl, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RA.

[0090] In some embodiments, R1is , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

[0091] In some embodiments R1is

[0092] In some embodiments, R1is

[0093] In some embodiments, R1is

[0094] In some embodiments R1is

[0095] In some embodiments, R1is as selected from one of the substituents of Table 1, Table 1a, or Table 1b.

[0096] As described generally above, RAis 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, hydroxy-C1-C6alkyl, haloC1-C6alkyl, an optionally substituted 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.

[0097] In some embodiments, RAis independently selected at each occurrence from the group consisting of halogen, -OR, or an optionally substituted C1-6aliphatic group. In some embodiments, RAis independently selected at each occurrence from a halogen. In some embodiments, RAis independently selected at each occurrence from an -OR. In some embodiments RAis an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, RAis an optionally substituted C3- C6cycloalkyl. In some embodiments, RAis independently selected at each occurrence from an optionally substituted C1-6aliphatic group.

[0098] In some embodiments, RAis as selected from one of the substituents of Table 1, Table 1a, or Table 1b.

[0099] As described generally above, R2is C(RB)2C(O)N(R)R2A, C(RB)2C(RB)2C(O)N(R)R2A, C(RB)2C(RB)2N(R)C(O) N(R)R2A, or C(RB)2C(RB)2N(R)C(O)R2A. In some embodiments, R2is C(RB)2C(O)N(R)R2A. In some embodiments, R2is C(RB)2C(RB)2C(O)N(R)R2A. In some embodiments, R2is C(RB)2C(RB)2N(R)C(O)N(R)R2A. In some embodiments, R2is C(RB)2C(RB)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, R2isCH2CH2N(R)C(O)N(R)R2A. In some embodiments, R2is CH2CH2N(H)C(O)R2A. In some embodiments, R2is C(RB)2C(O)N(H)R2A, wherein R2Ais phenyl or bicyclo[1.1.1]pentyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4alkyl, or haloC1- C4alkyl. In some embodiments, R2is C(RB)2C(O)N(H)R2A, wherein R2Ais phenyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4alkyl, or haloC1- C4alkyl. In some embodiments, R2is C(RB)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.

[0100] In some embodiments, R2is , , , , , , , , , , , , , , , , , ,

[0101] In some embodiments R2is

[0102] In some embodiments, R2is

[0103] In some embodiments R2is O

[0104] In some embodiments, R2is as selected from one of the substituents of Table 1, Table la, or Table lb.

[0105] As described generally above, RBis independently selected at each occurrence from hydrogen, -CH3, and -CH2CH3, or two RBtaken together with the carbon to which they are attached form a cyclopropyl ring. In some embodiments, RBis independently selected at each occurrence from hydrogen, -CH3, and -CH2CH3. In some embodiments, RBis hydrogen. In some embodiments, two RBtaken together with the carbon to which they are attached form a cyclopropyl ring.

[0106] In some embodiments, RBis as selected from one of the substituents of Table 1, Table 1a, or Table 1b.

[0107] 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 contains 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, haloC3-C6cycloalkoxy and –SF5; or two substituents on adjacent atoms of the phenyl or pyridyl together with said adjacent atoms form a 4-7 membered carbocyclyl fused to the phenyl or pyridyl; or two substituents on adjacent atoms of the phenyl or pyridyl together with said adjacent atoms 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 4-7 membered carbocyclyl or 4-7 membered heterocyclyl is substituted with 0-5 independently selected halogen, and wherein 2 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 unsaturated carbocyclyl, and ^ an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 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-C4aliphatic, haloC1-C4alkyl, and - OH.

[0108] 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.

[0109] In some embodiments, R2Ais phenyl 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, and –SF5, two substituents on adjacent atoms of the phenyl together with said adjacent atoms form a 4-7 membered carbocyclyl fused to the phenyl, and two substituents on adjacent atoms of the phenyl together with said adjacent atoms form a 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused to the phenyl.

[0110] In some embodiments, R2Ais phenyl 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, and –SF5. In some embodiments, R2Ais phenyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4alkyl, and haloC1-C4alkyl. In some embodiments, R2Ais phenyl optionally substituted with a halogen, C1-C4alkyl, and haloC1-C4alkyl. In some embodiments, R2Ais phenyl optionally substituted with 2 substituents independently selected from halogen, C1-C4alkyl, and haloC1- C4alkyl. In some embodiments, R2Ais phenyl optionally substituted with 3 substituents independently selected from halogen, C1-C4alkyl, and haloC1-C4alkyl.

[0111] In some embodiments, R2Ais pyridyl 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, and –SF5, two substituents on adjacent atoms of the pyridyl together with said adjacent atoms form a 4-7 membered carbocyclyl fused to the pyridyl, and two substituents on adjacent atoms of the pyridyl together with said adjacent atoms form a 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused to the pyridyl.

[0112] In some embodiments, R2Ais pyridyl 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, and –SF5. In some embodiments, R2Ais pyridyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1- C4alkyl, and haloC1-C4alkyl. In some embodiments, R2Ais pyridyl optionally substituted with a halogen, C1-C4alkyl, or haloC1-C4alkyl. In some embodiments, R2Ais pyridyl optionally substituted with 2 substituents independently selected from halogen, C1-C4alkyl, and haloC1- C4alkyl. In some embodiments, R2Ais pyridyl optionally substituted with 3 substituents independently selected from halogen, C1-C4alkyl, and haloC1-C4alkyl.

[0113] In some embodiments, 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 contains 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said cubanyl, 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-C6cycloalkyl, -OH, - CN, C1-C4alkoxy, haloC1-C4alkoxy, C3-C6cycloalkoxy, haloC3-C6cycloalkoxy and –SF5.

[0114] 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[2.2.2]octyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4alkyl, and haloC1-C4alkyl. In some embodiments, R2Ais bicyclo[3.1.0]pentyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4alkyl, and haloC1-C4alkyl. In some embodiments, R2Ais cubanyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4alkyl, and haloC1-C4alkyl. In some embodiments, R2Ais 2-oxabicyclo[2.1.1]hexan-4-yl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4alkyl, and haloC1-C4alkyl.

[0115] In some embodiments, R2Ais a saturated or partially unsaturated bridged 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, which contains 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, haloC3-C6cycloalkoxy and –SF5.

[0116] In some embodiments, R2Ais a saturated or partially unsaturated fused 5-, 6-, 7-, 8-, 9- , 10-, 11-, or 12-membered ring, which contains 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, haloC3-C6cycloalkoxy and –SF5.

[0117] In some embodiments, R2Ais a saturated or partially unsaturated spirocyclic 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, which contains 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, haloC3-C6cycloalkoxy and –SF5.

[0118] 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, haloC3-C6-cycloalkoxy 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.

[0119] In some embodiments, R2Ais Ring F selected from the group consisting of: , wherein x, y, and q are independently selected from 1, 2, or 3, Y1is independently selected from O, NR15, CHR15or CR15R15; R15is independently selected from halogen, C1-C4aliphatic, haloC1-C4alkyl, C3-C6cycloalkyl, haloC3- C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, C3-C6cycloalkoxy, haloC3-C6- cycloalkoxy and –SF5. R15

[0120] In some embodiments, R2Ais Ring F of the following structure , wherein R15is selected from halogen, C1-C4aliphatic, haloC1-C4alkyl, C3-C6cycloalkyl, haloC3- C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, C3-C6cycloalkoxy, haloC3-C6- cycloalkoxy and –SF5.

[0121] In some embodiments, 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. In some embodiments, R2Ais 2-benzimidazolyl optionally substituted with 1,2, or 3 substituents independently selected from halogen, C1-4alkyl and -OH. In some embodiments, R2Ais 3-quinolinyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-4alkyl, and -OH.

[0122] In some embodiments, R2Ais phenyl comprising a -CF3substituent or pyridyl comprising a -CF3 substituent.

[0123] In some embodiments, R2Ais bicyclo[1.1.1]pentyl comprising a -CF3 substituent or bicyclo[1.1.1]pentyl comprising a -CHF2substituent.

[0124] In some embodiments, R2Ais as selected from one of the substituents of Table 1, Table 1a, or Table 1b.

[0125] As described generally above, R3is hydrogen, C1-C4aliphatic, C3-C5cycloalkyl, C1- C4alkoxy, -NHR3A, -N(R3A)2or C1-C4alkylthio each of which, besides hydrogen, is optionally substituted with -OH, 1-5 independently selected halogen, or C1-C4alkoxy.

[0126] In some embodiments, R3is hydrogen. 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-C4alkoxy, -NHR3A, -N(R3A)2 or C1- C4alkylthio 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 - NHR3Aoptionally substituted with -OH, 1-5 independently selected halogen, or C1-C4alkoxy. In some embodiments, R3is -N(R3A)2 optionally substituted with -OH, 1-5 independently selected halogen, or C1-C4alkoxy. In some embodiments, R3is C1-C4alkylthio 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.

[0127] In some embodiments, R3is as selected from one of the substituents of Table 1, Table 1a, or Table 1b.

[0128] As described generally above, each R3Ais independently selected at each occurrence from C1-C4alkyl. In some embodiments, R3Ais -CH3. In some embodiments, R3Ais -CH2CH3. In some embodiments, R3Ais propyl. In some embodiments, R3Ais butyl.

[0129] In some embodiments, R3Ais as selected from one of the substituents of Table 1, Table 1a, or Table 1b.

[0130] As described generally above L is a linker selected from -C(O)-, -S(O)-, -S(O)2-, and .

[0131] In some embodiments, linker L is -C(O)-.

[0132] In some embodiments, linker L is -S(O)-.

[0133] In some embodiments, linker L is -S(O)2-.

[0134] In some embodiments, linker L is .

[0135] In some embodiments, linker L is as selected from one of the substituents of Table 1, Table 1a, or Table 1b.

[0136] As described generally above, R4is selected from one of a), b), and c): a) R4is a Ring B that is selected from the group consisting of and ; wherein * is a point of attachment to linker L that is bonded to Ring A in Formula I; and wherein: any substituents that are present on Ring B selected from R4A, R4B, R4C, R4D, R4E, and R4Fare each independently selected from hydrogen; halogen; -OH; -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 optionally substituted carbocyclyl, 4-7 membered optionally substituted heterocyclyl, or 5-6 membered optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring B; and any substituents that are present on Ring B 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 4-7 membered optionally substituted carbocyclyl, 4-7 membered optionally substituted heterocyclyl, or 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring B; and any substituents that are present on Ring B 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 R4Cand R4D, along with their intervening atoms, join to form 4-7 membered optionally substituted carbocyclyl, 4-7 membered optionally substituted heterocyclyl, or 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring B; and any substituents that are present on Ring B 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; orR4Eand R4A, along with their intervening atoms, join to form 5-6 membered optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring B; 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 optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring B; and any substituents that are present on Ring B selected from 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; R13is independently selected at each occurrence from hydrogen and C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; and R14is hydrogen; or NR13R14forms a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl, said heterocyclic ring optionally substituted with -CH3; or b) 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; or c) 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, and optionally substituted 5-6 membered heterocyclyloxy;

[0137] In some embodiments, R4is Ring B of the following structure:wherein * is a point of attachment to Linker L that is bonded to Ring A in Formula I; 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 or 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring B; 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; or NR13R14; and R13is independently selected at each occurrence from hydrogen and C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; R14is hydrogen or NR13R14forms a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl, said heterocyclic ring optionally substituted with -CH3.

[0138] In some embodiments, R4is Ring B of the following structure: wherein * is a point of attachment to Linker L that is bonded to Ring A in Formula I; 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 and C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; R14is hydrogen or NR13R14forms a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and 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.

[0139] In some embodiments, R4is Ring B of the following structure: wherein * is a point of attachment to Linker L that is bonded to Ring A in Formula I; 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 and C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; and R14is hydrogen; or NR13R14forms a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl, said heterocyclic ring optionally substituted with -CH3.

[0140] In some embodiments, R4is Ring B of the following structure:wherein * is a point of attachment to Linker L that is bonded to Ring A in Formula I; and wherein: R4A, R4C, and R4Dare each independently selected from hydrogen; halogen; and C1- C4alkyl.

[0141] In some embodiments, R4is Ring B of the following structure: wherein * is a point of attachment to Linker L that is bonded to Ring A in Formula I; and wherein: 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 (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring B; 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 4-7 membered carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring B; 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; or NR13R14; andR13is independently selected at each occurrence from hydrogen and Ci-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; andR14is hydrogen; or NR13R14forms a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl, said heterocyclic ring optionally substituted with -CH3.

[0142] In some embodiments, R4is Ring B of the following structure:OH wherein * is a point of attachment to Linker L that is bonded to Ring A in Formula I; and wherein:R4Aand R4B, along with their 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 B; andR4Cis hydrogen.

[0143] In some embodiments, R4is Ring B of the following structure: wherein * is a point of attachment to Linker L that is bonded to Ring A in Formula I; and wherein:R4Aand R4B, along with their intervening atoms, join to form 5-membered heterocyclyl (having 1 oxygen atom) that is fused to Ring B; andR4Cis hydrogen.

[0144] In some embodiments, R4is Ring B of the following structure:wherein * is a point of attachment to Linker L that is bonded to Ring A in Formula I; 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 4-7 membered carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring B; and R4Dis 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; and R13is independently selected at each occurrence from hydrogen and C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; and R14is hydrogen or NR13R14forms a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl, said heterocyclic ring optionally substituted with -CH3.

[0145] In some embodiments, R4is Ring B of the following structure: wherein * is a point of attachment to Linker L that is bonded to Ring A in Formula I; and wherein: R4Aand R4Dare each hydrogen; and R4Bis C1-C4alkyl.

[0146] In some embodiments, R4is Ring B of the following structure:wherein * is a point of attachment to Linker L that is bonded to Ring A in Formula I; 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 R13is independently selected at each occurrence from hydrogen and C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; and R14is hydrogen; or NR13R14forms a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl, said heterocyclic ring optionally substituted with -CH3.

[0147] In some embodiments, R4is Ring B of the following structure: wherein * is a point of attachment to Linker L that is bonded to Ring A in Formula I; and wherein: R4Aand R4Care each independently selected from hydrogen and C1-C4alkyl.

[0148] In some embodiments, R4is Ring B of the following structure:wherein * is a point of attachment to Linker L that is bonded to Ring A in Formula I; 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 or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring B; and R4C, R4D, 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 R4Cand R4D, along with their 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 B; 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 B; 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; andR13is independently selected at each occurrence from hydrogen and C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; and R14is hydrogen; or NR13R14forms a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl, said heterocyclic ring optionally substituted with -CH3.

[0149] In some embodiments, R4is Ring B of the following structure: wherein * is a point of attachment to Linker L that is bonded to Ring A in Formula I; and wherein: R4A, R4B, R4C, R4D, and R4Eare each independently selected from hydrogen; halogen; C1- C4alkyl; and C1-C4alkoxy; or R4Cand R4D, along with their intervening atoms, join to form a 4-7 membered heterocyclyl (having 1-3 nitrogen atoms) fused to Ring B; and R4A, R4B, and R4Eare each hydrogen.

[0150] In some embodiments, R4is Ring B of the following structure: wherein * is a point of attachment to Linker L that is bonded to Ring A in Formula I; 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 B; 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 NR13R14may combine with the N to which they are attached to form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl, said heterocyclic ring optionally substituted with -CH3.

[0151] In some embodiments, R4is Ring B of the following structure: wherein * is a point of attachment to Linker L that is bonded to Ring A in Formula I; and wherein: R4Fand R4A, along with their intervening atoms, join to form 5-6 membered heteroaryl (having 1-2 nitrogen atoms) fused to Ring B; and R4Band R4Care each hydrogen.

[0152] In some embodiments, R4is Ring B of the following structure: wherein * is a point of attachment to Linker L that is bonded to Ring A in Formula I; and wherein: R4A, R4C, R4D, 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; orR4Cand R4D, along with their intervening atoms, join to form 4-7 membered optionally substituted carbocyclyl or optionally substituted heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring B; and R4Aand 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 R4Fand R4A, along with their intervening atoms, join to form 5-6 membered optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring B; and 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 and C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; and R14is hydrogen; or NR13R14may combine with the N to which they are attached to form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl, said heterocyclic ring optionally substituted with -CH3.

[0153] 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.

[0154] 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.

[0155] 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, and optionally substituted 5-6 membered heterocyclyloxy. In some embodiments, R4is a C1-C4alkyl, substituted with 0-3independently 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.

[0156] In some embodiments, R4is an isoxazolyl substituted with -OH or C1-C4alkoxy.

[0157] 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) selected from the group consisting of 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 substituted with 0-4 groups independently selected from halogen, -OH, -CN, C1-C4alkyl, haloC1-C4alkyl, C3-C6cycloalkyl, and C1-C4alkoxy.

[0158] In some embodiments, R4is , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

[0159] In some embodiments, R4isOH OH OH OH OH OH OH OHOH

[0160] In some embodiments, R4is as shown in a substituent of Table 1, Table la, or Table lb.

[0161] As described generally above, each R is independently hydrogen, or an optionally substituted Ci-galiphatic 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 an optionally substituted 4-7 membered saturated ring, 4-7 membered partially unsaturated ring, or 5-6 membered heteroaryl ring (wherein said 4-7 membered saturated ring and 4-7 membered partially unsaturated ring has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and wherein said 5-6 membered heteroaryl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0162] In some embodiments, each R is independently hydrogen, or an optionally substituted Ci-ealiphatic 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).

[0163] In some embodiments, two R groups on the same atom are taken together with the same atom to form an optionally substituted 4-7 membered saturated ring, partially unsaturated ring, or heteroaryl ring (wherein said 4-7 membered saturated ring, partially unsaturated ring, or heteroaryl ring, has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0164] In some embodiments, each R is independently hydrogen or a Ci-ealkyl. In some embodiments, R is hydrogen.

[0165] In some embodiments, each R is as selected from one or more of the substituents of Table 1, Table la, or Table lb.

[0166] In some embodiments, the compound of Formula l is a compound of Formula I-a, or I- b or a pharmaceutically acceptable salt thereof:O OI-a I-b wherein Ring A, R1, R2, R3, and R4, are as defined herein, both singly and in combination.

[0167] In some embodiments, the compound of Formula I is a compound of Formula I-a, or I- b or a pharmaceutically acceptable salt thereof:I-a I-bwherein Ring A, R1, R2, R3, and R4, are as defined herein, both singly and in combination and R2a

[0168] In some embodiments, the compound of Formula I is a compound of Formula I-a, or I- b or a pharmaceutically acceptable salt thereof: wherein R1, R2, R3, and R4, are as defined herein, both singly and in combination, Ring A is

[0169] In some embodiments, the compound of Formula l is a compound of Formula Il-a, II- b, or II-c or a pharmaceutically acceptable salt thereof:Il-a Il-b II-c wherein Ring A, Linker L, R2, R3, Y, Z and R4, are as defined herein, both singly and in combination.

[0170] In some embodiments, the compound of Formula I is a compound of Formula ILd, II- e, or Il-f or a pharmaceutically acceptable salt thereofIl-f wherein Ring A, R2, R3, Y, Z and R4, are as defined herein, both singly and in combination.

[0171] In some embodiments, the compound of Formula I is a compound of Formula Ill-a, III- b, or III-c or a pharmaceutically acceptable salt thereof:Ill-a IILbIII-c wherein Ring A, R1, R2, Y, Z and R3, are as defined herein, both singly and in combination, and 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.

[0172] In some embodiments, the compound of Formula I is a compound of Formula IV-a, IV-b, or IV-c or a pharmaceutically acceptable salt thereof:IV-a IV-b IV-c wherein Ring A, R2, Y, Z and R3, are as defined herein, both singly and in combination and wherein: R5is -OH or halogen; and R6is halogen, C1-4alkyl, or C1-4alkoxy. In some embodiments: R5is -OH or fluoro; and R6is fluoro, -CH3, or -OCH3.

[0173] In some embodiments, the compound of Formula I is a compound of Formula V-a, V- b, or V-c or a pharmaceutically acceptable salt thereof: V-a V-bV-c wherein Ring A, R2, Y, Z and R3, are as defined herein, both singly and in combination, and wherein: X is CH, CR7, or N; and each R7is independently hydrogen, halogen, C1-4alkyl, or C1-4alkoxy. In some embodiments: X is CH or N; and R7is hydrogen, fluoro, -CH3, or -OCH3.

[0174] In some embodiments, the compound of Formula I is a compound of Formula VI-a, VI-b, or VI-c or a pharmaceutically acceptable salt thereof: VI-a VI-b VI-c wherein Ring A, R2, Y, Z and R3, are as defined herein, both singly and in combination, and wherein: R8is C1-4alkyl; and each of the 0-2 instances of R9are independently a hydrogen or C1-4alkyl. In some embodiments: R8is -CH3; and each instance of R9is independently a hydrogen or -CH3.

[0175] In some embodiments, the compound of Formula I is a compound of Formula VII-a, or VII-b or a pharmaceutically acceptable salt thereof:R2R2Vll-a VH-b wherein R1, R2, R3, RAand R4, are as defined herein, both singly and in combination.

[0176] In some embodiments, the compound of Formula I is a compound of Formula Vll-a, or Vll-b or a pharmaceutically acceptable salt thereof: wherein R1, R2, R3, RAand R4, are as definedCl herein, both singly and in combination and R2ais selected from

[0177] In some embodiments, the compound of Formula I is a compound of Formula VII-c,Vll-d, or Vll-e or a pharmaceutically acceptable salt thereof:Vll-ewherein R2, R3, Y, Z and R4, are as defined herein, both singly and in combination.

[0178] In some embodiments, the compound of Formula I is a compound of Formula VIII-a, VIII-b, or VIII-c or a pharmaceutically acceptable salt thereof: VIII-a VIII-b VIII-c wherein R1, R2, Y, Z and R3, are as defined herein, both singly and in combination, and 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; and each of the 0-2 instances of R9are 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; and each instance of R9is independently a hydrogen or -CH3.

[0179] In some embodiments, the compound of Formula l is a compound of Formula IX-a, IX-b, or IX-c or a pharmaceutically acceptable salt thereof:IX-c wherein Y, Z, R2and R3, are as defined herein, both singly and in combination and wherein:R5is -OH or halogen; andR6is halogen, Ci.4alkyl, or Ci.4alkoxy. In some embodiments: R5is -OH or fluoro; and R6is fluoro, -CH3, or -OCH3.

[0180] In some embodiments, the compound of Formula I is a compound of Formula X-a, X- b, or X-c or a pharmaceutically acceptable salt thereof:X-c wherein Y, Z, R2and R3, are as defined herein, both singly and in combination, and wherein:X is CH, CR7, or N; and each R7is independently hydrogen, halogen, Ci-4alkyl, or Ci-4alkoxy.

[0181] In some embodiments: X is CH or N; and each R7is independently hydrogen, fluoro, -CH3, or -OCH3.

[0182] In some embodiments, the compound of Formula I is a compound of Formula Xl-a, Xl-b, or XI-c or a pharmaceutically acceptable salt thereof:XI-c wherein Y, Z, R2, and R3, are as defined herein, both singly and in combination, and wherein:R8is Ci-4alkyl; andeach of the 0-2 instances of R9are independently a hydrogen or C1-4alkyl. In some embodiments: R8is -CH3; and each instance of R9is independently a hydrogen or -CH3.

[0183] In some embodiments, the compound of Formula I is a compound of Formula XII-a, XII-b, or XII-c or a pharmaceutically acceptable salt thereof: XII-a XII-b XII-c R2is C(RB)2C(O)NHR2A; RBis independently selected at each occurrence from hydrogen and -CH3; R2Ais phenyl, pyridyl, or bicyclo[1.1.1]pentyl, each of which is optionally substituted with 1, or 2, or 3 substituents independently selected from halogen, C1-C4alkyl, haloC1-C4alkyl, C3-C6- cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, and –SF5; 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; R3is C1-C4alkyl, C3-C5cycloalkyl, or C1-C4alkoxy, each of which is optionally substituted with - OH, 1-3 independently selected halogen, or C1-C4alkoxy; and each R7is independently hydrogen, halogen, C1-4alkyl, or C1-4alkoxy.

[0184] In some embodiments, the compound of Formula I is a compound of Formula XII-d, XII-e, or XII-f or a pharmaceutically acceptable salt thereof:XII-d XII-e XII-f R2is C(RB)2C(O)NHR2A; RBis independently selected at each occurrence from hydrogen and -CH3; R2Ais phenyl, pyridyl, or bicyclo[1.1.1]pentyl, each of which 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, and –SF5; 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; R3is C1-C4alkyl, C3-C5cycloalkyl, or C1-C4alkoxy, each of which is optionally substituted with - OH, 1-3 independently selected halogen, or C1-C4alkoxy; and each R7is independently hydrogen, halogen, C1-4alkyl, or C1-4alkoxy.

[0185] In some embodiments, the compound of Formula I is selected from one of those depicted in Table 1, Table 1a, or Table 1b, or a pharmaceutically acceptable salt thereof. Table 1, Table 1a, or Table 1b identifies compounds by their IUPAC name and Table 2, Table 2a or Table 2b or lists the same compounds and shows their chemical structure. In the event of any discrepancy between Table 1’s, Table 1a’s, or Table 1b’s, name for a compound and Table 2’s, Table 2a’s or Table 2b’s structure for that same compound, Table 2’s, Table 2a’s or Table 2b’s compoundstructures will dominate and identify the compound corresponding to each respective compound number (I-#) in Table 1, Table la, or Table lb.Table 1Table la an-4-yl)-5-ethyl- 7-oxooxazolo[4,5- yridin-4-yl)-6-(4- 4,5-b]pyridin-Table lb4. Pharmaceutical compositions, methods of treatment and uses o f compounds

[0186] 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 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 / or polyethylene glycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) absorbents, colorants, flavors and sweeteners.

[0187] 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.

[0188] There is also provided a pharmaceutical composition comprising a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.Uses

[0189] The compounds of Formula I 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.

[0190] Also provided is a compound of Formula I, 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 of Formula I, as described herein, as a research chemical, for example tool compound or chemical probe, in particular for research on WRN.

[0191] There is also provided a compound of Formula I as 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 of Formula I as 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).

[0192] There is also provided a compound of Formula I 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 microsatellite instability-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.

[0193] There is also provided a method of:• modulating WRN activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof,• inhibiting WRN in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of Formula I 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 of Formula I as described herein, or a pharmaceutically acceptable salt thereof, treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of the compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof,• treating cancer in a subject, comprising administering a compound of Formula I as described herein, 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.

[0194] There is also provided the use of a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof:• in therapy,• in the manufacture of a medicament,• in the manufacture of a medicament for the treatment of cancer. In particular, said cancer 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 treated by 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.

[0195] 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

[0196] 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 cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.

[0197] 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 claimed in Formula I. 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.

[0198] 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 acompound 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.

[0199] 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 3 IP, 32P, 35S, 36CI, 1231, 1241, and 1251, 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, orthose into which non-radioactive isotopes, such as 2H and 13C are present. Such 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 nonlabeled reagent previously employed.

[0200] 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 acceptablesalt of said zwitterionic or non-zwitterionic form thereof. “Zwitterion” or “zwitterionic form” means a compound containing both positive and negatively charged functional groups.

[0201] 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.

[0202] 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.

[0203] “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.

[0204] “Disease or condition mediated by WRN” includes a disease or condition, such as cancer, which is treated by WRN inhibition. In particular this may include cancers characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

[0205] “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.

[0206] 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. CritRev 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).

[0207] 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.

[0208] 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.

[0209] 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.

[0210] 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).

[0211] 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 orapproaches 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.

[0212] 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.

[0213] 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.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] 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.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] “May join” meansjoins or does not join.

[0222] “May be replaced by deuterium” means is replaced by deuterium, or is not replaced by deuterium.

[0223] 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

[0224] 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 (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 of the (R)- or (S)- configuration. Substituents at atoms with unsaturated double bonds may, if possible, be present in cis-(Z)- trans-(E)- form.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] Compounds of the invention, i.e. compounds of Formula I 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 of Formula I by known co-crystal forming procedures. Such procedures include grinding, heating, cosubliming, co-melting, or contacting in solution compounds of Formula I with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed. Suitable cocrystal formers include those described in WO 2004 / 078163. Hence the invention further provides co-crystals comprising a compound of Formula I.

[0229] 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.

[0230] The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that theinvention 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

[0231] 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

[0232] Combination” refers to either a fixed combination in one dosage unit form, or a combined administration where a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a combination partner (e.g. another drug as explained below, also referred to as “therapeutic agent” or “co-agent”) may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, 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 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.

[0233] 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, whereinsuch 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.

[0234] The combinations described herein can include a compound of Formula I 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 toxi cities or complications associated with the treatment.

[0235] There is also provided a combination comprising a compound of Formula I 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,• 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 (IFEXO), 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,• spartalizumab, or• tislelizumab (BGB-A317, Beigene).

[0236] In certain embodiments, the additional therapeutically active agent is:• a chemotherapy selected from anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-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, or• a PD-1 inhibitor selected from spartalizumab (Novartis), nivolumab (Bristol-Myers Squibb), 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). In a further embodiment, the additional therapeutically active agent is the chemotherapy irinotecan (Camptosar®).

[0237] 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 moleculeto PD-1 or PD-L1 . In another embodiment, the additional therapeutically active agent is an anti- PD-1 antibody molecule.

[0238] 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.”

[0239] In another embodiment, there is provided a combination of a compound of Formula I or a pharmaceutically acceptable salt thereof, and a chemotherapy, and a PD-1 inhibitor. In particular, the chemotherapy and PD-1 inhibitor are selected from those described above. In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered at a flat dose of between about 100 mg to about 600 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 100 mg to about 500 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 100 mg to about 400 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 100 mg to about 300 mg. In some embodiments, the PD- 1 inhibitor is administered at a dose of between about 100 mg to about 200 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 200 mg to about 600 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 200 mg to about 500 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 200 mg to about 400 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 200 mg to about 300 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 300 mg to about 600 mg. In some embodiments, the PD- 1 inhibitor is administered at a dose of between about 300 mg to about 500 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 300 mg to about 400 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 400 mg to about 600 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 400 mg to about 500 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 500 mg to about 600 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 600 mg to about 700 mg. In some embodiments, the PD- 1 inhibitor is administered at a dose of between about 700 mg to about 800 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 800 mg to about 900mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 900 mg to about 1000 mg.

[0240] In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered at a flat dose of about 100 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 200 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 300 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 400 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 500 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 600 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 700 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 800 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 900 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 1000 mg.

[0241] In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered once every ten weeks. In some embodiments, the PD-1 inhibitor is administered once every nine weeks. In some embodiments, the PD-1 inhibitor is administered once every eight weeks. In some embodiments, the PD-1 inhibitor is administered once every seven weeks. In some embodiments, the PD-1 inhibitor is administered once every six weeks. In some embodiments, the PD-1 inhibitor is administered once every five weeks. In some embodiments, the PD-1 inhibitor is administered once every four weeks. In some embodiments, the PD-1 inhibitor is administered once every three weeks. In some embodiments, the PD-1 inhibitor is administered once every two weeks. In some embodiments, the PD-1 inhibitor is administered once every week.

[0242] In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered intravenously.

[0243] In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered over a period of about 20 minutes to 40 minutes (e.g., about 30 minutes). In some embodiments, the PD- 1 inhibitor is administered over a period of about 30 minutes. In some embodiments, the PD-1 inhibitor is administered over a period of about an hour. In some embodiments, the PD-1 inhibitor is administered over a period of about two hours. In some embodiments, the PD-1 inhibitor is administered over a period of about three hours. In some embodiments, the PD-1 inhibitor is administered over a period of about four hours. In some embodiments, the PD-1 inhibitor isadministered over a period of about five hours. In some embodiments, the PD-1 inhibitor is administered over a period of about six hours.

[0244] In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered at a dose between about 300 mg to about 500 mg (e.g., about 400 mg), intravenously, once every four weeks. In some embodiments, the PD-1 inhibitor is administered at a dose between about 200 mg to about 400 mg (e.g., about 300 mg), intravenously, once every three weeks. In some embodiments, tislelizumab is administered at a dose of 400 mg, once every four weeks. In some embodiments, tislelizumab is administered at a dose of 300 mg, once every three weeks.

[0245] In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered at a dose between about 300 mg to about 500 mg (e.g., about 400 mg), intravenously, over a period of about 20 minutes to about 40 minutes (e.g., about 30 minutes), once every two weeks. In some embodiments, the PD-1 inhibitor is administered at a dose between about 200 mg to about 400 mg (e.g., about 300 mg), intravenously, over a period of about 20 minutes to about 40 minutes (e.g., about 30 minutes), once every three weeks.

[0246] In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered at a dose of about 100 mg per week. For example, if a 10-week dose is given to a patient, then the PD-1 inhibitor (e.g., tislelizumab) can be given at 1000 mg. If a 9-week dose is given, then the PD-1 inhibitor (e.g., tislelizumab) can be given at 900 mg. If an 8-week dose is given, then the PD-1 inhibitor (e.g., tislelizumab) can be given at 800 mg. If a 7-week dose is given, then the PD-1 inhibitor (e.g., tislelizumab) can be given at 700 mg. If a 6-week dose is given, then the PD-1 inhibitor (e.g., tislelizumab) can be given at 600 mg. If a 5-week dose is given, then the PD-1 inhibitor (e.g., tislelizumab) can be given at 500 mg. If a 4-week dose is given, then the PD-1 inhibitor (e.g., tislelizumab) can be given at 400 mg. If a 3-week dose is given, then the PD-1 inhibitor (e.g., tislelizumab) can be given at 300 mg. If a 2-week dose is given, then the PD-1 inhibitor (e.g., tislelizumab) can be given at 200 mg. If a 1-week dose is given, then the PD-1 inhibitor (e.g., tislelizumab) can be given at 100 mg.

[0247] For example, if an anti-PD-1 antibody, such as tislelizumab is used, it can be administered at a dose of 200 mg as an intravenous infusion, once every three weeks. Alternatively, tislelizumab can be administered at a dose of 300 mg as an intravenous infusion, once every four weeks. If an anti-PD-1 antibody, such as tislelizumab is used, it can be administered at a dose of300 mg as an intravenous infusion, once every three weeks. Alternatively, tislelizumab can be administered at a dose of 400 mg as an intravenous infusion, once every four weeks.

[0248] 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.

[0249] 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 of Formula I 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.

[0250] 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. 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.

[0251] 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.

[0252] 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.

[0253] 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.

[0254] 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.

[0255] 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

[0256] 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.

[0257] Referring to Scheme 1, amide synthesis achieved by coupling acyl chloride 2 (which contains the R1substituent of the present compounds) with primary amine 1 may produce 3. Intramolecular cyclization of 3 to produce oxazole 4 (the X and Y containing moiety of the present compounds) and subsequent amine protection provides 5. Butan-2one in the presence of strong base reacts with the ester of 5 to provide 6 which is subsequently brominated at the a ketoposition to furnish 7. Said bromine is displaced with a nucleophilic Ring A surrogate (protected piperidine in Step 7) to produce 10. 10 may undergo an intramolecular cyclization to produce an oxazolo[5,4-b]pyridin-7(4H)-one core of the present compounds in intermediate 11. Substituent R2may be introduced into the core of 11 via nucleophilic substitution of R2surrogate 12 to provide 13. Deprotection of 13 and amide coupling using R4surrogate 15 may furnish compounds of the disclosure such as 1-2.

[0258] Similar chemistry described in Scheme 1 may be used to form intermediates described infra and compounds of the disclosure. Those of skill in the art will readily be able to modify the order of introduction from Scheme 1 of substituents (e.g., R1, R2, R4, and Ring A) onto the compound intermediates in Scheme 2 by using alternative protecting group strategies and transition metal cross-couplings (see Step 1) well within the skill set of one having ordinary skill in the art.Scheme 1 : General synthetic methods of producing [5,4-b]pyridin-4(7H) intermediates of the disclosure such as 11FFScheme 2: General synthetic methods of producing [4,5-b]pyridin-4(7H) compounds of the disclosure□ HMDS, l2- *■THF, -30~25°C step 1oPd(dppf)CI2, K2CO3Pd(OAc)2, Xantphos, Cs2CO3dioxane / H2O, 60°C dioxane, 110°CIntermediate-1 step 1 step 2(BOC)2O, DIEADCM, 0°C step 8Intermediate-2

[0259] Those having ordinary skill in the art will be able to adapt such synthetic procedures to afford variably substituted compounds of Formula I for synthesis of the compounds of the disclosure.EXAMPLES

[0260] 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:H2O: waterACN: acetonitrileTHF : tetrahydrofuranFA: formic acidNa2SO4: sodium sulfateEtOAc: ethyl acetateHCl: hydrochloric acid DCM: dichloromethane pH: potential of hydrogen (Boc)2O: di-tert-butyl dicarbonate POCl3: phosphorus oxychloride EDCI: N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride LCMS: Liquid chromatography–mass spectrometry HPLC: High-performance liquid chromatography NH4Cl: ammonium chloride K3PO4: tripotassium phosphate TFA: trifluoroacetic acid NBS: N-bromosuccinimide DIEA: N,N-diisopropylethylamine Pd(dppf)2Cl2-CH2Cl2:1,1’-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex TsOH: 4-Methylbenzenesulfonic acid DMSO-d6: deuterated dimethyl sulfoxide NMP: N-methyl-2-pyrrolidone DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene LiHMDS: Lithium hexamethyldisilazide Prep-TLC: preparative thin layer chromatography s: singlet m: multiplet d: doublet dq: doublet of quartets t: triplet br: broad N: normality eq: equivalent M: molar concentration PE: Petroleum etheraq.: aqueousSOCh: thionyl chlorideMTBE: methyl tert-butyl etherKI: potassium iodidePMB-C1: 4-methoxybenzyl chloride t-BuOK: potassium t-butoxide CS2CO3: cesium carbonateDMF : N, A'-dimethyl formamideN2: nitrogenPOCI3: phosphoryl chlorideISfeSCU: sodium sulfateCDCI3: deuterated chloroformCD3OD: deuterated methanolExample 1: Synthesis of Compound of the Disclosure

[0261] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)piperazin-l-yl)-2-(2-methoxypyridin-4-yl)-7-oxooxazolo[4,5- b]pyridin-4(7H)-yl)acetamide (1-1) lntermediate-3

[0262] Intermdiate-3 and other intermediates in the following synthetic procedures may be synthesized as described infra.

[0263] Step 12. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5- hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl)-2-(2-methoxypyridin-4-yl)-7- oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide

[0264] To a solution of N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[5-ethyl-2-(2-methoxy-4- pyridyl)-7-oxo-6-piperazin-1-yloxazolo[4,5-b]pyridin-4-yl]acetamide (18 mg, 29 μmol, 1 eq, HCl salt) and 5-hydroxy-6-methyl-pyrimidine-4-carboxylic acid (7 mg, 43 μmol, 1.5 eq) in pyridine (0.4 mL) was added EDCI (11 mg, 57 μmol, 2 eq). The mixture was stirred at 25 °C for 4 h. The reaction mixture was quenched with H2O (10 mL). Then it was extracted with EtOAc (10 mL * 3). The combined organic phase was washed with brine (15 mL * 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by Prep-TLC (SiO2, DCM: MeOH = 10:1) to afford the title compound as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 11.82 (s, 1H), 8.58 (s, 1H), 8.51 (d, 1H), 8.47 (s, 1H), 8.34 (d, 1H), 7.63 (d, 1H), 7.60 (d, 1H), 7.55 (d, 1H), 7.49 (s, 1H), 5.69 - 5.55 (m, 1H), 5.24 (s, 2H), 4.84 - 4.74 (m, 1H), 4.06 - 4.02 (m, 2H), 4.00 (s, 3H), 3.51 - 3.53 (m, 1H), 3.22 - 3.18 (q, 2H), 3.06- 3.02 (m, 1H), 2.91 - 2.73 (m, 2H), 2.57 (s, 3H), 1.32 (t, 3H). LCMS: 727.2 [M+H]+.

[0265] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(2-methoxypyridin-4-yl)-7-oxooxazolo[5,4- b]pyridin-4(7H)-yl)acetamide (I-2)

[0266] Step 1. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5- hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(2-methoxypyridin-4-yl)-7- oxooxazolo[5,4-b]pyridin-4(7H)-yl)acetamide

[0267] To a solution of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(2- methoxypyridin-4-yl)-7-oxo-6-(piperazin-1-yl)oxazolo[5,4-b]pyridin-4(7H)-yl)acetamide hydrochloride (Intermediate-9) (45 mg, 72 μmol, 1 eq) and sodium 5-hydroxy-6- methylpyrimidine-4-carboxylate (Intermediate-10) (71 mg, 0.36 mmol, 5 eq) in pyridine (0.5 mL) was added EDCI (55 mg, 0.29 mmol, 4 eq). The reaction mixture was stirred at 25 °C for 1h. The reaction mixture was poured into H2O (10 mL) and was extracted with DCM (10 mL * 3). The combined organic layers were washed with brine (10 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO2, DCM:MeOH = 5:1) to afford the title compound.

[0268] 1H-NMR (400 MHz, CD3OD) δ ppm 8.27 (d, 1H), 8.14 (d, 1H), 8.07 (s, 1H), 7.82 (s, 1H), 7.67 - 7.52 (m, 2H), 7.39 (s, 1H), 5–66 - 5.24 (m, 2H), 4.66 - 4.65 (m, 2H), 3.95 (s, 3H), 3.92 - 3.70 (m, 2H), 3.53 - 3.38 (m, 1H), 3.15 (q, 2H), 3.10 - 3.02 (m, 1H), 2.90 - 2.79 (m, 1H), 2.75 - 2.62 (m, 1H), 2.40 (s, 3H), 1.29 (t, 3H).

[0269] LCMS: 727.3 [M+H]+.

[0270] Synthesis of 2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1- yl)-2-(2-methoxypyridin-4-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetamide (I-3)

[0271] Step 5. Synthesis of 2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4- carbonyl)piperazin-1-yl)-2-(2-methoxypyridin-4-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N- (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetamide

[0272] To a solution of 2-[5-ethyl-2-(2-methoxy-4-pyridyl)-7-oxo-6-piperazin-1-yl- oxazolo[4,5-b]pyridin-4-yl]-N-[3-(trifluoromethyl)-1 bicyclo[1.1.1]pentanyl]acetamide hydrochloride (Intermediate-15) (80 mg, 137 μmol, 1 eq) and sodium 5-hydroxy-6- methylpyrimidine-4-carboxylate (Intermediate-10) (54 mg, 274 μmol, 2 eq) in pyridine (1 mL) was added EDCI (79 mg, 412 μmol, 3 eq). The mixture was stirred at 25 °C for 4 h. To the reaction mixture was added H2O (10 mL). Then the mixture was extracted with EtOAc (10 mL * 3). The combined organic phase was washed with brine (15 mL * 2), dried over anhydrousNa2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by Prep- TLC (SiO2, DCM: MeOH = 10:1) to afford the title compound.

[0273] 1H NMR (400 MHz, CDCl3) δ ppm 11.82 (s, 1H), 8.57 (s, 1H), 8.31 (d, 1H), 7.54 (d, 1H), 7.43 (s, 1H), 6.81 (s, 1H), 5.63 - 5.60 (m, 1H), 5.00 (s, 2H), 4.84 - 4.73 (m, 1H), 4.04 (q, 2H), 3.99 (s, 3H), 3.55 - 3.42 (m, 1H), 3.04 - 3.02 (m, 3H), 2.89 - 2.75 (m, 2H), 2.57 (s, 3H), 2.34 (s, 6H), 1.26 (t, 3H).

[0274] LCMS: 683.2 [M+H]+.

[0275] Synthesis of 2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1- yl)-2-(2-methoxypyridin-4-yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetamide (I-4)

[0276] Step 3. Synthesis of 2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4- carbonyl)piperazin-1-yl)-2-(2-methoxypyridin-4-yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)-N- (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetamide

[0277] To a solution of 2-[5-ethyl-2-(2-methoxy-4-pyridyl)-7-oxo-6-piperazin-1-yl- oxazolo[5,4-b]pyridin-4-yl]-N-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]acetamide hydrochloride (Intermediate-13) (20 mg, 34 μmol, 1 eq) and sodium 5-hydroxy-6- methylpyrimidine-4-carboxylate (Intermediate-10) (34 mg, 172 μmol, 5 eq) in pyridine (0.2 mL) was added EDCI (26 mg, 137 μmol, 4 eq). The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into water (10 mL) and extracted with DCM (10 mL* 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC (SiO2, MeOH / DCM = 10:1) to afford the title compound.

[0278] 1H NMR (400 MHz, CD3OD) δ ppm 8.29 (d, 1H), 8.14 (s, 1H), 7.57 (d, 1H), 7.40 (s, 1H), 5.07 (s, 2H), 4.66 - 4.63 (m, 1H), 3.97 (s, 3H), 3.94 - 3.79 (m, 2H), 3.72 - 3.59 (m, 1H), 3.48 - 3.44 (m, 1H), 3.19 - 3.08 (m, 1H), 3.04 (q, 2H), 2.–86 - 2.82 (m, 1H), 2.70 - 2.66 (m, 1H), 2.42 (s, 3H), 2.32 (s, 6H), 1.24 (t, 3H).

[0279] LCMS: 683.3 [M+H]+. Table 2 Method (Mass_ (Retention_ No. Observed) time) [min] [g / mol] I-1 LCMS 1 727.2 0.43 I-2 LCMS 1 727.3 0.5530 OH■n 710 / — \ N^N< H i T)=1-3 ■ > X / >;—0 )< Z %—= 1 HT20 Z= V\NOZ^*\--FF F LCMS 2 683.2 0.53 kl 20° 0= OH o^ \ / _, — \ N^N ^ -z< rA J r1-4 ) — ' O^N^^—0 1 H\_-NOZF F LCMS 2 683.3 0.521-5LCMS 3 752.3 4.57

[0280] As can be appreciated by those skilled in the art, compounds of Table 2a may be accessed through Intermediate 1 (ethyl 2,4-diiodooxazole-5-carboxylate).Table 2aMass_No. Theoretical[g / mol]0I-2aH j> / X,oF 701.20OO r^N' YVI-3a p ci>yFF698.200 OH 9L / L AAO[NY 1I-4a rW;^ c.°F 758.200 OH01NY 1I-5a yx iyy "*"-O H 1;vW759.180 OHI-10aFJ^QXC,7741.19 bJ$ X O Z Q ZI0 OH ){( °^=\ 'O Z= -? oW°x J XI-lla Q)H I \°=^CQT o\ 716.20I-12a673.20O OHA OI-13a s^ G c ’ ~740.210 OHI-14a^ ,0 ^3 °z( o o=— 741.190 OHI-15a1 ^ .. ■AcloF 775.18| LL LLI-16a741.19O OHO° -I-17a716.20;Yvuc,°FI-18a / X I^ ft $ A / / ° 717.14 ^ 2 z — / °= I 0 ' 20 z= — A ° j Q QsQ) \ \ °z—I-19a _ / / \Z ° °= ft° ft p OzZ-Z- '' / z — A (z° \ / zr _ ft° / ft4. o « ■| | 692.14LL LL LL LL LL LLI-20a753.19I-21a728.20I-22a ° \ / ) / )Z. — — ~\\ / / / / 725.21Q Y < o o o o / == O O ZI ) / / °== ' 20 z= - Q\ \ \ \ \ °z—I-23a °z— / ( / / ° \z °= 20 O= Y °Z2 V — A 0 / = zV 726.19I-24a760.18HOiNQ / 0 I^'N^OI-25aXY^; / A °752.210 OH0r rYr o^i\rI-35a—o LH / 7^No L / <FF F 715.240X 1 N 0 fN|fI-36a—o L H ozF F 707.2300f'" JY J p-cCcI-37a—o IH / 7^Nq / LATF FF667.240 OH0j ^(Y O^N 1I-38a X c—o r H7TNQ / LK"FF F 711.26I-39aO z ^o zt 708.26O OH \o z= ?—01^N" l^ ll — \ < zz z— \"a°I-40aI A HA-N o' Y~1 / o JTJF F7^ z 725.280 OH0\ N^NN^\ X X / I-41aI H / 7"Noz\rFF F 618.25? 9"^ A AN01Nr if / N^N^AI-42aI H ZT'No7F F 643.240I-51aI H / 7^Nq / XA / Fx / \'~FF 673.250I-52a—0 L H> 0N\ _ 1FTFFF670.25O OH oH0HNr-^AN^ Nr:JiLrA0 / I-53a °\ / A X XI H / 7'N°0" 646.28O OH0O^A^N^1N<UWI-54a °\ Hl XI H Z7^N° kiF 634.260I-55a I H V-N, Q / 'Q2661.31 0~Z= 7 / —. / \ oy- — ro V OoI-56a AT < / V ■"O m\ / X _700.25O OHN^K0 / °\ j xI-57aI HV-M o641.260oI-58a pv v ”—o L HV-N o V-F F F 733.250o0C' a HZ K -pH0I-59IC H / 7^N0L\rFF F 669.250°LNoI-60aH0~ l H / T'N0L.\rFF F 711.260 N=\A A ,o0lNf |fI-61a—o LH / r'NQ / KFF F 707.23_ JI 1 N01N[ |fI-62a—o LHVNoZ667.28I-67a^,zO \V- 721.25 / / LL LL ( 0 P"^ _ OX 01=1 “" '“ 1 N01N|f y\ / = Zj —V QI-68a—o ^ o= r1H o >z 0> rx F' F 749.28 oz ^^.r.v >I-69a—o L H7TNo / ^2^F 699.280 O^N°x / n^ X TH0I-70aI H }7-\ oz\ / <FF F 699.26

[0281] As can be appreciated by those sk\i O O=lled i / )nz. — ~ the art, compounds of Table 2b may be / / accessed through one or more of the general synthetic routes described herein and / or using methods known to one skilled in the art.Table 2bNo. ( / / ° \ ° Mass_Theoretical[g / mol] Ir 6I-2b701.20I-4b712.18 o \ f= / / Z. ~ / / ( O O=I-5b \ Q \ ° ( / - / ° 711.18Q OTZO OH°I-6b" ^IYo,Yo1741.190 OH° ^N" JW.JFI-7b:TU„- 759.1811 T| T| Tl 11I-8b Vij a.xC. zO Oz Zl ) / O / Zl °== )( ) / ^ / o o=== 20== \O Z 20= Z= z — \ \ 701.16Q Q)) \°=Q?M MI-9b o' o / < / 717.14I-10b741.190 OH 0 1N0 1I-llb ■p-oX "759.18I-12b b " 9 O O Zl ) / / °==90=687.18Q)x / =z\ / > z oo= — / / 2( M o o= ^ o o=—I-13bQ\Z. \ ^ ~ z \ — ' \\ \\ °z^ °z^ / \z ° \= ° / Y / / ° ° 686.19 YMYM°Z5TZ°Z^TZ>9^ 666LL LL LL LLI-14b716.20I-15b734.190 OH o l^N< W J TI-16bX 9 xOz O Zl xx )(^? o==\O=716.20MX \o -n= QgI-17bQ>734.19I-18b “b^X X ”F>A^CI°F7 752.21°LI-19b- / XX752.21Tl TlI-20b bh" 99 ' ' O O o O zi zz ( ) / / / 2 o o==== \ 2 ' '0O z -Z== - -.727.21 0 O 2= 4 " ' z —I-21b727.210_ U 1 N 0 fN9r HI-22b—o r H / 7"Noz|Q^\_pFF F 707.230 OHN^-O?°\ / ^ZU XI-23bL H / 7^NQ / 656.30O OH0fI-24b ><HX LC F0\rFF F 725.28O OH0 ‘XJQ°\ Xd d 1I-25b ' — ' o^isr —I H77^NoZXFF 680.280 OHI-26b °\ / dzd TI H / rN0630.28O OH0‘XJQ°x \ - f H l II-27bI H0ZT'NXFF 666.260I-28b l H o / X~\ _ / F673.250I-29b—0 1 H#"NO | _\rFF F 670.250 OHI-30b °\ J XI H00" 646.280 OHI-31bL H / 7^N0> \\F 634.260 oN-^A^N>^\nd1HnX(N0 \ ]| ||and1\z / H0\I-32bI HVN<0 Q661.30O OH0X^N^ r iT^\ N^JLQ / I-33b °\ \ X XI H / r'No' ]□^V F' FF684.250 OH0— \I-34b °v y^'i iL H / 7^N° Hu,-700.25O OH0r^N" i<iT — \I-35b °\ \ — f / ^zo X^N^ X^I H ZT'NQ / L.641.26fl 11 1 fl-^ N0 NI XiHO^^ / H' X TI-36bI H / r'N°ZL\ FZrFF643.240 OH° PNrYFI-37b AJ—o r / »r H°Nfin 'y-FF F 715.240OI-38b—o I* H ozF F 667.240 OHI-39b—o ■^ O rc / r H1° ■' oz'N\ FrFF711.260 HO0( J and1 N:== / VI-40b0 L H\ / rN\ o7SrFF F 708.26 oI-41b L H o7F F 618.250fl 1^ U 1 fl-^ NJ HO^ JO^I-42b CniX I Hr oz\ Fr FF669.250 OH0i^NXi<ir^s>I-43b / ^cHik L r1"xr7" H oNQ^^y-F F F 755.290U 1 N 0 INr if / — \°x M 1 1I-44bI HVNO> \\rFF F 685.25 oA A N 0 rN[ ifI-45b —o LH / T'N0679.280VNI-46b pA AHoMO I H\ #N\ Q / MFF0CNo Pl\ J.- > / I-47b / N~^ IX Iand\^hol H0k.\rFF F 669.25 o °lXNoI-48b cf _ jf IandVH0I H / 7'N0kJ \rFF F 711.260 N=\U A xO 0 INf lfI-49b ■pX "—0 1 HX---N o kJ\cFFF707.23X 1 NO " JO Hcr ^^I-50b—o LH / r'N0667.28 b 1 N o |^r "OOI-51b ■p^'XC ' —o L H / r'N° 1681.29X X ,N0 " JOI-52b-o IH / 7^NO685.27X X0N" JO ■p^iZc ' —o L 53b SrHI- -N693.29o P"^ _ 11 1 N01NP lfI-54b—0 f H° nL-o 695.27_ 11 1 NO 1Nf |fI-55b l-X '0 721.25 o p^ _ 11 1 N° 1N|fI-56b—0 f H?rNo / T y V>\-FFF749.28A A N0lNi ifI-57b—o r HQ / F 699.28LCMS methodsLCMS 1Instrument Shimadzu LCMS-2020Stationary Phase Kinetex EVO Cl 8 2.1X30mm, 5|imMode Binary GradientMobile Phase A 0.025% NH3 H2O in water (v / v)Mobile Phase B AcetonitrileGradient 5 to 95% B in 0.8min, 95% B for 0.42min, 95 to 5% B in O.Olmin,5% B for 0.35 minFlow Rate 1.5 mL / minColumn Temperature 40 °CColumn 2.1X30mm, 5pmLCMS 2Instrument Shimadzu LCMS-2020Stationary Phase HALO C183.0X30mm, 5pm Mode Binary GradientMobile Phase A 0.0375% TFA in water (v / v)Mobile Phase B 0.01875% TFA in Acetonitrile (v / v)GradientTime(min) B(%) Flow(mL / min)0.0 5 1.50.50 95 1.50.80 95 1.50.81 5 1.51.05 5 1.5Flow Rate 1.5 mL / minColumn Temperature 50 °CColumn HALO C183.0X30mm, 5pmLCMS 3Instrument Agilent HPLC-1290Stationary Phase HALO C18, 100x4.6mm, 2.7pm Mode Binary GradientMobile Phase A H2O + 0.05% TFAMobile Phase B Acetonitrile + 0.05% TFAGradient 10% to 95% B in 6 min, hold 95% B in 2 minFlow Rate 1.5 mL / minColumn Temperature 40 °CColumn 100*4.6mm, 2.7pm

[0282] Intermediate- 1: ethyl 2,4-diiodooxazole-5-carboxylateLi HMDS, l2THF, -30~25°C step 1Step 1. Synthesis of ethyl 2,4-diiodooxazole-5-carboxylate (Intermediate 1)

[0283] To a solution of ethyl oxazole-5-carboxylate (10.00 g, 70.86 mmol, 1 eq) in THF (100 mL) was added LiHMDS (1 M, 248.01 mL, 3.5 eq) at -30°C and the mixture was stirred at -30°C for 1 h. Then I2 (53.95 g, 212.58 mmol, 3 eq) was added into the mixture and stirred at 25°C for 15 h. The mixture was poured into H2O (500 mL). Then extracted with EtOAc (200 mL * 3). The organic phase was washed with brine (500 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Eluent of EtOAc / PE) and triturated with EtOH (10 mL) to afford the title compound as a yellow solid.1H NMR (400 MHz, DMSO-t / e) 8 ppm 4.30 (q, 2H), 1.30 (t, 3H).LCMS: 394.0 [M+H]+.

[0284] Intermediate 2: tert-butyl 4-(5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-4,7- dihydrooxazolo[4,5-b]pyridin-6-yl)piperazine-l -carboxylateStep 1. Synthesis of ethyl 4-iodo-2-(2-methoxypyridin-4-yl)oxazole-5-carboxylate

[0285] To a solution of ethyl 2,4-diiodooxazole-5-carboxylate (4.90 g, 12.47 mmol, 1 eq), (2- methoxy-4-pyridyl)boronic acid (1.91 g, 12.47 mmol, 1 eq) and K2CO3(3.45 g, 24.94 mmol, 2 eq) in dioxane (100 mL) and H2O (20 mL) was added Pd(dppf)Cl2(913 mg, 1.25 mmol, 0.1 eq). The mixture was degassed and purged with N2 for 3 times, then stirred at 60°C for 16 h under N2 atmosphere. The mixture was poured into H2O (200 mL), extracted with EtOAc (100 mL * 3). The organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gelchromatography (Eluent of EtOAc / PE) and recrystallize with EtOH (50 mL) to afford the title compound as a light yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 8.32 (d, 1H), 7.54 (d, 1H), 7.43 (s, 1H), 4.46 (q, 2H), 4.00 (s, 3H), 1.46 (t, 3H).

[0286] LCMS: 375.1 [M+H]+. Step 2. Synthesis of ethyl 4-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)oxazole-5- carboxylate

[0287] To a solution of ethyl 4-iodo-2-(2-methoxy-4-pyridyl)oxazole-5-carboxylate (1.00 g, 2.67 mmol, 1 eq) and 1-(4-methoxyphenyl)-N-[(4-methoxyphenyl)methyl]methanamine (1.03 g, 4.01 mmol, 1.5 eq) in dioxane (20 mL) was added Pd(OAc)2 (60 mg, 267 μmol, 0.1 eq), Xantphos (155 mg, 267 μmol, 0.1 eq) and Cs2CO3(1.31 g, 4.01 mmol, 1.5 eq). The mixture was degassed and purged with N2for 3 times, and stirred at 110°C for 12 h under N2atmosphere. It was quenched with H2O (150 mL), then the mixture was extracted with EtOAc (150 mL * 3). The combined organic phase was washed with brine (150 mL * 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Eluent of EtOAc / PE) to afford the title compound as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 8.30 (d, 1H), 7.53 (d, 1H), 7.42 (s, 1H), 7.19 (d, 4H), 6.86 (d, 4H), 4.77 (s, 4H), 4.31 (q, 2H), 4.02 (s, 3H), 3.81 (s, 6H), 1.33 (t, 3H).

[0288] LCMS: 504.3 [M+H]+. Step 3. Synthesis of 4-(bis(4-methoxybenzyl)amino)-N-methoxy-2-(2-methoxypyridin-4-yl)-N- methyloxazole-5-carboxamide

[0289] A mixture of ethyl 4-[bis[(4-methoxyphenyl)methyl]amino]-2-(2-methoxy-4- pyridyl)oxazole-5-carboxylate (500 mg, 993μmol, 1 eq) and N-methoxymethanamine hydrochloride (484 mg, 4.96 mmol, 5.0 eq) in THF (12 mL) was added LiHMDS (1 M, 7.94 mL, 8 eq) at 0°C under N2atmosphere and the mixture was stirred at 0°C for 1 h under N2atmosphere. The reaction mixture was quenched with saturated NH4Cl aqueous solution (50 mL) at 0°C. Then the mixture was extracted with EtOAc (50 mL * 3). The combined organic phase was washed with brine (50 mL * 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to afford the title compound as a yellow gum, which was used into the next step directly without further purification.1H NMR (400 MHz, CDCl3) δ ppm 8.28 (d, 1H), 7.47 (d, 1H), 7.32 (s, 1H), 7.18 (d, 4H), 6.83 (d, 4H), 4.66 (s, 4H), 4.00 (s, 3H), 3.79 (s, 6H), 3.74 (s, 3H), 3.20 (s, 3H).

[0290] LCMS: 519.2 [M+H]+. Step 4. Synthesis of 1-(4-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)oxazol-5- yl)pentane-1,3-dione

[0291] A mixture of butan-2-one (556 mg, 7.71 mmol, 690 μL, 5.0 eq) and 4-[bis[(4- methoxyphenyl)methyl]amino]-N-methoxy-2-(2-methoxy-4-pyridyl)-N-methyl-oxazole-5- carboxamide (800 mg, 1.54 mmol, 1 eq) in THF (8 mL) was added LiHMDS (1 M, 7.71 mL, 5.0 eq) at 0°C under N2atmosphere. The mixture was stirred at 60°C for 1 h. The reaction mixture was quenched with saturated NH4Cl aqueous solution (100 mL) at 0°C. Then the mixture was extracted with EtOAc (100 mL * 3). The combined organic phase was washed with brine (100 mL * 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Eluent of EtOAc / PE) to afford the title compound as a yellow gum.

[0292] LCMS: 530.2 [M+H]+. Step 5. Synthesis of 1-(4-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)oxazol-5-yl)- 2-bromopentane-1,3-dione

[0293] A mixture of 1-[4-[bis[(4-methoxyphenyl)methyl]amino]-2-(2-methoxy-4- pyridyl)oxazol-5-yl]pentane-1,3-dione (320 mg, 604 μmol, 1 eq) in DCM (10 mL) was added NBS (86 mg, 483 μmol, 0.8 eq) at 0°C. The reaction was stirred at 0°C for 1 h. Then TsOH.H2O (21 mg, 121 μmol, 0.2 eq) was added into the mixture and stirred at 25°C for another 1 h. The reaction mixture was quenched with H2O (20 mL) at 25°C. Then the mixture was extracted with DCM (15 mL * 3). The combined organic phase was washed with brine (20 mL * 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to afford the title compound as a yellow oil, which was used into the next step directly without purification.

[0294] LCMS: 608.1 [M+H]+. Step 6. Synthesis of tert-butyl 4-(1-(4-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4- yl)oxazol-5-yl)-1,3-dioxopentan-2-yl)piperazine-1-carboxylate

[0295] To a solution of tert-butyl piperazine-1-carboxylate (107 mg, 575 μmol, 1 eq) in THF (7 mL) was added DIEA (149 mg, 1.15 mmol, 200 μL, 2 eq) and 1-[4-[bis[(4- methoxyphenyl)methyl]amino]-2-(2-methoxy-4-pyridyl)oxazol-5-yl]-2-bromo-pentane-1,3- dione (350 mg, 575 μmol, 1 eq). The mixture was stirred at 25°C for 16 h. It was quenched withH2O (30 mL), then extracted with EtOAc (30 mL * 3). The combined organic phase was washed with brine (30 mL * 2), dried over anhydrous Na2SO4, filtered and concentrated reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Eluent of EtOAc / PE) to afford the title compound as a yellow oil.

[0296] LCMS: 714.3 [M+H]+. Step 7. Synthesis of 5-ethyl-2-(2-methoxypyridin-4-yl)-6-(piperazin-1-yl)oxazolo[4,5-b]pyridin- 7(4H)-one

[0297] A solution of tert-butyl 4-[1-[4-[bis[(4-methoxyphenyl)methyl]amino]-2-(2-methoxy- 4-pyridyl)oxazole-5-carbonyl]-2-oxo-butyl]piperazine-1-carboxylate (300 mg, 420 μmol, 1 eq) in TFA (6 mL) was stirred at 50 °C for 1 h. The reaction was cooled to room temperature naturally and concentrated under reduced pressure to afford the title compound as a yellow oil, which was used into the next step directly without purification.

[0298] LCMS: 356.1 [M+H]+. Step 8. Synthesis of tert-butyl 4-(5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-4,7- dihydrooxazolo[4,5-b]pyridin-6-yl)piperazine-1-carboxylate

[0299] To a solution of 5-ethyl-2-(2-methoxy-4-pyridyl)-6-piperazin-1-yl-4H-oxazolo[4,5- b]pyridin-7-one (150 mg, 422 μmol, 1 eq) in DCM (5 mL) was added DIEA (55 mg, 422 μmol, 74 μL, 1 eq) and (Boc)2O (184 mg, 844 μmol, 194 μL, 2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. Then the reaction mixture was diluted with H2O (20 mL). Then the mixture was extracted with DCM (15 mL * 3). The combined organic phase was washed with brine (15 mL * 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography (Eluent of EtOAc / PE) to afford the title compound as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 8.26 (s, 1H), 7.52 (d, 1H), 7.39 (s, 1H), 4.16 - 4.01 (m, 2H), 3.94 (s, 3H), 3.91 - 3.80 (m, 2H), 3.02 - 2.93 (m, 4H), 2.66 (q, 2H), 1.50 (s, 9H), 1.35 (t, 3H).

[0300] LCMS: 456.2 [M+H]+.

[0301] Intermediate 3: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(2- methoxypyridin-4-yl)-7-oxo-6-(piperazin-1-yl)oxazolo[4,5-b]pyridin-4(7H)-yl)acetamide hydrochlorideStep 1. Synthesis of tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)- 5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-4,7-dihydrooxazolo[4,5-b]pyridin-6-yl)piperazine-1- carboxylate

[0302] To a solution of tert-butyl 4-[5-ethyl-2-(2-methoxy-4-pyridyl)-7-oxo-4H-oxazolo[4,5- b]pyridin-6-yl]piperazine-1- carboxylate (80 mg, 176 μmol, 1 eq) in DMF (2 mL) was added DIEA (68 mg, 527 μmol, 92 μL, 3 eq) and N-[2-chloro-4-(trifluoromethyl)phenyl]-2-iodo-acetamide (Intermediate-12) (83 mg, 228 μmol, 1.3 eq). The mixture was stirred at 60 °C for 1 h. The reaction mixture was cooled to 25°C and quenched with H2O (20 mL). Then it was extracted with EtOAc (15 mL * 3). The combined organic phase was washed with brine (15 mL * 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography (Eluent of EtOAc / PE) to afford the title compound as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 8.53 (d, 1H), 8.43 (s, 1H), 8.35 (d, 1H), 7.65 - 7.60 (m, 2H), 7.58 - 7.54 (m, 1H), 7.51 (s, 1H), 5.23 (s, 2H), 4.19 - 4.05 (m, 2H), 4.01 (s, 3H), 3.97 - 3.86 (m, 2H), 3.14 (q, 2H), 3.13 - 3.11 (m, 2H), 2.69 - 2.65 (m, 2H), 1.51 (s, 9H), 1.30 (t, 3H).

[0303] LCMS: 691.3 [M+H]+.

[0304] Step 2. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(2- methoxypyridin-4-yl)-7-oxo-6-(piperazin-1-yl)oxazolo[4,5-b]pyridin-4(7H)-yl)acetamide hydrochloride

[0305] To a solution of tert-butyl 4-[4-[2-[2-chloro-4-(trifluoromethyl)anilino]-2-oxo-ethyl]- 5-ethyl-2-(2-methoxy-4-pyridyl)-7-oxo-oxazolo[4,5-b]pyridin-6-yl]piperazine-1-carboxylate (20 mg, 29 μmol, 1 eq) in DCM (0.4 mL) was added HCl / dioxane (4 M, 0.40 mL, 55 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a yellow solid, which was used into the next step directly without purification.

[0306] LCMS: 591.2 [M+H]+.

[0307] Intermediate 4: 7-hydroxy-2,3-dihydrofuro[3,2-c]pyridine-6-carboxylic acid

[0308] Step 1. Synthesis of methyl 3-(bromomethyl)furan-2-carboxylate

[0309] 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 N2 and 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 the title compound.

[0310] LCMS: 219 / 221 [M+H]+.

[0311] Step 2. Synthesis of methyl 3-(((N-(2-methoxy-2-oxoethyl)-4- methylphenyl)sulfonamido)methyl)furan-2-carboxylate

[0312] 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 vacuum. The residue was purified by column chromatography on silica (Eluent of EtOAc / PE) to afford the title compound. LCMS: 382 [M+H]+.

[0313] Step 3. Synthesis of methyl 7-hydroxyfuro[3,2-c]pyridine-6-carboxylate

[0314] 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 mL) was added a 1 M solution of LiHMDS (14.2 mL, 14.2 mmol, 3.00 eq) in THF dropwise at - 78 °C under N2atmosphere. 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 the title compound.

[0315] LCMS: 194 [M+H]+.

[0316] Step 4. Synthesis of methyl 7-hydroxy-2,3-dihydrofuro[3,2-c]pyridine-6-carboxylate

[0317] 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 H2 gas (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 the title compound.

[0318] LCMS: 196 [M+H]+.

[0319] Step 5. Synthesis of 7-hydroxy-2,3-dihydrofuro[3,2-c]pyridine-6-carboxylic acid

[0320] 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 acidized by 3 N HCl. The precipitated solids were collected by filtration and dried to afford the title compound, which was used in the next step directly without further purification.

[0321] LCMS: 182 [M+H]+.

[0322] Intermediate-5: 4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carboxylic acidIntermediate 5

[0323] Step 1. Synthesis of methyl 2-(bromomethyl)furan-3-carboxylate

[0324] To a stirred solution of methyl 2-methylfuran-3 -carboxylate (10.0 g, 71.4 mmol, 1.00 eq) in CCh (55.0 mL) were 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 50 °C 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 the title compound. ’H NMR (400 MHz, DMSO-d6) 8 ppm 7.86 (d, 1H), 6.80 (d, 1H), 4.95 (s, 2H), 3.82 (s, 3H).

[0325] Step 2. Synthesis of methyl 2-(((N-(2-methoxy-2-oxoethyl)-4- methylphenyl)sulfonamido)methyl)furan-3-carboxylate

[0326] 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 N2 and 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 the title compound.

[0327] LCMS: 382.1 [M+H]+.

[0328] Step 3. Synthesis of methyl 4-hydroxyfuro[2,3-c]pyridine-5-carboxylate

[0329] 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 LiHMDS (70.0 mL, 70.0 mmol, 3.00 eq) in THF at -78 °C underN2. The resulting mixture was stirred for Ih at room temperature under N2. The reaction mixture was quenched with saturated NH4CI solution at 0 °C 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 the title compound. LCMS: 194.0 [M+H]+.

[0330] Step 4. Synthesis of methyl 4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carboxylate

[0331] 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%). 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 (Cl 8 column, H2O (lOmmol / L NH4HCO3)-ACN) to afford the title compound.

[0332] LCMS: 195.9 [M+H]+.

[0333] Step 5. Synthesis of 4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carboxylic acid

[0334] 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 60 °C. The mixture was acidified to pH = 3 with 1 N HQ. 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 the title compound, which was used in the next step directly without further purification.

[0335] LCMS: 181.9 |XI+I I ' .

[0336] Intermediate- 11 : methyl 5-methoxy-6-methylpyrimidine-4-carboxylate

[0337] Intermediate-6: 5-hydroxy-6-methylpyrimidine-4-carboxylic acidIntermediate 11 Intermediate 6

[0338] Step 1 : Synthesis of 4-chloro-5-methoxy-6-methylpyrimidine

[0339] 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 phase was washed with brine (100 mL), dried over 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 the title compound.

[0340] LCMS: 159.1 [M+H]+.

[0341] Step 2: Synthesis of methyl 5-methoxy-6-methylpyrimidine-4-carboxylate(Intermediate-11)

[0342] 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)C12-CH2C12 (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 the title compound.

[0343] LCMS: 183.1 [M+H]+.

[0344] Step 3: Synthesis of 5-hydroxy-6-methylpyrimidine-4-carboxylic acid

[0345] A mixture of methyl 5-methoxy-6-methylpyrimidine-4-carboxylate (16.00 g, 87.83 mmol, 1.0 eq) in HBr solution (aq.) (68.5 mL, 68%) was stirred at 50 °C overnight. Then HI solution (aq.) (67.2 mL, 56%) was added and stirred at 50 °C for 6 h. The reaction mixture was cooled to room temperature and basified with 50% NaOH solution (aq.) to pH 9 at 0 °C, then adjusted to pH 7 with 2 M HC1 solution (aq.) at 0 °C. The mixture was filtered, the filter cake was dried in vacuum to afford the title compound, which was used in the next step without furtherpurification. ’H NMR (400 MHz, DMSO-4) 8 ppm 15.96 - 15.12 (m, 1H), 8.37 (s, 1H), 2.34 (s, 3H).

[0346] LCMS: 155.1 [M+H]+.

[0347] Intermediate-7 : 1 -(5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)oxazol-4-yl)-2 -bromopentane- 1,3-dioneStep 1 Step 2 Step 3Cs2CO3, PMB-CI LiHMDSIntermediate-7

[0348] Step 1. Synthesis of 2-methoxyisonicotinoyl chloride

[0349] To a solution of 2-methoxypyridine-4-carboxylic acid (60.00 g, 391.8 mmol, 1 eq) in toluene (500 mL) was added SOCh (140 g, 1.18 mol, 85.4 mb, 3 eq) at 20 °C, then the reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered and washed with DCM(25 ml * 2), the combined filtrate was concentrated under reduced pressure to afford the title compound, which was used into the next step directly without purification.

[0350] Step 2. Synthesis of ethyl 2-cyano-2-(2-methoxyisonicotinamido)acetate

[0351] To a solution of ethyl amino(cyano)acetate 4-methylbenzenesulfonate (40.61 g, 135.2 mmol, 1 eq) in pyridine (70 mL) and DCM (100 mL) was added 2 methoxypyridine-4-carbonyl chloride (23.20 g, 135.2 mmol, 1 eq) in DCM (40 mL) at 0 °C. The mixture was stirred at 40 °C for 1 h. The reaction mixture was quenched by H2O (100 mL) and extracted with DCM (100 mL * 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Eluent of EtOH / DCM) to afford the title compound.

[0352] LCMS: 264.1 [M+H]+.

[0353] Step 3. Synthesis of ethyl 5-amino-2-(2-methoxypyridin-4-yl)oxazole-4-carboxylate

[0354] To ethyl 2-cyano-2-[(2-methoxypyridine-4-carbonyl)amino]acetate (18.00 g, 68.38 mmol, 1 eq) was added TFA (125 g, 1.09 mol, 81.3 mL, 16 eq). The mixture was stirred at 40 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with EtOH (40 ml) at 0 °C for 5 min and filtered, the filter cake was washed with EtOH (20 ml * 2) and MTBE (20 ml) and then dried under reduced pressure to afford the title compound.

[0355] 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.26 (d, 1H), 7.67 (s, 2H), 7.31 (d, 1H), 7.01 (s, 1H), 4.24 (q, 2H), 3.90 (s, 3H), 1.28 (t, 3H).

[0356] LCMS: 264.0 [M+H]+.

[0357] Step 4. Synthesis of ethyl 5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4- yl)oxazole-4-carboxylate

[0358] To a solution of ethyl 5-amino-2-(2-methoxy-4-pyridyl)oxazole-4-carboxylate (5.00 g, 19.0 mmol, 1 eq) in DMF (50 mL) was added Cs2CO3 (27.85 g, 85.47 mmol, 4.5 eq), KI (315 mg, 1.90 mmol, 0.1 eq) and 4-methoxybenzyl chloride (8.92 g, 57.0 mmol, 7.73 mL, 3 eq). The reaction mixture was stirred at 110°C for 1 h. The reaction mixture was poured into H2O (300 mL) and was extracted with EtOAc (150 mL * 3). The combined organic layers were washed with brine (100 mL * 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Eluent of EtOAc / PE) and reverse Phase HPLC (C18 column, water (FA)-ACN) to afford the title compound.

[0359] 1H-NMR (400 MHz, CDCl3) δ ppm 8.20 (d, 1H), 7.39 (d 1H), 7.22 - 7.14 (m, 5H), 6.87 (d, 4H), 4.70 (s, 4H), 4.38 (q, 2H), 3.96 (s, 3H), 3.81 (s, 6H), 1.39 (t, 3H).

[0360] LCMS: 504.2 [M+H]+.

[0361] Step 5. Synthesis of 1-(5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4- yl)oxazol-4-yl)-3-hydroxypent-2-en-1-one

[0362] To a solution of butan-2-one (752 mg, 10.4 mmol, 933 μL, 2.5 eq) in THF (10 mL) was added LiHMDS (1 M in THF, 10.43 mL, 2.5 eq) at 0 °C under N2atmosphere. The reaction mixture was stirred at 25 °C for 0.5 h. Then ethyl 5-[bis[(4-methoxyphenyl)methyl]amino]-2-(2- methoxy-4-pyridyl)oxazole-4-carboxylate (2.10 g, 4.17 mmol, 1 eq) dissolved in THF (10 mL) was added into the mixture. The reaction mixture was stirred at 60°C for 1 h under N2atmosphere. The reaction mixture was poured into saturated NH4Cl solution (200 mL) and extracted with EtOAc (80 mL *3). The combined organic layers were washed with brine (50 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Eluent of EtOAc / PE) to afford the title compound.

[0363] LCMS: 530.2 [M+H]+.

[0364] Step 6. Synthesis of 1-(5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4- yl)oxazol-4-yl)-2-bromopentane-1,3-dione

[0365] To a solution of 1-[5-[bis[(4-methoxyphenyl)methyl]amino]-2-(2-methoxy-4- pyridyl)oxazol-4-yl]-3-hydroxypent- 2-en-1-one (1.00 g, 1.89 mmol, 1 eq) in DCM (10 mL) was added NBS (269 mg, 1.51 mmol, 0.8 eq) at 0°C. The reaction mixture was stirred at 25°C for 1h. The reaction mixture was poured into H2O (100 mL) and was extracted with DCM (60 mL * 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound, which was used into the next step directly without purification.

[0366] LCMS: 610.1 [M+H]+.

[0367] Intermediate-8: 2-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-ethyl-2-(2- methoxypyridin-4-yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)acetic acidIntermediate-7Step 4BOC2OStep 6Intermediate-8

[0368] Step 1. Synthesis of tert-butyl 4-(l-(5-(bis(4-methoxybenzyl)amino)-2-(2- methoxypyridin-4-yl)oxazol-4-yl)-l,3-dioxopentan-2-yl)piperazine-l -carboxylate

[0369] To a solution of l-[5-[bis[(4-methoxyphenyl)methyl]amino]-2-(2-methoxy-4- pyridyl)oxazol-4-yl]-2-bromo-pentane- 1,3-dione (Intermediate-7) (700 mg, 1.15 mmol, 1 eq) and tert-butyl piperazine- 1 -carboxylate (214 mg, 1.15 mmol, 1 eq) in THF (7 mb) was added DIEA (298 mg, 2.30 mmol, 401 pL, 2 eq). The reaction mixture was stirred at 25 °C for 12 h.The reaction mixture was poured into H2O (100 mL) and extracted with EtOAc (60 mL * 3). The combined organic layers was washed with brine (50 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Eluent of EtOAc / PE) to afford the title compound.

[0370] 1H-NMR (400 MHz, CDCl3) δ ppm 8.22 (d, 1H), 7.26 (d, 1H), 7.17 (d, 4H), 7.06 (s, 1H), 6.88 (d, 4H), 5.28 (s, 1H), 4.97 - 4.86 (m, 2H), 4.84 - 4.70 (m, 2H), 3.98 (s, 3H), 3.81 (s, 6H), 3.48 - 3.44 (m, 4H), 2.90 - 2.54 (m, 6H), 1.44 (s, 9H), 1.10 (t, 3H).

[0371] LCMS: 714.3 [M+H]+.

[0372] Step 2. Synthesis of 1-(5-((4-methoxybenzyl)amino)-2-(2-methoxypyridin-4- yl)oxazol-4-yl)-2-(piperazin-1-yl)pentane-1,3-dione trifluoroacetate

[0373] To a solution of tert-butyl 4-[1-[5-[bis[(4-methoxyphenyl)methyl]amino]-2-(2- methoxy-4-pyridyl)oxazole-4-carbonyl]-2-oxo-butyl]piperazine-1-carboxylate (700 mg, 981 μmol, 1 eq) in TFA (7 mL) was stirred at 50°C for 1 h.The reaction was cooled to room temperature and concentrated under reduced pressure to afford the title compound, which was used into the next step directly without purification.

[0374] LCMS: 494.2 [M+H]+.

[0375] Step 3. Synthesis of tert-butyl 4-(1-(5-((4-methoxybenzyl)amino)-2-(2- methoxypyridin-4-yl)oxazol-4-yl)-1,3-dioxopentan-2-yl)piperazine-1-carboxylate

[0376] To a solution of 1-(5-((4-methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)oxazol-4- yl)-2-(piperazin-1-yl)pentane-1,3-dione trifluoroacetate (590 mg, 971 μmol, 1 eq) in DCM (6 mL) was added DIEA (377 mg, 2.91 mmol, 507 μL, 3 eq) and Boc2O (254 mg, 1.17 mmol, 267 μL, 1.2 eq). The reaction mixture was stirred at 25°C for 1 h. The reaction mixture was poured into H2O (50 mL) and was extracted with DCM (50 mL * 3). The combined organic layers were washed with brine (50 mL), 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 the title compound.

[0377] 1H-NMR (400 MHz, CDCl3) δ ppm 8.23 (d, 1H), 7.76 (s, 1H), 7.36 - 7.28 (m, 2H), 7.14 (s, 1H), 6.92 (d, 2H), 5.00 (s, 1H), 4.62 (d, 2H), 3.99 (s, 3H), 3.82 (s, 3H), 3.45 - 3.49 (m, 4H), 2.79 - 2.47 (m, 6H), 1.43 (s, 9H), 1.10 (t, 3H).

[0378] LCMS: 594.3 [M+H]+.

[0379] Step 4. Synthesis of tert-butyl 4-(1-(5-((2-(tert-butoxy)-2-oxoethyl)(4- methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)oxazol-4-yl)-1,3-dioxopentan-2-yl)piperazine- 1-carboxylate

[0380] To a solution of tert-butyl 4-(1-(5-((4-methoxybenzyl)amino)-2-(2-methoxypyridin-4- yl)oxazol-4-yl)-1,3-dioxopentan-2-yl)piperazine-1-carboxylate (460 mg, 775 μmol, 1 eq) and tert-butyl 2-bromoacetate (151 mg, 775 μmol, 114 μL, 1 eq) in THF (4.6 mL) was added t-BuOK (348 mg, 3.10 mmol, 4 eq). The reaction mixture was stirred at 50 °C for 0.5 h. Then second batch of tert-butyl 2-bromoacetate (151 mg, 775 μmol, 114 μL, 1 eq) was added to the mixture. The reaction mixture was stirred at 50 °C for another 0.5 h. Then the third batch of tert-butyl 2- bromoacetate (151 mg, 775 μmol, 114 μL, 1 eq) was added into the mixture and stirred at 50°C for another 0.5 h. The reaction mixture was diluted with H2O (50 mL) and extracted with DCM (40 mL*3). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of EtOAc / PE) to afford the title compound.

[0381] 1H-NMR (400 MHz, CDCl3) δ ppm 8.23 (d, 1H), 7.29 (s, 1H), 7.25 (d, 2H), 7.09 (s, 1H), 6.90 (d, 2H), 5.28 (s, 2H), 4.85 (s, 1H), 4.58 - 4.29 (m, 2H), 3.98 (s, 3H), 3.82 (s, 3H), 3.48 - 3.44 (m, 4H), 2.76 - 2.69 (m, 4H), 2.55 (q, 2H) ,1.44 (s, 9H), 1.42 (s, 9H), 1.09 (t, 3H).

[0382] LCMS: 708.4 [M+H]+.

[0383] Step 5. Synthesis of 2-(5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-6-(piperazin-1- yl)oxazolo[5,4-b]pyridin-4(7H)-yl)acetic acid Trifluoroacetic acid salt

[0384] To a solution of tert-butyl 4-[1-[5-[(2-tert-butoxy-2-oxo-ethyl)-[(4 methoxyphenyl)methyl]amino]-2-(2-methoxy-4-pyridyl)oxazole-4-carbonyl]-2-oxo- butyl]piperazine-1-carboxylate (400 mg, 565 μmol, 1 eq) in TFA (4 mL) was stirred at 120 °C for 3 h. The reaction mixture was concentrated under reduced pressure to afford the title compound, which was used into the next step directly without purification.

[0385] LCMS: 414.1 [M+H]+.

[0386] Step 6. Synthesis of 2-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-ethyl-2-(2- methoxypyridin-4-yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)acetic acid

[0387] To a solution of 2-(5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-6-(piperazin-1- yl)oxazolo[5,4-b]pyridin-4(7H)-yl)acetic acid Trifluoroacetic acid salt (290 mg, 550 μmol, 1 eq) in DCM (3 mL) was added DIEA (355 mg, 2.75 mmol, 479 μL, 5 eq) and (Boc)2O (180 mg, 825μmol, 190 μL, 1.5 eq). The reaction mixture was stirred at 25 °C for 0.5 h. The reaction mixture was poured into H2O (3 mL) and was extracted with DCM (4 mL * 3). The combined organic layers were washed with brine (5 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Eluent of MeOH / DCM) to afford the title compound.

[0388] LCMS: 514.1 [M+H]+.

[0389] Intermediate-9: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(2- methoxypyridin-4-yl)-7-oxo-6-(piperazin-1-yl)oxazolo[5,4-b]pyridin-4(7H)-yl)acetamide hydrochloride

[0390] Step 1. Synthesis of tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-4,7-dihydrooxazolo[5,4-b]pyridin-6- yl)piperazine-1-carboxylate

[0391] To a solution of 2-[6-(4-tert-butoxycarbonylpiperazin-1-yl)-5-ethyl-2-(2-methoxy-4- pyridyl)-7-oxo-oxazolo[5,4-b]pyridin-4-yl]acetic acid (80 mg, 0.16 mmol, 1 eq) and 2-chloro-4- (trifluoromethyl)aniline (40 mg, 0.20 mmol, 28 μL, 1.3 eq) in pyridine (0.8 mL) was addedPOCl3(36 mg, 0.23 mmol, 22 μL, 1.5 eq) at 0°C. The reaction mixture was stirred at 60°C for 1 h. The reaction mixture was poured into H2O (10 mL) and was extracted with DCM (10 mL * 3). The combined organic layers were washed with brine (10 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified reverse Phase HPLC (C18 column, water (FA)-ACN) to afford the title compound.

[0392] LCMS: 691.3 [M+H]+.

[0393] Step 2. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(2- methoxypyridin-4-yl)-7-oxo-6-(piperazin-1-yl)oxazolo[5,4-b]pyridin-4(7H)-yl)acetamide hydrochloride

[0394] To a solution of tert-butyl 4-[4-[2-[2-chloro-4-(trifluoromethyl)anilino]-2-oxo-ethyl]- 5-ethyl-2-(2-methoxy-4-pyridyl)-7-oxo-oxazolo[5,4-b]pyridin-6-yl]piperazine-1-carboxylate (50 mg, 72 μmol, 1 eq) in HCl / 1,4-dioxane (2 M, 0.5 mL) was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to afford the title compound, which was used into the next step directly without purification.

[0395] LCMS: 591.2 [M+H]+.

[0396] Intermediate-10: sodium 5-hydroxy-6-methylpyrimidine-4-carboxylate

[0397] Step 3. Synthesis of sodium 5-hydroxy-6-methylpyrimidine-4-carboxylate

[0398] To a solution of methyl 5-methoxy-6-methyl-pyrimidine-4-carboxylate (Intermediate- 11) (210 g, 1.15 mol, 1 eq) was added HBr (850 mL) at 20 °C. After addition, the mixture was stirred at 50°C for 16 h, and then was added HI (600 mL) at 50 °C. The resulting mixture was stirred at 50 °C for 6 h. The reaction mixture was filtered. The filtrate was adjusted to pH to 8~9 with aqueous NaOH solution (30% in water) at 0~5°C. The mixture was filtered, the filter cake was dried under reduced pressure to afford the title compound, which was used into next step directly without further purification.

[0399] 1H NMR (400 MHz, CD3OD) δ ppm 8.47 (s, 1H), 2.48 (s, 3H).

[0400] Intermediate-12: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide

[0401] Step 1. Synthesis of 2-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0402] To a solution of 2-chloro-4-(trifluoromethyl)aniline (19.1 g, 97.7 mmol, 1.0 eq) and TEA (19.76 g, 195.3 mmol, 2.0 eq) in DCM (200 mL) was added dropwise a solution of 2- chloroacetyl chloride (11.03 g, 97.7 mmol, 1.0 eq) in DCM (50 mL) at 0 °C. After addition, the resulting mixture was warmed to room temperature and stirred at room temperature overnight. The reaction mixture was purified by column chromatography on silica gel (Eluent of EtOAc / PE) to afford the title compound.

[0403] LCMS: 273.9 [M+H]+.

[0404] Step 2. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide

[0405] To a solution of 2-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (7.70 g, 28.3 mmol, 1.0 eq) in acetone (60 mL) was added KI (5.17 g, 31.1 mmol, 1.1 eq), the resulting mixture was stirred at 60 °C for 2 h. The mixture was cooled to room temperature, filtered and the filtrate was concentrated in vacuum to afford the title compound, which was used in the next step without further purification.

[0406] LCMS: 363.9 [M+H]+.

[0407] Intermediate-13: 2-(5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-6-(piperazin-1- yl)oxazolo[5,4-b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetamide hydrochloride

[0408] Step 1. Synthesis of tert-butyl 4-(5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-4-(2-oxo- 2-((3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)amino)ethyl)-4,7-dihydrooxazolo[5,4-b]pyridin- 6-yl)piperazine-1-carboxylate

[0409] To a mixture of 2-[6-(4-tert-butoxycarbonylpiperazin-1-yl)-5-ethyl-2-(2-methoxy-4- pyridyl)-7-oxo-oxazolo[5,4-b]pyridin-4-yl]acetic acid (Intermediate-8) (50 mg, 97 μmol, 1 eq) and 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (37 mg, 195 μmol, 2 eq) in DMF (0.5 mL) were added HATU (74 mg, 195 μmol, 2 eq) and DIEA (38 mg, 292 μmol, 51 μL, 3 eq). The mixture was stirred for 1 h at 25 °C. The reaction mixture was poured into water (20 mL) and was extracted with EtOAc (20 mL * 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Eluent of DCM / MeOH) to afford the title compound.

[0410] LCMS: 647.3 [M+H]+.

[0411] Step 2. Synthesis of 2-(5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-6-(piperazin-1- yl)oxazolo[5,4-b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetamide hydrochloride

[0412] A solution of tert-butyl 4-[5-ethyl-2-(2-methoxy-4-pyridyl)-7-oxo-4-[2-oxo-2-[[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]amino]ethyl]oxazolo[5,4-b]pyridin-6-yl]piperazine-1- carboxylate (25 mg, 39 μmol, 1 eq) in HCl / 1,4-dioxane (2 M, 0.2 mL) was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure directly to afford the title compound, which was used into the next step without further purification.

[0413] LCMS: 547.3 [M+H]+.

[0414] Intermediate-14: 2-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-ethyl-2-(2- methoxypyridin-4-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetic acid

[0415] Intermediate-15: 2-(5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-6-(piperazin-1- yl)oxazolo[4,5-b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetamide hydrochloride

[0416] Step 1. Synthesis of tert-butyl 4-(4-(2-ethoxy-2-oxoethyl)-5-ethyl-2-(2- methoxypyridin-4-yl)-7-oxo-4,7-dihydrooxazolo[4,5-b]pyridin-6-yl)piperazine-1-carboxylate

[0417] To a solution of tert-butyl 4-[5-ethyl-2-(2-methoxy-4-pyridyl)-7-oxo-4H-oxazolo[4,5- b] pyridin-6-yl] piperazine-1- carboxylate (Intermediate-2) (1.00 g, 2.20 mmol, 1 eq) and ethyl 2-bromoacetate (440 mg, 2.63 mmol, 292 μL, 1.2 eq) in dioxane (10 mL) was added DIEA (851 mg, 6.59 mmol, 1.15 mL, 3 eq). The mixture was stirred at 100°C for 0.5 h. The reaction mixture was diluted with H2O (200 mL) and extracted by EtOAc (250 mL * 2). The combined organic phase was washed with brine (100 mL * 1), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (Eluent of EtOAc / PE) to afford the title compound.

[0418] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (d, 1H), 7.60 (d, 1H), 7.37 (s, 1H), 5.23 (s, 2H), 4.21 (q, 2H), 3.94 - 3.85 (m, 5H), 3.63 (q, 2H), 2.95 - 2.58 (m, 4H), 2.59 - 2.56 (m, 2H), 1.43 (s, 9H), 1.23 (t, 3H), 1.11 (t, 3H).

[0419] LCMS: 542.2 [M+H]+.

[0420] Step 2. Synthesis of 2-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-ethyl-2-(2- methoxypyridin-4-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetic acid

[0421] To a solution of tert-butyl 4-[4-(2-ethoxy-2-oxo-ethyl)-5-ethyl-2-(2-methoxy-4- pyridyl)-7-oxo-oxazolo[4,5-b]pyridin-6-yl]piperazine-1-carboxylate (180 mg, 332 μmol, 1 eq) in EtOH (2 mL), THF (2 mL) and H2O (2 mL) was added LiOH.H2O (21 mg, 499 μmol, 1.5 eq). The mixture was stirred at 25 °C for 0.5 h. The mixture was adjusted pH to about 4 by addition of HCl (1M) dropwise at 25°C and the mixture was extracted with EtOAc (5 mL * 3). The combined organic phase was washed with brine (15 mL * 2), dried over anhydrous Na2SO4,filtered and concentrated in vacuum to afford the title compound, which was used into next step directly without further purification.

[0422] LCMS: 514.2 [M+H]+.

[0423] Step 3. Synthesis of tert-butyl 4-(5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-4-(2-oxo- 2-((3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)amino)ethyl)-4,7-dihydrooxazolo[4,5-b]pyridin- 6-yl)piperazine-1-carboxylate

[0424] To a solution of 2-[6-(4-tert-butoxycarbonylpiperazin-1-yl)-5-ethyl-2-(2-methoxy-4- pyridyl)-7-oxo-oxazolo[4,5-b] pyridin-4-yl] acetic acid (Intermediate-14) (180 mg, 294 μmol, 1 eq) and 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride salt (110 mg, 589 μmol, 2 eq) in DMF (2 mL) was added DIEA (114 mg, 883 μmol, 154 μL, 3 eq) and HATU (224 mg, 589 μmol, 2 eq). The mixture was stirred at 25 °C for 1 h. To the reaction mixture was added H2O (15 mL). Then the mixture was extracted with EtOAc (15 mL * 3). The combined organic phase was washed with brine (20 mL * 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (Eluent of EtOAc / PE) to afford the title compound.

[0425] LCMS: 647.3 [M+H]+

[0426] Step 4. Synthesis of 2-(5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-6-(piperazin-1- yl)oxazolo[4,5-b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetamide hydrochloride

[0427] A solution of tert-butyl 4-[5-ethyl-2-(2-methoxy-4-pyridyl)-7-oxo-4-[2-oxo-2-[[3- (trifluoromethyl)-1-bicyclo [1.1.1] pentanyl] amino] ethyl] oxazolo[4,5-b] pyridin-6-yl] piperazine-1-carboxylate (180 mg, 278 μmol, 1 eq) in HCl / dioxane (2 M, 3.6 mL, 26 eq) was stirred at 25 °C for 0.2 h. The mixture was concentrated in vacuum directly to afford the title compound, which was used into next step directly without further purification.

[0428] LCMS: 547.2 [M+H]+. Example 2: WRN (BV08) ADP-Glo assay protocol

[0429] 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 95°C for 5 minutes followed by slow cooling to room temperature. Compounds in 100% DMSO (0.1 pl) 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 pl) was added to columns 12, rows A-H and column 24, rows I-P for the maximum signal control. Compound NSC-617145 (0.1 pl) 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 pl 2X WRN (BV08), prepared as described below, in assay buffer containing 20 mM Bicine (pH = 7.5), 1 mM MgCL, 10 mM KC1, 0.1% Pluronic F- 127, 0.005% BSG, 1 mM TCEP. The reaction was initiated by the addition of 5 pl 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 pM 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 pM. 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)) x 100Where 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)AHill 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.WRN protein production

[0430] Molecular Biology and virus production. The DNA encoding human Werner helicase (Uniprot Q 14191 , amino acids 517-1235 with L1074F point mutation) was generated with codonoptimization for E.coli expression and subcloned into the pFastBac vector with a TEV cleavable8xHis tag (WRN-BV08). The baculovirus from the expression plasmid WRN-BV08 was generated from transfection and amplification following the manufacturer’s instructions.

[0431] Gene sequence of WRN-BV08 [pFastBacl-WRN-(517-1235 L1074F)-TEV-8His](SEQ ID NO.: 3)ATGAACGAGGGCGAAGAAGACGACGACAAGGACTTCCTGTGGCCTGCCCCTAACGAAGAACAAGTGACATGCCTGAAGATGTACTTCGGACACAGTAGCTTCAAGCCTGTGCAATGGAAGGTCATCCACTCCGTGCTGGAAGAAAGAAGGGACAACGTGGCTGTGATGGCTACCGGATACGGTAAGTCCCTGTGCTTCCAGTACCCTCCCGTGTACGTGGGCAAGATCGGTCTGGTGATCTCCCCTCTGATCTCTCTGATGGAGGACCAGGTGCTGCAATTGAAGATGTCCAACATCCCCGCTTGCTTCCTGGGTTCCGCTCAAAGTGAGAACGTGCTGACAGACATCAAGCTGGGCAAGTACCGCATCGTGTACGTGACCCCTGAGTACTGCTCCGGTAACATGGGTCTGCTGCAACAGCTGGAGGCTGACATCGGAATCACCCTGATCGCTGTGGACGAGGCTCACTGCATCTCCGAGTGGGGACACGACTTCCGCGACTCCTTCCGTAAGCTGGGATCCTTGAAGACCGCTCTCCCTATGGTGCCTATCGTGGCCCTGACCGCCACTGCTTCCTCCTCCATCCGCGAGGACATCGTGCGTTGCCTGAACCTGCGCAACCCTCAGATCACTTGCACCGGTTTCGACCGCCCTAACTTGTACCTCGAGGTGCGTCGCAAGACCGGTAACATCCTCCAGGACCTGCAGCCTTTCCTGGTCAAGACCTCCTCCCACTGGGAATTTGAGGGCCCTACCATCATCTACTGCCCTTCCCGCAAGATGACCCAGCAAGTCACCGGCGAGCTGCGCAAGCTCAACCTCTCCTGCGGTACCTACCACGCTGGTATGTCCTTCTCCACCCGCAAGGACATCCACCACCGCTTCGTCCGTGACGAAATCCAATGCGTCATCGCTACCATCGCTTTCGGAATGGGCATCAACAAGGCTGACATCCGCCAGGTGATCCACTACGGCGCCCCCAAGGACATGGAATCCTACTACCAGGAAATCGGTCGCGCCGGTCGCGACGGTCTGCAGTCTTCCTGTCACGTGCTGTGGGCCCCCGCTGACATCAACCTGAACCGCCACCTGCTGACCGAAATCCGCAACGAGAAGTTCCGCCTGTACAAGCTCAAGATGATGGCTAAGATGGAGAAGTACCTGCACTCCTCCCGCTGTCGCCGTCAGATCATCCTCTCCCACTTCGAGGACAAGCAAGTGCAAAAGGCTAGCCTGGGTATCATGGGCACCGAAAAGTGTTGTGACAACTGCCGCTCCCGCCTCGACCACTGCTACTCCATGGACGACAGCGAGGACACCTCCTGGGACTTCGGTCCTCAAGCTTTCAAGCTCTTGTCCGCTGTGGACATCCTGGGCGAGAAGTTCGGTATCGGTCTCCCCATCCTCTTCCTGCGTGGTAGCAACTCCCAACGCCTGGCTGACCAGTACCGCCGCCACTCCCTCTTCGGTACCGGT AAGGACCAGACCGAGTCCTGGTGGAAGGCTTTCTCTCGCCAACTGATCACCGAAGGTTTCCTGGTGGAGGTGTCCCGCTACAACAAGTTCATGAAGATCTGCGCTCTCACTAA GAAGGGAAGGAACTGGCTGCACAAGGCTAACACTGAGTCCCAATCCCTCATCCTGC AGGCTAACGAGGAGCTGTGCCCTAAGAAGTTCCTGCTGCCTTCCTCCAAGACCGTGT CCTCCGGAACAAAGGAACACTGCTACAACCAAGTCCCTGTGGAGCTCTCCACCGAG AAGAAGTCCAACCTGGAGAAGCTGTACAGCTACAAGCCTTGCGACAAGATCAGCTC CGGTTCCAACATCAGCAAGAAGTCCATCATGGTGCAATCCCCTGAAAAGGCCTACTC CAGCTCCCAACCTGTCATCTCCGCTCAAGAGCAAGAGACCCAGATCGTGCTGTACGG TAAGCTGGTCGAAGCCCGCCAAAAGCACGCTAACAAGATGGACGTCCCTCCCGCTA TCCTCGCCACCAACAAGATCCTCGTGGATATGGCTAAGATGCGCCCCACCACCGTCG AGAACGTGAAGCGCATCGACGGTGTCTCCGAGGGTAAGGCCGCTATGCTGGCTCCT CTGCTGGAAGTGATCAAGCACTTCTGCCAGACCAACTCCGTGCAGACCGACCTGTTC AGTAGTGAGAACCTGTACTTCCAAGGCCACCATCATCATCATCATCACCACTAA

[0432] Protein sequence of WRN-BV08 [pFastBacl-WRN-(517-1235 L1074F)-TEV-8His] (SEQ ID NO.: 4)MNEGEEDDDKDFLWPAPNEEQVTCLKMYFGHSSFKPVQWKVIHSVLEERRDNVAVMA TGYGKSLCFQYPPVYVGKIGLVISPLISLMEDQVLQLKMSNIPACFLGSAQSENVLTDIKL GKYRIVYVTPEYCSGNMGLLQQLEADIGITLIAVDEAHCISEWGHDFRDSFRKLGSLKTA LPMVPIVALT AT AS S SIREDIVRCLNLRNPQITCTGFDRPNL YLEVRRKTGNILQDLQPFL VKTSSHWEFEGPTIIYCPSRKMTQQVTGELRKLNLSCGTYHAGMSFSTRKDIHHRFVRD EIQCVIATIAFGMGINKADIRQVIHYGAPKDMESYYQEIGRAGRDGLQSSCHVLWAPADI NLNRHLLTEIRNEKFRLYKLKMMAKMEKYLHSSRCRRQIILSHFEDKQVQKASLGIMGT EKCCDNCRSRLDHCYSMDDSEDTSWDFGPQAFKLLSAVDILGEKFGIGLPILFLRGSNSQ RLADQYRRHSLFGTGKDQTESWWKAFSRQLITEGFLVEVSRYNKFMKICALTKKGRNW LHKANTESQSLILQANEELCPKKFLLPSSKTVSSGTKEHCYNQVPVELSTEKKSNLEKLY SYKPCDKISSGSNISKKSIMVQSPEKAYSSSQPVISAQEQETQIVLYGKLVEARQKHANK MDVPPAILATNKILVDMAI<MRPTTVENVI<RIDGVSEGI<AAMLAPLLEVII<HFCQTNSV QTDLF S SENLYFQGHHHHHHHH

[0433] S19 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, ImM PMSF,1 jj.g / ml Leupeptin, I pg / ml Pepstatin, and the Pierce Universal Nuclease and cocktail tablet. Cleared lysates were loaded onto a Ni Sepharose™ excel 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. ZnCh was added into the sample at final 15pM before loading onto a second Ni Sepharose™ excel 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 mMNaCl. 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).

[0434] The resultant IC50 results obtained for the tested compounds are shown below in Table 3. Compounds with an IC50 less than or equal to 0.005 pM are designated as “A.” Compounds with an IC50 greater than 0.005 pM and less than or equal to 0.05 pM are designated as “B.” Compounds with an IC50 greater than 0.05 pM and less than or equal to 0.1 pM are designated as “C.” Compounds with an IC50 greater than 0.1 pM or equal to 0.5 pM are designated as “D ” Table 3Cmpd. No. ADP-Glo_hWRN_IC50 [pM]1-1 A1-2 A1-3 B1-4 B1-5 AExample 3: Method for determining effect on p21 induction in cells.

[0435] 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 30pL of culture mediawere 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 cpds was lOuM 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 40pL of 4% paraformaldehyde solution to each well and incubated for 20 min at room temperature. The plate was then washed 4 times with lOOpL per well of wash buffer (PBS with 0.1% Tween- 20) using a microplate washer. Next, 30pL 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 lOOpL per well of wash buffer by a microplate washer, then 30pL per well of blocking buffer ((Intercept PBS blocking buffer (LI-COR 927-70001) with 0.05% Tween-20)) was added and the plate was incubated at room temperature with shaking for 2h. Next, to each test well, 20pL of primary antibody solution ((p21 Wafl / 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 lOOpL per well of wash buffer using a microplate washer for 5 min. 20pL 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 lOOpL 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 was generated after non-linear regression curve fitting using commercially available software.

[0436] The resultant EC50 results obtained for the tested compounds are shown below in Table 4. Compounds with an EC50 less than or equal to 0.50 pM are designated as “A.” Compoundswith an EC50 greater than 0.50 pM and less than or equal to 2.00 pM are designated as “B.” Compounds with an EC50 greater than 2.00 pM and less than or equal to 5.00 pM are designated as “C ” Compounds with an EC so greater than 5.00 pM are designated as “D ”Table 4Cmpd. No. P21_EC50 [pM]1-1 A1-2 A1-3 C1-4 D1-5 A

Claims

CLAIMSWe claim:A compound of Formula I”, or a pharmaceutically acceptable salt thereof:R2Rt wherein Ring A represents: a) a 4-7 membered saturated or partially unsaturated bivalent monocyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or b) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene and heterocyclylene (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein Ring A is substituted with 0-4 independently selected RAsubstituents; each of Y and Z is selected from N and O, wherein Y is N and Z is O or Y is O and Z is N, - denotes a single or double bond, and the 5-membered ring comprising Z and Y is aromatic;HNX z0 ^S'L is a linker selected from -C(O)-, -S(O)-, -S(O)2-, andR1is selected from one of groups a) to e): a) a 5-6 membered monocyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1-3 groups independently selected from halogen, Ci-Cealkyl, haloCi-Cealkyl, Cs-Cecycloalkyl, Ci-Cealkoxy, and C3- Cecycloalkoxy, wherein said 5-6 membered monocyclic heteroaryl is further substituted with 0-3 independently selected RA;b) a 9-10 membered bicyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1 or 2 groups independently selected from C1-C6aliphatic, C3-C6cycloalkyl, C1-C6alkoxy, and C3-C6cycloalkoxy, wherein said 9-10 membered bicyclic heteroaryl is further substituted with 0-3 independently selected RA; c) 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-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, and C3-C6cycloalkoxy, and -OR, wherein said 4-7 membered saturated or partially unsaturated monocyclic heterocyclyl is further substituted with 0-3 independently selected RA; d) a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl and heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected RA; and e) H, halogen, C1-C6aliphatic, C3-C7cycloalkyl, C1-C6alkylene-O-C1-C6alkyl, -CN, -OR, - NR10R11, -C(O)NR10R11,-CH2NR10R11, -SO2R12, wherein the C1-C6aliphatic, C3- C7cycloalkyl, or C1-C6alkylene-O-C1-C6alkyl is substituted with 0-5 independently selected RA; R10is H, C1-C6aliphatic, haloC1-C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, –C(O)C3- C6cycloalkyl, –C(O)C1-C6alkyl, or 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 RA; R11is H, C1-C6aliphatic, or C3-C6cycloalkyl, or R10and R11may combine 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) optionally substituted with 1 or 2groups independently selected from halogen, C1-C6aliphatic, haloC1-C6alkyl, C1-C6alkoxy, C3- C6cycloalkyl, and C3-C6cycloalkoxy; RAis 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, hydroxy-C1-C6alkyl, haloC1- C6alkyl, an optionally substituted 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; R2is selected from C(RB)2C(O)N(R)R2A, C(RB)2C(RB)2C(O)N(R)R2A, C(RB)2C(RB)2N(R)C(O) N(R)R2A, and C(RB)2C(RB)2N(R)C(O)R2A; RBis independently selected at each occurrence from hydrogen, -CH3, and -CH2CH3, or two RBtaken together with the carbon to which they are attached form a cyclopropyl ring; 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 contains 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-C6cycloalkoxy, haloC3-C6- cycloalkoxy and –SF5; or two substituents on adjacent atoms of the phenyl or pyridyl together with said adjacent atoms form a 4-7 membered carbocyclyl fused to the phenyl or pyridyl; or two substituents on adjacent atoms of the phenyl or pyridyl together with said adjacent atoms 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 4-7 membered carbocyclyl or 4-7 membered heterocyclyl is substituted with 0-5 independently selected halogen, and wherein 2 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 unsaturated carbocyclyl, and ^ an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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-C4aliphatic, haloC1-C4alkyl, and - OH; R3is hydrogen, C1-C4aliphatic, C3-C5cycloalkyl, C1-C4alkoxy, -NHR3A, -N(R3A)2, or C1- C4alkylthio, each of which, besides hydrogen, is optionally substituted with -OH, 1-5 independently selected halogen, -OR, -C(O)NR10R11, or N(R)C(O)R; each R3Ais independently selected at each occurrence from C1-C4alkyl; R4is phenyl or a first 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) wherein said phenyl or said first 5-6 membered heteroaryl are substituted with 0-5 RAor two substituents on adjacent atoms of said phenyl or said first 5-6 membered heteroaryl together with said adjacent atoms form a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl, or a second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to the phenyl or first 5-6 membered heteroaryl wherein said 4-7 membered carbocyclyl, 4-7 membered heterocyclyl, or second 5-6 membered heteroaryl are substituted with 0-3 RA; or R4is a C1-C4alkyl, C1-C4alkoxy, or C3-C6cycloalkyl, each of which is substituted with 0-3 groups independently selected from halogen, -CN, -OH, oxo, NH2, C1-C4alkyl, C1-C4alkoxy, optionally substituted 5-6 membered heterocyclyl, and optionally substituted 5-6 membered heterocyclyloxy;each R is independently hydrogen, or an optionally substituted Ci-ealiphatic 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 an optionally substituted 4-7 membered saturated ring, 4-7 membered partially unsaturated ring, or 5-6 membered heteroaryl ring (wherein said 4-7 membered saturated ring and 4-7 membered partially unsaturated ring has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and wherein said 5-6 membered heteroaryl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

2. A compound of Formula I, or a pharmaceutically acceptable salt thereof: wherein Ring A represents: a) a 4-7 membered saturated or partially unsaturated bivalent monocyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or b) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene and heterocyclylene (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein Ring A is substituted with 0-4 independently selected RAsubstituents; each of Y and Z is selected from N and O, wherein Y is N and Z is O or Y is O and Z is N, - denotes a single or double bond, and the 5-membered ring comprising Z and Y is aromatic;L is a linker selected from -C(O)-, -S(O)-, -S(O)2-, and ; R1is selected from one of groups a) to e): a) a 5-6 membered monocyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1-3 groups independently selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, and C3- C6cycloalkoxy, wherein said 5-6 membered monocyclic heteroaryl is further substituted with 0-3 independently selected RA; b) a 9-10 membered bicyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1 or 2 groups independently selected from C1-C6aliphatic, C3-C6cycloalkyl, C1-C6alkoxy, and C3-C6cycloalkoxy, wherein said 9-10 membered bicyclic heteroaryl is further substituted with 0-3 independently selected RA; c) 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-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, and C3-C6cycloalkoxy, and -OR, wherein said 4-7 membered saturated or partially unsaturated monocyclic heterocyclyl is further substituted with 0-3 independently selected RA; d) a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl and heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected RA; and e) H, halogen, C1-C6aliphatic, C3-C7cycloalkyl, C1-C6alkylene-O-C1-C6alkyl, -CN, -OR, - NR10R11, -C(O)NR10R11, -CH2NR10R11, -SO2R12, wherein the C1-C6aliphatic, C3- C7cycloalkyl, or C1-C6alkylene-O-C1-C6alkyl is substituted with 0-5 independently selected RA;R10is H, C1-C6aliphatic, haloC1-C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, –C(O)C3- C6cycloalkyl, –C(O)C1-C6alkyl, or 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 RA; R11is H, C1-C6aliphatic, or C3-C6cycloalkyl, or R10and R11may combine 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) optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1-C6alkyl, C1-C6alkoxy, C3- C6cycloalkyl, and C3-C6cycloalkoxy; RAis 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, hydroxy-C1-C6alkyl, haloC1- C6alkyl, an optionally substituted 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; R2is C(RB)2C(O)N(R)R2A; RBis independently selected at each occurrence from hydrogen, -CH3, and -CH2CH3, or two RBtaken together with the carbon to which they are attached form a cyclopropyl ring; 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-C6cycloalkyl, haloC3- C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, and –SF5; or two substituents on adjacent atoms of the phenyl or pyridyl together with said adjacent atoms form a 4-7 membered carbocyclylfused to the phenyl or pyridyl; or two substituents on adjacent atoms of the phenyl or pyridyl together with said adjacent atoms 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 4-7 membered carbocyclyl or 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-C4aliphatic, haloC1-C4alkyl, and - OH; R3is hydrogen, C1-C4aliphatic, C3-C5cycloalkyl, C1-C4alkoxy, -NHR3A, -N(R3A)2, or C1- C4alkylthio, each of which, besides hydrogen, is optionally substituted with -OH, 1-5 independently selected halogen, -OR, -C(O)NR10R11, or N(R)C(O)R; each R3Ais independently selected at each occurrence from C1-C4alkyl; R4is phenyl or a first 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) wherein said phenyl or said first 5-6 membered heteroaryl are substituted with 0-5 RAor two substituents on adjacent atoms of said phenyl or said first 5-6 membered heteroaryl together with said adjacent atoms form a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl, or a second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to the phenyl or first 5-6 membered heteroaryl wherein said 4-7 membered carbocyclyl, 4-7 membered heterocyclyl, or second 5-6 membered heteroaryl are substituted with 0-3 RA; or R4is a C1-C4alkyl, C1-C4alkoxy, or C3-C6cycloalkyl, each of which is substituted with 0-3 groups independently selected from halogen, -CN, -OH, oxo, NH2, C1-C4alkyl, C1-C4alkoxy, optionally substituted 5-6 membered heterocyclyl, and optionally substituted 5-6 membered heterocyclyloxy; 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); ortwo R groups on the same atom are taken together with the same atom to form an optionally substituted 4-7 membered saturated ring, 4-7 membered partially unsaturated ring, or 5-6 membered heteroaryl ring (wherein said 4-7 membered saturated ring and 4-7 membered partially unsaturated ring has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and wherein said 5-6 membered heteroaryl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, of one of the following formulas: wherein:R4is selected from one of a), b), and c): a) R4is a Ring B that is selected from the group consisting of: wherein * is a point of attachment to L that is bonded to Ring A in Formula I or I”, wherein L is-C(O)-; and wherein:any substituents that are present on Ring B selected from R4A, R4B, R4C, R4D, R4E, and R4Fare each independently selected from hydrogen; halogen; -OH; -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 optionally substituted carbocyclyl, 4-7 membered optionally substituted heterocyclyl, or 5-6 membered optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring B; and any substituents that are present on Ring B selected from R4C, R4D, R4E, and R4Fare each independently selected from hydrogen; halogen; -OH; -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 4-7 membered optionally substituted carbocyclyl, 4-7 membered optionally substituted heterocyclyl, or 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring B; and any substituents that are present on Ring B selected from R4A, R4D, R4E, and R4Fare each independently selected from hydrogen; halogen; -OH; -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 optionally substituted carbocyclyl, 4-7 membered optionally substituted heterocyclyl, or 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring B; and any substituents that are present on Ring B selected from R4A, R4B, R4Eand R4Fare each independently selected from hydrogen; halogen; -OH; -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; orR4Eis 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 optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring B; and R4B, R4C, and R4Dare each independently selected from hydrogen; halogen; -OH; -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 optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring B; and any substituents that are present on Ring B selected from R4B, R4C, and R4Dare each independently selected from hydrogen; halogen; -OH; -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 R14is hydrogen; or NR13R14forms a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, said heterocyclic ring optionally substituted with -CH3; or b) 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; or c) 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, and optionally substituted 5-6 membered heterocyclyloxy.

4. The compound of any one of claims 1-3, wherein the compound is of one of the following formulas: or VII-a VII-b or a pharmaceutically acceptable salt thereof.

5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from: , , , , , , , , , , and ; and wherein Ring A is substituted with 0-4 independently selected RAsubstituents.

6. The compound of any one of claims 1-5, wherein R1is halogen, C1-C6 alkyl, C2-C4 alkene, C2-C4 alkyne, CN, -OR10, -NR10R11, –C(O)NR10R11, –CH2NR10R11, –SO2R12, or a 3-7 membered carbocyclyl, wherein C1-C6alkyl, C2-C4alkene, C2-C4alkyne, and 3-7 membered carbocyclyl are substituted with 0-3 substituents independently selected from halogen, C3-C6cycloalkyl, haloC3- C6cycloalkyl, -OH, -CN, C1-C4alkoxy, and haloC1-C4alkoxy.

7. The compound of any one of claims 1-5, wherein R1is a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1-3 groups independently selected from halogen, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6alkoxy, and C3-C6cycloalkyl, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RA.

8. The compound of any one of claims 1-5, wherein R1is pyridyl substituted with C1- C4alkoxy and further substituted with 0-2 RA.

9. The compound of any one of claims 1-5, wherein R1is 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 substituted with a halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, or C3-C6cycloalkyl, and further substituted with 0-2 independently selected RA.

10. The compound of any one of claims 1-5, wherein R1is c) a 5-6 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), said heterocyclyl substituted with 0-2 groups 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; or d) 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 groups 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.

11. The compound of any one of claims 1-5, wherein R1is a 5-6 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), said heterocyclyl substituted with 0-2 groups 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.

12. The compound of any one of claims 1-5, wherein R1is selected from the group consisting of:, , , , , , , , , , , , , , , , , , , , , and .

13. The compound of any one of claims 1-12, wherein R4is Ring B of the following structure: , , , or wherein * is a point of attachment to L in Formula I; R4Ais hydrogen, halogen, -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; R13is independently selected at each occurrence from hydrogen and C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; and R14is hydrogen; or R13and R14are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl; wherein the heterocyclic ring is optionally substituted with -CH3; orR4is 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.

14. The compound of any one of claims 1-12, wherein R4is: or wherein * is a point of attachment to L in Formula I; wherein: R4Ais 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; R13is independently selected at each occurrence from hydrogen and C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; and R14is hydrogen; or R13and R14are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl; wherein the heterocyclic ring is optionally substituted with -CH3.

15. The compound of any one of claims 1-12, wherein 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.

16. The compound of any one of claims 1-12, wherein 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) selected from the group consisting of 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 substituted with 0-4 groups independently selected from halogen, -OH, -CN, C1-C4alkyl, haloC1-C4alkyl, C3- C6cycloalkyl, and C1-C4alkoxy.

17. The compound of claim 16, wherein R4is an isoxazolyl substituted with -OH or C1- C4alkoxy.

18. The compound of any one of claims 1-12, wherein R4is , , , , , , , , , , , , , , HO , -CH3, -CF3, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,, , , , , , , , , , , , , , or .

19. The compound of any one of claims 1-18, wherein R2Ais phenyl comprising a -CF3 substituent or pyridyl comprising a -CF3 substituent.

20. The compound of any one of claims 1-18, wherein R2is .

21. The compound of claim 1, or any one of claims 3-18, wherein R2is .

22. The compound of any one of claims 1-21, wherein R3is C1-C4alkyl or C3-C5cycloalkyl.

23. The compound of any one of claims 1-3 and 6-22, wherein Ring A and the 0-4 independently selected RAsubstituents with which Ring A is substituted are selected from24. The compound of any one of claims 1-3 and 6-22, wherein Ring A and the 0-4 independently selected RAsubstituents with which Ring A is substituted, is:

25. The compound of any one of claims 1-3 and 5-22, wherein Ring A is:

26. The compound of any one of claims 1-3 and 5-22, wherein Ring A is:

27. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)piperazin-l-yl)-2-(2-methoxypyridin-4-yl)-7-oxooxazolo[4,5- b]pyridin-4(7H)-yl)acetamide.

28. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof according to any one of claims 1- 27, and one or more pharmaceutically acceptable carriers.

29. A method of treating cancer in a subject, 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 according to any one of claims 1-27, or a pharmaceutically acceptable salt thereof.

30. A method of modulating WRN activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound according to any one of claims 1-27, or a pharmaceutically acceptable salt thereof.

31. A method of treating a disorder or disease which can be treated by WRN inhibition in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound according to any one of claims 1-27, or a pharmaceutically acceptable salt thereof.

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

33. The method of claim 31, wherein the disorder or disease is a cancer characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

34. The method of claim 33, 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.

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