WRN inhibitors

Abstract

The present disclosure is directed to compounds of 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

WRN INHIBITORSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of Provisional Application No. 63 / 613,656, filed December 21, 2023; and Provisional Application No. 63 / 660,951, filed June 17, 2024; the entireties of which are incorporated herein by reference.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 December 19, 2024, is named 407274-87WRWO_215143_SL.xml and is 9,769 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. ICO 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 (MSLH) 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 MSLH-dMMR metastatic colorectal cancer (CRC) which resultedin 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 and chromosome 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:L"RA4B cI wherein bicyclic Ring BC, linker L, R4, 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 earners.

[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 of the Invention:

[0016] In one aspect, the disclosure provides a compound of Formula I that is a compound ofFormula F, or a pharmaceutically acceptable salt thereof:r wherein:X1and X2are independently selected from N, C, and CH, provided that only one of X1and X2is N;W and V are independently selected from N and C; andR16, R17, X1, and X2combine to form Ring B fused to Ring C, wherein Ring B is 5-6 membered heteroaryl or 5-6 membered partially unsaturated heterocyclyl, said heteroaryl or heterocyclyl comprising 0, 1, 2, or 3, ring heteroatoms independently selected from O, S, N, and NR18; wherein Ring B is substituted with Rlaand z instances of Rlb;Ring C is selected from the group consisting of:wherein denotes the points of attachment to R16and R17, and ** denotes the point of attachment to Ring A; of Ring C denotes a single bond or a double bond;R18is H or optionally substituted C1-C6aliphatic; z is 0, 1, or 2; each Rlbgroup is independently selected from H, halogen, CN, OH, oxo, C1-C6aliphatic, C1- Cealkoxy, C3-C6cycloalkyl, C1-Cal6kylene-O-C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and C3-C6cycloalkoxy wherein said C1-C6aliphatic, Ca1-lkCo6xy, C3-C6cycloalkyl, alCky1-lCen6e-O- C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and Ca-Cecycloalkoxy are each independently and optionally substituted with 1-5 halogen, OH, CN, Ca1l-kCy6l, or C3-C6cycloalkyl groups; provided that when Ring B is a 5 membered ring then z is 0 or 1;Ring A is: a) a 4-7 membered saturated or partially unsaturated bivalent monocyclic carbocyclylene or 4-7 membered saturated or partially unsaturated bivalent monocyclic heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 nitrogen atoms in addition to the 1-4 heteroatoms); or b) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene or heterocyclylene (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein Ring A is substituted with 0-4 independently selected RBsubstituents;-L- is a linker selected fromRlais selected from; a) 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-C6aliphatic, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkoxy, and C3- Cecycloalkoxy, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RB; b) a 4-7 membered saturated or partially unsaturated monocyclic heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionallysubstituted with 1 or 2 groups independently selected from C1-C6aliphatic, C3- Cecycloalkyl, C1-C6alkoxy, C3-C6cycloalkoxy and -OR, wherein said 4-7 membered saturated or partially unsaturated heterocyclyl is further substituted with 0-3 independently selected RB; c) a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected RB; and d) H, halogen, C1-C6aliphatic, C3-C6cycloalkyl, C1-Cal6kylene-O-C1-C6alkyl, CN, -OR, - OR10, -NR10Rn, -C(O)NR10Rn-CH2NR10Rn, or -SO2R12, wherein said C1-C6aliphatic, C3-C?cycloalkyl, or C1-C6alkylene-O-C1-C6alkyl is substituted with 0-5 independently selected RB; or Rlaand one Rlbattached to adjacent atoms of Ring B, taken together with the adjacent atoms of ring Ring B, form a cyclic group fused to Ring B selected from phenyl, a 5-6 membered heteroaryl (having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), a 4-7 membered saturated or partially unsaturated carbocyclyl, or a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), wherein said cyclic group fused to Ring B is substituted with 0-3 independently selected RB;R2is selected from C(Rc)2C(O)N(R)R2A, C(Rc)2C(Rc)2C(O)N(R)R2A, C(Rc)2C(Rc)2N(R)C(O) N(R)R2A, and C(Rc)2C(Rc)2N(R)C(O)R2A;R2Ais cubanyl, a saturated or partially unsaturated 4-8 membered monocyclic ring, a saturated or partially unsaturated bridged, fused or spirocyclic 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, wherein said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring comprises 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said cubanyl, saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring are each optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4aliphatic, haloC1-C4alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, C3-C6cycloalkoxy haloC4-C6cyclalkoxy and -SFs, and wherein two optionalsubstituents on the same atom of said saturated or partially unsaturated monocyclic ring, or said saturated or partially unsaturated bridged, fused or spirocyclic ring form a cyclic group selected from:• an optionally substituted 3-7 membered saturated or partially 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;R3is hydrogen, C1-C4aliphatic, Cg-Cscycloalkyl, 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)NR10Rn, or N(R)C(O)R; each R3Ais independently selected 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 first 5-6 membered heteroaryl is substituted with 0-5 RB; and optionally two adjacent atoms of said phenyl or first 5-6 membered heteroaryl have two substituents that together with said adjacent atoms form a cyclic group fused to the phenyl or first 5-6 membered heteroaryl selected from a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or a second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said fused cyclic group is substituted with 0-3 independently selected RB; orR4is a C1-C4aliphatic, C1-C4alkoxy, or C3-C6cycloalkyl, each of which is substituted with 0-3 groups independently selected from halogen, -CN, -OH, C1-C4alkyl, C1-C4alkoxy, optionally substituted 5-6 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 5-6 membered heterocyclyloxy having 1- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R10is H, C1-C6aliphatic, haloC1-C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, -C(O)C1-Cealkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur); each R10except H being optionally substituted with 1 or 2 independently selected RB;R11is H, C1-C6aliphatic, or Cs-Cgcycloalkyl, or R10and R11are taken together with the nitrogen atom to which they are attached to form a 5-6 membered ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, -OH, -CN, C1-C4alkoxy, and haloC1- C4alkoxy;R12is C1-C6aliphatic, C3-C6cycloalkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R12optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1-C6alkyl, alkCox1-yC,6C3-C6cycloalkyl, and C3-C6cycloalkox;yRtiis independently selected at each occurrence from the group consisting of optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogen, optionally substituted C1-C6aliphatic, haloC1-C6alkyl, C3- Cecycloalkyl, haloC3-C6cycloalkyl, C1-Ca6lkoxy, haloC1-C6alkoxy, C3-Cscycloalkoxy, haloC3- Cecycloalkoxy, C1-C6alkylene-O-C1-C6alkyl, -CN, -NO2, oxo, OR, SR, NR2, S(O)2R, S(O)2NR2, S(O)R, S(O)NR2, C(O)R, C(O)OR, -C(O)NR2, C(O)N(R)OR, OC(O)R, OC(O)NR2, - N(R)C(O)OR, N(R)C(O)R,N(R)C(O)NR2, N(R)C(NR)NR2, N(R)S(O)2NR2, and -N(R)S(O)2R; or two RBgroups on the same atom are taken together with the same atom together to form a 3-7 membered carbocyclic ring;Rcis independently selected at each occurrence from hydrogen, -CH3, or -CH2CH3, or two Rctaken together with the carbon to which they are attached form a cyclopropyl ring; each R is independently hydrogen, or an optionally substituted C1-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); ortwo R groups on the same atom are taken together with the same atom to form a cyclic group selected from an optionally substituted 4-7 membered saturated ring, a 4-7 membered partially unsaturated ring, or a 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said cyclic group has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0017] In one aspect, the disclosure provides a compound of Formula I that is a compound ofFormula I”, or a pharmaceutically acceptable salt thereof:R4w-' R3R2I" wherein:X1and X2are independently selected from N, C, and CH, provided that only one of X1and X2is N;W and V are independently selected from N and C; andR16, R17, X1, and X2combine to form Ring B fused to Ring C, wherein Ring B is 5-6 membered heteroaryl or 5-6 membered partially unsaturated heterocyclyl, said heteroaryl or heterocyclyl containing 0, 1, 2, or 3, ring heteroatoms independently selected from O, S, N, and NR18; wherein Ring B is substituted with Rlaand z instances of Rlb;Ring C is selected from the group consisting of:wherein denotes the points of attachment to R16and R17, and ** denotes the point of attachment to Ring A;■■ ••• of Ring C denotes a single bond or a double bond;R18is H or optionally substituted C1-C6aliphatic; z is 0, 1, or 2; each Rlbgroup is independently selected from H, halogen, CN, OH, oxo, C1-C6aliphatic, C1- Cealkoxy, C3-C6cycloalkyl, C1-Cal6kylene-O-C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and C3-C6cycloalkoxy wherein said C1-C6aliphatic, Ca1-lkCo6xy, C3-C6cycloalkyl, alCky1-lCen6e-O- C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and Ca-Cecycloalkoxy are each independently and optionally substituted with 1-5 halogen, OH, CN, Ca1l-kCy6l, or C3-C6cycloalkyl groups; provided that when Ring B is a 5 membered ring then z is 0 or 1;Ring A is: a) a 4-7 membered saturated or partially unsaturated bivalent monocyclic carbocyclylene or 4-7 membered saturated or partially unsaturated bivalent monocyclic heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 nitrogen atoms in addition to the 1-4 heteroatoms); orb) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene or heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein Ring A is substituted with 0-4 independently selected RBsubstituents;HNX / OX-L- is a linker selected from -C(O)-, -C(O)C(R)2-, -C(R)2C(O)-, -S(O)-, -S(O)2-, andRlais selected from; a) 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-C6aliphatic, C3-C6cycloalkyl, haloC1-C6alkyl, alCk1o-xCy6, and Cg-Cecycloalkoxy, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RB; b) a 4-7 membered saturated or partially unsaturated monocyclic heterocyclyl (having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6aliphatic, C3- Cecycloalkyl, C1-C6alkoxy, C3-C6cycloalkoxy, and -OR, wherein said 4-7 membered saturated or partially unsaturated heterocyclyl is further substituted with 0-3 independently selected RB; c) a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected RB; and d) H, halogen, C1-C6aliphatic, C3-C?cycloalkyl, Ca1l-kCy6lene-O-C1-C6alkyl, CN, -OR, - OR10, -NR10Rn, -C(O)NR10Rn-CH2NR10Rn, or -SO2R12, wherein said C1- Cealiphatic, C3-C?cycloalkyl, or C1-Cal6kylene-O-C1-C6alkyl is substituted with 0-5 independently selected RB; or Rlaand one Rlbattached to adjacent atoms of Ring B, taken together with the adjacent atoms of ring Ring B, form a cyclic group fused to Ring B selected from phenyl, a 5-6 membered heteroaryl (having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), a 4-7membered saturated or partially unsaturated carbocyclyl, or a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), wherein said cyclic group fused to Ring B is substituted with 0-3 independently selected RB;R2is selected from C(Rc)2C(O)N(R)R2A, C(Rc)2C(Rc)2C(O)N(R)R2A, C(Rc)2C(Rc)2N(R)C(O) N(R)R2A, and C(Rc)2C(Rc)2N(R)C(O)R2A;R2Ais cubanyl, a saturated or partially unsaturated 3-8 membered monocyclic ring, a saturated or partially unsaturated bridged, fused or spirocyclic 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, wherein said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring comprises 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said cubanyl, saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring are each optionally substituted with 1, 2, or 3 substituents independently selected from optionally substituted phenyl, halogen, optionally substituted C1-C4aliphatic, haloC1-C4alkyl, Cs-Ce- cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, Cg-Cecycloalkoxy, haloC4-C6cyclalkoxy and -SFs, and wherein two optional substituents on the same atom of said saturated or partially unsaturated monocyclic ring, or said saturated or partially unsaturated bridged, fused or spirocyclic ring form a cyclic group selected from:• an optionally substituted 3-7 membered saturated or partially 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;R3is hydrogen, C1-C4aliphatic, Cg-Cscycloalkyl, 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)NR10Ru, or N(R)C(O)R; each R3Ais independently selected 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 first 5-6 membered heteroaryl is substituted with 0-5 RB; and optionally two adjacent atoms of said phenyl or first 5-6 memberedheteroaryl have two substituents that together with said adjacent atoms form a cyclic group fused to the phenyl or first 5-6 membered heteroaryl selected from a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or a second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said fused cyclic group is substituted with 0-3 independently selected RB; orR4is a C1-C4aliphatic, C1-C4alkoxy, or C3-C6cycloalkyl, each of which is substituted with 0-3 groups independently selected from halogen, -CN, -OH, C1-C4alkyl, C1-C4alkoxy, optionally substituted 5-6 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 5-6 membered heterocyclyl oxy having 1 - 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R10is H, C1-C6aliphatic, haloC1-C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, -C(O)C1- Cealkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R10except H being optionally substituted with 1 or 2 independently selected RB;R11is H, C1-C6aliphatic, or C3-C6cycloalkyl, or R10and R11are taken together with the nitrogen atom to which they are attached to form a 5-6 membered ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, -OH, -CN, C1-C4alkoxy, and haloC1- C4alkoxy;R12is C1-C6aliphatic, C3-C6cycloalkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R12optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1-C6alkyl, alkCox1-yC,6C3-C6cycloalkyl, and Ca-Cecycloalkoxy;RBis independently selected at each occurrence from the group consisting of optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogen, optionally substituted C1-C6aliphatic, haloC1-C6alkyl, Ca- Cecycloalkyl, haloC3-C6cycloalkyl, C1-Ca6lkoxy, haloC1-C6alkoxy, C3-C6cycloalkoxy haloCa-Cecycloalkoxy, C1-C6alkylene-O-C1-C6alkyl, -B(OR)2, -CN, -NO2, oxo, -OR, -SR, NR2, S(O)2R, S(O)2NR2, S(O)R, S(O)NR2, C(O)R, C(O)OR, -C(O)NR2, C(O)N(R)OR, OC(O)R, OC(O)NR2, -N(R)C(O)OR, N(R)C(O)R,N(R)C(O)NR2, N(R)C(NR)NR2, N(R)S(O)2NR2, and -N(R)S(O)2R; or two RBgroups on the same atom are taken together with the same atom together to form a 3-7 membered carbocyclic ring;Rcis independently selected at each occurrence from hydrogen, -CH3, or -CH2CH3, or two Rctaken together with the carbon to which they are attached form a cyclopropyl ring; each R is independently hydrogen, or an optionally substituted C1-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 a cyclic group selected from an optionally substituted 4-7 membered saturated ring, a 4-7 membered partially unsaturated ring, or a 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said cyclic group has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0018] In one embodiment, the disclosure provides a compound of Formula F, or a pharmaceutically acceptable salt thereof, wherein bicyclic Ring BC is selected from the group consisting of:wherein denotes the point of attachment to Ring A; wherein each R,bgroup is independently selected from H, halogen, CN, OH, C1-C6aliphatic, C1- Cealkoxy, C3-C6cycloalkyl, C1-Cal6kylene-O-C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and C3-C6cycloalkoxy wherein said C1-C6aliphatic, Ca1-lkCo6xy, C3-C6cycloalkyl, alCky1-lCen6e-O- C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and Ca-Cecycloalkoxy are each independently andoptionally substituted with 1-5 halogen, OH, CN, Ca1l-kCy6l, or C3-C6cycloalkyl groups; wherein z is 0, 1, or 2;Ring A is: a) a 4-7 membered saturated or partially unsaturated bivalent monocyclic carbocyclylene or 4-7 membered saturated or partially unsaturated bivalent heterocyclylene ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 nitrogen atoms in addition to the 1-4 heteroatoms); or b) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene or heterocyclylene (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein Ring A is substituted with 0-4 independently selected RBsubstituents;-L- is a linker selected fromRlais selected from; a) 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-C6aliphatic, Cg-Cscycloalkyl, haloC1-C6alkyl, C1-C6alkoxy, and Cg- Cficycloalkoxy, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RB; b) a 4-7 membered saturated or partially unsaturated monocyclic heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6aliphatic, Cg- Cecycloalkyl, C1-C6alkoxy, Cg-Cecycloalkoxy, and -OR, wherein said 4-7 membered saturated or partially unsaturated heterocyclyl is further substituted with 0-3 independently selected RB; c) a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl or heterocyclyl (having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected RB; and d) H, halogen, C1-C6aliphatic, C3-C6cycloalkyl, C1-Cal6kylene-O-C1-C6alkyl, CN, -OR, - OR10, -NR10Rn, -C(O)NR10Rn-CH2NR10Rn, or -SO2R12, wherein said C1-C6aliphatic, Ca-Cvcycloalkyl, or C1-C6alkylene-O-C1-C6alkyl is substituted with 0-5 independently selected RB; or Rlaand one Rlbon adjacent atoms of Ring B, taken together with the adjacent atoms of Ring B form a cyclic group fused to Ring B selected from phenyl, a 5-6 membered heteroaryl (having 1- 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), a 4-7 membered saturated or partially unsaturated carbocyclyl, or a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), wherein said cyclic group fused to Ring B is substituted with 0-3 independently selected RB;R2is selected from C(Rc)2C(O)N(R)R2A, C(Rc)2C(Rc)2C(O)N(R)R2A, C(Rc)2C(Rc)2N(R)C(O) N(R)R2A, and C(Rc)2C(Rc)2N(R)C(O)R2A;R2Ais cubanyl, a saturated or partially unsaturated 4-8 membered monocyclic ring, a saturated or partially unsaturated bridged, fused or spirocyclic 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, wherein said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring comprises 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said cubanyl, saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring are each optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4aliphatic, haloC1-C4alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, C3-C6cycloalkoxy, haloC4-C6cyclalkoxy and -SFs, and wherein two optional substituents on the same atom of said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring form a cyclic group selected from: an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl, andan optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R3is hydrogen, C1-C4aliphatic, Ca-Cscycloalkyl, 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)NR10Rn, or N(R)C(O)R; each R3Ais independently selected 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 first 5-6 membered heteroaryl is substituted with 0-5 RB; and optionally two adjacent atoms of said phenyl or first 5-6 membered heteroaryl have two substituents that together with said adjacent atoms form a cyclic group fused to the phenyl or first 5-6 membered heteroaryl selected from a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or a second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said fused cyclic group is substituted with 0-3 independently selected RB; orR4is a C1-C4aliphatic, C1-C4alkoxy, or C3-C6cycloalkyl, each of which is substituted with 0-3 groups independently selected from halogen, -CN, -OH, C1-C4alkyl, C1-C4alkoxy, optionally substituted 5-6 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 5-6 membered heterocyclyloxy having 1- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R10is H, C1-C6aliphatic, haloC1-C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, -C(O)C1- Cealkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R10except H being optionally substituted with 1 or 2 independently selected RB;R11is H, C1-C6aliphatic, or C3-C6cycloalkyl, or R10and R11are taken together with the nitrogen atom to which they are attached to form a 5-6 membered ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, -OH, -CN, C1-C4alkoxy, and haloC1- C4alkoxy;R12is C1-C6aliphatic, C3-C6cycloalkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R12optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1-C6alkyl, alkCox1-yC,6C3-C6cycloalkyl, and C3-C6cycloalkox;yRBis independently selected at each occurrence from the group consisting of optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogen, optionally substituted C1-C6aliphatic, haloC1-C6alkyl, C3- Cecycloalkyl, haloC3-C6cycloalkyl, C1-Ca6lkoxy, haloC1-C6alkoxy, Cg-Cecycloalkoxy, haloCg- Cecycloalkoxy, C1-C6alkylene-O-C1-C6alkyl, -CN, -NO2, oxo, -OR, -SR, NR2, S(O)2R, S(O)2NR2, S(O)R, S(O)NR2, C(O)R, C(O)OR, -C(O)NR2, C(O)N(R)OR, OC(O)R, OC(O)NR2, - N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR2, N(R)C(NR)NR2, N(R)S(O)2NR2, and -N(R)S(O)2R;Rcis independently selected at each occurrence from hydrogen, -CH3, or -CH2CH3, or two Rctaken together with the carbon to which they are attached form a cyclopropyl ring; each R is independently hydrogen, or an optionally substituted C1-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 a cyclic group selected from an optionally substituted 4-7 membered saturated ring, a 4-7 membered partially unsaturated ring, or a 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said cyclic group has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0019] In one embodiment, the disclosure provides a compound of Formula I”, or a pharmaceutically acceptable salt thereof, wherein bicyclic Ring BC is selected from the group consisting of:wherein denotes the point of attachment to Ring A; wherein each R,bgroup is independently selected from H, halogen, CN, OH, C1-C6aliphatic, C1- Cealkoxy, C3-C6cycloalkyl, C1-Cal6kylene-O-C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and C3-C6cycloalkoxy wherein said C1-C6aliphatic, Ca1-lkCo6xy, C3-C6cycloalkyl, alCky1-lCen6e-O- C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and Ca-Cecycloalkoxy are each independently and optionally substituted with 1-5 halogen, OH, CN, Ca1l-kCy6l, or C3-C6cycloalkyl groups; wherein z is 0, 1, or 2;Ring A is: a) a 4-7 membered saturated or partially unsaturated bivalent monocyclic carbocyclylene or 4-7 membered saturated or partially unsaturated bivalent heterocyclylene ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 nitrogen atoms in addition to the 1-4 heteroatoms); or b) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene or heterocyclylene (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein Ring A is substituted with 0-4 independently selected RBsubstituents;-L- is a linker selected fromRlais selected from;a) 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-C6aliphatic, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkoxy, and C3- Cecycloalkoxy, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RB; b) a 4-7 membered saturated or partially unsaturated monocyclic heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6aliphatic, C3- Cecycloalkyl, C1-C6alkoxy, C3-C6cycloalkoxy, and -OR, wherein said 4-7 membered saturated or partially unsaturated heterocyclyl is further substituted with 0-3 independently selected RB; c) a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected RB; and d) H, halogen, C1-C6aliphatic, Cs-Cycycloalkyl, C1-Cal6kylene-O-C1-C6alkyl, CN, -OR, - OR10, -NR10Rn, -C(O)NR10R11, -CH2NR10R11, or -SO2R12, wherein said C1-C6aliphatic, C3-C?cycloalkyl, or C1-C6alkylene-O-C1-C6alkyl is substituted with 0-5 independently selected RB; or Rlaand one Rlbon adjacent atoms of Ring B, taken together with the adjacent atoms of Ring B form a cyclic group fused to Ring B selected from phenyl, a 5-6 membered heteroaryl (having 1- 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), a 4-7 membered saturated or partially unsaturated carbocyclyl, or a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), wherein said cyclic group fused to Ring B is substituted with 0-3 independently selected RB;R2is selected from C(Rc)2C(O)N(R)R2A, C(Rc)2C(Rc)2C(O)N(R)R2A, C(Rc)2C(Rc)2N(R)C(O) N(R)R2A, and C(Rc)2C(Rc)2N(R)C(O)R2A;R2Ais cubanyl, a saturated or partially unsaturated 3-8 membered monocyclic ring, a saturated or partially unsaturated bridged, fused or spirocyclic 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring,wherein said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring comprises 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said cubanyl, saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring are each optionally substituted with 1, 2, or 3 substituents independently selected from optionally substituted phenyl, halogen, optionally substituted C1-C4aliphatic, haloC1-C4alkyl, Cg-Ce- cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, Cg-Cecycloalkoxy, haloC4-C6cyclalkoxy and -SF5, and wherein two optional substituents on the same atom of said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring form a cyclic group selected from: an optionally substituted 3-7 membered saturated or partially 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;R3is hydrogen, C1-C4aliphatic, Cg-Cscycloalkyl, 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 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 first 5-6 membered heteroaryl is substituted with 0-5 RB; and optionally two adjacent atoms of said phenyl or first 5-6 membered heteroaryl have two substituents that together with said adjacent atoms form a cyclic group fused to the phenyl or first 5-6 membered heteroaryl selected from a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or a second 5-6 membered heteroaiyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said fused cyclic group is substituted with 0-3 independently selected RB; orR4is a C1-C4aliphatic, C1-C4alkoxy, or C3-C6cycloalkyl, each of which is substituted with 0-3 groups independently selected from halogen, -CN, -OH, C1-C4alkyl, C1-C4alkoxy, optionallysubstituted 5-6 membered heterocyclyl having 1 -3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 5-6 membered heterocyclyloxy having 1- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R10is H, C1-C6aliphatic, haloC1-C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, -C(O)C1- Cealkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R,(1except H being optionally substituted with 1 or 2 independently selected RB;R11is H, C1-C6aliphatic, or C3-C6cycloalkyl, or R10and R11are taken together with the nitrogen atom to which they are attached to form a 5-6 membered ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, -OH, -CN, C1-C4alkoxy, and haloC1- C4alkoxy;R12is C1-C6aliphatic, C3-C6cycloalkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R12optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, andC3-C6cycloalkoxyRBis independently selected at each occurrence from the group consisting of optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl (having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogen, optionally substituted C1-C6aliphatic, haloC1-C6alkyl, C3- Cecycloalkyl, haloC3-C6cycloalkyCl,1-C6alkoxy, haloC1-C6alkoxy, C3-C6cycloalkoxy, haloCg- Cecycloalkoxy, C1-C6alkylene-O- C1-C6alkyl, -B(0R)2, -CN, -NO2, oxo, -OR, -SR, NR2, S(O)2R, S(O)2NR2, S(O)R, S(O)NR2, C(O)R, C(O)OR, -C(O)NR2, C(O)N(R)OR, OC(O)R, OC(O)NR2, -N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR2, N(R)C(NR)NR2, N(R)S(O)2NR2, and - N(R)S(O)2R;Rcis independently selected at each occurrence from hydrogen, -CH3, or -CH2CH3, or two Rctaken together with the carbon to which they are attached form a cyclopropyl ring; each R is independently hydrogen, or an optionally substituted C1-ealiphatic 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 a cyclic group selected from an optionally substituted 4-7 membered saturated ring, a 4-7 membered partially unsaturated ring, or a 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said cyclic group has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[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.2. Compounds and Definitions:

[0021] 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 .

[0022] Compound structures shown throughout the present specification and in the examples or claims contain designations at certain stereocenters. Stereocenters marked with “abs” intend to cover material wherein the marked stereocenter is of the stereochemistry shown in the diagram. Stereocenters marked with “&1” or “andl” indicate that the compound material has a mixture of R and S-configured stereoisomers with respect to the marked stereocenter and is in the same relative configuration to each other if they share the same label such as “andl” or “&1” as in Example I-2a.

[0023] The term “aliphatic” or “aliphatic group,” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0024] 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 C1-12 straight or branched saturated aliphatic group. In certain instances, alkyl refers to a C1-s straight or branched saturated aliphatic group or a C1-6 straight or branched saturated aliphatic group. The term “lower alkyl” refers to a C1.4 straight or branched alkyl group.

[0025] 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 referredto interchangeably herein as 2-butyl, iBu, 'Bu and i-Bu) and tert-butyl (also referred to interchangeably herein as 2-methyl-2 -butyl, tBu,lBu and t-Bu).

[0026] The term “alkenyl” refers to a C2-12 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon double bond. In certain instances, alkenyl refers to a C2-8 or a C2-6 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon double bond. The term “lower alkenyl” refers to a C2-4 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon double bond. Alkenyl groups include both cis (Z) and trans (E) regioisomers. Exemplary lower alkenyl groups are vinyl, allyl, 2-propenyl, and butenyl isomers (-CH2CH2CH=CH2, - CH2CH=CHCH3and -CH=CHCH2CH3).

[0027] 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 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon triple bond. Exemplary lower alkynyl groups are ethynyl, 1-propynyl, 2-propynyl, 1- butynyl, 2-butynyl, and 3-butynyl.

[0028] 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.

[0029] 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-2 / f-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl).

[0030] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.

[0031] The term “cubanyl” refers to a substituent of cubane as shown below.

[0032] The substituent -Me, as used herein refers to a methyl group, -CHa.

[0033] As used herein, the term “bivalent C1-8 (or C1-6 i.e., )C s1a-tCu6rated or unsaturated, straight or branched, hydrocarbon chain,” refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0034] 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. Nonlimiting examples include

[0035] “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.Different examples Different examples cyclopropyl l b l

[0036] A carbocyclylene may be saturated as in the examples shown above or partially unsaturated as in the examples shown below.

[0037] 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 carbocyclylenesfused bicyclic carbocyclylenes bridged bicyclic carbocyclylenes

[0038] “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.Heterocy clylene 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 heterocyclylenesfused bicyclic heterocyclylenes bridged bicyclic heterocyclylenes

[0039] “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.% / wxr ww

[0040] “Arylene” as used herein refers to a mono or multi-cyclic aryl (i.e., phenyl or a multicyclic 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.

[0041] “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.

[0042] 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 bridged, fused or spirocyclic ring comprises 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur” refers to bicyclic, tricyclic, or tetracyclic bridged, fused or spirocyclic 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered rings, wherein one ring of said multicyclic ring system may be an aryl ring and the other ring(s) of the multicyclic ring system may be unsaturated or partially unsaturated. Representative examples include:

[0043] 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.

[0044] “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 carboncarbon 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 NHunsaturated heterocyclyl fused to the phenyl, i.e."heterocyclyl fused to phenyl fl

[0045] A further example below shows a carbocyclyl moiety fused to a Ring E as defined in the embodiments herein. Said carbocyclyl does not explicitly require a descriptor of “partially unsaturated” to describe said carbocyclyl because it shares two carbons with the aromatic pyridine to which it is fused. Such language is used herein to describe such systems, for example, “R4Aand R4B, along with their intervening atoms, join to form 4-7 membered carbocyclyl that is fused to Ring E” as shown in the image below. As such, “Ring E” may refer to a monocyclic ring (i.e., the pyridine shown below and its substituents which do not form a fused ring), without any further fused rings created by its substituents (i.e., R4Aand R4B). Any further fused ring created by the substituents of Ring E is described as being “fused to Ring E.” Likewise, R4Aand R4B, along with their intervening atoms, join to form 4-7 membered carbocyclyl or heterocyclyl (having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring E (not pictured), is subject to the same interpretation. mberedca ocyclyl that isRing E fused to Ring E

[0046] 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.

[0047] The term “halogen" means F, Cl, Br, or I.

[0048] The term “aryl" used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy," or aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system comprises 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl" refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0049] 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]pyri din-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, 477- 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.

[0050] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. Said 7-10-membered bicyclic heterocyclic moiety that is partially unsaturated may include an aryl or heteroaryl ring fused to a non-aromatic ring. For example, said 7-10-membered bicyclic heterocyclic moiety may include a bicyclic heterocyclyl as shown below:When used in 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-2J7-pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in TV-substituted pyrrolidinyl).

[0051] 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, 3 / / indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclyl alkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0052] “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.

[0053] “Heterocyclyloxy,” as used herein, refers to an -OR group wherein the R is a heterocyclyl. Nonlimiting examples are shown below.

[0054] 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.

[0055] 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.

[0056] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)o4B(OR°)2; -(CH2)O4RO; -(CH2)Q_40RO; - 0(CH2)O-4R°; -0-(CH2)O4C(O)ORO; -(CH2)O 4CH(ORO)2; -(CH2)O 4SRO; -(CH2)O 4Ph. which may 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°; -NO2; -CN; -N3; -(CH2)0_4N(R°)2; -(CH2)0 4N(R°)C(O)R°; -N(R°)C(S)R°;(CH2)o4N(R°)C(0)NRO2; -N(RO)C(S)NR°2; -(CH2)O4N(R°)C(O)ORO; -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(R°)2; (CH2)O-4C(0)R°;C(S)R°; (CH2)o4C(O)ORO; ~(CH2)O4C(O)SR°: (CH2)O4C(O)OSiR°3; -(CH2)o4OC(O)R°;OC(0)(CH2)O4SRO; -(CH2)O4SC(O)RO; -(CH2)O4C(O)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°; -(CI I2)(i 4SSR°; -(CH2)O 4S(O)2RO; -(CH2)O4S(O)2ORO; -(CII2)0 4OS(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(0)2RO; -(CH2)O-4P(0)R°2; -(CH2)O40P(0)RO2; -(CH2)O4OP(O)(OR°)2; -SiR°3; -(CI4straight 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, Ci6 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 0-4heteroatoms 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.

[0057] 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)o2R*, -(haloR*), -(CH2)o2OH, -(CH2)O2OR*, -(CH2)O2CH(OR*)2; -O(haloR*), -CN, -N3, -(CH2)02C(O)Re, -(CH2)O 2C(O)OH, -(CH2)O 2C(O)OR*, -(CH2)O 2SR*, -(CH2)O 2SH, -(CH2)O 2NH2, - (CH2)O2NHR*, -(CH2)O-2NR*2, -NO2, -SiR*3, -OSiR*3, -C(O)SR* -(C1-4 straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-6 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.

[0058] 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(O)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 ealiphatic 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)23O-, wherein each independent occurrence of R* is selected from hydrogen, C1-ealiphatic 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.

[0059] Suitable ssuubbssttiittuueennttss on the aliphatic group ooff 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 oneor more halogens, and is independently C1-4aliphatic, -CH2PI1, -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.

[0060] Suitable substituents on a substitutable nitrogen of an “optionally substituted" group include -C(O)CH2C(O)Rt, -S(O)2Rt,wherein each R;is independently hydrogen, C1-ealiphatic 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 R\ taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0061] Suitable substituents on the aliphatic group of R;are independently halogen, -R’, -(haloR*), -OH, -OR’, -O(haloR’), -CN, -C(O)OH, -C(O)OR’, -NH2, -NHR’, -NR’2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4aliphatic, -CH2PI1, -O(CH2)Q iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0062] 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, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0063] 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.

[0064] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, Z and E conformational isomers and Ra (or M) and Sa(or P) atropisomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. In certain embodiments, Ring A of a provided compound may be substituted with one or more deuterium atoms.

[0065] 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:

[0066] In one aspect, the disclosure provides a compound of Formula I that is a compound ofFormula F : or a pharmaceutically acceptable salt thereof:I’ wherein X1and X2are independently selected from N and C, provided that only one of X1and X2may be N; W and V are independently selected from N and C; R16, R17, X1and X2combine to form Ring B which is selected from a 5 -6 membered heteroaryl ring or a 5 -6 membered partially saturated heterocyclic ring wherein said Ring B contains 0, 1, 2 or 3, heteroatoms independently selected from O, S and N and wherein Ring B is substituted with one Rlaand Ring B is optionally substituted with 0, 1, or 2 instances of Rlb; Ring C is selected fromwherein denotes the point of attachment to R16, R17, and Ring A; wherein each Rlbgroup is independently selected from H, halogen, CN, OH, oxo, C1-C6aliphatic, C1-C6alkoxy, C3-C6cycloalkyl, C1-Ca6lkylene-O-C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy,and C3-C6cycloalkoxy, wherein said C1-C6aliphatic, Ca1l-kCo6xy, C3-C6cycloalkyl, C1- Cealkylene-O-C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and C3-C6cycloalk aorxey each independently and optionally substituted with 1-5 halogen, OH, CN, aClk1-yCl,6or C3- Cecycloalkyl groups; provided that when Ring B is a 5 membered ring then Rlbis 0 or 1;Ring A is: a) a 4-7 membered saturated or partially unsaturated bivalent monocyclic carbocyclylene or 4-7 membered saturated or partially unsaturated bivalent heterocyclylene ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 nitrogen atoms in addition to the 1-4 heteroatoms); or b) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene or heterocyclylene (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein Ring A is substituted with 0-4 independently selected RBsubstituents;HNS / O ;st-L- is a linker selected from -C(O)-, -S(O)-, -S(O)2-, andRlais selected from; a) 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-C6aliphatic, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkoxy, and C3- Cecycloalkoxy, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RB; b) a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6aliphatic, C3-C6cycloalkyl, aClk1-oCx6y, C3- Cecycloalkoxy, and -OR, wherein said 4-7 membered saturated or partially unsaturated heterocyclyl is further substituted with 0-3 independently selected RB;c) a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected RB; and d) H, halogen, C1-C6aliphatic, C3-C6cycloalkyl, C1C6kylene-O-C1-C6alkyl, CN, -OR, - OR10, -NR10Rn, -C(O)NR,0Rn-CH2NR,0Rn, or -S-O2R12, wherein said C1-C6aliphatic, Ca-Cvcycloalkyl, or C1-C6alkylene-O-C1-C6alkyl is substituted with 0-5 independently selected RB; or Rlaand one Rlbattached to adjacent atoms of Ring B, taken together with the adjacent Ring B atoms to which they are attached, form a cyclic group fused to Ring B selected from phenyl, a 5- 6 membered heteroaryl (having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), a 4-7 membered saturated or partially unsaturated carbocyclyl, or a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), wherein said cyclic group fused to Ring B is substituted with 0-3 independently selected RB;R2is selected from C(Rc)2C(O)N(R)R2A, C(Rc)2C(Rc)2C(O)N(R)R2A, C(Rc)2C(Rc)2N(R)C(O) N(R)R2A, and C(Rc)2C(Rc)2N(R)C(O)R2A;R2Ais cubanyl, a saturated or partially unsaturated 4-8 membered monocyclic ring, a saturated or partially unsaturated bridged, fused or spirocyclic 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, wherein said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring comprises 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said cubanyl, saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring 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-Cecycloalkoxy, haloC4-C6cyclalkoxy and -SF5, and wherein two optional substituents on the same atom of said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring form a cyclic group selected from:an optionally substituted 3-7 membered saturated or partially 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;R3is hydrogen, C1-C4aliphatic, Cg-Cscycloalkyl, 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)NR10Rn, or N(R)C(O)R; each R3Ais independently selected 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 first 5-6 membered heteroaryl is substituted with 0-5 RB; and optionally two adjacent atoms of said phenyl or first 5-6 membered heteroaryl have two substituents that together with said adjacent atoms form a cyclic group fused to the phenyl or first 5-6 membered heteroaryl selected from a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or a second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said fused cyclic group is substituted with 0-3 independently selected RB; orR4is a C1-C4aliphatic, C1-C4alkoxy, or C3-C6cycloalkyl, each of which is substituted with 0-3 groups independently selected from halogen, -CN, -OH, C1-C4alkyl, C1-C4alkoxy, optionally substituted 5-6 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 5-6 membered heterocyclyloxy having 1- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R10is H, C1-C6aliphatic, haloC1-C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, -C(O)C1- Cealkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R10except H being optionally substituted with 1 or 2 independently selected RB;R11is H, C1-C6aliphatic, or C1-cCy6cloalkyl, or R10and R11are taken together with the nitrogen atom to which they are attached to form a 5-6 membered ring optionally substituted with 1, 2, or3 substituents independently selected from halogen, -OH, -CN, C1-C4alkoxy, and haloC1- C4alkoxy;R12is C1-C6aliphatic, C3-C6cycloalkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R12optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1-C6alkyl, alkCox1-yC,6C3-C6cycloalkyl, and C3-C6cycloalkox;yRBis independently selected at each occurrence from the group consisting of optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogen, optionally substituted C1-C6aliphatic, haloC1-C6alkyl, C3- Cecycloalkyl, haloC3-C6cycloalkyl, C1-Ca6lkoxy, haloC1-C6alkoxy, C3-C6cycloalkoxy haloCs- Cecycloalkoxy, C1-C6alkylene-O-C1-C6alkyl, -CN, -NO2, oxo, -OR, -SR, NR2, S(O)2R, S(O)2NR2, S(O)R, S(O)NR2, C(O)R, C(O)OR, -C(O)NR2, C(O)N(R)OR, OC(O)R, OC(O)NR2, - N(R)C(O)OR, N(R)C(O)R,N(R)C(O)NR2, N(R)C(NR)NR2, N(R)S(O)2NR2, and -N(R)S(O)2R;Rcis independently selected at each occurrence from hydrogen, -CH3, or -CH2CH3, or two Rctaken together with the carbon to which they are attached form a cyclopropyl ring; each R is independently hydrogen, or an optionally substituted C1-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 a cyclic group selected from an optionally substituted 4-7 membered saturated ring, a 4-7 membered partially unsaturated ring, or a 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said cyclic group has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0067] In one aspect, the disclosure provides a compound of Formula I that is a compound ofFormula I”: or a pharmaceutically acceptable salt thereof:I" wherein X1and X2are independently selected from N and C, provided that only one of X1and X2may be N; W and V are independently selected from N and C; R16, R17, X1and X2combine to form Ring B which is selected from a 5 -6 membered heteroaryl ring or a 5 -6 membered partially saturated heterocyclic ring wherein said Ring B contains 0, 1, 2 or 3, heteroatoms independently selected from O, S and N and wherein Ring B is substituted with one Rlaand Ring B is optionally substituted with 0, 1, or 2 instances of Rlb; Ring C is selected fromwherein denotes the point of attachment to R16, R17, and Ring A; wherein each Rlbgroup is independently selected from H, halogen, CN, OH, oxo, C1-C6aliphatic, C1-C6alkoxy, C3-C6cycloalkyl, C1-C6alkylene-O-C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and C3-C6cycloalkoxy, wherein said C1-C6aliphatic, C3-C6cycloalkyl , C1- Cealkylene-O-C1-C6alkyl, halo C1-C6alkyl, haloC1-C6alkoxy, and C3-C6cycloalkox,y are eachindependently and optionally substituted with 1 -5 halogen, OH, CN, aClk1-yCl,6or C3- Cecycloalkyl groups; provided that when Ring B is a 5 membered ring then Rlbis 0 or 1;Ring A is: a) a 4-7 membered saturated or partially unsaturated bivalent monocyclic carbocyclylene or 4-7 membered saturated or partially unsaturated bivalent heterocyclylene ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 nitrogen atoms in addition to the 1-4 heteroatoms); or b) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene or heterocyclylene (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein Ring A is substituted with 0-4 independently selected RBsubstituents;-L- is a linker selected fromRlais selected from: a) 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-C6aliphatic, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkoxy, and C3- Cecycloalkoxy, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RB; b) a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6aliphatic, Cj-Cecycloalkyl, Cal1k-oCx6y, C3- Cecycloalkoxy, and -OR, wherein said 4-7 membered saturated or partially unsaturated heterocyclyl is further substituted with 0-3 independently selected RB; c) a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl or heterocyclyl (having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected RB; and d) H, halogen, C1-C6aliphatic, C3-C6cycloalkyl, C1-Cal6kylene-O-C1-C6alkyl, CN, -OR, - OR10, -NR10Rn, -C(O)NR10Rn-CH2NR10Rn, or -SO2R12, wherein said C1-C6aliphatic, Ca-Cvcycloalkyl, or C1-C6alkylene-O-C1-C6alkyl is substituted with 0-5 independently selected RB; or Rlaand one Rlbattached to adjacent atoms of Ring B, taken together with the adjacent Ring B atoms to which they are attached, form a cyclic group fused to Ring B selected from phenyl, a 5- 6 membered heteroaryl (having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), a 4-7 membered saturated or partially unsaturated carbocyclyl, or a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), wherein said cyclic group fused to Ring B is substituted with 0-3 independently selected RB;R2is selected from C(Rc)2C(O)N(R)R2A, C(Rc)2C(Rc)2C(O)N(R)R2A, C(Rc)2C(Rc)2N(R)C(O) N(R)R2A, and C(Rc)2C(Rc)2N(R)C(O)R2A;R2Ais cubanyl, a saturated or partially unsaturated 3-8 membered monocyclic ring, a saturated or partially unsaturated bridged, fused or spirocyclic 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, wherein said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring comprises 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said cubanyl, saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring are each optionally substituted with 1, 2, or 3 substituents independently selected from optionally substituted phenyl, halogen, optionally substituted C1-C4aliphatic, haloC1-C4alkyl, C3-C6- cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, C3-C6cycloalkoxy haloC4-C6cyclalkoxy and -SF5, and wherein two optional substituents on the same atom of said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring form a cyclic group selected from: an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl, andan optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R3is hydrogen, C1-C4aliphatic, Ca-Cscycloalkyl, 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)NR10Rn, or N(R)C(O)R; each R3Ais independently selected 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 first 5-6 membered heteroaryl is substituted with 0-5 RB; and optionally two adjacent atoms of said phenyl or first 5-6 membered heteroaryl have two substituents that together with said adjacent atoms form a cyclic group fused to the phenyl or first 5-6 membered heteroaryl selected from a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or a second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said fused cyclic group is substituted with 0-3 independently selected RB; orR4is a C1-C4aliphatic, C1-C4alkoxy, or C3-C6cycloalkyl, each of which is substituted with 0-3 groups independently selected from halogen, -CN, -OH, C1-C4alkyl, C1-C4alkoxy, optionally substituted 5-6 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 5-6 membered heterocyclyloxy having 1- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R10is H, C1-C6aliphatic, haloC1-C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, -C(O)C1- Cealkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R10except H being optionally substituted with 1 or 2 independently selected RB;R11is H, C1-C6aliphatic, or C3-C6cycloalkyl, or R10and R11are taken together with the nitrogen atom to which they are attached to form a 5-6 membered ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, -OH, -CN, C1-C4alkoxy, and haloC1- C4alkoxy;R12is C1-C6aliphatic, C3-C6cycloalkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R12optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1-C6alkyl, alkCox1-yC,6C3-Cecycloalkyl, and C3-C6cycloalkox;yRBis independently selected at each occurrence from the group consisting of optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogen, optionally substituted C1-C6aliphatic, haloC1-C6alkyl, C3- Cecycloalkyl, haloC3-C6cycloalkyl, C1-Ca6lkoxy, haloC1-C6alkoxy, Cg-Cecycloalkoxy, haloCg- Cecycloalkoxy, C1-C6alkylene-O-C1-C6alkyl, -B(OR)2, -CN, -NO2, oxo, -OR, -SR, NR2, S(O)2R, S(O)2NR2, S(O)R, S(O)NR2, C(O)R, C(O)OR, -C(O)NR2, C(O)N(R)OR, OC(O)R, OC(O)NR2, -N(R)C(O)OR, N(R)C(O)R,N(R)C(O)NR2, N(R)C(NR)NR2, N(R)S(O)2NR2, and -N(R)S(O)2R;Rcis independently selected at each occurrence from hydrogen, -CH3, or -CH2CH3, or two Rctaken together with the carbon to which they are attached form a cyclopropyl ring; each R is independently hydrogen, or an optionally substituted C1-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 a cyclic group selected from an optionally substituted 4-7 membered saturated ring, a 4-7 membered partially unsaturated ring, or a 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said cyclic group has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0068] In one embodiment, the disclosure provides a compound of Formula F:or a pharmaceutically acceptable salt thereof, wherein bicyclic Ring BC is selected from one of the following:wherein denotes the point of attachment to Ring A; wherein each Rlbgroup is independently selected from H, halogen, CN, OH, C1-C6aliphatic, C1- Cealkoxy, C3-C6cycloalkyl, C1-Cal6kylene-O-C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and Cg-Cecycloalkoxy, wherein said C1-C6aliphatic, C1-C6alkoxy, C3-C6cycloalkyl, alCky1-lCen6e-O- C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and Ca-Cecycloalkoxy are each independently and optionally substituted with 1-5 halogen, OH, CN, Ca1l-kCy6l, or C3-C6cycloalkyl groups; wherein z is 0, 1 or 2;Ring A is: a) a 4-7 membered saturated or partially unsaturated bivalent monocyclic carbocyclylene or 4-7 membered saturated or partially unsaturated bivalent heterocyclylene ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 nitrogen atoms in addition to the 1-4 heteroatoms); or b) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene or heterocyclylene (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein Ring A is substituted with 0-4 independently selected RBsubstituents;-L- is a linker selected fromRlais selected from; a) 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-C6aliphatic, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkoxy, and C3- Cecycloalkoxy, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RB; b) a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6aliphatic, Ca-Cecycloalkyl, aClk1o-Cxy6, C3- Cecycloalkoxy, and -OR, wherein said 4-7 membered saturated or partially unsaturated heterocyclyl is further substituted with 0-3 independently selected RB; c) a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected RB; and d) H, halogen, C1-C6aliphatic, Cs-Cvcycloalkyl, C1-Cal6kylene-O-C1-C6alkyl, CN, -OR, - OR10, -NR10Rn, -C(O)NR10Rn-CH2NR10Rn, or -SO2R12, wherein said C1-C6aliphatic, Cg-Cvcycloalkyl, or C1-C6alkylene-O-C1-C6alkyl is substituted with 0-5 independently selected RB; or Rlaand one Rlbon adjacent atoms of Ring B, taken together with the adjacent Ring B atoms to which they are attached, form a cyclic group fused to Ring B selected from phenyl, a 5-6 membered heteroaryl (having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), a 4- 7 membered saturated or partially unsaturated carbocyclyl, or a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), wherein said cyclic group fused to Ring B is substituted with 0-3 independently selected RB;R2is selected from C(Rc)2C(O)N(R)R2A, C(Rc)2C(Rc)2C(O)N(R)R2A, C(Rc)2C(Rc)2N(R)C(O) N(R)R2A, and C(Rc)2C(Rc)2N(R)C(O)R2A;R2Ais cubanyl, a saturated or partially unsaturated 4-8 membered monocyclic ring, a saturated or partially unsaturated bridged, fused or spirocyclic 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, wherein said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring comprises 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said cubanyl, saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring are each optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4aliphatic, haloC1-C4alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, C3-C6cycloalkoxy, haloC4-Cecyclalkoxy and -SFs, and wherein two optional substituents on the same atom of said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring form a cyclic group selected from;• an optionally substituted 3-7 membered saturated or partially 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;R3is hydrogen, C1-C4aliphatic, Ca-Cscycloalkyl, 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 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 first 5-6 membered heteroaryl is substituted with 0-5 RB; and optionally two adjacent atoms of said phenyl or first 5-6 membered heteroaryl have two substituents that together with said adjacent atoms form a cyclic group fused to the phenyl or first 5-6 membered heteroaryl selected from a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or a second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur); wherein said fused cyclic group is substituted with 0-3 independently selected RB; orR4is a C1-C4aliphatic, C1-C4alkoxy, or C3-C6cycloalkyl, each of which is substituted with 0-3 groups independently selected from halogen, -CN, -OH, C1-C4alkyl, C1-C4alkoxy, optionally substituted 5-6 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 5-6 membered heterocyclyloxy having 1- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R10is H, C1-C6aliphatic, haloC1-C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, -C(O)C1- Cealkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R10except H being optionally substituted with 1 or 2 independently selected RB;R11is H, C1-C6aliphatic, or C3-C6cycloalkyl, or R10and R11are taken together with the nitrogen atom to which they are attached to form a 5-6 membered ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, -OH, -CN, C1-C4alkoxy, and haloC1- C4alkoxy;R12is C1-C6aliphatic, C3-C6cycloalkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R12optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1-C6alkyl, alkCox1-yC,6C3-C6cycloalkyl, and C3-C6cycloalkoxyRBis independently selected at each occurrence from the group consisting of optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogen, optionally substituted C1-C6aliphatic, haloC1-C6alkyl, Cg- Cecycloalkyl, haloC3-C6cycloalkyl, C1-Ca6lkoxy, haloC1-C6alkoxy, Cg-Cscycloalkoxy, haloCg- Cecycloalkoxy, C1-C6alkylene-O-C1-C6alkyl, -CN, -NO2, oxo, -OR, -SR, NR2, S(O)2R, S(O)2NR2, S(O)R, S(O)NR2, C(O)R, C(O)OR, -C(O)NR2, C(O)N(R)OR, OC(O)R, OC(O)NR2, - N(R)C(O)OR, N(R)C(O)R,N(R)C(O)NR2, N(R)C(NR)NR2, N(R)S(O)2NR2, and -N(R)S(O)2R; or two RBtaken together with the carbon to which they are attached form a 3-7 membered saturated carbocyclic ring;Rcis independently selected at each occurrence from hydrogen, -CH3, or -CH2CH3, or two Rctaken together with the carbon to which they are attached form a cyclopropyl ring; each R is independently hydrogen, or an optionally substituted C1-ealiphatic group, an optionally substituted phenyl, aann ooppttiioonnaallllyy ssuubbssttiittuutteedd 33--77 mmeemmbbeerreedd ssaattuurraatteedd or partially unsaturated carbocyclic ring, aann ooppttiioonnaallllyy ssuubbssttiittuutteedd 33--77 mmeemmbbeerreedd ssaattuurraatteedd or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or two R groups on the same atom are taken together with the same atom to form a cyclic group selected from an optionally substituted 4-7 membered saturated ring, a 4-7 membered partially unsaturated ring, or a 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said cyclic group has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0069] In one embodiment, the disclosure provides a compound of Formula I” : or a pharmaceutically acceptable salt thereof, wherein bicyclic Ring BC is selected from one of the following:wherein denotes the point of attachment to Ring A; wherein each Rlbgroup is independently selected from H, halogen, CN, OH, C1-C6aliphatic, C1- Cealkoxy, C3-C6cycloalkyl, C1-Cal6kylene-O-C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and Cg-Cecycloalkoxy, wherein said C1-C6aliphatic, C1-C6alkoxy, C3-C6cycloalkyl, alCky1-lCen6e-O- C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and Ca-Cecycloalkoxy are each independently andoptionally substituted with 1-5 halogen, OH, CN, Ca1l-kCy6l, or C3-C6cycloalkyl groups; wherein z is 0, 1 or 2;Ring A is: a) a 4-7 membered saturated or partially unsaturated bivalent monocyclic carbocyclylene or 4-7 membered saturated or partially unsaturated bivalent heterocyclylene ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 nitrogen atoms in addition to the 1-4 heteroatoms); or b) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene or heterocyclylene (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein Ring A is substituted with 0-4 independently selected RBsubstituents;-L- is a linker selected fromRlais selected from; a) 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-C6aliphatic, Cg-Cscycloalkyl, haloC1-C6alkyl, C1-C6alkoxy, and Cg- Cficycloalkoxy, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RB; b) a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6aliphatic, C3-C6cycloalkyl, aClk1o-Cxy6, C3- Cecycloalkoxy, and -OR, wherein said 4-7 membered saturated or partially unsaturated heterocyclyl is further substituted with 0-3 independently selected RB; c) a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected RB; andd) H, halogen, C1-C6aliphatic, Ca-Cvcycloalkyl, C1-Cal6kylene-O-C1-C6alkyl, CN, -OR, - OR10, -NR10Rn, -C(O)NR10Rn-CH2NR10Rn, or -SO2R12, wherein said C1-C6aliphatic, C3-C?cycloalkyl, or C1-C6alkylene-O-C1-C6alkyl is substituted with 0-5 independently selected Rti; or Rlaand one Rlbon adjacent atoms of Ring B, taken together with the adjacent Ring B atoms to which they are attached, form a cyclic group fused to Ring B selected from phenyl, a 5-6 membered heteroaryl (having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), a 4- 7 membered saturated or partially unsaturated carbocyclyl, or a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), wherein said cyclic group fused to Ring B is substituted with 0-3 independently selected RB;R2is selected from C(Rc)2C(O)N(R)R2A, C(Rc)2C(Rc)2C(O)N(R)R2A, C(Rc)2C(Rc)2N(R)C(O) N(R)R2A, and C(Rc)2C(Rc)2N(R)C(O)R2A;R2Ais cubanyl, a saturated or partially unsaturated 3-8 membered monocyclic ring, a saturated or partially unsaturated bridged, fused or spirocyclic 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, wherein said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring comprises 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said cubanyl, saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring are each optionally substituted with 1, 2, or 3 substituents independently selected from optionally substituted phenyl, halogen, optionally substituted C1-C4aliphatic, haloC1-C4alkyl, Ca-Ce- cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, C3-C6cycloalkoxy haloC4-Cecyclalkoxy and -SFs, and wherein two optional substituents on the same atom of said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring form a cyclic group selected from:• an optionally substituted 3-7 membered saturated or partially 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;R3is hydrogen, C1-C4aliphatic, Cg-Cscycloalkyl, 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)NR10Rn, or N(R)C(O)R; each R3Ais independently selected 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 first 5-6 membered heteroaryl is substituted with 0-5 RB; and optionally two adjacent atoms of said phenyl or first 5-6 membered heteroaryl have two substituents that together with said adjacent atoms form a cyclic group fused to the phenyl or first 5-6 membered heteroaryl selected from a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or a second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said fused cyclic group is substituted with 0-3 independently selected RB; orR4is a C1-C4aliphatic, C1-C4alkoxy, or C3-C6cycloalkyl, each of which is substituted with 0-3 groups independently selected from halogen, -CN, -OH, C1-C4alkyl, C1-C4alkoxy, optionally substituted 5-6 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 5-6 membered heterocyclyloxy having 1- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R10is H, C1-C6aliphatic, haloC1-C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, -C(O)C1- Cealkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R10except H being optionally substituted with 1 or 2 independently selected RB;R11is H, C1-C6aliphatic, or C3-C6cycloalkyl, or R10and R11are taken together with the nitrogen atom to which they are attached to form a 5-6 membered ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, -OH, -CN, C1-C4alkoxy, and haloC1- C4alkoxy;R12is C1-C6aliphatic, C3-C6cycloalkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R12optionally substituted with 1or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1-C6alkyl, alkCox1-yC,6C3-C6cycloalkyl, and C3-C6cycloalkox;yRBis independently selected at each occurrence from the group consisting of optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogen, optionally substituted C1-C6aliphatic, haloC1-C6alkyl, C3- Cecycloalkyl, haloC3-C6cycloalkyl, C1-Ca6lkoxy, haloC1-C6alkoxy, C3-C6cycloalko,xy haloCs- Cecycloalkoxy, C1-C6alkylene-O-C1-C6alkyl, -B(OR)2, -CN, -NO2, oxo, -OR, -SR, NR2, S(O)2R, S(O)2NR2, S(O)R, S(O)NR2, C(O)R, C(O)OR, -C(O)NR2, C(O)N(R)OR, OC(O)R, OC(O)NR2, -N(R)C(O)OR, N(R)C(O)R,N(R)C(O)NR2, N(R)C(NR)NR2, N(R)S(O)2NR2, and -N(R)S(O)2R; or two RBtaken together with the carbon to which they are attached form a 3-7 membered saturated carbocyclic ring;Rcis independently selected at each occurrence from hydrogen, -CHs, or -CH2CH3, or two Rctaken together with the carbon to which they are attached form a cyclopropyl ring; each R is independently hydrogen, or an optionally substituted C1-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 a cyclic group selected from an optionally substituted 4-7 membered saturated ring, a 4-7 membered partially unsaturated ring, or a 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said cyclic group has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0070] In some embodiments, Ring A is a 4-7 membered saturated or partially unsaturated bivalent monocyclic carbocyclylene or 4-7 membered saturated or partially unsaturated bivalent heterocyclylene ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 nitrogen atoms in addition to the 1-4 heteroatoms). In some embodiments, RingA is a 4-7 membered saturated or partially unsaturated bivalent monocyclic carbocyclylene, wherein Ring A is substituted with 0-4 independently selected RBsubstituents. In some embodiments, Ring A is a 4-7 membered saturated or partially unsaturated bivalent monocyclic heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 nitrogen atoms in addition to the 1-4 heteroatoms), wherein Ring A is substituted with 0-4 independently selected RBsubstituents.

[0071] 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 or heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Ring A is a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic and is a carbocyclylene, wherein Ring A is substituted with 0-4 independently selected RBsubstituents. 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 from nitrogen, oxygen, and sulfur), wherein Ring A is substituted with 0-4 independently selected RBsubstituents.

[0072] 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.NNN N N N

[0073] In some embodiments, Ring A isN X XN NVNVNVN VNNVNXN N NNVNNX'Nor VN

[0074] In some embodiments, Ring A is

[0075] In some embodiments, Ring A is

[0076] In some embodiments, Ring A is

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

[0078] As described generally above, L is a linker selected from -C(O)-, -S(O)-, -S(O)2-, and

[0079] In some embodiments, L is -C(O)C(R)2- or -C(R)2C(O)-.

[0080] In some embodiments, linker L is -C(O)-.

[0081] In some embodiments, linker L is -S(O)-.

[0082] In some embodiments, linker L is -S(O)2-.

[0083] In some embodiments, linker L

[0084] In some embodiments, linker L is as selected from one of the substituents of Table 1 or Table la.

[0085] As described generally above, Rlais selected from:a) 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-C6aliphatic, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkoxy, and C3- Cecycloalkoxy, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RB; b) a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or2 groups independently selected from C1-C6aliphatic, Ca-Cscycloalkyl, aClk1-oCx6y, C3- Cecycloalkoxy, and -OR, wherein said 4-7 membered saturated or partially unsaturated heterocyclyl is further substituted with 0-3 independently selected RB; c) a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected RB; and d) H, halogen, C1-C6aliphatic, C3-C6cycloalkyl, C1-Cal6kylene-O-C1-C6alkyl, CN, -OR, - OR10, -NR10Rn, -C(O)NR10Rn-CH2NR10Rn, -SO2R12, wherein said C1-C6aliphatic, C3- C?cycloalkyl, or C1-C6alkylene-O-C1-C6alkyl is substituted with 0-5 independently selected RB; or Rlaand one Rlbon adjacent atoms of Ring B, taken together with the adjacent Ring B atoms to which they are attached, form a cyclic group fused to Ring B selected from phenyl, a 5-6 membered heteroaryl (having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), a 4- 7 membered saturated or partially unsaturated carbocyclyl, or a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), wherein said cyclic group fused to Ring B is substituted with 0-3 independently selected RB.

[0086] In some embodiments, Rlais a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1 or 2 groups independently selected from C1-Ca6lkyl, C1-Cal6koxy, C3-C6cycloalkyl, and C3-C6cycloalkoxy wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RB. In some embodiments, Rlais a 4-6 membered saturated or partially unsaturated heterocyclyl(having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), said heterocyclyl substituted with 0-2 RBgroups independently selected from halogen, oxo, -NR2, optionally substituted Cwaliphatic, -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, Rlais a 6-8 membered saturated or partially unsaturated bridged bicyclic heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), said heterocyclyl substituted with 0-2 RBgroups independently selected from halogen, oxo, -NR2, optionally substituted Cwaliphatic, -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, Rlais a 3-7 membered optionally substituted carbocyclyl. In some embodiments, Rlais an optionally substituted C2-C4alkenyl. In some embodiments, Rlais cyclopropyl substituted C2-C4alkenyl. In some embodiments, Rlais methyl substituted C2-C4alkenyl.

[0087] In some embodiments, Rlais a 6-membered partially unsaturated heterocyclyl (having 1 oxygen atom). In some embodiments, Rlais a 4-8 membered saturated heterocyclyl (having 1 oxygen atom). In some embodiments, Rlais a 6-membered heteroaryl (having 1 nitrogen atom), said heteroaryl may be optionally substituted with 1 or 2 groups independently selected from C1- Cealkyl, C1-C6alkoxy, C3-C6cycloalkyl, and C3-C6cycloalkoxy wherein said heteroaryl is further substituted with 0-1 RB, wherein RBis an optionally substituted C1-ealiphatic group. In some embodiments, Rlais a 6-membered heteroaryl (having 2 nitrogen atoms), said heteroaryl may be optionally substituted with 1 or 2 groups independently selected from Cal1k-yCl6, aClk1-oCx6y, C3-C6cycloalkyl, and C3-C6cycloalkox,y wherein said heteroaryl is further substituted with 0-1 RB, wherein RBis an optionally substituted C1-ealiphatic group. In some embodiments, Rlais -NR10Rnwherein R10is a 5-6 membered heteroaryl (having 1 or 2 nitrogen atoms) optionally substituted with 1 or 2 groups independently selected from halogen, CH3, OCH3, Cs-Cscycloalkyl, and C3- Cecycloalkoxy and wherein R11is H or CH3. In some embodiments, Rlais -CH2NR10Rnwherein R10is a 5-6 membered heteroaryl (having 1 or 2 nitrogen atoms) optionally substituted with 1 or 2 groups independently selected from halogen, CH3, OCH3, C3-C6cycloalkyl, and C3-C6cycloalkoxy and wherein R11is H or CH3. In some embodiments, Rlais C2-C4alkene wherein said alkene is optionally substituted with OCH3 or 1, 2, or 3 fluorine. In some embodiments, Rlais C2-C4alkyne wherein said alkyne is optionally substituted with OCH3 or 1, 2, or 3 fluorine. In someembodiments, Rlais -SO2R12wherein R12is selected from CH3 or a 5-6 membered heteroaryl having 1-2 nitrogen heteroatoms optionally substituted with 1 or 2 groups independently selected from halogen and CH3. In some embodiments, Rlais cyclopropyl optionally substituted with 1-2 fluorine. In some embodiments, Rlais C1a-Clk6yl optionally substituted with OH or 1-2 fluorine. In some embodiments, Rlais -C(O)NR10R11wherein R10is H or CH3 and wherein R11is H or CH3.

[0088] In some embodiments, R,aaiiss aa 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-Ca6lkyl, C1-Cal6koxy, C3-C6cycloalkyl, and Ca-Cscycloalkoxy, wherein said 5-membered heteroaryl is optionally further substituted with 0-3 independently selected RB. In some embodiments, Rlais 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-aClk6yl, C1a-lCk6oxy, C3-C6cycloalkyl, and Cg-Cecycloalkoxy. In some embodiments, Rlais a 5-membered heteroaryl (having 2 nitrogen atoms) optionally substituted with 1 or 2 groups independently selected from C1-Ca6lkyl, C1-Cealkoxy, C3- Cecycloalkyl, and C3-C6cycloalkoxy, wherein said 5-membered heteroaryl is optionally further substituted with 0-1 RB, wherein RBis hydroxyl substituted C1-C4alkyl.

[0089] In some embodiments, Rlais a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with one group ofC1-C6alkoxy or C3-C6cycloalkyl, wherein said 5-6 membered heteroaryl is optionally further substituted with 0-3 independently selected RB.

[0090] In some embodiments, Rlais pyridyl substituted with C1-C4alkoxy and further substituted with 0-2 RB.

[0091] In some embodiments, Rlais 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 C1a-lCk6yl, or C3- Cscycloalkyl and further substituted with 0-2 RB.

[0092] In some embodiments, Rlais selected from groups a-d: a) 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 fromC1-C6alkyl, C1-C6cycloalkyl, C1-C6alkoxy, and C1-C6cycloalkoxy, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RB; b) a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-Ca6lkyl, C3-C6cycloalkyl, C1-aCl6koxy, C3- Cecycloalkoxy, and -OR, wherein said 4-7 membered saturated or partially unsaturated heterocyclyl is further substituted with 0-3 independently selected RB; c) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene or heterocyclylene (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), said carbocyclylene or heterocyclylene is substituted with 0-3 independently selected RB; and d) H, halogen, C1-C6alkyl, C2-C4 alkenyl, C2-C4 alkynyl, Ca-Cvcycloalkyl, alkCy1l--CO6-C1- Cealkyl, CN, -OR, -NR10Rn, -C(O)NR10Rn-CH2NR10Rn, -SO2R12, wherein C1-C6alkyl, C2-C4 alkenyl, C2-C4alkynyl, Cs-Cvcycloalkyl, or C1-aClk6ylene-O-C1-C6alkyl may be substituted with 0-5 independently selected RB.

[0093] In some embodiments, Rlais a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from alkCy1l-,C C61-C6cycloalkyl, C1-C6alkoxy, and C3-C6cycloalkoxy and -OR, wherein said 4-7 membered saturated or partially unsaturated heterocyclyl is further substituted with 0-3 independently selected RB.

[0094] In some embodiments, Rlais a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1 or 2 groups independently selected from C1-Ca6lkyl, C3-C6cycloalkyl, C1a-lCk6oxy, and Cg-Cecycloalkoxy, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RB.

[0095] In some embodiments, Rlais selected from the group consisting of:wherein * is the point of attachment to Ring B.

[0096] In some embodiments, Rlais

[0097] In some embodiments, RlaisN

[0098] In some embodiments, Rlais

[0101] In some embodiments, Rlais as selected from one of the substituents of Table 1 orTable la.

[0102] As described generally above, each Rlbis independently selected from H, halogen, CN, OH, C1-C6aliphatic, C1-Ca6lkoxy, C3-C6cycloalkyl, C1a-lCky6lene-O-C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and C3-C6cycloalkoxy , wherein said C1-C6aliphatic, C1-C6alkoxy, C3- Cecycloalkyl, C1-C6alkylene-O-C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and C3- Cecycloalkoxy are each independently and optionally substituted with 1-5 halogen, OH, CN, C1- Cealkyl, or Cs-Cscycloalkyl groups.

[0103] In some embodiments, Rlaand one Rlbon adjacent atoms of Ring B, taken together with the adjacent Ring B atoms to which they are attached, form a cyclic group fused to Ring B selected from phenyl, a 5-6 membered heteroaryl (having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), a 4-7 membered saturated or partially unsaturated carbocyclyl, or a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), wherein said cyclic group fused to Ring B is substituted with 0-3 independently selected RB.

[0104] In some embodiments, Rlaaanndd oonnee RRllbbon adjacent atoms of Ring B, taken together with the adjacent Ring B atoms to which they are attached, form a cyclic group fused to Ring B of phenyl, wherein said cyclic group fused to Ring B is substituted with 0-3 independently selected RB. In some embodiments, Rlaand one Rlbon adjacent atoms of Ring B, taken together with the adjacent Ring B atoms to which they are attached, form a cyclic group fused to Ring B of a 5-6 membered heteroaryl (having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), wherein said cyclic group fused to Ring B is substituted with 0-3 independently selected RB. In some embodiments, Rlaand one Rlbon adjacent atoms of Ring B, taken together with the adjacent Ring B atoms to which they are attached, form a cyclic group fused to Ring B of a 4-7 membered saturated or partially unsaturated carbocyclyl, wherein said cyclic group fused to Ring B is substituted with 0-3 independently selected RB. In some embodiments, Rlaand one Rlbon adjacent atoms of Ring B, taken together with the adjacent Ring B atoms to which they are attached, form a cyclic group fused to Ring B of a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), wherein said cyclic group fused to Ring B is substituted with 0-3 independently selected RB.

[0105] As described generally above, R2is C(Rc)2C(O)N(R)R2A. In some embodiments, R2is C(Rc)2C(Rc)2C(O)N(R)R2A. In some embodiments, R2is C(Rc)2C(Rc)2N(R)C(O)N(R)R2A. In some embodiments, R2is C(Rc)2C(Rc)2N(R)C(O)R2A. In some embodiments, R2is CH2C(O)N(H)R2A. In some embodiments, R2is CH2CH2C(O)N(H)R2A. In some embodiments, R2is CH2CH2N(R)C(O)N(R)R2A. In some embodiments, R2is CH2CH2N(H)C(O)R2A. In some embodiments, R2is C(Rc)2C(O)N(H)R2A, wherein R2Ais bicyclof l.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(Rc)2C(O)N(H)R2A, wherein R2Ais bicyclo[l.l. l]pentyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4alkyl, or haloC1-C4alkyl.

[0106] In some embodiments, R2isF FHN ' FF FOFHN OFO 0 oF. FFFHN HN HN .0 HN ' FFO O o OFF y HNHN HNF o o O Osome embodiments, R2iso FHNH o o.O.0.NHFHNF

[0107] In some embodiments R2is OHN

[0108] In some embodiments R2is O

[0109] In some embodiments, R2is as selected from one of the substituents of Table 1 orTable la

[0110] As described generally above, R2Ais cubanyl, a saturated or partially unsaturated 4-8 membered monocyclic ring, a saturated or partially unsaturated bridged, fused or spirocyclic 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, wherein said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring comprises 0, 1 , 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said cubanyl, saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring are each optionally substituted with 1, 2, or 3substituents independently selected from halogen, C1-C4aliphatic, haloC1-C4alkyl, Cs-Ce- cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, C3-C6cycloalk,oxy haloC4-C6cyclalkoxy and -SFs, and wherein two optional substituents on the same atom of said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring form a cyclic group selected from:• an optionally substituted 3-7 membered saturated or partially 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.

[0111] As described generally above, R2Ais cubanyl, a saturated or partially unsaturated 4-8 membered monocyclic ring, a saturated or partially unsaturated bridged, fused or spirocyclic 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, wherein said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring comprises 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said cubanyl, saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring are each optionally substituted with 1, 2, or 3 substituents independently selected from optionally substituted phenyl, halogen, optionally substituted C1-C4aliphatic, haloC1-C4alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1- C4alkoxy, haloC1-C4alkoxy, Cg-Cecycloalkoxy, haloC4-C6cyclalkoxy and -SFs, and wherein two optional substituents on the same atom of said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring form a cyclic group selected from: an optionally substituted 3-7 membered saturated or partially 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.

[0112] 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 6lhatoms 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.

[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 which comprises 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring are each optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4alkyl, haloC1-C4alkyl, C3-C6cycloalkyl, haloCa-Ce- cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, C3-C6cycloalkoxy haloC4-C6cyclalkoxy and -SFs. In some embodiments, R2Ais bicyclo[l .l . l]pentyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4alkyl, and haloC1-C4alkyl.

[0114] In some embodiments, R2Ais a saturated or partially unsaturated bridged 5-, 6-, 7-, 8-,9-, 10-, 11-, or 12-membered ring, which comprises 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said bridged ring is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4alkyl, haloC1-C4alkyl, C3- Cecycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, C3-C6cycloalkoxy haloC4-C6cy cialkoxy and -SF5.

[0115] In some embodiments, R2Ais a saturated or partially unsaturated fused 5-, 6-, 7-, 8-, 9,10-, 11-, or 12-membered ring, which comprises 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said fused ring is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4alkyl, haloC1-C4alkyl, Ca-Ce- cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, C3-C6cycloalkoxy haloC4-C6cy cialkoxy and -SF5.

[0116] In some embodiments, R2Ais a saturated or partially unsaturated spirocyclic 5-, 6-, 7-,8-, 9-, 10 11-, or 12-membered ring, which comprises 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said spirocyclic ring is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4alkyl, haloC1- C4alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, Ca-Cecycloalkoxy, haloC4-Cecyclalkoxy and -SF5.

[0117] In some embodiments, R2Ais bicyclo[l. l.l]pentyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4alkyl, haloC1-C4alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, C3-C6cycloalkoxy haloC4-Ce- cyclalkoxy and -SF5. In some embodiments, R2Ais bicyclo[l.l. l]pentyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4alkyl, and haloC1-C4alkyl. In some embodiments, R2Ais bicyclo[l.l.l]pentyl optionally substituted with a halogen, C1- C4alkyl, or haloC1-C4alkyl. In some embodiments, R2Ais bicyclo[l . l.l]pentyl optionally substituted with 2 substituents independently selected from halogen, C1-C4alkyl, and haloC1- C4alkyl. In some embodiments, R2Ais bicyclo[l. l.l]pentyl optionally substituted with 3 substituents independently selected from halogen, C1-C4alkyl, and haloC1-C4alkyl.

[0118] 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, CHR13or CR15R15, wherein R2Acomprises 0, 1, 2, or 3, instances of R15independently selected from H, halogen, C1- C4aliphatic, haloC1-C4alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, C3-C6cycloalkoxy, haloC4-C6cyclalkoxy and -SFs.

[0119] In some embodiments, R2Ais Ring F of the following structure , whereinR15is selected from halogen, C1-C4aliphatic, haloC1-C4alkyl, C3-C6cycloalkyl, haloCa-Ce- cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, C3-C6cycloalkoxy haloC4-Cecy cialkoxy and -SFs.

[0120] In some embodiments, R2Ais bicyclo[l.l. l]pentyl comprising a -CF3 substituent or bicyclofl. l.l]pentyl comprising a -CHF2 substituent.

[0121] In some embodiments, R2Ais as selected from one of the substituents of Table 1 orTable la.

[0122] As described generally above, R3is hydrogen, C1-C4alkyl, Cs-Cscycloalkyl, 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)NR10Rn, or N(R)C(O)R.

[0123] 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 Cs-Cscycloalkyl, 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 Cs-Cscycloalkyl 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 Cg-Cscycloalkyl.

[0124] In some embodiments, R3is as selected from one of the substituents of Table 1 orTable la.

[0125] As described generally above, each R3Ais independently selected at each occurrence from C1-C4alkyl. In some embodiments, R3Ais -CHg In some embodiments, R3Ais -CH2CH3. In some embodiments, R3Ais propyl. In some embodiments, R3Ais butyl.

[0126] In some embodiments, R3Ais as selected from one of the substituents of Table 1 orTable la.

[0127] In some embodiments, R4is selected from one of a), b), and c): a) R4is a Ring E that is selected from the group consisting of:R4FR4ANR4BR4Cwherein * is a point of attachment to L; andany substituents that are present on Ring E selected from R4A, R4B, R4C, R4D, R4E, and R4Fare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; C1-C4alkoxy; haloC1-C4alkyl; C1-Cialkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3- Cecycloalkoxy; and NR13R14; orR4Aand R4B, along with their intervening atoms, join to form 4-7 membered carbocyclyl substituted with 0-3 independently selected RB, a 4-7 membered heterocyclyl substituted with 0-3 independently selected RB, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and any substituents that are present on Ring E selected from R4C, R4D, R4E, and R4Fare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2- C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C6alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; orR4Band R4C, along with their intervening atoms, join to form a 4-7 membered carbocyclyl substituted with 0-3 independently selected RB, a 4-7 membered heterocyclyl substituted with 0-3 independently selected RB, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and any substituents that are present on Ring E selected from R4A, R4D, R4E, and R4Fare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2- C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C6alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; Cs-Cscycloalkyl; C3-C6cycloalkoxy; and NR13R14; orR4Cand R4D, along with their intervening atoms, join to form a 4-7 membered carbocyclyl substituted with 0-3 independently selected RB, a 4-7 membered heterocyclyl substituted with 0-3 independently selected RB, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E;and any substituents that are present on Ring E selected from R4A, R4B, R4Eand R4Fare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2- C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C6alkyl 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-C6alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; orR4B and R4A, along with their intervening atoms, join to form a 5-6 membered optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and R4B, R4C, and R4Dare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C6alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3- Cecycloalkyl; C3-C6cycloalkoxy; and NR13R14; orR4Fand R4A, along with their intervening atoms, join to form a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and R4Band R4Care each independently selected from hydrogen; halogen; -CN; C1- C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-Cgalkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3- Cecycloalkoxy; and NR13R14;R13is independently selected at each occurrence from hydrogen and C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; andR14is hydrogen, or R13and R14combine with the nitrogen atom to which they are attached to form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl, said heterocyclic ring optionally substituted with -CH3; orb) 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, halo C1-C4alkyl, C3-C6cycloalkyl , and C1-C4alkoxy; and 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 having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 5-6 membered heterocyclyloxy having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0128] In some embodiments, R4is Ring E of the following structure:wherein * is a point of attachment to linker L that is bonded to Ring A in Formula I; and wherein: are eacj1in(jepen(iently 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- Cecycloalkoxy; and NR13R14; orR4Cand R4D, along with their intervening atoms, join to form 4-7 membered carbocyclyl ) substituted with 0-3 independently selected RB, a 4-7 membered heterocyclyl substituted with 0-3 independently selected RB, or 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB, that is fused to Ring E; and R4Ais hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C3-C3alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1- C4alkoxy; C3-C6cycloalkyl C3-C6cycloalkoxy ; and NR,3R14; andR13is independently selected at each occurrence from hydrogen and C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; and NR13R14, taken in combination form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, said heterocyclic ring optionally substituted with -CH3.R14is hydrogen, or R13and R14combine with the nitrogen atom to which they are attached to form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, said heterocyclic ring optionally substituted with -CH3.

[0129] In some embodiments, R4is Ring E of the following structure:wherein * is a point of attachment to linker L that is bonded to Ring A 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-C6alkyl substituted with -OH, -OCH3, or - OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalk; o axnyd NR13R14; andR13is independently selected at each occurrence from hydrogen or C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; or NR13R14, taken in combination form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, said heterocyclic ring optionally substituted with -CH3;R14is hydrogen, or R13and R14combine with the nitrogen atom to which they are attached to form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, said heterocyclic ring optionally substituted with -CH3. orR4i is 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 issubstituted with 0-4 substituents independently selected from halogen, -OH, -CN, C1-C4alkyl, haloC1-C4alkyl, C3-C6cycloalkyl, and C1-C4alkoxy.

[0130] In some embodiments, R4is Ring E of the following structure:wherein * is a point of attachment to linker L that is bonded to Ring A 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-C6alkyl substituted with -OH, -OCH3, or - OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalk; o axnyd NR13R14; andR13is independently selected at each occurrence from hydrogen or C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; or NR13R14, taken in combination form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, said heterocyclic ring optionally substituted with -CH3; andR14is hydrogen.

[0131] In some embodiments, R4is Ring E of the following structure:OHR4ANR4DR4G wherein * is a point of attachment to linker L that is bonded to Ring A in Formula I; and wherein:R4A, R4(, and R4Dare each independently selected from hydrogen; halogen; and C1- C4alkyl.

[0132] In some embodiments, R4is Ring E of the following structure:OHR4AN R4BR4Cwherein * 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-C6alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl;C3-C6cycloalkoxy ; and NR13R14; orR4Aand R4B, along with their intervening atoms, join to form 4-7 membered carbocyclyl or heterocyclyl or 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring E; and R4Cis hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C6alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1- C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkox;y or NR13R14; orR4Band R4C, along with their intervening atoms, join to form a 4-7 membered carbocyclyl substituted with 0-3 independently selected RB, a 4-7 membered heterocyclyl substituted with 0-3 independently selected RD, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and R4Ais selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2- C4alkynyl; haloC1-C4alkyl; C1-C6alkyl substituted with -OH, -OCH3, or - OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalko;x aynd NR13R14; andR13is independently selected at each occurrence from hydrogen or C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; or NR13R14, taken in combination form aheterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, said heterocyclic ring optionally substituted with -CH3; andR14is hydrogen.

[0133] In some embodiments, R4is Ring E of the following structure:OHR4AN R4BR4C 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, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring E; andR4Cis hydrogen.

[0134] In some embodiments, R4is Ring E of the following structure:OHR4AN R4BR4Cwherein * 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 E; andR4Cis hydrogen.

[0135] In some embodiments, R4is Ring E of the following structure:wherein * is a point of attachment linker L that is bonded to Ring A in Formula I; and wherein:R4A, R4,\ and R4Dare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; C1-C4alkoxy; haloC1-C4alkyl; C1-C6alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl;C3-C6cycloalkoxy ; and NR13R14; orR4Aand R4B, along with their intervening atoms, join to form a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl, a 5-6 membered heteroaryl (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring E; and R4Dis hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2- C4alkynyl; haloC1-C4alkyl; C1-Cgalkyl substituted with -OH, -OCH3, or - OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalk; o oxryNR13R14; andR13is independently selected at each occurrence from hydrogen or C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; or NR13R14, taken in combination form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, said heterocyclic ring optionally substituted with -CH3; andR14is H.

[0136] In some embodiments, R4is Ring E of the following structure:wherein * is a point of attachment to linker L that is bonded to Ring A in Formula I; and wherein:R4Aand R4Dare each hydrogen; andR4Bis C1-C4alkyl.

[0137] In some embodiments, R4is Ring E of the following structure:wherein * is a point of attachment 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-C6alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; andR13is independently selected at each occurrence from hydrogen or C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; or NR13R14, taken in combination form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, said heterocyclic ring optionally substituted with -CH3; andR14is H.

[0138] In some embodiments, R4is Ring E of the following structure:wherein * is a point of attachment to linker L that is bonded to Ring A in Formula I; and wherein:R4Aand R4Care each independently selected from hydrogen and C1-C4alkyl.

[0139] In some embodiments, R4is Ring E of the following structure:wherein * is a point of attachment to linker L that is bonded to Ring A in Formula I; and wherein:R ', R4B, R4C, R4D, and R 44EEare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; C1-C4alkoxy; haloC1- C4alkyl; C1-C6alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-Cecycloalkyl; C3-C6cycloalkoxy; and NR13R14; orR4Aand R4B, along with their intervening atoms, join to form 4-7 membered carbocyclyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring E; and R4C, R4D, and R4Eare 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- Cecycloalkyl; C3-C6cycloalkoxy; and NR13R14; orR4Cand R4D, along with their intervening atoms, join to form 4-7 membered carbocyclyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring E; and R4A, R4B, and R4Eare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1- C3 alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3- Cecycloalkyl; 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-C6alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; Cs-Cgcycloalkyl; C3-C6cycloalkoxy; and NR13R14; orR4Eand R4A, along with their intervening atoms, join to form 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused to Ring E; and R4B, R4C, and R4Dare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1- C4alkyl; C1-Cgalkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; andR13is independently selected at each occurrence from hydrogen or C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; or NR13R14, taken in combination form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, said heterocyclic ring optionally substituted with -CH3; andR14is H.

[0140] In some embodiments, R4is Ring E of the following structure:wherein * is a point of attachment to linker L that is bonded to Ring A in Formula I; and wherein:R4A, R4B, R4C, R4I\ and R 44EEare each independently selected from hydrogen; halogen; C1-C4alkyl; and C1-C4alkoxy; orR4Cand R4D, along with their intervening atoms, join to form a 4-7 membered heterocyclyl (having 1-3 nitrogen atoms) fused to Ring E; and R4A, R4B, and R4Eare each hydrogen.

[0141] In some embodiments, R4is Ring E of the following structure:R4FR4AN R4BR4C 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 E; and R4Band R4Care each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C6alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3- Cecycloalkyl; C3-C6cycloalkoxy; and NR13R14;R13is independently selected at each occurrence from hydrogen or C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; or NR13R14, taken in combination form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, said heterocyclic ring optionally substituted with -CH3; andR14is H.

[0142] In some embodiments, R4is Ring E of the following structure:R4FR4ATlNR4BR4C 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 E; and R4Band R4Care each hydrogen.

[0143] 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.

[0144] 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, - CHa, -CHF2, cyclopropyl, and -OCH3.

[0145] In some embodiments, R4is a C1-C4alkyl, C1-C4alkoxy, or C3-C6cycloalkyl, each of which is substituted with 0-3 groups independently selected from halogen, -CN, -OH, C1-C4alkyl, C1-C4alkoxy, optionally substituted 5-6 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 5-6 membered heterocyclyl oxy having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R4is a C1-C4alkyl, substituted with 0-3 independently selected halogen, -CN, -OH, C1-C4alkyl, and C1-C4alkoxy. In some embodiments, R4is a C1-C4alkoxy, substituted with 0-3 independently selected halogen, -CN, -OH, C1-C4alkyl, and C1-C4alkoxy. In some embodiments, R4is a C3-C6cycloalkyl, substituted with 0-3 independently selected halogen, -CN, -OH, C1-C4alkyl, and C1-C4alkoxy.

[0146] In some embodiments, R4is an isoxazolyl substituted with -OH or C1-C4alkoxy.

[0147] In some embodiments, R 44is 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 thiophenyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, oxazolyl, isoxazolyl, 1,2,4- oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, wherein said heteroaryl is optionally substituted with 0-4 groups independently selected from halogen, -OH, -CN, C1-C4alkyl, haloC1-C4alkyl, C3- Cecycloalkyl, and C1-C4alkoxy.

[0148] In some embodiments, R4is selected from the group consisting of:wherein * indicated the point of attachment to L, wherein:X is CH, CR7, or N;R5is -OH or halogen;R6is halogen, C1-4alkyl, or C1-4alkoxy; each R7is independently hydrogen, halogen, Ci.4alkyl, or Cwalkoxy;R8is Cwalkyl; 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.

[0149] In some embodiments, R4isww

[0150] In some embodiments, R4is

[0151] In some embodiments, R4is as shown in a substituent of Table 1 or Table la.

[0152] As described generally above, R10is H, C1-C6aliphatic, haloC1-Cgalkyl, C3-Cecycloalkyl, haloC3-C6cycloalkyl, -C(O)C1-C6alkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R10except H being optionally substituted with 1 or 2 independently selected RB.

[0153] In some embodiments, R10is H. In some embodiments, R10is C1-Cgaliphatic, haloC1- C6alkyl, C3-C6cycloalkyl,, haloC3-C6cycloalkyl,, -C(O)C1-C6alkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R10being optionally substituted with 1 or 2 independently selected RB. In some embodiments, R10is C1- Cgaliphatic, haloC1-C6alkyl C3-C6cycloalkyl, haloC3-C6cycloalkyl, or -C(O)C1-C6alkyl; each R10being optionally substituted with 1 or 2 independently selected RB. In some embodiments, R10is a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); R10being optionally substituted with 1 or 2 independently selected RB.

[0154] In some embodiments, R10is as shown in a substituent of Table 1 or Table la.

[0155] As described generally above, R11is H, C1-C6aliphatic, or C3-C6cycloalkyl, or R10and R11are taken together with the nitrogen atom to which they are attached to form a 5-6 membered ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, -OH, -CN, C1-C4alkoxy, and haloC1-C4alkoxy.

[0156] In some embodiments, R11is H, C1-C6aliphatic, or C3-C6cycloalkyl. In some embodiments, R11is H. In some embodiments, R11is C1-C6aliphatic. In some embodiments, R11is C3-Cecycloalkyl. In some embodiments, R10and R11are taken together with the nitrogen atom to which they are attached to form a 5-6 membered ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, -OH, -CN, C1-C4alkoxy, and haloC1-C4alkoxy.

[0157] In some embodiments, R11is as shown in a substituent of Table 1 or Table la.

[0158] As described generally above, R12is C1-C6aliphatic, C3-C6cycloalkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R12optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1-C6alkyl, C1-Ca6lkoxy, C3-Cecycloalkyl, and C3-Cecycloalkoxy.

[0159] In some embodiments, R12is C1-C6aliphatic optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1-C6alkyl, C1-C6alkoxy, C3- Cecycloalkyl, and Cg-Cecycloalkoxy. In some embodiments, R12is C1-C6aliphatic optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1- Cealkyl, C1-C6alkoxy, C3-C6cycloalkyl, and C3-C6cycloalko. x Iyn some embodiments, R12is C3- Cecycloalkyl optionally substituted with 1 or 2 groups independently selected from halogen, C1- Cealiphatic, haloC1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, and Cs-Cgcycloalkoxy. In some embodiments, R12is a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, and C3- Cecycloalkoxy.

[0160] As described generally above, RBis independently selected at each occurrence from the group consisting of optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur),optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl (having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogen, optionally substituted C1-C6aliphatic, haloC1-C6alkyl, C3-C6cycloalkyl, halo-C3-C6cycloalkyl, alCk1o-xCy6, halo-C1-C6alkoxy, C3-C6cycloalkoxy, halo-Cs-Cecycloalkoxy, 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.

[0161] As also described generally above, in some embodiments, RBis independently selected at each occurrence from the group consisting of optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogen, optionally substituted C1-C6aliphatic, haloC1-C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, C1-Ca6lkoxy, haloC1-C6alkoxy, C3-C6cycloalko,xy haloCs-Cecycloalkoxy, C1-C6alkylene-O-C1-C6alkyl, -B(OR)2, -CN, -NO2, oxo, -OR, -SR, NR2, S(O)2R, S(O)2NR2, S(O)R, S(O)NR2, C(O)R, C(O)OR, -C(O)NR2, C(O)N(R)OR, OC(O)R, OC(O)NR2, - N(R)C(O)OR, N(R)C(O)R,N(R)C(O)NR2, N(R)C(NR)NR2, N(R)S(O)2NR2, and -N(R)S(O)2R; or two RBtaken together with the carbon to which they are attached form a 3-7 membered saturated carbocyclic ring.

[0162] In some embodiments, RBis independently selected at each occurrence from the group consisting of halogen, -OR, or an optionally substituted C1-ealiphatic group. In some embodiments, Rtiis independently selected at each occurrence from a halogen. In some embodiments, RBis independently selected at each occurrence from -OR. In some embodiments, RBis independently selected at each occurrence from an optionally substituted C1-ealiphatic group.

[0163] In some embodiments, RBis as selected from one of the substituents of Table 1 orTable la.

[0164] As described generally above, Rcis independently selected at each occurrence from hydrogen, -CH3, and -CH2CH3, or two Rctaken together with the carbon to which they are attached form a cyclopropyl ring. In some embodiments, Rcis independently selected at each occurrence from hydrogen, -CH3, and -CH2CH3. In some embodiments, Rcis hydrogen. In someembodiments, one Rcis -CH3, and the other Rcis hydrogen. In some embodiments, two Rctaken together with the carbon to which they are attached form a cyclopropyl ring.

[0165] In some embodiments, Rcis as selected from one of the substituents of Table 1 orTable la.

[0166] As described generally above, each R is independently hydrogen, or an optionally substituted C1-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 a cyclic group selected from an optionally substituted 4-7 membered saturated ring, a 4-7 membered partially unsaturated ring, or a 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said cyclic group has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0167] In some embodiments, each R is hydrogen. In some embodiments, each R is independently an optionally substituted C1-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).

[0168] In some embodiments, two R groups on the same atom are taken together with the same atom to form a cyclic group selected from an optionally substituted 4-7 membered saturated ring, a 4-7 membered partially unsaturated ring, or a 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said cyclic group has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, each R is independently hydrogen or a C1-6 alkyl.

[0169] In some embodiments, each R is as selected from one or more of the substituents ofTable 1 or Table la.

[0170] In some embodiments, the compound of Formula I is a compound of Formula Il-a -Formula II-z”:n-g ll-h ll-ill-m I l-n ll-o 4ll-rll-s ll-tILx' II-x"II-z' II-Z" or a pharmaceutically acceptable salt thereof; wherein Rla, Rlb, Ring A, linker L, R2, R3, 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 Ila -Formula Ils:II-d Il-e Il-fII-p Il-q Il-rII-W' II-W"II-z' II-z" or a pharmaceutically acceptable salt thereof; wherein Rla, Ring A, R2, R3, and R4, are as defined herein, both singly and in combination.

[0172] In some embodiments, the compound of Formula I is a compound of Formula Ila -Formula Ils:II-a Il-b II-cII-p Il-q Il-rII-W' II-w"ILz' ILz" or a pharmaceutically acceptable salt thereof; wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination, Ring A isN N NN N and , and R2ais selected from,F F' F FF F 5

[0173] In some embodiments, the compound of Formula I is a compound of Formula Ill-a:Ill-a or a pharmaceutically acceptable salt thereof; wherein Rla, Rlb, R2, R3, and R4, are as defined herein, both singly and in combination.

[0174] In some embodiments, the compound of Formula I is a compound of Formula Ill-b:Ill-b or a pharmaceutically acceptable salt thereof; wherein Rla, Rlb, R2, R3, and R4, are as defined herein, both singly and in combination.

[0175] In some embodiments, the compound of Formula I is a compound of III-c:III-c or a pharmaceutically acceptable salt thereof; wherein Rla, Rlb, R2, R3, and R4, are as defined herein, both singly and in combination.

[0176] In some embodiments, the compound of Formula I is a compound of Formula Ill-d:Ill-d or a pharmaceutically acceptable salt thereof; wherein Rla, Rlb, R2, R3, and R4, are as defined herein, both singly and in combination.

[0177] In some embodiments, the compound of Formula I is a compound of Formula Ill-e:Ill-e or a pharmaceutically acceptable salt thereof; wherein Rla, Rlb, R2, R3, 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 Ill-f:Ill-f or a pharmaceutically acceptable salt thereof; wherein Rla, Rlb, R2, R3, and R4, are as defined herein, both singly and in combination.

[0179] In some embodiments, the compound of Formula I is a compound of Formula Ill-g:g or a pharmaceutically acceptable salt thereof; wherein Rla, Rlb, R2, R3, and R4, are as defined herein, both singly and in combination.

[0180] In some embodiments, the compound of Formula I is a compound of Formula Ill-h:Ill-h or a pharmaceutically acceptable salt thereof; wherein Rla, Rlb, R2, R3, and R4, are as defined herein, both singly and in combination.

[0181] In some embodiments, the compound of Formula I is a compound of Formula Ill-i:Ill-i or a pharmaceutically acceptable salt thereof; wherein Rla, each independently defined Rlb, R2, R3, and R4, are as defined herein, both singly and in combination.

[0182] In some embodiments, the compound of Formula I is a compound of Formula Ill-j:Ill-j or a pharmaceutically acceptable salt thereof; wherein Rla, each independently defined Rlb, R2, R3, and R4, are as defined herein, both singly and in combination.

[0183] In some embodiments, the compound of Formula I is a compound of Formula Ill-k:III-k or a pharmaceutically acceptable salt thereof; wherein Rla, each independently defined Rlb, R2, R3, and R4, are as defined herein, both singly and in combination.

[0184] In some embodiments, the compound of Formula I is a compound of Formula III-l:OR1 bO R4R1 aNR1 bR3R2III-l or a pharmaceutically acceptable salt thereof; wherein Rla, each independently defined Rlb, R2, R3, and R4, are as defined herein, both singly and in combination.

[0185] In some embodiments, the compound of Formula I is a compound of Formula Ill-m:Ill-m or a pharmaceutically acceptable salt thereof; wherein Rla, each independently defined Rlb, R2, R3, and R4, are as defined herein, both singly and in combination.

[0186] In some embodiments, the compound of Formula I is a compound of Formula Ill-n:O o R4R1 aNR1 bN R3R2Ill-n or a pharmaceutically acceptable salt thereof; wherein Rla, Rlb, R2, R3, and R4, are as defined herein, both singly and in combination.

[0187] In some embodiments, the compound of Formula I is a compound of Formula III-o;ON AR4III-o or a pharmaceutically acceptable salt thereof; wherein Rla, each independently defined Rlb, R2, R3, and R4, are as defined herein, both singly and in combination.

[0188] In some embodiments, the compound of Formula I is a compound of Formula III-p:OR1 bO R4R1 aNNR1 bN R3R2III-p or a pharmaceutically acceptable salt thereof;wherein Rla, each independently defined Rlb, R2, R3, and R4, are as defined herein, both singly and in combination.

[0189] In some embodiments, the compound of Formula I is a compound of Formula Ill-q:OR1 bo z R4R1 aNNR1 bR3R2Ill-q or a pharmaceutically acceptable salt thereof; wherein Rla, each independently defined Rlb, R2, R3, and R4, are as defined herein, both singly and in combination.

[0190] In some embodiments, the compound of Formula I is a compound of Formula Ill-r:Ill-r or a pharmaceutically acceptable salt thereof; wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination.

[0191] In some embodiments, the compound of Formula I is a compound of Formula III-s :OO z R4R1aN~N NR1 bN R3R2III-s or a pharmaceutically acceptable salt thereof; wherein Rla, Rlb, R2, R3, and R4, are as defined herein, both singly and in combination.

[0192] In some embodiments, the compound of Formula I is a compound of Formula Ill-t:111-t or a pharmaceutically acceptable salt thereof; wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination.

[0193] In some embodiments, the compound of Formula I is a compound of Formula III-u’:OO N R4N NR1a-S N R3l R2III-U* or a pharmaceutically acceptable salt thereof; wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination.

[0194] In some embodiments, the compound of Formula I is a compound of Formula III-u”:III-u" or a pharmaceutically acceptable salt thereof; wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination.

[0195] In some embodiments, the compound of Formula I is a compound of Formula III-v’:OO N R4N NR1 aO N R3l R2III-V' or a pharmaceutically acceptable salt thereof; wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination.

[0196] In some embodiments, the compound of Formula I is a compound of Formula III-v”:OO z R4O NR1 aN N R3l R2III-v" or a pharmaceutically acceptable salt thereof;wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination.

[0197] In some embodiments, the compound of Formula I is a compound of Formula III-w’:III-W' or a pharmaceutically acceptable salt thereof; wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination.

[0198] In some embodiments, the compound of Formula I is a compound of Formula III-w”:III-W" or a pharmaceutically acceptable salt thereof; wherein Rl a, R2, R3, and R4, are as defined herein, both singly and in combination.

[0199] In some embodiments, the compound of Formula I is a compound of Formula III-x’:III-x'or a pharmaceutically acceptable salt thereof; wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination.

[0200] In some embodiments, the compound of Formula I is a compound of Formula III-x”:III-X" or a pharmaceutically acceptable salt thereof; wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination.

[0201] In some embodiments, the compound of Formula I is a compound of Formula Ill-y ’ :III-y' or a pharmaceutically acceptable salt thereof; wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination.

[0202] In some embodiments, the compound of Formula I is a compound of Formula Ill-y”:R4R1 aR2Ill-y" or a pharmaceutically acceptable salt thereof; wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination.

[0203] In some embodiments, the compound of Formula I is a compound of Formula III-z’:III-z' or a pharmaceutically acceptable salt thereof; wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination.

[0204] In some embodiments, the compound of Formula I is a compound of Formula III-z”:III-Z" or a pharmaceutically acceptable salt thereof; wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination.

[0205] In some embodiments, the compound of Formula I is a compound of Formula Ill-a: oR4RlaNR3Ill-a or a pharmaceutically acceptable salt thereof; wherein Rla, Rlb, R2, R3, and R4, are as defined herein, both singly and in combination and R2ais selected from,

[0206] In some embodiments, the compound of Formula I is a compound of Formula Ill-b: oR4R1aR3Ill-b or a pharmaceutically acceptable salt thereof; wherein Rla, Rlb, R2, R3, and R4, are as defined herein, both singly and in combination and R2aisF FF selected from, F ■I- F ? , and

[0207] In some embodiments, the compound of Formula I is a compound of IH-c:III-C or a pharmaceutically acceptable salt thereof; wherein Rla, Rlb, R2, R3, and R4, are as defined herein, both singly and in combination and R2ais selected from

[0208] In some embodiments, the compound of Formula I is a compound of Formula IFI-d:Hl-d or a pharmaceutically acceptable salt thereof; wherein Rla, Rlb, R2, R3, and R4, are as defined herein, both singly and in combination and R2ais selected from,5 ,

[0209] In some embodiments, the compound of Formula I is a compound of Formula Ill-e:Ill-e or a pharmaceutically acceptable salt thereof; wherein Rla, Rlb, R2, R3, and R4, are as defined herein, both singly and in combination and R2ais ed from, V F select2 , and

[0210] In some embodiments, the compound of Formula I is a compound of Formula Ill-f:Ill-f or a pharmaceutically acceptable salt thereof; wherein Rla, Rlb, R2, R3, and R4, are as defined herein, both singly and in combination and R2aisFF selected from, F , and

[0211] In some embodiments, the compound of Formula I is a compound of Formula Ill-g:O z R4III-g or a pharmaceutically acceptable salt thereof; wherein Rla, Rlb, R2, R3, and R4, are as defined herein, both singly and in combination and R2ais selected from

[0212] In some embodiments, the compound of Formula I is a compound of Formula Ill-h:0R4Ill-h or a pharmaceutically acceptable salt thereof; wherein Rl a, each independently selected R1b, R2, R3, and R4, are as defined herein, both singly and in combination and R2ais selected fro

[0213] In some embodiments, the compound of Formula I is a compound of Formula Ill-i:Ill-i or a pharmaceutically acceptable salt thereof; wherein Rla, each independently selected Rlb, R2, R3, and R4, are as defined herein, both singlyF and in combination and R2ais selected from, F 7 , andF

[0214] In some embodiments, the compound of Formula I is a compound of Formula Ill-j:Ill-j or a pharmaceutically acceptable salt thereof; wherein Rla, each independently selected Rlb, R2, R3, and R4, are as defined herein, both singly c ZK F F and in combination and R2ais selected from, F 7 , and

[0215] In some embodiments, the compound of Formula I is a compound of Formula Ill-k:Ill-k or a pharmaceutically acceptable salt thereof; wherein Rla, each independently selected Rlb, R2, R3, and R4, are as defined herein, both singlyFF and in combination and R2ais selected from, F 5 , andF[00216J In some embodiments, the compound of Formula I is a compound of Formula III-l:0R1 b0 R4RlaNR1 bR3R2III-l or a pharmaceutically acceptable salt thereof; wherein Rla, each independently selected Rlb, R2, R3, and R4, are as defined herein, both singlyFF and in combination and R2ais selected from, F 2 , andF

[0217] In some embodiments, the compound of Formula I is a compound of Formula Ill-m:Ill-m or a pharmaceutically acceptable salt thereof; wherein Rla, each independently selected Rlb, R2, R3, and R4, are as defined herein, both singlyF and in combination and R2ais selected from, F 7 , andF

[0218] In some embodiments, the compound of Formula I is a compound of Formula Ill-n:OO z R4R1 aNR1 bN R3R2Ill-n or a pharmaceutically acceptable salt thereof; wherein Rla, Rlb, R2, R3, and R4, are as defined herein, both singly and in combination and R2aisFF■v F selected from F F 5 , and

[0219] In some embodiments, the compound of Formula I is a compound of Formula III-o:OR4III-o or a pharmaceutically acceptable salt thereof; wherein Rla, each independently selected Rlb, R2, R3, and R4, are as defined herein, both singlyFF and in combination and R2ais selected from F 5 , andF[00220J In some embodiments, the compound of Formula I is a compound of Formula III-p:OR1 bO z R4RlaNNR1 bN R3R2III-p or a pharmaceutically acceptable salt thereof; wherein Rla, each independently selected Rlb, R2, R3, and R4, are as defined herein, both singlyFF and in combination and R2ais selected from F 2 , andF

[0221] In some embodiments, the compound of Formula I is a compound of Formula Ill-q:OR1 bo R4R1 aNNR1 bR3R2Ill-q or a pharmaceutically acceptable salt thereof; wherein Rla, each independently selected Rlb, R2, R3, and R4, are as defined herein, both singlyF and in combination and R2ais selected from F 7 , andF

[0222] In some embodiments, the compound of Formula I is a compound of Formula Ill-r:Ill-r or a pharmaceutically acceptable salt thereof; wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination and R2ais selected from

[0223] In some embodiments, the compound of Formula I is a compound of Formula III-s:or a pharmaceutically acceptable salt thereof; wherein Rla, Rlb, R2, R3, and R4, are as defined herein, both singly and in combination and R2ais selected from

[0224] In some embodiments, the compound of Formula I is a compound of Formula Ill-t:OIll-t or a pharmaceutically acceptable salt thereof; wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination and R2aisF selected from2 ,

[0225] In some embodiments, the compound of Formula I is a compound of Formula III-u’:III-u' or a pharmaceutically acceptable salt thereof; wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination and R2aisFF selected from F , and

[0226] In some embodiments, the compound of Formula I is a compound of Formula III-u”:III-U" or a pharmaceutically acceptable salt thereof; wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination and R2aisFFF selected from F F •> , and

[0227] In some embodiments, the compound of Formula I is a compound of Formula III-v’:III-V* or a pharmaceutically acceptable salt thereof; wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination and R2aisFF selected from F , and

[0228] In some embodiments, the compound of Formula I is a compound of Formula III-v”:III-v" or a pharmaceutically acceptable salt thereof; wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination and R2aisFF selected from F •> , and

[0229] In some embodiments, the compound of Formula I is a compound of Formula III-w’:III-w' or a pharmaceutically acceptable salt thereof; wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination and R2aisFF selected from F •> , and

[0230] In some embodiments, the compound of Formula I is a compound of Formula III-w”:OO N R4N NR1 aNN R3R2III-w" or a pharmaceutically acceptable salt thereof; wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination and R2aisFF( F cted from • F sele F 1 F 9 , and

[0231] In some embodiments, the compound of Formula I is a compound of Formula III-x’:o R4N- NR1 aR3iR2III-X' or a pharmaceutically acceptable salt thereof; wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination and R2ais<. / K F FF selected from F •> , and

[0232] In some embodiments, the compound of Formula I is a compound of Formula III-x”:III-X" or a pharmaceutically acceptable salt thereof; wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination and R2aisFF selected from F , and

[0233] In some embodiments, the compound of Formula I is a compound of Formula Ill-y ’ :or a pharmaceutically acceptable salt thereof; wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination and R2ais selected from

[0234] In some embodiments, the compound of Formula I is a compound of Formula III-y”:or a pharmaceutically acceptable salt thereof; wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination and R2ais selected from

[0235] In some embodiments, the compound of Formula I is a compound of Formula III-z’:IILz' or a pharmaceutically acceptable salt thereof; wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination and R2ais selected fr

[0236] In some embodiments, the compound of Formula I is a compound of Formula III-z”:111-z" or a pharmaceutically acceptable salt thereof; wherein Rla, R2, R3, and R4, are as defined herein, both singly and in combination and R2aisFF selected from, F 9 , and

[0237] In some embodiments, the compound of Formula I is a compound of Formula IV-aIV-i:IV-h IV-i or a pharmaceutically acceptable salt thereof; wherein RB, R2, R3, Ring A, linker L and R4, are as defined herein, both singly and in combination.

[0238] In some embodiments, the compound of Formula I is a compound of Formula V-a:V-a or a pharmaceutically acceptable salt thereof; wherein RB, R2, R3, and R4, are as defined herein, both singly and in combination.

[0239] In some embodiments, the compound of Formula I is a compound of Formula V-b:OO N RR^4N NS N NXR3R2V-b or a pharmaceutically acceptable salt thereof; wherein RB, R2, R3, and R4, are as defined herein, both singly and in combination.

[0240] In some embodiments, the compound of Formula I is a compound of Formula V-c:V-c or a pharmaceutically acceptable salt thereof; wherein RB, R2, R3, and R4, are as defined herein, both singly and in combination.

[0241] In some embodiments, the compound of Formula I is a compound of Formula V-d:V-d or a pharmaceutically acceptable salt thereof; wherein RB, R2, R3, and R4, are as defined herein, both singly and in combination.

[0242] In some embodiments, the compound of Formula I is a compound of Formula V-e:V-e or a pharmaceutically acceptable salt thereof; wherein RB, R2, R3, and R4, are as defined herein, both singly and in combination.

[0243] In some embodiments, the compound of Formula I is a compound of Formula V-f:V-f or a pharmaceutically acceptable salt thereof; wherein RB, R2, R3, and R4, are as defined herein, both singly and in combination.

[0244] In some embodiments, the compound of Formula I is a compound of Formula V-g:V-g or a pharmaceutically acceptable salt thereof; wherein RB, R2, R3, and R4, are as defined herein, both singly and in combination.

[0245] In some embodiments, the compound of Formula I is a compound of Formula V-h:V-h or a pharmaceutically acceptable salt thereof; wherein RB, R2, R3, and R4, are as defined herein, both singly and in combination.

[0246] In some embodiments, the compound of Formula I is selected from one of those depicted in Table 1 or Table la, or a pharmaceutically acceptable salt thereof. Table 1 or Table la, identifies compounds by their IUPAC name and Table 2 or Table 2a lists the same compounds and shows their chemical structure. In the event of any discrepancy between Table 1’s or Table la’s name for a compound and Table 2’s or Table 2a’ s structure for that same compound, Table 2’s or Table 2a’ s compound structures will dominate and identify the compound corresponding to each respective compound number (I-#) in Table 1 or Table la.Table 1No. IUPAC Name2-(2-(dimethylamino)-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-1-1 carbonyl)piperazin-l-yl)-8-oxopyrido[2,3-b]pyrazin-5(8H)-yl)-N-(3-(trifluoromethyl)bicyclo[ 1.1.1 Jpentan- 1 -yl)acetamide rel-2-(2-(dimethylamino)-6-ethyl-7-((l S,6S)-5-(5-hydroxy-6-methylpyrimidine-1-24-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-8-oxopyrido[2,3-b]pyrazin-5(8H)-yl)-N-(3-(trifluoromethyl)bicyclo[l. l. l]pentan-l-yl)acetamide2-(7-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl)-2-1-3 methyl-5-oxopyrido[2,3-b]thieno[3,2-e]pyrazin-8(5H)-yl)-N-(3-(trifluoromethyl)bicyclof 1.1. 1 ]pentan- 1 -yl)acetamide2-(5-ethyl-6-(4-(5-hydroxy-6-rnethylpyrimidine-4-carbonyl)piperazin-l-yl)-2-(2-1-4 methoxypyridin-4-yl)-7-oxo-[l, 2, 4]tri azolof l,5-a]pyrimidin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[l .1 .1 ]pentan-l -yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-1-5 c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxo-[l,2,4]triazolo[l,5-a]pyrimidin-4(7H)-yl)-N-(3 -methylbicyclofl .1. l]pentan-l-yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-1-6 c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxo-[l,2,4]triazolo[l,5-a]pyrimidin-4(7H)-yl)-N-(3 -fluorobicyclofl .1. l]pentan-l-yl)acetamideN-(3-(l, l-difluoroethyl)bicyclo[l . 1. l]pentan-l-yl)-2-(2-(3,6-dihydro-2H-pyran- 4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-1-7 carbonyl)piperazin-l-yl)-7-oxo-[ 1,2, 4]tri azolof 1, 5-a]pyrimidin-4(7H)- yl)acetamideN-(3-(difluoromethyl)bicyclo[l. l.l]pentan-l-yl)-2-(2-(3,6-dihydro-2H-pyran-4- yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-1-8 carbonyl)piperazin- 1 -yl)-7-oxo-[ 1 , 2, 4]tri azolof 1 ,5 -a]pyrimidin-4(7H)- yl)acetamideN-(3-cyclopropylbicyclo[l.l. l]pentan-l-yl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-1-9 ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l- yl)-7-oxo-[ 1 , 2, 4]tri azolof 1 , 5-a]pyrimidin-4(7H)-yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-1-10 methoxypyri din-4-yl)-7-oxo-[l, 2, 4]tri azolof l,5-a]pyrimidin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclofl .1. l]pentan-l-yl)acetamide2-(2-(l-acetyl-l,2,3,6-tetrahydropyridin-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3- dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxo-[l, 2, 4]tri azolof 1,5-1-11 a]pyrimidin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[l.l.l]pentan-l- yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-1-12 c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxo-[l, 2, 4]tri azolof l,5-a]pyrimidin-4(7H)-yl)-N-(3-methoxybicyclo[l . 1. l]pentan-l-yl)acetamide3-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl)-2-(2-1-13 methoxypyridin-4-yl)-7-oxo-[l, 2, 4]tri azolof l,5-a]pyrimidin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[l .1 .1 ]pentan-l -yl)propanamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-1-14 c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxo-[l,2,4]triazolo[l,5-a]pyrimidin-4(7H)-yl)-N-(3 -ethylbicy clo[ 1.1.1 Jpentan- 1 -yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-1-15 c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxo-[ 1,2, 4]tri azolof l,5-a]pyrimidin- 4(7H)-yl)-N-(3 -isopropylbicyclofl .1 ,l]pentan-l-yl)acetamide2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl)-2-(2-1-16 methoxypyridin-4-yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclof 1.1.1 Jpentan- 1 -yl)acetamide2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl)-2-(2-1-17 methoxypyridin-4-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclofl .1. l]pentan-l-yl)acetamideN-(3-cyclopropylbicyclo[l.l. l]pentan-l-yl)-2-(5-ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)piperazin-l-yl)-2-(l-(2-methoxyacetyl)-l,2,3,6-1-18 tetrahydropyridin-4-yl)-7-oxo-[l,2,4]triazolo[l,5-a]pyrimidin-4(7H)- yl)acetamide2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl)-2-(2-1-19 methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-(trifluoromethyl)bicyclo[l.l. l]pentan-l-yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-1-20 methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)- N-(3-(trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide2-(5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin- l-yl)-2-(l-(2-methoxyacetyl)-l,2,3,6-tetrahydropyridin-4-yl)-7-oxo-1-21[ 1 , 2, 4]tri azolof 1 , 5-a]pyrimidin-4(7H)-yl)-N-(3 -(trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide2-(2-(dimethylamino)-5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-1-22 carbonyl)piperazin-l-yl)-7-oxo-[l, 2, 4]tri azoIofl, 5-a]pyrimidin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclof 1.1.1 Jpentan- 1 -yl)acetamide2-(5 -ethyl-6-(4-(6-hy droxybenzofd] oxazol e-7-carbonyl )piperazin- 1 -yl )-2-(2-1-23 methoxypyridin-4-yl)-7-oxo-[l, 2, 4]tri azolof l,5-a]pyrimidin-4(7H)-yl)-N-(3- ethylbicy clof 1.1.1 Jpentan- 1 -yl)acetamide2-(5-ethyl-6-((lS,6S)-5-(6-hydroxybenzo[d]oxazole-7-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl)-2-(2-methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-1-24 [l,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-(trifluoromethyl)bicyclo[l.l. l]pentan-l- yl)acetamide2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl)-2-(2-1-25 methoxypyridin-4-yl)-7-oxothiazolo[4,5-b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclof 1.1.1 Jpentan- 1 -yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-1-26 4-carbonyl)piperazin- l-yl)-7-oxo-[l, 2, 4]tri azolof l,5-a]pyrimidin-4(7H)-yl)-N-(l-(trifluoromethyl)-2-oxabicyclo[2.1. l]hexan-4-yl)acetamide2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl)-2-(2-1-27 methoxypyridin-4-yl)-7-oxo-[l,2,4]triazolo[l,5-a]pyrimidin-4(7H)-yl)-N-(3-(trifluoromethyl)cyclobutyl)acetamideN-(3-cyclobutylbicyclo[l. l.l]pentan-l-yl)-2-(5-ethyl-6-(4-(6-1-28 hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-methoxypyridin-4-yl)-7-oxo-[l, 2, 4]tri azolof l,5-a]pyrimidin-4(7H)-yl)acetamideN-(3-cyclopropylbicyclo[l.l. l]pentan-l-yl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-1-29 ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-7-oxo-[1, 2, 4]tri azolof l,5-a]pyrimidin-4(7H)-yl)acetamideN-(3-cyclopropylbicyclo[l.l. l]pentan-l-yl)-2-(5-ethyl-6-(4-(5-hydroxy-6-1-30 methylpyrimidine-4-carbonyl)piperazin-l-yl)-2-(2-methoxypyridin-4-yl)-7-oxo- 2,7-dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-1-31 methoxypyridin-4-yl)-7-oxo-[l,2,4]triazolo[l,5-a]pyrimidin-4(7H)-yl)-N-(3-(2- fluoroethyl)bi cyclofl .1.1 ]pentan-l -yl)acetamideN-(3-cyclopropylbicyclo[l.l. l]pentan-l-yl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-1-32 ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl)-7-oxo- [1, 2, 4]tri azolof l,5-a]pyrimidin-4(7H)-yl)acetamide 2-(2-(dimethylamino)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-1-33 carbonyl)piperazin- 1 -yl)-7-oxo-[ 1 , 2, 4]tri azolof 1 ,5 -a]pyrimidin-4(7H)-yl)-N-(3 - (trifluoromethyl)bicyclof 1.1.1 Jpentan- 1 -yl)acetamideN-(2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-1-34 methoxypyridin-4-yl)-7-oxo-[l, 2, 4]tri azolof l,5-a]pyrimidin-4(7H)-yl)ethyl)-3- (trifluoromethyl)bicyclof 1.1.1 Jpentyl- 1 -carboxamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-1-35 methoxypyridin-4-yl)-7-oxo-[l, 2, 4]tri azolof 1, 5-a]pyrimidin-4(7H)-yl)-N-(3- isopropylbicyclof 1.1.1 ]pentan- 1 -yl)acetamideN-(3-cyclopropylbicyclo[l .1 , l]pentan-l-yl)-2-(5-ethyl-6-(4-(6-1-36 hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-methoxypyridin-4-yl)- 7-oxo-[l, 2, 4]tri azolof l,5-a]pyrimidin-4(7H)-yl)acetamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-1-37 methoxypyridin-4-yl)-7-oxothiazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclofl .1. l]pentan-l-yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-1-38 methoxypyri din-4-yl)-7-oxo-[l, 2, 4]tri azolof l,5-a]pyrimi din-4(7H)-yl)-N-(3- (perfluoroethyl)bicyclof 1.1.1 Jpentan- 1 -yl)acetamideN-(3-cy cl opropylbicyclof 1.1.1 ]pentan-l-yl )-2-(5-ethyl-6-(4-(4-hy droxy-2-1-39 methoxy-5-methylnicotinoyl)piperazin-l-yl)-2-(2-methoxypyridin-4-yl)-7-oxo- [1, 2, 4]tri azolof l,5-a]pyrimidin-4(7H)-yl)acetamide2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl)-2-(2-1-40 methoxypyridin-4-yl)-7-oxo-[l, 2, 4]tri azolof l,5-a]pyrimidin-4(7H)-yl)-N-(3- isopropylbicyclof 1.1.1 ]pentan- 1 -yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-1-41 methoxypyridin-4-yl)-7-oxo-[l, 2, 4]tri azolof l,5-a]pyrimidin-4(7H)-yl)-N-(3-(1,1 ,2,2-tetrafluoroethyl)bicyclo[l .1.1 ]pentan-l -yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-1-42 carbonyl)piperazin- 1 -yl)-7-oxo-[ 1 , 2, 4]tri azolof 1 ,5 -a]pyrimidin-4(7H)-yl)-N-(3 - isopropylbicyclo[ 1.1.1 Jpentan- 1 -yl)acetamide2-(2-(dimethylamino)-5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-1-43 carbonyl)piperazin- 1 -yl)-7-oxo-[ 1 , 2, 4]tri azolof 1 ,5 -a]pyrimidin-4(7H)-yl)-N-(3 - isopropylbicyclof 1.1.1 Jpentan- 1 -yl)acetamide2-(5 -ethyl-6-(4-(6-hy droxybenzofd] oxazol e-7-carbonyl )piperazin- 1 -yl )-2-(2-1-44 methoxypyridin-4-yl)-7-oxo-[l, 2, 4]tri azolof l,5-a]pyrimidin-4(7H)-yl)-N-(l- (trifluoromethyl)-2-oxabicyclo[2.1. l]hexan-4-yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-1-45 methoxypyridin-4-yl)-7-oxo-[l, 2, 4]tri azolof l,5-a]pyrimidin-4(7H)-yl)-N-(4- (trifluoromethyl)bicyclo[2.2.2]octan-l-yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-1-46 methoxypyridin-4-yl)-7-oxo-[l, 2, 4]tri azolof l,5-a]pyrimidin-4(7H)-yl)-N-(3- (oxetan-3-yl)bicyclo[l .1. l]pentan-l-yl)acetamide2-(5-ethyl-6-((lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl)-2-(2-methoxypyridin-4-yl)-7-oxo-1-48[1, 2, 4]tri azolof 1, 5-a]pyrimidin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclof 1.1.1 Jpentan- 1 -yl)acetamideN-(3-cyclopropylbicyclo[l.l. l]pentan-l-yl)-2-(5-ethyl-6-((l S,6S)-5-(5-hydroxy- 6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(2-1-49 methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[ 1,2, 3]triazolo[4,5-b]pyri din-4- yl)acetamide2-(5-ethyl-6-((lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl)-2-(2-methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-1-50 [l,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-(trifluoromethyl)bicyclo[l.l. l]pentan-l- yl)acetamideN-{3-cyclopropylbicyclo[l. l.l]pentan-l-yl}-2-[2-(3,6-dihydro-2H-pyran-4-yl)- 5-ethyl-6-[(l S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-1-52 diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4- yl]acetamide2-{2-cyclopropyl-5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4- carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-1-53[1,2,3 ]triazolo[4, 5-b]pyridin-4-yl } -N-{ 3 -cyclopropylbicyclo[ 1.1.1 Jpentan- 1 - yl} acetamide2-{6-[(4aS,7aS)-4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-octahydro-lH- cyclopenta[b]pyrazin-l-yl]-5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-1-54[l,2,3]triazolo[4,5-b]pyridin-4-yl}-N-{3-cyclopropylbicyclo[l.l.l]pentan-l- yl} acetamideN-{3-cyclopropylbicyclo[l.l.l]pentan-l-yl}-2-[2-(l,5-dimethyl-lH-pyrazol-3- yl)-5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-1-55 diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4- yl]acetamide2-[2-(l,5-dimethyl-lH-pyrazol-3-yl)-5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-1-562H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl]-N-[3-(propan-2- yl)bicyclo[ 1.1.1 Jpentan- 1 -yl]acetamide2-[2-(l,5-dimethyl-lH-pyrazol-3-yl)-5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-1-572H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl]-N-{spiro[3.3]heptan-2- yl} acetamide2-{5-ethyl-6-[4-(3-hydroxy-5-methoxypyridine-4-carbonyl)piperazin-l-yl]-2-(2-1-58 methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl}-N-[3- (propan-2-yl)bicyclo[l .1. l]pentan-l-yl]acetamide2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-[4-(5-hydroxy-6-methylpyrimidine-1-59 4-carbonyl)piperazin-l-yl]-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl]- N-[3-(propan-2-yl)bicyclo[l .1.1 ]pentan-l -yl]acetamide2-{6-[(4aS,7aS)-4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-octahydro-lH- cyclopenta[b]pyrazin-l-yl]-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-1-60 2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl}-N-{3- cy clopropylbicyclo[ 1.1.1 Jpentan- 1 -yl } acetamide2-{5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-1-61[1.2.3]triazolo[4,5-b]pyridin-4-yl}-N-[3-(trifluoromethoxy)bicyclo[l.l. l]pentan- l-yl]acetamide rel-2-{5-ethyl-6-[(lR,6S)-3-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-3- azabicyclo[4.1.0]heptan-6-yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-1-62[1.2.3]triazolo[4,5-b]pyridin-4-yl}-N-[3-(propan-2-yl)bicyclo[l.l.l]pentan-l- yl]acetamide rel-2-{5-ethyl-6-[(lR,6S)-3-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-3- azabicyclo[4.1.0]heptan-6-yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-1-63[1.2.3]triazolo[4,5-b]pyridin-4-yl}-N-[3-(propan-2-yl)bicyclo[l.l. l]pentan-l- yl]acetamide rel-2-[5-ethyl-6-(4-{4-hydroxy-2-methoxy-5-[(3R)-oxolan-3-yl]pyridine-3- carbonyl}piperazin-l-yl)-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-1-64[1.2.3]triazolo[4,5-b]pyridin-4-yl]-N-[3-(propan-2-yl)bicyclo[l. l.l]pentan-l- yl]acetamide rel-2-[5-ethyl-6-(4-{4-hydroxy-2-methoxy-5-[(3R)-oxolan-3-yl]pyridine-3- carbonyl } piperazin- 1 -yl)-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-1-65[1.2.3]triazolo[4,5-b]pyridin-4-yl]-N-[3-(propan-2-yl)bicyclo[l .1 l]pentan-l- yl]acetamide2-(5-ethyl-6-{4-[4-hydroxy-2-(2-methoxyethoxy)-5-methylpyridine-3- carbonyl]piperazin-l-yl}-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-1-66[1.2.3]triazolo[4,5-b]pyridin-4-yl)-N-[3-(propan-2-yl)bicyclo[l. l.l]pentan-l- yl]acetamide 2-[2-(l-cyclopropyl-lH-pyrazol-4-yl)-5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-1-67 2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl]-N-{3- cy clopropylbicyclo[ 1.1.1 ]pentan- 1 -yl } acetamide2-{5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-1-68 diazabicyclo[4.2.0]octan-2-yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[1.2.3]triazolo[4,5-b]pyridin-4-yl}-N-{6-fluorospiro[3.3]heptan-2-yl}acetamide 2-{5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-1-69[1.2.3]triazolo[4,5-b]pyridin-4-yl}-N-[3-(propan-2-yl)bicyclo[l.l. l]pentan-l- yl]acetamide2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-1-70 2H, 4H,7H-[ 1,2,3 ]triazolo[4,5-b]pyridin-4-yl]-N-[3 -(propan-2 - yl)bicyclo[ 1.1.1 Jpentan- 1 -yl]acetamide 2-(5-ethyl-6-{4-[4-hydroxy-2-methoxy-5-(methoxymethyl)pyridine-3- carbonyl]piperazin-l-yl}-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-1-71[1.2.3]triazolo[4,5-b]pyridin-4-yl)-N-[3-(propan-2-yl)bicyclo[l. l.l]pentan-l- yl]acetamide 2-(6-{4-[5-(difluoromethyl)-4-hydroxy-2-methoxypyridine-3-carbonyl]piperazin-1-72 1-yl}-5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5- b]pyridin-4-yl)-N-[3-(propan-2-yl)bicyclo[l. l. l]pentan-l-yl]acetamide2-{6-[(lS,6S)-5-(l,3-benzoxazole-7-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-1-73 yl]-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5- b]pyridin-4-yl }-N-[3-(propan-2-yl)bicyclo[l .1.1 ]pentan-l -yl]acetamide2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-[(lS,6S)-5-(2-methoxybenzoyl)-2,5-1-74 diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4- yl]-N-[3-(propan-2-yl)bicyclo[l . 1. l]pentan-l-yl]acetamide2-(6-{4-[2-(difluoromethoxy)-4-hydroxy-5-methylpyridine-3-carbonyl]piperazin-1-76 1-yl}-5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5- b]pyridin-4-yl)-N-[3-(propan-2-yl)bicyclo[l .1.1 ]pentan-l -yl] acetamide2-[2-(l-cyclopropyl-lH-pyrazol-4-yl)-5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-1-77 2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl]-N-[3-(propan-2- yl)bicyclo[ 1.1.1 Jpentan- 1 -y l]acetam i de2-[2-(l -cyclopropyl- lH-pyrazol-3-yl )-5-ethyl-6-[(l S,6S)-5-(5-hy droxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-1-78 2H, 4H,7H-[ 1,2,3 ]triazolo[4,5-b]pyridin-4-yl]-N-[3 -(propan-2 - yl)bicyclo[ 1.1.1 Jpentan- 1 -yl]acetamideN-[3-(l,l-difluoroethyl)bicyclo[l. l.l]pentan-l-yl]-2-{5-ethyl-6-[(lS,6S)-5-(5- hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-2-1-79 (2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4- yl) acetamideN-{3-cyclobutylbicyclo[l.l. l]pentan-l-yl}-2-{5-ethyl-6-[(lS,6S)-5-(5-hydroxy- 6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-2-(2-1-80 methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4- yl} acetamide 2-[5-ethyl-6-(4-{4-hydroxy-5-methyl-2-[(l-methyl-lH-pyrazol-4- yl)oxy]pyridine-3-carbonyl}piperazin-l-yl)-2-(2-methoxypyridin-4-yl)-7-oxo-1-81 2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl]-N-[3-(propan-2- yl)bicyclo[ 1.1.1 ]pentan- 1 -yl]acetamide2-{5-ethyl-6-[4-(4-hydroxy-2,5-dimethoxypyridine-3-carbonyl)piperazin-l-yl]-2-1-82 (2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl}-N- [3-(propan-2-yl)bicyclo[l .1 ,l ]pentan-l-yl]acetamide2-{6-[4-(5-cyclopropyl-4-hydroxy-2-methoxypyridine-3-carbonyl)piperazin-l-1-83 yl]-5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5- b]pyridin-4-yl}-N-[3-(propan-2-yl)bicyclo[l. l.l]pentan-l-yl]acetamide 2-{5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-1-84 diazabicyclo[4.2.0]octan-2-yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[1.2.3]triazolo[4,5-b]pyridin-4-yl}-N-{spiro[3.4]octan-6-yl}acetamide N-{ l,l-difluorospiro[2.5]octan-6-yl}-2-{5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-2-(2-1-85 methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4- yl} acetamideN-{7,7-difluorospiro[3.5]nonan-2-yl}-2-{5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-2-(2-1-86 methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4- yl} acetamide 2-{5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-1-87 diazabicyclo[4.2.0]octan-2-yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[1.2.3]triazolo[4,5-b]pyridin-4-yl}-N-{l-fluorospiro[2.3]hexan-5-yl} acetamide N-{6,6-difluorospiro[3.3]heptan-2-yl }-2-{5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-2-(2-1-88 methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4- yl} acetamide2-{5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-1-89[1.2.3]triazolo[4,5-b]pyridin-4-yl}-N-{l-methoxyspiro[3.3]heptan-2- yl} acetamideN-{6,6-dimethylspiro[3.3]heptan-2-yl}-2-{5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-2-(2-1-90 methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4- yl} acetamideN-{3-cyclopropylbicyclo[l. l.l]pentan-l-yl}-2-{5-ethyl-6-[(lS,6S)-5-(4- hydroxy-2-methoxy-5-methylpyridine-3-carbonyl)-2,5-diazabicyclo[4.2.0]octan-1-91 2-yl]-2-(2-methylpyridin-4-yl)-7-oxo-2H,4H,7H-[ 1,2, 3]triazolo[4,5-b]pyri din-4- yl} acetamide2-(5-ethyl-6-{4-[4-hydroxy-2-methoxy-5-(oxolan-3-yl)pyridine-3- carbonyl ] pi perazin - 1 -y 1 } -2-(2-methoxypy ri din-4-yl )-7-oxo-2H,4H, 7H-1-92[l,2,3]triazolo[4,5-b]pyridin-4-yl)-N-[3-(propan-2-yl)bicyclo[l. l.l]pentan-l- yl]acetamide rel-2-{6-[(4aR,7aS)-4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-octahydro- lH-cyclopenta[b]pyrazin-l-yl]-5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-1-93 2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl}-N-[3-(propan-2- yl)bicyclo[l .1.1 ]pentan-l -yl]acetamide rel-2-{6-[(4aR,7aS)-4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-octahydro- lH-cyclopenta[b]pyrazin-l-yl]-5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-1-94 2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl}-N-[3-(propan-2- yl)bicyclo[ 1.1.1 ]pentan- 1 -yljacetamide2-{5-ethyl-6-[l-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-5-methyl-l,2,3,6- tetrahydropyridin-4-yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-1-95[l,2,3]triazolo[4,5-b]pyridin-4-yl}-N-[3-(propan-2-yl)bicyclo[l.l. l]pentan-l- yl]acetamide2-{5-ethyl-6-[l-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-l,2,3,6- tetrahydropyridin-4-yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-1-96[ 1 ,2,3 ]triazolo[4, 5-b]pyridin-4-yl } -N-[3 -(propan-2-yl)bicy clo[ 1.1.1 Jpentan- 1 - yl]acetamide rel-2-{5-ethyl-6-[(3R)-l-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-3-methyl- l,2,3,6-tetrahydropyridin-4-yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-1-97[l,2,3]triazolo[4,5-b]pyridin-4-yl}-N-[3-(propan-2-yl)bicyclo[l.l. l]pentan-l- yl]acetamiderel-2-{5-ethyl-6-[(3R)-l-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-3-methyl- l,2,3,6-tetrahydropyridin-4-yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-1-98 [ 1 ,2,3 ]triazolo[4, 5-b]pyridin-4-yl } -N-[3 -(propan-2-yl)bicyclo[ 1.1. 1 ]pentan- 1 - yl]acetamideN-{3-cyclopropylbicyclo[l. l.l]pentan-l-yl}-2-{5-ethyl-6-[(lS,6S)-5-(5- hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-2-1-99 (2-methylpyridin-4-yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4- yl} acetamide 2-{5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-1-100 diazabicyclo[4.2.0]octan-2-yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[1.2.3]triazolo[4,5-b]pyridin-4-yl}-N-{spiro[3.3]heptan-2-yl}acetamide 2-{5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-1-101 diazabicyclo[4.2.0]octan-2-yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[1.2.3]triazolo[4,5-b]pyridin-4-yl}-N-{2-methylspiro[3.3]heptan-2-yl}acetamide 2-{5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-1-102 diazabicyclo[4.2.0]octan-2-yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[1.2.3]triazolo[4,5-b]pyridin-4-yl}-N-{6-methylspiro[3.3]heptan-2-yl}acetamide 2-{5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-1-103 diazabicyclo[4.2.0]octan-2-yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[1.2.3]triazolo[4,5-b]pyridin-4-yl}-N-{spiro[3.4]octan-2-yl}acetamide 2-{5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2-(pyridin-2-yl)-2H,4H,7H-1-104[ 1 ,2,3 ]triazolo[4, 5-b]pyridin-4-yl } -N-[3 -(propan-2-yl)bicy clo[ 1.1.1 Jpentan- 1 - yl]acetamide2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-[(lS,6S)-5-(4-hydroxy-2-methoxy-5- methylpyridine-3-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-1-105[1.2.3]triazolo[4,5-b]pyridin-4-yl]-N-[3-(propan-2-yl)bicyclo[l. l.l]pentan-l- yl]acetamide2-{5-ethyl-6-[(lS,6S)-5-(4-hydroxy-2-methoxy-5-methylpyridine-3-carbonyl)-1-106 2,5-diazabicyclo[4.2.0]octan-2-yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl}-N-{spiro[3.3]heptan-2-yl}acetamide2-{5-ethyl-6-[(lS,6S)-5-(4-hydroxy-2-methoxy-5-methylpyridine-3-carbonyl)- 2,5-diazabicyclo[4.2.0]octan-2-yl]-2-(2-methylpyridin-4-yl)-7-oxo-2H,4H,7H-1-107 [1, 2, 3]triazolo[4,5-b]pyridin-4-yl}-N-[3-(propan-2-yl)bi cyclofl .1 . l]pentan-l - yl]acetamideN-{3-cyclopropylbicyclo[l. l.l]pentan-l-yl}-2-[2-(3,6-dihydro-2H-pyran-4-yl)-1-108 5-ethyl-6-[4-(4-hydroxy-2-methoxy-5-methylpyridine-3-carbonyl)piperazin-l- yl]-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl]acetamide2-{6-[4-(2-ethoxy-4-hydroxy-5-methylpyridine-3-carbonyl)piperazin-l-yl]-5-1-109 ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl } -N-[3 -(propan-2-yl)bicyclo[ 1.1.1 ]pentan- 1 -yl]acetamide2-{5-ethyl-6-[4-(4-hydroxy-2-methoxy-5-methylpyridine-3-carbonyl)piperazin-l-1-110 yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[ 1,2, 3]triazolo[4,5-b]pyri din-4- yl}-N-{spiro[3.4]octan-2-yl}acetamide2-{5-ethyl-6-[4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl]-7-1-111 oxo-2-(pyridin-2-yl)-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl}-N-[3-(propan- 2-yl)bicyclo[ 1.1.1 Jpentan- 1 -yl]acetamide2-{5-ethyl-6-[4-(4-hydroxy-2-methoxy-5-methylpyridine-3-carbonyl)piperazin-l-1-112 yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[ 1,2, 3]triazolo[4,5-b]pyri din-4- yl} -N-{6-methylspiro[3.3 ]heptan-2-yl } acetamideN-{6,6-difluorospiro[3.3]heptan-2-yl }-2-{5-ethyl-6-[4-(4-hydroxy-2-m ethoxy-5-1-113 methylpyridine-3-carbonyl)piperazin-l-yl]-2-(2-methoxypyridin-4-yl)-7-oxo- 2H, 4H,7H-[1, 2, 3 ]triazolo[4,5-b]pyridin-4-yl} acetamideN-{6,6-dimethylspiro[3.3]heptan-2-yl}-2-{5-ethyl-6-[4-(4-hydroxy-2-methoxy-1-114 5-methylpyridine-3-carbonyl)piperazin-l-yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl}acetamideN-{7,7-difluorospiro[3.5]nonan-2-yl}-2-{5-ethyl-6-[4-(4-hydroxy-2-methoxy-5-1-115 methylpyridine-3-carbonyl)piperazin-l-yl]-2-(2-methoxypyridin-4-yl)-7-oxo- 2H, 4H,7H-[ 1,2, 3 ]triazolo[4,5-b]pyridin-4-yl } acetamide2-{6-[(lS,6S)-5-(l,3-benzoxazole-7-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-1-116 yl]-5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5- b]pyridin-4-yl }-N-[3-(propan-2-yl)bicyclo[l .1.1 ]pentan-l -yl]acetamideN-{3-cyclopropylbicyclo[l. l.l]pentan-l-yl}-2-{5-ethyl-6-[4-(6-hydroxy-2-1-117 methoxy-3-methylbenzoyl)piperazin-l-yl]-2-(2-methoxypyridin-4-yl)-7-oxo- 2H, 4H,7H-[1, 2, 3 ]triazolo[4,5-b]pyridin-4-yl} acetamide2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-[4-(4-hydroxy-2-methoxy-5-1-118 methylpyridine-3-carbonyl)piperazin-l-yl]-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5- b]pyridin-4-yl]-N-[3-(propan-2-yl)bicyclo[l.l. l]pentan-l-yl]acetamide2-{5-ethyl-6-[4-(4-hydroxy-2-methoxy-5-methylpyridine-3-carbonyl)piperazin-l-1-119 yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4- yl } -N-[3 -(propan-2-yl)bicy clo[ 1.1.1 Jpentan- 1 -y I Jacetami de2-{5-ethyl-6-[(lS,6S)-5-(4-hydroxy-2-methoxy-5-methylpyridine-3-carbonyl)- 2,5-diazabicyclo[4.2.0]octan-2-yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-1-120 [1,2,3 ]triazolo[4, 5-b]pyridin-4-yl } -N-[3 -(propan-2-yl)bicyclo[ 1.1.1 ]pentan- 1 - yl]acetamide2-{5-ethyl-6-[(lS,6S)-5-(4-hydroxy-2-methoxy-5-methylpyridine-3-carbonyl)- 2,5-diazabicyclo[4.2.0]octan-2-yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-1-121 [l,2,3]triazolo[4,5-b]pyridin-4-yl}-N-[3-(trifluoromethyl)bicyclo[l.l. l]pentan-l- yl]acetamide2-{5-ethyl-6-[4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl]-2-(2-1-122 methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl}-N-{ spi ro[3.3 ] heptan-2-y 1 } acetami deN-[3-(2,2-difluoroethyl)bicyclo[l. l.l]pentan-l-yl]-2-{5-ethyl-6-[4-(4-hydroxy-2-1-123 methoxy-5-methylpyridine-3-carbonyl)piperazin-l-yl]-2-(2-methoxypyri din-4- yl)-7-oxo-2H,4H,7H-[ 1,2, 3]triazolo[4,5-b]pyridin-4-yl [acetamideN-[3-(l,l-difluoroethyl)bicyclo[l. l.l]pentan-l-yl]-2-{5-ethyl-6-[4-(4-hydroxy-2-1-124 methoxy-5-methylpyridine-3-carbonyl)piperazin-l-yl]-2-(2-methoxypyri din-4- yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl}acetamide 2-{5-ethyl-6-[4-(4-hydroxy-2-methoxy-5-methylpyridine-3-carbonyl)piperazin-l-1-125 yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[ 1,2, 3]triazolo[4,5-b]pyri din-4- yl }-N-[3-(oxolan-3-yl)bicyclo[l .1.1 ]pentan-l -yl]acetamide2-{5-ethyl-6-[4-(4-hydroxy-2-methoxy-5-methylpyridine-3-carbonyl)piperazin-l-1-126 yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[ 1,2, 3]triazolo[4,5-b]pyri din-4- yl } -N-[3 -(pyrrolidin- 1 -yl)bicyclo[ 1.1.1 Jpentan- 1 -yl]acetamide2-{5-ethyl-6-[4-(4-hydroxy-2-methoxy-5-methylpyridine-3-carbonyl)piperazin-l-1-127 yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4- yl } -N- { spiro[3.3 ]heptan-2-yl } acetamide2-{5-ethyl-6-[4-(4-hydroxy-2-methoxy-5-methylpyridine-3-carbonyl)piperazin-l-1-128 yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4- yl]-N-[3-(trifluoromethyl)bicyclo[l. l.l]pentan-l-yl]acetamideN-{3-cyclopropylbicyclo[l. l.l]pentan-l-yl]-2-{5-ethyl-6-[4-(4-hydroxy-2-1-129 methoxy-5-methylpyridine-3-carbonyl)piperazin-l-yl]-2-(2-methoxypyri din-4- yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl}acetamide 2-{5-ethyl-6-[4-(4-hydroxy-2-methoxy-5-methylpyridine-3-carbonyl)piperazin-l-1-130 yl]-2-(2-methylpyridin-4-yl)-7-oxo-2H,4H,7H-[ 1,2, 3]triazolo[4,5-b]pyri din-4- yl } -N-[3 -(propan-2-yl)bicyclo[ 1.1.1 ]pentan- 1 -yl] acetamide2-{5-ethyl-6-[4-(4-hydroxy-2-methoxy-5-methylpyridine-3-carbonyl)piperazin-l-1-131 yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[ 1,2, 3]triazolo[4,5-b]pyri din-4- yl}-N-[3-(2,2,2-trifluoroethyl)bicyclo[l. l.l]pentan-l-yl]acetamideN-{3-cyclopropylbicyclo[l. l.l]pentan-l-yl}-2-{5-ethyl-6-[4-(2-hydroxy-4,6-1-132 dimethoxybenzoyl)piperazin-l-yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H- [l,2,3]triazolo[4,5-b]pyridin-4-yl} acetamide 2-{5-ethyl-6-[4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl]-7-1-133 oxo-2-(pyridin-4-yl)-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl}-N-[3-(propan- 2-yl)bicyclo[ 1.1.1 Jpentan- 1 -yl] acetamideN-{3-cyclopropylbicyclo[l. l.l]pentan-l-yl}-2-(5-ethyl-6-{4-[2-hydroxy-6-1-135 (trifluoromethoxy)benzoyl]piperazin-l-yl}-2-(2-methoxypyridin-4-yl)-7-oxo- 2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide 2-{5-ethyl-6-[(lS,6S)-5-(6-hydroxy-l,3-benzoxazole-7-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-1-136[1.2.3]triazolo[4,5-b]pyridin-4-yl}-N-[3-(propan-2-yl)bicyclo[l .1 . l]pentan-l - yl]acetamide 2-{5-ethyl-6-[4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl]-7-1-137 oxo-2-(pyridin-4-yl)-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl}-N-{3- ethylbicy clo[ 1.1.1 Jpentan- 1 -yl } acetamide N-{3-cyclobutylbicyclo[l .l . l]pentan-l-yl}-2-{5-ethyl-6-[4-(5-hydroxy-6-1-138 methylpyrimidine-4-carbonyl)piperazin-l-yl]-2-(2-methoxypyridin-4-yl)-7-oxo- 2H, 4H,7H-[ 1,2, 3 ]triazolo[4,5-b]pyridin-4-yl } acetamide N-{3-cyclobutylbicyclo[l.l. l]pentan-l-yl}-2-{5-ethyl-6-[4-(5-hydroxy-6-1-139 methylpyrimidine-4-carbonyl)piperazin-l-yl]-7-oxo-2-(pyridin-4-yl)-2H,4H,7H-[1.2.3]triazolo[4,5-b]pyridin-4-yl}acetamide 2-{5-ethyl-6-[4-(4-hydroxy-2-methoxypyridine-3-carbonyl)piperazin-l-yl]-2-(2-1-141 methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl }-N-[3- (trifluoromethyl)bicyclo[l .1. l]pentan-l-yl]acetamide 2-{5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl]-2-(4-methoxyphenyl)-7-oxo-2H,4H,7H-1-145[1.2.3]triazolo[4,5-b]pyridin-4-yl}-N-[3-(propan-2-yl)bicyclo[l.l.l]pentan-l- yl]acetamide 2-{5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl]-2-(6-methoxypyridin-3-yl)-7-oxo-2H,4H,7H-1-146[l,2,3]triazolo[4,5-b]pyridin-4-yl}-N-[3-(propan-2-yl)bicyclo[l.l. l]pentan-l- yl]acetamide2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-[(lS,6S)-5-(6-methoxy-lH- pyrrolo[2,3-b]pyridine-5-carbonyl}-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-1-147 2H, 4H,7H-[ 1,2,3 ]triazolo[4,5-b]pyridin-4-yl]-N-[3 -(propan-2 - yl)bicyclo[l .1.1 ]pentan-l -yl]acetamide2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-[(lS,6S)-5-(8-hydroxyquinoline-2- carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-1-148[l,2,3]triazolo[4,5-b]pyridin-4-yl]-N-[3-(propan-2-yl)bicyclo[l. l.l]pentan-l- yl]acetamide2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-[(lS,6S)-5-(8-hydroxyquinoline-7- carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-1-149[1.2.3]triazolo[4,5-b]pyridin-4-yl]-N-[3-(propan-2-yl)bicyclo[l. l.l]pentan-l- yl]acetamide2-{5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl]-2-{2-oxaspiro[3.3]heptan-6-yl}-7-oxo-2H,4H,7H-1-150[1.2.3]triazolo[4,5-b]pyridin-4-yl}-N-[3-(propan-2-yl)bicyclo[l.l. l]pentan-l- yljacetamide2-(4-{4-[({3-cyclopropylbicyclo[l.l.l]pentan-l-yl}carbamoyl)methyl]-5-ethyl-2-1-151 (2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-6- yl (piperazine- 1 -carbonyl)benzoic acid methyl (lS,6S)-5-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4-({[3-(propan-1-152 2-yl)bicyclo[l.l. l]pentan-l-yl]carbamoyl}methyl)-2H,4H,7H-[l,2,3]triazolo[4,5- b]pyridin-6-yl]-2,5-diazabicyclo[4.2.0]octane-2-carboxylate2-[5-ethyl-2-(3-fluoropyridin-2-yl)-6-[(lS,6S)-5-(5-hydroxy-6-methylpyrimidine- 4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-1-153[1.2.3]triazolo[4,5-b]pyridin-4-yl]-N-[3-(propan-2-yl)bicyclo[l. l.l]pentan-l- yljacetamideN-{3-cyclopropylbicyclo[l.l.l]pentan-l-yl}-2-{5-ethyl-6-[(lS,6S)-5-(5- hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-2-1-154 (6-methyl-3,6-dihydro-2H-pyran-4-yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5- b]pyridin-4-yl} acetamide2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-[(lS,6S)-5-[2-methoxy-5-(4- methylpiperazin-l-yl)benzoyl]-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-1-155 2H, 4H,7H-[ 1,2,3 ]triazolo[4,5-b]pyridin-4-yl]-N-[3 -(propan-2 - yl)bicyclo[l .1.1 ]pentan-l -yl]acetamide2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-[(lS,6S)-5-(4-methoxy-lH-pyrazole-5-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-1-156[l,2,3]triazolo[4,5-b]pyridin-4-yl]-N-[3-(propan-2-yl)bicyclo[l. l.l]pentan-l- yl]acetamide2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-[(lS,6S)-5-(5-methoxypyrimidine-4- carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-1-157[l,2,3]triazolo[4,5-b]pyridin-4-yl]-N-[3-(propan-2-yl)bicyclo[l. l.l]pentan-l- yl]acetamide2-{6-[(lS,6S)-5-(3-cyano-5-methoxypyridine-4-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl]-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-1-1582H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl}-N-[3-(propan-2- yl)bicyclo[ 1.1.1 ]pentan- 1 -yljacetamide2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-[(lS,6S)-5-[2-methoxy-3-(4- methylpiperazin-l-yl)benzoyl]-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-1-1592H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl]-N-[3-(propan-2- yl)bicyclo[ 1.1.1 Jpentan- 1 -yl]acetamide2-{6-[(lS,6S)-5-(4-cyano-lH-imidazole-5-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl]-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-1-1602H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl}-N-[3-(propan-2- yl)bicyclo[ 1.1.1 Jpentan- 1 -yl]acetamide2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-[(lS,6S)-5-(4-hydroxy-l,2-oxazole-3-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-1-161[l,2,3]triazolo[4,5-b]pyridin-4-yl]-N-[3-(propan-2-yl)bicyclo[l. l.l]pentan-l- yl]acetamideN-{3-cyclopropylbicyclo[l. l.l]pentan-l-yl}-2-{5-ethyl-6-[(lS,6S)-5-(5- hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-2-1-162 (2-methyl-3,6-dihydro-2H-pyran-4-yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5- b]pyridin-4-yl} acetamideN-{3-cyclopropylbicyclo[l. l.l]pentan-l-yl}-2-{5-ethyl-6-[(lS,6S)-5-(5- hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-2-1-163 (4-methoxycyclohex-l-en-l-yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4- yl} acetamide2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-[(lS,6S)-5-(3-methoxy-l,2-thi azole-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-1-164[l,2,3]triazolo[4,5-b]pyridin-4-yl]-N-[3-(propan-2-yl)bicyclo[l. l.l]pentan-l- yljacetamideN-{3-cyclopropylbicyclo[l. l.l]pentan-l-yl}-2-{5-ethyl-6-[(lS,6S)-5-(5- hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-1-165 oxo-2-[2-(trifluoromethyl)pyridin-4-yl]-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin- 4-yl} acetamide2-{5-ethyl-6-[(lS,6S)-5-(5-fluoro-4-hydroxy-2-methoxypyridine-3-carbonyl)- 2,5-diazabicyclo[4.2.0]octan-2-yl]-2-(2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-1-166 [l,2,3]triazolo[4,5-b]pyridin-4-yl}-N-[3-(propan-2-yl)bicyclo[l.l. l]pentan-l- yljacetamideN-{3-cyclopropylbicyclo[l. l.l]pentan-l-yl}-2-{5-ethyl-6-[(3R)-4-(5-hydroxy-6-1-167 methylpyrimidine-4-carbonyl)-3-methylpiperazin-l-yl]-2-(2-methoxypyridin-4- yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl}acetamide2-{5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl]-2-(6-methylpyridin-2-yl)-7-oxo-2H,4H,7H-1-168 [1,2,3 ]triazolo[4, 5-b]pyridin-4-yl } -N-[3 -(propan-2-yl)bicyclo[ 1.1.1 ]pentan- 1 - yljacetamideN-{3-cyclopropylbicyclo[l. l.l]pentan-l-yl}-2-{5-ethyl-6-[(lS,6S)-5-(5- hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-2-[-1-169 2-methyl-3,6-dihydro-2H-pyran-4-yl]-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5- b]pyridin-4-yl } acetamide (single stereoisomer, first eluting peak)N-{3-cyclopropylbicyclo[l. l.l]pentan-l-yl}-2-{5-ethyl-6-[(lS,6S)-5-(5- hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-2-[-1-170 2-methyl-3,6-dihydro-2H-pyran-4-yl]-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5- b]pyridin-4-yl (acetamide (single stereoisomer, second eluting peak)N-{3-cyclopropylbicyclo[l.l.l]pentan-l-yl(-2-{2-[2-(difluoromethyl)pyri din-4- yl]-5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-1-171 diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4- yl} acetamideN-{3-cyclopropylbicyclo[l. l.l]pentan-l-yl(-2-[2-(3,6-dihydro-2H-pyran-4-yl)- 5-ethyl-6-[(lS,6S)-5-(5-fluoro-3-hydroxy-2-methoxypyridine-4-carbonyl)-2,5-1-172 diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4- yl]acetamide2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-[(lS,6S)-5-(pyridine-2-1-173 carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-2H,4H,7H-[l,2,3]triazolo[4,5- b]pyridin-4-yl]-N-[3-(propan-2-yl)bicyclo[l .1. l]pentan-l-yl]acetamideN-{3-cyclopropylbicyclo[l. l.l]pentan-l-yl(-2-{2-[l-(2,2-difluoroethyl)-l,2,3,6- tetrahydropyridin-4-yl]-5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-1-174 carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-[ 1,2, 3]triazolo[4,5-b]pyridin-4-yl (acetamideN-{3-cyclopropylbicyclo[l. l.l]pentan-l-yl}-2-[2-(3,6-dihydro-2H-pyran-4-yl)- 5-ethyl-6-[(lS,6S)-5-[5-(3-hydroxy-3-methylpyrrolidin-l-yl)-2-methoxypyridine-1-175 3-carbonyl]-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H- [l,2,3]triazolo[4,5-b]pyridin-4-yl]acetamide2-{5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl]-2-(l-methyl-lH-pyrazol-3-yl)-7-oxo-2H,4H,7H-1-176 [ 1 ,2,3 ]triazolo[4, 5-b]pyridin-4-yl } -N-[3 -(propan-2-yl)bicyclo[ 1.1. 1 ]pentan- 1 - yl]acetamideN-{3-cyclopropylbicyclo[l. l.l]pentan-l-yl}-2-{5-ethyl-6-[(lS,6S)-5-(5- hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-2-1-177 (2-methoxypyridin-4-yl)-7-oxo-2H,4H,7H-pyrazolo[4,3-b]pyridin-4- yl} acetamideN-{3-cyclopropylbicyclo[l.l.l]pentan-l-yl}-2-{6-[(lS,6S)-5-[6- (difluoromethyl)-4-hydroxy-2-methoxy-5-methylpyridine-3-carbonyl]-2,5-1-178 diazabicyclo[4.2.0]octan-2-yl]-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo- 2H,4H,7H-[ 1 ,2,3 ]triazolo[4,5-b]pyridin-4-yl } acetamide2-[2-(3,6-dihydro-2H-pyran-4-yl)-6-[(lS,6S)-5-(2,4-dimethoxypyridine-3- carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-5-ethyl-7-oxo-2H,4H,7H-1-179 [l,2,3]triazolo[4,5-b]pyridin-4-yl]-N-[3-(propan-2-yl)bicyclo[l. l.l]pentan-l- yl]acetamideN-{3-cyclopropylbicyclo[l.l.l]pentan-l-yl}-2-[2-(3,6-dihydro-2H-pyran-4-yl)- 5-ethyl-6-[(lS,6S)-5-(6-methoxy-l,3-benzoxazole-7-carbonyl)-2,5-1-180 diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4- yl]acetamide2-{6-[(lS,6S)-5-(4-amino-6-methoxypyrimidine-5-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl]-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-1-1812H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl}-N-{3- cyclopropylbicyclo[ 1.1.1 Jpentan- 1 -yl } acetamideN-{3-cyclopropylbicyclo[l. l.l]pentan-l-yl}-2-[2-(3,6-dihydro-2H-pyran-4-yl)- 5-ethyl-6-[(lS,6S)-5-(5-fluoro-6-hydroxy-l,3-benzoxazole-7-carbonyl)-2,5-1-182 diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4- yl]acetamideN-{3-cyclopentylbicyclo[l.l. l]pentan-l-yl}-2-{5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-2-(2-1-183 methoxypyridin-4-yl)-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4- yl} acetamideN-{3-tert-butylbicyclo[l. l. l]pentan-l-yl}-2-[2-(3,6-dihydro-2H-pyran-4-yl)-5- ethyl-6-[(l S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-1-184 diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4- yl]acetamide2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-[(lS,6S)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-1-1852H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl]-N-{spiro[3.3]heptan-2- yl} acetamide2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-[(lS,6S)-5-(2-methoxypyridine-3- carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-1-186[l,2,3]triazolo[4,5-b]pyridin-4-yl]-N-[3-(propan-2-yl)bicyclo[l. l.l]pentan-l- yl]acetamide2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-[(lS,6S)-5-(2-oxo-2,3- dihydro-l,3-benzoxazole-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-1-1872H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl]-N-[3-(propan-2- yl)bicyclo[ 1.1.1 Jpentan- 1 -yl]acetamide2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-[(lS,6S)-5-(3-methoxypyrazine-2- carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-1-188[l,2,3]triazolo[4,5-b]pyridin-4-yl]-N-[3-(propan-2-yl)bicyclo[l. l.l]pentan-l- yl]acetamide2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-[(lS,6S)-5-(4-methoxypyrimidine-5- carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-1-189[l,2,3]triazolo[4,5-b]pyridin-4-yl]-N-[3-(propan-2-yl)bicyclo[l. l.l]pentan-l- yl]acetamide2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-[(lS,6S)-5-(4-methoxypyridine-3- carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-1-191[l,2,3]triazolo[4,5-b]pyridin-4-yl]-N-[3-(propan-2-yl)bicyclo[l. l.l]pentan-l- yl]acetamide2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-[(lS,6S)-5-(3-methoxypyridine-2- carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-1-192[l,2,3]triazolo[4,5-b]pyridin-4-yl]-N-[3-(propan-2-yl)bicyclo[l. l.l]pentan-l- yl]acetamideN-{3-cyclopropylbicyclo[l.l.l]pentan-l-yl}-2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-[(lS,6S)-5-(4-methyl-3,4-dihydro-2H-l,4-benzoxazine-8-carbonyl)-1-1932,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5- b]pyridin-4-yl]acetamide2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-[(lS,6S)-5-(l-methyl-lH-pyrazole-4- carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-1-194[l,2,3]triazolo[4,5-b]pyridin-4-yl]-N-[3-(propan-2-yl)bicyclo[l. l.l]pentan-l- yl]acetamide2-{6-[(lS,6S)-5-[2-(difluoromethoxy)pyridine-3-carbonyl]-2,5- diazabicyclo[4.2.0]octan-2-yl]-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-1-1952H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl}-N-[3-(propan-2- yl)bicyclo[ 1.1.1 Jpentan- 1 -yl]acetamide2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-[(lS,6S)-5-(3-methoxypyridine-4- carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-1-196[l,2,3]triazolo[4,5-b]pyridin-4-yl]-N-[3-(propan-2-yl)bicyclo[l. l.l]pentan-l- yl]acetamide2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-[(lS,6S)-5-(3-methoxy-l-methyl- lH-pyrazole-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-1-197[l,2,3]triazolo[4,5-b]pyridin-4-yl]-N-[3-(propan-2-yl)bicyclo[l. l.l]pentan-l- yl]acetamide2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-[(lS,6S)-5-(5-methoxy-l-methyl- lH-pyrazole-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-1-198 [l,2,3]triazolo[4,5-b]pyridin-4-yl]-N-[3-(propan-2-yl)bicyclo[l. l.l]pentan-l- yl]acetamideN-{3-cyclopropylbicyclo[l. l.l]pentan-l-yl}-2-[2-(3,6-dihydro-2H-pyran-4-yl)-1-199 5-ethyl-6-[(lS,6S)-5-[2-methoxy-6-(methoxymethyl)benzoyl]-2,5- diazabicyclo[4.2.0]octan-2-yl]-7-oxo-2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4- yl]acetamide 2-{6-[(lS,6S)-5-(5-chloro-4-hydroxy-2-methoxypyridine-3-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl]-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-1-200 2H,4H,7H-[l,2,3]triazolo[4,5-b]pyridin-4-yl}-N-{3- cy clopropylbicyclo[ 1.1.1 Jpentan- 1 -yl } acetamide 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-((lS,6S)-5-(3-(4-methylpiperazin-l- yl)benzoyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-7-oxo-2,7-dihydro-4H-1-201[1.2.3]triazolo[4,5-b]pyridin-4-yl)-N-(3-isopropylbicyclo[l.l. l]pentan-l- yl)acetamide 2-((lS,6S)-5-(5-ethyl-4-(2-((3-isopropylbicyclo[l. l.l]pentan-l-yl)amino)-2-1-202 oxoethyl)-2-(2-methoxypyridin-4-yl)-7-oxo-4,7-dihydro-2H-[l,2,3]triazolo[4,5- b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]octane-2-carbonyl)nicotinic acid N-(3-cyclobutylbicyclo[l. l.l]pentan-l-yl)-2-(2-(dimethylamino)-5-ethyl-6-(4-(6-1-203 hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-7-oxo-[l,2,4]triazolo[l,5- a]pyrimidin-4(7H)-yl)acetamide(2-(( 1 S, 6 S)-5 -(2-(3 , 6-dihy dro-2H-pyran-4-yl )-5 -ethyl-4-(2-((3 - isopropylbicyclo[l. l.l]pentan-l-yl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-2H-1-204[1.2.3]triazolo[4,5-b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]octane-2-carbonyl)-3- methoxyphenyl)boronic acid2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-((lS,6S)-5-(2-hydroxy-4- methoxynicotinoyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-7-oxo-2,7-dihydro-4H-1-205 [l,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-isopropylbicyclo[l.l. l]pentan-l- yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-1-206 m ethoxypyri di n-4-yl )-7-oxo- [ 1 ,2,4]tri azol o[ 1 , 5 -a]pyrimi di n-4(7H)-yl )-N- (spiro[3.3]heptan-2-yl)acetamide2-((lS,6S)-5-(5-ethyl-4-(2-((3-isopropylbicyclo[l. l. l]pentan-l-yl)amino)-2-1-207 oxoethyl)-2-(2-methoxypyridin-4-yl)-7-oxo-4,7-dihydro-2H-[l,2,3]triazolo[4,5- b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]octane-2-carbonyl)benzoic acidN-(3-cyclopropylbicyclo[l.l. l]pentan-l-yl)-2-(5-ethyl-6-((l S,6S)-5-(5-hydroxy-1-208 6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(2- methoxypyridin-4-yl)-7-oxo-[l, 2, 4]tri azoIofl, 5-a]pyrimidin-4(7H)-yl)acetamideN-(3-cyclopropylbicyclo[l.l. l]pentan-l-yl)-2-(7-ethyl-6-((lS,6S)-5-(5-hydroxy- 6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(2-1-209 methoxypyridin-4-yl)-3,5-dioxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyrimidin- 8(5H)-yl)acetamideN-(3-cyclobutylbicyclo[l. l.l]pentan-l-yl)-2-(6-ethyl-7-((lS,6S)-5-(5-hydroxy-6-1-210 methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2,3-dimethyl- 8-oxopyrido[2,3-b]pyrazin-5(8H)-yl)acetamideN -(3 -cy cl obuty Ibicy cl of 1.1.1 ]pentan- 1 -y 1 ) -2- (2 -(3 ,6-dihydro-2H-pyran-4-yl)-5-1-211 ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l- yl)-7-oxo-[ 1 , 2, 4] tri azolof 1 , 5-a]pyrimidin-4(7H)-yl)acetamideN-(3-cyclopropylbicyclo[l.l. l]pentan-l-yl)-2-(6-ethyl-5-((lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(2-1-212 methoxypyridin-4-yl)-4-oxo-2,4-dihydro-7H-pyrazolo[3,4-b]pyridin-7- yl)acetamide2-(6-(4-(benzo[d]oxazole-7-carbonyl)piperazin-l-yl)-5-ethyl-2-(2-1-213 methoxypyridin-4-yl)-7-oxo-[l, 2, 4]tri azolof l,5-a]pyrimidin-4(7H)-yl)-N-(3- isopropylbicyclof 1.1.1 Jpentan- 1 -yl)acetamide2-(6-((l S,6S)-5-(benzo[d]oxazole-7-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-1-214 yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[l, 2, 4]tri azolof l,5-a]pyrimidin-4(7H)-yl)-N-(3 -isopropylbicyclofl . 1. l]pentan-l-yl)acetamide2-(5-ethyl-6-(4-(6-hydroxy-2-methylbenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-1-215 2-(2-methoxypyridin-4-yl)-7-oxo-[l, 2, 4]tri azolof l,5-a]pyrimidin-4(7H)-yl)-N-(3- ethylbi cyclofl .1 .1 ]pentan-l -yl)acetamide2-(4-(4-(2-((3-cyclopropylbicyclo[l .1.l]pentan-l-yl)amino)-2-oxoethyl)-5-ethyl-1-216 2-(2-methoxypyridin-4-yl)-7-oxo-4,7-dihydro-2H-[l,2,3]triazolo[4,5-b]pyridin-6- yl)piperazine-l-carbonyl)nicotinic acid2-(5-ethyl-6-(4-(4-hydroxy-2-methoxy-5-methylnicotinoyl)piperazin-l-yl)-2-(2-1-217 methylpyridin-4-yl)-7-oxo-[l,2,4]triazolo[l,5-a]pyrimidin-4(7H)-yl)-N-(3- isopropylbicyclof 1.1.1 Jpentan- 1 -yl)acetamide2-(2-(dimethylamino)-6-ethyl-7-((lS,6S)-5-(6-hydroxybenzo[d]oxazole-7-1-218 carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-8-oxopyrido[2,3-b]pyrazin-5(8H)- yl)-N-(3 -isopropylbicyclofl.1.1 ]pentan-l-yl)acetamideN-(3-cyclobutylbicyclo[l .1. l]pentan-l-yl)-2-(5-ethyl-6-(4-(5-hydroxy-6-1-219 methylpyrimidine-4-carbonyl)piperazin-l-yl)-7-oxo-2-(pyridin-4-yl)- [l,2,4]triazolo[l,5-a]pyrimidin-4(7H)-yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-1-220 methoxypyri din-4-yl)-7-oxo-[l, 2, 4]tri azolof 1, 5-a]pyrimidin-4(7H)-yl)-N-(4- (trifluoromethyl)cuban- 1 -yl)acetamideN-(3-cyclopropylbicyclo[l.l. l]pentan-l-yl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5- ethyl-6-((lS,6S)-5-(5-(2-hydroxypropan-2-yl)-2-methoxynicotinoyl)-2,5-1-221 diazabicyclo[4.2.0]octan-2-yl)-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5- b]pyridin-4-yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-((lS,6S)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-7-oxo-1-222[ 1 , 2, 4] tri azolof 1 , 5-a]pyrimidin-4(7H)-yl)-N-(3 -isopropylbicyclof 1.1.1 Jpentan- 1 - yl)acetamideN-(3-cyclopropylbicyclo[l.l. l]pentan-l-yl)-2-(2-(2-(difluoromethoxy)pyridin-4- yl)-5-ethyl-6-((lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-1-223 diazabicyclo[4.2.0]octan-2-yl)-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5- b]pyridin-4-yl)acetamideN-(3-cyclopentylbicyclo[l. l.l]pentan-l-yl)-2-(2-(dimethylamino)-6-ethyl-7-1-224 ((1 S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl)-8-oxopyrido[2,3-b]pyrazin-5(8H)-yl)acetamideN-(3-cy cl opropylbicyclof 1.1.1 ]pentan-l-yl )-2-(2-(3,6-dihy dro-2H-pyran -4-yl)-5- ethyl-6-((lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-1-225 diazabicyclo[4.2.0]octan-2-yl)-7-oxo-[l,2,4]triazolo[l,5-a]pyrimidin-4(7H)- yl)acetamideN-(3-cyclobutylbicyclo[l.l.l]pentan-l-yl)-2-(2-(dimethylamino)-6-ethyl-7-1-226 ((lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl)-8-oxopyrido[2,3-b]pyrazin-5(8H)-yl)acetamideN-(3-cyclopropylbicyclo[l.l. l]pentan-l-yl)-2-(6-ethyl-7-((lS,6S)-5-(5-hydroxy-1-227 6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2,3- dimethyl-8-oxopyrido[2,3-b]pyrazin-5(8H)-yl)acetamideN-(3-cyclopropylbicyclo[l.l. l]pentan-l-yl)-2-(5-ethyl-6-(4-(5-hydroxy-6-1-228 methylpyrimidine-4-carbonyl)-3,3-dirnethylpiperazin-l-yl)-2-(2-methoxypyridin- 4-yl)-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide2-(2-(dimethylamino)-6-ethyl-7-((lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-1-229 carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-8-oxopyrido[2,3-b]pyrazin-5(8H)- yl)-N-(spiro[3.3]heptan-2-yl)acetamide2-(2-(dimethylamino)-6-ethyl-7-((lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-1-230 carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-8-oxopyrido[2,3-b]pyrazin-5(8H)- yl)-N-(spiro[3.4]octan-2-yl)acetamide2-(6-(4-(benzo[d]oxazole-7-carbonyl)piperazin-l-yl)-5-ethyl-2-(2-1-231 methoxypyridin-4-yl)-7-oxo-[l,2,4]triazolo[l,5-a]pyrimidin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamideN-(3-cyclopropylbicyclo[l.l. l]pentan-l-yl)-2-(2-(dimethylamino)-6-ethyl-7-1-232 ((lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl)-8-oxopyrido[2,3-b]pyrazin-5(8H)-yl)acetamideN-(3-cyclopropylbicyclo[l.l. l]pentan-l-yl)-2-(2-(dimethylamino)-6-ethyl-7-1-233 ((lS,6S)-5-(4-hydroxy-2-methoxy-5-methylnicotinoyl)-2,5- diazabicyclo[4.2.0]octan-2-yl)-8-oxopyrido[2,3-b]pyrazin-5(8H)-yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-1-234 4-carbonyl)piperazin-l-yl)-7-oxo-[l,2,4]triazolo[l,5-a]pyrimidin-4(7H)-yl)-N-(3- isopropylbicyclo[ 1.1.1 Jpentan- 1 -yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-((lS,6S)-5-(2-(6-oxopiperidin-2-yl)acetyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2,7-dihydro-4H-1-235[l,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-isopropylbicyclo[l.l. l]pentan-l- yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2-methoxy-5-1-236 methylnicotinoyl)piperazin-l-yl)-7-oxo-[l,2,4]triazolo[l,5-a]pyrimidin-4(7H)- yl)-N-(3-(trifluoromethyl)bicyclo[ l .1. l]pentan-l-yl)acetamide2-(2-(dimethylamino)-6-ethyl-7-((lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-1-237 carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-8-oxopyrido[2,3-b]pyrazin-5(8H)- yl)-N-(3-(trifluoromethoxy)bicyclo[l .1. l]pentan-l-yl)acetamide2-(2-(dimethylamino)-6-ethyl-7-((lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-1-238 carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-8-oxopyrido[2,3-b]pyrazin-5(8H)- yl)-N-(6-methylspiro[3.3]heptan-2-yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2-1-239 methoxynicotinoyl)piperazin-l-yl)-7-oxo-[l,2,4]triazolo[l,5-a]pyrimidin-4(7H)- yl)-N-(3-(trifluoromethyl)bicyclo[l.l. l]pentan-l-yl)acetamide2-(2-(dimethylamino)-6-ethyl-7-(4-(4-hydroxy-2-methoxy-5-1-240 methylnicotinoyl)piperazin-l-yl)-8-oxopyrido[2,3-b]pyrazin-5(8H)-yl)-N-(3-(trifluoromethyl)bicyclo[ 1.1.1 Jpentan- 1 -yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-1-241 methoxypyridin-4-yl)-7-oxo-[l, 2, 4]tri azolof l,5-a]pyrimidin-4(7H)-yl)-N-(3- methoxybicyclof 1.1.1 ]pentan- 1 -yl)acetamide2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl)-2-(2-1-242 methoxypyridin-4-yl)-7-oxo-[l,2,4]triazolo[l,5-a]pyrimidin-4(7H)-yl)-N-((lr,4r)-4-(trifluoromethyl)cyclohexyl)acetamideN-(3-cyclobutylbicyclo[l. l.l]pentan-l-yl)-2-(5-ethyl-6-(4-(6-1-243 hy droxybenzo[d]oxazole-7-carbonyl)piperazin- 1 -yl)-7-oxo-[ 1 ,2,4]triazolo[ 1,5- a]pyrimidin-4(7H)-yl)acetamide rac-N-((lR,2S)-2-(2,6-difluorophenyl)cyclopropyl)-2-(5-ethyl-2-(2-1-244 methoxypyridin-4-yl)-6-(4-(l -methyl- lH-pyrazole-4-carbonyl)piperazin-l-yl)-7- oxo-[l,2,4]triazolo[l,5-a]pyrimidin-4(7H)-yl)acetamide2-(l-cyclopropyl-5-ethyl-6-((lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4- carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-7-oxo-l,7-dihydro-4H-1-245 [l,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-cyclopropylbicyclo[l. l.l]pentan-l- yl)acetamide2-(5-ethyl-2-(2-methoxypyridin-4-yl)-6-(4-(l-methyl-lH-pyrazole-4-1-246 carbonyl)piperazin- 1 -yl)-7-oxo-[ 1 , 2, 4]tri azolof l,5-a]pyrimidin-4(7H)-yl)-N-(5- fluoro-2,3-dihydro-lH-inden-2-yl)acetamide2-(5-ethyl-2-(2-methoxypyridin-4-yl)-6-(4-(l-methyl-lH-pyrazole-4-1-247 carbonyl)piperazin- 1 -yl)-7-oxo-[ 1 , 2, 4]tri azolof 1 ,5 -a]pyrimidin-4(7H)-yl)-N-(l - fluorospiro[2.3 ]hexan-5 -yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(l-methyl-lH-pyrazole-4-1-248 carbonyl)piperazin- 1 -yl)-7-oxo-[ 1 , 2, 4]tri azolof 1 ,5 -a]pyrimidin-4(7H)-yl)-N-(5- fluoro-2,3-dihydro-lH-inden-2-yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(l-methyl-lH-pyrazole-4-1-249 carbonyl)piperazin- 1 -yl)-7-oxo-[ 1 , 2, 4]tri azolof 1 ,5 -a]pyrimidin-4(7H)-yl)-N-(l - fluorospiro[2.3]hexan-5-yl)acetamiderel-2-(6-ethyl-7-((lR,6R)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl)-2-(((lr,3R)-3-methoxycyclobutyl)(methyl)amino)-3-I-9a methyl-8-oxopyrido[2,3-b]pyrazin-5(8H)-yl)-N-(3- (trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide rel-2-(6-ethyl-7-((lR,6R)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-1-1 Oa diazabicyclo[4.2.0]octan-2-yl)-8-oxo-2-(pyrrolidin-l -yl)pyrido[2,3-b]pyrazin-5(8H)-yl)-N-(3-(trifluoromethyl)bicyclo[l.l. l]pentan-l-yl)acetamide rel-2-(7-ethyl-6-((lR,6R)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-I-lla diazabicyclo[4.2.0]octan-2-yl)-2-methyl-5-oxopyrido[2,3-b]thieno[3,2-e]pyrazin-8(5H)-yl)-N-(3-(trifluoromethyl)bicyclo[l.l. l]pentan-l-yl)acetamide rel-2-(6-ethyl-7-((lR,6R)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-I-12a diazabicyclo[4.2.0]octan-2-yl)-2-methyl-8-oxopyrido[2,3-b]thiazolo[4,5-e]pyrazin-5(8H)-yl)-N-(3-(trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide rel-2-(6-ethyl-7-((lR,6R)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl)-l-methyl-8-oxo-l,2,3,8-tetrahydro-5H-pyrido[2,3-I-13a b]pyrrolo[2,3-e]pyrazin-5-yl)-N-(3-(trifluoromethyl)bicyclo[l .1. l]pentan-l- yl)acetamide rel-2-(2-(dimethylamino)-6-ethyl-7-((lR,6R)-5-(5-hydroxy-6-methylpyrimidine-4-I-14a carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-3-methyl-8-oxopyrido[2,3-b]pyrazin-5(8H)-yl)-N-(3-(trifluoromethyl)bicyclo[l.l. l]pentan-l-yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-I-15a carbonyl)piperazin-l-yl)-7-oxo-[l,2,4]triazolo[l,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)cuban- 1 -yl)acetamide2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl)-2-(2-I-16a methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)-N- (4-(trifluoromethyl)cuban-l-yl)acetamide2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl)-2-(2-I-17a methoxypyridin-4-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(4-(trifluoromethyl)cuban- 1 -yl)acetamide2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl)-2-(2-I-18a methoxypyridin-4-yl)-7-oxothiazolo[4,5-b]pyridin-4(7H)-yl)-N-(4- (trifluoromethyl)cuban- 1 -yl)acetamide2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl)-7-oxo-I-19a [ 1 ,2,4]triazolo[ 1 , 5 -a]py rimidin-4(7H)-yl)-N-(3 -(trifluoromethoxy)bicyclo[l .1 .1 ]pentan-l -yl)acetamide2-(5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-I-20a yl)-7-oxo-[ 1 ,2, 4]tri azolof 1 , 5-a]pyrimidin-4(7H)-yl)-N-(3 -(trifluorom ethoxy )bicyclo[l .1. l]pentan-l-yl)acetamideN-(3-cyclopropylcyclobutyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-I-21a carbonyl)piperazin-l -yl)-2-(2-methoxypyridin-4-yl)-7-oxo-[ 1,2, 4]tri azolof 1,5- a]pyrimidin-4(7H)-yl)acetamide2-(5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-I-22a yl)-2-(2-methoxypyridin-4-yl)-7-oxo-[l, 2, 4]tri azolof l,5-a]pyrimidin-4(7H)-yl)-N- (3-isopropylbicyclo[l .1. l]pentan-l-yl)acetamide2-(5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-I-23a yl)-2-(2-methoxypyri din-4-yl)-7-oxo-[l, 2, 4]tri azolof 1, 5-a]pyrimidin-4(7H)-yl)-N- (3-ethylbicyclo[ 1.1.1 Jpentan- 1 -yl)acetamide2-(5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-I-24a yl)-2-(2-methoxypyri din-4-yl)-7-oxo-[ 1,2, 4]tri azolof l,5-a]pyrimidin-4(7H)-yl)-N- (3-(2-fluoroethyl)bicyclo[l .1. l]pentan-l-yl)acetamideN-(3-cyclobutylbicyclo[l. l.l]pentan-l-yl)-2-(5-ethyl-6-(4-(4-hydroxy-2,3-I-25a dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-yl)-2-(2-methoxypyridin-4-yl)- 7-oxo-[l, 2, 4]tri azolof l,5-a]pyrimidin-4(7H)-yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-I-26a c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxothiazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclofl .1. l]pentan-l-yl)acetamide2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl)-2-(2-I-27a methoxypyridin-4-yl)-7-oxothiazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclof 1.1.1 Jpentan- 1 -yl)acetamide2-(5-ethyl-6-(4-(5-fluoro-4-hydroxy-2-methoxynicotinoyl)piperazin-l-yl)-2-(2-I-28a methoxypyridin-4-yl)-7-oxothiazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[ 1.1. 1 ]pentan- 1 -yl)acetamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-29a methoxypyridin-4-yl)-7-oxothiazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[l .1 .1 ]pentan-l -yl)acetamide 2-(5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-l-yl)-2-(2-methoxypyridin-4-yl)-7-I-30a oxothiazolo[5,4-b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[l. l.l]pentan-l- yl)acetamide2-(5-ethyl-6-(4-(4-hydroxy-2-methoxy-5-methylnicotinoyl)piperazin-l-yl)-2-(2-I-31a methoxypyridin-4-yl)-7-oxothiazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide2-(5-ethyl-6-((lS,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-I-32a diazabicyclo[4.2.0]octan-2-yl)-2-(2-methoxypyridin-4-yl)-7-oxothiazolo[5,4- b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide 2-(2-(l-acetyl-l,2,3,6-tetrahydropyridin-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-I-33a dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxothiazolo[5,4-b]pyridin- 4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide 2-(2-(dimethylamino)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-I-34a carbonyl)piperazin-l-yl)-7-oxothiazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[ 1.1.1 ]pentan- 1 -yl)acetamide2-(2-(dimethylamino)-5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-I-35a carbonyl)piperazin-l-yl)-7-oxothiazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-7-oxo-2-I-36a (pyrrolidin-l-yl)thiazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide 2-(5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-I-37a yl)-2-(l-(2-methoxyacetyl)-l,2,3,6-tetrahydropyridin-4-yl)-7-oxothiazolo[5,4- b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[l.l.l]pentan-l-yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-I-38a morpholino-7-oxothiazolo[5,4-b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[ 1.1. 1 ]pentan- 1 -yl)acetamideN-(3-cyclopropylbicyclo[l.l.l]pentan-l-yl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-I-39a ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-yl)-7- oxothiazolo[5,4-b]pyridin-4(7H)-yl)acetamideN-(3-(l, l-difluoroethyl)bicyclo[l .1.l]pentan-l-yl)-2-(2-(3,6-dihydro-2H-pyran-4-I-40a yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l- yl)-7-oxothiazolo[5,4-b]pyridin-4(7H)-yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-I-41a c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxothiazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- methylbicyclo[l .1. l]pentan-l-yl)acetamideN-(3-(difluoromethyl)bicyclo[l .1. l]pentan-l-yl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-I-42a 5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-yl)- 7-oxothiazolo[5,4-b]pyridin-4(7H)-yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-((5-hydroxy-6-methylpyrimidin-4-I-43a yl)methyl)piperazin-l-yl)-7-oxothiazolo[5,4-b]pyridin-4(7H)-yl)-N-(l-(trifluoromethyl)-2-oxabicyclo[2.1. l]hexan-4-yl)acetamide2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl)-2-(2-I-44a methoxypyridin-4-yl)-7-oxothiazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)cyclobutyl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-I-45a c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxothiazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- methoxybicyclo[ 1.1.1 ]pentan- 1 -yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-I-46a c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxothiazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- fluorobicyclo[ 1.1.1 Jpentan- 1 -yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxypyrimidine-4-I-47a carbonyl)piperazin-l-yl)-7-oxothiazolo[5,4-b]pyridin-4(7H)-yl)-N-(3-(2- fluoroethyl)bicy clo[ 1.1.1 Jpentan- 1 -yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-I-48a c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxothiazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethoxy)bicyclo[l .1. l]pentan-l-yl)acetamideN-(3-cyanobicyclo[l. l.l]pentan-l-yl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-I-49a (4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-yl)-7- oxothiazolo[5,4-b]pyridin-4(7H)-yl)acetamideN-(3 -cyclopropylbicy clo[ 1.1.1 Jpentan- 1 -yl)-2-(5-ethyl-6-(4-(6-I-50a hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-methoxypyridin-4-yl)-7- oxothiazolo[5,4-b]pyridin-4(7H)-yl)acetamide 2-(5-ethyl-6-((lS,6S)-5-(6-methoxybenzo[d]oxazole-7-carbonyl)-2,5-I-51a diazabicyclo[4.2.0]octan-2-yl)-2-(2-methoxypyridin-4-yl)-7-oxothiazolo[5,4- b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[l.l.l]pentan-l-yl)acetamide2-(2-(dimethylamino)-5-ethyl-6-((lS,6S)-5-(6-methoxybenzo[d]oxazole-7-I-52a carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-7-oxothiazolo[5,4-b]pyridin-4(7H)- yl)-N-(3 -(trifluoromethyl)bicyclo[ 1.1.1 Jpentan- 1 -yl)acetamide 2-(5-ethyl-6-((lS,6S)-5-(6-methoxybenzo[d]oxazole-7-carbonyl)-2,5-I-53a diazabicyclo[4.2.0]octan-2-yl)-2-morpholino-7-oxothiazolo[5,4-b]pyridin-4(7H)- yl)-N-(3 -(trifluoromethyl)bicyclo[ 1.1.1 Jpentan- 1 -yl)acetamide 2-(5-ethyl-6-(4-(5-hydroxybenzo[d]oxazole-4-carbonyl)piperazin-l-yl)-2-(2-I-54a methoxypyridin-4-yl)-7-oxothiazolo[5,4-b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[ 1.1.1 ]pentan- 1 -yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-55a methoxypyridin-4-yl)-7-oxothiazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- ethylbicyclo[ 1.1.1 ]pentan- 1 -yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-56a methoxypyridin-4-yl)-7-oxothiazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- isopropylbicyclo[ 1.1.1 Jpentan- 1 -yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-57a methoxypyridin-4-yl)-7-oxothiazolo[5,4-b]pyridin-4(7H)-yl)-N-(3-(2- fluoroethyl)bicy clo[ 1.1.1 Jpentan- 1 -yl)acetamideN-(3-cyclobutylbicyclo[l .1. l]pentan-l-yl)-2-(5-ethyl-6-(4-(6-I-58a hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-methoxypyridin-4-yl)-7- oxothiazolo[5,4-b]pyridin-4(7H)-yl)acetamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-59a methoxypyridin-4-yl)-7-oxothiazolo[5,4-b]pyridin-4(7H)-yl)-N-(3-(oxetan-3- yl)bi cyclofl .1.1 ]pentan-l -yl)acetamideN-(2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-60a methoxypyridin-4-yl)-7-oxothiazolo[5,4-b]pyridin-4(7H)-yl)ethyl)-3- (trifluoromethyl)bicyclofl .1. l]pentyl-l -carboxamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-61a methoxypyridin-4-yl)-7-oxothiazolo[5,4-b]pyridin-4(7H)-yl)-N-(4- (trifluoromethyl)bicyclo[2.2.2]octan-l-yl)acetamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-62a methoxypyridin-4-yl)-7-oxothiazolo[5,4-b]pyridin-4(7H)-yl)-N-((3s,6s)-6- (trifluoromethyl)bicyclo[3.1.0]hexan-3-yl)acetamideN-(3 -cyclopropylbicyclof 1.1.1 ]pentan- 1 -yl)-2-(2-(3 , 6-dihy dro-2H-pyran -4-yl)-5-I-64a ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-7- oxothiazolo[5,4-b]pyridin-4(7H)-yl)acetamideN-(3 -cy cl opropylbicyclof 1.1.1 ]pentan-l -yl)-2-(2-(3, 6-dihy dro-2H-pyran -4-yl)-5-I-65a ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl)-7- oxothiazolo[5,4-b]pyridin-4(7H)-yl)acetamideN-(3-cy cl opropylbicyclo[l.l.l]pentan-l-yl)-2-(2-(3, 6-dihy dro-2H-pyran-4-yl)-5-I-67a ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-yl)-7- oxothiazolo[4,5-b]pyridin-4(7H)-yl)acetamide 2-(2-(l-acetyl-l,2,3,6-tetrahydropyridin-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-I-68a dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxothiazolo[4,5-b]pyridin- 4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamideN-(3-(l,l-difluoroethyl)bicyclo[l. l.l]pentan-l-yl)-2-(2-(3,6-dihydro-2H-pyran-4-I-69a yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l- yl)-7-oxothiazolo[4,5-b]pyridin-4(7H)-yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-I-70a c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxothiazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- methylbicyclo[ 1.1.1 Jpentan- 1 -yl)acetamideN-(3-(difluoromethyl)bicyclo[l .1 ,l]pentan-l-yl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-I-71a 5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-yl)- 7-oxothiazolo[4,5-b]pyridin-4(7H)-yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-I-72a carbonyl)piperazin-l-yl)-7-oxothiazolo[4,5-b]pyridin-4(7H)-yl)-N-(l- (trifluoromethyl)-2-oxabicyclo[2.1.1 ]hexan-4-yl)acetamide2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl)-2-(2-I-73a methoxypyridin-4-yl)-7-oxothiazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)cyclobutyl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-I-74a c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxothiazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- methoxybicyclo[l .1.1 Jpentan- l-yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-I-75a c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxothiazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- fluorobicyclo[ 1.1.1 ]pentan- 1 -yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxypyrimidine-4-I-76a carbonyl)piperazin-l-yl)-7-oxothiazolo[4,5-b]pyridin-4(7H)-yl)-N-(3-(2- fluoroethyl)bicyclo[l .1.1 ]pentan-l -yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-I-77a c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxothiazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[l .1.1 Jpentan- l-yl)acetami de2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-I-78a c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxothiazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- (trifluorom ethoxy )bicyclo[l .1. l]pentan-l-yl)acetamideN-(3-cyanobicyclo[l. l.l]pentan-l-yl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-I-79a (4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-yl)-7- oxothiazolo[4,5-b]pyridin-4(7H)-yl)acetamide2-(5-ethyl-6-(4-(5-fluoro-4-hydroxy-2-methoxynicotinoyl)piperazin-l-yl)-2-(2-I-80a methoxypyridin-4-yl)-7-oxothiazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[ 1.1. 1 ]pentan- 1 -yl)acetamide2-(5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-l-yl)-2-(2-methoxypyridin-4-yl)-7-I-81a oxothiazolo[4,5-b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[l. l.l]pentan-l- yl)acetamide 2-(5-ethyl-6-(4-(4-hydroxy-2-methoxy-5-methylnicotinoyl)piperazin-l-yl)-2-(2-I-82a methoxypyridin-4-yl)-7-oxothiazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide 2-(5-ethyl-6-((lS,6S)-5-(5-hydroxypyrimidine-4-carbonyl)-2,5-I-83a diazabicyclo[4.2.0]octan-2-yl)-2-(2-methoxypyridin-4-yl)-7-oxothiazolo[4,5- b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[l.l.l]pentan-l-yl)acetamide 2-(2-(dimethylamino)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-I-84a carbonyl)piperazin-l-yl)-7-oxothiazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[ 1.1.1 Jpentan- 1 -yl)acetamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-7-oxo-2-I-85a (pyrrolidin-l-yl)thiazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide2-(5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-I-86a yl)-2-(l-(2-methoxyacetyl)-l,2,3,6-tetrahydropyridin-4-yl)-7-oxothiazolo[4,5- b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-I-87a morpholino-7-oxothiazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide2-(5-ethyl-6-((lS,6S)-5-(6-hydroxybenzo[d]oxazole-7-carbonyl)-2,5-I-88a diazabicyclo[4.2.0]octan-2-yl)-2-(2-methoxypyridin-4-yl)-7-oxothiazolo[4,5- b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[l.l.l]pentan-l-yl)acetamide 2-(2-(dimethylamino)-5-ethyl-6-((lS,6S)-5-(6-hydroxybenzo[d]oxazole-7-I-89a carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-7-oxothiazolo[4,5-b]pyridin-4(7H)- yl)-N-(3-(trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide2-(5-ethyl-6-((lS,6S)-5-(6-hydroxybenzo[d]oxazole-7-carbonyl)-2,5-I-90a diazabicyclo[4.2.0]octan-2-yl)-2-morpholino-7-oxothiazolo[4,5-b]pyridin-4(7H)- yl)-N-(3-(trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide 2-(5-ethyl-6-(4-(5-hydroxybenzo[d]oxazole-4-carbonyl)piperazin-l-yl)-2-(2-I-91a methoxypyridin-4-yl)-7-oxothiazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[l .1 .1 ]pentan-l -yl)acetamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-92a methoxypyridin-4-yl)-7-oxothiazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- ethylbicyclo[ 1.1.1 ]pentan- 1 -yl)acetamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-93a methoxypyridin-4-yl)-7-oxothiazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- isopropylbicyclo[ 1.1.1 Jpentan- 1 -yl)acetamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-94a methoxypyridin-4-yl)-7-oxothiazolo[4,5-b]pyridin-4(7H)-yl)-N-(3-(2- fluoroethyl)bicy clo[ 1.1.1 Jpentan- 1 -yl)acetamideN-(3-cyclobutylbicyclo[l .1. l]pentan-l-yl)-2-(5-ethyl-6-(4-(6-I-95a hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-methoxypyridin-4-yl)-7- oxothiazolo[4,5-b]pyridin-4(7H)-yl)acetamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-96a methoxypyridin-4-yl)-7-oxothiazolo[4,5-b]pyridin-4(7H)-yl)-N-(3-(oxetan-3- yl)bicyclo[ 1.1.1 ]pentan- 1 -yl)acetamide N-(2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-97a methoxypyridin-4-yl)-7-oxothiazolo[4,5-b]pyridin-4(7H)-yl)ethyl)-3- (trifluoromethyl)bicyclo[ 1.1.1 Jpentyl- 1 -carboxamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-98a methoxypyridin-4-yl)-7-oxothiazolo[4,5-b]pyridin-4(7H)-yl)-N-(4- (trifluoromethyl)bicyclo[2.2.2]octan-l-yl)acetamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-99a methoxypyridin-4-yl)-7-oxothiazolo[4,5-b]pyridin-4(7H)-yl)-N-(4- fluorobicyclo[2.2.2]octan-l-yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I- 100a methoxypyridin-4-yl)-7-oxothiazolo[4,5-b]pyridin-4(7H)-yl)-N-((3s,6s)-6- (trifluoromethyl)bicyclo[3.1.0]hexan-3-yl)acetamideN-(3-cy cl opropylbicyclo[ 1.1.1 ]pentan-l -yl)-2-(2-(3, 6-dihy dro-2H-pyran -4-yl)-5-I-101a ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-7- oxothiazolo[4,5-b]pyridin-4(7H)-yl)acetamideN-(3 -cyclopropylbicy clo[ 1.1.1 Jpentan- 1 -yl)-2-(2-(3 , 6-dihy dro-2H-pyran -4-yl)-5-I-102a ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl)-7- oxothi azol o [4, 5 -b ]py ri din-4(7H)-y 1 )acetami deN-(3 -cyclopropylbicy clo[ 1.1.1 Jpentan- 1 -yl)-2-(5-ethyl-6-(4-(6-I-103a hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-methoxypyridin-4-yl)-7- oxothiazolo[4,5-b]pyridin-4(7H)-yl)acetamide 2-(2-(dimethylamino)-5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-I-104a carbonyl)piperazin-l-yl)-7-oxothiazolo[4,5-b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[ 1.1.1 Jpentan- 1 -yl)acetamideN-(3 -cyclopropylbicy clo[ 1.1.1 ]pentan- 1 -yl)-2-(2-(3 , 6-dihy dro-2H-pyran -4-yl)-5-I- 105a ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl)-7- oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-I-106a c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[ 1.1.1 ]pentan- 1 -yl)acetamide2-(5-ethyl-6-(4-(5-fluoro-4-hydroxy-2-methoxynicotinoyl)piperazin-l-yl)-2-(2-I- 107a methoxypyridin-4-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-108a methoxypyridin-4-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide2-(5-ethyl-6-(4-(4-hydroxy-2-methoxy-5-methylnicotinoyl)piperazin-l-yl)-2-(2-I-109a methoxypyridin-4-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[ 1.1.1 Jpentan- 1 -yl)acetamide2-(5-ethyl-6-(4-(4-hydroxy-2-methoxy-5-methylnicotinoyl)piperazin-l-yl)-2-(2-I- 100a methoxypyridin-4-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[ 1.1. 1 ]pentan- 1 -yl)acetamide 2-(5-ethyl-6-((lR,6R)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-I-llla diazabicyclo[4.2.0]octan-2-yl)-2-(2-methoxypyridin-4-yl)-7-oxooxazolo[4,5- b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[l .1.1 ]pentan-l -yl)acetamide 2-(2-(l-acetyl-l,2,3,6-tetrahydropyridin-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-I-112a dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxooxazolo[4,5-b]pyridin- 4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide 2-(2-(dimethylamino)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-I-114a carbonyl)piperazin-l-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide 2-(2-(dimethylamino)-5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-I-115a carbonyl)piperazin-l-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[ 1.1.1 Jpentan- 1 -yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-7-oxo-2-I-116a (pyrrolidin-l-yl)oxazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide 2-(5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-I-117a yl)-2-(l-(2-methoxyacetyl)-l,2,3,6-tetrahydropyridin-4-yl)-7-oxooxazolo[4,5- b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-I-118a morpholino-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamideN-(3 -cyclopropylbicy clo[ 1.1.1 ]pentan- 1 -yl)-2-(5-ethyl-6-(4-(6-I-119a hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-methoxypyridin-4-yl)-7- oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamideN-(3 -cyclopropylbicyclo[ 1.1.1 ]pentan- 1 -yl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-I-120a ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-yl)-7- oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamideN-(3-(l, l-difluoroethyl)bicyclo[l .1 ,l]pentan-l-yl)-2-(2-(3,6-dihydro-2H-pyran-4-I-121a yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l- yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-I-122a c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- methylbicyclo[l .1 .1 Jpentan- l-yl)acetami deN-(3-(difluoromethyl)bicyclo[l .1.1 Jpentan- l-yl)-2-(2-(3, 6-dihy dro-2H-pyran-4-yl)-I-123a 5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-yl)- 7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide2-(2-(3, 6-dihy dro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-I-124a carbonyl)piperazin-l-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(l-(trifluoromethyl)-2-oxabicyclo[2.1.1 ]hexan-4-yl)acetamide2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl)-2-(2-I-125a methoxypyridin-4-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)cyclobutyl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-I-126a c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- methoxybicyclo[ 1.1.1 jpentan- 1 -yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-I-127a c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- fluorobicyclo[ 1.1.1 ]pentan- 1 -yl)acetamide rel-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-((lR,6R)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-7-I-128a oxooxazolo[4, 5-b]pyridin-4(7H)-yl)-N-(3 -(2-fluoroethyl)bicyclo[ 1.1.1 Jpentan- 1 - yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-I-129a c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(3-(trifluoromethoxy)bicyclo[l .1.1 Jpentan- l-yl)acetamideN-(3-cyanobicyclo[l. l.l]pentan-l-yl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-I-130a (4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-yl)-7- oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide rel-2-(5-ethyl-6-((lR,6R)-5-(6-hydroxybenzo[d]oxazole-7-carbonyl)-2,5-I-131a diazabicyclo[4.2.0]octan-2-yl)-2-(2-methoxypyridin-4-yl)-7-oxooxazolo[4,5- b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[l .1.1 Jpentan-1 -yl)acetamide rel-2-(2-(dimethylamino)-5-ethyl-6-((lR,6R)-5-(6-hydroxybenzo[d]oxazole-7-I-132a carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)- yl)-N-(3-(trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide rel-2-(5-ethyl-6-((lR,6R)-5-(6-hydroxybenzo[d]oxazole-7-carbonyl)-2,5-I-133a diazabicyclo[4.2.0]octan-2-yl)-2-morpholino-7-oxooxazolo[4,5-b]pyridin-4(7H)- yl)-N-(3-(trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide 2-(5-ethyl-6-(4-(5-hydroxybenzo[d]oxazole-4-carbonyl)piperazin-l-yl)-2-(2-I-134a methoxypyridin-4-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[ 1.1.1 Jpentan- 1 -yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-135a methoxypyridin-4-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- ethylbicy cl o [ 1.1.1 Jpentan- 1 -yl)acetamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-136a methoxypyridin-4-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(3- isopropylbicyclofl .1. l]pentan-l-yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-137a methoxypyridin-4-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(3-(2- fluoroethyl)bicyclo[ 1.1.1 Jpentan- 1 -yl)acetamideN-(3 -cyclobutylbicyclo[ 1.1.1 Jpentan- 1 -yl)-2-(5-ethyl-6-(4-(6-I-138a hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-methoxypyridin-4-yl)-7- oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-139a methoxypyridin-4-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(3-(oxetan-3- yl)bicy clo[ 1.1.1 Jpentan- 1 -yl)acetamideN-(2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-140a methoxypyridin-4-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)ethyl)-3- (trifluoromethyl)bicyclo[ 1.1. 1 ]pentyl- 1 -carboxamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-141a methoxypyridin-4-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(4- (trifluoromethyl)bicyclo[2.2.2]octan-l -yl)acetamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-142a methoxypyridin-4-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(4- fluorobicyclo[2.2.2]octan-l-yl)acetamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-I-143a morpholino-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-((3r,6r)-6- (trifluoromethyl)bicyclo[3.1.0]hexan-3-yl)acetamideN-(3 -cyclopropylbicyclo[ 1.1. 1 Jpentan- 1 -yl)-2-(2-(3 ,6-dihydro-2H-pyran-4-yl)-5-I-144a ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-7- oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-145a methoxypyridin-4-yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamideN-(3-cyclopropylbicyclo[l.l.l]pentan-l-yl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-I-146a ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-yl)-7- oxooxazolo[5,4-b]pyridin-4(7H)-yl)acetamide 2-(2-(l-acetyl-l,2,3,6-tetrahydropyridin-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-I-147a dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxooxazolo[5,4-b]pyridin- 4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide N-(3-(l,l-difluoroethyl)bicyclo[l. l.l]pentan-l-yl)-2-(2-(3,6-dihydro-2H-pyran-4-I-148a yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l- yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)acetamide 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-I-149a c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- methylbicyclo[l .1. l]pentan-l-yl)acetamideN-(3 -(difluoromethyl)bicyclo[ 1.1.1 Jpentan- 1 -yl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-I- 150a 5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-yl)- 7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-I-151a carbonyl)piperazin-l-yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)-N-(l-(trifluoromethyl)-2-oxabicyclo[2.1 .1 ]hexan-4-yl)acetamide2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl)-2-(2-I-152a methoxypyridin-4-yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)cyclobutyl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-I-154a c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- methoxybicyclo[l .1. l]pentan-l-yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-I-155a c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- fluorobicy clo[ 1.1.1 Jpentan- 1 -yl)acetamide rel-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-((lR,6R)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-7-I-156a oxooxazolo[5,4-b]pyridin-4(7H)-yl )-N-(3 -(2-fluoroethyl)bicyclo[ 1.1.1 ]pentan- 1 - yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-I-157a c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-I-158a c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)-N-(3-(trifluoromethoxy)bicyclo[l .1. l]pentan-l-yl)acetamideN-(3-cyanobicyclo[l. l.l]pentan-l-yl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-I-159a (4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-yl)-7- oxooxazolo[5,4-b]pyridin-4(7H)-yl)acetamide2-(2-(dimethylamino)-5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-I-160a carbonyl)piperazin-l-yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[ 1.1. 1 ]pentan- 1 -yl)acetamide 2-(5-ethyl-6-(4-(5-fluoro-4-hydroxy-2-methoxynicotinoyl)piperazin-l-yl)-2-(2-I-161a methoxypyridin-4-yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[l .1 .1 ]pentan-l -yl)acetamide 2-(5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-l-yl)-2-(2-methoxypyridin-4-yl)-7-I-162a oxooxazolo[5,4-b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[l. l.l]pentan-l- yl)acetamide2-(5-ethyl-6-(4-(4-hydroxy-2-methoxy-5-methylnicotinoyl)piperazin-l-yl)-2-(2-I-163a methoxypyridin-4-yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide rel-2-(5-ethyl-6-((lR,6R)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-I-164a diazabicyclo[4.2.0]octan-2-yl)-2-(2-methoxypyridin-4-yl)-7-oxooxazolo[5,4- b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide 2-(2-(dimethylamino)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-I-165a carbonyl)piperazin-l-yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-7-oxo-2-I-166a (pyrrolidin-l-yl)oxazolo[5,4-b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[ 1.1.1 ]pentan- 1 -yl)acetamide 2-(5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-I-167a yl)-2-(l-(2-methoxyacetyl)-l,2,3,6-tetrahydropyridin-4-yl)-7-oxooxazolo[5,4- b]pyridin-4(7H)-yl)-N-(3 -(trifluoromethyl)bicy clo[l .1.1 ]pentan- 1 -yl)acetamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-I-168a morpholino-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamideN-(3 -cyclopropylbicyclo[ 1.1.1 ]pentan- 1 -yl)-2-(5-ethyl-6-(4-(6-I-169a hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-methoxypyridin-4-yl)-7- oxooxazolo[5,4-b]pyridin-4(7H)-yl)acetamiderel-2-(5-ethyl-6-((lR,6R)-5-(6-hydroxybenzo[d]oxazole-7-carbonyl)-2,5-I- 170a diazabicyclo[4.2.0]octan-2-yl)-2-(2-methoxypyridin-4-yl)-7-oxooxazolo[5,4- b]pyridin-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[l. l.l]pentan-l-yl)acetamide rel-2-(2-(dimethylamino)-5-ethyl-6-((lR,6R)-5-(6-hydroxybenzo[d]oxazole-7-I-171a carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)- yl)-N-(3-(trifluoromethyl)bicyclo[l .1 . l]pentan-l-yl)acetamide rel-2-(5-ethyl-6-((lR,6R)-5-(6-hydroxybenzo[d]oxazole-7-carbonyl)-2,5-I-172a diazabicyclo[4.2.0]octan-2-yl)-2-morpholino-7-oxooxazolo[5,4-b]pyridin-4(7H)- yl)-N-(3-(trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide 2-(5-ethyl-6-(4-(5-hydroxybenzo[d]oxazole-4-carbonyl)piperazin-l-yl)-2-(2-I-173a methoxypyridin-4-yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- (trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-174a methoxypyridin-4-yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- ethylbicy clo[ 1.1.1 Jpentan- 1 -yl)acetamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-175a methoxypyridin-4-yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)-N-(3- isopropylbicyclo[l .1. l]pentan-l-yl)acetamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-176a methoxypyridin-4-yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)-N-(3-(2- fluoroethyl)bicyclo[l .1.1 ]pentan-l -yl)acetamideN-(3 -cyclobutylbicyclo[ 1.1.1 ]pentan- 1 -yl)-2-(5-ethyl-6-(4-(6-I-177a hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-methoxypyridin-4-yl)-7- oxooxazolo[5,4-b]pyridin-4(7H)-yl)acetamide 2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-178a methoxypyridin-4-yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)-N-(3-(oxetan-3- yl)bicyclo[ 1.1.1 Jpentan- 1 -yl)acetamide N-(2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-179a methoxypyridin-4-yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)ethyl)-3- (trifluoromethyl)bicyclo[l .1. l]pentyl-l -carboxamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I- 180a methoxypyridin-4-yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)-N-(4-(trifluoromethyl)bicyclo[2.2.2]octan-l-yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-181a methoxypyridin-4-yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)-N-(4- fluorobicyclo[2.2.2]octan-l-yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I- 182a methoxypyridin-4-yl)-7-oxooxazolo[5,4-b]pyridin-4(7H)-yl)-N-((3r,6r)-6-(trifluoromethyl)bicyclo[3.1.0]hexan-3-yl)acetamideN-(3 -cyclopropylbicy clo[ 1.1.1 Jpentan- 1 -yl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-I-183a ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-7- oxooxazolo[5,4-b]pyridin-4(7H)-yl)acetamideN-(3 -cyclopropylbicyclo[ 1.1. 1 Jpentan- 1 -yl)-2-(2-(3 ,6-dihydro-2H-pyran-4-yl)-5-I-184a ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl)-7- oxooxazolo[5,4-b]pyridin-4(7H)-yl)acetamide2-(5-ethyl-6-((lR,6R)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl)-2-(2-methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-I- 185a [l,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-(trifluoromethyl)bicyclo[l. l.l]pentan-l- yl)acetamide2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-I-186a c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5- b]pyridin-4-yl)-N-(3-(trifluoromethyl)bicyclo[ 1.1.1 Jpentan- 1 -yl)acetamide2-(5-ethyl-6-(4-(5-fluoro-4-hydroxy-2-methoxynicotinoyl)piperazin-l-yl)-2-(2-I-187a methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-(trifluoromethyl)bicyclo[l. l.l]pentan-l-yl)acetamide2-(5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-l-yl)-2-(2-methoxypyridin-4-yl)-7-I-188a oxo-2, 7-dihydro-4H-[ 1,2, 3]triazolo[4, 5-b]pyridin-4-yl)-N-(3-(trifluoromethyl)bicyclo[ 1.1.1 Jpentan- 1 -yl)acetamide2-(5-ethyl-6-(4-(4-hydroxy-2-methoxy-5-methylnicotinoyl)piperazin-l-yl)-2-(2-I-189a methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-(trifluoromethyl)bicyclo[l. l. l]pentan-l-yl)acetamide2-(2-(l-acetyl-l,2,3,6-tetrahydropyridin-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3- dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxo-2,7-dihydro-4H-I-190a[l,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-(trifluoromethyl)bicyclo[l .1 l]pentan-l - yl)acetamide2-(2-(dimethylamino)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-I-191a carbonyl)piperazin-l-yl)-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-(trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide2-(2-(dimethylamino)-5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-I-192a carbonyl)piperazin-l-yl)-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)- N-(3-(trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-7-oxo-2-I-193a (pyrrolidin-l-yl)-2,7-dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-(trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)acetamide2-(5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l- yl)-2-(l-(2-methoxyacetyl)-l,2,3,6-tetrahydropyridin-4-yl)-7-oxo-2,7-dihydro-4H-I-194a[l,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-(trifluoromethyl)bicyclo[l. l.l]pentan-l- yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-I-195a morpholino-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-(trifluoromethyl)bicyclo[ 1.1.1 Jpentan- 1 -yl)acetamide2-(5-ethyl-6-((lR,6R)-5-(6-hydroxybenzo[d]oxazole-7-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl)-2-(2-methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-I-196a[l,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-(trifluoromethyl)bicyclo[l. l.l]pentan-l- yl)acetamideN-(3 -cyclopropylbicy clo[ 1.1.1 ]pentan- 1 -yl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-I-197a ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-yl)-7- oxo-2, 7-dihydro-4H-[ 1,2, 3]triazolo[4,5-b]pyridin-4-yl)acetamideN-(3-(l, l-difluoroethyl)bicyclo[l .1 ,l]pentan-l-yl)-2-(2-(3,6-dihydro-2H-pyran-4-I-198a yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l- yl)-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-I-199a c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5- b]pyridin-4-yl)-N-(3-methylbicyclo[l .1 . l]pentan-l -yl)acetamide N-(3-(difluoromethyl)bicyclo[l .1.l]pentan-l-yl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-I-200a 5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-yl)- 7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-I-201a carbonyl)piperazin-l-yl)-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)- N-(l -(trifluoromethyl)-2-oxabicyclo[2.1.1 ]hexan-4-yl)acetamide 2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl)-2-(2-I-202a methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)-N- (3-(trifluoromethyl)cyclobutyl)acetamide 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-I-203a c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5- b]pyridin-4-yl)-N-(3-methoxybicyclo[ 1.1.1 ]pentan- 1 -yl)acetamide 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-I-204a c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5- b]pyridin-4-yl)-N-(3-fluorobicyclo[ 1.1.1 Jpentan- 1 -yl)acetamide 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-I-205a carbonyl)piperazin-l-yl)-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)- N-(3-(2-fluoroethyl)bicyclo[l .1. l]pentan-l-yl)acetamide 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-2,3-dihydrofuro[2,3-I-206a c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5- b]pyridin-4-yl)-N-(3-(trifluorom ethoxy )bicyclo[ 1.1.1 Jpentan- 1 -yl)acetamide N-(3-cyanobicyclo[l. l.l]pentan-l-yl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-I-207a (4-(4-hydroxy-2,3-dihydrofuro[2,3-c]pyridine-5-carbonyl)piperazin-l-yl)-7-oxo- 2, 7 -dihy dro-4H- [1,2,3 ]triazolo[4, 5 -b]py ridin-4-y l)acetamideN-(3-cyclopropylbicyclo[l .1. l]pentan-l -yl)-2-(5 -ethyl -6-(4-(6-I-208a hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-methoxypyridin-4-yl)-7- oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide rel-2-(2-(dimethylamino)-5-ethyl-6-((lR,6R)-5-(6-hydroxybenzo[d]oxazole-7- carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-7-oxo-2,7-dihydro-4H-I-209a [l,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-(trifluoromethyl)bicyclo[l .1 l]pentan-l - yl)acetamide rel-2-(5-ethyl-6-((lR,6R)-5-(6-hydroxybenzo[d]oxazole-7-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl)-2-morpholino-7-oxo-2,7-dihydro-4H-I-210a [l,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-(trifluoromethyl)bicyclo[l. l.l]pentan-l- yl)acetamide2-(5-ethyl-6-(4-(5-hydroxybenzo[d]oxazole-4-carbonyl)piperazin-l-yl)-2-(2-1-21 la methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-(trifluoromethyl)bicyclo[l .1. l]pentan-l -yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-214a methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-isopropylbicyclo[l .1. l]pentan-l-yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-215a methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-(2-fluoroethyl)bicyclo[l .1. l]pentan-l-yl)acetamideN-(3-cyclobutylbicyclo[l .1. l]pentan-l-yl)-2-(5-ethyl-6-(4-(6-I-216a hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-methoxypyridin-4-yl)-7- oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-217a methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-(oxetan-3-yl)bicyclo[ 1.1.1 ]pentan-l-yl)acetamideN-(2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-218a methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4- yl)ethyl)-3-(trifluoromethyl)bicyclo[l.l.l]pentyl-l -carboxamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-219a methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)-N- (4-(trifluoromethyl)bicyclo[2.2.2]octan-l-yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-220a methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)-N- (4-fluorobicyclo[2.2.2]octan-l-yl)acetamide2-(5-ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-2-(2-I-221a methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)-N- ((3r,6r)-6-(trifluoromethyl)bicyclo[3.1.0]hexan-3-yl)acetamideN-(3 -cyclopropylbicy clo[ 1.1.1 jpentan- 1 -yl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-I-222a ethyl-6-(4-(6-hydroxybenzo[d]oxazole-7-carbonyl)piperazin-l-yl)-7-oxo-2,7- dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)acetamideN-(3 -cyclopropylbicyclo[ 1.1. 1 jpentan- 1 -yl)-2-(2-(3 ,6-dihydro-2H-pyran-4-yl)-5-I-223a ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-l-yl)-7-oxo-2,7- dihydro-4H-[l,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide4. Pharmaceutical compositions, methods of treatment and uses of compounds

[0247] 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) di si nt egrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) absorbents, colorants, flavors and sweeteners.

[0248] 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.

[0249] 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

[0250] 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.

[0251] 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.

[0252] 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).

[0253] 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 ccoorrppuuss endometrial ccaarrcciinnoommaa,, 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.

[0254] 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.

[0255] 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.

[0256] 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 colorect...

Claims

CLAIMSWe Claim:

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof:AL"R4B CI wherein bicyclic Ring BC is selected from one of the following;wherein denotes the point of attachment to Ring A; each Rlbgroup is independently selected from H, halogen, CN, OH, C1-C6aliphatic, C1- Cealkoxy, C3-C6cycloalkyl, C1-Cal6kylene-O-C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and C3-C6cycloalkoxy wherein said C1-C6aliphatic, C1-C6alkoxy, C3-C6cycloalkyl, alCky1-lCen6e-O- C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and Ca-Cecycloalkoxy are each independently and optionally substituted with 1-5 halogen, OH, CN, Ca1l-kCy6l, or C3-C6cycloalkyl groups; wherein z is 0, 1, or 2;Ring A is: a) a 4-7 membered saturated or partially unsaturated bivalent monocyclic carbocyclylene or 4-7 membered saturated or partially unsaturated bivalent heterocyclylene ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 nitrogen atoms in addition to the 1-4 heteroatoms); or b) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene or heterocyclylene (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein Ring A is substituted with 0-4 independently selected RBsubstituents;-L- is a linker selected fromR1* is selected from: a) 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-C6aliphatic, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkoxy, and C3- Cecycloalkoxy, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RB; b) a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6aliphatic, C3-C6cycloalkyl, aClk1o-Cxy6, C3- Cscycloalkoxy, and -OR, wherein said 4-7 membered saturated or partially unsaturated heterocyclyl is further substituted with 0-3 independently selected RB; c) a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected RB; and d) H, halogen, C1-C6aliphatic, Cs-Cvcycloalkyl, C1-Cal6kylene-O-C1-C6alkyl, CN, -OR, - OR10, -NR10Rn, -C(O)NR10Rn-CH2NR10Rn, -SO2R12, wherein said C1-C6aliphatic, C3- C?cycloalkyl, or C1-C6alkylene-O-C1-C6alkyl is substituted with 0-5 independently selected RB; or Rlaand one Rlbon adjacent atoms of Ring B, taken together with the adjacent Ring B atoms to which they are attached, form a cyclic group fused to Ring B selected from phenyl, a 5-6 membered heteroaryl (having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), a 4- 7 membered saturated or partially unsaturated carbocyclyl, or a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), wherein said cyclic group fused to Ring B is substituted with 0-3 independently selected RB;R2is selected from C(Rc)2C(O)N(R)R2A, C(Rc)2C(Rc)2C(O)N(R)R2A, C(Rc)2C(Rc)2N(R)C(O) N(R)R2A, and C(Rc)2C(Rc)2N(R)C(O)R2A;R2Ais cubanyl, a saturated or partially unsaturated 4-8 membered monocyclic ring, a saturated or partially unsaturated bridged, fused or spirocyclic 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, wherein said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring comprises 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said cubanyl, saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring are each optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-C4aliphatic, haloC1-C4alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, C3-C6cycloalkoxy, haloC4-Cecyclalkoxy and -SFs, and wherein two optional substituents on the same atom of said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring form a cyclic group selected from;• an optionally substituted 3-7 membered saturated or partially 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;R3is hydrogen, C1-C4aliphatic, Ca-Cscycloalkyl, 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 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 first 5-6 membered heteroaryl is substituted with 0-5 RB; and optionally two adjacent atoms of said phenyl or first 5-6 membered heteroaryl have two substituents that together with said adjacent atoms form a cyclic group fused to the phenyl or first 5-6 membered heteroaryl selected from a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or a second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur); wherein said fused cyclic group is substituted with 0-3 independently selected RB; orR4is a C1-C4aliphatic, C1-C4alkoxy, or C3-C6cycloalkyl, each of which is substituted with 0-3 groups independently selected from halogen, -CN, -OH, C1-C4alkyl, C1-C4alkoxy, and optionally substituted 5-6 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 5-6 membered heterocyclyloxy having 1- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R10is H, C1-C6aliphatic, haloC1-C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, -C(O)C1- Cealkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R10except H is optionally substituted with 1 or 2 independently selected RB;R11is H, C1-C6aliphatic, or C3-C6cycloalkyl, or R10and R11are taken together with the nitrogen atom to which they are attached to form a 5-6 membered ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, -OH, -CN, C1-C4alkoxy, and haloC1- C4alkoxy;R12is C1-C6aliphatic, C3-C6cycloalkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R12is optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1-C6alkyl, alkoCx1y-C,6C3-C6cycloalkyl, andC3-C6cycloalkoxyRBis independently selected at each occurrence from the group consisting of optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogen, optionally substituted C1-C6aliphatic, haloC1-C6alkyl, Cg- Cecycloalkyl, haloC3-C6cycloalkyl, C1-Ca6lkoxy, haloC1-C6alkoxy, Cg-Cscycloalkoxy, haloCg- Cecycloalkoxy, C1-C6alkylene-O-C1-C6alkyl, -CN, -NO2, oxo, -OR, -SR, NR2, S(O)2R, S(O)2NR2, S(O)R, S(O)NR2, C(O)R, C(O)OR, -C(O)NR2, C(O)N(R)OR, OC(O)R, OC(O)NR2, - N(R)C(O)OR, N(R)C(O)R,N(R)C(O)NR2, N(R)C(NR)NR2, N(R)S(O)2NR2, and -N(R)S(O)2R;Rcis independently selected at each occurrence from hydrogen, -CH3, or -CH2CH3, or two Rctaken together with the carbon to which they are attached form a cyclopropyl ring; each R is independently hydrogen, or an optionally substituted C1-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 a cyclic group selected from an optionally substituted 4-7 membered saturated ring, a 4-7 membered partially unsaturated ring, or a 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said cyclic group has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

2. A compound of Formula I, or a pharmaceutically acceptable salt thereof:L"RA4B CI wherein bicyclic Ring BC is selected from one of the following:wherein denotes the point of attachment to Ring A;wherein each Rlbgroup is independently selected from H, halogen, CN, OH, C1-C6aliphatic, C1- Cealkoxy, C3-C6cycloalkyl, C1-Cal6kylene-O-C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and Cg-Cecycloalkoxy, wherein said C1-C6aliphatic, Ca1-lkCo6xy, C3-C6cycloalkyl, alCky1-lCen6e-O- C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkoxy, and Cg-Cecycloalkoxy are each independently and optionally substituted with 1-5 halogen, OH, CN, C1-C6alkyl, or Cg-Cscycloalkyl groups; wherein z is 0, 1, or 2;Ring A is: a) a 4-7 membered saturated or partially unsaturated bivalent monocyclic carbocyclylene or 4-7 membered saturated or partially unsaturated bivalent heterocyclylene ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 nitrogen atoms in addition to the 1-4 heteroatoms); or b) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene or heterocyclylene (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein Ring A is substituted with 0-4 independently selected RBsubstituents;-L- is a linker selected fromRlais selected from; a) 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-C6aliphatic, Cg-Cscycloalkyl, haloC1-C6alkyl, C1-C6alkoxy, and Cg- Cficycloalkoxy, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RB; b) a 4-7 membered saturated or partially unsaturated monocyclic heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6aliphatic, Cg- Cecycloalkyl, C1-C6alkoxy, Cg-Cecycloalkoxy, and -OR, wherein said 4-7 memberedsaturated or partially unsaturated heterocyclyl is further substituted with 0-3 independently selected RB; c) a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected RB; and d) H, halogen, C1-C6aliphatic, Cg-Cycycloalkyl, C1-Cal6kylene-O-C1-C6alkyl, CN, -OR, - OR10, -NR10Rn, -C(O)NR10Rn-CH2NR10R11, or -SO2R12, wherein said C1-C6aliphatic, C3-C?cycloalkyl, or C1-C6alkylene-O-C1-C6alkyl is substituted with 0-5 independently selected RB; or Rlaand one Rlbon adjacent atoms of Ring B, taken together with the adjacent atoms of Ring B form a cyclic group fused to Ring B selected from phenyl, a 5-6 membered heteroaryl (having 1- 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), a 4-7 membered saturated or partially unsaturated carbocyclyl, or a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), wherein said cyclic group fused to Ring B is substituted with 0-3 independently selected RB;R2is selected from C(Rc)2C(O)N(R)R2A, C(Rc)2C(Rc)2C(O)N(R)R2A, C(Rc)2C(Rc)2N(R)C(O) N(R)R2A, and C(Rc)2C(Rc)2N(R)C(O)R2A;R2Ais cubanyl, a saturated or partially unsaturated 3-8 membered monocyclic ring, a saturated or partially unsaturated bridged, fused or spirocyclic 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, wherein said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring comprises 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said cubanyl, saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring are each optionally substituted with 1, 2, or 3 substituents independently selected from optionally substituted phenyl, halogen, optionally substituted C1-C4aliphatic, haloC1-C4alkyl, Cg-Ce- cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1-C4alkoxy, haloC1-C4alkoxy, Cg-Cscycloalkoxy, haloC4-Cecyclalkoxy and -SFs, and wherein two optional substituents on the same atom of said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused or spirocyclic ring form a cyclic group selected from:an optionally substituted 3-7 membered saturated or partially 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;R3is hydrogen, C1-C4aliphatic, Cg-Cscycloalkyl, 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)NR10Rn, or N(R)C(O)R; each R3Ais independently selected 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 first 5-6 membered heteroaryl is substituted with 0-5 RB; and optionally two adjacent atoms of said phenyl or first 5-6 membered heteroaryl have two substituents that together with said adjacent atoms form a cyclic group fused to the phenyl or first 5-6 membered heteroaryl selected from a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or a second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said fused cyclic group is substituted with 0-3 independently selected RB; orR4is a C1-C4aliphatic, C1-C4alkoxy, or C3-C6cycloalkyl, each of which is substituted with 0-3 groups independently selected from halogen, -CN, -OH, C1-C4alkyl, C1-C4alkoxy, optionally substituted 5-6 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 5-6 membered heterocyclyloxy having 1- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R10is H, C1-C6aliphatic, haloC1-C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, -C(O)C1- Cealkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R10except H being optionally substituted with 1 or 2 independently selected RB;R11is H, C1-C6aliphatic, or C1-cCy6cloalkyl, or R10and R11are taken together with the nitrogen atom to which they are attached to form a 5-6 membered ring optionally substituted with 1, 2, or3 substituents independently selected from halogen, -OH, -CN, C1-C4alkoxy, and haloC1- C4alkoxy;R12is C1-C6aliphatic, C3-C6cycloalkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R12optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6aliphatic, haloC1-C6alkyl, alkCox1-yC,6C3-C6cycloalkyl, and C3-C6cycloalkox;yRBis independently selected at each occurrence from the group consisting of optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogen, optionally substituted C1-C6aliphatic, haloC1-C6alkyl, C3- Cecycloalkyl, haloC3-C6cycloalkyl, C1-Ca6lkoxy, haloC1-C6alkoxy, C3-C6cycloalkoxy haloCs- Cecycloalkoxy, C1-C6alkylene-O-C1-C6alkyl, -B(OR)2, -CN, -NO2, oxo, -OR, -SR, NR2, S(O)2R, S(O)2NR2, S(O)R, S(O)NR2, C(O)R, C(O)OR, -C(O)NR2, C(O)N(R)OR, OC(O)R, OC(O)NR2, -N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR2, N(R)C(NR)NR2, N(R)S(O)2NR2, and - N(R)S(O)2R;Rcis independently selected at each occurrence from hydrogen, -CH3, or -CH2CH3, or two Rctaken together with the carbon to which they are attached form a cyclopropyl ring; each R is independently hydrogen, or an optionally substituted C1-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 a cyclic group selected from an optionally substituted 4-7 membered saturated ring, a 4-7 membered partially unsaturated ring, or a 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein said cyclic group has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

3. A compound of claim 1 of a formula selected from the group consisting of:Il-d II-e Il-fn-j Il-k II-I11 -in Il-n II-oII-x” II-y’ Il-y”or a pharmaceutically acceptable salt thereof; wherein R, ais selected from groups a)-d); a) 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 Ca-Cecycloalkyl and Cg-Cecycloalkoxy, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RB; b) a 4-6 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), said heterocyclyl substituted with 0-2 RBgroups independently selected from halogen, oxo, NR2, optionally substituted C1-C4aliphatic, -OR, azetidinyl optionally substituted with 1 or 2 independently selected halogen, and pyrrolidinyl optionally substituted with 1 or 2 independently selected halogen; c) a 6-8 membered saturated or partially unsaturated bridged bicyclic heterocyclyl (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), said heterocyclyl substituted with 0-2 RBgroups independently selected from halogen, oxo, NR2, optionally substituted C1-C4aliphatic, -OR, azetidinyl optionally substituted with 1 or 2 independently selected halogen, and pyrrolidinyl optionally substituted with 1 or 2 independently selected halogen; and d) H, halogen, C1-C6alkyl, C2-C4alkene, C2-C4alkyne, CN, -OR10, -NR10Rn, -C(O)NR10Rn-CH2NR10Rn, -SO2R12, a 3-7 membered carbocyclyl, wherein said C1-aClk6yl, C2- C4alkene, C2-C4alkyne, or 3-7 membered carbocyclyl may be optionally substituted with 0-3 independently selected RB.

4. A compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, whereinR4is selected from one of a), b), and c): a) R4is a Ring E that is selected from the group consisting of:wherein * is a point of attachment to L or -C(O)-; and: any substituents that are present on Ring E selected from R4A, R4B, R4C, R4D, R4E, and R4Fare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; C1-C4alkoxy; haloC1-C4alkyl; C1-Cgalkyl substituted with -OH, -OCH3, or - OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalk; o axnyd NR13R14; orR4Aand R4B, along with their intervening atoms, join to form 4-7 membered carbocyclyl substituted with 0-3 independently selected RB, a 4-7 membered heterocyclyl substituted with 0-3 independently selected RB, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and any substituents that are present on Ring E selected from R4C, R4D, R4E, and R4Fare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1- Csalkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl;C3-C6cycloalkoxy ; and NR13R14; orR4Band R4t, along with their intervening atoms, join to form a 4-7 membered carbocyclyl substituted with 0-3 independently selected RB, a 4-7 membered heterocyclyl substituted with 0-3 independently selected RB, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and any substituents that are present on Ring E selected from R4A, R4D, R4E, and R4Fare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1- Cbalkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-Cecycloalkoxy; and NR13R14; orR4Cand R4D, along with their intervening atoms, join to form a 4-7 membered carbocyclyl substituted with 0-3 independently selected RB, a 4-7 membered heterocyclyl substituted with 0-3 independently selected RB, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and any substituents that are present on Ring E selected from R4A, R4B, R4Eand R4Eare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C6alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3- Cscycloalkoxy; 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- C3 alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; Cs-Cecycloalkoxy; and NR13R14; orR4Eand R4A, along with their intervening atoms, join to form a 5-6 membered optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and R4B, R4C, and R4Dare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C6alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; orR4Fand R4A, along with their intervening atoms, join to form a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and R4Band R4Care each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C6alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkox;y and NR13R14;R13is independently selected at each occurrence from hydrogen and C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; andR14is hydrogen, or R13and R14combine with the nitrogen atom to which they are attached to form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, said heterocyclic ring optionally substituted with -CH3; b) 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; and 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 having 1 -3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 5-6 membered heterocyclyloxy having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected fromNN N N NNN N N N N NN N N NN NVNN, andwherein Ring A is substituted with 0-4 independently selected RBsubstituents.

6. The compound of claim 1 or 2 of formula:Ill-j Ill-k III-lIII-p Ill-q Ill-rIII-s Ill-t III-u’III-w’ III-w” III-x’III-z”III-z’ or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, whereinR4is selected from one of a), b), and c): a) R4is a Ring E that is selected from the group consisting of:R4FR4AN R4BR4Cwherein * is a point of attachment to L; and any substituents that are present on Ring E selected from R4A, R4B, R4C, R4D, R4E, and R4Fare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; C1-C4alkoxy; haloC1-C4alkyl; C1-Caalkyl substitutedwith -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3- Cecycloalkoxy; and NR13R14; orR4Aand R4B, along with their intervening atoms, join to form 4-7 membered carbocyclyl substituted with 0-3 independently selected RB, a 4-7 membered heterocyclyl substituted with 0-3 independently selected RB, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and any substituents that are present on Ring E selected from R4C, R4D, R4E, and R4Fare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2- C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C6alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; orR4Band R4C, along with their intervening atoms, join to form a 4-7 membered carbocyclyl substituted with 0-3 independently selected RB, a 4-7 membered heterocyclyl substituted with 0-3 independently selected RB, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and any substituents that are present on Ring E selected from R4A, R4D, R4E, and R4Fare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2- C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C6alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; Cs-Cscycloalkyl; C3-C6cycloalkoxy; and NR13R14; orR4Cand R4D, along with their intervening atoms, join to form a 4-7 membered carbocyclyl substituted with 0-3 independently selected RB, a 4-7 membered heterocyclyl substituted with 0-3 independently selected RB, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and any substituents that are present on Ring E selected from R4A, R4B, R4Eand R4Fare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2- C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C6alkyl 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-C6alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3-C6cycloalkoxy; and NR13R14; orR4Eand R4A, along with their intervening atoms, join to form a 5-6 membered optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and R4B, R4C, and R4Dare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C6alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3- Cecycloalkyl; C1-C6cycloalkoxy; and NR13R14; orR4Fand R4A, along with their intervening atoms, join to form a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 0-3 independently selected RB; that is fused to Ring E; and R4Band R4Care each independently selected from hydrogen; halogen; -CN; C1- C4alkyl; C2-C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C6alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyl; C3- Cecycloalkoxy; and NR13R14; andRL3 is independently selected at each occurrence from hydrogen and C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3; andR14is hydrogen, or R13and R14combine with the nitrogen atom to which they are attached to form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, said heterocyclic ring optionally substituted with -CH?; 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; andc) R4is a C1-C4alkyl, C1-C4alkoxy, or C3-C6cycloalkyl, each of which is substituted with 0-3 groups independently selected from halogen, -CN, -OH, C1-C4alkyl, C1-C4alkoxy, optionally substituted 5-6 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 5-6 membered heterocyclyloxy having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

8. The compound of claim 7, wherein Rlais a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1-3 groups selected from halogen, C1-aClk6yl, haloC1-C6alkyl Cal1k-Cox6y and C3-C6cycloalkyl, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected RBand Rlbis selected from H, halogen, C1-Ca6lkyl, haloC1-C6alkyl, C1-Cal6koxy, and haloC1- Ce alkoxy.

9. The compound of claim 7, wherein Rlais a 4-6 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), said heterocyclyl substituted with 0-2 RBgroups independently selected from halogen, oxo, NR2, optionally substituted C1-C4aliphatic, -OR, azetidinyl optionally substituted with 1 or 2 independently selected halogen, and pyrrolidinyl optionally substituted with 1 or 2 independently selected halogen; and each Rlbis independently selected from H, halogen, aClk1-yCl,6haloC1- Cealkyl, C1-C6alkoxy, and haloC1-C6alkoxy.

10. The compound of claim 7, wherein Rlais halogen, Cal1k-yCl6, C2-C4alkene, C2-C4alkyne, CN, -OR10, -NR10Rn, -C(O)NR10R11, -CH2NR10R11, -SO2R12, a C3-C7cycloalkyl, wherein said C1-C6alkyl, C2-C4alkene, C2-C4alkyne, and C3-C?cycloalkyl is substituted with 0-3 RBindependently selected from halogen, C3-C6cycloalkyl, haloC3-C6cycloalkyl, -OH, -CN, C1- C4alkoxy, and haloC1-C4alkoxy; and Rlbis selected from H, halogen, alCky1-lC, h6aloC1-C6alkyl, C1-C6alkoxy, and haloC1-C6alkoxy.

11. The compound of claim 7, wherein Rlais pyridyl optionally substituted with C1-C4alkoxy and further substituted with 0-2 RB; and Rlbis selected from H, halogen, Ca1l-kCy6l, haloC1- Cealkyl, C1-C6alkoxy, and haloC1-C6alkoxy.

12. The compound of claim 7, wherein Rlais 5-membered heteroaryl (having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 additional ring nitrogenatoms), wherein said 5-membered heteroaryl is optionally substituted with a Cs-Cscycloalkyl and further substituted with 0-2 independently selected RB; and Rlbis selected from H, halogen, C1- Cealkyl, haloC1-C6alkyl, C1-Ca6lkoxy, and haloC1-C6alkoxy.

13. The compound of claim 1 or 2, wherein Rlais 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 RBindependently selected from halogen, oxo, NR2, optionally substituted C 1-4aliphatic, -OR, azetidinyl optionally substituted with 1 or 2 independently selected halogen, and pyrrolidinyl optionally substituted with 1 or 2 independently selected halogen; and Rlbis selected from H, halogen, CiValkyl, haloC1-C6alkyl, Ca1l-kCo6xy, and haloC1-C6alkoxy.

14. The compound of claim 1 or 2 of formula:IV-c IV-dIV-g IV-hIV-i or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 or 2, wherein Rlais selected from the group consisting of:

16. The compound of any one of claims 1-15, wherein R4is Ring E of the following structure:OH,wherein * is a point of attachment to L or -C(O)-;R4Ais hydrogen, -CH3, -CH2CH3, -F, -CF2H, -CF3, -OCH3, -OCF3, -OCH2CH3, or -OCHF2;R4B, R4Caanndd RR44UUare each independently selected from hydrogen; halogen; -CN; C1-C4alkyl; C2- C4alkenyl; C2-C4alkynyl; haloC1-C4alkyl; C1-C6alkyl substituted with -OH, -OCH3, or -OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyCl;3-C6cycloalkoxy ; and NR13R14; andR13is independently selected at each occurrence from hydrogen or C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3, and R14is H; or NR13R14, taken in combination form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, said heterocyclic ring 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 RBindependently selected from halogen, -OH, -CN, C1-C4alkyl, haloC1- C4alkyl, C3-C6cycloalkyl, and C1-C4alkoxy.

17. The compound of any one of claims 1-15, wherein R is:wherein * is a point of attachment to L or -C(O)-;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-C6alkyl substituted with -OH, -OCH3, or - OCH2CH3; haloC1-C4alkoxy; C3-C6cycloalkyCl;3-C6cycloalkoxy ; and NR13R14; andR13is independently selected at each occurrence from hydrogen or C1-C4alkyl optionally substituted with -OH, -OCH3, or -OCH2CH3, andR14is H; orNR13R14, taken in combination, form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, said heterocyclic ring optionally substituted with -CH3.

18. The compound of any one of claims 1-15, 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 RBindependently selected from halogen, -OH, -CN, C1-C4alkyl, haloC1-C4alkyl, C3-C6cycloalkyl, and C1-C4alkoxy.

19. The compound of any one of claims 1-15, 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 thiophenyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, oxazolyl, isoxazolyl, 1,2,4- oxadiazolyl, 1,2,3-triazolyl, and 1,2,4-triazolyl, wherein said heteroaryl is optionally substituted with 0-4 RBindependently selected from halogen, -OH, -CN, C1-C4alkyl, haloC1-C4alkyl, C3- Cecycloalkyl, and C1-C4alkoxy.

20. The compound of claim 19, wherein R4is an isoxazolyl substituted with -OH or C1- C4alkoxy.

21. The compound of any one of claims 1-15, wherein R4iso22. The compound of any one of claims 1-21, wherein R2Acomprises a -CF3 substituent.

23. The compound of claim 1, or any one of claims 3-22, wherein R2is24. The compound of any one of claims 1-23, wherein R3is C1-C4alkyl or Cs-Cscycloalkyl.

25. The compound of any one of claims 1-24, wherein Ring A and the 0-4 independently selected RBsubstituents with which Ring A is substituted, is:NN(RB)0-426. The compound of any one of claims 1-5 and 7-25, wherein Ring A is:NN27. The compound of any one of claims 1-5 and 7-24, wherein Ring A is:NN28. 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 ccaanncceerr i inn 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 32, 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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