Pyrrolidinyl compounds as inhibitors of cgas

Abstract

Compounds having formula (I), and enantiomers, and diastereomers, stereoisomers, pharmaceutically˗acceptable salts thereof, Formula (I) are useful as modulators of cGAS. The variables, R1, R2, R3, R4, R5, and R6 are as defined herein.

Description

[0001] PYRROLIDINYL COMPOUNDS AS INHIBITORS OF cGAS CROSS REFERENCE TO RELATED APPLICATIONS This application is entitled to priority pursuant to 35 U.S.C. §119(e) to Indian provisional patent application No.202411051052 filed July 3, 2024, which is incorporated herein in its entirety. FIELD OF THE INVENTION The present invention relates to novel compounds that inhibit cGAS or salts thereof, and methods of making and using the same. Specifically, the present invention relates to pyrrolidinyl compounds as inhibitors of cGAS. BACKGROUND OF THE INVENTION The innate immune system plays a crucial role in defending the host against microbial threats and maintaining tissue homeostasis. However, dysregulation of innate immune signaling pathways can lead to chronic inflammation and contribute to the pathogenesis of various diseases (Decout, A. et al. Nat. Rev. Immunol., 21, 548-569, 2021), including autoimmune disorders, neurodegenerative conditions, cardiovascular disease, and cancer. Among the key regulators of innate immunity, cyclic GMP-AMP synthase (cGAS) has emerged as a central player in sensing cytoplasmic DNA and initiating immune responses. The discovery of cGAS as a cytosolic DNA sensor has revolutionized our understanding of innate immune signaling and provided new insights into the pathogenesis of inflammatory disorders. Upon recognition of cytoplasmic DNA, cGAS catalyzes the synthesis of cyclic GMP-AMP (cGAMP), which directly binds and activates the STimulator of InterferoN Genes (STING) pathway (Sun, L. et al. Science 339, 786- 791, 2013; Wu, J. et al. Science 339, 826-830, 2013; Diner, E. et al. Cell Rep., 3, 1355- 1361, 2013). Upon activation, STING elicits proinflammatory cytokines including type I interferon (IFN-I), NF-kB, autophagy and inflammasome activation. Therefore, sustained activation of cGAS has been strongly implicated in the pathogenesis of autoimmune diseases and sterile inflammation. Inflammatory diseases directly associated with cytosolic DNA exposure from the nucleus or mitochondria – such as scleroderma (SSc), Aicardi- Goutières syndrome (AGS), systemic lupus erythematosus (SLE) and Sjögren’s syndrome (SS) – are indications that could benefit from a cGAS therapeutic intervention. Antinuclear and anti-DNA antibodies are a common feature associated with SSc that are linked to clinical features and severity. Fibroblasts collected from SSc patients demonstrate elevated levels of cGAMP as well as type I interferon, and both are remediated by the introduction of a cGAS inhibitor (Paul, S. et al. Nat. Commun.13, 7074, 2022). AGS is a rare autoinflammatory disorder that is linked to defects in cytosolic nucleic acid detection and / or processing. Mutations in TREX1, a 3’-5’ DNA exonuclease, is one driver of AGS that leads to an increase in cytoplasmic double stranded DNA. In a TREX1- / - murine model, cGAS KO rescues the natural lethality imposed by loss of TREX1 (Gray, E. et al. J. Immun.195(5), 1939-1943, 2015; Gao, D. et al. PNAS 112(42), E5699-E5705, 2015). SLE is a heterogenous autoimmune disease that is also characterized by high amount of dsDNA antibodies. Notably, a subset of SLE patients demonstrate elevated levels of cGAS and cGAMP in their peripheral blood mononuclear cells (An, J. et al. Arthritis Rheumatol.69(4), 800-807, 2017). In addition, plasmacytoid dendritic cells isolated from SLE and SS patients demonstrated elevated levels of pSTING, a marker for STING activation, when exposed to cGAMP compared to healthy volunteers (Huijser, E. et al. Rheumatology.61(8), 3491-3496, 2022). Neuroinflammation and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD) have also been linked to aberrant cGAS activation. Cytoplasmic accumulation of TDP-43 is a hallmark of ALS that leads to DNA release from the mitochondria into the cytosol, resulting in cGAS activation and subsequent IFN-I and NF-kB signaling. Pharmacological inhibition or genetic deletion of cGAS in an induced pluripotent stem cell (iPSC)-derived motor neuron TDP-43 ALS model has been shown to attenuate ensuing IFN-I and NF-kB signaling. Moreover, elevated levels of cGAMP have also been found in the spinal cord samples of ALS patients (Yu, C.-H. et al. Cell 183(3), 636–649, 2020). Amyloid-β (Aβ) plaques within the cerebral cortex are a hallmark feature of AD. Primary cultured microglia, neurons and astrocytes treated with oligomeric Aβ42 exhibit heightened levels of cGAMP as well as IFN-I. In addition, elevated levels of cGAS / STING pathway activation markers including phosphorylated STING, TBK1, p65 and IRF3 have also been observed in cortical tissues from AD patients (Xie, X. et al. Nat. Aging 3(2), 202-212, 2023). Consequently, therapeutically disruption of cGAS is an attractive strategy for bringing relief to various autoimmune and related diseases. SUMMARY OF THE INVENTION The present invention provides novel triazolopyridinyl compounds including stereoisomers, tautomers, isotopes, prodrugs, pharmaceutically acceptable salts, salts, or solvates thereof, which are useful as inhibitors of cGAS. The present invention also provides processes and intermediates for making the compounds of the present invention. The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, isotopes, prodrugs, pharmaceutically acceptable salts, salts, or solvates thereof. The compounds of the invention may be used in the treatment and / or prophylaxis of conditions associated with cGAS. The compounds of the present invention may be used in therapy. The compounds of the present invention may be used for the manufacture of a medicament for the treatment and / or prophylaxis of a condition associated with aberrant cGAS activity. In another aspect, the present invention is directed to a method of treating diseases mediated at least partially by cGAS including inflammatory diseases, immunological disorders, autoimmune disorders, neuroinflammation, and neurodegenerative diseases, which method comprises administering to a patient in need of such treatment a compound of the present invention as described above. The compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more, preferably one to two other agent(s). These and other features of the invention will be set forth in expanded form as the disclosure continues. DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION In one aspect, the present invention provides, inter alia, compounds of Formula (I) or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein wherein, independently for each occurrence: R1is −CH= or −N=; R2is −N= or −C(R2a)=; wherein at least 2 of R1s and R2are N; R2ais H or F; R3is −H, −CH3, -OH, −OCH3, −N(CH3)2, −OCH2CH2OH, C1-2alkyl, C1-2alkoxy, C1-2fluoroalkyl, C1-2fluoroalkoxy, cyclopropyl, flurocyclopropyl, 2,5˗dihydrofuran-3- yl, or 3,3-difluoroazetidin-1-yl;

[0002] R4is 2-(difluoromethyl)morpholin-4-yl,

[0003] R5is −H, halo, −CN, C1-6 alkyl, C1-6 alkenyl, C1-6 haloalkyl, C1-3 alkoxy, C1-3 fluoroalkoxy, C3-6cycloalkyl, C1-3alkoxy, C1-3fluoroalkoxy, cyclohexenyl, C3-6cycloalkyl-ethynyl, C3˗6cycloalkyl-ethenyl, C4-6alkoxymethyl-alkynyl, phenyloxy, pyridinyloxy, pyrmidinyloxy, pyrazolyloxy, , fluorophenyloxy, -C1-6- alkyl-R15, ˗C2-6-alkenyl-R15, ˗C2˗6˗alkynyl-R15, ˗OC(O)NRaR15, – (CH2)n˗OC(O)˗R15, ˗C2˗6˗alkynyl-R16, ˗NH(CO)-Ra, ˗NH(CO)-phenyl, ˗NH(CO)- (fluorophenyl), a ˗(CH2)n- 4-10 membered heterocycle having 1-3 heteroatoms selected from N, O and S, a –(CH2)n-5-10 membered heteroaryl having 1-3 heteroatoms selected from N, O and S, -S(O)2-C1-4alkyl, -S(O)2-C3-5cycloalkyl, - S(O)2- C4-6cycloalkylalkyl, -CH2-N(Ra)2, –(CH2)n˗N(Ra)C(O)Ra, – (CH2)n˗N(Ra)C(O)ORa, ˗(CH2)n˗OC(O)N(Ra)2, , , wherein the cycloalkyl, cyclohexenyl, phenyl, phenyloxy, pyridyloxy, pyrmidinyloxy, pyrazolyloxy, heterocycle or heteroaryl are substituted with 0-3 R5a; R5ais halo, =O, CN, C1-6alkyl, C1-6hydroxyalkyl, C1-6alkoxy, C1-6haloalkyl, C3-6cycloalkyl substituted with 0-1 -CH2OH, phenyl substituted with 0-1 F, -C(O)O- C1-6alkyl, ˗N(Ra)2, -C(O)N(Ra)2, -O-Ra, -C(O)C1-6alkyl, or C(O)-R14,-S(O)2-C1-6alkyl, azetidinyl substituted with 0-2 substituents selected from -CH3or F, morpholinyl, or pyrazolyl; Rais H, C1-6alkyl, C1-6fluoroalkyl, C3-6cycloalkyl, C3-6cyclofluoroalkyl, fluorophenyl, or pyridinyl; R6is imidazolyl, furanyl, pyrazolyl, thiazolyl, thiophenyl, pyrrolyl, pyridazinyl, pyrazinyl, or isothiazolyl, any of which are substituted with 0-2 R6a; or R6is phenyl, or pyridinyl, either of which are substituted with 0-4 R6b; R6ais H, halo, CN, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, cyclopropyl, or phenyl; R6bis H, halo, CN, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, C1-3haloalkoxy, -N(Ra)2, C3˗6cycloalkyl, C3-6cycloalkoxy, -CH2COOH , or ˗O˗(C1˗3alkyl)˗C(O)N(Ra)2,or 4 to 6 membered heterocycle; R7is −H, -OH, or −F, or -S(O)2-C1-3alkyl; R8is H, -C(O)OCH3, or -C(O)CH3, -C(O)-C1-3alkoxyalkyl, -C(O)-CH2CH2N(CH3)2, - C(O)-CH2S(O)2CH3, -C(O)O-tetrahydrofuranyl,; R9is −H, −CH3,-CH2CH3, CF3, -CHF2, CHF2, -CH2OH,or cyclopropyl; R10is −H, −F, −OCH3, −OCHF2, or C1-2hydroxyalkyl; R11is −H, −F, or −OCH3, or -OCHF2; R12is H, C1-3alkyl, C1-3hydroxyalkyl, C1-2fluoroalkyl, -CH2OCH3, and R14is C3-6cycloalkyl, C3-6cycloalkoxy, oxetan-3-yloxy, or –ORa; R15is phenyl, azaspiro[3.3]heptanyl, azabicyclo[2.2.1]heptanyl, oxa- azabicyclo[3.2.1]octanyl, oxa-azabicyclo[3.1.1]heptanyl, azabicyclo[2.2.2]octanyl, diazabicyclo[3.2.1]octanyl, azepanyl, azaspiro[3.4]octanyl, oxa- azabicyclo[3.2.1]octanyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, pyridinyl, pyrimidinyl, pyrazinyl, -N(Ra)2, -OC(O)N(Ra)2, wherein the phenyl, piperidinyl, morpholinyl, pyrrolidinyl, pyridinyl, pyrimidinyl, pyrazinyl are substituted with 0-2 substituents selected from F, CH3, OH, C1-2fluoroalkyl, C1-2alkoxy; and R16is -H, -F, or -OH. Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein compound for Formula (I) is: wherein, independently for each occurrence: R1is −CH= or −N=; R2is −N= or −C(R2a)=; wherein at least 2 of R1s and R2are N; R2ais H or F; R3is −H, −CH3, −OCH3, −N(CH3)2, −OCH2CH2OH, C1-2alkyl, C1-2alkoxy, C1-2fluoroalkyl, C1-2fluoroalkoxy, cyclopropyl, or fluorocyclopropyl; 2,5˗dihydrofuran-3-yl, or 3,3-difluoroazetidin-1-yl; R4is 2-(difluoromethyl)morpholin-4-yl, , ,, ,

[0004] R5is −H, halo, −CN, C1-6alkyl, C1-6haloalkyl, C1-3alkoxy, C1-3fluoroalkoxy, C3-6cycloalkyl, cyclohexenyl, C3-6cycloalkyl-ethynyl, C3-6cycloalkyl-ethenyl, C4-5alkoxymethyl-alkynyl, phenyloxy, pyridyloxy, fluorophenyloxy, phenyl, a 5-6 membered heterocycle, a 5-6 membered heteroaryl, -S(O)2-C1-4alkyl, -S(O)2-C3-5cycloalkyl, -S(O)2-C1-4cycloalkyl-C4-6-alkyl, , wherein the cycloalkyl, cyclohexenyl, phenyl, heterocycle or heteroaryl are substituted with 0-2 R5a; R5ais halo, CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C(O)O-C1-6alkyl, C(O)N(Ra)2, O-Ra, C(O)C1-6alkyl, or C(O)-R14; Rais H, or C1-6alkyl, C1-6fluoroalkyl, C3-6cycloalkyl, or C3-6cyclofluoroalkyl; R6is imidazolyl, furanyl, pyrazolyl, thiazolyl, thiophenyl, pyrrolyl, pyridazinyl, pyrazinyl, or isothiazolyl, any of which are substituted with 0-2 R6a; or R6is phenyl, or pyridinyl, either of which are substituted with 0-4 R6b; R6ais H, halo, CN, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, cyclopropyl, or phenyl; R6bis H, halo, CN, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, C1-3haloalkoxy, -N(Ra)2, C3˗6cycloalkyl, C3-6cycloalkoxy, -CH2COOH , or ˗O˗(C1˗3alkyl)˗C(O)N(Ra)2,or 4 to 6 membered heterocycle; R7is −H, -OH, or −F; R8is H, -C(O)OCH3, -C(O)CH3, or -SO2Me R9is −H, −CH3,-CH2CH3, CF3, -CHF2, CHF2, -CH2OH,or cyclopropyl; R10is −H, −F, −OCH3, −OCHF2, or C1-2hydroxyalkyl ; R11is −H, −F, or −OCH3, or -OCHF2; R12is H, C1-3alkyl, C1-3hydroxyalkyl, C1-2fluoroalkyl, -CH2OCH3, and R14is C3-6cycloalkyl, C3-6cycloalkoxy, oxetan-3-yloxy, or –ORa. Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein compound for Formula (I) is a compound of Formula (Ia), Another embodiment provides a compound of Formula (I) or (Ia), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein the compound is a compound of Formula (2a), (2b), (2c), or 2(d), Another embodiment provides a compound of Formula (I) (Ia), (2a), (2b), (2c), or 2(d), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R5is −H, halo, −CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, cyclohexenyl, C3-6cycloalkyl-ethynyl, C3-6cycloalkyl-ethenyl, phenyl, a 5-6 membered heterocycle, wherein the heterocycle is oxetanyl, oxolanyl, dihydrofuranyl, dihydropyranyl, dihydropyrrolyl, dihydropyridinyl, or tetrahydropyridinyl, or a 5-6 membered heteroaryl, wherein the heteroaryl is pyridinyl, furanyl, or benzofuranyl wherein the cycloalkyl, cyclohexenyl, phenyl, heterocycle or heteroaryl are substituted with 0-1 R5a. Another embodiment provides a compound of Formula (I) (Ia), (2a), (2b), (2c), or 2(d), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R4is 2-(difluoromethyl)morpholin-4-yl, Another embodiment provides a compound of Formula (I) (Ia), (2a), (2b), (2c), or 2(d), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R6is imidazolyl, furanyl, pyrazolyl, thiazolyl, thiophenyl, pyrrolyl, or pyrazolyl, any of which are substituted with 0-2 R6a. Another embodiment provides a compound of Formula (I) (Ia), (2a), (2b), (2c), or 2(d), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R5is − C3-6cycloalkyl-ethynyl, phenyl, a 5-6 membered heterocycle, wherein the heterocycle is oxetanyl, oxolanyl, dihydrofuranyl, dihydropyranyl, dihydropyrrolyl, dihydropyridinyl, or tetrahydropyridinyl, or a 5-6 membered heteroaryl, wherein the heteroaryl is pyridinyl, wherein the cycloalkyl, cyclohexenyl, phenyl, heterocycle or heteroaryl are substituted with 0-1 R5a. Another embodiment provides a compound of Formula (I) (Ia), (2a), (2b), (2c), or 2(d), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R5is, C3-6 cycloalkyl-ethynyl, C3˗6 cycloalkyl-ethenyl, C4-6 alkoxymethyl-alkynyl, ˗C2˗6˗alkenyl-R15, ˗C2˗6˗alkynyl-R15, ˗OC(O)NRaR15, ˗OC(O)˗R15, -C2˗6-alkynyl- R16, ˗NH(CO)-phenyl, ˗NH(CO)-(fluorophenyl), a –(CH2)n- 4-10 membered heterocycle having 1-3 heteroatoms selected from N, O and S, wherein the cycloalkyl, cyclohexenyl, phenyl, phenyloxy, pyridyloxy, pyrmidinyloxy, pyrazolyloxy, heterocycle or heteroaryl are substituted with 0-3 R5a. Another embodiment provides a compound of Formula (I) (Ia), (2a), (2b), (2c), or 2(d), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R5is, C3-6cycloalkyl-ethynyl, C3˗6cycloalkyl-ethenyl, C4-6alkoxymethyl-alkynyl, ˗C2˗6˗alkenyl-R15, ˗C2˗6˗alkynyl-R15, ˗OC(O)NRaR15, ˗OC(O)˗R15, -C2˗6-alkynyl- R16, ˗NH(CO)-phenyl, ˗NH(CO)-(fluorophenyl), a 4-10 membered heterocycle having 1˗3 heteroatoms selected from N, O and S, wherein the heterocycle is oxetanyl, oxolanyl, dihydrofuranyl, dihydropyranyl, dihydropyrrolyl, dihydropyridinyl, or tetrahydropyridinyl, or a 4-10 membered heteroaryl, wherein the heteroaryl is pyridinyl, wherein the cycloalkyl, cyclohexenyl, phenyl, phenyloxy, pyridyloxy, pyrmidinyloxy, pyrazolyloxy, heterocycle or heteroaryl are substituted with 0-3 R5a; R5ais halo, CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C(O)O-C1-6alkyl, C(O)N(Ra)2, O˗Ra, C(O)C1-6alkyl, or C(O)-R14; Rais H, or C1-6alkyl; and R15is phenyl, azaspiro[3.3]heptanyl, azabicyclo[2.2.1]heptanyl, oxa- azabicyclo[3.2.1]octanyl, oxa-azabicyclo[3.1.1]heptanyl, azabicyclo[2.2.2]octanyl, diazabicyclo[3.2.1]octanyl, azepanyl, azaspiro[3.4]octanyl, oxa- azabicyclo[3.2.1]octanyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, pyridinyl, pyrimidinyl, pyrazinyl, wherein the phenyl, piperidinyl, morpholinyl, pyrrolidinyl, pyridinyl, pyrimidinyl, pyrazinyl are substituted with 0-2 substituents selected from F, CH3, OH, C1-2fluoroalkyl, C1-2alkoxy. Another embodiment provides a compound of Formula (I) (Ia), (2a), (2b), (2c), or 2(d), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R5is C3-6cycloalkyl-ethynyl, C3˗6cycloalkyl-ethenyl, C4-6alkoxymethyl-alkynyl, ˗C2˗6˗alkenyl-R15, ˗C2˗6˗alkynyl-R15; R5ais halo, CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C(O)O-C1-6alkyl, C(O)N(Ra)2, O˗Ra, C(O)C1-6alkyl, or C(O)-R14; Rais H, or C1-6alkyl; and R15is phenyl, azaspiro[3.3]heptanyl, azabicyclo[2.2.1]heptanyl, oxa- azabicyclo[3.2.1]octanyl, oxa-azabicyclo[3.1.1]heptanyl, azabicyclo[2.2.2]octanyl, diazabicyclo[3.2.1]octanyl, azepanyl, azaspiro[3.4]octanyl, oxa- azabicyclo[3.2.1]octanyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, pyridinyl, pyrimidinyl, pyrazinyl, wherein the phenyl, piperidinyl, morpholinyl, pyrrolidinyl, pyridinyl, pyrimidinyl, pyrazinyl are substituted with 0-2 substituents selected from F, CH3, OH, C1-2fluoroalkyl, C1-2alkoxy. Another embodiment provides a compound of Formula (I) (Ia), (2a), (2b), (2c), or 2(d), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R5is ˗C2-6-alkenyl-R15, ˗C2˗6˗alkynyl-R15; and R15is azepanyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, pyridinyl, pyrimidinyl, pyrazinyl, wherein the piperidinyl, morpholinyl, pyrrolidinyl, pyridinyl, pyrimidinyl, pyrazinyl are substituted with 0-2 substituents selected from F, CH3, OH, C1-2fluoroalkyl, and C1-2alkoxy. Another embodiment provides a compound of Formula (I) (Ia), (2a), (2b), (2c), or 2(d), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R4is R9is selected from H, CH3, CHF2, CH2CH3,CF3, CH2F, or cyclopropyl. Another embodiment provides a compound of Formula (I) (Ia), (2a), (2b), (2c), or 2(d), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R6is phenyl or pyridinyl, either of which are substituted with 0-4 R6b. Another embodiment provides a compound of Formula (I) (Ia), (2a), (2b), (2c), or 2(d), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R6is furanyl, thiophenyl, pyrrolyl, any of which are substituted with 0-2 R6a; and R6ais H, Cl, CH3, CH2CH3, methoxy, or cyclopropyl. Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein the compound is Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein the compound is

[0005] . Another embodiment provides a compound of Formula (I) (Ia), (2a), (2b), (2c), or 2(d), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein . Another embodiment provides a compound of Formula (I) (Ia), (2a), (2b), (2c), or 2(d), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R5is 2-cyclopropylthynyl, pyridiyl substituted with 0-1 R5aor . Another embodiment provides a compound of Formula (I) (Ia), (2a), (2b), (2c), or 2(d), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein Another embodiment provides a compound of Formula (I) (Ia), (2a), (2b), (2c), or 2(d), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R6is furanyl, pyrazolyl or thiophenyl, any of which are substituted with 0-2 R6a. Another embodiment provides a compound of Formula (I) (Ia), (2a), (2b), (2c), or 2(d), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R6is furanyl-2-yl, pyrazol-2-yl, thiophen-2-yl, any of which are substituted with 0-2 R6a. Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein the compound is selected from the examples. The present invention is also directed to pharmaceutical compositions useful in treating diseases associated with modulation of cGAS, comprising compounds of formula (I), or pharmaceutically˗acceptable salts thereof, and pharmaceutically˗acceptable carriers or diluents. The invention further relates to methods of treating diseases associated modulation of cGAS, comprising administering to a patient in need of such treatment a therapeutically˗effective amount of a compound according to formula (I). The present invention also provides processes and intermediates for making the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof. The present invention also provides a method for treating proliferative diseases, allergic diseases, autoimmune diseases and inflammatory diseases and fibrotic diseases, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof. The present invention also provides a method of treating a condition comprising administering to a patient in need of such treatment a therapeutically˗effective amount of a compound of formula (I), wherein the condition is selected from scleroderma (SSc), systemic lupus erythematosus (SLE), Aicardi- Goutières syndrome (AGS), amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), chronic obstructive pulmonary disease (COPD), Sjögren’s syndrome (SS), type 1 diabetes, rheumatoid arthritis (RA), senescence, STING-associated vasculopathy with onset in infancy (SAVI), silicosis, inflammation associated with aging, inflammatory bowel disease (IBD), and neurodegenerative disease caused by traumatic injury. The present invention also provides a method of treating a condition comprising administering to a patient in need of such treatment a therapeutically˗effective amount of a compound of formula (I), wherein the condition is selected from multiple sclerosis, psoriasis, idiopathic pulmonary fibrosis (IPF), atherosclerosis, frontotemporal dementia (FTD), hypertension, dermatomyositis, cardiomyopathy, prostate cancer, pancreatic cancer, Parkinson’s disease, pancreatitis (acute or chronic), Huntington disease, nephropathy (acute or chronic), breast cancer, ovarian cancer, COPA syndrome, nonalcoholic steatohepatitis (NASH), sepsis, myocardial infarction, chronic heart failure, atopic dermatitis, melanoma, asthma, colorectal cancer, lung cancer, and macular degeneration. The present invention also provides a method of treating a condition comprising administering to a patient in need of such treatment a therapeutically˗effective amount of a compound of formula (I), wherein the condition is selected fromscleroderma (SSc) and systemic lupus erythematosus (SLE). The present invention also provides a method of treating diseases, comprising administering to a patient in need of such treatment a therapeutically˗effective amount of a compound of formula (I), or pharmaceutically acceptable salt thereof, in combination with other therapeutic agents. The present invention also provides the compounds of the present invention or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, for use in therapy. In another embodiment, compounds of formula (I), are selected from exemplified examples or combinations of exemplified examples or other embodiments herein. The present invention also provides the use of the compounds of the present invention or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, for the treatment of cancers, an autoimmune disease, an inflammatory disease, a neurodegenerative or neuroinflammatory disease, as described elsewhere. The present invention also provides the use of the compounds of the present invention or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, for the manufacture of a medicament for the treatment of cancers, an autoimmune disease, an inflammatory disease, a neurodegenerative or neuroinflammatory disease. The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of preferred aspects and / or embodiments of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also to be understood that each individual element of the embodiments is its own independent embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment. The following are definitions of terms used in this specification and appended claims. The initial definition provided for a group or term herein applies to that group or term throughout the specification and claims, individually or as part of another group, unless otherwise indicated. Unless specifically stated otherwise herein, references made in the singular may also include the plural. For example, “a” and “an” may refer to either one, or one or more. When any variable (e.g., R3) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0˗2 R3, then said group may optionally be substituted with up to two R3groups and R3at each occurrence is selected independently from the definition of R3. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. Unless otherwise indicated, any carbon or heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences. When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. In cases wherein there are nitrogen atoms (e.g., amines) on compounds of the present invention, these can be converted to N˗oxides by treatment with an oxidizing agent (e.g., MCPBA and / or hydrogen peroxides) to afford other compounds of this invention. Thus, all shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N˗oxide (N→O) derivative. In accordance with a convention used in the art, is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure. A dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, ˗CONH2is attached through the carbon atom. The term “optionally substituted” in reference to a particular moiety of the compound of Formula (I), (e.g., an optionally substituted heteroaryl group) refers to a moiety having 0, 1, 2, or more substituents. For example, “optionally substituted alkyl” encompasses both “alkyl” and “substituted alkyl” as defined below. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non˗feasible and / or inherently unstable. As used herein, the term “alkyl” or “alkylene” is intended to include both branched and straight˗chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, “C1˗10alkyl” (or alkylene), is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10alkyl groups. Additionally, for example, “C1˗C6alkyl” denotes alkyl having 1 to 6 carbon atoms. Alkyl groups can be unsubstituted or substituted so that one or more of its hydrogens are replaced by another chemical group. Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n˗propyl and isopropyl), butyl (e.g., n˗butyl, isobutyl, t˗butyl), pentyl (e.g., n˗pentyl, isopentyl, neopentyl), and the like. When the term “alkyl” is used together with another group, such as in “arylalkyl”, this conjunction defines with more specificity at least one of the substituents that the substituted alkyl will contain. For example, “arylalkyl” refers to a substituted alkyl group as defined above where at least one of the substituents is an aryl, such as benzyl. Thus, the term aryl(C0˗4)alkyl includes a substituted lower alkyl having at least one aryl substituent and also includes an aryl directly bonded to another group, i.e., aryl(C0)alkyl. The term “heteroarylalkyl” refers to a substituted alkyl group as defined above where at least one of the substituents is a heteroaryl. “Alkenyl" or “alkenylene” is intended to include hydrocarbon chains of either straight or branched configuration and having one or more double carbon˗carbon bonds that may occur in any stable point along the chain. For example, “C2˗6alkenyl” (or alkenylene), is intended to include C2, C3, C4, C5, and C6alkenyl groups. Examples of alkenyl include, but are not limited to, ethenyl, 1˗propenyl, 2˗propenyl, 2˗butenyl, 3˗butenyl, 2˗pentenyl, 3, pentenyl, 4˗pentenyl, 2˗hexenyl, 3˗hexenyl, 4˗hexenyl, 5˗hexenyl, 2˗methyl˗2˗propenyl, 4˗methyl˗3˗pentenyl, and the like. "Alkynyl" or “alkynylene” is intended to include hydrocarbon chains of either straight or branched configuration and having one or more triple carbon˗carbon bonds that may occur in any stable point along the chain. For example, “C2˗6alkynyl” (or alkynylene), is intended to include C2, C3, C4, C5, and C6alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like. When reference is made to a substituted alkenyl, alkynyl, alkylene, alkenylene, or alkynylene group, these groups are substituted with one to three substituents as defined above for substituted alkyl groups. The term “alkoxy” refers to an oxygen atom substituted by alkyl or substituted alkyl, as defined herein. For example, the term “alkoxy” includes the group ˗O˗C1˗6alkyl such as methoxy, ethoxy, propoxy, isopropoxy, n˗butoxy, sec˗butoxy, tert˗butoxy, pentoxy, 2˗pentyloxy, isopentoxy, neopentoxy, hexoxy, 2˗hexoxy, 3˗hexoxy, 3˗methylpentoxy, and the like. “Lower alkoxy” refers to alkoxy groups having one to four carbons. It should be understood that the selections for all groups, including for example, alkoxy, thioalkyl, and aminoalkyl, will be made by one skilled in the field to provide stable compounds. The term "substituted", as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom’s normal valence is not exceeded. When a substituent is oxo, or keto, (i.e., =O) then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. Unless otherwise specified, substituents are named into the core structure. For example, it is to be understood that when (cycloalkyl)alkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture to a useful degree of purity, and subsequent formulation into an efficacious therapeutic agent. It is preferred that the presently recited compounds do not contain a N˗halo, S(O)2H, or S(O)H group. The term “carbocyclyl” or “carbocyclic” refers to a saturated or unsaturated, or partially unsaturated, monocyclic or bicyclic ring in which all atoms of all rings are carbon. Thus, the term includes cycloalkyl and aryl rings. Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shown above, bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane). Carbocycles, can include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. When the term “carbocycle” is used, it is intended to include “aryl”. A bridged ring occurs when one or more carbon atoms link two non˗adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a bicyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge. The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, and naphthyl groups, each of which may be substituted. A preferred aryl group is optionally˗substituted phenyl. The term “cycloalkyl” refers to cyclized alkyl groups, including mono˗, bi˗ or poly˗cyclic ring systems. C3˗7cycloalkyl is intended to include C3, C4, C5, C6, and C7cycloalkyl groups. Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like, which optionally may be substituted at any available atoms of the ring(s). The terms “heterocycloalkyl”, “heterocyclo”, “heterocycle”, “heterocyclic”, or “heterocyclyl” may be used interchangeably and refer to substituted and unsubstituted aromatic or non˗aromatic 3˗to 7˗membered monocyclic groups, 7˗to 11˗membered bicyclic groups, and 10˗to 15˗membered tricyclic groups, in which at least one of the rings has at least one heteroatom (O, S or N; or O, S, N, or Se), said heteroatom containing ring preferably having 1, 2, or 3 heteroatoms selected from O, S, and N; or having 1, 2, or 3 heteroatoms selected from O, S, N or Se. Each ring of such a group containing a heteroatom can contain one or two oxygen or sulfur atoms and / or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less, and further provided that the ring contains at least one carbon atom. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The heterocyclo group may be attached at any available nitrogen or carbon atom. The term “heterocycle” includes “heteroaryl” groups. As valence allows, if said further ring is cycloalkyl or heterocyclo it is additionally optionally substituted with =O (oxo). Exemplary monocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl, 2˗oxopiperazinyl, 2˗oxopiperidyl, 2˗oxopyrrolodinyl, 2˗oxoazepinyl, azepinyl, 1˗pyridonyl, 4˗piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3˗dioxolane and tetrahydro˗1,1˗dioxothienyl and the like, including the exemplary groups listed under “heteroaryl”. Exemplary bicyclic heterocyclo groups include quinuclidinyl. The term “heteroaryl” refers to substituted and unsubstituted aromatic 5˗ or 6˗membered monocyclic groups, 9˗ or 10˗membered bicyclic groups, and 11˗ to 14˗membered tricyclic groups which have at least one heteroatom (O, S or N) in at least one of the rings, said heteroatom˗containing ring preferably having 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and / or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non˗aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. As valence allows, if said further ring is cycloalkyl or heterocyclo it is additionally optionally substituted with =O (oxo). Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like. Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydroisoindolyl, tetrahydroquinolinyl, and the like. Exemplary tricyclic heteroaryl groups include carbazolyl, benzindolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like. Unless otherwise indicated, when reference is made to a specifically˗named aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl), heterocyclo (e.g., pyrrolidinyl, piperidinyl, and morpholinyl) or heteroaryl (e.g., tetrazolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, and furyl) the reference is intended to include rings having 0 to 3, preferably 0˗2, substituents, as appropriate. The term “halo” or “halogen” refers to chloro, bromo, fluoro and iodo. The term “haloalkyl” means a substituted alkyl having one or more halo substituents. For example, “haloalkyl” includes mono, di, and trifluoromethyl. The term “haloalkyl” means a substituted alkyl having one or more halo substituents. For example, “haloalkyl” includes mono, di, and trifluoromethyl. The term “haloalkoxy” means an alkoxy group having one or more halo substituents. For example, “haloalkoxy” includes OCF3. The term “deuteroalkyl” means a substituted alkyl having one or more deuterium atom. For example, the term “deuteroalkyl” includes mono, di, and trideuteromethyl. The term “heteroatoms” shall include oxygen, sulfur and nitrogen. When the term “unsaturated” is used herein to refer to a ring or group, the ring or group may be fully unsaturated or partially unsaturated. One skilled in the field will understand that, when the designation “CO2” is used Oherein, this is intended to refer to the groupCO .Throughout the specification, groups and substituents thereof may be chosen by one skilled in the field to provide stable moieties and compounds and compounds useful as pharmaceutically˗acceptable compounds and / or intermediate compounds useful in making pharmaceutically˗acceptable compounds. The compounds of formula (I) may exist in a free form (with no ionization) or can form salts which are also within the scope of this invention. Unless otherwise indicated, reference to an inventive compound is understood to include reference to the free form and to salts thereof. The term “salt(s)” denotes acidic and / or basic salts formed with inorganic and / or organic acids and bases. In addition, the term “salt(s) may include zwitterions (inner salts), e.g., when a compound of formula (I), contains both a basic moiety, such as an amine or a pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid. Pharmaceutically acceptable (i.e., non˗toxic, physiologically acceptable) salts are preferred, such as, for example, acceptable metal and amine salts in which the cation does not contribute significantly to the toxicity or biological activity of the salt. However, other salts may be useful, e.g., in isolation or purification steps which may be employed during preparation, and thus, are contemplated within the scope of the invention. Salts of the compounds of the formula (I) may be formed, for example, by reacting a compound of the formula (I) with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, 2˗hydroxyethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid), 2˗naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3˗phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; barium, zinc, and aluminum salts; salts with organic bases (for example, organic amines) such as trialkylamines such as triethylamine, procaine, dibenzylamine, N˗benzyl˗β˗phenethylamine, 1˗ephenamine, N,N'˗dibenzylethylene˗diamine, dehydroabietylamine, N˗ethylpiperidine, benzylamine, dicyclohexylamine or similar pharmaceutically acceptable amines and salts with amino acids such as arginine, lysine and the like. Basic nitrogen˗containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. In one embodiment, salts include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate or nitrate salts. The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non˗toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non˗toxic inorganic or organic acids. For example, such conventional non˗toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2˗acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, the disclosure of which is hereby incorporated by reference. All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. Stereoisomers may include compounds which are optical isomers through possession of one or more chiral atoms, as well as compounds which are optical isomers by virtue of limited rotation about one or more bonds (atropisomers). The definition of compounds according to the invention embraces all the possible stereoisomers and their mixtures. It very particularly embraces the racemic forms and the isolated optical isomers having the specified activity. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates from the conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization. The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. As an example, an alkyl substituent is intended to cover alkyl groups have either hydrogen, deuterium, and / or some combination thereof. Isotopes of carbon include13C and14C. Isotopically˗labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically˗labeled reagent in place of the non˗labeled reagent otherwise employed. Prodrugs and solvates of the inventive compounds are also contemplated. The term “prodrug” denotes a compound which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the formula (I), and / or a salt and / or solvate thereof. Any compound that will be converted in vivo to provide the bioactive agent (i.e., the compound for formula (I)) is a prodrug within the scope and spirit of the invention. For example, compounds containing a carboxy group can form physiologically hydrolyzable esters which serve as prodrugs by being hydrolyzed in the body to yield formula (I) compounds per se. Such prodrugs are preferably administered orally since hydrolysis in many instances occurs principally under the influence of the digestive enzymes. Parenteral administration may be used where the ester per se is active, or in those instances where hydrolysis occurs in the blood. Examples of physiologically hydrolyzable esters of compounds of formula (I) include C1˗6alkylbenzyl, 4˗methoxybenzyl, indanyl, phthalyl, methoxymethyl, C1˗6alkanoyloxy˗C1˗6alkyl, e.g. acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl, C1˗6alkoxycarbonyloxy˗C1˗6alkyl, e.g. methoxycarbonyl˗oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5˗methyl˗2˗oxo˗1,3˗dioxolen˗4˗yl)˗methyl and other well known physiologically hydrolyzable esters used, for example, in the penicillin and cephalosporin arts. Such esters may be prepared by conventional techniques known in the art. Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol.112, pp.309˗396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krosgaard˗Larsen and H. Bundgaard, Chapter 5, “Design and Application of Prodrugs,” by H. Bundgaard, pp.113˗191 (1991); and c) H. Bundgaard, Advanced Drug Delivery Reviews, Vol.8, pp.1˗38 (1992), each of which is incorporated herein by reference. Compounds of the formula (I) and salts thereof may exist in their tautomeric form, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that the all tautomeric forms, insofar as they may exist, are included within the invention. Compounds of this invention may have one or more asymmetric centers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms of compounds of the present invention are included in the present invention. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. The present compounds can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated. All geometric isomers, tautomers, atropisomers, hydrates, solvates, polymorphs, and isotopically labeled forms of the compounds referred to herein, and mixtures thereof, are considered within the scope of the present invention. Methods of solvation are generally known in the art. For some examples of the present invention, the absolute stereochemistry of the enantiomers and / or diastereomers has not been specifically identified. However, the racemic mixtures and all enantiomers and diastereomers are included in the present invention. Even where the specific enantiomers and / or diastereomers are isolated, but the absolute stereochemistry was not specifically determined and drawn, one of skill in the art can easily identify and draw the structures of the individual stereoisomers or diastereomers. “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The present invention is intended to embody stable compounds. UTILITY The compounds of the invention are modulators of cGAS. Accordingly, compounds of formula (I) have utility in treating conditions associated with the modulation of cGAS. As used herein, the terms “treating” or “treatment” encompass the treatment of a disease state in a mammal, particularly in a human, and include: (a) preventing or delaying the occurrence of the disease state in a mammal, in particular, when such mammal is predisposed to the disease state but has not yet been diagnosed as having it; (b) inhibiting the disease state, i.e., arresting its development; and / or (c) achieving a full or partial reduction of the symptoms or disease state, and / or alleviating, ameliorating, or lessening the disease or disorder and / or its symptoms. In view of their activity as inhibitors of cGAS, compounds of Formula (I) are useful in treating cGAS-associated conditions including, but not limited to, autoimmune, inflammatory, and neuro diseases such scleroderma (SSc), systemic lupus erythematosus (SLE), Aicardi- Goutières syndrome (AGS), amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), chronic obstructive pulmonary disease (COPD), Sjögren’s syndrome, type 1 diabetes, rheumatoid arthritis (RA), senescence, STING-associated vasculopathy with onset in infancy (SAVI), silicosis, inflammation associated with aging, inflammatory bowel disease (IBD), and neurodegenerative disease caused by traumatic injury. In view of their activity as inhibitors of cGAS, compounds of Formula (I) are useful in treating cGAS-associated conditions including, but not limited to, diseases such as multiple sclerosis, psoriasis, idiopathic pulmonary fibrosis (IPF), atherosclerosis, hypertension, dermatomyositis, prostate cancer, pancreatic cancer, Parkinson’s disease, pancreatitis (acute or chronic), Huntington disease, breast cancer, ovarian cancer, COPA syndrome, nonalcoholic steatohepatitis (NASH), sepsis, myocardial infarction, chronic heart failure, atopic dermatitis, melanoma, asthma, colorectal cancer, lung cancer, and macular degeneration. In view of their activity as inhibitors of cGAS, compounds of Formula (I) are useful in treating cGAS-associated conditions including, but not limited to, diseases such as scleroderma (SSc), systemic lupus erythematosus (SLE), and Aicardi- Goutières syndrome (AGS). In view of their activity as inhibitors of cGAS, compounds of Formula (I) are useful in treating cGAS-associated conditions including, but not limited to, diseases such as scleroderma (SSc), and systemic lupus erythematosus (SLE). Alternatively preferred methods of treatment are those wherein the condition is selected from ischemia reperfusion injury, including cerebral ischemia reperfusions injury arising from stroke and cardiac ischemia reperfusion injury arising from myocardial infarction. When the terms “cGAS˗associated condition” or “cGAS˗associated disease or disorder” are used herein, each is intended to encompass all of the conditions identified above as if repeated at length, as well as any other condition that is affected by cGAS activity. The present invention thus provides methods for treating such conditions, comprising administering to a subject in need thereof a therapeutically˗effective amount of at least one compound of Formula (I) or a salt thereof. “Therapeutically effective amount” is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination to inhibit cGAS. The methods of treating cGAS signalling disorders may comprise administering compounds of Formula (I) alone or in combination with each other and / or other suitable therapeutic agents useful in treating such conditions. Accordingly, “therapeutically effective amount” is also intended to include an amount of the combination of compounds claimed that is effective to inhibit cGAS and / or treat diseases associated with cGAS. Exemplary of such other therapeutic agents include, but are not limited to, corticosteroids, cyclosporine, azathioprine, hydroxychloroquine, chloroquine, cyclophosphamide, rolipram, calphostin, cytokine˗suppressive anti˗inflammatory drugs (CSAIDs), interleukin˗10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear translocation inhibitors such as deoxyspergualin (DSG); non˗steroidal antinflammatory drugs (NSAIDs) such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisone or dexamethasone; anti˗inflammatory antibodies such as vedolizumab and ustekinumab; anti˗inflammatory kinase inhibitors such as TYK2 inhibitors; toll-like receptor (TLR) inhibitors such as afimetoran; JAK inhibitors such as ruxolitinib; anti-IFN antibodies; antiviral agents such as abacavir; antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, Prograf); cytotoxic drugs such as azathiprine and cyclophosphamide; TNF˗α inhibitors such as tenidap, anti˗TNF antibodies or soluble TNF receptor, rapamycin (sirolimus or Rapamune) or derivatives thereof, and agonists of FGF21. The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians’ Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art. In the methods of the present invention, such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the administration of the inventive compounds. The present invention also provides pharmaceutical compositions capable of treating cGAS signaling ˗associated disorders. The inventive compositions may contain other therapeutic agents as described above and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (e.g., excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation. Accordingly, the present invention further includes compositions comprising one or more compounds of Formula (I) and a pharmaceutically acceptable carrier. A “pharmaceutically acceptable carrier” refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals. Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include without limitation the type and nature of the active agent being formulated; the subject to which the agent˗containing composition is to be administered; the intended route of administration of the composition; and, the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non˗aqueous liquid media, as well as a variety of solid and semi˗solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Remington’s Pharmaceutical Sciences, 17th ed., 1985, or a more recent edition, which is incorporated herein by reference in its entirety. The compounds of Formula (I) may be administered by any means suitable for the condition to be treated, which may depend on the need for site˗specific treatment or quantity of drug to be delivered. Topical administration is generally preferred for skin˗related diseases, and systematic treatment preferred for cancerous or pre˗cancerous conditions, although other modes of delivery are contemplated. For example, the compounds may be delivered orally, such as in the form of tablets, capsules, granules, powders, or liquid formulations including syrups; topically, such as in the form of solutions, suspensions, gels or ointments; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (e.g., as sterile injectable aq. or non˗aq. solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; rectally such as in the form of suppositories; or liposomally. Dosage unit formulations containing non˗toxic, pharmaceutically acceptable vehicles or diluents may be administered. The compounds may be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved with suitable pharmaceutical compositions or, particularly in the case of extended release, with devices such as subcutaneous implants or osmotic pumps. Exemplary compositions for topical administration include a topical carrier such as PLASTIBASE®(mineral oil gelled with polyethylene). Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and / or lactose and / or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. The inventive compounds may also be orally delivered by sublingual and / or buccal administration, e.g., with molded, compressed, or freeze˗dried tablets. Exemplary compositions may include fast˗dissolving diluents such as mannitol, lactose, sucrose, and / or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (AVICEL®) or polyethylene glycols (PEG); an excipient to aid mucosal adhesion such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), and / or maleic anhydride copolymer (e.g., GANTREZ®); and agents to control release such as polyacrylic copolymer (e.g., CARBOPOL 934®). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use. Exemplary compositions for nasal aerosol or inhalation administration include solutions which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance absorption and / or bioavailability, and / or other solubilizing or dispersing agents such as those known in the art. Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non˗toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3˗butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono˗ or diglycerides, and fatty acids, including oleic acid. Exemplary compositions for rectal administration include suppositories which may contain, for example, suitable non˗irritating excipients, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures but liquefy and / or dissolve in the rectal cavity to release the drug. The therapeutically˗effective amount of a compound of the present invention may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for a mammal of from about 0.05 to 1000 mg / kg; 1˗1000 mg / kg; 1˗50 mg / kg; 5˗250 mg / kg; 250˗1000 mg / kg of body weight of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day. It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition. Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats, horses, and the like. Thus, when the term “patient” is used herein, this term is intended to include all subjects, most preferably mammalian species, that are affected by mediation of cGAS activation. Enzymatic LC / MS assay for human cGAS The enzymatic assay (prepared in 384-REMP plates, Brooks Automation #1800030) was conducted as follows. Each well contained a total of 40 µL reaction and 0.2 µL of a DMSO solution containing a compound of interest. Twenty µL of human cGAS enzyme / poly dI-dC was added to each well in assay buffer containing 50 mM Tris pH 7.5 + 150 mM NaCl + 5 mM MgCl2+ 0.5 mM TCEP + 0.005% Tween-20 + 50 µg / ml BSA, using a multidrop Combi, so the final concentration in the assay is 10 nM cGAS enzyme and 10 µM poly dI-dC. The compound-enzyme / DNA mix was pre-incubated at 37 °C for 30 minutes. After 30 minutes, 20 µL of substrate was added by multidrop Combi so that the final concentrations of GTP and ATP were 300 µM respectively in assay buffer. The assay was incubated at 37 °C for 2.5 hours. The assay was quenched by the addition of 10 µL of 1% formic acid containing 100 nM cAMP. After all additions, the plates were shaken to ensure proper mixing, centrifuged at 5,000 x g for 1 minute. For LC / MS analysis, using the Sound Analytics LS1 system coupled to a Sciex 6500+ triple-quadrupole mass spectrometer with a TurboFlow source with ESI probe, the plates were placed on the system for analysis. Samples were separated using an organic solvent of acetonitrile containing 0.1% formic acid and an aqueous solvent of water containing 0.1% formic acid over a Phenomenex Luna Omega column (C18). All valves were washed with a 1:1 acetonitrile:water mix in formic acid. MSMS separation was utilized for both analyte and internal standard monitoring the MSMS of cGAMP (analyte) 675.1 m / z to 524.1 and the MSMS of cAMP (internal standard) 330.05 m / z to 136.2. Enzyme activities of the above assay was reflected by the peak area ratios for LC / MS assays that were calculated from the peak of analyte / peak of internal standard. The ratio of activities from the titration of compound / the activities of the DMSO control was used to calculate % inhibition occurring at each concentration of inhibitor. The following equation was used to calculate the % inhibition at each concentration of inhibitor (Dotmatics): Y=A+(B-A) / (1+(C / x)^D ) where A = minimal Y value (activity level of inhibited sample), B = maximal Y value (activity level of uninhibited sample), C = LogIC50, D = Hill Slope, x = concentration of inhibitor. The Examples were tested in the assay described above with the following result: Example LC / MS-IC50 Example LC / MS-IC50 # (uM) # (uM) 1 0.0761-50.0891-1<0.0021-60.3861-20.0071-70.0651-30.1551-80.1481-40.2991-90.029 Example LC / MS-IC50Example LC / MS-IC50# (uM) # (uM) 1-100.0451-400.0431-110.0241-411.8721-120.0091-420.2941-130.0351-430.5711-140.1471-440.9681-150.0171-450.2531-160.2461-460.0291-170.0301-470.0021-180.9551-480.4631-190.0181-490.0161-200.6801-500.0251-210.6381-510.0231-220.0291-520.1831-230.0061-530.6491-240.0051-54 0.033 1-250.0131-55 0.013 1-260.1091-56 0.027 1-270.1571-57 0.030 1-280.0031-58 0.203 1-290.0011-59 0.085 1-300.6711-60 0.171 1-310.0021-61 0.019 1-320.0121-620.0301-330.0461-630.0361-340.0621-640.0071-350.3021-650.1541-360.1581-661.0571-370.0841-670.0281-380.0621-680.0461-390.2551-690.009 Example LC / MS-IC50Example LC / MS-IC50# (uM) # (uM) 1-700.0301-1010.2521-710.0221-1020.1001-720.0121-1031.9611-730.0171-1042.4131-740.7181-1050.5521-750.0061-1060.0291-760.1162 0.008 1-770.0262-10.0101-780.0792-20.1811-791.2042-30.4551-800.9662-40.5691-810.5412-50.7891-820.0342-60.0031-830.0162-70.0211-840.0932-80.0051-850.0102-100.0111-860.5912-110.0431-870.8862-120.0051-880.2292-130.0051-890.0032-140.0031-900.0182-150.0011-910.0112-160.0041-920.0232-170.0051-930.0042-180.0051-940.0082-190.0051-950.0192-200.0051-95a0.0062-210.0061-960.0122-220.0071-970.1952-230.0051-993.6822-240.007 Example LC / MS-IC50Example LC / MS-IC50# (uM) # (uM) 2-250.0326-90.7202-260.0266-100.4692-270.0026-110.0212-280.0056-120.0982-290.0016-130.13130.1346-140.13840.0046-150.1774-10.0096-160.2814-20.0056-170.3674-30.0066-180.8824-40.0036-190.2334-50.0046-200.0374-60.0196-210.2724-70.0166-220.0084-80.0066-230.3224-90.0026-240.2474-100.0176-250.6244-110.0096-260.24650.2766-270.4995-10.1666-280.1495-21.14570.13360.6347-10.0676-10.1737-20.0086-20.0087-30.0096-30.0537-40.0096-40.2557-50.0056-50.5857-60.0096-60.7717-70.0116-70.9247-80.0066-80.5767-90.008 Example LC / MS-IC50Example LC / MS-IC50# (uM) # (uM) 7-100.0097-400.0547-110.0347-410.1327-120.0647-420.0527-130.0227-430.0747-140.1007-440.1867-150.0057-450.3797-160.0147-460.8927-170.0407-470.2897-180.0047-490.0087-190.0307-500.0447-200.0017-510.0057-210.0157-520.0027-220.0067-530.0087-230.0127-540.0257-240.0057-550.0227-250.0087-560.0467-260.0077-570.0307-270.1757-580.0027-280.187-590.0057-290.0217-600.0647-300.0467-610.0077-310.0457-620.0027-320.0547-630.0197-330.2347-640.0027-340.3407-650.0047-350.0267-660.0117-360.8047-670.0057-370.0607-680.0047-380.1527-690.0047-390.2167-700.005 Example LC / MS-IC50Example LC / MS-IC50# (uM) # (uM) 7-710.00110 0.004 7-720.00910-1 0.006 7-730.00610-2 0.003 7-740.00510-3 0.003 7-750.01510-4 0.004 7-760.00210-5 0.104 7-770.05710-60.0077-780.03010-70.0207-790.00510-80.0137-800.01510-90.0037-810.00410-100.0057-820.00310-110.0137-830.00610-120.0017-840.00610-130.0107-850.00110-140.0017-860.00810-150.0117-870.00910-160.0027-880.00910-170.0137-890.00410-180.0087-900.00510-190.0147-910.00410-200.0347-920.00610-210.0027-930.00510-220.1257-940.00710-230.00480.01610-240.01690.13110-250.0119-10.01010-260.0979-20.00610-270.0049-30.01110-280.0079-40.00110-290.001 Example LC / MS-IC50Example LC / MS-IC50# (uM) # (uM) 10-300.00610-610.00610-310.00110-620.00610-320.00310-630.00510-330.00110-640.00310-340.00110-650.00910-350.00410-660.00110-360.00610-670.00610-370.00810-680.00810-380.00410-690.00110-390.00310-700.00710-400.00410-710.01210-410.00510-720.00510-420.00910-730.00710-430.00510-740.00310-440.00510-750.00710-460.01710-760.00510-470.01710-770.00110-480.00410-780.00710-490.00410-790.00110-500.00410-800.00410-510.00210-810.01010-520.00110-820.00810-530.00510-830.00110-540.00510-840.00310-550.03110-850.00510-560.00410-860.02410-570.00510-870.01210-580.00610-880.00810-590.00510-890.00510-600.00610-900.006 Example LC / MS-IC50Example LC / MS-IC50# (uM) # (uM) 10-910.00110-1220.01510-920.00510-1230.00810-930.00110-1240.00510-940.00710-1250.00410-950.00910-1260.00310-960.00810-1270.00710-970.00510-1280.00710-980.00910-1290.00110-990.00510-1300.01110-1000.00610-1310.00710-1010.00510-1320.00510-1020.00610-1330.00510-1030.00710-1340.00710-1040.00510-1350.00810-1050.00510-1360.00710-1060.00610-1370.00310-1070.00510-1380.00410-1080.00310-1400.00310-1090.01110-1410.00410-1100.00510-1420.00310-1110.00610-1430.00610-1120.00510-1440.00310-1130.01210-1450.00610-1140.00510-1460.00710-1150.00310-1470.00510-1160.008110.01210-1170.006120.32110-1190.010130.02210-1200.008140.06610-1210.006150.050 Example LC / MS-IC50Example LC / MS-IC50# (uM) # (uM) 15-11.55528-30.013160.00528-40.003170.00228-50.009180.004290.051190.00529-10.005200.00429-20.005210.00529-30.005220.004300.00522-20.00730-10.00622-40.00530-20.00723-10.00630-30.00223-30.00630-40.00723-50.00730-50.00323-60.00530-60.00423-100.20330-70.00523-110.08730-80.00423-120.01630-90.004240.00430-100.008250.00530-110.00525-10.00630-120.006260.00830-130.004270.00930-140.00327-10.03930-150.00427-20.02030-160.01127-30.01830-170.00327-40.03230-180.005280.01530-190.00628-10.01930-200.00828-1a0.00530-210.00328-20.59230-220.003 Example LC / MS-IC50Example LC / MS-IC50# (uM) # (uM) 30-230.00332-110.00330-240.00632-120.001310.00732-130.00231-10.05932-140.00631-20.02232-150.00531-30.01232-160.00731-40.01032-170.01131-50.00332-180.01131-60.00132-190.00731-70.24532-220.00431-80.01232-230.02531-90.00432-240.02031-100.00432-250.01131-110.00132-260.00131-120.00232-270.00131-130.01932-280.00431-150.00332-290.00431-160.03932-300.00931-170.00932-310.01931-180.00932-320.00331-190.01632-330.00831-200.01232-340.013320.00732-350.22132-10.00432-360.02632-20.08532-370.00232-50.07332-380.00332-60.01332-390.00432-70.00632-400.00432-80.04232-410.00132-100.00832-420.007 Example LC / MS-IC50Example LC / MS-IC50# (uM) # (uM) 32-430.00534-10- 32-440.00434-110.01232-450.010350.53732-460.01535-20.57432-470.005360.00632-480.00336-20.02032-490.01936-30.00932-500.00936-40.02032-511.10436-50.03132-520.084370.05332-530.00637-10.02832-540.011380.17132-550.00538-10.01232-560.00138-20.09532-570.00638-30.51933-10.13838-40.06933-30.02238-50.02433-40.07238-60.05333-60.21938-70.05733-80.22038-80.00533-100.019390.01833-110.016400.00333-120.00440-10.09034-10.01240-20.08134-20.00640-30.05334-30.004410.00134-50.011420.02734-60.00642-10.01634-70.05043-10.00134-90.178 Methods of Preparation Compounds of Formula (I), and intermediates used in the preparation of compounds of Formula (I), can be prepared using procedures shown in the following examples and related procedures. The methods and conditions used in these examples, and the actual compounds prepared in these examples, are not meant to be limiting, but are meant to demonstrate how the compounds of Formula (I) can be prepared. Starting materials and reagents used in these examples, when not prepared by a procedure described herein, are generally either commercially available, or are reported in the chemical literature, or may be prepared by using procedures described in the chemical literature. Me methyl Et ethyl Pr propyl i-Pr isopropyl Bu butyl t-Bu tert-butyl Ph phenyl Bn benzyl Boc tert-butyloxycarbonyl ACN acetonitrile AcOH or HOAc acetic acid DAST Diethylaminosulfur trifluoride DIPEA N,N-Diisopropylethylamine DCM dichloromethane DMA dimethylacetamide DMF dimethylformamide DMSO dimethyl sulfoxide dppf 1,1'-Bis(diphenylphosphino)ferrocene EtOAc ethyl acetate EtOH ethanol h hour HCl hydrochloric acid i-PrOH or IPA isopropanol iso Isolates – isolated stereoisomer or regioisomers LAH Lithium aluminum hydride MeCN or ACN acetonitrile MeOH methanol MS Mass spectra rt Room temperature RT Retention time SEM trimethylsilylethoxymethyl SFC Supercritical fluid chromatography TEA triethyl amine TFA trifluoroacetic acid THF Tetrahydrofuran TMS trimethylsilyl The compounds of the present invention may be synthesized by many methods available to those skilled in the art of organic. General synthetic schemes for preparing compounds of the present invention are described below. These schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to prepare the compounds disclosed herein. The numbering of R groups within the scheme are for illustrative purposes and are not intended to limit the claims. Different methods to prepare the compounds of the present invention will be evident to those skilled in the art. Additionally, the various steps in the synthesis may be performed in an alternate sequence to give the desired compound or compounds. The following schemes are illustrative for the preparation of the compounds of the present invention. The R groups in the schemes do not necessarily correlate with the R groups elsewhere in the specification and are not meant to limit the embodiments of the invention. The disclosed Examples could be assembled in a modular manner using key building blocks (see A, B & C in Scheme A) that are either acquired from commercial sources or readily prepared using methodologies well precedented in the art. In general, one could start from proline A and introduce either fragment B or C, followed by the incorporation of the third remaining fragment, and multiple complementary routes are described below towards achieving such end. Scheme A In Scheme 1, base-mediated coupling of proline A with pyridine B could afford pyridine ether I, which could be elaborated to proline acid II (q = H; through a standard acid-catalyzed Boc-deprotection) or to proline ester II (q = Me; through a combination of esterification and acid catalyzed Boc-deprotection). Alternatively, ether I could be functionalized to introduce new moieties on the pyridine portion (e.g., in the case where ‘r’ = Cl or Br, one could use established metal-mediated coupling reactions), and the resultant product III could be elaborated to II in the same manner as described in going directly from I to II. Proline II - as either an acid or ester - could be elaborated to final product IV through base-mediated coupling protocols. It is of note that proline acid III will likely be the better substrate for the final coupling step as its ester variant could be prone to epimerization at the carbon carrying the ester moiety.

[0006] Scheme 1 In scheme 2, proline A could be coupled with fragment C followed by coupling with fragment B, both steps through variations of base-mediated protocols. Here again, the use of acid version of V in the final coupling step minimizes potential epimerization issue at the carbon carrying the ester moiety. It should be noted that precursor V could also be assembled through alternate routes as described in Schemes 3 and 4, which should enable access to a diverse pool of heteroaromatic substituents. For example, in Scheme 3, halide VI could be subjected to direct SNAr coupling with azoles such as pyrazole or metal-mediated coupling with either boronate or stannane precursors. Alternatively, halide VI could be converted to stannane VII, which could in turn be coupled with various aryl and heteroaryl halides. In scheme 4, appropriately substituted precursor C would allow regiocontrolled functionalization of two vectors to access a substrate pool V, via the intermediacy of either IX or VI. Scheme 2

[0007] Scheme 4 In Schemes 5 and 6, advanced intermediates X or XI, containing a moiety that could serve as a handle for additional functionalization, could be assembled through similar routes as described in Scheme 1 or 2, and the functional handle (such as a halide) could be elaborated further through metal-assisted cross-coupling protocols to furnish final product IV.

[0008] Scheme 5 Scheme 6

[0009] Scheme 7 amines Ris H or alkylIn scheme 7, functional handles present in Example (IV) could be further elaborated to furnish new Examples (XII) through a combination of alkylation followed by ester hydrolysis (for the phenols) or through established variations of metal-assisted couplings, including those involving decarboxylative approaches, for the halides. It is understood that in certain cases, protecting groups might be present to facilitate the reaction (such as the incorporation of certain azoles through metal-mediated coupling process as in, for example, going from stannane VII to V) and that the protecting group when present could be removed incidentally during the said coupling process or could be removed intentionally at an appropriate subsequent step. Also, in certain other cases, a final product could be further elaborated to provide yet another final product through the manipulation of a functional element that might be present such as, for example, a double or a triple bond that could be subjected to hydrogenation or a halide moiety that could be subjected to metal-mediated coupling. The above noted metal-mediated cross-coupling reactions could involve, but are not limited to, established reactions such as Suzuki, Sonogashira, or Stille coupling protocols. Base-assisted coupling steps could involve, but are not limited to, the use of DIPEA, sodium hydride, or Cs2CO3, depending on the specific substrate involved, along with a suitable solvent. METHODS OF PREPARATION Intermediates Prep HPLC Conditions Method PA: Column: Sunfire C18, 30 x 100 mm, 5 µm particles; Mobile Phase A: 0.1% TFA in water / ACN 90:10, Mobile Phase B: 0.1% TFA in water / ACN 10:90; Flow rate: 42.5 mL / min; Gradient 10% B for 1.1 min, 10% B to 100% B in 13 min, hold at 100% B for 2.2 min; Wavelength: 220 / 254 nm. Method PB: Column: C18, 50 x 300mm, 10 μm particles; Mobile Phase A: 0.1% TFA in water / ACN 95:5, Mobile Phase B: 0.1% TFA in water / ACN 5:95; Flow rate: 125 mL / min; Gradient: 10 % B to 100 % B over 23 min, then a 7 min hold at 100 %B; Wavelength: 214 / 254 nm Method PC: Column: Luna C18, 30 x 100 mm, 5 μm particles; Mobile Phase A: 0.1% TFA in water / ACN 95:5, Mobile Phase B: 0.1% TFA in water / ACN 5:95; Flow rate: 42.5 mL / min; Gradient: 10 % B to 100 % B over 14 min, then a 2 min hold at 100 %B; Wavelength: 214 / 254 nm. Method PD: Column: Luna C18, 30 x 100 mm, 5 μm particles; Mobile Phase A: 0.1% TFA in water / ACN 90:10, Mobile Phase B: 0.1% TFA in water / ACN 10:90; Flow rate 42.5 mL / min; Column Temperature: 25 °C; Gradient: 10 % B to 100 % B in 20 min, hold at 100 % B for 3 min; Detection: UV at 214 nm and 254 nm. Proton NMRs may have been run with water suppression. Intermediate A1 Step-1 A solution of ethyl 1-acetylcyclopropane-1-carboxylate (5 g, 32 mmol) and phenylmethanamine (4 g, 38.4 mmol) in Toluene (100 mL) was heated at 130 °C using Dean-stark apparatus for 20h. The reaction mixture was concentrated under reduced pressure and purified by silica-gel column chromatography using 10% ethyl acetate in hexanes as eluent. The desired fractions were concentrated to afford A1-1 (6.5 g) as yellow oil. MS (ES): m / z = 246.2 [M+H]+. Step-2 To the stirred solution of A1-1 (6 g, 24 mmol) and acetic acid (1.4 mL, 24.5 mmol) in Acetonitrile (100 mL) at 0 °C, sodium triacetoxyborohydride (20.7 g, 98 mmol) was added portion wise. The reaction mixture was stirred at 0 °C for 6 h. The reaction mixture was partitioned between saturated sodium carbonate solution (500 mL) and ethyl acetate (250 mL). The organic layer was separated, dried over sodium sulphate and concentrated to afford A1-2 (6 g) as yellow oil. MS (ES): m / z = 248.2 [M+H]+. Step-3 To the stirred solution of A1-2 (6 g, 24 mmol) in THF (60 mL) cooled at -78 °C, LDA (18.2 mL, 36.4 mmol) was added dropwise over 5 min. After 1 h, ethyl chloroformate (7 mL, 73 mmol) was added dropwise over 5 min. The reaction mixture was stirred at -78 °C for 1 h. Then, it was quenched with saturated ammonium chloride solution (500 mL) and diluted with ethyl acetate (200 mL). The organic layer was separated, dried over sodium sulphate and concentrated to afford yellow residue which was purified by silica-gel column chromatography using 10% ethyl acetate in hexanes as eluent. The desired fractions were concentrated to afford A1-3 (3.6 g) as yellow oil. MS (ES): m / z = 320.2 [M+H]+. Step-4 To the stirred solution of A1-3 (2 g, 6.3 mmol) in THF (20 mL) at -10 °C, LAH (18.8 mL, 18.8 mmol) was added dropwise for 5 min. The reaction mixture was stirred at -10 °C for 30 min. Then, it was diluted with ethyl acetate (2 mL) followed by quenching with saturated ammonium chloride solution (5 mL). The reaction mixture was diluted with THF (50 mL), filtered through celite bed and the filtrate was concentrated to afford A1-4 (1 g) as yellow oil. MS (ES): m / z = 236.3 [M+H]+. Step-5 To a stirred solution of A1-4 (1 g, 4.3 mmol) in THF (10 mL) at -78 °C, n-butyl lithium (1.7 mL, 4.3 mmol) was added. The reaction mixture was stirred at -78 °C for 30 min and p-toluenesulfonyl chloride (0.65 g, 3.4 mmol) in THF (5 mL) was added. The reaction mixture was gradually brought to RT and stirred for 1 h. 30% sodium methoxide in methanol (2.75 mL, 12.7 mmol) was added dropwise to it and heated at 70 °C for 12 h. The reaction mixture was partitioned between water (100 mL) and DCM (100 mL). The organic layer was separated, dried over sodium sulphate and concentrated to afford dark yellow oil which was purified on silica gel using 4% MeOH in DCM as eluent. The desired fractions were concentrated to afford A1-5 (400 mg) as a yellow oil. MS (ES): m / z = 218.2 [M+H]+. Step-6 To a degassed solution of A1-5 (200 mg, 0.9 mmol) in MeOH (3 mL), 10% Pd / C (98 mg, 0.5 mmol) was added. The reaction mixture was stirred under H2atmosphere (bladder) for 16 h. The reaction mixture was diluted with methanol (10 mL) and filtered through a celite bed. The filtrate was concentrated to afford A1 (100 mg) as a yellow oil. The crude was taken as such to next step as a mixture of stereoisomers. Intermediate A2 Step-1 To a stirred solution of tert-butyl (S)-2-methyl-4-oxopiperidine-1-carboxylate (2 g, 9.4 mmol) in DCM (30 mL) at -78 °C, DAST (3.7 mL, 28 mmol) was added. The reaction mixture was stirred at 0 °C for 4 h. Then, it was diluted with DCM (50 mL) and poured into 10% sodium bicarbonate solution (200 mL). The organic layer was separated, dried over sodium sulphate and concentrated to afford a yellow residue which was purified on silica gel using 15% ethyl acetate in hexanes. The desired fractions were concentrated to afford A2-1 (800 mg) as a yellow solid.1H NMR (300 MHz, CDCl3): δ ppm 4.67 - 4.49 (m, 1H), 4.17 - 3.97 (m, 1H), 3.18 - 2.96 (m, 1H), 2.20 - 1.71 (m, 4H), 1.50 - 1.40 (m, 9H), 1.30 - 1.13 (m, 3H). Step-2 To a stirred solution of A2-1 (700 mg, 3.0 mmol) in DCM (70 mL) at 0 °C, TFA (3.4 mL, 44.6 mmol) was added. The reaction mixture was stirred at 0 °C for 4 h. The reaction mixture was evaporated to dryness to afford A2 (400 mg, 3 mmol) as a brown semisolid (TFA salt). MS (ES): m / z = 136.2 [M+H]+. Intermediate A3 Iso-1 & 2 Iso-1 & 2Step-1 To a stirred solution of tert-butyl (S)-2-methyl-4-oxopiperidine-1-carboxylate (3 g, 14 mmol) in MeOH (30 mL) at 0 °C, was added NaBH4(0.8 g, 21 mmol). The reaction mixture was stirred at rt for 2 h. The reaction mixture was partitioned between 10% ammonium chloride solution (100 mL) and ethyl acetate (100 mL). The organic layer was separated, dried over sodium sulphate and concentrated to afford A3-1 (2.85 g). The crude obtained was used directly in the next step. Step-2 To a stirred solution of A3-1 (1 g, 4.6 mmol) in DMF (10 mL) was added NaH (0.6 g, 13.9 mmol) portion wise and stirred at rt for 5 min. MeI (0.9 mL, 13.9 mmol) was added to the reaction mixture and stirred at rt for 30 min. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL) The organic layer was separated, dried over sodium sulphate and concentrated to afford a brown residue which was purified on silica- gel using 10-15% ethyl acetate in hexanes as eluent which afford two isomers of A3-2. A3-2 (Iso-1; first eluent): 400 mg;1H NMR (300 MHz, CDCl3): δ ppm 4.26 - 4.09 (m, 1H), 3.79 - 3.65 (m, 1H), 3.53 - 3.41 (m, 1H), 3.29 - 3.22 (m, 3H), 3.16 - 2.97 (m, 1H), 1.81 - 1.69 (m, 2H), 1.68 - 1.54 (m, 1H), 1.39 (s, 9H), 1.23 - 1.13 (m, 3H). A3-2 (Iso-2; second eluent): 120 mg;1H NMR (300 MHz, CDCl3) δ ppm 4.52 - 4.35 (m, 1H), 4.09 - 3.90 (m, 1H), 3.46 - 3.34 (m, 1H), 3.28 (s, 3H), 2.87 - 2.72 (m, 1H), 2.00 -1.88 (m, 1H), 1.85 - 1.75 (m, 1H), 1.39 (s, 9H), 1.28 - 1.11 (m, 3H), 1.11 - 1.04 (m, 3H). Step-3 To a solution of A3-2 (Iso-1, 300 mg, 1.3 mmol) in DCM (2 mL) was added TFA (0.5 mL, 6.5 mmol) and the solution was stirred at rt for 1 h. The reaction mixture was concentrated to afford A3 (Iso-1) (120 mg) as a brown semisolid (TFA salt). Analogous to the preparation of A3 (Iso-1), the reaction of A3-2 (Iso-2, 160 mg, 0.7 mmol) and TFA (0.3 mL, 3.5 mmol) afforded A3 (Iso-2) (90 mg) as a brown semisolid (TFA salt). Intermediate A4 Step-1 To a stirred solution of tert-butyl (2S)-4-hydroxy-2-methylpiperidine-1-carboxylate (1.3 g, 6 mmol) and potassium acetate (0.6 g, 6 mmol) in DCM (5 mL) and water (5 mL), trimethyl(bromodifluoromethyl)silane (2.5 g, 12 mmol) was added. The reaction mixture was stirred at rt for 12 h. The reaction mixture was partitioned between water (20 mL) and DCM (25 mL). The organic layer was separated, dried over sodium sulphate and concentrated to afford colorless liquid which was purified on silica gel using 10% ethyl acetate in hexanes as an eluent. The desired fractions were evaporated under reduced pressure to afford A4-1 (450 mg) as a colorless liquid. Step-2 To a stirred solution of A4-1 (415 mg, 1.6 mmol) in DCM (5 mL), TFA (1.8 mL, 23.5 mmol) was added and reaction mixture was stirred at rt for 2 h. The reaction mixture was evaporated under reduced pressure to afford A4 as a brown semisolid (TFA salt). It was used directly in the next step as a mixture of stereoisomers. Intermediate A5 Step-1 To a stirred solution of tert-butyl 2-methyl-3-oxo-piperidine-1-carboxylate (1 g, 4.7 mmol) in MeOH (10 mL) at 0 °C, sodium borohydride (0.2 g, 5.6 mmol) was added. The reaction mixture was stirred at rt for 12 h. The reaction mixture was concentrated, partitioned between saturated NaHCO3(10 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford A5-1 (900 mg) as an off- white semisolid. Step-2 To a stirred solution of A5-1 (600 mg, 2.8 mmol) in THF (2 mL) at 0 °C, NaH (0.1 g, 4.2 mmol) was added followed by iodomethane (0.9 mL, 14 mmol). The reaction mixture was stirred at rt for 3 h. The reaction mixture was partitioned between saturated NaHCO3(10 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford A5-2 (532 mg) as a yellow semisolid. Step-3 To the stirred solution of A5-2 (600 mg, 2.6 mmol) in DCM (5 mL) was added TFA (2 mL, 26 mmol). The reaction mixture was stirred at rt for 4 h and concentrated to afford A5.TFA salt (312 mg) as a yellow semisolid. The crude was used directly in the next step as a mixture of stereoisomers. Intermediate A6 Step-1 To a solution of tert-butyl 2-methyl-3-oxopiperidine-1-carboxylate (500 mg, 2.3 mmol) in DCM (5 mL) at -78 °C, DAST (1.0 mL, 7 mmol) was added dropwise and the reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with DCM (50 mL) and poured into 10% sodium bicarbonate solution (50 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford a yellow residue, which was purified on silica gel using 15% ethyl acetate in hexanes as eluent. The desired fractions were concentrated to afford A6-1 (400 mg) as a brown liquid. Step-2 Analogous to the preparation of A5, the reaction of A6-1 (1.5 g, 6.4 mmol) and TFA (7.37 mL, 96 mmol) afforded A6.TFA salt (1.5 g) as a mixture of stereoisomers. The crude was used directly in the next step. Intermediate A7 Step-1 To a stirred solution of tert-butyl (S)-2-methylpiperazine-1-carboxylate (0.65 g, 3.25 mmol) in DCM (10 mL) were added triethylamine (0.9 mL, 6.49 mmol) and methyl chloroformate (0.25 mL, 3.25 mmol). The mixture was stirred at RT for 30 min. Water (30 mL) was added to the mixture and diluted with DCM (50 mL). The combined organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to afford A7-1 (670 mg).1H NMR (400 MHz, DMSO- d6): δ ppm 4.12 (br s, 1H), 3.85 (br d, J = 9.5 Hz, 1H), 3.69 (br dd, J = 3.0, 13.0 Hz, 2H), 3.61 (s, 3H), 3.08 - 2.90 (m, 2H), 2.90 - 2.80 (m, 1H), 1.40 (s, 9H), 1.03 (d, J = 7.0 Hz, 3H). Step-2 To a solution of A7-1 (0.67 g, 2.6 mmol) in DCM (15 mL) was added TFA (1.0 mL, 13.0 mmol) and stirred at RT for 14 h. The reaction mixture was concentrated to remove TFA completely, 10% sodium bicarbonate solution (30 mL) was added and extracted with DCM (3 X 50 mL). The combined organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate, and evaporated under reduced pressure to afford A7 (350 mg).1H NMR (400 MHz, DMSO-d6): δ ppm 3.82 - 3.70 (m, 2H), 3.58 (s, 3H), 2.81 (br d, J = 12.0 Hz, 2H), 2.76 - 2.63 (m, 1H), 2.43 - 2.23 (m, 2H), 0.93 (d, J = 6.0 Hz, 3H) ppm. Intermediate A8 Step-1 To the stirred solution of tert-butyl 2-methyl-3-oxo-piperidine-1-carboxylate (2 g, 9.4 mmol) in MeOH (20 mL) at 0 °C, sodium borohydride (0.71 g, 18.8 mmol) was added. The reaction mixture was stirred at RT for 12 h. The reaction mixture was concentrated, partitioned between saturated NaHCO3 (20 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulphate and concentrated to afford A8-1 (1.9 g, 94 % yield) as an off-white semisolid.1H NMR (300 MHz, DMSO-d6): δ ppm 4.84 (d, J = 3.9 Hz, 1H), 4.19 (m, 1H), 3.66 (m, 1H), 3.46 (br d, J = 5.4 Hz, 1H), 2.72 - 2.58 (m, 1H), 1.63 - 1.50 (m, 2H), 1.41 - 1.37 (s, 9H), 1.35 - 1.15 (m, 2H), 0.96 (d, J = 7.2 Hz, 3H). Step-2 To the stirred solution of A8-1 (1 g, 4.6 mmol) in DCM (15 mL) cooled at at 0 °C, were added triethylamine (0.47 g, 4.6 mmol) and methane sulfonyl chloride (0.53 g, 4.6 mmol). The reaction mixture was stirred at RT for 2h. The reaction mixture was concentrated, partitioned between saturated NaHCO3(20 mL) and DCM (50 mL). The organic layer was separated, dried over sodium sulphate and concentrated to afford A8-2 (1.2 g, 88 % yield) as a colorless sticky solid.1H NMR (300 MHz, DMSO-d6): δ ppm 4.63 - 4.44 (m, 2H), 3.71 (br dd, J = 3.8, 13.8 Hz, 1H), 3.23 (s, 3H), 2.74 (br d, J = 1.8 Hz, 1H), 1.92 - 1.61 (m, 3H), 1.54 - 1.43 (m, 1H), 1.40 (s, 9H), 1.08 (d, J = 6.8 Hz, 3H). Step-3 To the stirred solution of A8-2 (1.2 g, 4 mmol) in ethanol (10 mL) cooled at 0 °C was added sodium thiomethoxide (0.72 g, 10.2 mmol). The reaction mixture was stirred at 80 °C for 12h. The reaction mixture was concentrated, partitioned between water (20 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulphate and concentrated to afford A8-3 (600 mg, 60 % yield) as a pale-yellow liquid.1H NMR (300 MHz, DMSO-d6): δ ppm 4.41 - 4.23 (m, 1H), 3.76 (br d, J = 11.5 Hz, 1H), 2.88 - 2.65 (m, 2H), 2.06 (s, 3H), 1.81 - 1.60 (m, 2H), 1.39 (m, 11H), 1.18 (d, J = 6.8 Hz, 3H). Step-4 To the stirred solution of A8-3 (3.2 g, 13 mmol) in 2-propanol (15 mL) and H2O (15 mL) cooled at 0 °C, was added OXONE®, monopersulfate (16 g, 26.1 mmol). The reaction mixture was stirred at RT for 4h. Then it was concentrated, partitioned between water (50 mL) and ethyl acetate (200 mL). The organic layer was separated, dried over Na2SO4and concentrated under reduced pressure to afford A8-4 (3.4 g, 94 % yield) as a pale-yellow sticky liquid, which was taken as such for next step. Step-5 To a solution of A8-4 (470 mg, 1.7 mmol) in DCM (5 mL) was added TFA (1.3 mL, 17 mmol). The reaction mixture was stirred at RT for 2h and concentrated to afford A8.TFA salt (290 mg, 1.636 mmol, 97 % yield) as yellow semisolid. The crude was taken as such to the next step as a mixture of stereoisomers. Intermediate A9 Analogous to the preparation of A8, A9 was synthesized from tert-butyl 2-methyl-3- oxopyrrolidine-1-carboxylate. Intermediate A10 A10-1 A10Step-1 To a stirred solution of tert-butyl 5-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate (0.21 mL, 1.18 mmol) in DCM (5 mL) cooled at 0 °C, were added DAST (1.56 mL, 11.8 mmol) and ethanol (0.5 mL). The reaction mixture was stirred at RT for 12h. Then it was partitioned between 10% sodium bicarbonate solution (50 mL) and DCM (20 mL). The organic layer was separated, dried over Na2SO4and concentrated under reduced pressure to get crude which was purified on silica gel using 15% ethylacetate in hexanes to afford A10-1 (250 mg, 90 % yield) as pale-yellow semisolid.1H NMR (300MHz, CDCl3): δ ppm 4.40 - 4.17 (m, 1H), 3.54 - 3.35 (m, 1H), 3.25 (br d, J = 4.3 Hz, 1H), 2.78 (m, 1H), 2.18 - 1.99 (m, 2H), 1.92 - 1.76 (m, 2H), 1.46 (s, 9H). Step-2 To the stirred solution of A10-1 (280 mg, 1.2 mmol) in 1.4-dioxane (5 mL) was added HCl in 1,4-dioxane (4N, 1.5 mL, 6 mmol) and stirred at RT for 2h. The reaction mixture was evaporated under reduced pressure to afford A10.HCl salt (150 mg, quant.) as an off- white solid. MS (ES): m / z = 133.1 [M+H]+ The following intermediates were prepared in an analogous manner to intermediate A10 using appropriate precursors. MS MS Intermediate Structure (ES) Intermediate Structure (ES) [M+H]+[M+H]+H H N N A10a 148.1 A10c 148.1 FFF F H H N N A10b 148.1 A10d 136.1 F FFF Intermediate A10-I A10-IStep-1 To a stirred solution of 4,4-difluoropiperidine (2.44 g, 20 mmol) in diethyl ether (10 mL) kept at 0 °C, was added 3-bromoprop-1-yne (1 g, 6.7 mmol). The reaction mixture was stirred at RT for 12h. Then it was diluted with water (10 mL) and DCM (20 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to afford A10-I (1 g, 93 % yield) as brown oil. MS (ES): m / z = 160.1 [M+H]+. The following intermediates were prepared in an analogous manner to intermediate A10-I using appropriate precursors. Intermedia MS MS teStructure(ES) Intermediate Structure (ES) [M+H]+[M+H]+ A10-IaN160.1 A10-IdN154.1 F FON A10-Ib 154.1 A10-IeN152.1 OH OA10-IcN154.1 OHIntermediate A11 Step-1 To the stirred solution of prop-2-yn-1-ol (600 mg, 10.7 mmol) and 4-nitrophenyl carbonochloridate (2.15 g, 10.7 mmol) in DCM (10 mL) at 0 °C, was added triethylamine (1.6 mL, 12 mmol). The reaction mixture was stirred at RT for 4h. Then it was partitioned between water (10 mL) and DCM (50 mL). The organic layer was separated, dried over sodium sulphate and evaporated under reduced pressure to afford A11-1 (2.1 g, 89%) as pale-yellow viscous liquid which was used as such for next reaction. Step-2 To the stirred solution of A11-1 (2 g, 9 mmol) in DCM (20 mL) at 0 °C were added N- methylpropan-1-amine (0.661 g, 9 mmol) and triethylamine (1.5 mL, 11 mmol). The reaction mixture was stirred at RT for 12h. Then it was partitioned between water (20 mL) and DCM (50 mL). The organic layer was separated, dried over sodium sulphate and evaporated under reduced pressure to afford crude which was purified on silica gel using 40% ethylacetate in hexanes as an eluant to afford A11 (900 mg, 64% yield) as a colourless oil. MS (ES): m / z = 156.1 [M+H]+. Intermediate B1 Step-1 Racemate 9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-7-one (which was prepared according to WO-2022 / 238327) was resolved using the following preparative SFC condition: Column / dimensions: LUX I AMYLOSE 3 [(250 x 50 mm; 5 u): %CO2: 75%: %Co-solvent: 25% of methanol; Total Flow: 300 g / min; Back Pressure: 100 bar; Temperature: 40 °C; UV: 220 nm]. First elute (B1-1a; RT = 3.50 min): SOR: +64.0, MS (ES): m / z = 158.1 [M+H]+. Second elute (B1-1b; RT = 4.80 min): SOR: -64.0, MS (ES): m / z = 158.1 [M+H]+. The second elute, the absolute stereochemistry of which was confirmed through single crystal XRD analysis, was advanced to the next step. Step-2 To a stirred solution of B1-1b (30.5 g, 194 mmol) in THF (1250 ml) under nitrogen atmosphere at 0 °C was added dropwise LiAlH4(2 M in THF) (194 mL, 388 mmol). The reaction mixture was stirred at RT for 14 h, cooled to 0 °C, diluted with diethyl ether (800 mL) and quenched slowly with water (15 mL) followed by 15% NaOH (15 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford a brown residue which was purified on silica gel (5% methanol in chloroform as eluent) to afford B1-2 (19.5 g). Step-3 To the solution of 5-chloro-3-fluoro-2-nitropyridine (5.0 g, 28.3 mmol) and B1-2 (4.46 g, 31.2 mmol) in Acetonitrile (50 mL) was added K2CO3(7.8 g, 56.6 mmol). The reaction mixture was heated at 65 °C for 24 h and concentrated to afford a yellow residue. To the residue was added water (100 mL) and ethyl acetate (5 mL), triturated, precipitated solid was filtered and dried to afford B1 (7.0 g) as a yellow solid. MS (ES): m / z = 300.2 [M+H]+. The following intermediates were prepared in an analogous manner to intermediate B1 using appropriate precursors. Of note, B1c (Iso-1) and B1c (Iso-2) were prepared from piperidines A3 (Iso-1) and A3 (Iso-2), respectively. Intermedi MS ateStructureMS (ES) Interme [M+H]+diateStructure(ES) [M+H]+O O2N NO2NN No N (S) N B1a 284.1 B1m ionizati Cl Cl on F F O NO 2N2N N 1b 292.1 B1n ( N B N R) 228.1 Cl Cl H3CONO2NO2B1c N No N N (S) N 286.1 B1o ionizati (Iso-1) Cl Cl on H3CONO2NO B1c2N N N 286.1 B1p N 254.1 (Iso-2) Cl Cl F2HCONO2O NO2B1d N N N 322.1 B1q O N 346.0 Cl Br NO2NO2B1eMeON F N N 286.1 B1r FN338.0 Cl Cl NO2O2N N B1f F N F N 292.0 B1s N Cl 269.8 Cl O O NO O NO2B1g N2B N N 1t N 315.0 MeO2S N 334.1 (Iso-1) ClCl O2NNO 1hN 2B B1u N N MeO 270.22S N 334.1 Cl (Iso-2) OClNO2NO2F N B1v N N B1i N MeO 278.12S F 334.0 (Iso-3) ClClF NO2F NO2N N MeO N N B1x2S B1j 278.2 334.0 (Iso-4)ClCl FFNO2MeO NO2S 2 N N N B1y B1k N 264.2 320.1 (Iso-1) Cl Cl F NO N2F O2MeO2S N N N N B1z B1l 250.1 320.1 (Iso-2) Cl Cl B1t & B1u: Preparative SFC (Condition: Column / dimensions: FlowRate: 3 ml / min Column Name: CHIRALPAK IG (250*4.6)mm.5μ Co-Solvent : 30%; Co-Solvent Name : 0.2% Ammonia in Methanol Injected Volume : 7 μl; Outlet Pressure: 100 bar Temperature : 40 °C UV: 240 nm). First elute, B1t (Iso-1) (50 mg, 3% yield) as yellow solid (RT = 3.88 min;). MS (ES): m / z = 334.15 [M+H]+and Second elute B1u (Iso-2) (50 mg, 3% yield) as yellow solid (RT = 4.97 min;). MS (ES): m / z = 334.15 [M+H]+. B1v & B1x: Preparative SFC (Condition: Column / dimensions: FlowRate: 3 ml / min Column Name : CHIRALPAK IG (250*4.6)mm.5μ Co-Solvent : 30%;Co-Solvent Name : 0.2% Ammonia in Methanol Injected Volume : 7 μl; Outlet Pressure: 100 bar Temperature : 40 °C UV: 240 nm). First elute, B1v (Iso-3) (55 mg, 3.2 % yield) as yellow solid (RT = 5.17 min;). MS (ES): m / z = 334.0 [M+H]+and Second elute B1x (Iso-4) (80 mg, 0.240 mmol, 4.67 % yield) as yellow solid (RT = 5.58 min;). MS (ES): m / z = 334.0 [M+H]+. B1y & B1z: Preparative SFC condition: Column / dimensions: Chiralpak AD-H (250 X 30) mm, 5μ: %CO2: 75%: % Co solvent: 25% of 5 mM ammonium acetate in ACN:MeOH (1:1) ; Total Flow: 120 g / min; Back Pressure:100 bar; Temperature: 40 °C; UV: 240 nm. First elute B1y (Iso-1) (RT = 1.99 min; Purity: >99%) and Second elute B1z (Iso-2) (RT = 2.70 min, Purity: >99%). Intermediate B1-I DIPEA (0.148 mL, 0.850 mmol) was added to a solution of 5-chloro-3-fluoro-2- nitropyridine (50.0 mg, 0.283 mmol) and (S)-3-methylmorpholine-HCl (39.0 mg, 0.283 mmol) in THF (1.5 mL). The resulting reaction mixture was stirred at room temperature for 20 h, then heated to 80 °C and stirred for 24 h. The reaction mixture was diluted with water and extracted with DCM. The organic fraction was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified via silica gel chromatography using 0 to 100% ethyl acetate in hexanes as eluent to afford B1-I (39 mg) as a yellow oil. MS (ES): m / z = 257.9 [M+H]+. Intermediate B2 Step-1 To a degassed solution of B1q (1.5 g, 4.4 mmol) and Tributyl(1-ethoxyvinyl)tin (1.7 g, 4.8 mmol) in Dioxane (15 mL), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (0.3 g, 0.4 mmol) was added and heated at 80 °C for 5 h. The reaction mixture was evaporated to remove volatiles and partitioned between water (20 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford a dark yellow residue which was purified on silica gel using 20% ethyl acetate in hexanes as eluent. The desired fractions were concentrated to afford B2-1 (1 g) as a yellow oil. MS (ES): m / z = 336.1 [M+H]+. Step-2 To the stirred solution of B2-1 (1 g, 3 mmol) in THF (10 mL), 4N aq. HCl (7.5 mL, 30 mmol) was added. The reaction mixture was stirred at rt for 2 h. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford B2-2 (900 mg) as a pale brown oil. MS (ES): m / z = 308.2 [M+H]+. Step-3 To the stirred solution of B2-2 (200 mg, 0.7 mmol) in DCM (4 mL) kept at 0 °C, DAST (0.4 mL, 3.3 mmol) was added. The reaction was stirred at rt for 8 h, then diluted with chloroform (10 mL) and poured into saturated sodium bicarbonate solution (20 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford B2 (100 mg) as a yellow oil. MS (ES): m / z = 330.2 [M+H]+. Intermediate B3 Step-1 To a degassed solution of B1q (2.0 g, 5.8 mmol), 2,4,6-trivinylcyclotriboroxane pyridine complex (2.80 g, 11.6 mmol) and K3PO4(2M, 5.8 mL, 11.6 mmol) in THF (20 mL), Pd(Ph3P)4 (0.68 g, 0.6 mmol) was added. The reaction mixture was heated at 75 °C for 16 h. The reaction mixture was concentrated to afford a brown residue, which was purified on silica gel using 30% ethyl acetate in hexanes as eluent. The desired fractions were evaporated under reduced pressure to afford B3-1 (950 mg) as a yellow gummy solid. MS (ES): m / z = 292.2 [M+H]+. Step-2 To the solution of B3-1 (840 mg, 2.9 mmol) in THF (5 mL), sodium iodide (430 mg, 2.9 mmol) and trimethyl(trifluoromethyl)silane (2.1 g, 14.4 mmol) were added. The reaction mixture was heated at 65 °C for 48 h and concentrated to afford a yellow residue which was purified on silica gel using 40% ethyl acetate in hexanes as eluent. The desired fractions were concentrated to afford B3 (350 mg) as a yellow gummy solid. The sample was advanced as a mixture of diastereomers. MS (ES): m / z = 342.1 [M+H]+. Step-1 To the stirred solution of tert-butyl (S)-2-methyl-4-oxopiperidine-1-carboxylate (6.0 g, 28.1 mmol) in THF (60 mL) kept at -78 °C, LDA (17 mL, 33.8 mmol) was added. The reaction mixture was stirred at -78 °C for 1 h and N-Phenyl- bis(trifluoromethanesulfonimide) (12 g, 33.8 mmol) in THF (60 mL) was added dropwise for 5 min. The reaction mixture was brought to RT gradually and stirred for 6 h. The reaction mixture was partitioned between ethyl acetate (250 mL) and water (150 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford a yellow residue which was purified on silica gel using 7% ethyl acetate in hexanes as eluent. The desired fractions were concentrated to afford B4-1 (7 g; regiochemical make up was not determined) as a yellow oil. Step-2 To a degassed solution of B4-1 (4 g, 11.58 mmol) in THF (80 mL), lithium chloride (3.9 g, 93 mmol) was added followed by Pd(PPh3)4(0.7 g, 0.579 mmol). tri-n-butyltin hydride (4.6 mL, 17.37 mmol) was added dropwise to the reaction mixture and stirred at rt for 2 h. The reaction mixture was partitioned between ethyl acetate (150 mL) and 1M KF solution (50 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford a yellow residue which was purified on silica gel using 5% ethyl acetate in hexanes as eluent. The desired fractions were concentrated to afford B4-2 (2 g; olefin regiochemical make up was not determined) as a yellow oil. Step-3 To the stirred solution of B4-2 (1 g, 5.1 mmol) in diethyl ether (10 mL), 4M HCl in dioxane (12.7 mL, 51 mmol) was added. The reaction mixture was stirred at rt for 2 h. The reaction mixture was evaporated under reduced pressure to afford crude B4-3 of unknown olefin regiochemical make up (400 mg) which was used directly in the next step. Step-4 To the stirred solution of B4-3 (0.55 g, 5.66 mmol) and 5-chloro-3-fluoro-2-nitropyridine (1.0 g, 5.66 mmol) in Acetonitrile (15 mL), K2CO3(2.4 g, 16.99 mmol) was added. The reaction mixture was heated at 60 °C for 6 h. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (30 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford a yellow residue which was purified on silica gel using 10% ethyl acetate in hexanes as eluent. The desired fractions were concentrated to afford a mixture of B4-4 (1.4 g; olefin regiochemical make up was not determined) as a yellow semisolid. MS (ES): m / z = 254.1 [M+H]+. Step-5 To the stirred solution of B4-4 (400 mg, 1.58 mmol) and tetrabutylammonium bromide (25 mg, 0.08 mmol) in toluene (1 mL), trimethyl(bromodifluoromethyl)silane (960 mg, 4.73 mmol) was added. The reaction mixture was heated at 110 °C for 6 h. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (30 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford a yellow residue which was purified by Prep-HPLC. The desired fractions were evaporated under reduced pressure to afford B4 (80 mg; stereochemical make up was not determined) as a yellow semisolid. MS (ES): m / z = 304.1 [M+H]+at rt = 9.428 min. The regiochemistry of B4 was confirmed by 2D NMR studies. Preparative method: column; X Select C18 (250*20*5u); Mobile Phase A:10 mm ammonium bicarbonate in water pH-9.5; Mobile Phase B: ACN:MeOH (1:1) Flow: 20ml\min; temperature: 27 °C; detection: UV at 220 nm. Intermediate B5 Step-1 Analogous to the preparation of B1, the reaction of 5-chloro-3-fluoro-2-nitropyridine (1 g, 5.7 mmol) and (R)-morpholin-2-ylmethanol (0.8 g, 6.8 mmol) afforded B5-1 (1.3 g) as a yellow oil. MS (ES): m / z = 274.0 [M+H]+. Step-2 To the stirred solution of oxalyl chloride (0.5 mL, 5.5 mmol) in DCM (5 mL) kept at -78 °C, DMSO (0.7 mL, 9.1 mmol) was added. The reaction mixture was stirred at -78 °C for 30 minutes and a solution of B5-1 (0.5 g, 1.827 mmol) in DCM (5 mL) was added dropwise. After 1 h, the reaction mixture was quenched with triethylamine (1.3 mL, 9.2 mmol). The reaction mixture was stirred at rt for 1 h. The reaction mixture was partitioned between ice cold water (10 mL) and DCM (30 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford B5-2 (500 mg) as a yellow gummy solid. MS (ES): m / z = 272.0 [M+H]+. Step-3 Analogous to the preparation of A6-1, the reaction of B5-2 (500 mg, 1.8 mmol) and DAST (1.0 mL, 7.4 mmol) afforded B5 (200 mg) as a yellow gummy solid. MS (ES): m / z = 294.0 [M+H]+. Intermediate B5a Analogous to the preparation of B5, B5a (350 mg) was synthesized as a yellow gummy solid using (S)-morpholin-2-ylmethanol. MS (ES): m / z = 294.0 [M+H]+. Intermediate B5b Step-1 To a stirred solution of 3-methylthiomorpholine hydrochloride (435 mg, 2.8 mmol) in Acetonitrile (2 mL) were added 5-chloro-3-fluoro-2-nitropyridine (500 mg, 2.8 mmol) and potassium carbonate (979 mg, 7.1 mmol). The reaction mixture was heated at 55 °C for 12h. The reaction mixture was partitioned between water (50 mL) and DCM (50 mL). The organic layer was separated, dried over sodium sulphate and evaporated under reduced pressure to afford crude B5b-1 (350 mg, 45 % yield) which was taken as such to next step. MS (ES): m / z = 274.2 [M+H]+. Step-2 To a stirred solution of B5b-1 (300 mg, 1.1 mmol) in DCM (10 mL) at 0oC was added m- CPBA (473 mg, 2.7 mmol). The reaction mixture was stirred at RT overnight. Then it was partitioned between DCM (50mL) and 10% NaHCO3solution (50 mL). The organic layer was dried over anhydrous Na2SO4and evaporated under reduced pressure to afford crude B5b (250 mg, 0.818 mmol, 74.6 % yield) which was taken forward as a racemate.1H NMR (300 MHz, CDCl3): δ ppm 8.41 - 8.22 (m, 1H), 7.77 (d, J = 2.2 Hz, 1H), 3.77 (ddd, J = 2.7, 6.3, 9.3 Hz, 1H), 3.65 - 3.54 (m, 1H), 3.51 - 3.39 (m, 1H), 3.31 - 3.19 (m, 1H), 3.17 - 3.05 (m, 2H), 3.03 - 2.91 (m, 1H), 1.07 (d, J = 6.5 Hz, 3H). Intermediate B6 Step-1 To a solution of 2,4,6-trivinylcyclotriboroxane pyridine complex (100 mg, 0.4 mmol) and B1 (286 mg, 0.8 mmol) in dioxane (2 mL) and water (1 mL), were added K3PO4(0.246 g, 0.9 mmol) and tetrakis(triphenylphosphine)palladium(0) (9.6 mg, 8.3 µmol). The reaction mixture was stirred at 90 °C for 3 h. The reaction mixture was evaporated under reduced pressure to afford a dark brown residue. The residue was partitioned between water (50 mL) and ethyl acetate (2 x 50 mL). The organic layer was separated, dried over sodium sulphate, and concentrated under reduced pressure to afford B6-1 (0.16 g). MS (ES): m / z = 292.1 [M+H]+. Step-2 To a stirred solution of B6-1 (0.1 g, 0.3 mmol) in THF (1 mL) and water (0.5 mL) were added osmium tetroxide (2.2 µL, 6.9 µmol) and sodium periodate (0.147 g, 0.7 mmol) at RT. The reaction mixture was stirred at rt for 2 h. Then, it was diluted with water (20 mL) and ethyl acetate (30 ml). Organic layer was collected, washed with brine solution, dried over anhydrous sodium sulphate, and evaporated under reduced pressure to afford B6-2 (0.08 g): MS (ES): m / z = 294.1 [M+H]+. Step-3 To a stirred solution of B6-2 (0.08 g, 0.3 mmol) in DCM (2 mL) was added DAST (0.04 mL, 0.3 mmol) at - 40 °C and stirred at rt for 2 h. To this reaction mixture, 10% sodium bicarbonate solution (20 mL) was added slowly and extracted with DCM (3 X 20 mL). The combined organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate, and evaporated under reduced pressure to afford B6 (0.07 g). MS (ES): m / z = 316.1 [M+H]+. Intermediate B7 Step-1 To a stirred solution of B1 (300 mg, 1 mmol) and 4-methoxy-1H-pyrazole (49.1 mg, 0.5 mmol) in DMSO (6 mL) was added cesium carbonate (326 mg, 1 mmol) and heated at 60oC for 16 h. Reaction mixture was diluted with ethyl acetate (30 mL), filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified on silica gel using 30 % ethyl acetate in hexanes as an eluent. The desired fractions were evaporated under reduced pressure to afford B7 (100 mg, 28 % yield) as yellow gummy solid. MS (ES): m / z = 362.2 [M+H]+. Intermediate C1 Step-1 To a stirred solution of B1q (2 g, 5.8 mmol) in acetonitrile (40 mL) was added TBAF (1M in THF, 11.6 mL, 11.6 mmol). The reaction mixture was heated at 60 °C for 3h. Then it was partitioned between water (100 mL) and ethylacetate (50 mL). The organic layer was separated, dried over sodium sulphate and evaporated under reduced pressure to get crude which was purified on silica gel using 40% ethyl acetate in hexanes as an eluant to afford C1-1 (1.6 g, 5 mmol, 87 % yield) as a pale-yellow solid. MS (ES): m / z = 319.1 [M+2H]+. Step-2 To a degassed solution of C1-1 (2 g, 6.3 mmol), potassium acetate (1.25 g, 12.6 mmol) and bis(pinacolato)diboron (1.9 g, 7.6 mmol) in dioxane (20 mL) was added [1,1- bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.23 g, 0.3 mmol) and reaction mixture was heated at 90 °C for 6h. Reaction mixture was diluted ethyl acetate (40 mL), filtered and filtrate was evaporated under reduced pressure to afford C1-2 (2.0 g, 87 % yield) as a brown sticky liquid. MS (ES): m / z = 365.3 [M+H]+. Step-3 To a degassed solution of C1-2 (600 mg, 1.65 mmol), E7 (380 mg, 1.65 mmol) and potassium carbonate (2M, 0.83 mL, 1.65 mmol) in dioxane (8 mL) was added XPhos Pd G2 (44 mg, 0.06 mmol) and reaction mixture was heated at 100oC for 3h. The reaction mixture was diluted with ethyl acetate (20 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to afford residue, which was purified on silica gel using 40% ethyl acetate in hexanes. The desired fractions were evaporated under reduced pressure to afford C1 (95 mg, 15 % yield) as yellow gummy solid. MS (ES): m / z = 388.2 [M+H]+. The following intermediates were prepared in an analogous manner to intermediate C1 using appropriate precursors. Intermedi Structure MS (ES) Interme Structure MS (ES) ate [M+H]+diate [M+H]+F F N N O N O N C1a OH 388.2 C1d N 347.2 O O NOMeN F F N N O N O N C1b 365.1 C1e N 347.2 O S O O N N NH OMe F F N N O N O N C1c N 347.2 C1f N 347.2 O O OMe N N OMeIntermediate C2 Step-1 To a solution of B1 (500 mg, 1.67 mmol) and pyridin-3-ol (160 mg, 1.67 mmol) in acetonitrile (10 mL) was added Cs2CO3(1.1 g, 3.34 mmol) and heated at 80oC for 16 h. Reaction mixture was diluted with ethyl acetate (30 mL), filtered and the filtrate was concentrated to afford crude which was purified on silica gel using 45% ethyl acetate in hexanes. The desired fractions were evaporated under reduced pressure to afford C2-1 (280 mg, 47% yield) as yellow gummy solid. MS (ES): m / z = 359.1 [M+H]+.1H NMR (300 MHz, CDCl3): δ ppm 8.55 (dd, J = 4.3, 1.8 Hz, 1H), 8.51 (d, J = 2.5 Hz, 1H), 7.81 (d, J = 2.5 Hz, 1H), 7.47 - 7.33 (m, 2H), 7.13 (d, J = 2.5 Hz, 1H), 4.79 - 4.67 (m, 1H), 4.59 (d, J = 6.8 Hz, 1H), 4.52 - 4.45 (m, 1H), 4.40 - 4.37 (m, 1H), 3.84 - 3.67 (m, 3H), 3.35 - 3.23 (m, 1H), 2.65 (dt, J = 12.1, 2.7 Hz, 1H), 1.09 (d, J = 6.8 Hz, 3H). Step-2 A mixture of C2-1 (150 mg, 0.42 mmol) and CsF (320 mg, 2.1 mmol) in DMF (2 mL) was heated at 100oC for 16 h. Reaction mixture was diluted with ethyl acetate (15 mL), filtered, filtrate was concentrated to afford the crude which was purified on silica gel using 50% ethyl acetate in hexanes. The desired fractions were evaporated under reduced pressure to afford C2 (70 mg, 50% yield) as yellow thick liquid. MS (ES): m / z = 332.2 [M+H]+.1H NMR (300 MHz, CDCl3): δ ppm 8.45 - 8.38 (m, 2H), 7.51 (t, J = 2.5 Hz, 1H), 7.33 - 7.28 (m, 2H), 6.93 (dd, J = 8.4, 2.7 Hz, 1H), 4.77 (q, J = 6.8 Hz, 2H), 4.52 - 4.38 (m, 2H), 4.26 (q, J = 6.5 Hz, 1H), 3.92 - 3.81 (m, 1H), 3.74 (td, J = 11.5, 3.2 Hz, 1H), 3.28 (td, J = 11.6, 3.8 Hz, 1H), 2.70 (br d, J = 11.8 Hz, 1H), 1.02 (d, J = 6.8 Hz, 3H). The following intermediates were prepared in an analogous manner to intermediate C2 using appropriate precursors. Intermed Structure MS Intermedi Structure MS (ES) iate (ES) ate [M+H]+[M+H]+F F N N O N OMe O N C2a 362.2 C2dO OM361.2 OO NO eF F N N O N O N C2b N OOOMe 362.2 C2e 347.2 NOON F F N N ONOMe N C2c 361.2 C2f O 335.2 OON OONIntermediate C3a & C3b Intermediate C3 (1.50 g, 5.07 mmol; cis-racemate prepared according to protocols described in WO2022 / 238335) was subjected to purification via preparative SFC chromatography (Column: Chiralpak IA, 30 x 250 mm, 5 µM particles, Flow Rate: 90 mL / min, Column Temperature: 45 °C, Mobile Phase A: CO2, Mobile Phase B: methanol / acetonitrile (1:1), Gradient: isocratic 10% B). Fraction collection was triggered by UV (220 – 300 nm), and fractions containing the desired product were combined and dried to afford a first eluting isomer defined as C3a (628 mg, RT: 3.82 min, >99% ee, m / z 296.1 [M+H]+) as a white solid and a second eluting isomer defined as C3b (632 mg, RT: 4.60 min, 98.8% ee, m / z 296.1 [M+H]+) as a white solid. Analytical SFC was used to determine the enantiomeric excess and MS readout (Column: Chiralpak AD-H, 4.6 x 100 mm, 5 µM particles, Flow Rate: 2 mL / min, Mobile Phase A: CO2, Mobile Phase B: methanol / acetonitrile (1:1), Column Temperature: 50 °C, Gradient: isocratic 10% B). Absolute stereochemistry was assigned retrospectively based on the co-crystal structure of a derivative with human cGAS. Intermediate C4 To a degassed suspension of C3b (400 mg, 1.4 mmol), potassium carbonate (467 mg, 3.4 mmol) and XPhos (64.5 mg, 0.13 mmol) in acetonitrile (3.5 mL) were added ethynylcyclopropane (358 mg, 5.4 mmol) and bis(acetonitrile) dichloropalladium(II) (35 mg, 0.13 mmol). The reaction mixture was heated at 80 °C for 12 h. Then it was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to get the crude which was purified on silica gel using 50 % ethyl acetate in hexanes as eluent. Fractions containing desired product were concentrated under reduced pressure to afford C4 (280 mg, 63.6 % yield). MS (ES): m / z = 326.2 [M+H]+. Intermediate C5 Step-1 C5-1 was prepared as per the reported procedure. WO 2024 / 099908 Step-2 To a solution of C5-1 (500 mg, 1.5 mmol) in 1,4-Dioxane (5 mL) was added HCl in 1,4- dioxane (4N, 3.6 mL, 14.5 mmol). The reaction mixture was stirred at RT for 4h and evaporated under reduced pressure to afford crude C5-2.HCl salt as an off-white solid. MS (ES): m / z = 245.0 [M+H]+. Step-3 To the stirred solution of C5-2 (1 g, 4.1 mmol) in DCM (10 mL) at 0 °C, was added triethylamine (1.7 mL, 12.3 mmol) followed by methyl chloroformate (0.32 mL, 4 mmol). The reaction mixture was stirred at 0 °C for 2h, partitioned between DCM (10 mL) and water (10 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to afford yellow residue which was purified by Prep- HPLC to afford C5 (Dia.mix-1) (120 mg, 10% yield) and C5 (Dia.mix-2) (150 mg, 12% yield) as yellow solid. MS (ES): m / z = 303.1 [M+H]+. Prepartive HPLC condition: Column: Gemini NX C18, 250 x 21 mm, 5 µm particles; Mobile Phase A: 10 mM Ammonium acetate pH-4.5 with CH3COOH; Mobile Phase B: acetonitrile; Gradient: 0 – 100 % B over 11 minutes, then a 5-minute hold at 50% B; Flow: 20 mL / min).

[0010] Intermediate C5a Step-1 To a degassed solution of tert-butyl (3S,4R)-4-(5-chloro-2-fluoropyridin-3-yl)-4-fluoro-3- methylpiperidine-1-carboxylate (Prepared as per the reported procedure WO 2024 / 099908) (500 mg, 1.44 mmol), 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (439 mg, 1.8 mmol) and K2CO3(2M, 1.4 mL, 2.9 mmol) in Dioxane (5 mL), was added Xphos PdG2 (122 mg, 0.144 mmol). The reaction mixture was heated at 80 °C for 12 h. The reaction mixture was diluted with ethylacetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to afford C5a-1(500 mg, 78% yield) as brown semisolid. MS (ES): m / z= 419.1 [M+H]+. Step-2 Analogous to preparation of C5-2, the reaction of C5a-1 and 4N HCl in 1,4-dioxane afforded C5a-2. MS (ES): m / z = 319.1 [M+H]+. Step-3 To a stirred solution of C5a-2 (100 mg, 0.3 mmol) and tetrahydrofuran-3-yl 1H- imidazole-1-carboxylate (68.7 mg, 0.38 mmol) (Prepared as per the patent reported CN109970675, 2019, A) in 1,2-dichloroethane (2 mL) cooled at 0 °C, was added TEA (0.13 mL, 0.9 mmol). The reaction mixture was stirred at RT for 2h. Then it was diluted with ethylacetate (50 mL) and washed with saturated brine solution (50 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to afford C5a (100 mg, 74% yield) as brown gummy solid. MS (ES): m / z= 433.2 [M+H]+. Intermediate C6 Step-1 To a stirred solution of B1q (2 g, 5.8 mmol) in acetonitrile (40 mL) was added TBAF (1M in THF, 11.6 mL, 11.6 mmol). The reaction mixture was heated at 60 °C for 3h. Then it was partitioned between water (100 mL) and ethylacetate (50 mL). The organic layer was separated, dried over sodium sulphate and evaporated under reduced pressure to get crude which was purified on silica gel using 40% ethyl acetate in hexanes as an eluant to afford C6-1 (1.6 g, 5 mmol, 87 % yield) as a pale-yellow solid. MS (ES): m / z = 319.1 [M+2H]+. Step-2 To a degassed solution of C6-1 (1.4 g, 4.4 mmol), potassium(tert- butoxycarbonylamino)methyl-trifluoro-boranuide (1.26 g, 5.3 mmol) and cesium carbonate (2.88 g, 8.8 mmol) in Toluene (7mL) and H2O (3 mL) was added CataCXium A Palladacycle G3 (0.32 g, 0.44 mmol). The reaction mixture was heated at 90 °C for 12h. Then it was partitioned between water (50 mL) and ethylacetate (100 mL). The organic layer was separated, dried over sodium sulphate and evaporated under reduced pressure to afford crude which was purified on silica gel using 80% ethyl acetate in hexanes as an eluant to afford C6-2 (1.1 g, 68 % yield) as brown solid. MS (ES): m / z = 368.0 [M+H]+. Step-3 To a stirred solution of C6-2 (750 mg, 2 mmol) in DMF (7 mL) at 0 °C, was added NaH (245 mg, 6 mmol). After 15 min, iodomethane (0.15 mL, 2.5 mmol) was added and the reaction mixture was stirred at RT for 2h. Then it was partitioned between water (50 mL) and ethylacetate (50 mL). The organic layer was separated, dried over sodium sulphate and evaporated under reduced pressure to afford C6-3 (600 mg, 77 % yield) as brown solid. MS (ES): m / z = 382.1 [M+H]+. Step-4 To a stirred solution of C6-3 (200 mg, 0.5 mmol) in DCM (5 mL) at 0 °C, was added TFA (0.4 mL, 5.2 mmol) and the reaction mixture was stirred at RT for 3h. The reaction mixture was concentrated under reduced pressure to afford crude C6-4.TFA salt (130 mg, 88 % yield) as brown amorphous solid which was used as such in next step. MS (ES): m / z = 282.1 [M+H]+. Step-5 To a stirred solution of C6-4 (130 mg, 0.5 mmol) in DCM (5 mL) at 0 °C, were added TEA (0.2 mL, 1.4 mmol) and methyl chloroformate (0.04 mL, 0.6 mmol). The reaction mixture was stirred at 0 °C for 2h, partitioned between DCM (20 mL) and water (10 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to afford C6 (120 mg, 77 % yield) as brown solid. MS (ES): m / z = 340.2 [M+H]+. Intermediate C6a Step 1: Analogous to preparation of C6, the reaction of C6-4 (150 mg, 0.5 mmol) and isopropyl chloroformate (0.32 mL, 0.6 mmol) afforded C6a (150 mg, 77 % yield). MS (ES): m / z = 368.4 [M+H]+. Intermediate C7 Step 1 Analogous to preparation of C6-2, the reaction of C6-1 (600 mg, 1.9 mmol) and potassium benzyloxymethyltrifluoroborate (518 mg, 2.3 mmol) afforded C7-1 (600 mg, 88 % yield) as a brown solid. MS (ES): m / z = 359.2 [M+H]+. Step-2 To a degassed solution of C7-1 (500 mg, 1.4 mmol)) in MeOH (10 mL) was added Palladium on carbon,10% (445 mg, 4.2 mmol). The reaction mixture was stirred at RT for 6h under hydrogen balloon. The reaction mixture was filtered through celite and concentrated under reduced pressure to afford C7-2 (300 mg, 80 % yield) as an off-white solid. MS (ES): m / z = 269.1 [M+H]+. Step-3 To a stirred solution of C7-2 (250 mg, 0.9 mmol) and sodium tert-butoxide (90 mg, 0.9 mmol) in THF (3 mL) at 0oC, was added 4-nitrophenyl ethyl(methyl)carbamate (230 mg, 1.025 mmol). The reaction mixture was stirred at 0oC for 2h. Then it was partitioned between water (10 mL) and ethylacetate (50 mL). The organic layer was separated, dried over sodium sulphate and evaporated under reduced pressure to afford C7 (250 mg, 76 % yield) as yellow solid. MS (ES): m / z = 354.2 [M+H]+.

[0011] Intermediate D1 Step-1 To the stirred solution of B1 (2.5 g, 8.3 mmol) and (2S,4S)-1-(tert-butoxycarbonyl)-4- hydroxypyrrolidine-2-carboxylic acid (3 g, 13.4 mmol) in DMA (30 mL) cooled at 0 °C, NaH (1.3 g, 33.4 mmol) was added portion-wise. The reaction mixture was gradually brought to RT and stirred for 2 h. The reaction mixture was acidified with 1.5N HCl solution till the pH 5 and diluted with ethyl acetate (250 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford D1-1 (3.5 g) as a pale red oil. MS (ES): m / z = 506.3 [M+Na]+. Step-2 To the stirred solution of D1-1 (3 g, 6.2 mmol) in DCM (50 mL), TFA (4.8 mL, 62 mmol) was added. The reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated to afford D1.TFA salt (2.1 g) as a brown paste. MS (ES): m / z = 384.2 [M+H]+. The following intermediates were prepared in an analogous manner to intermediate D1 using appropriate precursors. Intermediate StructureMS (ES)[M+H]+HO O HN D1a O N 429.6 N Br O O Intermediate D2 Step-1 To a stirred solution of D1-1 (0.8 g, 1.7 mmol) in MeOH (20 mL) was added (trimethylsilyl)diazomethane solution in hexane (8.3 mL, 16.5 mmol) and TBAF (0.216 g, 0.827 mmol) at 0 °C. The resulting mixture was stirred at rt for 16 h. After completion, the reaction was quenched with the acetic acid until nitrogen evolution stopped, then diluted with water and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulphate,and evaporated under reduced pressure to afford D2- 1 (0.61 g). MS (ES): m / z = 498.2 [M+H]+. Step-2 To a stirred solution of D2-1 (0.6g, 1.2 mmol) in DCM (10 mL) was added TFA (0.46 mL, 6.0 mmol) at RT and stirred at rt for 14 h. The reaction mixture was concentrated to remove TFA completely, quenched with 10% NaHCO3 solution, and extracted with DCM (3 x 50 mL). The combined organic layer was dried over anhydrous Sodium sulphate and evaporated under reduced pressure to afford crude compound, which was purified on silica gel column using 7% MeOH in DCM as an eluent. The desired fractions were evaporated to afford D2 as a gummy liquid (0.42 g) which was used directly for the subsequent step. MS (ES): m / z = 398.0 [M+H]+.

[0012] Intermediate D3 To a degassed solution of D1-1 (5.6 g, 11.6 mmol), 2M K3PO4(17.4 mL, 34.7 mmol), XPhos Pd G3 (0.98 g, 1.2 mmol) in dioxane (50 mL), trimethylboroxine (16.2 mL, 116 mmol) was added. The reaction mixture was heated to 100 °C for 16 h. The reaction mixture was concentrated to afford a dark brown residue which was purified on Redisep Gold column using 0.1 % NH4OAc (pH-4.5) in ACN / water gradient. The desired fractions were evaporated under reduced pressure to afford D3 (1 g) as an off-white solid. MS (ES): m / z = 364.3 [M+H]+. Intermediate D4 Step-1 To a degassed solution of D1-1 (350 mg, 0.723 mmol) in dioxane (3 mL) was added potassium carbonate (0.9 mL, 1.808 mmol), Pd(PPh3)4 (84 mg, 0.07 mmol), XPhosPdG3 (61.2 mg, 0.07 mmol) and methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5- dihydro-1H-pyrrole-1-carboxylate (458 mg, 1.8 mmol). The reaction mixture was heated at 100 °C for 18h. After completion of the reaction, it was neutralized with dilute HCl. The solution was extracted with DCM (3 x 30 mL), the organic layer was dried over sodium sulphate,and concentrated to afford crude product D4-1 (300 mg). Crude product was taken to the next step without further purification. MS (ES): m / z = 575.4 [M+H]+. Alternatively, D4-1 could be prepared as follows using the corresponding bromide D1-1a: A degassed solution of D1-1a (123 mg, 0.233 mmol; prepared similarly as its chloride counterpart D1-1), methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro- 1H-pyrrole-1-carboxylate (88 mg, 0.349 mmol), tripotassium phosphate (2 M in water) (0.582 mL, 1.164 mmol), and XPhos Pd G2 (18.32 mg, 0.023 mmol) in Dioxane (2.0 mL) was stirred at 80 °C for 2 h. The reaction mixture was diluted with 80 mL of EtOAc which was washed with 20 mL of 1N HCl solution, 20 mL of brine, and dried over magnesium sulphate. The organic layer was filtered and concentrated to afford a crude product which was purified by Prep-HPLC (Method PB) to yield D4-1. Step-2 Analogous to the preparation of D1, the reaction of D4-1 (100 mg, 0.17 mmol) and TFA (0.013 mL, 0.17 mmol) afforded crude compound D4 (TFA salt, 78 mg). MS (ES): m / z = 475.3 [M+H]+. Crude compound obtained was taken to the next step without further purification. The following intermediates were prepared in an analogous manner to intermediate D4 using appropriate precursors. Intermediate StructureMS (ES)[M+H]+O H N OH D4a O N 466.2 N O O O OH HN O D4b N ON456.2 O O Intermediate D5 Step-1 A degassed solution of D1-1a (100 mg, 0.189 mmol), ethynylcyclopropane (0.096 mL, 1.136 mmol), Cs2CO3(123 mg, 0.379 mmol), XPhos (9.02 mg, 0.019 mmol), and PdCl2(CH3CN)2(2.5 mg, 9.5 µmol) in Acetonitrile (5 mL) was heated at 80 °C for 24 h. The reaction mixture was diluted with 80 mL of EtOAc which was washed with 20 mL of 1N HCl solution, 20 mL of brine, and dried over Magnesium sulphate. The organic layer was filtered and concentrated to afford D5-1 (115 mg) which was used in the next step without further purification. MS (ES): m / z = 514.5 [M+H]+. Step-2 Analogous to the preparation of D1, the reaction of D5-1 (115.4 mg, 0.201 mmol) and TFA (0.292 mL, 3.79 mmol) afforded D5 (34 mg). MS (ES): m / z = 414.2 [M+H]+. Intermediate D6 D6-1 D6-2 D6 Cis diastereo mix. Peak-2 advanced (desired isomer)Single diastereomerStep-1 To a stirred solution of C3 and (2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2- carboxylic acid (2.15 g, 9.30 mmol) in DMF (25 mL), NaH (1.52 g, 38.0 mmol) was added at 0 °C and stirred the reaction mixture at rt for 3 h. After completion, the reaction mixture was quenched with water, neutralized with 1.5N HCl, and extracted with DCM (3 x 100 mL). The combined organic layer was dried over sodium sulphate, filtered, and concentrated under reduced pressure to afford crude product D6-1 which was taken to the next step without further purification. MS (ES): m / z = 505.0 [M-H]+. Step-2 To a stirred solution of D6-1 in MeOH (50 mL) at 0 °C were added TMS-diazomethane (37.7 mL, 75 mmol) and TBAF (2.32 g, 8.88 mmol) drop wise under nitrogen atmosphere. The reaction mixture was stirred at rt for 18h. After completion, the reaction mixture was quenched with acetic acid at 0 °C and partitioned between EtOAc (200 mL) and water (100 mL). The organic layer was dried over sodium sulphate, filtered, and concentrated under reduced pressure to afford the crude product D6-2 (5.5 g). To the crude compound, MeOH (25 mL) was added and triturated. The precipitated solid was filtered, washed with MeOH, and dried under vacuo to get the product as an off-white solid. The residue was a diastereomeric mixture which was separated by chiral SFC (SFC Method: Chiralpak IC (250 x 4.6 mm) 5 micron; 0.2% DEA in IPA, Flow: 4.0 mL / min, temperature: 35 °C, UV: 254 nm). The first eluting compound (Rt= 4.58 min) was designated as Peak-I (800 mg), MS (ES): m / z = 420.1 [M-Boc+H]+, and the second eluting compound (Rt= 5.83 min) was designated as Peak-II (D6-2, 800 mg), MS (ES): m / z = 420.1 [M-Boc+H]+. Peak-II, the absolute stereochemistry of which was assigned as indicated based on the co-crystal structure of a derivative with human cGAS, was progressed to the next step. MS (ES): m / z = 420.1 [M-Boc]+. Step-3 Analogous to the preparation of D1, the reaction of D6-2 (peak-II) and TFA afforded crude compound D6 (120 mg) which was taken to the next step without further purification. MS (ES): m / z = 421.2 [M+H]+. Intermediate D7 Step-1 To a stirred solution of 1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (10 g, 43.2 mmol) in THF (100 mL) was added 2-tert-butyl-1,3-diisopropyl-isourea (17.4 g, 86 mmol). The reaction mixture was heated to 70 °C for 18 h and filtered through celite. The filtrate was evaporated under reduced pressure and purified on silica gel using 30% ethyl acetate in hexanes. The desired fractions were evaporated under reduced pressure to afford D7-1 (8.4 g, 68 % yield) as yellow thick liquid.1H NMR (300 MHz, DMSO-d6): δ ppm 4.95 - 4.89 (m, 1H), 4.24 - 4.12 (m, 1H), 4.08 - 4.01 (m, 1H), 3.48 (dd, J = 5.7, 11.1 Hz, 1H), 3.09 (dd, J = 4.3, 10.8 Hz, 1H), 2.38 - 2.20 (m, 1H), 1.78 (td, J = 4.6, 12.7 Hz, 1H), 1.43 - 1.33 (m, 18H). Step-2 Analogous to the preparation of D1-1, the reaction of D7-1 (5 g, 17.4 mmol) and B1q (6.0 g, 17.4 mmol) afforded D7-2 (8.6 g, 85 % yield) as yellow solid. MS (ES): m / z = 584.2 [M+H]+. Step-3 To a degassed solution of D7-2 (3 g, 5 mmol), potassium acetate (1.26 g, 12.8 mmol) and bis(pinacoloto)diboron (1.57 g, 6.2 mmol) in dioxane (30 mL) was added [1,1- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.38 g, 0.5 mmol). The reaction mixture was heated at 90 °C for 4h, partitioned between water (30 mL) and ethyl acetate (150 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to afford D7-3 (4 g, 63 %yield) as brown solid. MS (ES): m / z = 632.4 [M+H]+. Step-4 To a stirred solution of D7-3 (3 g, 4.8 mmol) in THF (18 mL) and H2O (18 mL) was added sodium perborate monohydrate (1.9 g, 19 mmol) and stirred at RT for 16h. The reaction mixture was diluted with ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure and the residue obtained was purified on silica gel using 70% ethyl acetate in hexanes as an eluant. The desired fractions were evaporated under reduced pressure to afford crude D7-4 as yellow gummy solid which was taken as such to next step. MS (ES): m / z = 522.5 [M+H]+. Step-5 To a stirred solution of D7-4 (540 mg, 1 mmol) in Pyridine (3 mL) was added ethyl(methyl)carbamic chloride (190 mg, 1.6 mmol) and the reaction mixture was heated at 90 °C for 12h. Then it was evaporated under reduced pressure, partitioned between water (20 mL) and ethylacetate (50 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to afford D7-5 (500 mg, 80 % yield) as yellow gummy solid. MS (ES): m / z = 607.4 [M+H]+. (The epimerized product was observed by LCMS. The crude was carried forward as such and the two diastereomers were separated in the final step). Step-6 To a stirred solution of D7-5 (500 mg, 0.8 mmol) in DCM (2.5 mL) was added TFA (2.5 mL, 32.4 mmol) and stirred at RT for 16h. The reaction mixture was concentrated under reduced pressure to afford D7.TFA salt (450 mg, 97 % yield) as yellow solid. MS (ES): m / z = 451.5 [M+H]+. The following intermediates were prepared in an analogous manner to intermediate D7 using appropriate precursors. Interm MS Structure(ES) IntermStructuMS (ES) ediate ediatere[+[M+H]+M+H] H O H O N N OH OH O O D7aN437.4 D7eNON479.1 O N O OO OO ON N O H O H O N N OH OH O O N N D7b O N 465.2 D7 O N O f O 513.1 OO OON N FFH O H O N N OH OH O O D7cN NON463.2 D7gO N465.2 O O OO O ON N H O N OH O D7dNON477.5 O OON The following intermediates were synthesized from appropriate precursors according to procedures described in the noted references.Intermediate StructureMS (ES)[M+H]+ ReferenceE1F N Br- Genentech WO2014 / 1377 F Eisai R D Management E2 161.1 MeO N ClUS2012 / 95031 E3 F ON Br- Eternygen UK WO2023 / 285583 F Intermediate E2a E2aAnalogous to the preparation of Intermediate E2, the reaction of 6-chloro-3-fluoropyridin- 2-ol (500 mg, 3.4 mmol), ethyl iodide (1.4 mL, 17 mmol) and silver carbonate (1.9 g, 6.8 mmol) afforded E2a (400 mg) as a pale green oil. MS (ES): m / z = 176.0 [M+H]+. Intermediate E3a To the stirred solution of 2,6-dibromopyridine (1 g, 4.2 mmol) in DMF (10 mL), sodium hydride (0.17 g, 4.2 mmol). 2,2,2-trifluoroethan-1-ol (0.5 g, 5.1 mmol) was added to the reaction mixture and heated at 60 °C for 2 h. The reaction mixture was partitioned between water (10 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford E3a (0.9 g) as a yellow oil. The crude obtained was used directly in the next step. Intermediate E4 To a stirred solution of 5-bromo-3-(trifluoromethyl)-1H-pyrazole (500 mg, 2.3 mmol) in DCM (5 mL), 3,4-dihydro-2H-pyran (0.4 mL, 4.7 mmol) and p-toluenesulfonic acid monohydrate (44 mg, 0.2 mmol) were added. The reaction mixture was stirred at rt for 12 h. The reaction mixture was partitioned between sodium bicarbonate solution (20 mL) and DCM (50 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford E4 as a yellow semisolid. The crude obtained was used directly in the next step. Regiochemical makeup, although inconsequential, was not determined. Intermediate E5 Analogous to the preparation of A6-1, the reaction of 5-bromothiophene-3-carbaldehyde (1 g, 5.2 mmol) and DAST (2.3 mL, 15.7 mmol) afforded E5 (160 mg) as a colourless oil. Intermediate E6 To a stirred suspension of 5-bromothiazole-2-carboxylic acid (620 mg, 3 mmol) and ammonium chloride (320 mg, 6 mmol) in THF (10 mL) were added DIPEA (1.6 mL, 9 mmol) and HATU (1.36 g, 3.6 mmol). The reaction mixture was stirred at RT for 2 h. Then it was quenched with ice cold water, precipitated solid was collected by filtration and dried under vacuum to afford E6 (320 mg, 52% yield) as yellow solid. MS (ES): m / z = 207.1 [M+H]+. Intermediate E7 Step-1 To a solution of methyl (6-bromo-2-pyridinyl)acetate (950 mg, 4.13 mmol) in DMF (10 mL) at 0oC, was added sodium hydride (400 mg, 16.5 mmol) followed by methyl iodide (1.8 mL, 30 mmol). The reaction mixture was stirred at RT for 16h. Then it was partitioned between saturated ammonium chloride solution (50 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to get the crude which was purified on silica gel using 40% ethyl acetate in hexanes. The desired fractions were evaporated under reduced pressure to afford E7-1 (1 g, 94% yield) as a yellow liquid. MS (ES): m / z = 258.0 [M+H]+. Step-2 To a solution of E7-1 (900 mg, 3.5 mmol) in THF (10 mL) at -78oC, was added 1 M LiAlH4in THF (7 mL, 7 mmol) dropwise and reaction mixture was stirred at -78oC for 1h. Then, it was quenched with saturated ammonium chloride solution (15 mL) and diluted with ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to afford E7 (650 mg, 81 % yield) as a yellow liquid.1H NMR (400 MHz, DMSO-d6): δ ppm 7.72 - 7.67 (m, 1H), 7.41 - 7.37 (m, 1H), 7.21 - 7.15 (m, 1H), 4.71 (t, J = 4 Hz, 1H), 3.58 - 3.53 (m, 2H), 1.25 (s, 6H). Intermediate E7a Analogous to the preparation of E7, E7a was synthesized from methyl 2-(4-bromopyridin- 2-yl)acetate.1H NMR (400 MHz, DMSO-d6): δ ppm 8.53 - 8.47 (m, 1H), 7.42 - 7.36 (m, 1H), 7.20 - 7.15 (m, 1H), 4.68 (t, J = 4 Hz,), 3.57 - 3.52 (m, 2H), 1.24 (s, 6H). Intermediate E8 Step-1 To a stirred solution of 2,6-dibromopyridine (5.0 g, 21.1 mmol) in ethanol (100 mL) was added NaOH (1.1 g, 27.4 mmol) at RT and stirred at 90 °C for 2 h. The reaction mixture was concentrated and diluted with water and ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous sodium sulphate, and evaporated under reduced pressure to afford E8-1 (3.3 g). MS (ES): m / z = 203.9 [M+2H]+. Step-2 To a solution of E8-1 (0.5 g, 2.475 mmol) in Dioxane (10 mL) were added bis(pinacolato)diboron (1.26 g, 4.95 mmol), potassium acetate (0.607 g, 6.19 mmol) and PdCl2(dppf)-CH2Cl2adduct (0.202 g, 0.247 mmol) at RT. Reaction mixture was stirred at 90 °C for 2 h. After cooling, it was filtered through celite using ethyl acetate and the filtrate was concentrated under reduced pressure to afford E8 (0.21 g) as a brown solid. MS (ES): m / z = 168.1 [M+H]+. Intermediate E9 Step-1 To a solution of cyclopropanol (29.7 mg, 0.511 mmol) in THF (5 mL), was added sodium hydride (61.4 mg, 1.02 mmol) at 0 °C, followed by addition of 2-bromo-6-fluoropyridine (90.0 mg, 0.511 mmol). The reaction mixture was heated at 60 °C for 2 h, quenched with methanol (1 mL), then concentrated and purified by a flash column chromatography on silica to afford E9-1 (82 mg). MS (ES): m / z = 215.8 [M+2H]+. Step-2 Analogous to the preparation of E8, the reaction of E9-1 (25.0 mg, 0.117 mmol) and bis(pinacolato)diboron (32.6 mg, 0.128 mmol) afforded E9. MS (ES): m / z = 278.9 [M+NH4]+. Intermediate E10 Analogous to the preparation of E8, the reaction of 2-bromo-6-isopropoxypyridine (30.0 mg, 0.139 mmol) and bis(pinacolato)diboron (44.1 mg, 0.174 mmol) afforded E10. MS (ES): m / z = 264.7 [M+H]+. Intermediate E11 Step-1 To a solution of 5-bromo-6-fluoropyridin-3-ol (500 mg, 2.6 mmol) in DMF (5 mL) cooled at 0°C, was added NaH (125 mg, 5.2 mmol) followed by iodomethane (1.3 mL, 20.8 mmol). The reaction mixture was stirred at RT for 12h. Then it was partitioned between water (10 mL) and ethylacetate (50 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to afford E11-1 (230 mg, 43% yield) as yellow semisolid. MS (ES): m / z = 208.1 [M+2H]+. Step-2 Analogous to the preparation of E8, E11 was synthesized from E11-1. MS (ES): m / z = 254.1 [M+H]+. Intermediate E12 Analogous to the preparation of E8, the reaction of 5-bromo-4-fluoro-2- methoxybenzonitrile (300 mg, 1.3 mmol) and bis(pinacolato)diboron (400 mg, 1.6 mmol) afforded E12 (300 mg, 83% yield) as a brown semi solid.1H NMR (400 MHz, DMSO-d6): δ ppm 7.93 (s, 1H), 7.88 - 7.85 (m, 1H), 3.96 (s, 3H), 1.29 (s, 12H). The following intermediates were prepared in an analogous manner to intermediate E12 using appropriate precursors MS IntermediatStructureMS (ES) IntermediatSt(ES) e [M+H]+eructure[M+H] + O O E12a O O B B E12b 254.2 F F 254.4 N N OMe OMeO No O 12cBion O B E O O izatio E12d N 275.1 N n in MS N O H The following intermediates were synthesized from appropriate precursors according to procedures described in the noted references. Intermediate StructureMS (ES)[M+H]+ ReferenceO O B Incyte Holdings - E12e O - US2016 / 289238, 2016 N O O Hangzhou Bangshun E12f OBN - Pharmaceutical - CN116262753, OO2023 O B GENENTECH - E12g O O - F WO2015 / 52264, 2015 O F O Fimbrion therapeutics - E12h OBO N WO2017 / 156508, 2017 Intermediate E13 Step-1 E13-1 was prepared as per the reported procedure. (PFIZER - US2010 / 197591, 2010, A1) Step-2 Analogous to the preparation of E8, the reaction of E13-1 (1 g, 4.4 mmol) and bis(pinacolato)diboron (1.33 g, 5.2 mmol) afforded E13 (500 mg, 41.5 % yield). The crude was taken as such to next step. The following intermediates were prepared in an analogous manner to intermediate E13 using appropriate precursors Intermediate StructureMS (ES)Intermediate SMS (ES) [M+H]+ tructure[M+H]+O No O No E13aOE13 O B b B F ionization ionization OH in MS OH in MSOONo B E13c ionization OH in MS FFIntermediate E14 Br Br OStep-1 Step-2OH O E14-1 Step-1 E14-1 was prepared as per the reported procedure. PFIZER - WO2006 / 51373, 2006, A1 Step-2 Analogous to the preparation of E8, the reaction of E14-1 and bis(pinacolato)diboron afforded E14. The crude obtained was taken as such to next step. The following intermediates were prepared in an analogous manner to intermediate E14 using appropriate precursors Intermediate StructureMS (ES)InteMS (ES) [M+H]+ rmediate Structure[M+H]+No O O No E14a O O B B ionizat F F ion E14b ionization OH in MS OH in MS OMeO O No O O No B B E14c F ionization E14d ionization in MS OH in MS OH OMe O O No O O No E14e B B ionization E14f F ionization N in MS in MS OH OH Intermediate E15 Step-1 To a solution of 3-(3-bromophenyl)-3-methylbutanoic acid (1 g, 3.9 mmol) in THF (10 mL) at -70oC, was added borane dimethyl sulfide complex (1.1 mL, 11.7 mmol) and the reaction mixture was stirred for at RT for 2h. Reaction mixture was carefully quenched with methanol and heated at 80oC for 1h. Then it was evaporated under reduced pressure and the residue obtained was partitioned between ethyl acetate (50 mL) and saturated sodium bicarbonate solution (100 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to afford E15-1 (800 mg, 85% yield) as yellow oil.1H NMR (300 MHz, DMSO-d6): δ ppm 7.53 - 7.44 (m, 1H), 7.41 - 7.32 (m, 2H), 7.31 - 7.23 (m, 1H), 4.25 (t, J = 5.0 Hz, 1H), 3.18 (ddd, J = 8.4, 7.0, 5.0 Hz, 2H), 1.83 - 1.74 (m, 2H), 1.26 (s, 6H). Step-2 Analogous to the preparation of E8, the reaction of E15-1 (450 mg, 1.85 mmol) and bis(pinacolato)diboron (570 mg, 2.2 mmol) afforded E15 (480 mg, 89 % yield) as brown gummy solid.1H NMR (400 MHz, DMSO-d6): δ ppm 7.68 - 7.56 (m, 1H), 7.55 - 7.43 (m, 2H), 7.39 - 7.25 (m, 1H), 3.24 - 3.10 (m, 2H), 1.83 - 1.74 (m, 2H), 1.30 (s, 12H), 1.27 (s, 6H). Intermediate E16 Step-1 To the stirred solution of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5- dihydro-1H-pyrrole-1-carboxylate (7 g, 23.7 mmol) in DCM (70 mL), TFA (27.4 mL, 356 mmol) was added. The reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated to afford E16-1 (TFA salt, 4.6 g) as a brown semisolid. MS (ES): m / z = 196.2 [M+H]+. Step-2 To the stirred solution of E16-1 (7 g, 36 mmol) in DCM (100 mL) at 0 °C, triethylamine (25 mL, 179 mmol) was added followed by methyl chloroformate (3.3 mL, 43 mmol). The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was partitioned between water (50 mL) and DCM (100 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford E16 (5 g) as a brown solid. The crude obtained was used directly in the next step. The following intermediates were prepared in an analogous manner to intermediate E16 using appropriate precursors. Intermediate StructureMS (ES)IntermMS (ES) [M+H]+ ediate Structure[M+H]+O OB OB OE16a 267.1 E16f 296.2 N N O O O O O O O BB OE16b 282.3 E16g 268.2 N N O O O O O O BOO B E16c - E16h - N N O O O O O BOO BOE16d N - E16i 238.2 O N O O O BOE16e N - O O O Intermediate F1 To a degassed solution of 4,6-dichloro-2-(difluoromethyl)pyrimidine (200 mg, 1 mmol), (3-(dimethylamino)phenyl)boronic acid (166 mg, 1 mmol) and K3PO4(2M, 1.51 mL, 3 mmol) in Dioxane (2 mL), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (73 mg, 0.1 mmol) was added. The reaction mixture was heated at 90 °C for 3 h. The reaction mixture was partitioned between water (2 mL) and ethyl acetate (10 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford F1 (250 mg) as a brown semisolid. MS (ES): m / z = 286.1 [M+H]+. The following intermediates were prepared in an analogous manner to intermediate F1 using appropriate precursors. IntermediStructureMS (ES)Intermediate StruMS (ES) ate [M+H]+cture[M+H]+F F N F1a NCF26MeONN FN 7.9 F1b N 272.0 Cl Cl Intermediate F2 Step-1 To a degassed suspension of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole-1-carboxylate (440 mg, 1.5 mmol), 4,6-dichloro-2- (difluoromethyl)pyrimidine (500 mg, 2.5 mmol) and K3PO4(2M, 2 mL, 3.8 mmol) in dioxane (3 mL), PdCl2(dppf)-CH2Cl2adduct (180 mg, 0.3 mmol) was added. The reaction mixture was irradiated under microwave at 100 °C for 2 h and filtered through celite. The filtrate was concentrated to afford F2-1 (300 mg) as a yellow gummy solid. MS (ES): m / z = 231.1 [M+H]+. Step-2 To the stirred solution of F2-1 (200 mg, 0.87 mmol) in THF (2 mL) was added NaH (60%, 100 mg, 4.3 mmol) followed by iodomethane (0.3 mL, 4.3 mmol). The reaction mixture was heated at 65 °C for 16 h. The reaction mixture was quenched with methanol and concentrated to afford a yellow gummy solid which was purified on silica gel using 50% ethyl acetate in hexanes as eluent. The desired fractions were concentrated to afford F2 (100 mg) as a yellow gummy solid. MS (ES): m / z = 245.1 [M+H]+. The following intermediate was prepared in an analogous manner to intermediate F2 using appropriate precursors. Intermediate StructureMS (ES)[M+H]+F F NNF F2a N 295.3 F N Cl Intermediate F3 Analogous to the preparation of F2-1, the reaction of 2,4-dichloro-6- (difluoromethyl)pyrimidine (50 mg, 0.25 mmol) and tert-butyl 2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1-carboxylate (73.7 mg, 0.251 mmol) afforded crude product F3 (65 mg) which was used directly in the next step without further purification. MS (ES): m / z = 330.0 [M+H]+. Intermediate F4 Analogous to the preparation of F2-1, the reaction of 2,4-dichloro-6- (difluoromethyl)pyrimidine (100 mg, 0.50 mmol) and 2-thienylboronic acid (57.9 mg, 0.45 mmol) afforded F4 (200 mg). MS (ES): m / z [M+H]+= 247.1. The following intermediates were prepared in an analogous manner to intermediate F4 using appropriate precursors. IntermediStructureMS (ES)IntermeMS ate [M+H]+diate Structure(ES) [M+H] + F F S F F4a 260SFN N.0 F4b NN260.0 Cl Cl Intermediate F5 To a stirred solution of 4,6-dichloro-2-methoxypyrimidine (0.05 g, 0.3 mmol) and E8 (0.061 g, 0.4 mmol) in Dioxane (2 mL) and water (0.1 mL) was added potassium phosphate (0.146 g, 0.838 mmol) and PdCl2(dppf)-CH2Cl2adduct (0.023 g, 0.03 mmol). Then, it was stirred at 100 °C for 3 h. After cooling, mixture was diluted with ethyl acetate, filtered through celite and concentrated under reduced pressure to afford a brown color solid as product. The residue was purified by silica gel column chromatography using 40% ethyl acetate in hexanes as eluent to afford F5 (0.06 g). MS (ES): m / z = 266.1 [M+H]+. Intermediate F6 To a degassed solution of 4,6-dichloro-2-(difluoromethyl)pyrimidine (1 g, 5 mmol), thiophen-2-ylboronic acid (0.6 g, 5 mmol) and K2CO3(2M, 7.54 mL, 15.1 mmol) in THF (10 mL), Pd(PPh3)4(0.58 g, 0.503 mmol) was added. The reaction mixture was heated at 70 °C for 4 h. Then, it was partitioned between ethyl acetate (50 mL) and water (10 mL). The organic layer was separated, dried over sodium sulphate, and concentrated under reduced pressure to afford a brown residue which was purified by silica-gel column chromatography using 17% ethyl acetate in hexanes as eluent. The desired fractions were evaporated under reduced pressure to afford Intermediate F6 (800 mg) as an off-white solid. MS (ES): m / z = 247.0 [M+H]+. Intermediate F7 A degassed solution of 2,4-dichloro-6-methyl-1,3,5-triazine (300 mg, 1.829 mmol), thiophene-2-boronic acid (176 mg, 1.38 mmol), tripotassium phosphate (2 M, 2.1 mL, 4.1 mmol) and bis(triphenylphosphine)palladium(II) dichloride (57.9 mg, 0.083 mmol) was stirred at rt for 7 h. The reaction mixture was partitioned between ethylacetate (20 mL) and water (10 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to afford crude product which was purified on silica gel column chromatography with Hexanes / EtOAc as eluent to afford F7 (125 mg). MS (ES): m / z = 212.0 [M+H]+. Intermediate F7a Analogous to the preparation of F7, F7a was synthesized from 2,4-dichloro-6-ethyl-1,3,5- triazine. MS (ES): m / z = 226.1 [M+H]+. Intermediate F7b Analogous to the preparation of F7, the reaction of 2,4-dichloro-6-methyl-1,3,5-triazine (350 mg, 2.132 mmol) and N-Boc-2-pyrroleboronic acid (300 mg, 1.422 mmol) afforded F7b (151 mg). MS (ES): m / z = 295.0 [M+H]+. Intermediate F7c Analogous to the preparation of F7, the reaction of 2,4-dichloro-6-ethyl-1,3,5-triazine and N-Boc-2-pyrroleboronic acid afforded F7c. MS (ES): m / z = 308.9 [M+H]+. The following intermediates were prepared in an analogous manner to intermediate F7 using appropriate precursors.Intermediate StructureMS (ES)MS (ES) [M+H]+ Intermediate Structure[M+H]+OSe FN ON F F7d N 320.9 F7e N 295.0 NNCl Cl ONF7f N N 196.1 Cl Intermediate F8 Step 1 To a solution of 1H-pyrrole-2-carbonitrile (10 g, 109 mmol) and hydroxylamine hydrochloride (15.1 g, 217 mmol) in a mixture of ethanol (140 mL) and water (70 mL), K2CO3(22.5 g, 163 mmol) was added and the resulting mixture was stirred for 3 h at 85 °C. The residual ethanol was removed under reduced pressure and the remaining solution was extracted with ethyl acetate (3 x 150 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get a crude compound which was triturated with diethyl ether, filtered, and dried under vaccum to afford F8-1 (10.8 g) as a pale-yellow solid. MS (ES): m / z = 126.2 [M+H]+. Step 2 To a solution of F8-1 (10 g, 80 mmol), and acetic acid (4.6 mL, 80 mmol) in methanol (100 mL) at room temperature, 10% Pd-C (8.50 g, 7.99 mmol) was added, and the resultant reaction mixture was stirred at room temperature under H2bladder pressure for 20 h. The reaction mixture was carefully filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to afford F8-2 (10.5 g) as an acetic acid salt which was used in the next step without further purification. MS (ES): m / z = 110.3 [M+H]+. Step 3 To a solution of F8-2 (10.5 g, 60 mmol) in anhydrous THF (100 mL) at 0 °C, was added sodium methoxide (19.6 mL, 92 mmol) followed by 2,2,2-trichloroacetonitrile (5.71 mL, 55.3 mmol) and the resultant reaction mixture was stirred at RT for 12 h. The reaction mixture was filtered through a pad of celite, then concentrated under reduced pressure to afford F8-3 (17 g) which was used to next step without any purification. MS (ES): m / z = 253 / 255 [M+H]+. Step 4 To a solution of F8-3 (17 g, 36.9 mmol) in anhydrous THF (170 mL) at 0 °C, difluoroacetic anhydride (9.17 mL, 73.8 mmol) was added and the resultant reaction mixture was stirred at RT for 12 h. The reaction mixture was concentrated and the crude residue was purified by silica gel chromatography using 5-10% ethyl acetate in petroleum ether as eluent. Fractions containing desired product were concentrated under reduced pressure to afford F8 (10.5 g). MS (ES): m / z = 311 / 313 [M+H]+. The following intermediates were prepared in an analogous manner to intermediate F8 using appropriate precursors. MS Intermed MS (ES) Intermedia Structure+Structure (ES) iate [M+H] te [M+H]+F F S N O N F F F8aN N296 F8bN N- CCl3CCl3SCF3 NHCF3F8c N N N F8d N 348 / 350 N N 331 / 333 CCl3 CCl3F8a:1H NMR (400 MHz, CDCl3): δ ppm 8.40 (dd, J = 1.3, 3.9 Hz, 1H), 7.80 (dd, J = 1.3, 4.9 Hz, 1H), 7.28 - 7.25 (m, 1H), 6.77 - 6.49 (m, 1H) F8b:1H NMR (400 MHz, DMSO-d6): δ ppm 8.26 (dd, J = 0.8, 1.6 Hz, 1H), 7.85 (dd, J = 0.8, 3.6 Hz, 1H), 7.23 - 6.96 (m, 1H), 6.92 (dd, J = 1.8, 3.6 Hz, 1H). Intermediate G1 Step-1 To the stirred suspension of cis-4-Hydroxy-L-proline methyl ester Hydrochloride (5.5 g, 30 mmol) and 4,6-dichloro-2-(difluoromethyl)pyrimidine (6 g, 30 mmol) in DMSO (60 mL), DIPEA (10.5 mL, 60.3 mmol) was added. The reaction mixture was stirred at rt for 4 h. The reaction mixture was partitioned between water (500 mL) and ethyl acetate (250 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford G1-1 (8.2 g) as a pale brown solid. MS (ES): m / z = 308.1 [M+H]+. Step-2 To the degassed solution of G1-1 (500 mg, 1.6 mmol) and hexamethylditin (0.4 mL, 1.9 mmol) in Dioxane (7 mL), 1,1'-bis(di-tert-butylphosphino)ferrocene-palladium dichloride (106 mg, 0.16 mmol) was added. The reaction mixture was heated at 90 °C for 4 h. The reaction mixture was filtered through celite, and the filtrate was concentrated to afford G1- 2 (600 mg) as a brown oil. MS (ES): m / z = 438.0 [M+H]+. Step-3 To the degassed solution of G1-2 (500 mg, 1.2 mmol) and E8-1(230 mg, 1.5 mmol) in dioxane (5 mL), 1,1'-bis(di-tert-butylphosphino)ferrocene-palladium dichloride (75 mg, 0.12 mmol) was added. The reaction mixture was heated at 105 °C for 6 h. The reaction mixture was cooled to rt, filtered through celite, and the filtrate was concentrated to afford G1-3 (400 mg) as a brown oil. MS (ES): m / z = 395.2 [M+H]+. Step-4 To the stirred solution of G1-3 (400 mg, 1 mmol) in THF (4 mL), 2.5 N NaOH (2 mL, 5.1 mmol) was added. The reaction mixture was stirred at rt for 4 h. The reaction mixture was evaporated to remove volatiles, acidified with 1N HCl to pH 5, and diluted with ethyl acetate (20 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford G1 (300 mg) as a brown semisolid. MS (ES): m / z = 381.2 [M+H]+. The following intermediates were prepared in an analogous manner to intermediate G1 using appropriate precursors. Inter mediStructureMS (ES)Interme MS (ES) [M+H]+ diStructure +ateate[M+H] F F F O NN CHF2EtO NN CHF2N N G1a O 401.1 G1f O N 399.1 N OH OH HO HO F NN CHF2F O NN CHF2F N F N G1b O 385.2 G1g O 417.1 N N OH OH HO HO O F F O NN CHF2O NN CHF2F N G1c N 397.3 G1h O N 435.1 O N OH OH HO HO N CHF F C2N 3N O NCHF2NN O G1d NNO 368.2 G1i OH THP N 478.1 N OH HO HO F MeO NN CHF2G1e N O 385.1 N OH HO Intermediate G1j To a degassed solution of G1-2 (120 mg, 0.28 mmol) and E5 (59 mg, 0.275 mmol) in Dioxane (2 mL) was added 1,1'-bis(di-tert-butylphosphino) ferrocene-palladium dichloride (18 mg, 0.03 mmol). The reaction mixture was heated at 90 °C for 16 h. The reaction mixture was diluted with ethyl acetate (15 mL), filtered, and concentrated to afford G1j (100 mg) as a brown oily mass, which was used directly in the next step. MS (ES): m / z = 392.1 [M+H]+. Intermediate G1k Analogous to the preparation of G1j, the reaction of G1-2 (200 mg, 0.46 mmol) and 2- bromo-4-methylthiazole (82 mg, 0.46 mmol) afforded G1k (120 mg) as a brown oily mass, which was used directly in the next step. MS (ES): m / z = 357.2 [M+H]+. Intermediate G2 Step-1 To the degassed solution of 6-bromo-2-fluoro-3-methylpyridine (218 mg, 1.1 mmol) and G1-2 (500 mg, 1.1 mmol) in Dioxane (5 mL), 1,1'-bis(di-tert- butylphosphino)ferrocenepalladium dichloride (74.7 mg, 0.1 mmol) was added. The reaction mixture was heated at 100 °C for 6 h. The reaction mixture was filtered through celite and the filtrate was concentrated to afford G2-1 (400 mg) as a brown semisolid. MS (ES): m / z = 383.3 [M+H]+. Step-2 To the stirred solution of G2-1 (250 mg, 0.7 mmol) in Methanol (2 mL), cesium carbonate (852 mg, 2.6 mmol) was added. The reaction mixture was heated at 80 °C for 4 h. The reaction mixture was partitioned between 1.5N HCl (5 mL) and ethyl acetate (20 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford G2 (250 mg) as a brown solid. MS (ES): m / z = 381.2 [M+H]+. Intermediate G2a Analogous to the preparation of Intermediate G2, the reaction of G2-1 (250 mg, 0.7 mmol) and cesium carbonate (852 mg, 2.6 mmol) in Ethanol (2 mL) afforded G2a (250 mg) as a brown solid. MS (ES): m / z= 395.1 [M+H]+. Intermediate G3 Step-1 To the solution of 2-bromo-1H-imidazole (1.0 g, 4.7 mmol) in THF (10 mL) at 0 °C was added sodium hydride (0.2 g, 7.5 mmol). The reaction mixture was stirred at 0 °C for 30 min and a solution of SEM-Cl (1.6 mL, 8.9 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred at rt for 16 h, partitioned between ice cold water (15 mL) and ethyl acetate (40 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford G3-1 (1.3 g) as a yellow gummy solid. MS (ES): m / z = 277.1 [M+H]+. Step-2 Analogous to the preparation of G1j, the reaction of G1-2 (150 mg, 0.35 mmol) and G3-1 (145 mg, 0.52 mmol) afforded G3 (134 mg) as a brown solid. MS (ES): m / z = 456.3 [M+H]+. Intermediate G3a Analogous to the preparation of G3, G3a (120 mg) was prepared as a brown solid using the corresponding 4-bromo-1H-imidazole. The SEM-regiochemical makeup of G3a was not determined. MS (ES): m / z = 456.3 [M+H]+. Intermediate G4 Step-1 To a degassed solution of 4-chloro-2-(methylsulfonyl)pyrimidine (1.5 g, 7.8 mmol) and hexamethylditin (2.1 mL, 10 mmol) in dioxane (20 mL), 1,1'-bis(di-tert- butylphosphino)ferrocene-palladium dichloride (0.36 g, 0.6 mmol) was added and the reaction mixture was heated at 100 °C for 4 h. The reaction mixture was concentrated and the residue was purified on silica gel using 40% ethyl acetate in hexanes as eluent. The desired fractions were concentrated to afford G4-1 (1.5 g) as a brown oil. MS (ES): m / z = 323.0 [M+H]+. Step-2 To a degassed solution of methyl G1-1 (300 mg, 0.98 mmol) and G4-1(469 mg, 1.5 mmol) in dioxane (1 mL), 1,1'- bis(di-tert-butylphosphino)ferrocene-palladium dichloride (64 mg, 0.1 mmol) was added and the reaction mixture was heated at 105 °C for 4 h. The reaction mixture was filtered through syringe filter and the filtrate was concentrated to afford G4-2 (350 mg) as a brown semisolid. MS (ES): m / z = 430.1 [M+H]+. Step-3 To the stirred solution of G4-2 (150 mg, 0.35 mmol) in MeOH (1 mL), cesium carbonate (341 mg, 1 mmol) was added. Mixture was heated at 60 °C for 2 h. It was concentrated to remove volatiles and cooled to 0 °C. The reaction mixture was acidified with TFA till the pH reached 5 and diluted with ethyl acetate (10 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford G4 (90 mg) as a brown semisolid. MS (ES): m / z = 368.1 [M+H]+. Intermediate G4a To the stirred solution of G4-2 (150 mg, 0.35 mmol) in EtOH (1 mL), cesium carbonate (341 mg, 1 mmol) was added, and the mixture was heated at 60 °C for 4 h. The reaction mixture was concentrated to remove volatiles and cooled to 0 °C. The reaction mixture was acidified with TFA till the pH reached 5 and diluted with ethyl acetate (10 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford G4a (100 mg) as a brown semisolid. MS (ES): m / z = 382.1 [M+H]+. Intermediate G5 Step-1 To a stirred solution of methyl (2S,4S)-4-hydroxypyrrolidine-2-carboxylate (0.037 g, 0.3 mmol) in DMSO (1 mL) were added DIPEA (0.121 mL, 0.7 mmol) and 4,6-dichloro-2- (trifluoromethyl)pyrimidine (0.05 g, 0.2 mmol). The mixture was stirred at 80 °C for 2 h. To the reaction mixture, water was added (20 mL) and extracted with ethyl acetate (3 X 10 mL). The combined organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate, and evaporated under reduced pressure to afford G5-1 (0.06 g). MS (ES): m / z = 326.1 [M+H]+. Step-2 To a stirred solution of G5-1 (0.15 g, 0.46 mmol) and E8 (0.1 g, 0.6 mmol) in dioxane (2 mL) and water (0.1 mL) were added potassium phosphate (0.241 g, 1.4 mmol) and PdCl2(dppf)-CH2Cl2adduct (0.038 g, 0.05 mmol) at RT. The mixture was stirred at 100 °C for 3 h. After cooling, it was diluted with ethyl acetate, filtered through celite, and concentrated under reduced pressure to give a brown color solid. The crude product was dissolved in ethyl acetate and washed with water, brine solution, dried over anhydrous sodium sulphate,and evaporated under reduced pressure to afford G5 (0.11 g) which was used directly in the subsequent step. MS (ES): m / z = 413.2 [M+H]+. Intermediate G6 Step-1 To a degassed solution G1-1 (200 mg, 0.7 mmol), thiophen-2-ylboronic acid (83 mg, 0.7 mmol) and K3PO4(2M, 0.4 mL, 1.3 mmol) in Dioxane (5 mL) was added PdCl2(dppf)- CH2Cl2adduct (54 mg, 0.07 mmol). The reaction mixture was heated at 90 °C for 5 h. The reaction mixture was partitioned between ethyl acetate (20 mL) and water (10 mL). The organic layer was separated, dried over sodium sulphate, and concentrated under reduced pressure to afford a yellow gummy solid which was purified on silica gel using 60% ethyl acetate in hexanes as eluent. The desired fractions were evaporated under reduced pressure to afford G6-1 (100 mg) as a yellow gummy solid. MS (ES): m / z = 256.1 [M+H]+. Step-2 Analogous to the preparation of G1, the reaction of G6-1 (100 mg, 0.3 mmol) and 2.5 M NaOH (0.3 mL, 0.8 mmol) afforded G6 (90 mg) as a yellow gummy solid. MS (ES): m / z = 342.1 [M+H]+. The following intermediates were prepared in an analogous manner to intermediate G6 using appropriate precursors. IntermediStructureMS (ES)Intermediate StrucMS (ES) ate [M+H]+ture[M+H]+S FSFN F N F N G6a O N N 356.2 G6b O 356.2 N OH OH HO HO Intermediate G7 To a degassed solution of G1-1 (100 mg, 0.3 mmol), 2-(4-methoxythiophen-2-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (78 mg, 0.3 mmol) and K3PO4(2M, 0.3 mL, 0.8 mmol) in dioxane (3 mL) was added [1,1 bis(diphenylphosphino)ferrocene]dichloropalladium(II) (24 mg, 0.03 mmol) and heated at 100 °C for 16 h. Methyl ester hydrolysis was observed under the reaction conditions. The reaction mixture was acidified with 1.5N HCl to pH 1 and diluted with ethyl acetate (10 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford G7 (90 mg) as a yellow gummy solid. MS (ES): m / z = 372.1 [M+H]+. The following intermediates were prepared in an analogous manner to intermediate G7 using appropriate precursors. IntermediStruMS (ES) Interme MS (ES) atecture[M+H]+diateStructure[M+H]+SF NS FN N F N F N N G7a O 343.2 G7c O N 343.2 N OH OH HO HO S F N N F N G7b O N 357.2 OH HO Step-1 To the degassed solution of G1-1 (500 mg, 1.6 mmol), 4-bromothiophen-2-ylboronic acid (400 mg, 1.9 mmol) and K3PO4(2M, 1.3 mL, 2.4 mmol) in dioxane (3 mL) was added [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (120 mg, 0.16 mmol) and irradiated in the microwave at 100 °C for 2 h. The reaction mixture was partitioned between ethyl acetate (20 mL) and water (10 mL). The organic layer was separated, dried over sodium sulphate, and concentrated under reduced pressure to afford G8-1 (610 mg) as a brown gummy solid. MS (ES): m / z = 434.0 [M+H]+. Step-2 To a degassed solution of G8-1 (60 mg, 0.138 mmol), 2-cyclopropyl-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (140 mg, 0.8 mmol) and K2CO3(2M, 0.1 mL, 0.3 mmol) in dioxane (3 mL) was added [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 0.02 mmol) and heated at 90°C for 6 h. The reaction mixture was concentrated, pH was adjusted to 3 using 1.5N HCl and diluted with ethyl acetate (10 mL). The organic layer was separated, dried over sodium sulphate, and concentrated under reduced pressure to afford G8 (34 mg) as a brown gummy solid. MS (ES): m / z = 382.3 [M+H]+. Intermediate G9 Step-1 To the degassed solution of G8-1 (60 mg, 0.14 mmol) and 4,4,5,5-tetramethyl-2-phenyl- 1,3,2-dioxaborolane (42 mg, 0.2 mmol) and K3PO4(2M, 0.1 mL, 0.2 mmol) in dioxane (2 mL) was added [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 0.02 mmol) and the reaction was irradiated in the microwave at 100 °C for 2 h. The reaction mixture was partitioned between ethyl acetate (20 mL) and water (10 ml). The organic layer was separated, dried over sodium sulphate, and concentrated under reduced pressure to afford G9-1 (45 mg) as a brown gummy solid. MS (ES): m / z = 432.2 [M+H]+. Step-2 Analogous to the preparation of G1, the reaction of G9-1 (80 mg, 0.2 mmol) and 2.5 M NaOH (0.5 ml, 0.5 mmol) afforded G9 (80 mg) as a yellow gummy solid. MS (ES): m / z = 418.2 [M+H]+. Intermediate G10 Step-1 Analogous to the preparation of G9-1, the reaction of G8-1 (60 mg, 0.14 mmol) and 4,4,5,5- tetramethyl-2-vinyl-1,3,2-dioxaborolane (130 mg, 0.8 mmol) afforded G10-1 (45 mg) as a brown gummy solid. MS (ES): m / z = 382.2 [M+H]+. Step-2 To a degassed solution of G10-1 (100 mg, 0.3 mmol) in MeOH (5 mL) was added Pd / C (50% wet, 150 mg, 0.7 mmol). The reaction mixture was stirred at rt for 16 h under hydrogen balloon. The reaction mixture was filtered and concentrated to afford G10-2 (87 mg) as a yellow gummy solid. MS (ES): m / z = 384.2 [M+H]+. Step-3 Analogous to the preparation of G1, the reaction of G10-2 (80 mg, 0.21 mmol) and 2.5 M NaOH (0.5 ml, 0.63 mmol) afforded G10 (56 mg) as a yellow gummy solid. MS (ES): m / z = 370.3 [M+H]+. Intermediate G11 To a degassed solution G1-1 (50 mg, 0.16 mmol) and 2-(tributylstannyl)thiazole (0.05 mL, 0.16 mmol) in dioxane (1 mL) was added bis(triphenylphosphine)palladium(II) dichloride (11 mg, 0.02 mmol). The reaction mixture was heated at 100 °C for 16 h and filtered through celite. The filtrate was concentrated to afford G11 (50 mg) which was used directly in the next step. MS (ES): m / z = 343.2 [M+H]+. Intermediate G12 Step-1 To the stirred solution of 4,6-dichloro-2-(difluoromethyl)pyrimidine (2.5 g, 12.6 mmol) and (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid (1.65 g, 12.56 mmol) in DMSO (10 mL) was added DIPEA (4.6 mL, 25 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water (50 mL), acidified to pH 2 with 1.5 N HCl, and diluted with ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford G12-1 (3.2 g) as a yellow gummy mass. MS (ES): m / z = 294.1 [M+H]+. Step-2 To a degassed solution G12-1 (360 mg, 1.23 mmol), (5-chlorothiophen-2-yl)boronic acid (200 mg, 1.23 mmol) and 2M K3PO4(2 M, 1.5 mL, 3.1 mmol) in dioxane (3 mL) was added bis(diphenylphosphino)ferrocene]dichloropalladium(II) (100 mg, 0.12 mmol). The reaction mixture was heated at 90 °C for 16 h. The reaction mixture was diluted with water (50 mL), acidified to pH 2 with 1.5 N HCl, and diluted with ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulphate, and concentrated under reduced pressure to afford G12 (360 mg) as a brown gummy mass. MS (ES): m / z = 376.2 [M+H]+. The following intermediates were prepared in an analogous manner to intermediate G12 using appropriate precursors. Intermediate Structure MS (ES)m / z [M+H]+ F S N F G12-Ia N O N 342.1 OH HO F NH N F G12-Ib N O 325.2 N OH HO Intermediate G12a To a solution of 4,6-dichloro-2-(difluoromethyl)pyrimidine (0.5 g, 2.51 mmol) and (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid (0.330 g, 2.51 mmol) in acetonitrile (12 mL) was added potassium carbonate (0.347 g, 2.51 mmol). The resulting mixture was heated at 60 °C for 16 h. The reaction solution was used in the next step without further purification. To a portion of the reaction solution (2 mL; ~0.4 mmol of G12-1) was added furan-2-ylboronic acid (49 mg, 0.44 mmol), tripotassium phosphate (2 M aqueous, 0.60 mL, 1.2 mmol) and Pd(dppf)Cl2(23 mg, 0.032 mmol). The reaction vial was purged with nitrogen, then sealed with a pressure relief cap, and heated to 100 °C for 16 h. The reaction mixture was diluted with methanol, filtered through a 0.45 µm syringe filter, and purified by Prep-HPLC (Method PA) to afford G12a (87 mg). MS (ES): m / z = 325.9 [M+H]+. The following intermediates were prepared using a similar synthetic protocol as that of G12a. In the case of pyrrole, Boc-protected precursors were used but the Boc group is incidentally removed during the described coupling protocol. Intermediate Structure MS (ES)m / z [M+H]+ O N N G12b F O N 308.0 OH HO O NNN G12c O N 319.0 OH HO OFF N F N G12d O N 343.9 OH HO O N N G12e O N 276.0 OH HO NH N N G12f F O N 306.9 OH HO NH NON G12g O N 305.0 OH HO NH N N G12h O N 289.0 OH HONH FF N F N G12i O N 342.9 OH HO NH N N G12j O N 275.0 OH HO F F N NNG12k N F 306.9 O N OH HO NH F N F N G12l O N 325.0 OH HO N F N F N G12m O 339.0 N OH HO NH F N F G12n N O 339.0 N OH HO F ONN F N G12o O 366.9 N OH HO F N N F O N G12p O 366.9 N OH HO F N N F N G12q O 350.7 N OH HO NNH FN F N G12r O 339.9 N OH HO OFN F N G12s O 426.0 N OH HO F N O N F N G12t O 394.9 N OH HO F N O N F N G12u O 393.0 N OH HO Intermediate G12v Step-1 To a stirred solution of methyl (2S,4S)-4-hydroxypyrrolidine-2-carboxylate (0.892 g, 6.15 mmol) in DMSO (20 mL) were added DIPEA (2.9 mL, 16.8 mmol) and 4,6-dichloro-2- methoxypyrimidine (1.0 g, 5.6 mmol). The mixture was stirred at 80 °C for 2 h. After cooling, it was diluted with ethyl acetate and water. The organic layer was collected, washed with water, brine solution, dried over anhydrous sodium sulphate, and evaporated under reduced pressure to afford G12v-1 (1.3 g). MS (ES): m / z = 288.1 [M+H]+. Step-2 To a stirred solution of G12v-1 (1.3 g, 4.5 mmol) in MeOH (20 mL) and water (10 mL) was added NaOH (0.361 g, 9.0 mmol). The mixture was stirred at rt for 2 h. Then, it was concentrated and acidified with 1.5N HCl solution. The solid that precipitated out was filtered and dried under reduced pressure to afford G12v-2 (1.0 g). MS (ES): m / z = 274.0 [M+H]+. Step-3 To a stirred solution of G12v-2 (0.15 g, 0.5 mmol) and thiophen-2-ylboronic acid (0.09 g, 0.7 mmol) in Dioxane (3 mL) and Water (0.5 mL) were added potassium phosphate (0.29 g, 1.6 mmol) and PdCl2(dppf)-CH2Cl2adduct (0.045 g, 0.05 mmol) at RT. The mixture was stirred at 100 °C for 3 h. After cooling, it was diluted with ethyl acetate, filtered through celite, and concentrated under reduced pressure to give a brown solid. The crude product was dissolved in ethyl acetate (30 mL), washed with water, brine solution, dried over anhydrous sodium sulphate, and evaporated under reduced pressure to afford G12v (0.13 g). MS (ES): m / z = 322.0 [M+H]+. Intermediate G12w To a mixture of 1-Boc-pyrrole-2-boronic acid (311 mg, 1.47 mmol), G12-1 (361 mg, 1.23 mmol), and potassium phosphate tribasic (2 M in water, 2.46 mL, 4.92 mmol) in dioxane (8.2 mL) was added XPhos Pd G3 (104 mg, 0.123 mmol). The resulting mixture was sparged with nitrogen and then stirred at rt for 15 min. The mixture was diluted with water and washed with EtOAc. The organic layer was discarded. The aqueous layer was acidified to pH 3 by the addition of 1 N aqueous HCl. The acidified aqueous layer was extracted with EtOAc (3X). The combined organic extracts were dried over magnesium sulphate, filtered, and concentrated in vacuo to afford G12w (372 mg) which was used in the next step without further purification.1H NMR (500 MHz, DMSO-d6): δ ppm 7.49 - 7.20 (m, 1H), 6.78 (s, 1H), 6.71 - 6.62 (m, 1H), 6.59 - 6.41 (m, 1H), 6.33 (s, 1H), 4.73 - 4.61 (m, 1H), 4.50 - 4.29 (m, 1H), 3.76 - 3.67 (m, 1H), 3.38 - 3.34 (m, 1H), 1.43 - 1.28 (m, 9H). MS ESI 425.0 (M+H)+. Intermediate G12x G12xTo a suspension of F7 (2.7 g, 12.8 mmol) and (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid (1.7 g, 12.8 mmol) in DMSO (30 mL) was added DIPEA (3.4 mL, 19.2 mmol). The reaction mixture was stirred at RT for 8h. Then it was diluted with ice cold water (30 mL), pH was adjusted to 2 using 1.5N HCl and diluted with ethyl acetate (50 mL). The organic layer was washed with brine solution (1 x 10 mL), dried over sodium sulphate, filtered and concentrated to afford G12x (2.4 g, 61 % yield) as yellowish solid. MS (ES): m / z = 307.1 [M+H]+. The following intermediates were prepared in an analogous manner to intermediate G12x using appropriate precursors. Intermediate Structure MS Intermediate Structure MS (ES) (ES) [M+H]+[M+H]+NBoc NBoc N N G12x-aN NO 390.1 G12x-cN NO 404.1 N OH N OH HO HO S F N NBoc N F G12x-bN NO 321 G12x-dN NO 426.1 N OH N OH HO HO Intermediate G12y Step-1. To a solution of 2,4-dichloro-6-methoxy-1,3,5-triazine (471 mg, 2.62 mmol) in acetonitrile (16 mL), was added (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid (343 mg, 2.62 mmol) and NaHCO3 (439 mg, 5.23 mmol). The reaction mixture was stirred at room temperature overnight, filtered and the filtrate was evaporated under reduced pressure to afford G12y- 1. The reaction solution was used in the next step without further manipulation. MS (ES): m / z = 274.7 [M+H]+. Step-2. To a solution of G12y-1 in dioxane (4 mL), was added furan-2-ylboronic acid (73.3 mg, 0.655 mmol), K3PO4(2 M aqueous, 0.983 mL, 1.966 mmol) and PdCl2(PPh3)2(36.8 mg, 0.052 mmol). The reaction vial was purged with nitrogen, sealed with a pressure relief cap, and heated at 80oC overnight. The reaction mixture was concentrated and purified by Prep- HPLC to give G12y (92 mg). MS (ES): m / z = 306.7 [M+H]+. Intermediate G13 To a solution of G12l (6.0 mg, 0.019 mmol) in dioxane (1 mL) was added N- chlorosuccinimide (3.0 mg, 0.022 mmol), and the resulting mixture was stirred at room temperature overnight. A mixture of G13 and a di-chlorinated byproduct was observed by LCMS. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extract was washed sequentially with saturated aqueous sodium bicarbonate and brine, then dried over sodium sulfate, filtered, and concentrated to afford the mixture of G13 and a di-chlorinated byproduct. The crude mixture was used in the next step without further purification. Regiochemistry of G13 is not confirmed. MS (ES): m / z = 358.9 [M+H]+. Intermediate G14 Step-1 To a solution of 4,6-dichloro-2-(difluoromethyl)pyrimidine (20 mg, 0.101 mmol) in acetonitrile (3 mL) was added 1H-pyrazole (6.84 mg, 0.101 mmol) and potassium carbonate (15.3 mg, 0.111 mmol). The resulting mixture was heated at 80 °C overnight to afford G14-1. The reaction solution was used in the next step without further purification. MS (ES): m / z = 231.0 [M+H]+. Step-2 To a solution of G14-1 in acetonitrile was added (2S,4S)-4-hydroxypyrrolidine-2- carboxylic acid (13.2 mg, 0.101 mmol), and the resulting mixture was heated at 80 °C for 5 h. The reaction mixture was purified by Prep-HPLC (Method PA) to afford G14 (8 mg). MS (ES): m / z = 326.0 [M+H]+. Intermediate G15 Step-1 To a stirred solution of methyl (2S,4S)-4-hydroxypyrrolidine-2-carboxylate (1.0 g, 7.2 mmol) in DMSO (20 mL) were added DIPEA (3.46 mL, 19.8 mmol) and 4,6-dichloro-2- (methylsulfonyl)pyrimidine (1.5 g, 6.6 mmol). The mixture was stirred at 80 °C for 2 h. After cooling, it was diluted with ethyl acetate and water. The organic layer was collected, washed with water and brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure to afford G15-1 (1.63 g). MS (ES): m / z = 336.0 [M+H]+. Step-2 To a stirred solution of G15-1 (0.3 g, 0.9 mmol) and E8 (0.19 g, 1.2 mmol) in dioxane (8 mL) and Water (0.1 mL) were added potassium phosphate (0.47 g, 2.7 mmol) and PdCl2(dppf)-CH2Cl2adduct (0.07 g, 0.09 mmol) at rt. The mixture was stirred at 100 °C for 3 h. After cooling, the reaction mixture was diluted with ethyl acetate, filtered through Celite, and concentrated under reduced pressure to give a brown solid. The crude product was diluted with ethyl acetate and water. The organic layer was collected, washed with water, then brine solution, then dried over anhydrous sodium sulphate, and evaporated under reduced pressure to afford G15-2 (0.21 g). MS (ES): m / z = 423.3 [M+H]+. Step-3 To a stirred solution of G15-2 (0.2 g, 0.5 mmol) in DMF (2 mL) were added Cs2CO3(0.308 g, 0.9 mmol) and 2-((tert-butyldimethylsilyl)oxy)ethan-1-ol (0.083 g, 0.473 mmol) at RT. The mixture was stirred at 70 °C for 12 h. After cooling, water was added to the mixture and the solution was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to afford G15 (0.15 g). MS (ES): m / z = 505.4 [M+H]+. Intermediate G16 Step-1 Analogous to the preparation of G15-2, the reaction of G15-1 (0.3 g, 0.9 mmol) and thiophen-2-ylboronic acid (0.149 g, 1.2 mmol) afforded G16-1 (0.23 g). MS (ES): m / z = 384.1 [M+H]+. Step-2 To a stirred solution of G16-1 (0.05 g, 0.13 mmol) in DMF (2 mL) were added Cs2CO3(0.085 g, 0.3 mmol) and dimethylamine-HCl salt (0.02 g, 0.3 mmol) at RT. The mixture was stirred at 80 °C for 12 h. After cooling, the mixture was diluted with water and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate, and evaporated under reduced pressure to afford G16 (0.03 g). MS (ES): m / z = 335.1 [M+H]+. Intermediate G17 Analogous to the preparation of G16, the reaction of G15-2 (0.05 g, 0.12 mmol) and 3,3- difluoroazetidine hydrochloride (0.03 g, 0.2 mmol) afforded G17 (0.025 g). MS (ES): m / z = 436.3 [M+H]+. Intermediate G18 Step-1 To a stirred solution of methyl (2S,4S)-4-hydroxypyrrolidine-2-carboxylate (0.701 g, 4.8 mmol) in DMSO (20 mL) were added DIPEA (2.299 mL, 13.2 mmol) and 2-bromo-4,6- dichloropyrimidine (1.0 g, 4.4 mmol). The mixture was stirred at 80 °C for 2 h. After cooling, the mixture was diluted with water and extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed with water and brine solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to afford G18-1 (0.91 g). MS (ES): m / z = 338.0 [M+H]+. Step-2 Analogous to the preparation of G15-2, the reaction of G18-1 (0.15 g, 0.4 mmol) and 2- (2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.096 g, 0.5 mmol) afforded G18-2 (0.11 g). MS (ES): m / z = 326.2 [M+H]+. Step-3 Analogous to the preparation of G15-2, the reaction of G18-2 (0.15 g, 0.5 mmol) and E8 (0.077 g, 0.5 mmol) afforded G18 (0.13 g). MS (ES): m / z = 413.2 [M+H]+. Intermediate G19 Step-1 To a solution of cis-4-hydroxy-L-proline methyl ester hydrochloride (2.23 g, 12.27 mmol) in DMF (20 mL) were added 2,4-dichloro-6-methylpyrimidine (2.0 g, 12.3 mmol) and K2CO3(4.24 g, 30.7 mmol), and the resulting mixture was heated at 80 °C for 160 min. After completion, the reaction mixture was diluted with water and extracted with DCM (3 x 75 mL). The combined organic layer was dried over sodium sulphate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica-gel chromatography using 10-20% EtOAc in hexanes as eluent to afford G19-1a (800 mg, second eluting peak) and G19-1b (300 mg, first eluting peak). G19-1a: MS (ES) (Method D): RT = 0.82 min, m / z [M+H]+= 272.0.1H NMR (400MHz, CDCl3): δ ppm 6.51 (s, 1H), 4.61 (d, J = 9.0 Hz, 1H), 4.54 - 4.45 (m, 1H), 4.01 (br d, J = 12.5 Hz, 1H), 3.82 (s, 3H), 3.78 (br d, J = 4.5 Hz, 1H), 3.43 - 3.29 (m, 1H), 2.52 - 2.41 (m, 1H), 2.31 (br s, 3H), 2.25 (s, 1H). MS (ES): m / z [M+H]+= 272.0. G19-1b: MS (ES) (Method D): RT = 1.16 min, m / z [M+H]+= 272.0.1H NMR (400MHz, CDCl3): δ ppm 6.15 (br s, 1H), 4.79 - 4.64 (m, 1H), 4.61 - 4.49 (m, 1H), 3.85 (s, 3H), MS (ES): m / z [M+H]+= 272.0.3.78 (s, 1H), 3.73 - 3.56 (m,2H), 2.42 (br dd, J = 4.8, 9.8 Hz, 1H), 2.38 (s, 3H), 2.32 - 2.21 (m, 1H). MS (ES): m / z [M+H]+= 272.0. MS (ES): m / z [M+H]+= 272.0. Step-2 Analogous to the preparation of G15-2, the reaction of G19-1b (25 mg, 0.09 mmol) and phenylboronic acid (11.2 mg, 0.09 mmol) afforded crude product G19 which was taken to the next step without further purification. MS (ES): m / z = 315.2 [M+H]+. The following intermediates were prepared in an analogous manner to intermediate G19 using appropriate precursors. IntermeStructureMS (ES) IntermediStructurMS (ES) diate[M+H]+atee[M+H]+N O N O G19aNN NOS 315.2 G19bNN O 320.1 HO HO Intermediate G20 To a solution of G12-1 (20 mg, 0.068 mmol) in DMF (1.0 mL) was added 2- (tributylstannyl)pyridine (28 mg, 0.075 mmol) and Pd(dppf)Cl2(5.0 mg, 0.007 mmol). The reaction vial was purged with nitrogen, then sealed with a pressure relief cap, and heated to 100 °C for 48 h. The reaction mixture was purified by Prep-HPLC (Method PA) to afford G20 (8 mg). MS (ES): m / z 336.9 [M+H]+. Intermediate G21 Step-1 A mixture of 2,6-dichloro-4-(trifluoromethyl)pyridine (1.05 g, 4.86 mmol), (2S,4S)-4- hydroxypyrrolidine-2-carboxylic acid (0.765 g, 5.83 mmol), and cesium carbonate (4.75 g, 14.6 mmol) in DMF (21 mL) was sealed and heated at 85 °C for 2 h. The reaction mixture was cooled to rt, poured into water (80 mL), and washed with EtOAc. The organic layer was discarded. The remaining aqueous layer was acidified with 1 M aqueous HCl (~20 mL) to pH 3 and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine, dried over magnesium sulphate, filtered, evaporated in vacuo to afford G21-1 (1.90 g). MS (ES): m / z = 310.8 [M+H]+. Step-2 A vial containing G21-1 (240 mg, 0.610 mmol), thiophen-2-ylboronic acid (102 mg, 0.793 mmol), cesium carbonate (597 mg, 1.831 mmol), XPhos Pd G3 (25.8 mg, 0.031 mmol) and dioxane (8 mL) / water (1 mL) was evacuated under vacuum and back-filled with nitrogen. This process was repeated twice. The reaction mixture was stirred at rt for 2 h, then poured into water and washed with EtOAc. The organic layer was discarded. The remaining aqueous layer was acidified with 1 M aqueous HCl (~3 mL) to pH 3 and extracted with EtOAc. The organic layer was washed with brine, dried over magnesium sulphate, filtered, and evaporated in vacuo to afford G21 (200 mg). MS (ES): m / z = 359.0 [M+H]+. Intermediate G22 G21-1 Analogous to the preparation of G21, the reaction of G21-1 (240 mg, 0.610 mmol) and (1- (tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid (142 mg, 0.671 mmol) afforded G22 (199 mg) which was used for the next reaction without further purification. MS (ES): m / z = 442.0 [M+H]+. Intermediate G23 Step-1 To a mixture of 2,4-dichloro-6-(difluoromethyl)pyridine (3.8 g, 19.2 mmol) and (2S,4S)- 4-hydroxypyrrolidine-2-carboxylic acid (2.52 g, 19.2 mmol) in DMSO (20 mL) was added DIPEA (10.0 mL, 57.6 mmol). The resulting mixture was brought to 120 °C under microwave irradiation and stirred 30 min. The reaction mixture was concentrated in vacuo. The remaining residue was purified via preparative reverse phase chromatography (XBridge C18, 19 mm x 150 mm, 5 μm particles; Column Temperature: ambient; ACN / H2O with 5 mM ammonium formate) to afford two regioisomeric products: G23-1a (Peak 1, 1.1 g):1H NMR (400 MHz, DMSO-d6): δ ppm 12.01 (s, 1H), δ 6.66 (d, J = 2.00 Hz, 1H), 6.32-6.59 (m, 2H), 4.44-4.46 (m, 1H), 4.34-4.36 (m, 1H), 3.43-3.47 (m, 1H), 3.35-3.37 (m, 1H), 2.31-2.36 (m, 2H). MS ESI 293.0 (M+H)+. G23-1b (Peak 2, 270 mg):1H NMR (400 MHz, DMSO-d6): δ ppm 12.01 (s, 1H), δ 6.66 (d, J = 2.00 Hz, 1H), 6.32-6.59 (m, 2H), 4.44-4.46 (m, 1H), 4.34-4.36 (m, 1H), 3.43-3.47 (m, 1H), 3.35-3.37 (m, 1H), 2.31-2.36 (m, 2H). MS ESI 293.0 (M+H)+. Step-2 Analogous to the preparation of G21, the reaction of G23-1a (27 mg, 0.092 mmol) and 1- Boc-pyrrole-2-boronic acid (21.4 mg, 0.101 mmol) afforded crude G23 (26.8 mg) which was used in the next step without further purification. MS ESI m / z = 425.0 (M+H)+. Using similar procedure as that described for Intermediate G23, the following Intermediates were synthesized from appropriate precursors, obtained either from commercial sources or prepared internally. Intermediate Structure Precursors MS (ES)m / z [M+H]+S F N F G23a O N G23-1a 340.8 OH HO S F F N G23b O N G23-1b 340.8 OH HO O NOF G23c F N G23-1b 424.0 O N OH HO O NOF G23d F N G23-1c 424.0 O N OH HO S F F N G23e O N G23-1c 340.8 OH HO Intermediate H1 Step-1 To a stirred solution of 4,6-dichloro-2-methylpyrimidine (3.0 g, 18 mmol) and cis-4- hydroxy-L-proline methyl ester hydrochloride (2.7 g, 18.4 mmol) in DMF (50 mL), potassium carbonate (5 g, 37 mmol) was added. The reaction mixture was heated at 70 °C for 4 h. After cooling, the mixture was partitioned between water (200 mL) and ethyl acetate (150 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford crude H1-1 as a brown semisolid which was used directly in the next step. MS (ES): m / z = 272.1 [M+H]+. Step-2 To a stirred solution of H1-1 (3 g, 11 mmol) in THF (20 mL) and water (10 mL), NaOH (530 mg, 13 mmol) was added. The reaction mixture was stirred at rt for 3 h. Then, the mixture was evaporated to remove volatiles and acidified with 1N HCl to pH 5. The mixture was diluted with ethyl acetate (20 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to afford H1-2 (2.5 g) as a brown semisolid. MS (ES): m / z = 258.1 [M+H]+. Step-3 Analogous to the preparation of D1-1, the reaction of H1-2 and B1 afforded H1. MS (ES): m / z = 510.3 [M+H]+. Intermediate H2 Step-1 Analogous to the preparation of H1-1, the reaction of 4,6-dibromopyrimidine (3 g, 12.6 mmol) and cis-4-hydroxy-L-proline methyl ester hydrochloride (2.86 g, 15.8 mmol) afforded crude H2-1 as a brown semisolid which was used directly in the next step. MS (ES): m / z= 303.1 [M+H]+. Step-2 Analogous to the preparation of H1-2, the reaction of H2-1 (800 mg, 2.7 mmol) and NaOH (530 mg, 13.2 mmol) afforded H2-2 (500 mg) as a brown semisolid. MS (ES): m / z= 289.1 [M+2H]+. Step-3 Analogous to the preparation of D1-1, the reaction of H2-2 (400 mg, 1.4 mmol) and B1 (415 mg, 1.4 mmol) afforded H2 (500 mg) as a yellow gummy solid. MS (ES): m / z = 540.1 [M+H]+. Intermediate H3 To the stirred solution of 4,6-dichloro-2-(difluoromethyl)pyrimidine (0.52 g, 2.6 mmol) and D1 (1 g, 2.6 mmol) in DMSO (10 mL), DIPEA (1.8 mL, 10.4 mmol) was added. The reaction mixture was stirred at rt for 2 h and then partitioned between 1.5N HCl (10 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure. The resultant material was purified on a reverse phase HPLC (Redisep Gold column using 0.1% TFA in ACN / water gradient) to afford H3 (475 mg) as yellow solid. MS (ES): m / z = 546.1 [M+H]+. Intermediate H4 Analogous to the preparation of D1-1, the reaction of D3 (1.83 g, 5.00 mmol) and 4,6- dichloro-2-(difluoromethyl)pyrimidine (1.0 g, 5.0 mmol) afforded H4 (1.0 g) as a brown semisolid. MS (ES): m / z = 526.2 [M+H]+. Intermediate I1 To a stirred solution of G6 (500 mg, 1.5 mmol) and B1k (386 mg, 0.63 mmol) in DMA (2 mL) at 0 °C, sodium hydride (105 mg, 2.63 mmol) was added portion wise. The reaction mixture was stirred at rt for 3 h. Then, it was quenched with 1.5 N aq. HCl to pH 3 and diluted with ethyl acetate (20 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford I1 (400 mg) as a yellow semisolid, which was used as is. MS (ES): m / z = 558.2 [M+H]+. The following intermediates were prepared in an analogous manner to intermediate I1 using appropriate precursors. Intermediat MS (ES) Interme MS (E eStructureS) [M+H]+diateStructure[M+H]+SFS F N N F F N N O O N N I1a OH 564.2 I1c OH 586.2 O O N N N N O F ClFCl S F S F N F N F N N O O N N OH I1b OH 609.3 I1d O 632.1 O O N N N N ONF F Br Cl (Mixture of diastereomers) Intermediate I2 Step-1 To the stirred solution of G6 (200 mg, 0.58 mmol) and 3-bromo-5-chloro-2-fluoropyridine (136 mg, 0.64 mmol) in DMF (3 mL), Cs2CO3(764 mg, 2.34 mmol) was added. The reaction mixture was heated at 90 °C for 5 h. After completion, the reaction mixture was brought to rt and quenched with ice cold water. Solid residue precipitated out which was filtered and dried under reduced pressure to afford I2-1 (150 mg) as a yellow solid. MS (ES): m / z = 531.1 [M+H]+. Step-2 To a degassed solution of I2-1 (100 mg, 0.086 mmol), E16h (75 mg, 0.159 mmol) and K2CO3(26.2 mg, 0.190 mmol) in THF (2 mL) and water (0.2 mL), Pd(PPh3)4(21.0 mg, 0.012 mmol) was added. The reaction mixture was heated at 70 °C for 5 h. The crude reaction mixture was concentrated to afford I2 (100 mg), which was used for next step without further purification. MS (ES): m / z = 592.2 [M+H]+. Intermediate I3 Intermediate I3 was prepared from G10 and B1q according to the procedure described for the preparation of D1-1. MS (ES): m / z = 666.3 [M+H]+. Intermediate I4 & I4a To a solution of G12y (190 mg, 0.620 mmol) in DMF (4 mL) at 0 °C, was added B1q (214 mg, 0.620 mmol) and sodium hydride (60% w / w in mineral oil, 74.4 mg, 1.86 mmol). The mixture was stirred at 0 °C for 20 min, then heated at 60 °C for 1h. The reaction mixture was quenched with methanol and purified by Prep-HPLC to afford I4 (MS (ES): m / z = 603.9 [M+H]+) and I4a (MS (ES): m / z = 590.8 [M+H]+). The following intermediates were prepared in an analogous manner to intermediate I4 using appropriate precursors. Interme MS Structure(ES) IntermeSMS (ES) diate diatetructure[M++[M+H]+H] S N N N O H N NN NO NCOOHN OH I4b 603.8 I4f 617.3 O O N N ONO N O BrO BrNH N O N S H N NN NO NCOOHN OH I4c 604.7 I4g 600.3 O O N N ONO N O BrO BrS N F S N F NNO N O N N OH OH I4d 603.4 I4h 638.3 O O N N O NONBr OBrO NH F N NH N F NNO N O N N OH OH I4e 586.4 I4i 621.2 O O N N ONONBr OBrO Intermediate I5 I5-4 I5-5 I5Step-1 To a degassed solution of thiophen-2-ylboronic acid (9 g, 70.5 mmol), 2,4,6-trichloro- 1,3,5-triazine (20 g, 108 mmol) in toluene (600 mL) was added K2CO3(40.5 g, 293 mmol) followed by bis(triphenylphosphine)palladium(II) dichloride (3.8 g, 5.4 mmol) and the reaction mixture was heated at 60 °C for 16h. The reaction mixture was then diluted with ethyl acetate (250 mL) and washed with brine solution (250 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to get a crude which was purified on silica gel using 5% ethyl acetate in hexanes as eluent to afford I5-1 (8 g, 31.8 % yield). The crude obtained was used as such in next step. Step-2 To a solution of methyl (2S,4S)-4-hydroxypyrrolidine-2-carboxylate.HCl (1.32 g, 7.2 mmol) and I5-1 (2.1 g, 9.1 mmol) in THF (40 mL) at -78 °C was added triethylamine (2.5 mL, 18.1 mmol) and the reaction mass was stirred at RT for 1h. Then it was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to afford I5-2 (2.5 g, 81 % yield) as brown solid. MS (ES): m / z = 341.2 [M+H]+. Step-3 To a degassed solution of I5-2 (800 mg, 2.35 mmol), allylboronic acid pinacol ester (552 mg, 3.3 mmol) in THF (20 mL) were added cesium fluoride (535 mg, 3.5 mmol) and tetrakis(triphenylphosphine)palladium (271 mg, 0.24 mmol) and the reaction mixture was heated at 80 °C for 16h. Then it was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure and the residue obtained was purified on silica gel using 25% ethylacetate in hexanes as eluant to afford I5-3 (500 mg, 61.5 % yield) as colourless semisolid. MS (ES): m / z = 347.2 [M+H]+. Step-4 To a solution of I5-3 (1.5 g, 4.3 mmol) and B1q (1.490 g, 4.3 mmol) in NMP (15 mL) was added NaH (0.16 g, 6.5 mmol) and the reaction mixture was stirred at RT for 16h. The reaction mixture was cooled to 0oC, pH was adjusted to 5 using 1.5 N HCl and diluted with ethyl acetate (20 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to afford I5-4 (200 mg, 7.4 % yield) as brown semisolid. MS (ES): m / z = 631.3 [M+2H]+. Step-5 To a solution of I5-4 (1.5 g, 2.4 mmol) in a mixture of THF (50 mL) and water (50 mL) were added sodium (meta)periodate (1.274 g, 6 mmol) and potassium osmate dihydrate (0.044 g, 0.12 mmol). The reaction mixture was stirred at RT for 2h. Then it was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to afford I5-5 (500 mg, 33.2 % yield) as brown solid which was used as such for next reaction. Step-6 To a solution of I5-5 (100 mg, 0.16 mmol) in DCM (5 mL) at -20 °C was added (diethylamino)sulfur trifluoride (128 mg, 0.8 mmol) and the reaction mixture was allowed to stir at for 1h. The reaction mixture was quenched with sodium bicarbonate solution (10 mL) and diluted with DCM (20 mL), The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to afford I5 (80 mg, 0.122 mmol, 77 % yield) as brown solid. MS (ES): m / z = 655.2 [M+2H]+. Intermediate J1 To a degassed solution of I4e (100 mg, 0.17 mmol), bis(pinacolato)diboron (47.6 mg, 0.19 mmol) and potassium acetate (34 mg, 0.34 mmol) in dioxane (20 mL) was added [1,1- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13.9 mg, 0.02 mmol) and reaction mixture was heated at 80°C for 16h. Then it was diluted ethyl acetate (10 mL), filtered and filtrate was evaporated under reduced pressure to afford J1 (100 mg, 93% yield) as a brown solid which was taken as such to next step. MS (ES): m / z = 634.3 [M+H]+. Intermediate J1a Analogous to the preparation of J1, the reaction of I4d (300 mg, 0.5 mmol) and bis(pinacolato)diboron (150 mg, 0.6 mmol) afforded J1a (300 mg, 93 % yield) as a brown sticky liquid. MS (ES): m / z = 651.3 [M+H]+. Intermediate K1 Step-1 To a stirred solution of D1a (700 mg, 1.6 mmol) and F7b (482 mg, 1.6 mmol) in DMF (5 mL) was added DIPEA (0.85 mL, 4.9 mmol). The reaction mixture was heated at 80 °C for 1h. Then it was cooled to 0 °C, pH was adjusted to 3 using 1N HCl and diluted with ethyl acetate (150 mL). The organic layer was separated, dried over sodium sulphate, concentrated under reduced pressure and the residue obtained was purified on silica gel using 50 % ethyl acetate in hexanes as an eluent. The desired fractions were evaporated under reduced pressure to afford K1-1 (400 mg, 56 % yield) as brown semisolid. MS (ES): m / z = 688.2 [M+2H]+. Step-2 To a degassed suspension of K1-1 (80 mg, 0.13 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) pyridine (76 mg, 0.34 mmol) and potassium phosphate (72.4 mg, 0.34 mmol) in a mixture of dioxane (2 mL) and water (0.1 mL) was added Xphos PdG3 (20 mg, 0.014 mmol). The reaction mixture was heated at 80oC for 10 h. The reaction mixture was partitioned between water (10 mL) and ethyl acetate (10 mL). The organic layer was separated, dried over sodium sulphate and concentrated to afford K1 (60 mg, 73.0 % yield) which was taken to next step without further purification. MS (ES): m / z = 603.1 [M+H]+. Intermediate K1a Analogous to the preparation of K1, K1a was synthesized from F7. MS (ES): m / z = 620.3 [M+H]+. Intermediate L1 4-(4-(Dimethylamino)pyridine (6.61 mg, 0.054 mmol) was added to a solution of oxepane- 4-carboxylic acid (78 mg, 0.541 mmol), 2-hydroxyisoindoline-1,3-dione (88 mg, 0.541 mmol), and N,N'-diisopropylcarbodiimide (93 µL, 0.595 mmol) in DCM (2.75 mL). The reaction mixture was stirred at rt overnight, then diluted with DCM and concentrated onto silica gel for dry loading and purification by column chromatography using 0 to 100% ethyl acetate in DCM as eluent to afford L1 (108 mg) as a white solid. MS (ES): m / z = 289.9 [M+H]+.1H NMR (500 MHz, CDCl3): δ ppm 7.94 - 7.87 (m, 2H), 7.83 - 7.77 (m, 2H), 3.93 - 3.74 (m, 3H), 3.72 - 3.65 (m, 1H), 3.11 - 3.04 (m, 1H), 2.30 - 2.21 (m, 2H), 2.20 - 2.10 (m, 1H), 2.08 - 1.94 (m, 2H), 1.89 - 1.76 (m, 1H). The following intermediates were prepared in an analogous manner to Intermediate L1 using appropriate precursors. Inter MS (ES) Interme MS (ES) media Structure H]+Structure [M+ diate [M+H]+te O O O No O L1a N O L1b N O 275.9 O ionization OOO O O O No L1cOONNo L1dO Nionizatio ioniz O O ation O n Intermediate M1 Step-1 To a stirred solution of G12x-c (150 mg, 0.37 mmol) and C3b (110 mg, 0.37 mmol) in DMA (2 mL) at 0 °C, sodium hydride (52 mg, 1.30 mmol) was added portion wise. The reaction mixture was stirred at rt for 3 h. Then, pH was adjusted to 3 using 1.5 N aq. HCl and diluted with ethyl acetate (20 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford M1 (400 mg, 20.4%) as a yellow semisolid which was taken as such to next step. MS (ES): m / z = 583.2 [M+H]+.1H NMR (400 MHz, DMSO- d6): δ ppm 11.72 - 11.37 (m, 1H), 10.13 (br s, 1H), 8.31 (dd, J = 2.6, 4.4 Hz, 1H), 7.78 (dd, J = 2.6, 5.4 Hz, 1H), 7.05- 6.86 (m, 2H), 6.33 - 6.06 (m, 1H), 5.62 - 5.35 (m, 1H), 4.78 - 4.57 (m, 1H), 4.57 - 4.30 (m, 1H), 3.64 (dt, J = 4.5, 13.4 Hz, 1H), 3.21 - 3.08 (m, 4H), 3.07 - 2.91 (m, 1H), 2.89 - 2.75 (m, 1H), 2.65 - 2.54 (m, 2H), 2.28 - 2.14 (m, 2H), 2.04 (s, 1H), 1.30 - 1.17 (m, 3H), 0.67 (d, J = 6.8 Hz, 3H)..The following intermediates were prepared in an analogous manner to intermediate M1 using appropriate precursors. Interme MS Stru(ES) Intermedia MS diatecture Structure[M+H]+te(ES) [M+H] + N N S NNS ON NO N OH N OH M1a 597.2 M1c 582.1 O O N N O O S S O FO FClClF N N F N HN NN O HN NO N OH N M1b 565.1 M1d OH 601.2 O N O O N S O OFS ClO F Cl Intermediate N1 Step-1 To the solution of I4e (2 g, 3.41 mmol) in THF (20 mL) kept in a microwave vial, was added tert-Butyl N,N'-diisopropylcarbamimidate (3.1 mL, 13.6 mmol). The reaction mixture was irradiated at 80 °C in a microwave reactor for 1h. Reaction mixture was filtered through celite bed and the filtrate was evaporated under reduced pressure. The residue obtained was purified on silica gel using 70% ethyl acetate in hexanes. The desired fractions were evaporated under reduced pressure to afford N1-1 (2 g, 91 % yield) as brown semisolid. MS (ES): m / z = 644.4 [M+2H]+. Step-2 To the stirred solution of N1-1 (2.1 g, 3.3 mmol) in DCM (20 mL) were added di-tert-butyl dicarbonate (0.9 mL, 3.9 mmol) and TEA (0.9 mL, 6.5 mmol). The reaction mixture was stirred at RT for 2h and partitioned between water (20 mL) and DCM (100 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure and the crude obtained was purified on silical gel using 5% MeOH in DCM as an eluant to afford N1-2 (1.7 g, 70% yield) as a brown solid. MS (ES): m / z = 744.4 [M+2H]+. Step-3 To the argon purged suspension of N1-2 (1.7 g, 2.3 mmol), prop-2-yn-1-ol (0.26 g, 4.6 mmol), cesium carbonate (1.5 g, 4.6 mmol) and X-Phos (0.22 g, 0.46 mmol) in acetonitrile (10 mL) was added bis(acetonitrile)dichloropalladium(II) (0.03 g, 0.11 mmol). The reaction mixture was heated at 60oC for 3h. The reaction mixture was filtered through celite bed and the filtrate was evaporated under reduced pressure. The residue obtained was purified on silica gel using 5% MeOH in DCM. The desired fractions were evaporated under reduced pressure to afford N1-3 (1 g, 61 % yield) as yellow semisolid. MS (ES): m / z = 718.5 [M+H]+. Step-4 To the stirred solution of N1-3 (750 mg, 1.1 mmol) in DCM (8 mL) kept at 0 °C were added triethylamine (0.44 mL, 3.1 mmol) and methanesulfonyl chloride (0.12 mL, 1.6 mmol). The reaction mixture was stirred at 0 °C for 1h. The reaction mixture was partitioned between water (10 mL) and DCM (50 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to afford N1 (800 mg, 96% yield) as brown semisolid. MS (ES): m / z = 696.5 [M+H]+. Intermediate N1a Step-1 Analogous to the preparation of N1-1, the reaction of I4d (2.5 g, 4.1 mmol) and tert-Butyl N,N'-diisopropylcarbamimidate (3.3 g, 16.6 mmol) afforded N1a-1 (2.4 g, 88 % yield) as yellow solid. MS (ES): m / z = 659.2 [M+H]+. Step-2 Analogous to the preparation of N1-3, the reaction of N1a-1 (1.3 g, 2 mmol) and prop-2- yn-1-ol (442 mg, 7.9 mmol) afforded N1a-2 (750 mg, 60 % yield) as yellow semisolid. MS (ES): m / z = 635.3 [M+H]+. Step-3 Analogous to the preparation of N1, the reaction of N1a-2 (600 mg, 0.95 mmol) and methanesulfonyl chloride (0.1 mL, 1.2 mmol) afforded N1a (650 mg, 96 % yield) as brown solid. MS (ES): m / z = 713.2 [M+H]+. Intermediate O1 Step-1 Analogous to the preparation of K1-1, the reaction of D1a and F4 afforded O1-1. MS (ES): m / z = 638.4 [M+H]+. Step-2 To a degassed solution of O1-1 (300 mg, 0.47 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2- dioxaborolane (181 mg, 1.18 mmol) and tripotassium phosphate (249 mg, 1.18 mmol) in 1,4-dioxane (2.5 mL) and water (0.25 mL), was added Xphos Pd G2 (38.4 mg, 0.05 mmol). The reaction mixture was heated at 80oC for 5h. Then it was partitioned between ethylacetate (50mL) and 1.5N HCl (50 mL). The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to afford O1-2 (200 mg, 72.7 % yield). MS (ES): m / z = 586.4 [M+H]+. Crude product was taken to the next step without further purification. Step-3 To a stirred solution of O1-2 (250 mg, 0.4 mmol) in 1,4-Dioxane (2 mL) and water (1 mL), were added OsO4(109 mg, 0.4 mmol) and sodium periodate (457 mg, 2 mmol). The reaction mixture was stirred at RT for 4h. Then it was partitioned between DCM (50mL) and water (50 mL). The organic layer was dried over anhydrous Na2SO4and evaporated under reduced pressure to afford crude O1 (130 mg, 52 % yield). MS (ES): m / z = 588.3 [M+H]+. Intermediate P1 Step-1 To a degassed solution of D7-2 (500 mg, 0.9 mmol), methyl carbamate (321 mg, 4.3 mmol) and cesium carbonate (697 mg, 2.14 mmol) in Toluene (5 mL) was added XPhos Pd G2 (67.3 mg, 0.1 mmol). The reaction mixture was heated at 100 °C for 12h. The reaction mixture was partitioned between water (10 mL) and ethylacetate (50 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to afford crude P1-1 which was taken as such to next step. MS (ES): m / z = 579.3 [M+H]+. Step-2 Analogous to the preparation of D7, the reaction of P1-1 (250 mg, 0.36 mmol) and TFA afforded P1-2.TFA salt (170 mg. quant.). MS (ES): m / z = 479.5 [M+H]+. Step-3 To the stirred solution of P1-2 (200 mg, 0.418 mmol) and F7b (123 mg, 0.418 mmol) in DMSO (50 mL) was added DIPEA (0.365 mL, 2.090 mmol). The reaction mixture was stirred at RT for 16h. The reaction mixture was concentrated under reduced pressure to afford crude P1 which was taken as such to next step. MS (ES): m / z = 737.4 [M+H]+. Intermediate Q1 Step-1 To a solution of C5a-1 (200 mg, 0.48 mmol) and G12x-a (186 mg, 0.48 mmol) in DMF (2 mL) was added NaH (17. mg, 0.7 mmol). The reaction mixture was stirred at RT for 2h. Reaction mixture was partitioned between 1.5 N HCl (10 mL) and ethyl acetate (20 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to afford Q1-1 (250 mg, 76 % yield) as brown solid. MS (ES): m / z = 688.3 [M+H]+. Step-2 To a solution of Q1-1 (300 mg, 0.44 mmol), tetrabutylammonium fluoride solution in THF (1M, 0.2 mL, 0.22 mmol) in MeOH (2 mL) was added (trimethylsilyl)diazomethane solution in hexanes (2M, 2 mL, 4.36 mmol) and the reaction mixture was stirred at RT for 4h. Then it was evaporated to remove volatiles and the residue was purified on silica gel using 20% ethyl acetate in hexanes. The desired fractions were evaporated under reduced pressure to afford Q1-2 (160 mg, 52 % yield) as yellow semisolid. MS (ES): m / z = 702.1 [M+H]+.. Step-3 To a solution of Q1-2 (250 mg, 0.4 mmol) in DCM (2 mL) was added TFA (0.14 mL, 1.8 mmol). The reaction mixture was stirred at RT for 2h and evaporated under reduced pressure to afford Q1-3.TFA salt (180 mg, 84 % yield) as brown semisolid. MS: [M+H]+= 602.3 [M+H]+.. Step-4 To a solution of Q1-3 (60 mg, 0.1 mmol) in DMF (2 mL) were added HATU (57 mg, 0.15 mmol), 2-methoxyacetic acid (9 mg, 0.1 mmol) followed by DIPEA (0.03 mL, 0.15 mmol) The reaction mixture was stirred at RT for 2h. Reaction mixture was diluted with water (10 mL) and ethyl acetate (20 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to afford Q1 (60 mg, 89 % yield) as brown solid. MS (ES): m / z = 674.1 [M+H]+.. The following intermediates were prepared in an analogous manner to intermediate Q1 using appropriate precursors. Intermediate StructureMS (ES)[M+H]+NH N NNO N O Q1a O O N 701.3 N F N OMe NH N NNO N O Q1b O O N 722.1 O N S F O OMe NH N NNO N O Q1c O O N 688.2 N F O OMe Intermediate Q2 Step-1 Analogous to the preparation of Q1-1, the reaction of tert-butyl (3S,4R)-4-(5-chloro-2- fluoropyridin-3-yl)-4-fluoro-3-methylpiperidine-1-carboxylate (Prepared as per the reported procedure WO 2024 / 099908) (192 mg, 0.55 mmol) and G12x-d (180 mg, 0.55 mmol) afforded Q2-1 (300 mg, 83 % yield) as yellow solid. MS (ES): m / z = 650.4 [M- H]+. Step-2 Analogous to the preparation of Q1-3, the reaction of Q2-1 (300 mg, 0.46 mmol) and TFA afforded Q2.TFA salt (240 mg, 95 % yield) as an off-white solid. MS (ES): m / z = 552.3 [M+H]+. Intermediate Q3 Step-1 To the stirred solution of tert-butyl (3S,4R)-4-(5-chloro-2-fluoropyridin-3-yl)-4-fluoro-3- methylpiperidine-1-carboxylate (Prepared as per the reported procedure WO 2024 / 099908) (200 mg, 0.58 mmol) in 1,4-dioxane was added HCl in 1,4-dioxane (4N, 1.44 mL, 5.8 mmol) and stirred at RT for 2h. Reaction mixture was evaporated under reduced pressure to afford Q3-1. HCl salt (140 mg, 98 % yield) as an off-white solid. MS (ES): m / z = 247.1 [M+H]+.. Step-2 To the stirred solution of Q3-1 (200 mg, 0.81 mmol) and triethylamine (0.22 mL, 1.6 mmol) in DCM (2 mL) cooled at 0oC, methyl chloroformate (0.08 mL, 0.97 mmol) was added and stirred for 1h. Reaction mixture was partitioned between water (10 mL) and DCM (20 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to afford Q3-2 (200 mg, 77 % yield) as yellow gummy solid. MS (ES): m / z= 305.1 [M+H]+; Step-3 Analogous to the preparation of Q2-1, the reaction of Q3-2 (200 mg, 0.67 mmol) and G12x- d (235 mg, 0.72 mmol) afforded Q3 (250 mg, 62 % yield) as brown solid. MS (ES): m / z = 610.1 [M+H]+. EXAMPLES LC-MS conditions: Method A: Column: XBridge BEH XP C18 (50 x 2.1) mm, 2.5 μm; Mobile phase A: 10 mM NH4OAc, Acetonitrile (95:5); Mobile phase B: 10 mM NH4OAc: Acetonitrile (5:95); Gradient = 0-100% B over 3 minutes; Temperature: 50°C; Flow rate: 1.1 mL / min; Detection: UV at 220 nm. Method B: Column: XBridge BEH XP C18 (50 x 2.1) mm, 2.5 μm; Mobile phase A: 0.1% TFA in water, Acetonitrile (95:5); Mobile phase B: 0.1% TFA in water, Acetonitrile (5:95); Gradient = 0-100% B over 3 minutes; Temperature: 50°C; Flow rate: 1.1 mL / min; Detection: UV at 220 nm. Method C: Column: Kinetex XB C18 (75 x 3) mm, 2.6 μ; Mobile phase A: 5mM HCOONH4 in water (pH 3.3); Mobile phase B: Acetonitrile (100); Gradient = 20 -100% B over 4 minutes; Temperature: 50°C; Flow rate: 1.0 mL / min; Detection: UV at 300 nm. Method D: Column: AQUITY UPLC BEH C18 (3.0 x 50mm)1.7μm; Mobile phase A: 2.5 mM NH4OAc, Acetonitrile (95:5); Mobile phase B: 2.5 mM NH4OAc: Acetonitrile (5:95); Gradient = 0-100% B over 2.5 minutes; Flow rate: 0.7 mL / min; Detection: UV at 220 nm. Method E: Column: XBridge C18, 2.1 x 50 mm, 1.7 μm particles; Mobile Phase A: 10 mM NH4OAc in water / ACN 95:5, Mobile Phase B: 10 mM NH4OAc in water / ACN 5:95; Flow rate: 1.0 mL / min; Gradient: 0% B to 100% B in 3 min, hold at 100% B for 0.5 min; Column Temperature: 50 °C; Detection: UV at 220 nm. Method F: Column: XBridge C18, 2.1 x 50 mm, 1.7 μm particles; Mobile Phase A: 0.05% TFA in water / ACN 95:5, Mobile Phase B: 0.05% TFA in water / ACN 5:95; Flow rate: 1.0 mL / min; Gradient: 0% B to 100% B in 3 min, hold at 100% B for 0.5 min; Column Temperature: 50 °C; Detection: UV at 200 nm. Method G: Column: AQUITY UHPLC BEH C18 (2.1 x 50mm)1.7μm; Mobile phase A: 10 mM NH4OAc in Acetonitrile:Water (5:95); Mobile phase B: 10 mM NH4OAc in Acetonitrile:water (95:5); Gradient = 0-100% B over 3.0 minutes; Flow rate: 1.0 mL / min; Detection: UV at 220 nm and 254 nm. Method H: Kinetex XB – C18 (75 x 3.0) mm, 2.6 μm; Mobile phase A: 5 mm ammonium formate in water (pH 3.3): acetonitrile (98:02); mobile phase B: acetonitrile: buffer (98:02); flow rate 1.0 mL / min; Gradient: 20% of B to 100% of B over 4 min, then a hold at 100% of B for 0.6 min, flow rate increase to 1.5 mL / min. then 100 % to 20% of B over 0.1 min and flow rate decrease to 1.0 mL / min, then 0.3 min hold at 20% of B. Detection by MS and UV. Method I: Kinetex XB- C18 (75 x 3) mm, 2.6 µm; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Flow rate 1.0 mL / min; gradient 5% of B to 95% of B over 2.5 min, then 2.0 min hold at 95% of B, then 95% to 5% of B over 0.01 min, then 0.99 min hold at 5% of B. Detection by MS and UV. Prep-HPLC conditions: Method P1: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile Phase A: 0.05% TFA in water / ACN 95:5, Mobile Phase B: 0.05% TFA in water / ACN 5:95; Flow rate 20 mL / min; Column Temperature: 25 °C; [Gradient]; Detection: MS (ESI+). Method Gradient Method P1a 35% B to 75% B in 20 min, 75% B to 100% B in 0.1 min, hold at 100% B for 3.9 min Method P1b 13% B to 53% B in 20 min, 53% B to 100% B in 0.1 min, hold at 100% B for 3.9 min Method P1c 29% B to 69% B in 20 min, 69% B to 100% B in 0.1 min, hold at 100% B for 3.9 min Method P2: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile Phase A: 10 mM NH4OAc in water / ACN 95:5, Mobile Phase B: 10 mM NH4OAc in water / ACN 5:95; Flow rate 20 mL / min; Column Temperature: 25 °C; [Gradient]; Detection: MS (ESI+). Method Gradient Method P2a 22% B to 62% B in 20 min, 62% B to 100% B in 0.1 min, hold at 100% B for 3.9 min Method P2b 24% B to 54% B in 20 min, 54% B to 100% B in 0.1 min, hold at 100% B for 3.9 min Method P2c 25% B to 65% B in 20 min, 65% B to 100% B in 0.1 min, hold at 100% B for 3.9 min Method P3: Column: XBridge C18, 19 x 150 mm, 5 μm particles; Mobile Phase A: 10 mM NH4OAc in water / ACN 95:5, Mobile Phase B: 10 mM NH4OAc in water / ACN 5:95; Flow rate 20 mL / min; Column Temperature: 25 °C; [Gradient]; Detection: MS (ESI+). Method Gradient Method P3a 15% B to 82% B in 15 min, 82% B to 100% B in 1 min, hold at 100% B for 3.9 min Method P3b 21% B to 75% B in 18 min, 75% B to 100% B in 1 min, hold at 100% B for 3.9 min Example 1: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8- yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(6-ethoxypyridin-2-yl)pyrimidin-4- yl)pyrrolidine-2-carboxylic acid To a stirred solution of Intermediate G1 (200 mg, 0.526 mmol) and Intermediate B1 (189 mg, 0.63 mmol) in DMA (2 mL) at 0 °C, sodium hydride (105 mg, 2.63 mmol) was added portion wise. The reaction mixture was stirred at RT for 3 h. Then, it was quenched with 1.5 N aq. HCl until the pH reached to 3 and diluted with ethyl acetate (20 mL). The organic layer was separated, dried over sodium sulphate, and concentrated to afford the crude residue which was purified by Prep-HPLC (Method P3) to afford Example 1 (250 mg) as a brown semisolid. LC-MS (Method D): RT = 1.45 min, [M+H]+= 633.1. Using similar procedures as that described for Example 1, the following Examples were synthesized from appropriate precursors, either prepared internally or obtained from commercial source.1H NMR spectral data and, where relevant, preparative conditions used to separate diastereomeric mixtures (resultant individual isomers are designated as Iso-1 & Iso-2) are provided below the table. LC-MS Example Structure Precursors Method LC-MS T (min) (+R M+H) S NCHF2N O Example N OH 1-1 G6 & B1A: 1.55B:594 O2.10N ONO Cl F NCHF2FONN O Example N OH 1-2 G1a & B1A: 1.77B: 2.655.2 O33N O N O Cl FN CHF2NN F O Example N OH 1-3 G1b & B1A: 1.69B: 2639.1 O.25N O N O Cl MeO NCHF2MeONN Example O N 1-4 OHG1c & B1 A: 1.78B: 2.32649.2O N O N O Cl N NCHF2MeO N N O Example N 1-5 OH G1d & B1A: 1.56B: 2620.2 O.11N O N O Cl N NCHF2MeONN O Example N OH 1-6 G4 & B1A: 1.51B: 2.0620.2 O5N O N O Cl N NCHF2EtONN O Example N OH 1-7 G4a & B1A: 1.59B 634.2 O: 2.16N ONO Cl NCHF2MeONN O Example N OH 1-8 G2 & B1A: 1.88B: 2633.2 O.49N O N O Cl NCHF2EtONN O Example N OH 1-9G2a & B1 A: 2.04B: 2.647.2O67N O N O Cl F NCHF2MeONN O Example N 1-10 OH G1e & B1A: 1.78B:637.2 O2.37N O N O Cl F NCHF2EtONN O Example N 1-11 OH G1f & B1A: 1.90651.2 OB: 2.51N O N O Cl NCHF2FONN F O Example N OH 1-12 G1g & B1A: 1.90669.2 OB: 2.43N O N O Cl FN CHF2FONN F O Example N OH 1-13G1h & B1 A: 2.08B:687.2O2.59N O N O Cl F F N N O S OH Example N 1-14 G6 & B4 C: 3.01 598.1 F O F N N Cl (Mixture of diastereomers) F F N N O Example S OH N 1-15 G6 & B1a C: 2.99 578.1 (Iso-1) O N N O Cl F F N N O Example S OH N 1-16 G6 & B1a C: 2.97 578.1 (Iso-2) O N N O Cl CHF N2S N O Example N OH 1-17 G6 & B1bA: 1.96B: 2.586.1 O58N F N F Cl F F S N N O Example 1-18 N OH (Iso-1) G6 & B1cA: 1.76B: 1.91580.1 ONN H3CO Cl F F S N N O Example 1-19 N OHA: 1.7(Iso-2)G6 & B1c 5B: 1.91580.1ONN H3COCl F F S N N O Example 1-20 N OH (Iso-1) G6 & B1dA: 1.93B: 2.23616.1 ONN F2HCO Cl F F S N N O Example 1-21 N OHA: 1.9(Iso-2) G6 & B1d3B: 2.21616.1 ONN F2HCO Cl F F S N N O OH Example N 1-22 G6 & B2A: 1.67B: 2.1624.1 O4N ONF F O S NCHF2N O Example N OH 1-23G6 & B1q A: 1.66B: 2.640.0O18N ONO Br S NCHF2N O Example N OH 1-24 G6a & B1A: 1.76B: 2.608.2 O38N O N O Cl S ON CHF2N O Example N OH 1-25 G7 & B1A: 1.77624.1 OB: 2.32N O N O Cl Cl S NCHF2N O Example N 1-26 OH G12 & B1 C: 2.91 628.1 O N ONO Cl S NCHF2N O Example N 1-27 OHG6b & B1 A: 1.74B: 2.608.1O31N O N O Cl S NCHF2N O Example N OH 1-28 G10 & B1A: 1.97622.2 OB: 2.56N O N O Cl S NCHF2N O Example N OH 1-29G8 & B1 A: 2.00B: 2.5634.2O9N ONO Cl S NCHF2N O Example N OH 1-30 G9 & B1A: 2.08B:670.2 O2.65N ONO Cl S NCHF2N O Example N OH 1-31 G6a & B1qA: 1.77B:654.2 O2.30N O N O Br S NCHF2N N O Example N OH 1-32 G11 & B1A: 1.54B: 2595.1 O.06N O N O Cl S NCHF2N N O Example N OH 1-33 G1k & B1A: 1.66609.1 OB: 2.21N O N O Cl S NN CHF2N O Example N OH 1-34 G7a & B1A: 1.53B: 2.595.1 O05N O N O Cl S NN CHF2N O Example N OH 1-35 G7b & B1A: 1.51609.1 OB: 1.96N O N O Cl NSN CHF2N O Example N OH 1-36 G7c & B1A: 1.63B: 2595.1 O.18N O N O Cl S NCHF2N O Example N OH 1-37 G6 & B1i C: 3.13 572.05 O N N F F Cl S NCHF2N O Example N 1-38 OHG6 & B1jA: 1.87572.1OB: 2.50F N N F Cl S NCHF2N O Example N 1-39 OHG6 & B1lA: 1.72B: 2. 544.1O36F N N F Cl S NCHF2N O Example N 1-40 OH G6 & B1mA: 1.94B 536.1 O: 2.40N N Cl S NCHF2N O Example N 1-41 OH G6 & B1nA: 1.82522.1 OB: 2.46N N (R) Cl S NCHF2N O Example N 1-42 OH G6 & B1oA: 1.80B: 2.4522.1 O4N N (S) Cl S NCHF2N O Example N 1-43 OH G6 & B1pA: 2.10B:548.1 O2.64N N Cl S NCHF2N O Example N 1-44 OH G6 & A5A: 1.82B:580.2 Iso-1 O2.25N N MeO Cl S NCHF2N O Example N 1-45 OH G6 & A5A: 1.82B: 2.2580.2 Iso-2 O5N N MeO Cl S NCHF2N O Example N 1-46 OH G6 & A6A: 2.18-1B586.1 Iso O: 2.75N N F F Cl S NCHF2N O Example N 1-47 OH G6 & A6 A: 2.17Iso-2B:586.1O2.75N N F F Cl S NCHF2N O Example N 1-48 OHG6a & A6A: 2.26B: 2. 600.1Iso-1 O85N N F F Cl S NCHF2N O Example N 1-49 OH G6a & A6A: 2.26600.1 Iso-2 OB: 2.83N N F F Cl S NCHF2N O Example N OH 1-50 G6 & B3A: 1.64B: 2.636.2 Iso-1 O09N O N O F F S NCHF2N O Example N OH 1-51 G6 & B3A: 1.64so-2B: 2636.2 I O.09N O N O F F S NCHF2N O Example N OH 1-52 G6 & B5A: 1.70B: 2588.1 O.26N O N (R) F Cl F S NCHF2N O Example N OH 1-53 G6 & B5aA: 1.69B: 2.27588.1 O N O N (S) F Cl F S N O N O Example N OH 1-54 G12v & B1A: 1.78B: 1.574.1 O95N O N O ClS FN F N O Example N OH 1-55 G6 & B6A: 1.58B 610.2 O: 2.04N O N O F F N CF3ONN O Example N OH 1-56 G5 & B1A: 2.0B:651.2 O2.6N O N O Cl F F N N ONN Example O N 1-57 OH G17 & B1A: 2.17B: 2.05674.2 O N O N O Cl O N ONN O Example N 1-58 OH G18 & B1A: 1.92B: 2.0651.2 O5N O N O Cl NNO Example N OH 1-59G19 & B1 A: 1.73B: 1.8552.2O7N O N OCl N NNO Example N OH 1-60 G19a & B1A: 1.37553.2 OB: 1.45N O N OClS NNO Example N OH 1-61 G19b & B1A: 1.90B: 1.89558.1 O N O N OClSF FF N O N Example OH 1-62G21 & B1E: 2.01F611.1O: 2.46N ONO Cl NHF FF N O N Example OH 1-63 G22 & B1E: 1.91594.2 OF: 2.39N O N O Cl Example 1-1: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(thiophen-2- yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-2: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(6-(6-(difluoromethoxy)pyridin-2-yl)-2- (difluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-3: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(6- (difluoromethyl)pyridin-2-yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-4: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(4,6- dimethoxypyridin-2-yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-5: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(6-methoxypyrazin-2- yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-6: (2S,4S)-4-((5-chloro-3-(( )-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-2'-methoxy-[4,4'- bipyrimidin]-6-yl)pyrrolidine-2-carboxylic acid Example 1-7: 2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-2'-ethoxy-[4,4'- bipyrimidin]-6-yl)pyrrolidine-2-carboxylic acid Example 1-8: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(6-methoxy-5- methylpyridin-2-yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-9: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(6-ethoxy-5- methylpyridin-2-yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-10: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(5-fluoro-6- methoxypyridin-2-yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-11: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(6-ethoxy-5- fluoropyridin-2-yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-12: (2S,4S)-4-((5-chloro-3-(( S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(6-(6-(2,2-difluoroethoxy)pyridin-2-yl)-2- (difluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-13: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(6-(2,2,2- trifluoroethoxy)pyridin-2-yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-14: (2S,4S)-4-((5-chloro-3-((4S)-7,7-difluoro-4-methyl-3- azabicyclo[4.1.0]heptan-3-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(thiophen-2- yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-15: (Iso-1) (2S,4S)-4-((5-chloro-3-(5-methyl-2-oxa-6- azaspiro[3.4]octan-6-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(thiophen-2- yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-16: (Iso-2) (2S,4S)-4-((5-chloro-3-(5-methyl-2-oxa-6- azaspiro[3.4]octan-6-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(thiophen-2- yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-17: (2S,4S)-4-((5-chloro-3-((S)-4,4-difluoro-2-methylpiperidin-1- yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(thiophen-2-yl)pyrimidin-4-yl)pyrrolidine- 2-carboxylic acid Example 1-18: (Iso-1) (2S,4S)-4-((5-chloro-3-((2S)-4-methoxy-2-methylpiperidin- 1-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(thiophen-2-yl)pyrimidin-4- yl)pyrrolidine-2-carboxylic acid Example 1-19: (Iso-2) (2S,4S)-4-((5-chloro-3-((2S)-4-methoxy-2-methylpiperidin- 1-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(thiophen-2-yl)pyrimidin-4- yl)pyrrolidine-2-carboxylic acid Example 1-20: (Iso-1) (2S,4S)-4-((5-chloro-3-((2S)-4-(difluoromethoxy)-2- methylpiperidin-1-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(thiophen-2- yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-21: (Iso-2) (2S,4S)-4-((5-chloro-3-((2S)-4-(difluoromethoxy)-2- methylpiperidin-1-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(thiophen-2- yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-22: (2S,4S)-4-((5-(1,1-difluoroethyl)-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(thiophen-2- yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-23: (2S,4S)-4-((5-bromo-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(thiophen-2- yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-24: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(4-methylthiophen-2- yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-25: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(4-methoxythiophen- 2-yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-26: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(6-(5-chlorothiophen-2-yl)-2- (difluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-27: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(5-methylthiophen-2- yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-28: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(4-ethylthiophen-2- yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-29: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(6-(4-cyclopropylthiophen-2-yl)-2- (difluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-30: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(4-phenylthiophen-2- yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-31: (2S,4S)-4-((5-bromo-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(4-methylthiophen-2- yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-32: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(thiazol-2- yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-33: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(4-methylthiazol-2- yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-34: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(thiazol-5- yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-35: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(4-methylthiazol-5- yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-36: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(isothiazol-5- yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-37: (2S,4S)-4-((5-chloro-3-(3,3-difluoropiperidin-1-yl)pyridin-2- yl)oxy)-1-(2-(difluoromethyl)-6-(thiophen-2-yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-38: (2S,4S)-4-((5-chloro-3-(4,4-difluoropiperidin-1-yl)pyridin-2- yl)oxy)-1-(2-(difluoromethyl)-6-(thiophen-2-yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-39: (2S,4S)-4-((5-chloro-3-(3,3-difluoroazetidin-1-yl)pyridin-2- yl)oxy)-1-(2-(difluoromethyl)-6-(thiophen-2-yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-40: (2S,4S)-4-((5-chloro-3-((S)-2-methylpyrrolidin-1-yl)pyridin-2- yl)oxy)-1-(2-(difluoromethyl)-6-(thiophen-2-yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-41: (2S,4S)-4-((5-chloro-3-((R)-2-methylazetidin-1-yl)pyridin-2- yl)oxy)-1-(2-(difluoromethyl)-6-(thiophen-2-yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-42: (2S,4S)-4-((5-chloro-3-((S)-2-methylazetidin-1-yl)pyridin-2- yl)oxy)-1-(2-(difluoromethyl)-6-(thiophen-2-yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-43: (2S,4S)-4-((5-chloro-3-(5-azaspiro[2.4]heptan-5-yl)184yridine-2- yl)oxy)-1-(2-(difluoromethyl)-6-(thiophen-2-yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-44: (Iso-1) (2S,4S)-4-((5-chloro-3-(3-methoxy-2-methylpiperidin-1- yl)184yridine-2-yl)oxy)-1-(2-(difluoromethyl)-6-(thiophen-2-yl)pyrimidin-4- yl)pyrrolidine-2-carboxylic acid Example 1-45: (Iso-2) (2S,4S)-4-((5-chloro-3-(3-methoxy-2-methylpiperidin-1- yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(thiophen-2-yl)pyrimidin-4-yl)pyrrolidine- 2-carboxylic acid Example 1-46: (Iso-1) (2S,4S)-4-((5-chloro-3-(3,3-difluoro-2-methylpiperidin-1- yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(thiophen-2-yl)pyrimidin-4-yl)pyrrolidine- 2-carboxylic acid Example 1-47: (Iso-2) (2S,4S)-4-((5-chloro-3-(3,3-difluoro-2-methylpiperidin-1- yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(thiophen-2-yl)pyrimidin-4-yl)pyrrolidine- 2-carboxylic acid Example 1-48: (Iso-1) (2S,4S)-4-((5-chloro-3-(3,3-difluoro-2-methylpiperidin-1- yl)184yridine-2-yl)oxy)-1-(2-(difluoromethyl)-6-(4-methylthiophen-2-yl)pyrimidin-4- yl)pyrrolidine-2-carboxylic acid Example 1-49: (Iso-2) (2S,4S)-4-((5-chloro-3-(3,3-difluoro-2-methylpiperidin-1- yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(4-methylthiophen-2-yl)pyrimidin-4- yl)pyrrolidine-2-carboxylic acid Example 1-50: (Iso-1) (2S,4S)-4-((5-(2,2-difluorocyclopropyl)-3-((S)-9-methyl- 2,5-dioxa-8-azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6- (thiophen-2-yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-51: (Iso-2) (2S,4S)-4-((5-(2,2-difluorocyclopropyl)-3-((S)-9-methyl- 2,5-dioxa-8-azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6- (thiophen-2-yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-52: (2S,4S)-4-((5-chloro-3-((R)-2- (difluoromethyl)morpholino)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(thiophen-2- yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-53: (2S,4S)-4-((5-chloro-3-((S)-2-(difluoromethyl)morpholino)pyridin- 2-yl)oxy)-1-(2-(difluoromethyl)-6-(thiophen-2-yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-54: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-methoxy-6-(thiophen-2-yl)pyrimidin-4- yl)pyrrolidine-2-carboxylic acid Example 1-55: (2S,4S)-4-((5-(difluoromethyl)-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(thiophen-2- yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-56: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(6-(6-ethoxypyridin-2-yl)-2- (trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-57: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(3,3-difluoroazetidin-1-yl)-6-(6- ethoxypyridin-2-yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-58: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(2,5-dihydrofuran-3-yl)-6-(6- ethoxypyridin-2-yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-59: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(4-methyl-6-phenylpyrimidin-2- yl)pyrrolidine-2-carboxylic acid Example 1-60: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(4-methyl-6-(pyridin-3-yl)pyrimidin-2- yl)pyrrolidine-2-carboxylic acid Example 1-61: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(4-methyl-6-(thiophen-2-yl)pyrimidin-2- yl)pyrrolidine-2-carboxylic acid Example 1-62: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(6-(thiophen-2-yl)-4- (trifluoromethyl)pyridin-2-yl)pyrrolidine-2-carboxylic acid Example 1-63: (2S,4S)-1-(6-(1H-pyrrol-2-yl)-4-(trifluoromethyl)pyridin-2-yl)-4- ((5-chloro-3-((S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl)pyridin-2- yl)oxy)pyrrolidine-2-carboxylic acid Example 1-1:1H NMR (400 MHz, CD3OD): δ ppm 7.91 (br d, J = 3.0 Hz, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.61 (dd, J = 1.0, 5.0 Hz, 1H), 7.21 - 7.17 (m, 2H), 6.95 (br s, 1H), 6.58 - 6.31 (t, J = 56 Hz, 1H), 5.67 (br s, 1H), 4.86 - 4.83 (m, 1H), 4.73 (d, J = 6.5 Hz, 1H), 4.56 (d, J = 7.0 Hz, 1H), 4.40 - 4.38 (m, 1H), 4.31 (d, J = 7.0 Hz, 1H), 4.29 - 4.19 (m, 1H), 3.99 - 3.96 (m, 1H), 3.86 - 3.73 (m, 2H), 3.36-3.37 (m, 2H), 2.94-2.90 (m, 1H), 2.80 - 2.64 (m, 2H), 0.90 (d, J = 8.0 Hz, 3H). Example 1-15, (Iso-1) & Example 1-16, (Iso-2): Preparative SFC Condition: Column / dimensions: Chiralcel OJ-H (250 X 30) mm, 5u: %CO2: 60%: %Co solvent: 40% of 0.2% Methanolic ammonia in methanol; Total Flow: 160 g / min; Back Pressure:100 bar; Temperature: 40 °C; UV: 254 nm). First elute (Iso-1; RT = 2.30 min; >99%). Second elute (Iso-2; RT = 3.40 min; 98.7%). Example 1-20, & Example 1-21, (Iso-2): Preparative SFC Condition: Column / dimensions: Chiralcel OJ-H (250 X 30) mm, 5u: %CO2: 70%: %Co solvent: 30% of 0.2% Methanolic ammonia in methanol; Total Flow: 160 g / min; Back Pressure:100 bar; Temperature: 40 °C; UV: 254 nm). First elute (Iso-1; RT = 2.65 min; 98.6%). Second elute (Iso-2; RT = 3.02 min; 97.3%). Example 1-24,:1H NMR (400 MHz, DMSO-d6): δ ppm 7.94 - 7.75 (m, 2H), 7.34 (s, 1H), 7.23 – 6.97 (m, 2H), 6.75 - 6.48 (m, 1H), 5.59 - 5.41 (m, 1H), 4.81-4.57 (m, 2H), 4.47 - 4.37 (m, 1H), 4.34 - 4.12 (m, 3H), 3.78 - 3.70 (m, 2H), 3.62 - 3.59 (m, 1H), 3.24 - 3.09 (m, 2H), 2.90 - 2.84 (m, 1H), 2.74 - 2.64 (m, 2H), 2.26 (s, 3H), 0.77 (br s, 3H). Example 1-45, (Iso-1) & Example 1-46, (Iso-2): Preparative SFC Conditions: Column / dimensions: Chiralcel OJ-H (250 X 30) mm, 5u: %CO2: 80%: %Co solvent: 20% of 0.7% Methanolic ammonia in methanol; Total Flow: 130 g / min; Back Pressure:100 bar; Temperature: 40 °C; UV: 220 nm). First elute (Iso-1; RT = 6.37 min; >99%). Second elute (Iso-2; RT = 7.55 min; >99%). No stereochemical determination was done for either isolate. Example 1-47, (Iso-1) & Example 1-48, (Iso-2): Preparative SFC Condition: Column / dimensions: Chiralcel OJ-H (250 X 30) mm, 5u: %CO2: 80%: %Co solvent: 20% of 0.2% Methanolic ammonia in methanol; Total Flow: 160 g / min; Back Pressure:100 bar; Temperature: 40 °C; UV: 254 nm). First elute (Iso-1; RT = 4.64 min; >99%). Second elute (Iso-2; RT = 6.13 min, Purity: 83.8%). Example 1-49, (Iso-1) & Example 1-50, (Iso-2). Preparative SFC Condition: Column / dimensions: Chiralpak IG (250 X 30) mm,5u: %CO2: 80%; %Co solvent: 20% of 0.2% Methanolic ammonia in methanol; Total Flow:160 g / min; Back Pressure: 100 bar; Temperature: 40 °C; UV: 254 nm). First elute (Iso-1; RT = 11.26 min, purity = 98.5%). Second elute (Iso-2; RT = 11.73 min, purity = 90.5%). Example 1-52, (Iso-1) & Example 1-53, (Iso-2): Preparative SFC Condition: Column / dimensions: Lux i-Amylose-3 (250 x 50) mm, 5u: %CO2: 85%; %Co solvent: 35% of 0.2% ammonia in methanol; Total Flow: 200 g / min; Back Pressure: 100 bar; Temperature: 35 °C; UV: 254 nm). First elute (Iso-1; RT = 9.3 min). Second elute (Iso-2; RT = 10.4 min). Example 1-64: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8- yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(furan-2-yl)pyrimidin-4-yl)pyrrolidine-2- carboxylic acid To a stirred solution of Intermediate G12a (10 mg, 0.031 mmol) in DMF (0.5 mL) at 0 °C, sodium hydride (60% dispersion in mineral oil, 7.4 mg, 0.31 mmol) was added. The reaction mixture was stirred at rt for 15 min, followed by addition of Intermediate B1 (9.2 mg, 0.031 mmol). The reaction mixture was heated to 60 °C and stirred for 2 h, then cooled to rt and quenched with methanol (0.5 mL). The reaction mixture was filtered through a 0.45 µm syringe filter and purified by Prep-HPLC (Method P1). Fractions containing the desired product were combined and evaporated to afford Example 1-64 (6.9 mg). LC-MS (Method E): RT = 1.56 min, [M+H]+= 578.1. Using similar procedure as that described for Example 1-64, the following Examples were synthesized from appropriate precursors, either prepared internally or acquired from commercial source. Select1H NMR spectral data is provided below the table. LC-MS Example StructurePrecurMetho LC-MS sorsd:+RT (min) (M+H) O N N F O Example N OH G12b 1-65& B1E: 1.61 560.2O O N N O Cl O NNN O Example N OH G12c 1-66&E: 1.75 570.9OB1O N N O Cl O F F N F N O Example N OH G12d 1-67E: 1.76 596.1O& B1O N N O Cl O N N O Example N OH G12e 1-68E: 1.41 528.1O& B1O N N O Cl NH N N F O Example N OH G12f 1-69E: 1.62 559.2O& B1O N N O Cl NH NON O Example N OH G12g 1-70E: 1.53 557.1O& B1O N N O Cl NH N N O Example N OH G12h 1-71& BE: 1.44 541.2O1O N N O Cl NH F F N F N O Example N OH G12i 1-72E: 1.77 595.2O& B1O N N O Cl NH N N O Example N OH G12j 1-73& BE: 1.43 527.1O1O N N O Cl F F N NNN F Example O N G12k 1-74 OH& B1E: 1.56 610.0O O N N O Cl NH F N F N O Example N OH G12l 1-75& B1E: 1.68 577.0O O N N O Cl N F N F N O Example N 1-76 OH G12m &E: 1.71 591.2OB1O N N O Cl NH F N F N O Example N G12n 1-77 OH& B1E: 1.76 591.3O O N N O Cl F ONN F N O Example N OH G12o 1-78& BE: 1.77 619.0O1O N N O Cl F N N F O N O Example N OH G12p 1-79E: 1.64 619.1O& B1O N N O Cl F N N F N O Example N OH G12q 1-80E: 1.59 603.2O& B1O N N O Cl NNHF N F N O Example N OH G12r 1-81E: 1.55 592.1O& B1O N N O Cl F ONF N O Example N OH G12s 1-82E: 1.59 577.9O& B1O N N O Cl F N O N F N O Example N OH G12t 1-83& BE: 2.04 647.0O1O N N O Cl F N O N F N O Example N OH G12u 1-84E: 1.89 645.2O& B1O N N O Cl Cl NH F N F N O Example N G13 1-85 OH& B1E: 1.76 611.0O O N N O Cl N F N N F N O Example N OH G14 1-86E: 1.60 577.9O& B1O N N O Cl F N N F N O Example N OH G20 1-87E: 1.60 589.3O& B1O N N O Cl Example 1-65: (2S,4S)-4-({5-chloro-3-[(9S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[5-fluoro-6-(furan-3-yl)-2-methylpyrimidin- 4-yl]pyrrolidine-2-carboxylic acid Example 1-66: (2S,4S)-4-({5-chloro-3-[(9S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[2-(dimethylamino)-6-(furan-2- yl)pyrimidin-4-yl]pyrrolidine-2-carboxylic acid Example 1-67: (2S,4S)-4-({5-chloro-3-[(9S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[6-(furan-2-yl)-2- (trifluoromethyl)pyrimidin-4-yl]pyrrolidine-2-carboxylic acid Example 1-68: (2S,4S)-4-({5-chloro-3-[(9S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[6-(furan-2-yl)pyrimidin-4-yl]pyrrolidine-2- carboxylic acid Example 1-69: (2S,4S)-4-({5-chloro-3-[(9S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[5-fluoro-2-methyl-6-(1H-pyrrol-2- yl)pyrimidin-4-yl]pyrrolidine-2-carboxylic acid Example 1-70: (2S,4S)-4-({5-chloro-3-[(9S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[2-methoxy-6-(1H-pyrrol-2-yl)pyrimidin-4- yl]pyrrolidine-2-carboxylic acid Example 1-71: (2S,4S)-4-({5-chloro-3-[(9S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[2-methyl-6-(1H-pyrrol-2-yl)pyrimidin-4- yl]pyrrolidine-2-carboxylic acid Example 1-72: (2S,4S)-4-({5-chloro-3-[(9S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[6-(1H-pyrrol-2-yl)-2- (trifluoromethyl)pyrimidin-4-yl]pyrrolidine-2-carboxylic acid Example 1-73: (2S,4S)-4-({5-chloro-3-[(9S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[6-(1H-pyrrol-2-yl)pyrimidin-4- yl]pyrrolidine-2-carboxylic acid Example 1-74: (2S,4S)-4-({5-chloro-3-[(9S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-{6-[1-(difluoromethyl)-1H-pyrazol-4-yl]-5- fluoro-2-methylpyrimidin-4-yl}pyrrolidine-2-carboxylic acid Example 1-75: (2S,4S)-4-({5-chloro-3-[(9S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[2-(difluoromethyl)-6-(1H-pyrrol-2- yl)pyrimidin-4-yl]pyrrolidine-2-carboxylic acid Example 1-76: (2S,4S)-4-({5-chloro-3-[(9S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[2-(difluoromethyl)-6-(1-methyl-1H-pyrrol- 2-yl)pyrimidin-4-yl]pyrrolidine-2-carboxylic acid Example 1-77: (2S,4S)-4-({5-chloro-3-[(9S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[2-(difluoromethyl)-6-(5-methyl-1H-pyrrol- 2-yl)pyrimidin-4-yl]pyrrolidine-2-carboxylic acid Example 1-78: (2S,4S)-4-({5-chloro-3-[(9S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[2-(difluoromethyl)-6-(6-methoxypyridin-2- yl)pyrimidin-4-yl]pyrrolidine-2-carboxylic acid Example 1-79: (2S,4S)-4-({5-chloro-3-[(9S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[2-(difluoromethyl)-6-(2-methoxypyridin-3- yl)pyrimidin-4-yl]pyrrolidine-2-carboxylic acid Example 1-80: (2S,4S)-4-({5-chloro-3-[(9S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[2-(difluoromethyl)-6-(5-methylpyridin-2- yl)pyrimidin-4-yl]pyrrolidine-2-carboxylic acid Example 1-81: (2S,4S)-4-({5-chloro-3-[(9S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[2-(difluoromethyl)-6-(4-methyl-1H- pyrazol-5-yl)pyrimidin-4-yl]pyrrolidine-2-carboxylic acid Example 1-82: (2S,4S)-4-({5-chloro-3-[(9S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[2-(difluoromethyl)-6-(furan-3- yl)pyrimidin-4-yl]pyrrolidine-2-carboxylic acid Example 1-83: (2S,4S)-4-({5-chloro-3-[(9S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[2-(difluoromethyl)-6-[6-(propan-2- yloxy)pyridin-2-yl]pyrimidin-4-yl]pyrrolidine-2-carboxylic acid Example 1-84: (2S,4S)-4-({5-chloro-3-[(9S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[6-(6-cyclopropoxypyridin-2-yl)-2- (difluoromethyl)pyrimidin-4-yl]pyrrolidine-2-carboxylic acid Example 1-85: (2S,4S)-1-[6-(5-chloro-1H-pyrrol-2-yl)-2- (difluoromethyl)pyrimidin-4-yl]-4-({5-chloro-3-[(9S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)pyrrolidine-2-carboxylic acid Example 1-86: (2S,4S)-4-({5-chloro-3-[(9S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[2-(difluoromethyl)-6-(1H-pyrazol-1- yl)pyrimidin-4-yl]pyrrolidine-2-carboxylic acid Example 1-87: (2S,4S)-4-({5-chloro-3-[(9S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[2-(difluoromethyl)-6-(pyridin-2- yl)pyrimidin-4-yl]pyrrolidine-2-carboxylic acid Example 1-75:1H NMR (500 MHz, DMSO-d6): δ ppm 11.57 - 11.50 (br s, 1H), 7.81 - 7.76 (m, 1H), 7.24 - 7.18 (m, 1H), 7.00 - 6.84 (m, 3H), 6.70 - 6.39 (m, 1H), 6.19 - 6.11 (m, 1H), 5.65 - 5.38 (m, 1H), 4.82 - 4.73 (m, 1H), 4.59 - 4.50 (m, 2H), 4.39 - 4.33 (m, 1H), 4.17 - 4.03 (m, 2H), 3.77 - 3.63 (m, 2H), 3.61 - 3.51 (m, 1H), 2.90 - 2.77 (m, 1H), 2.69 - 2.60 (m, 1H), 2.49 - 2.43 (m, 3H), 0.80 - 0.74 (m, 3H). Example 1-88: (2S,4S)-4-((5-chloro-3-(hexahydro-4H-furo[3,2-b]pyrrol-4-yl)pyridin-2- yl)oxy)-1-(2-(difluoromethyl)-6-(1H-pyrrol-2-yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid A mixture of G12w (31.3 mg, 0.074 mmol) and B1s (22.1 mg, 0.074 mmol) in DMSO (738 µL) was treated with potassium tert-butoxide (20.7 mg, 0.184 mmol). The resulting mixture was stirred at rt for 3 h, then quenched by the addition of acetic acid (29.6 µL, 0.516 mmol). The reaction mixture was diluted to 2 mL total volume by the addition of DMSO and filtered. The filtrate was purified via prep-HPLC (Method P2). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 1-88 (14.3 mg).1H NMR (500 MHz, DMSO-d6): δ ppm 11.62 - 11.48 (m, 1H), 7.58 (br d, J=2.1 Hz, 1H), 7.07 - 6.79 (m, 4H), 6.76 - 6.43 (m, 1H), 6.24 - 6.12 (m, 1H), 5.75 - 5.46 (m, 1H), 4.92 - 4.66 (m, 2H), 4.55 - 4.39 (m, 1H), 4.29 - 3.89 (m, 1H), 3.77 - 3.42 (m, 1H), 3.32 - 3.10 (m, 2H), 2.87 - 2.67 (m, 1H), 2.45 - 2.29 (m, 1H), 2.02 - 1.80 (m, 4H), 1.58 - 1.37 (m, 1H), 2 protons presumed suppressed along with water. LC-MS (Method E): RT = 1.66 min, [M+H]+= 547.0. Using similar procedure as that described for Example 1-88, the following Examples were synthesized from appropriate precursors, either prepared internally or acquired from commercial source. LC-MS Example StructurePrecurM LC-MS sorsethod: (+RT (min) M+H) S F N F O Example N OH G23a 1-89E: 1.71 593.2O& B1O N N O Cl S F F N O Example N OH G23b 1-90E: 1.83 593.2O& B1O N N O Cl NH F F N O Example N OH G23c 1-91E: 1.71 576.2O& B1O N N O Cl NH F F N O Example N OH G23d 1-92E: 1.86 575.9O& B1N O N O Cl S F F N O Example N OH G23e 1-93E: 1.92 593.1O& B1N O N O Cl F N N F H N O Example N G12l OH 1-94 & E: 1.66 621.0 O B1q O N NO BrF F N O N OH Example N G12a O 1-95 & E: 1.67 623.6 O B1q ONNO Br NH F N F O Example N OH G23 1-95aE: 1.58 576.1O& B1O N N O Cl Example 1-89: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(thiophen-2- yl)pyridin-4-yl)pyrrolidine-2-carboxylic acid Example 1-90: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(6-(difluoromethyl)-4-(thiophen-2- yl)pyridin-2-yl)pyrrolidine-2-carboxylic acid Example 1-91: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(6-(difluoromethyl)-4-(1H-pyrrol-2- yl)pyridin-2-yl)pyrrolidine-2-carboxylic acid Example 1-92: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(4-(difluoromethyl)-6-(1H-pyrrol-2- yl)pyridin-2-yl)pyrrolidine-2-carboxylic acid Example 1-93: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(4-(difluoromethyl)-6-(thiophen-2- yl)pyridin-2-yl)pyrrolidine-2-carboxylic acid Example 1-94: (2S,4S)-4-((5-bromo-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(1H-pyrrol-2- yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-95: (2S,4S)-4-((5-bromo-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(furan-2- yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid Example 1-95a: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(1H-pyrrol-2- yl)pyridin-4-yl)pyrrolidine-2-carboxylic acid Example 1-96(Iso-1) & Example 1-97 (Iso-2): (2S,4S)-4-((5-chloro-3-(3-methyl-1,1- dioxidothiomorpholino)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(thiophen-2- yl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, Iso-2) To a stirred solution of B5b (223 mg, 0.65 mmol) and G6 (223 mg, 0.65 mmol) in DMF (10 mL) was added NaH (92 mg, 2.3 mmol) and stirred at RT for 1h. The reaction mixture was quenched with methanol (1 mL) and purified by Prep-HPLC (Method P2) followed by Prepartive SFC (Method: Column: Chiralcel OJ-H (250*4.6)mm. 5μ Co-Solvent Name: 0.2% Ammonia in methanol, Flow Rate: 3 mL / min. Co-Solvent Percentage: 30%, Back Pressure : 100 Bar; Temperature: 40 °C; UV: 240 nm) to afford Example 1-96, Iso-1 (11.5 mg, 0.019 mmol, 2.93 % yield), LC-MS (Method A): RT = 1.50 min, [M+H]+= 601.2, LC- MS (Method B): RT = 2.03 min, [M+H]+= 601.2.1H NMR (400 MHz, DMSO-d6): δ ppm 8.16 - 7.85 (m, 2H), 7.75 (dd, J = 4.9, 15.1 Hz, 1H), 7.45 (br d, J = 14.8 Hz, 1H), 7.20 (td, J = 4.3, 16.9 Hz, 1H), 7.14 (s,1H), 7.02 (br s, 1H), 6.64 (dt, J = 12.5, 54.8 Hz, 1H), 5.72 - 5.43 (m, 1H), 4.88 (br d, J = 9.5 Hz, 1H), 4.68 (br s, 1H), 4.18 - 4.02 (m, 2H), 3.91 (s, 1H), 3.84 -3.68 (m, 1H), 3.61 - 3.53 (m, 1H), 3.47 (br s, 1H), 3.09 - 2.97 (m, 1H), 2.74 (s, 1H), 2.64 - 2.58 (m, 1H), 2.42 (br d, J = 14.8 Hz, 1H), 1.24 (s, 1H), 1.09 (d, J = 6.5 Hz, 3H). Example 1-97, Iso-2 (11.5 mg, 0.019 mmol, 2.93 % yield), LC-MS (Method A): RT = 1.50 min, [M+H]+= 601.2, LC-MS (Method B): RT = 2.03 min, [M+H]+= 601.2.1H NMR (400 MHz, DMSO-d6): δ ppm 8.17 - 7.86 (m, 2H), 7.74 (dd, J = 5.0, 17.3 Hz, 1H), 7.46 (dd, J = 1.9, 18.6 Hz, 1H), 7.28 - 7.07 (m, 1H), 6.97 (br d, J =1.0 Hz, 1H), 6.63 (dt, J = 12.5, 54.8 Hz, 1H), 5.74 - 5.37 (m, 1H), 4.88 (br d, J = 9.5 Hz, 1H), 4.68 (br s, 1H), 4.31 - 4.05 (m, 2H), 3.91 (s, 1H), 3.82 - 3.56 (m, 3H), 3.09 - 2.98 (m, 1H), 2.78 - 2.70 (m, 1H), 2.60 (br s, 1H), 2.42 (br d, J = 14.3 Hz, 1H), 1.24 (s, 1H), 1.09 (d, J = 6.5 Hz, 3H). Using similar procedures as that described for Example 1-96, the following Examples were synthesized from appropriate precursors, either prepared internally or obtained from commercial source.1H NMR spectral data and, where relevant, preparative conditions used to separate diastereomeric mixtures (resultant individual isomers are designated as Iso-1 & Iso-2) are provided below the table. ExampleStructure Precurs LCMC LCMS Name ors Method (M+H)+RT (min) Example S F (2S,4S)-4-((5- 1-98 N F N chloro-3-((S)-9- (Iso-1) methyl-2,5-dioxa-8- NCOOHA: 1.48 628.0 azaspiro[3.5]nonan- O G6+ B: 2.10 8-yl)pyridin-2- N B1t yl)oxy)-1-(2- N (difluoromethyl)-6- MeO2SCl (thiophen-2- yl)pyrimidin-4- yl)pyrrolidine-2- carboxylic acid Example S F (2S,4S)-4-((5- 1-99 N F chloro-3-((S)-9- N (Iso-3) methyl-2,5-dioxa-8- NCOOHG6 + A: 1.61 628.1 azaspiro[3.5]nonan- B1v B: 2.14 8-yl)pyridin-2- O N yl)oxy)-1-(2- N (difluoromethyl)-6- MeO2SCl (thiophen-2- yl)pyrimidin-4- yl)pyrrolidine-2- carboxylic acid Example S F N (2S,4S)-4-((5- 1-100 F chloro-3-((S)-9- N (Iso-4) methyl-2,5-dioxa-8- NCOOHG6 + A: 1.66 628.1 azaspiro[3.5]nonan- B1x B: 2.13 8-yl)pyridin-2- O N yl)oxy)-1-(2- N (difluoromethyl)-6- MeO2SCl (thiophen-2- yl)pyrimidin-4- yl)pyrrolidine-2- carboxylic acid (2S,4S)-4-((5- F chloro-3-(2-methyl- S N 3- F Example N (methylsulfonyl)pyr 1-101 rolidin-1- NCOOHG6 + yl)pyridin-2- (Iso-1) O B1y A: 1.59 614.1 B: 2.11 yl)oxy)-1-(2- N (difluoromethyl)-6- N (thiophen-2- MeO2SCl yl)pyrimidin-4- yl)pyrrolidine-2- carboxylic acid (2S,4S)-4-((5- F chloro-3-(2-methyl- S N 3- Example F (methylsulfonyl)pyr 1-102 N rolidin-1- NCOOH(Iso-2) G6 + yl)pyridin-2- O B1z A: 1.54 614.1 B: 2.04 yl)oxy)-1-(2- N (difluoromethyl)-6- N (thiophen-2- MeO2SCl yl)pyrimidin-4- yl)pyrrolidine-2- carboxylic acid Example NH F (2S,4S)-4-((5- 1-103 N F N chloro-3-(4- N (Iso-1) O hydroxy-1- N OH (methoxycarbonyl)- G12x A: 1.47 3-methylpiperidin- O -d O N + C5 B: 1.98 608.1 4-yl)pyridin-2- N (Dia-1 yl)oxy)-1-(4- O OH ) Cl (difluoromethyl)-6- (1H-pyrrol-2-yl)- 1,3,5-triazin-2- yl)pyrrolidine-2- carboxylic acid Example NH F (2S,4S)-4-((5- 1-104 N F N chloro-3-(4- N (Iso-2) O hydroxy-1- N OH (methoxycarbonyl)- G12x-d A: 1.47 608.1 3-methylpiperidin- O O N + C5 B: 1. 4-yl)pyridin-2- N O H (Dia- 93 O 1) yl)oxy)-1-(4- Cl (difluoromethyl)-6- (1H-pyrrol-2-yl)- 1,3,5-triazin-2- yl)pyrrolidine-2- carboxylic acid Example NH F (2S,4S)-4-((5- 1-105 N F N chloro-3-(4- N (Iso-3) O A: 1.5 hydroxy-1- N OH G12x-d 1 608.1 (methoxycarbonyl)- + C5 B: 1.99 3-methylpiperidin- O O N (Dia-2) 4-yl)pyridin-2- N yl)oxy)-1-(4- O OH Cl (difluoromethyl)-6- (1H-pyrrol-2-yl)- 1,3,5-triazin-2- yl)pyrrolidine-2- carboxylic acid Example NH F (2S,4S)-4-((5- 1-106 N F N chloro-3-(4- N O A: 1. hydroxy-1- N G12x-d 48 (Iso-4) OH 608.1 (methoxycarbonyl)- + C5 B: 2.02 3-methylpiperidin- O O N (Dia-2) 4-yl)pyridin-2- N yl)oxy)-1-(4- O OH Cl (difluoromethyl)-6- (1H-pyrrol-2-yl)- 1,3,5-triazin-2- yl)pyrrolidine-2- carboxylic acid Example NH N (2S,4S)-4-((3- 1-107 NNO ((3S,4R)-4-fluoro- (Iso-1)NA: 1 3-methyl-1- OH G12x-a .76 702.3 (((tetrahydrofuran- O O N + C5a B: 1.89 3- N O F yl)oxy)carbonyl)pip O eridin-4-yl)-5-(4- methoxyphenyl)pyr OMe idin-2-yl)oxy)-1-(4- methyl-6-(1H- pyrrol-2-yl)-1,3,5- triazin-2- yl)pyrrolidine-2- carboxylic acid Example NH N (2S,4S)-4-((3- 1-108 NN((3S,4R)-4-fluoro- O (Iso-2)NA: 1. 3-methyl-1- OH G12x-a 77 702.3 (((tetrahydrofuran- O O N + C5a B: 1.88 3- N yl)oxy)carbonyl)pip O F O eridin-4-yl)-5-(4- methoxyphenyl)pyr OMe idin-2-yl)oxy)-1-(4- methyl-6-(1H- pyrrol-2-yl)-1,3,5- triazin-2- yl)pyrrolidine-2- carboxylic acid Example 1-103 (Iso-1) & Example 1-104 (Iso-2): Preparative SFC Condition: Column / dimensions: Chiralpak AS-H (250 X 30) mm, 5μ: %CO2: 75%: % Co solvent: 25% of 0.2% Ammonia in MeOH; Total Flow: 150 g / min; Back Pressure:100 bar; Temperature: 40 °C; UV: 240 nm. First elute (Iso-1; RT = 1.74 min; Purity: 98%). Second elute (Iso-2; RT = 2.29 min, Purity: >99%). Example 1-105 (Iso-3) & Example 1-106 (Iso-4): Preparative SFC Condition: Column / dimensions: Chiralpak AD-H (250 X 30) mm, 5μ: %CO2: 70%: % Co solvent: 30% of 0.2% Ammonia in MeOH; Total Flow: 150 g / min; Back Pressure:100 bar; Temperature: 40 °C; UV: 240 nm. First elute (Iso-1; RT = 1.99 min; Purity: >99%). Second elute (Iso-2; RT = 3.37 min, Purity: 94%). Example 2: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8- yl)pyridin-2-yl)oxy)-1-(4-methyl-6-(1H-pyrrol-2-yl)-1,3,5-triazin-2-yl)pyrrolidine-2- carboxylic acid A solution of D1 (30 mg, 0.060 mmol), F7b (21 mg, 0.072 mmol), and DIPEA (0.053 mL, 0.301 mmol) in DMSO (0.5 mL) was stirred at 20 °C for 30 min. The reaction mixture was diluted with EtOAc (50 mL) which was washed sequentially with water (20 mL) and brine (20 mL), then dried over MgSO4, filtered, and concentrated to yield a crude product which was dissolved in TFA (0.232 mL, 3.01 mmol) and stirred at rt for 1 hr. The reaction mixture was purified by Prep-HPLC (Method P2). Fractions containing the desired product were combined and dried via centrifugal evaporation to yield Example 2 (17.2 mg). LC-MS (Method E): RT = 1.39 min, [M+H]+= 542.1.1H NMR (500 MHz, DMSO-d6): δ ppm 11.64 - 11.50 (m, 1H), 7.82 (br s, 1H), 7.24 (br d, J = 6.6 Hz, 1H), 7.04 - 6.89 (m, 2H), 6.19 (br d, J =11.0 Hz, 1H), 5.57 - 5.40 (m, 1H), 4.93 - 4.69 (m, 1H), 4.64 - 4.53 (m, 2H), 4.47 - 4.20 (m, 3H), 4.13 (br d, J = 6.0 Hz, 1H), 3.87 - 3.56 (m, 2H), 3.25 (br d, J = 1.0 Hz, 2H), 2.96 - 2.78 (m, 1H), 2.75 - 2.63 (m, 1H), 2.44 - 2.27 (m, 4H), 0.79 (br d, J = 6.5 Hz, 3H). Using similar procedure as that described for Example 2, the following Examples were synthesized from appropriate precursors, obtained either from commercially sources or prepared internally. LC-MS Example Structure Precursors Method LC-MS T (min) (M+R +H) S N N HO N O N Example 2-1 O N D1 & F7 E: 1.54 559.1 N Cl O O Example 2-1: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(4-methyl-6-(thiophen-2-yl)-1,3,5-triazin-2- yl)pyrrolidine-2-carboxylic acid Example 2-1:1H NMR (500 MHz, DMSO- d6): δ ppm 8.06 - 7.80 (m, 2H), 7.30 - 7.01 (m, 3H), 5.58 - 5.46 (m, 1H), 4.76 (br dd, J = 6.1, 3.6 Hz, 1H), 4.65 - 4.54 (m, 2H), 4.43 - 4.20 (m, 3H), 4.16 - 4.10 (m, 1H), 3.92 - 3.57 (m, 2H), 3.03 - 2.87 (m, 2H), 2.74 (s, 1H), 2.66 (br d, J = 11.4 Hz, 1H), 2.45 - 2.34 (m, 4H), 0.79 (br d, J = 6.6 Hz, 3H). Example 2-2: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8- yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(3-(dimethylamino)phenyl)pyrimidin-4- yl)pyrrolidine-2-carboxylic acid To a stirred solution of Intermediate D1 (541 mg, 1.40 mmol) and Intermediate F1 (200 mg, 0.7 mmol) in DMSO (3 mL), DIPEA (0.49 mL, 2.8 mmol) was added. The reaction mixture was heated at 70 °C for 12 h. It was evaporated to dryness and purified by reverse phase chromatography to afford Example 2-2 (60 mg) as a yellow solid. LC- MS (Method C): RT = 3.30 min, [M+H]+= 631.2.1H NMR (400 MHz, DMSO-d6): δ ppm 12.50 (br s, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.56 – 7.43 (m, 2H), 7.35 - 7.29 (m, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.12 (br s, 1H), 6.89 – 6.87 (m, 1H), 6.83 – 6.55 (m, 1 H), 5.53 (br s, 1H), 4.86 (br s, 1H), 4.60 - 4.56 (m, 2H), 4.41 – 4.39 (d, J = 8.0 Hz, 1H), 4.29 – 4.22 (m , 2H), 4.13 (d, J = 8.0 Hz, 1H), 3.82 – 3.76 (m, 2H), 3.64 – 3.59 (m, 1H), 3.25 – 3.22 (m, 1H), 2.97 (s, 6H), 2.89 – 2.80 (m, 1H), 2.73 – 2.67 (m, 2H), 0.80 (d, J = 6.8 Hz, 3H). Using similar procedure as that described for Example 2-2, the following Examples were synthesized from noted precursor, either commercially available or prepared internally. LC-MS Exa Precur MethmpleStructureod LC-MS sors RT(M+H)+ Name(min) F F N (2S,4S)-4-((5-chloro-3- Exa N O ((S)-9-methyl-2,5-dioxa-8- OH mple N azaspiro[3.5]nonan-8- NC 2-3 D1 +C: 3.41 613.yl)pyridin-2-yl)oxy)-1-(6- F1a1(3-cyanophenyl)-2- O N (difluoromethyl)pyrimidin- ON4-yl)pyrrolidine-2- Cl carboxylic acid O NNF (2S,4S)-4-((5-chloro-3- N F ((S)-9-methyl-2,5-dioxa-8- Exa N O azaspiro[3.5]nonan-8- mple N D1 + A: 1.5 yl)pyridin-2-yl)oxy)-1-(2- 2-4 OH 2 F2B: 2592.1(difluoromethyl)-6-(1- O.00methyl-1H-pyrazol-3- N yl)pyrimidin-4- O N yl)pyrrolidine-2-carboxylic O Cl acid F FNNF (2S,4S)-4-((5-chloro-3- N F ((S)-9-methyl-2,5-dioxa-8- Exa N azaspiro[3.5]nonan-8- mple O D1 + A: 1.64 yl)pyridin-2-yl)oxy)-1-(6- 2-5 N OH F2aB: 2.15642.2(1-(2,2-difluoroethyl)-1H- pyrazol-3-yl)-2- O N (difluoromethyl)pyrimidin- O N 4-yl)pyrrolidine-2- Cl carboxylic acid O F F (2S,4S)-4-((5-chloro-3- S ExaN N((S)-9-methyl-2,5-dioxa-8- O mple N azaspiro[3.5] nonan-8- 2-6 OH D1 + A: 1.46594.1yl)pyridin-2-yl)oxy)-1-(4- O F4B: 1.16(difluoromethyl)-6- N (thiophen-2-yl)pyrimidin- O N (S) 2-yl)pyrrolidine-2- Cl carboxylic acid O F (2S,4S)-4-((5-chloro-3- F S N ((S)-9-methyl-2,5-dioxa-8- ExaNO azaspiro[3.5]nonan-8- mple N D1 + A: 1. yl)pyridin-2-yl)oxy)-1-(4- 2-7 OH 97 F4aB608.1(difluoromethyl)-6-(5- O: 2.46methylthiophen-2- N O N yl)pyrimidin-2- (S) yl)pyrrolidine-2-carboxylic O Cl acid F (2S,4S)-1-(4- F S N (difluoromethyl)-6- N O (thiophen-2-yl)pyrimidin- Exa N 2-yl)-4-((5-(1- mple OH D (methoxycarbonyl)-2,5- 2-8 4 + A: 1.61 O F4B685.2dihydro-1H-pyrrol-3-yl)-3- N: 2.08O N ((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8- O yl)pyridin-2- N O yl)oxy)pyrrolidine-2- O carboxylic acid F (2S,4S)-1-(4- F S (difluoromethyl)-6-(5- NNO methylthiophen-2- Exa N yl)pyrimidin-2-yl)-4-((5- mple OH D4 + A: 1.7 (1-(methoxycarbonyl)-2,5- 2-9 9 O F4a699.2dihydro-1H-pyrrol-3-yl)-3- NB: 2.22O N ((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8- O yl)pyridin-2- N O yl)oxy)pyrrolidine-2- O carboxylic acid Example 2-8:1H NMR (400 MHz, DMSO-d6): δ ppm 8.16 - 8.04 (m, 1H), 7.91 - 7.79 (m, 2H), 7.42 (s, 1H), 7.32 (br d, J = 4.0 Hz, 1H), 7.27 - 7.18 (m, 1H), 6.96 -6.49 (m, 1H), 6.41 (br d, J = 8.0 Hz, 1H), 5.86 - 5.46 (m, 1H), 4.73 (br dd, J = 4.3, 9.5 Hz, 1H), 4.67 - 4.62 (m, 1H), 4.61 - 4.54 (m, 1H), 4.48 (br s, 2H), 4.41 - 4.37 (m, 1H), 4.34 - 4.21 (m, 4H), 4.20 - 4.05 (m, 1H), 3.88 - 3.71 (m, 2H), 3.69 - 3.59 (m, 5H), 3.05 - 2.90 (m, 1H), 2.68 (dt, J = 1.5,3.9 Hz, 1H), 2.47 - 2.34 (m, 1H), 0.80 (br d, J = 6.5 Hz, 3H). Example 2-10: (2S,4S)-4-((5-bromo-3-((S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8- yl)pyridin-2-yl)oxy)-1-(4-(difluoromethyl)-6-(thiophen-2-yl)-1,3,5-triazin-2- yl)pyrrolidine-2-carboxylic acid To a solution of D1a (30 mg, 0.068 mmol) and F8a (27.5 mg, 0.082 mmol) in DMSO (0.75 mL) at room temperature. To this reaction mixture DIPEA (0.036 mL, 0.204 mmol) was added and stirred for 1 h at 120 °C under microwave irradiation. The crude reaction mass was purified by prep-HPLC to afford Example 2-10 (15.5 mg). LC-MS (Method H): RT = 2.55 min, [M+H]+= 639.0.1H NMR: (400 MHz, DMSO-d6): δ ppm 8.10 - 8.01 (m, 1H), 7.95 - 7.89 (m, 2H), 7.32 - 7.23 (m, 2H), 6.85 - 6.52 (m, 1H), 5.48 (ddd, J = 2.4, 5.5, 8.4 Hz, 1H), 4.80 - 4.71 (m, 1H), 4.63 - 4.52 (m, 2H), 4.44 - 4.21 (m, 3H), 4.13 - 4.06 (m, 1H), 3.95 - 3.73 (m, 2H), 3.61 (br t, J = 11.0 Hz, 1H), 3.27 - 3.20 (m, 1H), 2.97 - 2.83 (m, 1H), 2.70 - 2.62 (m, 1H), 2.46 - 2.38 (m, 1H), 0.78 (J = 6.5 Hz, 3H). Using similar procedure as that described for Example 2-10, the following Examples were synthesized from appropriate precursors, obtained either from commercial sources or prepared internally. LC-MS Example Structure Precursors Method LC-MS + RT (min) (M+H) F F N N O N COOH N Example 2-11 F8b & D1a H: 2.11 623.0 O N N Br O O F F N N NH N COOH N Example 2-12 F8 & D1a H: 2.80 622.0 O N N Br O O F F N N S N COOH N Example 2-13 F8a & D1 H: 3.45 596.0 O N N Cl O O Example 2-11: (2S,4S)-4-((5-bromo-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(4-(difluoromethyl)-6-(furan-2-yl)-1,3,5- triazin-2-yl)pyrrolidine-2-carboxylic acid Example 2-12: (2S,4S)-4-((5-bromo-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(4-(difluoromethyl)-6-(1H-pyrrol-2-yl)- 1,3,5-triazin-2-yl)pyrrolidine-2-carboxylic acid Example 2-13: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(4-(difluoromethyl)-6-(thiophen-2-yl)-1,3,5- triazin-2-yl)pyrrolidine-2-carboxylic acid Example 2-11:1H NMR (400 MHz, DMSO-d6): δ ppm 12.90 - 12.75 (m, 1H), 8.04 (ddd, J = 0.8, 1.7, 2.4 Hz, 1H), 7.90 (dd, J = 2.2, 3.3 Hz, 1H), 7.53 - 7.40 (m, 1H), 7.37 - 7.26 (m, 1H), 6.88 - 6.50 (m, 2H), 5.55 - 5.45 (m, 1H), 4.85 - 4.75 (m, 1H), 4.64 - 4.49 (m, 2H), 4.40 - 4.18 (m, 3H), 4.11 (dd, J = 2.1, 6.8 Hz, 1H), 3.89 (br t, J = 14.7 Hz, 1H), 3.76 (br d, J = 10.1 Hz, 1H), 3.60 (dt, J = 2.5, 11.5 Hz, 1H), 3.28 - 3.19 (m, 1H), 2.99 - 2.87 (m, 1H), 2.69 - 2.62 (m, 1H), 2.44 (br s, 1H), 0.81 - 0.74 (m, 3H). Example 2-12:1H NMR (400 MHz, DMSO-d6): δ ppm 12.71 (br s, 1H), 11.85 - 11.66 (m, 1H), 7.91 (dd, J = 1.3, 2.0 Hz, 1H), 7.33 (dd, J = 2.1, 5.6 Hz, 1H), 7.13 - 7.01 (m, 2H), 6.79 - 6.45 (m, 1H), 6.28 - 6.23 (m, 1H), 5.58 - 5.46 (m, 1H), 5.04 - 4.74 (m, 1H), 4.65 - 4.52 (m, 2H), 4.44 - 4.35 (m, 1H), 4.34 - 4.20 (m, 2H), 4.13 (d, J = 6.8 Hz, 1H), 3.97 - 3.74 (m, 2H), 3.66 - 3.57 (m, 1H), 3.30 - 3.21 (m, 1H), 2.99 - 2.85 (m, 1H), 2.71 - 2.64 (m, 1H), 2.49 - 2.40 (m, 1H), 0.86 - 0.74 (m, 3H) Example 2-13:1H NMR (400 MHz, DMSO-d6): δ ppm 12.92 - 12.75 (m, 1H), 8.76 (d, J = 2.0 Hz, 1H), 8.60 (dd, J = 1.5, 4.9 Hz, 1H), 8.12 - 8.02 (m, 2H), 8.00 - 7.93 (m, 2H), 7.51 - 7.46 (m, 1H), 7.36 (d, J = 1.8 Hz, 1H), 7.28 (dd, J = 3.8, 5.0 Hz, 1H), 6.88 - 6.55 (m, 1H), 5.59 (dt, J = 3.0, 5.8 Hz, 1H), 4.85 - 4.78 (m, 1H), 4.65 - 4.54 (m, 2H), 4.40 - 4.22 (m, 3H), 4.15 - 4.10 (m, 1H), 4.03 - 3.89 (m, 1H), 3.79 (br d, J = 11.1 Hz, 1H), 3.63 (dt, J = 2.5, 11.4 Hz, 1H), 3.27 (td, J = 1.5, 3.0 Hz, 1H), 3.06 - 2.94 (m, 1H), 2.47 (br s, 1H), 0.80 (d, J = 6.5 Hz, 3H). Example 2-14 (Iso-1) and Example 2-15 (Iso-2): (2S,4S)-4-((3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)-5-(2-phenylcyclopropyl)pyridin-2-yl)oxy)-1-(4-methyl-6-(1H- pyrrol-2-yl)-1,3,5-triazin-2-yl)pyrrolidine-2-carboxylic acid To a mixture of F7b (38.0 mg, 0.129 mmol) and D4a (60 mg, 0.129 mmol) in DMSO (1.29 mL) was added DIPEA (135 µL, 0.773 mmol). The resulting mixture was stirred at rt for 45 min. The mixture was quenched by the addition of acetic acid (51.6 µL, 0.902 mmol) and was then diluted with EtOAc. The mixture was washed with 10% aqueous lithium chloride, saturated aqueous sodium chloride, dried over MgSO4, filtered, and concentrated in vacuo to give the crude product which was used in the next step without further purification. The crude product in DCM (1.29 mL) was treated with TFA (149 µL, 1.93 mmol), and the resulting mixture was stirred at rt overnight. The reaction mixture was concentrated in vacuo. The remaining residue was dissolved in DMF (2 mL). The resulting mixture was filtered and the filtrate was purified via prep-HPLC (Method P2). Fractions containing the desired product were combined and dried via centrifugal evaporation to give a mixture of 2 isomers. Separation of isomers was achieved via preparative SFC with the following conditions: Column: Chiralpak AD-H, 30 mm x 250 mm, 5 μm particles; CO2 / IPA with 0.1% DEA; Flow Rate: 100.00 mL / min; Column Temperature: 50 °C. Fraction collection was triggered by PDA (220 nm). Fractions containing the desired product were combined and dried via centrifugal evaporation to give two diastereomeric products. Enantiopurity was determined by analytical SFC with the following conditions: Column: Chiral AD, 4.6 mm x 100 mm, 5 μm particles; Mobile Phase A: CO2; Mobile Phase B: Isopropanol with 0.1% DEA; Temperature: 50 °C; Isocratic elution at 35% B over 10 min; Flow: 2 mL / min; Detection: UV (220 nm). First eluting isomer: Example 2-14 (Iso-1) (7.1 mg),1H NMR (500 MHz, DMSO- d6) δ ppm 11.60 (br s, 1H), 7.67 (br d, J=4.9 Hz, 1H), 7.33 - 7.23 (m, 2H), 7.22 - 7.11 (m, 3H), 7.05 - 6.86 (m, 3H), 6.25 - 6.09 (m, 1H), 5.51 - 5.29 (m, 1H), 4.77 - 4.12 (m, 6H), 3.98 - 3.20 (m, 3H), 2.94 - 2.60 (m, 4H), 2.38 - 2.11 (m, 6H), 1.52 - 1.34 (m, 3H), 0.80 (br d, J = 6.6 Hz, 3H), LC-MS (Method E): RT = 1.82 min, [M+H]+= 624.0, SFC Purity: 99 %ee; RT: 2.4 min.; Second eluting isomer: Example 2-15 (Iso-2) (7.5 mg),1H NMR (500 MHz, DMSO-d6) δ ppm 11.40 - 11.26 (m, 1H), 7.42 (br d, J = 1.3 Hz, 1H), 7.04 (br d, J = 7.4 Hz, 2H), 6.93 (br d, J =7.0 Hz, 3H), 6.77 - 6.65 (m, 3H), 5.97 - 5.87 (m, 1H), 5.26 - 5.06 (m, 1H), 4.56 - 3.87 (m, 6H), 3.72 - 2.91 (m, 3H), 2.58 (br d, J = 7.2 Hz, 3H), 2.14 - 1.86 (m, 6H), 1.18 (br s, 4H), 0.54 (br d, J = 6.5 Hz, 3H), LC-MS (Method E): RT = 1.79 min, [M+H]+= 623.8, SFC Purity: 99 %ee; RT: 4.5 min. Example 2-16: (2S,4S)-4-({5-[1-(methoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl]-3-[(9S)- 9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[4-methyl-6-(1H- pyrrol-2-yl)-1,3,5-triazin-2-yl]pyrrolidine-2-carboxylic acid A solution of Intermediate D4 (15 mg, 0.025 mmol), Intermediate F7b (7.5 mg, 0.025 mmol), and DIPEA (0.022 mL, 0.13 mmol) in DMSO (0.5 mL) was heated to 100 °C for 10 min. The reaction mixture was diluted with 80 mL of EtOAc, washed with 20 mL of 1 N HCl solution and 20 mL of brine, and dried over MgSO4. The organic layer was filtered and concentrated. The resultant crude material was treated with TFA (0.098 mL, 1.27 mmol) and stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure and purified by prep-HPLC (Method P1b) to afford Example 2-16 (7.8 mg). LC-MS (Method E): RT = 1.37 min, m / z [M+H]+= 633.3; LC-MS (Method F): RT = 1.48 min, m / z [M+H]+= 633.2.1H NMR (500 MHz, DMSO-d6): δ ppm 7.83 (br s, 1H), 7.34 - 7.25 (m, 1H), 7.20 - 7.04 (m, 3H), 6.40 (br d, J = 9.6 Hz, 1H), 6.32 - 6.21 (m, 1H), 5.61 - 5.48 (m, 1H), 5.07 - 4.74 (m, 1H), 4.68 - 4.52 (m, 2H), 4.52 - 4.38 (m, 3H), 4.37 - 4.20 (m, 4H), 4.19 - 4.11 (m, 1H), 4.02 - 3.91 (m, 1H), 3.78 (br d, J = 12.3 Hz, 1H), 3.66 (br d, J = 6.2 Hz, 1H), 3.39 - 3.24 (m, 1H), 2.99 - 2.83 (m, 1H), 2.75 - 2.62 (m, 1H), 2.51 (br d, J = 1.3 Hz, 3H), 2.42 - 2.35 (m, 3H), 0.78 (br d, J = 6.2 Hz, 3H). The following Example was synthesized from noted precursors using the procedure described for Example 2-16. Exa Structure Precur LC-MS LC-MS Name mple sors Method (M+H)+RT (min) NH N (2S,4S)-4-{[5-(2- NNO cyclopropylethynyl)-3- N [(9S)-9-methyl-2,5-dioxa-8- Exa OH F azaspiro[3.5]nonan-8- mple O 7b & E: 1.62572.2yl]pyridin-2-yl]oxy}-1-[4- 2-17 N D5F: 1.78O N methyl-6-(1H-pyrrol-2-yl)- 1,3,5-triazin-2- O yl]pyrrolidine-2-carboxylic acid Example 2-17:1H NMR (500 MHz, DMSO-d6): δ ppm 7.86 - 7.79 (m, 1H), 7.16 - 7.09 (m, 1H), 7.05 - 6.90 (m, 2H), 6.23 - 6.15 (m, 1H), 5.58 - 5.43 (m, 1H), 4.93 - 4.68 (m, 1H), 4.66 - 4.53 (m, 2H), 4.48 - 4.30 (m, 2H), 4.30 - 4.19 (m, 2H), 4.16 - 4.10 (m, 1H), 3.86 - 3.68 (m, 2H), 3.67 - 3.16 (m, 1H), 2.96 - 2.78 (m, 1H), 2.65 - 2.24 (m, 5H merge with DMSO), 1.62 - 1.47 (m, 1H), 0.95 - 0.85 (m, 2H), 0.74 (app br s, 5H). Example 2-18: (2S,4S)-4-{[5-(4-methoxyphenyl)-3-[(9S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl]pyridin-2-yl]oxy}-1-[4-methyl-6-(thiophen-2-yl)-1,3,5-triazin-2- yl]pyrrolidine-2-carboxylic acid A solution of Intermediate D4b (30 mg, 0.053 mmol), Intermediate F7 (11.2 mg, 0.053 mmol) and DIPEA (0.046 mL, 0.263 mmol) in DMSO (0.5 mL) was stirred at 20 °C for 1 hr. The reaction mixture was directly subjected to prep-HPLC purification (Method P2c) to afford Example 2-18 (14.1 mg). LC-MS (Method E): RT = 1.71 min, m / z [M+H]+= 631.2; LC-MS (Method F): RT = 2.12 min, m / z [M+H]+= 631.1.1H NMR (500 MHz, DMSO-d6): δ ppm 8.08 - 7.99 (m, 1H), 7.96 (br d, J=1.8 Hz, 1H), 7.82 (br s, 1H), 7.65 - 7.57 (m, 2H), 7.34 (br s, 1H), 7.25 - 7.18 (m, 1H), 7.05 - 7.00 (m, 2H), 5.59 - 5.45 (m, 1H), 4.80 - 4.55 (m, 3H), 4.42 (br dd, J=13.4, 6.3 Hz, 1H), 4.31 (dt, J=14.3, 6.9 Hz, 2H), 4.19 - 4.11 (m, 1H), 3.80 (s, 5H), 3.71 - 3.60 (m, 1H), 2.90 (d, J=2.3 Hz, 1H), 2.79 - 2.68 (m, 2H), 2.59 - 2.32 (m, 4H merge with DMSO), 0.85 - 0.74 (m, 3H). The following Example was synthesized from noted precursors using the procedures as described for Example 2-18. Examp Structure Precur LC-MS LC-MS Name le sors Method (M+H)+RT (min) Examp S CF N (2S,4S)-4-((5-(4- le N N O methoxyphenyl)-3-((S)-9- 2-19 N OH A: 1 methyl-2,5-dioxa-8- F8c + .37 685.2 azaspiro[3.5]nonan-8- O N D4b B: 1.49 yl)pyridin-2-yl)oxy)-1-(4- O N (thiophen-2-yl)-6- (trifluoromethyl)-1,3,5- O OMetriazin-2-yl)pyrrolidine-2- carboxylic acid Examp NH CF N (2S,4S)-4-((5-(4- le N N O methoxyphenyl)-3-((S)-9- 2-20 N OH methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8- O N F8d + A: 1.72 668.2 yl)pyridin-2-yl)oxy)-1-(4- O N D4b (thiophen-2-yl)-6- (trifluoromethyl)-1,3,5- O OMetriazin-2-yl)pyrrolidine-2- carboxylic acid S N (2S,4S)-1-(4-ethyl-6- N (thiophen-2-yl)-1,3,5- N O N triazin-2-yl)-4-((5-(1- Examp OH (methoxycarbonyl)-2,5- le O F7a &Edihydro-1H-pyrrol-3-yl)-3- 2-21 ND4: 1.65 664.0((S)-9-methyl-2,5-dioxa-8- O N azaspiro[3.5]nonan-8- O N yl)pyridin-2- OOyl)oxy)pyrrolidine-2- carboxylic acid S N (2S,4S)-4-((5- N N O (cyclopropylethynyl)-3- Examp N OH ((S)-9-methyl-2,5-dioxa-8- le azaspiro[3.5]nonan-8- 2-22 F7 & O ND5E: 1.82 589.2yl)pyridin-2-yl)oxy)-1-(4- N methyl-6-(thiophen-2-yl)- O 1,3,5-triazin-2- O yl)pyrrolidine-2- carboxylic acid H N N N HO N O Examp N le 2-23 F7c & O ND5E: 1.74 586.6N O O H N N N HO Examp N O N le 2-24 F7d & O ND5E: 1.84 598.2N O O O N N HO N O Examp N le 2-25 F7f & O ND5E: 1.67 573.1N O O D1 & N 2- N HO N O chloro Examp N -4- le 2-26 methy O N l-6- E: 1.98 553.2 pheny N Cl l- O 1,3,5- O triazin e Example 2-23: (2S,4S)-4-((5-(cyclopropylethynyl)-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(4-ethyl-6-(1H-pyrrol-2-yl)-1,3,5-triazin-2- yl)pyrrolidine-2-carboxylic acid Example 2-24: (2S,4S)-1-(4-cyclopropyl-6-(1H-pyrrol-2-yl)-1,3,5-triazin-2-yl)-4- ((5-(cyclopropylethynyl)-3-((S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl)pyridin-2- yl)oxy)pyrrolidine-2-carboxylic acid Example 2-25: (2S,4S)-4-((5-(cyclopropylethynyl)-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(4-(furan-2-yl)-6-methyl-1,3,5-triazin-2- yl)pyrrolidine-2-carboxylic acid Example 2-26: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(4-methyl-6-phenyl-1,3,5-triazin-2- yl)pyrrolidine-2-carboxylic acid Example 2-20:1H NMR (400 MHz, DMSO-d6): δ ppm 12.09 - 11.61 (m, 1H), 8.05 (t, J = 2.1 Hz, 1H), 7.68 - 7.57 (m, 2H), 7.36 (dd, J = 2.1, 6.4 Hz, 1H), 7.17 - 7.05 (m, 2H),7.03 (dd, J = 2.0, 9.0 Hz, 2H), 6.28 (dt, J = 2.1, 4.1 Hz, 1H), 5.67 - 5.48 (m, 1H), 5.07 - 4.73 (m, 1H), 4.66 (dd, J = 4.4, 6.4 Hz, 1H), 4.58 (dd, J = 6.8, 8.8 Hz, 1H), 4.45 - 4.21 (m, 3H), 4.14 (dd, J = 1.3, 6.8 Hz, 1H), 4.01 (br d, J = 13.3 Hz, 1H), 3.88 - 3.76 (m, 5H), 3.65 (br t, J = 11.5 Hz, 1H), 3.46 (br s, 1H), 3.05 -2.88 (m, 2H), 2.75 (br d, J = 11.8 Hz, 1H), 0.81 (dd, J = 3.3, 6.5 Hz, 3H). Example 2-21:1H NMR (500 MHz, DMSO-d6): δ ppm 8.07 - 7.94 (m, 1H), 7.89 - 7.80 (m, 2H), 7.35 - 7.16 (m, 2H), 6.40 (br d, J=10.5 Hz, 1H), 5.59 - 5.45 (m, 1H), 4.81 - 4.71 (m, 1H), 4.68 - 4.62 (m, 1H), 4.62 - 4.54 (m, 1H), 4.53 - 4.36 (m, 3H), 4.34 - 4.20 (m, 4H), 4.16 - 4.10 (m, 1H), 3.86 - 3.25 (m, 7H), 3.03 - 2.85 (m, 1H), 2.72 - 2.58 (m, 3H), 2.45 - 2.34 (m, 1H), 1.23 (dt, J=19.1, 7.5 Hz, 3H), 0.78 (br d, J=5.9 Hz, 3H) Example 2-23:1H NMR (500 MHz, DMSO-d6) δ ppm 11.61 - 11.47 (m, 1H), 7.83 (br d, J=3.7 Hz, 1H), 7.11 (br d, J=9.8 Hz, 1H), 7.04 - 6.89 (m, 2H), 6.24 - 6.14 (m, 1H), 5.59 - 5.41 (m, 1H), 4.90 - 4.67 (m, 1H), 4.66 - 4.54 (m, 2H), 4.45 - 4.19 (m, 3H), 4.17 - 4.09 (m, 1H), 3.84 - 3.69 (m, 2H), 3.65 - 3.19 (m, 1H), 2.99 - 2.80 (m, 1H), 2.66 - 2.55 (m, 4H), 2.44 - 2.29 (m, 1H), 1.61 - 1.49 (m, 1H), 1.29 - 1.17 (m, 3H), 0.94 - 0.85 (m, 2H), 0.79 - 0.70 (m, 5H) Example 2-24:1H NMR (500 MHz, DMSO-d6) δ ppm 11.56 - 11.40 (m, 1H), 7.81 (br d, J=1.4 Hz, 1H), 7.10 (br d, J=6.9 Hz, 1H), 7.02 - 6.86 (m, 2H), 6.18 (br d, J=9.6 Hz, 1H), 5.57 - 5.40 (m, 1H), 4.88 - 4.52 (m, 3H), 4.39 (br d, J=6.9 Hz, 1H), 4.32 - 4.08 (m, 3H), 3.83 - 3.48 (m, 2H), 3.29 - 3.14 (m, 1H), 2.96 - 2.78 (m, 1H), 2.61 - 2.54 (m, 1H merge with DMSO), 2.43 - 2.26 (m, 1H), 1.99 - 1.82 (m, 1H), 1.58 - 1.47 (m, 1H), 1.07 (br d, J=11.9 Hz, 2H), 1.03 - 0.93 (m, 3H), 0.93 - 0.84 (m, 2H), 0.76 - 0.70 (m, 5H). The following Examples were synthesized from noted precursors using the procedure described for Example 2-10. Example Structure Precursors LC-MS LC-MS Method (M+H)+RT (min) F F N N Example S N COOH N 2-27 O N F8a & D5 H: 2.77 625.2 N O O F F N N Example NH N COOH 2-28 N F8 & D1 H: 2.74 578.4 O N N Cl O O Example 2-27: (2S,4S)-4-((5-(cyclopropylethynyl)-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(4-(difluoromethyl)-6-(thiophen-2-yl)-1,3,5- triazin-2-yl)pyrrolidine-2-carboxylic acid Example 2-28: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)-1-(4-(difluoromethyl)-6-(1H-pyrrol-2-yl)- 1,3,5-triazin-2-yl)pyrrolidine-2-carboxylic acid Example 2-27:1H NMR (400 MHz, DMSO-d6) δ 13.24 - 12.65 (m, 1H), 8.10 - 8.01 (m, 1H), 7.93 (d, J = 4.5 Hz, 1H), 7.85 - 7.81 (m, 1H), 7.26 (td, J = 3.5, 5.0 Hz, 1H), 7.11 (d, J = 1.9 Hz, 1H), 6.87 - 6.53 (m, 1H), 5.51 (td, J = 3.1, 6.0 Hz, 1H), 4.81 - 4.71 (m, 1H), 4.64 - 4.51 (m, 2H), 4.43 - 4.34 (m, 1H), 4.32 - 4.21 (m, 2H), 4.13 - 4.07 (m, 1H), 3.94 - 3.72 (m, 2H), 3.61 (br t, J = 10.7 Hz, 1H) Example 2-28:1H NMR (400 MHz, DMSO-d6) δ 12.75 - 12.62 (m, 1H), 11.87 - 11.68 (m, 1H), 7.84 (dd, J = 1.1, 2.2 Hz, 1H), 7.25 (dd, J = 2.3, 5.5 Hz, 1H), 7.13 - 7.01 (m, 2H), 6.79 - 6.45 (m, 1H), 6.26 (tt, J = 2.2, 4.0 Hz, 1H), 5.59 - 5.47 (m, 1H), 5.03 - 4.75 (m, 1H), 4.63 - 4.54 (m, 2H), 4.42 - 4.36 (m, 1H), 4.35 - 4.21 (m, 2H), 4.13 (dd, J = 1.6, 6.8 Hz, 1H), 3.98 - 3.74 (m, 2H), 3.66 - 3.58 (m, 1H), 3.29 - 3.21 (m, 1H), 2.99 - 2.85 (m, 1H), 2.68 (td, J = 2.3, 4.1 Hz, 1H), 2.48 - 2.40 (m, 1H), 0.80 (d, J = 6.5 Hz, 3H). The following Example was synthesized from noted precursors using the procedure described for Example 2-2. Example Structure Precursors LC-MS LC-MS Method (M+H)+RT (min) F F SeNN HO Example O N 2-29 O N F7e & D4 E: 1.68 733.2 O N N O O O Example 2-29: (2S,4S)-1-(2-(difluoromethyl)-6-(selenophen-2-yl)pyrimidin-4-yl)- 4-((5-(1-(methoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)-3-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)pyridin-2-yl)oxy)pyrrolidine-2-carboxylic acid Example 2-29:1H NMR (500 MHz, DMSO- d6) δ ppm 8.45 - 8.07 (m, 2H), 7.84 (br s, 1H), 7.51 - 7.37 (m, 1H), 7.37 - 7.27 (m, 1H), 7.25 - 6.98 (m, 1H), 6.80 - 6.47 (m, 1H), 6.40 (br d, J=9.8 Hz, 1H), 5.72 - 5.36 (m, 1H), 4.90 - 4.68 (m, 1H), 4.68 - 4.55 (m, 2H), 4.45 - 4.45 (m, 1H), 4.54 - 4.37 (m, 2H), 4.25 (br s, 4H), 4.14 (br d, J=6.7 Hz, 1H), 3.78 (br d, J=10.1 Hz, 1H), 3.71 - 3.61 (m, 3H), 2.97 - 2.76 (m, 1H), 2.74 - 2.61 (m, 1H), 2.51 (m, 4H), 0.80 (br d, J=6.3 Hz, 3H). Example 3: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8- yl)pyridin-2-yl)oxy)-1-(6-(6-ethoxypyridin-2-yl)-2-methoxypyrimidin-4-yl)pyrrolidine-2- carboxylic acid To a stirred solution of D2 (0.1 g, 0.3 mmol) in DMSO (1 mL) was added DIPEA (0.13 mL, 0.8 mmol) and F5 (0.067 g, 0.3 mmol) and the resulting mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The resultant crude product (0.06 g, 0.1 mmol) was dissolved in MeOH (2 mL) and Water (1 mL) and treated with LiOH (4.6 mg, 0.19 mmol). The mixture was stirred at rt for 2 h, concentrated, and purified by prep HPLC (Method P3a) to afford Example 3 (1.3 mg). LC-MS (Method A): RT = 1.12 min, [M+H]+= 613.2; LC-MS (Method B) : RT = 1.50 min, [M+H]+= 613.2.1H NMR (400 MHz, DMSO-d6): δ ppm 7.85 - 7.92 (m, 1H) 7.83 (d, J = 2.00 Hz, 1H) 7.21 - 7.25 (m, 1H) 7.07 - 7.13 (m, 1H) 6.96 (s, 1H) 6.92 (br d, J = 8.00 Hz, 1H) 5.46 - 5.62 (m, 1H) 4.71 - 4.80 (m, 1H) 4.55 - 4.64 (m, 2H) 4.37 - 4.45 (m, 2H) 4.09 - 4.21 (m, 2H) 3.88 (br s, 3H) 3.73 - 3.83 (m, 2H) 3.60 (br dd, J = 11.94, 2.56 Hz, 2H) 3.23 - 3.30 (m, 2H) 3.13 - 3.19 (m, 1H) 2.86 - 2.97 (m, 1H) 2.40 (br dd, J = 11.38, 2.13 Hz, 1H) 1.38 (t, J = 7.00 Hz, 3H) 0.78 (d, J = 6.50 Hz, 3H). Example 4: (2S,4S)-4-((6-(1-hydroxy-2-methylpropan-2-yl)-5'-((S)-9-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)-[2,3'-bipyridin]-6'-yl)oxy)-1-(4-methyl-6-(1H-pyrrol-2-yl)- 1,3,5-triazin-2-yl)pyrrolidine-2-carboxylic acid To a solution of G12x-a (45 mg, 0.16 mmol) and C1 (60 mg, 0.16 mmol) in DMF (0.5 mL) was added sodium hydride (20 mg, 0.78 mmol) and reaction mixture was stirred at rt for 2h. Then it was quenched with methanol, filtered and filtrate was purified by preparative HPLC (Method: Column: Xbridge C18, 150 x 19 mm, 5 µm particles; Mobile Phase A: 10 mM Ammonium acetate in water; Mobile Phase B: acetonitrile; Gradient: 5- 100% B over 16 minutes, then a 4-minute hold at 100% B; Flow: 20 mL / min) to afford Example 4 (11 mg, 10.3% yield) as pale yellow solid. LC-MS (Method A): RT = 1.495 min, [M+H]+= 657.3; LC-MS (Method B): RT = 1.377 min, [M+H]+= 657.3.1H NMR (400 MHz, DMSO-d6): δ ppm 12.70 (br s, 1H), 11.62 (br d, J = 28.0 Hz, 1H), 8.53 (dd, J = 3.4, 2.1 Hz, 1H), 7.88 - 7.83 (m, 1H), 7.79 (d, J = 3.8 Hz, 2H), 7.38 - 7.34 (m, 1H), 7.02 - 6.93 (m, 2H), 6.22 - 6.19 (m, 1H), 5.66 - 5.56 (m, 1H), 4.95 - 4.74 (m, 1H), 4.71 - 4.58 (m, 3H), 4.47 - 4.25 (m, 3H), 4.18 (d, J = 6.8 Hz, 1H), 3.63 (d, J = 5.5 Hz, 6H), 3.00 - 2.90 (m, 1H), 2.77 (br d, J = 12.0 Hz, 1H), 2.47 - 2.25 (m, 4H), 1.35 (s, 6H), 0.85 (dd, J = 6.6, 2.4 Hz, 3H). Using similar procedures as that described for Example 4, the following Examples were synthesized from appropriate precursors, either prepared internally or obtained from commercial source. Examp Structure Precurs LCMC LCMS Name le ors Method (M+H)+RT (min) Examp NH N (2S,4S)-4-((2'-(1- le4-1N Nhydroxy-2- O N methylpropan-2- OH G12x-a A: 1.49 657.3 yl)-5-((S)-9-methyl- O + C1a B: 1.37 2,5-dioxa-8- N O N azaspiro[3.5]nonan- 8-yl)-[3,4'- O OH bipyridin]-6- N yl)oxy)-1-(4- methyl-6-(1H- pyrrol-2-yl)-1,3,5- triazin-2- yl)pyrrolidine-2- carboxylic acid Examp NH N (2S,4S)-4-((5-(2- le4-2 NNcarbamoylthiazol- O A: 5-yl)-3-((S)-9- N OH G12x-a 1.06 634.2 methyl-2,5-dioxa-8- + C1b B: 1.25 azaspiro[3.5]nonan- O N 8-yl)pyridin-2- O N yl)oxy)-1-(4- methyl-6-(1H- O S O pyrrol-2-yl)-1,3,5- N NH2triazin-2- yl)pyrrolidine-2- carboxylic acid Examp NH N (2S,4S)-4-((5-(2- le4-3N Nmethoxypyrimidin- O N 4-yl)-3-((S OH G12x A: 1.18 )-9- -a 616.2 methyl-2,5-dioxa-8- O + C1c B: 1.24 azaspiro[3.5]nonan- N 8-yl)pyridin-2- O N yl)oxy)-1-(4- O N methyl-6-(1H- OMe N pyrrol-2-yl)-1,3,5- triazin-2- yl)pyrrolidine-2- carboxylic acid Examp NH N (2S,4S)-4-((5-(4- le4-4N Nmethoxypyrimidin- O 2-yl)-3-((S OH -a A: 1 )-9- N G12x .51 616.3 methyl-2,5-dioxa-8- O + C1d B: 1.51 azaspiro[3.5]nonan- N 8-yl)pyridin-2- O N yl)oxy)-1-(4- O N methyl-6-(1H- N OMe pyrrol-2-yl)-1,3,5- triazin-2- yl)pyrrolidine-2- carboxylic acid Examp NH N (2S,4S)-4-((5-(5- le4-5 NNmethoxypyrimidin- O 2-yl)-3-((S) OH -a A: 1 -9- N G12x .22 616.3 methyl-2,5-dioxa-8- + C1e B: 1.32 azaspiro[3.5]nonan- O N 8-yl)pyridin-2- O N yl)oxy)-1-(4- N methyl-6-(1H- O N pyrrol-2-yl)-1,3,5- OMetriazin-2- yl)pyrrolidine-2- carboxylic acid Examp NH N (2S,4S)-4-((5-(6- leNmethoxypyridazin- 4-6NO 3-yl)-3-((S)-9- N OH A: 1. methyl-2,5-dioxa-8- G12x-a 17 616.3 azaspiro[3.5]nonan- O N + C1f B: 1.22 8-yl)pyridin-2- O N yl)oxy)-1-(4- N methyl-6-(1H- O N pyrrol-2-yl)-1,3,5- OMetriazin-2- yl)pyrrolidine-2- carboxylic acid Examp S N (2S,4S)-4-((5-(4- le4-7 NNmethoxypyrimidin- O 2-yl)-3-((S OH + A: 1 )-9- N G12x .50 633.2 methyl-2,5-dioxa-8- C1d B: 1.87 azaspiro[3.5]nonan- O N 8-yl)pyridin-2- O N yl)oxy)-1-(4- N methyl-6- O N OMe (thiophen-2-yl)- 1,3,5-triazin-2- yl)pyrrolidine-2- carboxylic acid Examp NH F (2S,4S)-1-(4- le4-8 N F N (difluoromethyl)-6- N O (1H-pyrrol-2 OH 2x-d A -yl)- N G1 : 1.48 652.3 1,3,5-triazin-2-yl)- + C1d B: 1.88 4-((5-(4- O N methoxypyrimidin- O N 2-yl)-3-((S)-9- methyl-2,5-dioxa-8- O N N OMe azaspiro[3.5]nonan- 8-yl)pyridin-2- yl)oxy)pyrrolidine- 2-carboxylic acid Examp NH F (2S,4S)-1-(4- le4-9 N F (difluoromethyl)-6- NNO A (1H-pyrrol-2-yl)- G12 : 1.35 N x-d 652.2 1,3,5-triazin-2-yl)- OH + C1e B: 1.83 4-((5-(5- O methoxypyrimidin- N ON2-yl)-3-((S)-9- methyl-2,5-dioxa-8- O N azaspiro[3.5]nonan- N 8-yl)pyridin-2- OMe yl)oxy)pyrrolidine- 2-carboxylic acid Examp NH N (2S,4S)-4-((5-(4- le methoxy-1H- 4-10N NO pyrazol-1-yl)-3- N OH -a A: ((S)-9-methyl-2,5- G12x 1.69 604.3 dioxa-8- O N + B7 B: 1.31 azaspiro[3.5]nonan- O N 8-yl)pyridin-2- yl)oxy)-1-(4- O NNmethyl-6-(1H- pyrrol-2-yl)-1,3,5- O triazin-2- yl)pyrrolidine-2- carboxylic acid Examp S N (2S,4S)-4-((5-(4- le NNmethoxy-1H- 4-11 O pyrazol-1-yl)-3- N OH A ((S)-9-methyl-2,5- G12x + : 1.35 621.2 dioxa-8- O N B7 B: 1.63 azaspiro[3.5]nonan- O N 8-yl)pyridin-2- NNyl)oxy)-1-(4- O methyl-6- O (thiophen-2-yl)- 1,3,5-triazin-2- yl)pyrrolidine-2- carboxylic acid Example 5: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8- yl)pyridin-2-yl)oxy)-1-(6-(3-methoxyphenyl)-2-methylpyrimidin-4-yl)pyrrolidine-2- carboxylic acid To a degassed solution of H1 (30 mg, 0.06 mmol), 3-methoxyphenyl boronic acid pinacol ester (14 mg, 0.06 mmol) and K2CO3(24 mg, 0.17 mmol) in Dioxane (2 mL) and water (0.2 mL), PdCl2(dppf) (4.3 mg, 5.9 µmol) was added. The reaction mixture was heated at 85 °C for 12 h. It was evaporated to dryness and purified by reverse phase column chromatography to afford Example 5 (1.9 mg). LC-MS (Method A): RT = 1.47 min, [M+H]+= 582.2; LC-MS (Method B): RT = 1.529 min, [M+H]+= 582.2.1H NMR (400 MHz, DMSO-d6): δ ppm 12.83 (br s, 1H), 7.83 (d, J = 2.3 Hz, 1H), 7.68 - 7.45 (m, 2H), 7.26 (d, J = 2.0 Hz, 1H), 7.24 - 7.11 (m, 2H), 7.10 - 6.88 (m, 1H), 5.58 (br s, 1H), 4.96 (br s, 1H), 4.58 (s, 2H), 4.38 (d, J = 6.8 Hz, 1H), 4.25 (br dd, J = 5.1, 13.4 Hz, 2H), 4.13 (br d, J = 6.8Hz, 1H), 4.06 - 3.92 (m, 1H), 3.87 (s, 3H), 3.79 – 3.76 (m, 1H), 3.61 – 3.58 (m, 1H), 3.29 - 3.23 (m, 2H), 2.89 - 2.76 (m, 1H), 2.73 - 2.64 (m, 1H), 2.57 (s, 3H), 0.80 (d, J = 6.8 Hz, 3H). Using similar procedures as that described for Example 5, the following Examples were synthesized from appropriate precursors, either prepared internally or obtained from commercial source. LC-MS LC- Exam pleStructure PrecursorsMethod MS RT (M+ Name (min) H)+(2S,4S)-4-((5-chloro-3- N N H1 + 2- ((S)-9-methyl-2,5- MeOExam N methoxy-6- dioxa-8- O ple N (4,4,5,5- azaspiro[3.5]nonan-8- OH 5-1 tetramethyl- A: 1.50583.2yl)pyridin-2-yl)oxy)-1- O 1,3,2-B: 1.55(6-(6-methoxypyridin- N dioxaborolan 2-yl)-2- O N -2- methylpyrimidin-4- O Cl yl)pyridine yl)pyrrolidine-2- carboxylic acid H (2S,4S)-4-((5-chloro-3- N 1 + S ((S)-9-methyl-2,5- N 4,4,5,5- Exam O tetramethyl- dioxa-8- ple N azaspiro[3.5]nonan-8- OH 2-(5- 5-2 methylthioph A: 1.54 yl)pyridin-2-yl)oxy)-1- OB: 1.54572.1(2-methyl-6-(5- N en-2-yl)- me O 1 thylthiophen-2- N ,3,2- dioxaborolan yl)pyrimidin-4- O Cl e yl)pyrrolidine-2- carboxylic acid Example 5-2:1H NMR (400 MHz, DMSO-d6): δ ppm 12.83 (br s, 1H), 7.83 (d, J = 2.3 Hz, 1H), 7.75 (br s, 1H), 7.25 (d, J = 2.3 Hz, 1H), 6.88 (dd, J = 1.0, 3.8 Hz, 1H), 6.78 (s, 1H), 5.55 (br s, 1H), 4.79 (dd, J = 3.0, 9.8 Hz, 1H), 4.65 - 4.53 (m, 2H), 4.40 (d, J = 6.8 Hz, 1H), 4.28 (br d, J = 7.0 Hz, 1H), 4.14 (d, J = 6.8 Hz, 2H), 3.81 - 3.67 (m, 2H), 3.66 - 3.55 (m, 1H), 3.29 - 3.21 (m, 2H), 2.89 - 2.76 (m, 1H), 2.73 - 2.64 (m, 1H), 2.48 (s, 3H), 2.36 (s, 3H), 0.81 (d, J = 6.8Hz, 3H). Example 6: (2S,4S)-4-((5-chloro-3-((S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8- yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(6-fluoropyridin-2-yl)pyrimidin-4- yl)pyrrolidine-2-carboxylic acid To a degassed solution of Intermediate H3 (20 mg, 0.04 mmol), 6-fluoropyridin-2- yl boronic acid (5.2 mg, 0.037 mmol), and K2CO3(2 M, 0.06 mL, 0.1 mmol) in Dioxane (2 mL), XPhos Pd G3 (3.1 mg, 3.7 µmol) was added. The reaction mixture was heated at 80 °C for 5 h. It was evaporated to dryness and purified by reverse phase chromatography to afford Example 6 (5 mg). LC-MS (Method A): RT = 1.53 min, [M+H]+= 607.2; LC- MS (Method B): RT = 2.04 min, [M+H]+= 607.2.1H NMR (400 MHz, DMSO-d6): δ ppm 8.30 (br d, J = 2.5 Hz, 1H), 8.24 - 8.13 (m, 1H), 7.84 (br d, J = 1.3 Hz, 1H), 7.38 - 7.21 (m, 3H), 6.96 - 6.54 (m, 1H), 5.68 - 5.37 (m, 1H), 4.97 - 4.70 (m, 1H), 4.64 - 4.50 (m, 2H), 4.40 (d, J = 6.8 Hz, 1H), 4.34 - 4.17 (m, 2H), 4.16 -4.02 (m, 1H), 3.89 - 3.71 (m, 2H), 3.66 - 3.58 (m, 1H), 3.24 - 3.14 (m, 1H), 2.97 - 2.78 (m, 1H), 2.73 - 2.56 (m, 2H), 0.86 - 0.67 (m, 3H). Using similar procedure as that described for Example 6, the following Examples were synthesized from noted intermediate and appropriate precursors, either commercially available or prepared internally. LC-MSExample StructureIntermeMethod LC-MS diateRT(M+H)+ Name(min) N N (2S,4S)-4-((5-chloro-3- Example O ((S)-9-methyl-2,5-dioxa- N 6-1 OH 8-azaspiro[3.5]nonan-8- H2A: 1.37538.2 yl)pyridin-2-yl)oxy)-1-(6- OB: 1.41phenylpyrimidin-4- N ONyl)pyrrolidine-2- carboxylic acid O Cl F F (2S,4S)-4-((5-chloro-3- N N O ((S)-9-methyl-2,5-dioxa- Example OH N 8-azaspiro[3.5]nonan-8- 6-2 H3 C: 3.45 588.1 yl)pyridin-2-yl)oxy)-1-(2- O (difluoromethyl)-6- N N phenylpyrimidin-4- O yl)pyrrolidine-2- Cl O carboxylic acid F F N (2S,4S)-4-((5-chloro-3- N O ((S)-9-methyl-2,5-dioxa- ExampleN NHOH N 8-azaspiro[3.5]nonan-8- 6-3 H3A: 1.38yl)pyridin-2-yl)oxy)-1-(2- B: 1.77578.1 (difluoromethyl)-6-(1H- O N pyrazol-5-yl)pyrimidin-4- ONyl)pyrrolidine-2- Cl carboxylic acid O F F (2S,4S)-1-(2- N N O (difluoromethyl)-6-(1H- ExampleN NHOH pyrazol-5-yl)pyrimidin-4- N 6-4A:yl)-4-((5-methyl-3-((S)-9- H41.31558.1methyl OB: 1.70-2,5-dioxa-8- azaspiro[3.5]nonan-8- N ONyl)pyridin-2- yl)oxy)pyrrolidine-2- CH O3carboxylic acid F O N F (2S,4S)-4-((5-chloro-3- Example N N ((S)-9-methyl-2,5-dioxa- O 6-5 O 8-azaspiro[3.5]nonan-8- N(S)OHA:yl)pyridin-2-yl)oxy)-1-(2- (S) H31.69B:2.649.1 (difluoromethyl)-6-(2,6- O24N dimethoxypyridin-3- yl)pyrimidin-4- O N (S)Cl yl)pyrrolidine-2- O carboxylic acid F F F (2S,4S)-4-((5-chloro-3- N N O ((S)-9-methyl-2,5-dioxa- Example N OH 8-azaspiro[3.5]nonan-8- 6-6 N yl)pyridin-2-yl)oxy)-1-(2- ONH3A:1.37B:1.83607.1 (difluoromethyl)-6-(3- fluoropyridin-4- NClyl)pyrimidin-4- O yl)pyrrolidine-2- O carboxylic acid F F (2S,4S)-4-((5-chloro-3- N ((S)-9-methyl-2,5-dioxa- Example N O N OH 8-azaspiro[3.5]nonan-8- 6-7 N N A:1yl)pyridin-2-yl)oxy)-1-(2- ONH3.51B:1.51632.2 (difluoromethyl)-6-(6- NCl(dimethylamino)pyridin- O 3-yl)pyrimidin-4- yl)pyrrolidine-2- O carboxylic acid F F (2S,4S)-4-((5-chloro-3- N N O ((S)-9-methyl-2,5-dioxa- Example N OH 8-azaspiro[3.5]nonan-8- 6-8 N FA:1.47yl)pyridin-2-yl)oxy)-1-(2- ONH3B:1.97607.2 (difluoromethyl)-6-(2- fluoropyridin-4- NClyl)pyrimidin-4- O yl)pyrrolidine-2- O carboxylic acid F F (2S,4S)-1-(2'-amino-2- N (difluoromethyl)-[4,5'- N N O Example H N OH bipyrimidin]-6-yl)-4-((5- N N 6-9A:1.25chloro-3-((S)-9-methyl- ONH3B:1.56605.1 2,5-dioxa-8- NClazaspiro[3.5]nonan-8- O yl)pyridin-2- O yl)oxy)pyrrolidine-2- carboxylic acid F F (2S,4S)-4-((5-chloro-3- N e N O ((S)-9-methyl-2,5-dioxa- Exampl F F N OH 8-azaspiro[3.5]nonan-8- 6-10 F N N A:1.yl)pyridin-2-yl)oxy)-1-(2- ONH362B:2.13657.1 (difluoromethyl)-6-(2- (trifluoromethyl)pyridin- NClO 4-yl)pyrimidin-4- yl)pyrrolidine-2- O carboxylic acid F F (2S,4S)-4-((5-chloro-3- N N O ((S)-9-methyl-2,5-dioxa- Example F OH 8-azaspiro[3.5]nonan-8- 6-11 N FFyl)pyridin-2-yl)oxy)-1-(2- FA: 1.86ONH3B: 2.38674.1(difluoromethyl)-6-(4- fluoro-3- NClO (trifluoromethyl)phenyl)p yrimidin-4-yl)pyrrolidine- O 2-carboxylic acid F F (2S,4S)-1-(6-(3- N (carboxymethyl)phenyl)- N O Example OH 2- 6-12 N (difluoromethyl)pyrimidin OHA: 1.11-4-yl)-4-((5-chloro-3-((S)- OO NH3B: 1.84646.1 9-methyl-2,5-dioxa-8- N Cl azaspiro[3.5]nonan-8- O yl)pyridin-2- yl)oxy)pyrrolidine-2- O carboxylic acid F F (2S,4S)-4-((5-chloro-3- F N N O ((S)-9-methyl-2,5-dioxa- Example OH 8-azaspiro[3.5]nonan-8- 6-13 N yl)pyridin-2-yl)oxy)-1-(2- ONH3A: 1.66B: 2.25620.1 (difluoromethyl)-6-(2- fluoro-3- NClO methylphenyl)pyrimidin- 4-yl)pyrrolidine-2- O carboxylic acid F F F (2S,4S)-4-((5-chloro-3- N N O ((S)-9-methyl-2,5-dioxa- Example OH 8-azaspiro[3.5]nonan-8- 6-14 N yl)pyridin-2-yl)oxy)-1-( ON3A:2- H1.68B: 2.26620.1 (difluoromethyl)-6-(2- fluoro-4- NClmethylphenyl)pyrimidin- O 4-yl)pyrrolidine-2- O carboxylic acid F F (2S,4S)-4-((5-chloro-3- N Example F N O ((S)-9-methyl-2,5-dioxa- OH 6-15 F N 8-azaspiro[3.5]nonan-8- A: 1.yl)pyridin-2-yl)oxy)-1-(2- ONH365B: 2.17638.1 (difluoromethyl)-6-(4- N Cl (difluoromethyl)phenyl)p O yrimidin-4-yl)pyrrolidine- O 2-carboxylic acid F F (2S,4S)-4-((5-chloro-3- N N O ((S)-9-methyl-2,5-dioxa- Example F OH 8-azaspiro[3.5]nonan-8- N 6-16A: 1.75yl)pyridin-2-yl)oxy)-1-(2- ONH3B: 2.31620.2(difluoromethyl)-6-(4- fluoro-3- NClO methylphenyl)pyrimidin- 4-yl)pyrrolidine-2- O carboxylic acid F F (2S,4S)-4-((5-chloro-3- N N O ((S)-9-methyl-2,5-dioxa- Example Cl OH 8-azaspiro[3.5]nonan-8- 6-17 N FA: 1.76yl)pyridin-2-yl)oxy)-1-(6- ONH3B: 2.33640.1 (4-chloro-3- fluorophenyl)-2- N Cl O (difluoromethyl)pyrimidin -4-yl)pyrrolidine-2- O carboxylic acid F F N (2S,4S)-4-((5-chloro-3- N O OH ((S)-9-methyl-2,5-dioxa- Example N 8-azaspiro[3.5]nonan-8- 6-18 F H3A: 1.57606 yl)pyridin-2-yl)oxy)-1-(2- ON B: 2.15(difluoromethyl)-6-(2- NClfluorophenyl)pyrimidin-4- O yl)pyrrolidine-2- O carboxylic acid F F (2S,4S)-1-(2- N Example N O (difluoromethyl)-6-(4- OH 6-19 F fluorophenyl)pyrimidin-4- N H4 A:1.49 yl)-4-((5-methyl-3-((S)-9- ON B:2.03586.1methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8- N yl)pyridin-2- O yl)oxy)pyrrolidine-2- O carboxylic acid F F (2S,4S)-1-(2- Example N N O (difluoromethyl)-6-(m- OH 6-20 tolyl)pyrimidin-4-yl)-4- N H4 A:2.32 ((5-methyl-3-((S)-9- ON B:2.32582.2methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8- N yl)pyridin-2- O yl)oxy)pyrrolidine-2- O carboxylic acid F (2S,4S)-1-(2- F (difluoromethyl)-6-(3- Example N N O (trifluoromethyl)phenyl)p 6-21 OH N yrimidin-4-yl)-4-((5- FFF H4 A:1.84636.2methyl-3-((S)-9-methyl- ON B:2.422,5-dioxa-8- N azaspiro[3.5]nonan-8- O yl)pyridin-2- O yl)oxy)pyrrolidine-2- carboxylic acid F F (2S,4S)-1-(6-(3- Example N N O chlorophenyl)-2- OH 6-22 (difluoromethyl)pyrimidin N Cl H4 A:1.78 -4-yl)-4-((5-methyl-3- ON B:2.38602.2((S)-9-methyl-2,5-dioxa- 8-azaspiro[3.5]nonan-8- N yl)pyridin-2- O yl)oxy)pyrrolidine-2- O carboxylic acid F F (2S,4S)-1-(2- N N O (difluoromethyl)-6-(3- Example OH methoxyphenyl)pyrimidin 6-23 N O H4 A:1.63 -4-yl)-4-((5-methyl-3- ON B:2.20598.3((S)-9-methyl-2,5-dioxa- 8-azaspiro[3.5]nonan-8- N O yl)pyridin-2- yl)oxy)pyrrolidine-2- O carboxylic acid F F (2S,4S)-1-(2- N (difluoromethyl)-6-(5- Example N O OH methylthiophen-2- 6-24 S N yl)pyrimidin-4-yl)-4-((5- H4 A:1.51 B:2.0758methyl-3-((S)-9-methyl- ON8.12,5-dioxa-8- N azaspiro[3.5]nonan-8- O yl)pyridin-2- yl)oxy)pyrrolidine-2- O carboxylic acid F F (2S,4S)-1-(6-(5- Example N N O cyanothiophen-2-yl)-2- 6-25 OH S (difluoromethyl)pyrimidin N N H4 A:1.53 -4-yl)-4-((5-methyl-3- ON B:1.99599.1((S)-9-methyl-2,5-dioxa- 8-azaspiro[3.5]nonan-8- N O yl)pyridin-2- yl)oxy)pyrrolidine-2- O carboxylic acid F F (2S,4S)-1-(6-(4- N cyclopropylphenyl)-2- N O OH (difluoromethyl)pyrimidin N Example H4 A:2.24 -4-yl)-4-((5-methyl-3- 6-26O N B:1.7608.3((S)-9-methyl-2,5-dioxa- 8-azaspiro[3.5]nonan-8- N O yl)pyridin-2- yl)oxy)pyrrolidine-2- O carboxylic acid F F (2S,4S)-1-(2- F Example N (difluoromethyl)-6-( N O 2,6- 6-27 OH difluorophenyl)pyrimidin- N F H4 A:1.42 4-yl)-4-((5-methyl-3-((S)- ON B:1.93604.29-methyl-2,5-dioxa-8- azaspiro[3.5]nonan-8- N O yl)pyridin-2- yl)oxy)pyrrolidine-2- O carboxylic acid F (2S,4S)-1-(2- F F (difluoromethyl)-6-(3 Example F - N N O OH (difluoromethyl)phenyl)p 6-28 N yrimidin-4-yl)-4-((5- H4 A:1.57 methyl-3-((S)-9- OB:2.0861methyl- N8.12,5-dioxa-8- N azaspiro[3.5]nonan-8- O yl)pyridin-2- O yl)oxy)pyrrolidine-2- carboxylic acid Example 7: (2S,4S)-4-((5-cyclopropyl-3-((S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8- yl)pyridin-2-yl)oxy)-1-(2-(difluoromethyl)-6-(6-ethoxypyridin-2-yl)pyrimidin-4- yl)pyrrolidine-2-carboxylic acid To a degassed solution of Example 1, cyclopropylboronic acid (41 mg, 0.47 mmol), XPhos Pd G3 (12 mg, 0.014 mmol) and K2CO3(26.2 mg, 0.19 mmol) in Dioxane (2 mL) and water (0.2 mL), Pd(PPh3)4(16.4 mg, 0.014 mmol) was added. The reaction mixture was heated at 105 °C for 12 h. The reaction mixture was evaporated to dryness and purified by Prep-HPLC (Method: Column: Xbridge C18, 150 x 19 mm, 5 µm particles; Mobile Phase A: 10 mM Ammonium acetate pH-4.5 with CH3COOH; Mobile Phase B: acetonitrile; Gradient: 10-50% B over 10 minutes, then a 5-minute hold at 50% B; Flow: 20 mL / min) to afford Example 7 (10 mg). LC-MS (Method A): RT = 1.89 min, [M+H]+= 639.2; LC-MS (Method B): RT = 2.48 min, [M+H]+= 639.2.1H NMR (400 MHz, DMSO-d6): δ ppm 7.99 - 7.93 (m, 1H), 7.91 - 7.81 (m, 1H), 7.59 (d, J = 1.5 Hz, 1H), 7.53 - 7.35 (m, 1H), 6.95 (br d, J = 4.5 Hz, 1H), 6.84 (d, J = 1.8 Hz, 1H), 6.79 - 6.50 (m, 1H), 5.62 - 5.37 (m, 1H), 4.93 - 4.72 (m, 1H), 4.69 - 4.59 (m, 1H), 4.59 - 4.54 (m, 1H), 4.52 - 4.33 (m, 3H), 4.30 - 4.03 (m, 3H), 3.86 - 3.72 (m, 2H), 3.64 - 3.58 (m, 1H), 3.26 - 3.19 (m, 2H), 3.02 - 2.82 (m, 1H), 2.59 – 2.54 (m, 1H), 1.93 - 1.77 (m, 1H), 1.38 – 1.23 (m, 3H), 0.97 - 0.86 (m, 2H), 0.76 (br d, J = 6.8 Hz, 3H), 0.71 - 0.60 (m, 2H). Using similar procedures as that described for Example 7, the following Examples were synthesized from appropriate precursors, either prepared internally or acquired from commercial source.1H NMR spectral data and, where relevant, preparative conditions used to separate diastereomers (resultant individual isomers are designated as Iso-1 & Iso- 2) are provided below the table. LC-MS Example Structure Precursors Method LC-MS (+RT (min) M+H) NCHF2Example 1 + ONN 2-(2,5- O Example N dihydrofuran 7-1 OH -3- yl)- O 4,4,5,5- A: 1.656NB: 2.2467.3tetramethyl- O N 1,3,2- dioxaborolan O O eN CHF2ONN O Example N 7-2 OH Example 1 + A: 1.72 O E1724.3N 6B: 2.29O N O NCOOMeF F S N N O OH Example N 7-3 Example 1-1 A: 1.67 O + E16a699.2NB: 2.21ONO N O O F F S N N O Example OH N 7-4 Example 1-1 O N+ E16bC: 3.50 713.1O N O N O O F F S N N O Example OH N 7-5 Example 1- A: 1.65 O N 23 + E16cB: 2.07711.2O N O N O O F F S N N O Example OH N 7-6 Example 1- O NC: 3.55 72N23 + E16d5.1O O N O O F F S N N O Example OH N 7-7 Example 1- A: 1.45 O N 23 + E16eB: 1.86727.2ONO N O O O F F S N N O OH Example N 7-8 Example 1-1 A: 1.94 O + E16f727.2NB: 2.40ONO N O O F NCHF2N Example 1-2 F O N + 2-(2,5- O Example N Dihydrofuran 7-9 OH -3-yl)- 4,4, A: 1.73 O 5,5-B689.2tetrame: 2.28N thyl- O N 1,3,2- dioxaborolan O O e F NCHFFONN O Example N 7-10 OH Example 1-2 O+ E1C: 3.32 746.2N6O N O NCOOMeFN CHFF ONN Example O N Example 1-2 7-11 OH + A: 1.93 O cyclopropylb661.2NB: 2.48O N oronic acid O FN CHF2Example 1-2 F ONN + 2-(3,6- O Example N dihydro-2H- OH 7-12 pyran-4-yl)- O 4,4,5,5- C: 3.41 703.3 N O N tetramethyl- 1,3,2- O dioxaborolan O e FN CHF2FONN O Example N Example 1-2 OH 7-13 + 4- O methoxyphen A: 1.94 NB: 2.39727.2ONylboronic acid O OMe F NCHF2FONN O N Example OH Example 1-2 7-14 O + 4- A: 1.85 N cyanophenylB: 2.29722.2O N boronic acid O CN CHF N2S N O Example N OH 7-15 Example 1- A: 1.91 O677.2N 17 + E16B: 2.40F N F NCOOMe F F S N N O Example 1- Example OH N 23 + 7-16 Potassium A: 1.32 trifluoro616.2O (oxetB:1.75N an-3- ONyl)borate O O F F N N O O Example 1- N H Example N MeO 78 + 2- 7-17 difluorometh A: 1.64 O yl pyridin-4-712.2NB: 2.14ONyl)boronic F acid O NFS NCHF2N O N Example OH 7-18 O Example 1-1 A: 1.55 N + E16B: 2.09685.2ONO NOO S NCHF2N O Example N Example 1-1 7-19 OH + A: 1.70 O cyclopropylbB: 2.24600.2N oronic acid O N O S NCHF2Example 1-1 N + 2-(2,5- O Example N dihydrofuran OH 7-20 -3-yl)- 4,4 A: 1.50 O ,5,5-628.2N tetramethyl-B: 2.02O N 1,3,2- dioxaborolan O O e S NCHF2Example 1-1 N O + 2-(3,6- Example N dihydro-2H- OH 7-21 pyran-4-yl)- 4,4 A: 1.59 O ,5,5-642.2N tetramethyl-B: 2.13O N 1,3,2- O dioxaborolan e O S NCHF2N O N Example OH 7-22 O Example 1- A: 1.67 N 24 + E16B: 2.22699.1O N O NOO S NCHF2N O N Example OH 7-23 Example 1- O 24 C: 3.19 727.2 N O N E16b O NOO S NCHF2Example 1- 24 N O + 2-(2,5- Example N OH dihydrofuran 7-24 -3-yl)- A: 1.67 O 4,4,5,5-642.1NB: 2.22O N tetramethyl- 1,3,2- O dioxaborolan O e S NCHF2N O N Example OH 7-25 Example 1- O 28 + E16 A: 1.69 NB: 2.13713.2O N O N O O S NCHF2N O N OH Example 7-26 O Example 1- A: 1.94 N 28 +741.3O N E16bB: 2.41O N O O S NCHF2N O N Example OH 7-27 O Example 1- A: 1.70 N 37 + E16B:2.24663.1N F F NOO S NCHF2N Example 1- O N 37 + 2- Example OH fluoro-4- 7-28 (4,4,5,5- O A:1.61 N tetramethyl- -B:2.675.2N 1,3,213F F dioxaborolan F -2- yl)benzamide NH2 O S NCHF2Example 1- N 37 + 3- O Example N (4,4,5,5- OH 7-29 tetramethyl- O 1,3,2- A:1.84 N rolanB:2.3639.2dioxabo0N -2- F F yl)benzonitril CN e S NCHF2Example 1- N 37 + 2-(2,5- O Example N dihydrofuran OH 7-30 -3-yl)- A:2 O 4,4,5,5- .01 N hyl-B:2.24606.2tetramet N 1,3,2- F F dioxaborolan O e S NCHF2Example 1- N 37 + 2-(3,4- O N dihydro-2H- Example OH pyran-5-yl)- 7-31 A:1. O 4,4,5,5- 72 N methyl-B:2620.1tetra.27N 1,3,2- F F dioxaborolan O e S NCHF2N Example 1- O 37 + 2-(3- Example N OH methoxyphen 7-32 yl)-4,4,5,5- A:1.94 O tetramethyl-B:2.41644.2N N 1,3,2- F dioxaborolan F OMe e S NCHF2N O Example N OH 7-33 Example 1- A:1.66 O677.2N 37 + E16gB:2.19N F F O N O S NCHF2Example 1- N O 37 + 2-(3,6- Example N dihydro-2H- OH 7-34 pyran-4-yl)- 4, A:1.71 O 4,5,5-620.2N tetramethyl-B:2.28N 1,3,2- F F dioxaborolan e O S NCHF2N O N Example OH 7-35 O Example 1- A:1.73 38 + E16B663.2F N:2.29N F NOO S NCHF2N O N Example OH 7-36 Example 1- A:1.66 O 38 + E16677.1N gB:2.22F N F O N O S NCHF2Example 1- N 38 + 2-(2,5- O Example N dihydrofuran OH 7-37 -3-yl)- 4,4,5 A:1.81 O ,5-B:2.606.1tetramethy42F N l- N F 1,3,2- dioxaborolan O e S NCHF2Example 1- N 38 + 2-(3,4- O Example N dihydro-2H- OH 7-38 pyran-5-yl)- 4, A:1.81 O 4,5,5-620.1tetramB:2.34F N ethyl- N F 1,3,2- dioxaborolan O e S NCHF2N O Example N OH Example 1- 7-39 38 + 3- A:1.92 O cyanophenyl639.2NB:2.39F N boronic acid F CN S NCHF2N Example 1- O 38 + 2-(3- Example N OH methoxyphen 7-40 yl)-4,4,5,5- A:1.95 O tetramethyl-644.2NB:2.45F N 1,3,2- F dioxaborolan OMe e S NCHF2N O N Example OH 7-41 O I1 + E16A:1.64B:2.649.2 N12N F F NOO S NCHF2N I1 + 2-(3,4- O dihydro-2H- Example N OH pyran-5-yl)- 7-42 4,4,5,5- A:1.64 O tetramethyl-606.1NB:2.12N 1,3,2- F F dioxaborolan O e S NCHF2I1 + 2-(2,5- N O dihydrofuran Example N OH -3-yl)- 7-43 4,4,5,5- A:1.59 O tetramethyl-B:2.592.1N12N 1,3,2- F dioxaborolan F e O S NCHF2N I1 + 2-(3- O Example N methoxyphen OH 7-44 yl)-4,4,5,5- tetr A:1.92 O amethyl- N ,3,2-B630.21:2.42N F dioxaborolan F e OMe S NCHF2N I1 + 3- O (4,4,5,5- Example N OH tetramethyl- 7-45 1,3,2- A:1.83 O dioxaborolanB:2625.1N.31N -2- F F yl)benzonitril CN e S NCHF2N O Example N OH 7-46 O I1 + E16gA:1.66B:2.22663.2 N N F F O N O S NCHF2N O Example N OH 7-47 (Iso-1) O Example I1d A:1.72 N + E16B:2.17677.2N F F NO...

Claims

WHAT IS CLAIMED IS:

1. A compound having formula (I), or salt thereof,wherein, independently for each occurrence: R1is −CH= or −N=; R2is −N= or −C(R2a)=; wherein at least 2 of R1s and R2are N; R2ais H or F; R3is −H, −CH3, -OH, −OCH3, −N(CH3)2, −OCH2CH2OH, C1-2alkyl, C1-2alkoxy, C1-2fluoroalkyl, C1-2fluoroalkoxy, cyclopropyl, flurocyclopropyl, 2,5˗dihydrofuran-3- yl, or 3,3-difluoroazetidin-1-yl; R4is 2-(difluoromethyl)morpholin-4-yl,,R5is −H, halo, −CN, C1-6alkyl, C1-6alkenyl, C1-6haloalkyl, C1-3alkoxy, C1-3fluoroalkoxy, C3-6cycloalkyl, C1-3alkoxy, C1-3fluoroalkoxy, cyclohexenyl, C3-6cycloalkyl-ethynyl, C3˗6 cycloalkyl-ethenyl, C4-6 alkoxymethyl-alkynyl, phenyloxy, pyridinyloxy, pyrmidinyloxy, pyrazolyloxy, , fluorophenyloxy, -C1-6- alkyl-R15, ˗C2-6-alkenyl-R15, ˗C2˗6˗alkynyl-R15, ˗OC(O)NRaR15,˗(CH2)n˗OC(O)˗R15, ˗C2˗6˗alkynyl-R16, ˗NH(CO)-Ra, ˗NH(CO)˗phenyl, ˗NH(CO)- (fluorophenyl), a ˗(CH2)n- 4-10 membered heterocycle having 1-3 heteroatoms selected from N, O and S, a –(CH2)n-5-10 membered heteroaryl having 1-3 heteroatoms selected from N, O and S, -S(O)2-C1-4alkyl, -S(O)2-C3-5cycloalkyl, - S(O)2- C4-6cycloalkylalkyl, -CH2-N(Ra)2, –(CH2)n˗N(Ra)C(O)Ra, ,, wherein the cycloalkyl, cyclohexenyl, phenyl, phenyloxy, pyridyloxy, pyrmidinyloxy, pyrazolyloxy, heterocycle or heteroaryl are substituted with 0-3 R5a; R5ais halo, =O, CN, C1-6alkyl, C1-6hydroxyalkyl, C1-6alkoxy, C1-6haloalkyl, C3-6cycloalkyl substituted with 0-1 -CH2OH, phenyl substituted with 0-1 F, -C(O)O- C1-6alkyl, ˗N(Ra)2, -C(O)N(Ra)2, -O-Ra, -C(O)C1-6alkyl, or C(O)-R14,-S(O)2-C1-6alkyl, azetidinyl substituted with 0-2 substituents selected from -CH3or F, morpholinyl, or pyrazolyl; Rais H, C1-6alkyl, C1-6fluoroalkyl, C3-6cycloalkyl, C3-6cyclofluoroalkyl, fluorophenyl, or pyridinyl; R6is imidazolyl, furanyl, pyrazolyl, thiazolyl, thiophenyl, pyrrolyl, pyridazinyl, pyrazinyl, or isothiazolyl, any of which are substituted with 0-2 R6a; or R6is phenyl, or pyridinyl, either of which are substituted with 0-4 R6b; R6ais H, halo, CN, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, cyclopropyl, or phenyl;R6bis H, halo, CN, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, C1-3haloalkoxy, -N(Ra)2, C3˗6cycloalkyl, C3-6cycloalkoxy, -CH2COOH , or ˗O˗(C1˗3alkyl)˗C(O)N(Ra)2,or 4 to 6 membered heterocycle; R7is −H, -OH, or −F, or -S(O)2-C1-3alkyl; R8is H, -C(O)OCH3, or -C(O)CH3, -C(O)-C1-3alkoxyalkyl, -C(O)-CH2CH2N(CH3)2, - C(O)-CH2S(O)2CH3, -C(O)O-tetrahydrofuranyl,; R9is −H, −CH3,-CH2CH3, CF3, -CHF2, CHF2, -CH2OH,or cyclopropyl; R10is −H, −F, −OCH3, −OCHF2, or C1-2hydroxyalkyl; R11is −H, −F, or −OCH3, or -OCHF2; R12is H, C1-3alkyl, C1-3hydroxyalkyl, C1-2fluoroalkyl, -CH2OCH3, and R14is C3-6cycloalkyl, C3-6cycloalkoxy, oxetan-3-yloxy, or –ORa; R15is phenyl, azaspiro[3.3]heptanyl, azabicyclo[2.2.1]heptanyl, oxa- azabicyclo[3.2.1]octanyl, oxa-azabicyclo[3.1.1]heptanyl, azabicyclo[2.2.2]octanyl, diazabicyclo[3.2.1]octanyl, azepanyl, azaspiro[3.4]octanyl, oxa- azabicyclo[3.2.1]octanyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, pyridinyl, pyrimidinyl, pyrazinyl, -N(Ra)2, -OC(O)N(Ra)2, wherein the phenyl, piperidinyl, morpholinyl, pyrrolidinyl, pyridinyl, pyrimidinyl, pyrazinyl are substituted with 0-2 substituents selected from F, CH3, OH, C1-2fluoroalkyl, C1-2alkoxy; and R16is -H, -F, or -OH.

2. A compound of claim 1, or salt thereof, wherein, R1is −CH= or −N=; R2is −N= or −C(R2a)=; wherein at least 2 of R1s and R2are N; R2ais H or F; R3is −H, −CH3, −OCH3, −N(CH3)2, −OCH2CH2OH, C1-2alkyl, C1-2alkoxy, C1-2fluoroalkyl, C1-2fluoroalkoxy, cyclopropyl, flurocyclopropyl, 2,5˗dihydrofuran-3- yl, or 3,3-difluoroazetidin-1-yl;R4is 2-(difluoromethyl)morpholin-4-yl, ,R5is −H, halo, −CN, C1-6alkyl, C1-6haloalkyl, C1-3alkoxy, C1-3fluoroalkoxy, C3-6cycloalkyl, C1-3alkoxy, C1-3fluoroalkoxy, cyclohexenyl, C3-6cycloalkyl-ethynyl, C3˗6cycloalkyl-ethenyl, C4-5alkoxymethyl-alkynyl, phenyloxy, pyridyloxy,fluorophenyloxy, phenyl, a 5-6 membered heterocycle, a 5-6 membered heteroaryl, -S(O)2-C1-4alkyl, -S(O)2-C3-5cycloalkyl, -S(O)2-C1-4C4-6cycloalkylalkyl,wherein the cycloalkyl, cyclohexenyl, phenyl, heterocycle or heteroaryl are substituted with 0-2 R5a; R5ais halo, CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C(O)O-C1-6alkyl, C(O)N(Ra)2, O-Ra, C(O)C1-6alkyl, or C(O)-R14; Rais H, or C1-6alkyl, C1-6fluoroalkyl, C3-6cycloalkyl, or C3-6cyclofluoroalkyl; R6is imidazolyl, furanyl, pyrazolyl, thiazolyl, thiophenyl, pyrrolyl, pyridazinyl, pyrazinyl, or isothiazolyl, any of which are substituted with 0-2 R6a; or R6is phenyl, or pyridinyl, either of which are substituted with 0-4 R6b; R6ais H, halo, CN, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, cyclopropyl, or phenyl; R6bis H, halo, CN, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, C1-3haloalkoxy, -N(Ra)2, C3˗6cycloalkyl, C3-6cycloalkoxy, -CH2COOH , or ˗O˗(C1˗3alkyl)˗C(O)N(Ra)2,or 4 to 6 membered heterocycle; R7is −H, -OH, or −F; R8is H, -C(O)OCH3, or -C(O)CH3; R9is −H, −CH3, -CH2CH3, CF3, -CHF2, CHF2, -CH2OH, or cyclopropyl; R10is −H, −F, −OCH3, −OCHF2, or C1-2hydroxyalkyl; R11is −H, −F, or −OCH3, or -OCHF2; R12is H, C1-3alkyl, C1-3hydroxyalkyl, C1-2fluoroalkyl, -CH2OCH3, and R14is C3-6cycloalkyl, C3-6cycloalkoxy, oxetan-3-yloxy, or –ORa.

3. The compound of claims 1-2, wherein compound for Formula (I) is a compound of Formula (Ia), or salt thereof4. The compound of claims 1-3, wherein the compound is a compound of Formula (2a), (2b), (2c), or (2d), or salt thereof5. The compound of claims 1-4, or salt thereof, wherein R5is −H, halo, −CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, cyclohexenyl, C3-6cycloalkyl-ethynyl, C3-6cycloalkyl-ethenyl, phenyl, a 5-6 membered heterocycle, wherein the heterocycle is oxetanyl, oxolanyl, dihydrofuranyl, dihydropyranyl, dihydropyrrolyl, dihydropyridinyl, or tetrahydropyridinyl, or a 5-6 membered heteroaryl, wherein the heteroaryl is pyridinyl, furanyl, or benzofuranyl wherein the cycloalkyl, cyclohexenyl, phenyl, heterocycle or heteroaryl are substituted with 0-1 R5a.

6. The compound of claims 1-5, or salt thereof, wherein R4is 2-(difluoromethyl)morpholin-4-yl,7. The compound of claims 1-6, or salt thereof, wherein R6is imidazolyl, furanyl, pyrazolyl, thiazolyl, thiophenyl, pyrrolyl, or pyrazolyl, any of which are substituted with 0-2 R6a.

8. The compound of claims 1-7, or salt thereof, whereinR5is − C3-6cycloalkyl-ethynyl, phenyl, a 5-6 membered heterocycle, wherein the heterocycle is oxetanyl, oxolanyl, dihydrofuranyl, dihydropyranyl, dihydropyrrolyl, dihydropyridinyl, or tetrahydropyridinyl, or a 5-6 membered heteroaryl, wherein the heteroaryl is pyridinyl, wherein the cycloalkyl, cyclohexenyl, phenyl, heterocycle or heteroaryl are substituted with 0-1 R5a.

9. The compound of claims 1-8, wherein R4isR9is selected from H, CH3, CHF2, CH2CH3,CF3, CH2F, or cyclopropyl.

10. The compound of claims 1-9, or salt thereof, wherein R6is phenyl or pyridinyl, either of which are substituted with 0-4 R6b.

11. The compound of claims 1-6 and 8-9, or salt thereof, wherein R6is furanyl, thiophenyl, pyrrolyl, any of which are substituted with 0-2 R6a; and R6ais H, Cl, CH3, CH2CH3, methoxy, or cyclopropyl.

12. A compound of claim 1, or salt thereof, wherein the compound is selected from the Examples.

13. A pharmaceutical composition comprising one or more compounds of claims 1-12, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

14. A method of inhibiting cGAS activity in a patient, comprising administering to the patient in need thereof, a therapeutically effective amount of one or more compounds according to claims 1-12.

15. A method for treating a disease comprising the administration to a subject in need thereof a therapeutically˗effective amount of at least one compound of claims 1-12, wherein the disease is selected from scleroderma (SSc), systemic lupus erythematosus (SLE), Aicardi- Goutières syndrome (AGS), amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), chronic obstructive pulmonary disease (COPD), Sjögren’s syndrome, type 1 diabetes, rheumatoid arthritis (RA), senescence, STING-associated vasculopathy with onset in infancy (SAVI), silicosis, inflammation associated with aging, inflammatory bowel disease (IBD), and neurodegenerative disease caused by traumatic injury.

16. A method for treating a disease comprising the administration to a subject in need thereof a therapeutically˗effective amount of at least one compound of claims 1-12, wherein the disease is selected from multiple sclerosis, psoriasis, idiopathic pulmonary fibrosis (IPF), atherosclerosis, hypertension, dermatomyositis, prostate cancer, pancreatic cancer, Parkinson’s disease, pancreatitis (acute or chronic), Huntington disease, breast cancer, ovarian cancer, COPA syndrome, nonalcoholic steatohepatitis (NASH), sepsis, myocardial infarction, chronic heart failure, atopic dermatitis, melanoma, asthma, colorectal cancer, lung cancer, and macular degeneration.

17. A method for treating a disease comprising the administration to a subject in need thereof a therapeutically˗effective amount of at least one compound of claims 1-12, wherein the disease is selected from scleroderma (SSc) and systemic lupus erythematosus (SLE).

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