Therapeutic compounds and methods of use thereof

Abstract

The invention provides a compound of formula I: or a salt thereof, wherein R1, R2, A, B, D, E, F, G, and X have any of the values described in the specification, as well as compositions comprising a compound of formula I. The compounds are useful as bromodomain inhibitors.

Description

[0001] THERAPEUTIC COMPOUNDS AND METHODS OF USE THEREOF CROSS-REFERENCE TO RELATED APPLICATION This application claims priority to United States Provisional Application Number 63 / 702,964 that was filed on October 3, 2024 and United States Provisional Application Number 63 / 848,791 that was filed on July 22, 2025. The entire content of the applications referenced above is hereby incorporated by reference herein. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH This invention was made with government support under GM140837 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND OF THE INVENTION Bromodomains act as “readers” for epigenetic modifications. Specifically, they bind N-ε- acetylated lysine residues on histones and transcription factors through protein-protein interactions to regulate cellular processes including the cell cycle, proliferation, and cellular differentiation (Filippakopoulos, P. et al. FEBS Lett.2012, 586, 2692–2704). The 61 human bromodomains, which are contained in 46 proteins, have been subdivided into eight classes based on structural or sequence similarities (Pervaiz, M. et al. Chem. Rec.2018, 18, 1–11). The Bromodomain and Extra Terminal (BET) family, which includes BRD2, BRD3, BRD4 and BRDT, has a similar domain architecture, including two tandem bromodomains and an extra- terminal domain. Inhibiting the protein-protein interactions between BET bromodomains and N-ε- acetylated lysine residues is a key target for potential treatment of BET related diseases, including cancer, inflammation and heart diseases (Pervaiz, M. et al. Chem. Rec.2018, 18, 1–11; Gallinari, P. et al. Cell Res.2007, 17, 195; Andrieu, G. et al. Drug Discov. Today Technol.2016, 19, 45–50 and Bhattacharya, S. et al. Clin. Adv. Hematol. Oncol.2018, 16, 504–515). For example, BRD4 can recognize N-ε-acetylated Lys310 in the RelA subunit of NF-κB, which is important for the activation of NF-κB, following inflammatory signaling (Huang, B. et al. Mol. Cell. Biol.2008, 29, 1375–1387). Additionally, the bromodomains of BRD4 and BRDT can recognize N-ε-acetylated lysine residues on histones and recruit transcription factors to super- enhancer regions. Inhibition of BRD4 at super-enhancer regions can reduce c-Myc expression, which could be a therapeutic strategy for treating cancer (Delmore, J. E. et al. Cell 2011, 146, 904–917). Given the significant roles that BET bromodomains play in oncogene expression and in inflammation, 19 clinical trials are underway to assess the therapeutic effects of BET inhibition. Several dual kinase-bromodomain inhibitors were discovered by screening kinase inhibitor libraries against BRD4-D1 (Ember, S. W. J. et al. ACS Chem. Biol.2014, 9, 1160– 1171; Carlino, L. et al. J. Med. Chem.2016, 59, 9305–9320; Boehm, J. C. et al. Bioorg. Med. Chem. Lett.2001, 11, 1123–1126; Ciceri, P. et al. Nat. Chem. Biol.2014, 10, 305–312; Martin, M. P. et al. ACS Chem. Biol.2013, 8, 2360–2365 and Urick, A. K. et al. ACS Chem. Biol.2015, 10, 2246–2256). In 2014, both Ciceri et al. and Ember et al. identified several dual kinase- bromodomain inhibitors including BI-2536, a PLK1 inhibitor with high affinity against BRD4- D1 (Ember, S. W. J. et al. ACS Chem. Biol.2014, 9, 1160–1171 and Ciceri, P. et al. Nat. Chem. Biol.2014, 10, 305–312) The dihydropteridinone carbonyl and the methylamino group function as the N-ε-acetylated lysine mimic. P38-BET inhibitors including SB-202190 and SB-203580 were also identified. Similarly, the CDK inhibitor Dinaciclib functions as a BRDT inhibitor (Martin, M. P. et al. ACS Chem. Biol.2013, 8, 2360–2365). The pyridine oxide serves as the N- ε-acetylated lysine mimic and is recognized by Asn109 on BRDT. Although modest in affinity, the molecule is of historical note, as the first dual kinase-bromodomain inhibitor reported. Since these reports, developing bromodomain inhibitors by kinase library screening has attracted more attention (Ember, S. W. J. et al. ACS Chem. Biol.2014, 9, 1160–1171; Ciceri, P. et al. Nat. Chem. Biol.2014, 10, 305–312; Urick, A. K. et al. ACS Chem. Biol.2015, 10, 2246–2256 and Ayaz, M. et al. Mol. Cancer Ther.2017, 16, 1054–1067). Urick et al. screened a library of 229 small molecules by protein-observed fluorine NMR and subsequently developed a dual p38α-BRD4- D1inhibitor named V (Urick, A. K. et al. ACS Chem. Biol.2015, 10, 2246–2256 and Divakaran, A. et al. J. Med. Chem.2018, 61, 9316–9334). While BI-2536 and Dinaciclib are pan-BET inhibitors, V was shown to selectively inhibit the N-terminal BET bromodomains with highest affinity for BRD4. Although, dual kinase-bromodomain inhibitors may produce synergistic effects in some cases (Carlino, L. et al. J. Med. Chem.2016, 59, 9305–9320; Ciceri, P. et al. Nat. Chem. Biol.2014, 10, 305–312; Ayaz, M. et al. Mol. Cancer Ther.2017, 16, 1054–1067 and Watts, E. et al. J. Med. Chem.2019, 62, 2618–2637), selective inhibition is ideal for understanding the physiological and pharmacological effect of BET inhibition as well as minimizing potential side effects (Chen, L. et al. ACS Med. Chem. Lett.2015, 6, 764–769). Currently there is a need for additional agents that are bromodomain (BRD) inhibitors. In particular, there is a need for compounds with improved properties, such as, for example, improved selectivity, uptake, or toxicity. Such agents would be useful for treating bromodomain mediated conditions, such as cancer, heart disease, or an inflammatory condition. SUMMARY OF THE INVENTION In one aspect the present invention provides compounds having bromodomain / BRD4 activity that are useful for treating cancer, inflammatory (e.g., liver inflammation) and / or heart disease. Accordingly, the invention provides a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: R1is aryl that is substituted with one or more nitro and that is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1- C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH; R2is aryl that is optionally substituted with one or more groups independently selected from the group consisting of selected from halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, and (C1-C6)alkoxy; X is: R3is selected from the group consisting of H, −C(=N(Ra))NRaRb, and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C3-C6)cycloalkyl, (C1-C6)alkoxy, −C(=N(Ra))NRaRb, and −NRaRb; each Raand Rbis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Raand Rbtogether with the nitrogen to which they are attached form a 4-6 membered ring heterocycle; A, B, D and E are each independently selected from CH or N; provided that no more than two of A, B, D and E are N; F is O, S, or NRk; G is CH or N; and Rkis H or (C1-C6)alkyl; or wherein R1is selected from H, halo, aryl, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2- C6)alkenyl, and (C2-C6)alkynyl, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, and (C2-C6)alkynyl, is optionally substituted with one or more groups independently selected from the group consisting of halo, oxo, −OH, cyano, (C3-C6)cycloalkyl, and (C1-C6)alkoxy; and wherein any aryl is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3- C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH; R2is aryl that is optionally substituted with one or more groups independently selected from the group consisting of selected from halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, and (C1-C6)alkoxy; X is Rm, (C3-C6)cycloalkyl, a 5-membered heterocycle, or a 6-10 membered bicyclic heterocycle, which (C3-C6)cycloalkyl 5-membered heterocycle, and 6-10 membered bicyclic heterocycle, is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C1- C6)alkoxycarbonyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1- C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1- C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, 5-membered heteroaryl, 6- membered heteroaryl, and (C1-C6)alkoxy; or X is: and R3is (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyl, -C(=O)NRgRh, -S(O)2NRgRh, -S(O)2(C1- C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C3-C6)cycloalkyl, or (C1-C6)alkyl, which (C1- C6)alkoxycarbonyl, (C3-C6)cycloalkyl is optionally substituted with halo, −OH, cyano, (C3- C6)cycloalkyl, (C1-C6)alkoxy, −C(=N(Ra))NRaRb, −NRaRb, -C(=O)NRgRh, -S(O)2NRgRh, -NS(O)2NRgRh, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, a 5-membered heteroaryl, a 6- membered heteroaryl, a carbon-linked 4-6 membered heterocycle, -C(=O)NRgRh, or -(OCH2CH2)n-NRgRh, and which (C1-C6)alkyl is substituted with (C1-C6)alkoxycarbonyl, -C(=O)NRgRh, -S(O)2NRgRh, -NS(O)2NRgRh, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, a 5- membered heteroaryl, a 6-membered heteroaryl, a carbon-linked 4-6 membered heterocycle, -C(=O)NRgRh, or -(OCH2CH2)n-NRgRh; each Raand Rbis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Raand Rbtogether with the nitrogen to which they are attached form a 4-6 membered ring heterocycle; each Rcand Rdis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, -SO2NReRf, and (C3-C6)cycloalkyl; or Rcand Rdtogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; each Reand Rfis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Reand Rftogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; each Rgand Rhis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Rgand Rhtogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; Rmis (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1- C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3- C6)cycloalkyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl , 5-10 membered heteroaryl, and a 5-10 membered heterocycle, which (C3-C6)cycloalkyl, 5-10 membered heteroaryl, and 5- 10 membered bicyclic heterocycle, is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3- C6)cycloalkyl, NRcRd, (C1-C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C1-C6)alkoxycarbonyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C1- C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, 5- membered heteroaryl, 6-membered heteroaryl, and (C1-C6)alkoxy; A, B, D and E are each independently selected from CH or N; provided that no more than two of A, B, D and E are N; F is O, S, or NRk; n is 1 or 2; G is CH or N; and Rkis H or (C1-C6)alkyl; or wherein R1is aryl that is substituted with one or more nitro and that is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1- C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH; R2is aryl that is optionally substituted with one or more groups independently selected from the group consisting of selected from halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, and (C1-C6)alkoxy; X is Rm, (C3-C6)cycloalkyl, a 5-membered heterocycle, or a 6-10 membered bicyclic heterocycle, which (C3-C6)cycloalkyl 5-membered heterocycle, and 6-10 membered bicyclic heterocycle, is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C1- C6)alkoxycarbonyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1- C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1- C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C3-C6)cycloalkyl, 5-membered heteroaryl, 6-membered heteroaryl, and (C1-C6)alkoxy; or X is: and R3is (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyl, -C(=O)NRgRh, -S(O)2NRgRh, -S(O)2(C1- C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C3-C6)cycloalkyl, or (C1-C6)alkyl, which (C1- C6)alkoxycarbonyl, (C3-C6)cycloalkyl is optionally substituted with halo, −OH, cyano, (C3- C6)cycloalkyl, (C1-C6)alkoxy, −C(=N(Ra))NRaRb, −NRaRb, -C(=O)NRgRh, -S(O)2NRgRh, -NS(O)2NRgRh, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, a 5-membered heteroaryl, a 6- membered heteroaryl, a carbon-linked 4-6 membered heterocycle, -C(=O)NRgRh, or -(OCH2CH2)n-NRgRh, and which (C1-C6)alkyl is substituted with (C1-C6)alkoxycarbonyl, -C(=O)NRgRh, -S(O)2NRgRh, -NS(O)2NRgRh, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, a 5- membered heteroaryl, a 6-membered heteroaryl, a carbon-linked 4-6 membered heterocycle, -C(=O)NRgRh, or -(OCH2CH2)n-NRgRh; each Raand Rbis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Raand Rbtogether with the nitrogen to which they are attached form a 4-6 membered ring heterocycle; each Rcand Rdis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, -SO2NReRf, and (C3-C6)cycloalkyl; or Rcand Rdtogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; each Reand Rfis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Reand Rftogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; each Rgand Rhis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Rgand Rhtogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; Rmis (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1- C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3- C6)cycloalkyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl , 5-10 membered heteroaryl, and a 5-10 membered heterocycle, which (C3-C6)cycloalkyl, 5-10 membered heteroaryl, and 5- 10 membered bicyclic heterocycle, is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3- C6)cycloalkyl, NRcRd, (C1-C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C1-C6)alkoxycarbonyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C1- C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, 5- membered heteroaryl, 6-membered heteroaryl, and (C1-C6)alkoxy; A, B, D and E are each independently selected from CH or N; provided that no more than two of A, B, D and E are N; F is O, S, or NRk; n is 1 or 2; G is CH or N; and Rkis H or (C1-C6)alkyl; or wherein R1is selected from H, halo, aryl, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2- C6)alkenyl, and (C2-C6)alkynyl, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, and (C2-C6)alkynyl, is optionally substituted with one or more groups independently selected from the group consisting of halo, oxo, −OH, cyano, (C3-C6)cycloalkyl, and (C1-C6)alkoxy; and wherein any aryl is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3- C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH; R2is aryl that is optionally substituted with one or more groups independently selected from the group consisting of selected from halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, and (C1-C6)alkoxy; X is selected from the group consisting of: A, B, D and E are each independently selected from CH or N; provided that no more than two of A, B, D and E are N; F is O, S, or NRk; n is 1 or 2; G is CH or N; and Rkis H or (C1-C6)alkyl. The invention also provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. The invention also provides a method for treating cancer, heart disease, or an inflammatory condition in an animal (e.g., a mammal such as a human) comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof to the animal. The invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in medical therapy. The invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment of cancer, heart disease, or an inflammatory condition. The invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof to prepare a medicament for treating cancer, heart disease, or an inflammatory condition in an animal (e.g. a mammal such as a human). The invention also provides processes and intermediates disclosed herein that are useful for preparing a compound of formula I or a salt thereof. 3 Detailed Description of the Invention The following definitions are used, unless otherwise described: halo or halogen is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, alkenyl, alkynyl, etc. denote both straight and branched groups; but reference to an individual radical such as propyl embraces only the straight chain radical, a branched chain isomer such as isopropyl being specifically referred to. The term "alkyl", by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e., C1-8means one to eight carbons). Examples include (C1-C8)alkyl, (C2-C8)alkyl, C1-C6)alkyl, (C2-C6)alkyl and (C3-C6)alkyl. Examples of alkyl groups include methyl, ethyl, n- propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and higher homologs and isomers. The term "alkenyl" refers to an unsaturated alkyl radical having one or more double bonds. Examples of such unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2- isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl) and the higher homologs and isomers. The term "alkynyl" refers to an unsaturated alkyl radical having one or more triple bonds. Examples of such unsaturated alkyl groups ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. The term "alkoxy" refers to an alkyl groups attached to the remainder of the molecule via an oxygen atom (“oxy”). The term “alkylthio” refers to an alkyl groups attached to the remainder of the molecule via a thio group. The term “cycloalkyl” refers to a saturated or partially unsaturated (non-aromatic) all carbon ring having 3 to 8 carbon atoms (i.e., (C3-C8)carbocycle). The term also includes multiple condensed, saturated all carbon ring systems (e.g., ring systems comprising 2, 3 or 4 carbocyclic rings). Accordingly, carbocycle includes multicyclic carbocyles such as a bicyclic carbocycles (e.g., bicyclic carbocycles having about 3 to 15 carbon atoms , about 6 to 15 carbon atoms, or 6 to 12 carbon atoms such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g tricyclic and tetracyclic carbocycles with up to about 20 carbon atoms). The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. For example, multicyclic carbocyles can be connected to each other via a single carbon atom to form a spiro connection (e.g., spiropentane, spiro[4,5]decane, etc), via two adjacent carbon atoms to form a fused connection (e.g., carbocycles such as decahydronaphthalene, norsabinane, norcarane) or via two non-adjacent carbon atoms to form a bridged connection (e.g., norbornane, bicyclo[2.2.2]octane, etc). Non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptane, pinane, and adamantane. The term “aryl” as used herein refers to a single all carbon aromatic ring or a multiple condensed all carbon ring system wherein at least one of the rings is aromatic. For example, in certain embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. Aryl includes a phenyl radical. Aryl also includes multiple condensed carbon ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., cycloalkyl. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the point of attachment of a multiple condensed ring system, as defined above, can be at any position of the ring system including an aromatic or a carbocycle portion of the ring. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, indanyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and the like. The term “heterocycle” refers to a single saturated or partially unsaturated ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; the term also includes multiple condensed ring systems that have at least one such saturated or partially unsaturated ring, which multiple condensed ring systems are further described below. Thus, the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) from about 1 to 6 carbon atoms and from about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The sulfur and nitrogen atoms may also be present in their oxidized forms. Exemplary heterocycles include but are not limited to azetidinyl, tetrahydrofuranyl and piperidinyl. The term “heterocycle” also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a single heterocycle ring (as defined above) can be condensed with one or more groups selected from cycloalkyl, aryl, and heterocycle to form the multiple condensed ring system. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring system may be connected in any order relative to one another. It is also to be understood that the point of attachment of a multiple condensed ring system (as defined above for a heterocycle) can be at any position of the multiple condensed ring system including a heterocycle, aryl and carbocycle portion of the ring. In one embodiment the term heterocycle includes a 3-15 membered heterocycle. In one embodiment the term heterocycle includes a 3-10 membered heterocycle. In one embodiment the term heterocycle includes a 3-8 membered heterocycle. In one embodiment the term heterocycle includes a 3-7 membered heterocycle. In one embodiment the term heterocycle includes a 3-6 membered heterocycle. In one embodiment the term heterocycle includes a 4-6 membered heterocycle. In one embodiment the term heterocycle includes a 3-10 membered monocyclic or bicyclic heterocycle comprising 1 to 4 heteroatoms. In one embodiment the term heterocycle includes a 3-8 membered monocyclic or bicyclic heterocycle heterocycle comprising 1 to 3 heteroatoms. In one embodiment the term heterocycle includes a 3-6 membered monocyclic heterocycle comprising 1 to 2 heteroatoms. In one embodiment the term heterocycle includes a 4-6 membered monocyclic heterocycle comprising 1 to 2 heteroatoms. Exemplary heterocycles include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4- tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3- dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, spiro[cyclopropane-1,1'- isoindolinyl]-3'-one, isoindolinyl-1-one, 2-oxa-6-azaspiro[3.3]heptanyl, imidazolidin-2-one imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, and 1,4-dioxane. The term “heteroaryl” as used herein refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; “heteroaryl” also includes multiple condensed ring systems that have at least one such aromatic ring, which multiple condensed ring systems are further described below. Thus, “heteroaryl” includes single aromatic rings of from about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic. Exemplary heteroaryl ring systems include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl. “Heteroaryl” also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a heteroaryl group, as defined above, is condensed with one or more rings selected from cycloalkyl, aryl, heterocycle, and heteroaryl. It is to be understood that the point of attachment for a heteroaryl or heteroaryl multiple condensed ring system can be at any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system including a carbon atom and a heteroatom (e.g., a nitrogen). Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, and quinazolyl. The term “alkoxycarbonyl” as used herein refers to a group (alkyl)-O-C(=O)-, wherein the term alkyl has the meaning defined herein. The term “alkanoyloxy” as used herein refers to a group (alkyl)-C(=O)-O-, wherein the term alkyl has the meaning defined herein. As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si). As used herein, the term "protecting group" refers to a substituent that is commonly employed to block or protect a particular functional group on a compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9- fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxy-protecting group" refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy- protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2- (trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2- (diphenylphosphino)-ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see P.G.M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis 4thedition, Wiley-Interscience, New York, 2006. As used herein a wavy line “ ” that intersects a bond in a chemical structure indicatesthe point of attachment of the bond that the wavy bond intersects in the chemical structure to the remainder of a molecule. The terms “treat”, “treatment”, or “treating” to the extent it relates to a disease or condition includes inhibiting the disease or condition, eliminating the disease or condition, and / or relieving one or more symptoms of the disease or condition. The terms “treat”, “treatment”, or “treating” also refer to both therapeutic treatment and / or prophylactic treatment or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as, for example, the development or spread of cancer. For example, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease or disorder, stabilized (i.e., not worsening) state of disease or disorder, delay or slowing of disease progression, amelioration or palliation of the disease state or disorder, and remission (whether partial or total), whether detectable or undetectable. “Treat”, “treatment”, or “treating,” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the disease or disorder as well as those prone to have the disease or disorder or those in which the disease or disorder is to be prevented. In one embodiment “treat”, “treatment”, or “treating” does not include preventing or prevention, The phrase "therapeutically effective amount" or “effective amount” includes but is not limited to an amount of a compound of the that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The term “mammal” as used herein refers to humans, higher non-human primates, rodents, domestic, cows, horses, pigs, sheep, dogs and cats. In one embodiment, the mammal is a human. The term “patient” as used herein refers to any animal including mammals. In one embodiment, the patient is a mammalian patient. In one embodiment, the patient is a human patient. The compounds disclosed herein can also exist as tautomeric isomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention. It is understood by one skilled in the art that this invention also includes any compound claimed that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium (2H or D). As a non-limiting example, a -CH3group may be substituted with -CD3. The pharmaceutical compositions of the invention can comprise one or more excipients. When used in combination with the pharmaceutical compositions of the invention the term “excipients” refers generally to an additional ingredient that is combined with the compound of formula (I) or the pharmaceutically acceptable salt thereof to provide a corresponding composition. For example, when used in combination with the pharmaceutical compositions of the invention the term “excipients” includes, but is not limited to: carriers, binders, disintegrating agents, lubricants, sweetening agents, flavoring agents, coatings, preservatives, and dyes. Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity. It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase. When a bond in a compound formula herein is drawn in a non-stereochemical manner (e.g. flat), the atom to which the bond is attached includes all stereochemical possibilities. When a bond in a compound formula herein is drawn in a defined stereochemical manner (e.g. bold, bold-wedge, dashed or dashed-wedge), it is to be understood that the atom to which the stereochemical bond is attached is enriched in the absolute stereoisomer depicted unless otherwise noted. In one embodiment, the compound may be at least 51% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 60% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 80% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 90% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 95 the absolute stereoisomer depicted. In another embodiment, the compound may be at least 99% the absolute stereoisomer depicted. The term “residue” as it applies to the residue of a compound refers to a compound that has been modified in any manner which results in the creation of an open valence wherein the site of the open valence. The open valence can be created by the removal of 1 or more atoms from the compound (e.g., removal of a single atom such as hydrogen or removal of more than one atom such as a group of atoms including but not limited to an amine, hydroxyl, methyl, amide (e.g., -C(=O)NH2) or acetyl group). The open valence can also be created by the chemical conversion of a first function group of the compound to a second functional group of the compound (e.g., reduction of a carbonyl group, replacement of a carbonyl group with an amine, ) followed by the removal of 1 or more atoms from the second functional group to create the open valence. Specific values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. It is to be understood that two or more values may be combined. It is also to be understood that the values listed herein below (or subsets thereof) can be excluded. Specifically, (C1-C6)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec- butyl, pentyl, 3-pentyl, or hexyl; (C3-C6)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (C3-C6)cycloalkyl(C1-C6)alkyl can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2- cyclopentylethyl, or 2-cyclohexylethyl; (C1-C6)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; (C2-C6)alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,-pentenyl, 2- pentenyl, 3-pentenyl, 4-pentenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl; (C2-C6)alkynyl can be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1- hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl; (C1-C6)alkanoyl can be acetyl, propanoyl or butanoyl; (C1-C6)alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, or hexyloxycarbonyl; (C1-C6)alkylthio can be methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, or hexylthio; (C2-C6)alkanoyloxy can be acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, or hexanoyloxy; aryl can be phenyl, indenyl, or naphthyl; and heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N- oxide) or quinolyl (or its N-oxide). A specific compound or pharmaceutically acceptable salt is a compound of formula (I) wherein: R1is aryl that is substituted with one or more nitro and that is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1- C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH; R2is aryl that is optionally substituted with one or more groups independently selected from the group consisting of selected from halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, and (C1-C6)alkoxy; X is: R3is selected from the group consisting of H, −C(=N(Ra))NRaRb, and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C3-C6)cycloalkyl, (C1-C6)alkoxy, −C(=N(Ra))NRaRb, and −NRaRb; each Raand Rbis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Raand Rbtogether with the nitrogen to which they are attached form a 4-6 membered ring heterocycle; A, B, D and E are each independently selected from CH or N; provided that no more than two of A, B, D and E are N; F is O, S, or NRk; G is CH or N; and Rkis H or (C1-C6)alkyl; or a pharmaceutically acceptable salt thereof. A specific compound or pharmaceutically acceptable salt is a compound of formula (I), wherein: R1is selected from H, halo, aryl, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2- C6)alkenyl, and (C2-C6)alkynyl, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, and (C2-C6)alkynyl, is optionally substituted with one or more groups independently selected from the group consisting of halo, oxo, −OH, cyano, (C3-C6)cycloalkyl, and (C1-C6)alkoxy; and wherein any aryl is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3- C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH; R2is aryl that is optionally substituted with one or more groups independently selected from the group consisting of selected from halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, and (C1-C6)alkoxy; X is (C3-C6)cycloalkyl or a 5-membered heterocycle, which (C3-C6)cycloalkyl and 5- membered heterocycle is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1- C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3- C6)cycloalkyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1- C6)alkanoyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3- C6)cycloalkyl, 5-membered heteroaryl, 6-membered heteroaryl, and (C1-C6)alkoxy; or X is: and R3is (C1-C6)alkanoyl, -C(=O)NRgRh, -S(O)2NRgRh, -S(O)2(C1-C6)alkyl, -S(O)2(C3- C6)cycloalkyl, (C3-C6)cycloalkyl, or (C1-C6)alkyl, which (C3-C6)cycloalkyl is optionally substituted with halo, −OH, cyano, (C3-C6)cycloalkyl, (C1-C6)alkoxy, −C(=N(Ra))NRaRb, −NRaRb, -C(=O)NRgRh, -S(O)2NRgRh, -NS(O)2NRgRh, -S(O)2(C1-C6)alkyl, -S(O)2(C3- C6)cycloalkyl, a 5-membered heteroaryl, a 6-membered heteroaryl, a carbon-linked 4-6 membered heterocycle, -C(=O)NRgRh, and which (C1-C6)alkyl is substituted with -C(=O)NRgRh, -S(O)2NRgRh, -NS(O)2NRgRh, -S(O)2(C1-C6)alkyl, -S(O)2(C3- C6)cycloalkyl, a 5-membered heteroaryl, a 6-membered heteroaryl, a carbon-linked 4-6 membered heterocycle, -C(=O)NRgRh, or -(OCH2CH2)n-NRgRh; each Rcand Rdis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, -SO2NReRf, and (C3-C6)cycloalkyl; or Rcand Rdtogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; each Reand Rfis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Reand Rftogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; each Rgand Rhis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Rgand Rhtogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; A, B, D and E are each independently selected from CH or N; provided that no more than two of A, B, D and E are N; F is O, S, or NRk; n is 1 or 2; G is CH or N; and Rkis H or (C1-C6)alkyl; or a pharmaceutically acceptable salt thereof. A specific compound or pharmaceutically acceptable salt is a compound of formula (I), wherein: R1is selected from H, halo, aryl, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2- C6)alkenyl, and (C2-C6)alkynyl, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, and (C2-C6)alkynyl, is optionally substituted with one or more groups independently selected from the group consisting of halo, oxo, −OH, cyano, (C3-C6)cycloalkyl, and (C1-C6)alkoxy; and wherein any aryl is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3- C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH; R2is aryl that is optionally substituted with one or more groups independently selected from the group consisting of selected from halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, and (C1-C6)alkoxy; X is Rm, (C3-C6)cycloalkyl, a 5-membered heterocycle, or a 6-10 membered bicyclic heterocycle, which (C3-C6)cycloalkyl 5-membered heterocycle, and 6-10 membered bicyclic heterocycle, is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C1- C6)alkoxycarbonyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1- C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1- C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, 5-membered heteroaryl, 6- membered heteroaryl, and (C1-C6)alkoxy; or X is: and R3is (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyl, -C(=O)NRgRh, -S(O)2NRgRh, -S(O)2(C1- C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C3-C6)cycloalkyl, or (C1-C6)alkyl, which (C1- C6)alkoxycarbonyl, (C3-C6)cycloalkyl is optionally substituted with halo, −OH, cyano, (C3- C6)cycloalkyl, (C1-C6)alkoxy, −C(=N(Ra))NRaRb, −NRaRb, -C(=O)NRgRh, -S(O)2NRgRh, -NS(O)2NRgRh, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, a 5-membered heteroaryl, a 6- membered heteroaryl, a carbon-linked 4-6 membered heterocycle, -C(=O)NRgRh, or -(OCH2CH2)n-NRgRh, and which (C1-C6)alkyl is substituted with (C1-C6)alkoxycarbonyl, -C(=O)NRgRh, -S(O)2NRgRh, -NS(O)2NRgRh, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, a 5- membered heteroaryl, a 6-membered heteroaryl, a carbon-linked 4-6 membered heterocycle, -C(=O)NRgRh, or -(OCH2CH2)n-NRgRh; each Rcand Rdis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, -SO2NReRf, and (C3-C6)cycloalkyl; or Rcand Rdtogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; each Reand Rfis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Reand Rftogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; each Rgand Rhis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Rgand Rhtogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; Rmis (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1- C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3- C6)cycloalkyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl , 5-10 membered heteroaryl, and a 5-10 membered heterocycle, which (C3-C6)cycloalkyl, 5-10 membered heteroaryl, and 5- 10 membered bicyclic heterocycle, is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3- C6)cycloalkyl, NRcRd, (C1-C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C1-C6)alkoxycarbonyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C1- C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, 5- membered heteroaryl, 6-membered heteroaryl, and (C1-C6)alkoxy; A, B, D and E are each independently selected from CH or N; provided that no more than two of A, B, D and E are N; F is O, S, or NRk; n is 1 or 2; G is CH or N; and Rkis H or (C1-C6)alkyl; or a pharmaceutically acceptable salt thereof. A specific compound or pharmaceutically acceptable salt is a compound of formula (I), wherein: R1is aryl that is substituted with one or more nitro and that is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1- C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH; R2is aryl that is optionally substituted with one or more groups independently selected from the group consisting of selected from halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, and (C1-C6)alkoxy; X is (C3-C6)cycloalkyl or a 5-membered heterocycle, which (C3-C6)cycloalkyl and 5- membered heterocycle is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1- C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3- C6)cycloalkyl, (and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1- C6)alkanoyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3- C6)cycloalkyl, 5-membered heteroaryl, 6-membered heteroaryl, and (C1-C6)alkoxy; or X is: and R3is (C1-C6)alkanoyl, -C(=O)NRgRh, -S(O)2NRgRh, -S(O)2(C1-C6)alkyl, -S(O)2(C3- C6)cycloalkyl, (C3-C6)cycloalkyl, or (C1-C6)alkyl, which (C3-C6)cycloalkyl is optionally substituted with halo, −OH, cyano, (C3-C6)cycloalkyl, (C1-C6)alkoxy, −C(=N(Ra))NRaRb, −NRaRb, -C(=O)NRgRh, -S(O)2NRgRh, -NS(O)2NRgRh, -S(O)2(C1-C6)alkyl, -S(O)2(C3- C6)cycloalkyl, a 5-membered heteroaryl, a 6-membered heteroaryl, a carbon-linked 4-6 membered heterocycle, -C(=O)NRgRh, or -(OCH2CH2)n-NRgRh, and which (C1-C6)alkyl is substituted with -C(=O)NRgRh, -S(O)2NRgRh, -NS(O)2NRgRh, -S(O)2(C1-C6)alkyl, -S(O)2(C3- C6)cycloalkyl, a 5-membered heteroaryl, a 6-membered heteroaryl, a carbon-linked 4-6 membered heterocycle, -C(=O)NRgRh, or -(OCH2CH2)n-NRgRh; each Rcand Rdis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, -SO2NReRf, and (C3-C6)cycloalkyl; or Rcand Rdtogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; each Reand Rfis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Reand Rftogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; each Rgand Rhis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Rgand Rhtogether with the nitrogen to which they are attached form a 4-6 membered heterocycle;A, B, D and E are each independently selected from CH or N; provided that no more than two of A, B, D and E are N; F is O, S, or NRk; n is 1 or 2; G is CH or N; and Rkis H or (C1-C6)alkyl; or a pharmaceutically acceptable salt thereof.. A specific compound or pharmaceutically acceptable salt is a compound of formula (I), wherein: R1is aryl that is substituted with one or more nitro and that is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1- C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH; R2is aryl that is optionally substituted with one or more groups independently selected from the group consisting of selected from halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, and (C1-C6)alkoxy; X is Rm, (C3-C6)cycloalkyl, a 5-membered heterocycle, or a 6-10 membered bicyclic heterocycle, which (C3-C6)cycloalkyl 5-membered heterocycle, and 6-10 membered bicyclic heterocycle, is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C1- C6)alkoxycarbonyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1- C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1- C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, 5-membered heteroaryl, 6- membered heteroaryl, and (C1-C6)alkoxy; or X is: and R3is (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyl, -C(=O)NRgRh, -S(O)2NRgRh, -S(O)2(C1- C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C3-C6)cycloalkyl, or (C1-C6)alkyl, which (C1- C6)alkoxycarbonyl, (C3-C6)cycloalkyl is optionally substituted with halo, −OH, cyano, (C3- C6)cycloalkyl, (C1-C6)alkoxy, −C(=N(Ra))NRaRb, −NRaRb, -C(=O)NRgRh, -S(O)2NRgRh, -NS(O)2NRgRh, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, a 5-membered heteroaryl, a 6- membered heteroaryl, a carbon-linked 4-6 membered heterocycle, -C(=O)NRgRh, or -(OCH2CH2)n-NRgRh, and which (C1-C6)alkyl is substituted with (C1-C6)alkoxycarbonyl, -C(=O)NRgRh, -S(O)2NRgRh, -NS(O)2NRgRh, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, a 5- membered heteroaryl, a 6-membered heteroaryl, a carbon-linked 4-6 membered heterocycle, -C(=O)NRgRh, or -(OCH2CH2)n-NRgRh; each Rcand Rdis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, -SO2NReRf, and (C3-C6)cycloalkyl; or Rcand Rdtogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; each Reand Rfis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Reand Rftogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; each Rgand Rhis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Rgand Rhtogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; Rmis (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1- C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3- C6)cycloalkyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl , 5-10 membered heteroaryl, and a 5-10 membered heterocycle, which (C3-C6)cycloalkyl, 5-10 membered heteroaryl, and 5- 10 membered bicyclic heterocycle, is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3- C6)cycloalkyl, NRcRd, (C1-C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C1-C6)alkoxycarbonyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C1- C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, 5- membered heteroaryl, 6-membered heteroaryl, and (C1-C6)alkoxy; A, B, D and E are each independently selected from CH or N; provided that no more than two of A, B, D and E are N; F is O, S, or NRk; n is 1 or 2; G is CH or N; and Rkis H or (C1-C6)alkyl; or a pharmaceutically acceptable salt thereof. A specific R1is 4-bromo-3-nitrophenyl. A specific X is: . A specific compound or pharmaceutically acceptable salt is selected from the group consisting of: and a pharmaceutically acceptable salt thereof. A specific compound or pharmaceutically acceptable salt is selected from the group consisting of: and a pharmaceutically acceptable salt thereof. A specific compound or pharmaceutically acceptable salt is selected from the group consisting of: N O N O N ON NOH NOMe FF3C(R)F3C(R) 3C N NHN (R)SN (R)()N NH N NH NN O N ON ON HO NNF3CN OFS3C NH2F3C O NNN SNO NHN2N(S)N(S)O N NO N O N ON N N O F3C O N NH F 23C SNN CNF3C )NN N(S (SO N N(S)ON N)NO N O N ONO NNF3C N F3C NNH2 F3C NN N N O NH N N N NOON ONF3C NNN ONH N2 F3C N OH NN N NFN3C NN H N N ON O N ON O NN OF3C NSF3C NN O NCN NNH N NF3C NN N N NO N O HO N ON N O FC NOH3SN OF C NN 3 N NO NNF3CNNN NHN(S) and a pharmaceutically acceptable salt thereof. A specific compound or pharmaceutically acceptable salt is selected from the group consisting of: NO N O N OO2NNNN NH2Br NHF NH ( 3C2F3C R) N NNN NN(S)NO N ON ON N OH FCF3C(R) N3HNNH NN (R)F3C 2N(S)N NH N N NO N ON ON O N H N OMe F OF3C NHF 3C N 3C(R)S NN 2N (R)NO NH(SN2N NHN)

[0002] and a pharmaceutically acceptable salt thereof. A specific compound or pharmaceutically acceptable salt is selected from the group consisting of: and a pharmaceutically acceptable salts thereof. A specific compound or pharmaceutically acceptable salt is selected from the group consisting of: and pharmaceutically acceptable salts thereof. A specific R1is (C1-C6)alkyl, wherein any (C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, oxo, −OH, cyano, (C3- C6)cycloalkyl, and (C1-C6)alkoxy. A specific R1is (C1-C6)alkyl. A specific R1is methyl. A specific R1is aryl and wherein any aryl is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3- C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH. A specific R1is aryl and wherein any aryl is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3- C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy. A specific R1is 4-(trifluoromethyl)phenyl, 4-bromophenyl, 4-bromo-3-fluorophenyl, or 4-bromo-3-nitrophenyl. A specific R1is 4-(trifluoromethyl)phenyl, 4-bromophenyl, or 4-bromo-3-fluorophenyl. A specific R1is 4-(trifluoromethyl)phenyl. A specific R1is aryl that is substituted with one or more nitro and that is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl (C3-C6)cycloalkyl (C1-C6)alkoxy (C2-C6)alkenyl (C2-C6)alkynyl (C1- C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH. A specific F is O. A specific R2is aryl that is optionally substituted with one or more groups independently selected from the group consisting of selected from halo, −OH, cyano, (C1-C6)alkyl, (C3- C6)cycloalkyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1- C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, and (C1-C6)alkoxy. A specific R2is 3,5-dimethylphenyl, 3-isopropyl-6-methylphenyl, 3-tertbutylphenyl, 3,5- dicyclopropylphenyl, or 3-propylphenyl. A specific X is (C3-C6)cycloalkyl which (C3-C6)cycloalkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1- C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C1-C6)alkoxycarbonyl, and (C1- C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkanoyl, (C1- C6)alkoxycarbonyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3- C6)cycloalkyl, NRcRd, (C1-6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1- C6)alkyl, -S(O)2(C3-C6)cycloalkyl, 5-membered heteroaryl, 6-membered heteroaryl, and (C1- C6)alkoxy. A specific X is (C3-C6)cycloalkyl which (C3-C6)cycloalkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1- C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C1-C6)alkoxycarbonyl, and (C1- C6)alkoxy. A specific X is (C3-C6)cycloalkyl which (C3-C6)cycloalkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1- C6)alkyl, (C3-C6)cycloalkyl and NRcRd. A specific X is (C3-C6)cycloalkyl which (C3-C6)cycloalkyl is optionally substituted with one or more NRcRd. A specific X is:

[0003] .A specific compound or pharmaceutically acceptable salt is selected from the group consisting of:

[0004] or a pharmaceutically acceptable salt thereof. A specific compound or pharmaceutically acceptable salt is selected from the group consisting of: 2-(4-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1-yl)piperidin- 1-yl)ethan-1-amine, 2-(4-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1-yl)piperidin- 1-yl)ethan-1-ol, 3-(4-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1-yl)piperidin- 1-yl)propan-1-amine, 2-(4-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1-yl)piperidin- 1-yl)acetamide, 2-(3,5-dimethylphenoxy)-6-(4-methyl-1-(1-(pyridin-2-ylmethyl)piperidin-4-yl)-1H- 1,2,3-triazol-5-yl)pyridine, 2-(3,5-dimethylphenoxy)-6-(4-methyl-1-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-1H- 1,2,3-triazol-5-yl)pyridine, 2-(3,5-dimethylphenoxy)-6-(4-methyl-1-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-1H- 1,2,3-triazol-5-yl)pyridine, 2-(1-(1-((1H-imidazol-2-yl)methyl)piperidin-4-yl)-4-methyl-1H-1,2,3-triazol-5-yl)-6- (3,5-dimethylphenoxy)pyridine, 2-((4-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1- yl)piperidin-1-yl)methyl)oxazole, 2-(4-(5-(6-(3,5-dicyclopropylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1- yl)piperidin-1-yl)ethan-1-amine, and 2-(4-(5-(6-(3,5-dicyclopropylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1- yl)piperidin-1-yl)acetamide, or a pharmaceutically acceptable salt thereof. A specific compound or pharmaceutically acceptable salt is selected from the group consisting of: or a pharmaceutically acceptable salt thereof. Processes for preparing compounds of formula I are provided as further embodiments of the invention and are illustrated by the following procedures in which the meanings of the generic radicals are as given above unless otherwise qualified. In cases where compounds are sufficiently basic or acidic, a salt of a compound of formula I can be useful as an intermediate for isolating or purifying a compound of formula I. Additionally, administration of a compound of formula I as a pharmaceutically acceptable acid or base salt may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, α- ketoglutarate, and α-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts. Salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made. The compounds of formula I can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes. Thus, the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained. The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices. The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions. For topical administration, the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid. Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol / glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers. Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user. Examples of useful dermatological compositions which can be used to deliver the compounds of formula I to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No.4,608,392), Geria (U.S. Pat. No.4,992,478), Smith et al. (U.S. Pat. No.4,559,157) and Wortzman (U.S. Pat. No.4,820,508). Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No.4,938,949. The amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye. The invention will now be illustrated by the following non-limiting Examples. Examples Example 1: Preparation of 2-(4-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3- triazol-1-yl)piperidin-1-yl)-N,N-dimethylethan-1-amine The title compound was prepared as described by Cui, H., et al., J. Med. Chem.2021, 64 (14), 10497–10511and used as >95% purity in various stoichiometries of HCl salts.1H NMR (500 MHz, MeOD) δ 8.07 (s, 1H), 7.49 (s, 1H), 7.19 (d, 7.62 Hz, 1H) 7.00 (s, 1H), 6.86 (b, 2H), 5.07 (b, 1H), 3.75 (m, 5H), 3.05 (s, 6H), 2.94 (b, 1H), 2.55 (m, 4H), 2.37 (s, 6H), 2.22 (b, 2H).13C NMR (126 MHz, MeOD) δ 164.00, 153.74, 142.16, 141.29, 139.95, 139.71, 134.59, 126.70, 119.75, 119.14, 112.81, 55.51, 52.17, 51.31, 50.76, 42.81, 29.12, 20.18, 9.22. Expected Mass [M+H]: 435.2867 Observed Mass [M+H]: 435.2882. Purity by HPLC area: >99%. Example 2: Preparation of: A 20 mL vial was charged with 254 mg (0.7 mmol, 1 eq) of 2-(3,5-dimethylphenoxy)-6- (4-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-5-yl)pyridine, 178 mg (0.8 mmol, 1.1 eq) of 2- (Boc-amino)ethyl bromide, 123 mg (0.8 mmol, 1.1 eq) NaI, 398 mg (2.8 mmol, 4 eq), K2CO3, and 3.5 mL of methyl ethyl ketone. The reaction mixture was heated to 50 °C and allowed to stir under air for 96 hours. The reaction mixture was then quenched with water and extracted with ethyl acetate. The organic layer was then washed with brine, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oil was purified by flash column chromatography (0-20% MeOH in DCM), yielding 111 mg (31%) as an off-white solid.1H NMR (400 MHz, MeOD) δ 7.99 (dd, J = 8.3, 7.4 Hz, 1H), 7.34 (dd, J = 7.5, 0.7 Hz, 1H), 7.09 (dd, J = 8.3, 0.7 Hz, 1H), 6.92 (s, 1H), 6.82 – 6.77 (m, 2H), 4.61 (tt, J = 11.7, 4.0 Hz, 1H), 2.85 (d, J = 11.1 Hz, 2H), 2.47 – 2.39 (m, 5H), 2.34 (s, 6H), 2.13 (qd, J = 12.7, 4.0 Hz, 2H), 1.79 – 1.68 (m, 4H), 1.47 (s, 9H). Note: DCM impurity observed at 5.51 ppm (s). A 20 mL vial was charged with 111 mg (0.2 mmol) of the Boc-protected intermediate, which was dissolved in 1 mL of a 4N HCl solution in dioxane and allowed to stir under air at room temperature for two hours. The resulting semisolid was dissolved in methanol and excess solvent was removed under reduced pressure. The product was isolated as an off-white solid (113 mg, quant.) and the stoichiometry of the HCl salt was determined via NMR with 2 μL of 2,2,2-trifluoroethanol as an internal standard1H NMR (400 MHz, MeOD) δ 7.97 (dd, J = 8.4, 7.4 Hz, 1H), 7.32 (d, J = 7.4 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.88 (s, 1H), 6.77 (s, 2H), 4.59 (ddd, J = 11.7, 7.7, 4.1 Hz, 1H), 2.87 – 2.76 (m, 2H), 2.45 (t, J = 6.4 Hz, 2H), 2.41 (s, 3H), 2.31 (s, 6H), 2.10 (td, J = 12.4, 4.0 Hz, 2H), 1.79 – 1.69 (m, 4H). Note: TFE internal standard at 3.86 ppm (q). Solvent impurity observed at 1.29 ppm (br s). Example 3: Preparation of A 20 mL vial was charged with 225 mg (0.52 mmol, 1 eq) of 2-(3,5-dimethylphenoxy)- 6-(4-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-5-yl)pyridine (2HCl salt), 142 mg (0.87 mmol, 1.5 eq) of 2-chloromethyl-pyridine hydrochloride, 85 mg (0.57 mmol, 1.1 eq) NaI, 288 mg (2.5 mmol, 4.2 eq), K2CO3, and 2.6 mL of methyl ethyl ketone. The reaction mixture was heated to 50 °C and allowed to stir under air for 96 hours. The reaction mixture was then quenched with water and extracted with ethyl acetate. The organic layer was then washed with brine, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oil was purified by flash column chromatography (0-20% MeOH in DCM), yielding 202 mg (86%) as an off-white solid.1H NMR (400 MHz, MeOD) δ 8.54 – 8.50 (m, 1H), 8.48 (dd, J = 4.9, 1.6 Hz, 1H), 7.99 (dd, J = 8.3, 7.4 Hz, 1H), 7.87 (dt, J = 7.8, 2.0 Hz, 1H), 7.46 (ddd, J = 7.8, 4.9, 0.9 Hz, 1H), 7.33 (dd, J = 7.4, 0.7 Hz, 1H), 7.09 (dd, J = 8.4, 0.8 Hz, 1H), 6.87 (s, 1H), 6.79 (d, J = 1.5 Hz, 2H), 4.60 (tt, J = 11.5, 4.1 Hz, 1H), 3.54 (s, 2H), 2.78 (d, J = 11.8 Hz, 2H), 2.42 (s, 3H), 2.32 (s, 6H), 2.13 (qd, J = 12.3, 4.3 Hz, 2H), 1.84 – 1.72 (m, 4H).13C NMR (126 MHz, MeOD) δ 165.0, 159.3, 155.1, 149.6, 145.9, 142.6, 142.0, 140.6, 138.6, 133.2, 127.8, 124.7, 123.8, 120.4, 120.1, 112.8, 64.5, 58.2, 53.7, 32.9, 21.6, 11.6. Example 4: Preparation of A 20 mL vial was charged with 199 mg (0.6 mmol, 1 eq) of 2-(3,5-dimethylphenoxy)-6- (4-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-5-yl)pyridine, 111 mg (0.7 mmol, 1.1 eq) of 3- picolyl chloride hydrochloride, 102 mg (0.7 mmol, 1.1 eq) NaI, 327mg (2.4 mmol, 4 eq), K2CO3, and 3 mL of methyl ethyl ketone. The reaction mixture was heated to 50 °C and allowed to stir under air for 96 hours. The reaction mixture was then quenched with water and extracted with ethyl acetate. The organic layer was then washed with brine, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oil was purified by flash column chromatography (0-20% MeOH in DCM), yielding 71 mg (26%) as an off-white solid.1H NMR (400 MHz, MeOD) δ 8.51 (d, J = 2.3 Hz, 1H), 8.48 (dd, J = 4.9, 1.7 Hz, 1H), 8.04 – 7.93 (m, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.45 (dd, J = 8.3, 5.4 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.87 (s, 1H), 6.78 (s, 2H), 4.65 – 4.53 (m, 1H), 3.54 (s, 2H), 2.77 (d, J = 12.2 Hz, 2H), 2.42 (s, 3H), 2.32 (s, 6H), 2.11 (td, J = 12.1, 3.5 Hz, 2H), 1.85 – 1.71 (m, 4H). Note: TFE internal standard at 3.88 ppm (q).13C NMR (126 MHz, MeOD) δ 163.6, 153.9, 149.4, 147.7, 144.6, 141.3, 140.7, 139.3, 137.8, 134.3, 131.9, 126.3, 123.8, 119.0, 118.8, 111.5, 59.2, 56.9, 53.4, 52.1, 31.5, 20.2, 10.1. Example 5: Preparation of A 20 mL vial was charged with 150 mg (0.26 mmol, 1 eq) of 2-(3,5-dimethylphenoxy)- 6-(4-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-5-yl)pyridine (6HCl salt), 50 mg (0.29 mmol, 1.1 eq) of 4-(chloromethyl)pyridine hydrochloride, 57 mg (0.35 mmol, 1.3 eq) NaI, 285 mg (2.1 mmol, 8 eq), K2CO3, and 1.7 mL of methyl ethyl ketone. The reaction mixture was heated to 50 °C and allowed to stir under air for 96 hours. The reaction mixture was then quenched with water and extracted with ethyl acetate. The organic layer was then washed with brine, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oil was purified by flash column chromatography (0-20% MeOH in DCM), yielding 39 mg (33%) as an off-white solid.1H NMR (400 MHz, MeOD) δ 8.54 – 8.47 (m, 2H), 7.98 (dd, J = 8.3, 7.4 Hz, 1H), 7.49 – 7.43 (m, 2H), 7.33 (dd, J = 7.4, 0.7 Hz, 1H), 7.09 (dd, J = 8.4, 0.7 Hz, 1H), 6.86 (s, 1H), 4.61 (ddt, J = 11.7, 7.7, 4.1 Hz, 1H), 3.55 (s, 2H), 2.77 (d, J = 11.9 Hz, 2H), 2.42 (s, 3H), 2.31 (s, 6H), 2.15 (qd, J = 12.6, 3.8 Hz, 2H), 1.85 – 1.72 (m, 4H). Note: TFE internal standard at 3.88 ppm (q). DCM solvent impurity observed at 5.51 ppm (s).13C NMR (126 MHz, MeOD) δ 163.7, 153.9, 149.1, 148.7, 144.6, 141.3, 140.7, 139.3, 131.9, 126.4, 124.2, 119.0, 118.8, 111.5, 60.9, 56.9, 52.3, 31.6, 20.1, 10.1. Example 6: Preparation of A 20 mL vial was charged with 120 mg (0.25 mmol, 1 eq) of 2-(3,5-dimethylphenoxy)- 6-(4-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-5-yl)pyridine (3HCl salt), 52 mg (0.33 mmol, 1.4 eq) of 2-(Chloromethyl)-1H-imidazole hydrochloride, 43 mg (0.28 mmol, 1.1eq) NaI, 213 mg (1.5 mmol, 6 eq), K2CO3, and 1.3 mL of methyl ethyl ketone. The reaction mixture was heated to 50 °C and allowed to stir under air for 96 hours. The reaction mixture was then quenched with water and extracted with ethyl acetate. The organic layer was then washed with brine, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oil was purified by flash column chromatography (0-20% MeOH in DCM), yielding 35 mg (31%) as an off-white solid.1H NMR (400 MHz, MeOD) δ 7.98 (dd, J = 8.3, 7.4 Hz, 1H), 7.32 (dd, J = 7.4, 0.7 Hz, 1H), 7.09 (dd, J = 8.3, 0.7 Hz, 1H), 7.00 (s, 2H), 6.88 (s, 1H), 6.80 – 6.75 (m, 2H), 4.58 (tt, J = 11.6, 4.1 Hz, 1H), 3.58 (s, 2H), 2.77 (d, J = 11.6 Hz, 2H), 2.42 (s, 3H), 2.32 (d, J = 0.7 Hz, 6H), 2.15 (qd, J = 12.1, 3.8 Hz, 2H), 1.88 – 1.71 (m, 4H). Note: DCM solvent impurity observed at 5.51 ppm (s). EtOAC solvent impurity observed at 4.12 ppm (q), 2.03 ppm (s), and 1.26 ppm (t).13C NMR (126 MHz, MeOD) δ 165.1, 155.2, 146.5, 145.9, 142.7, 142.1, 140.7, 133.4, 127.8, 120.4, 120.1, 112.8, 58.2, 55.9, 33.0, 21.5, 11.5.

[0005] Example 7: Preparation of A 20 mL vial was charged with 100 mg (0.2 mmol, 1 eq) of 2-(3,5-dimethylphenoxy)-6- (4-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-5-yl)pyridine (4HCl salt), 33 mg (0.28 mmol, 1.4 eq) of 2-chloromethyl-oxazole, 34 mg (0.22 mmol, 1.1eq) NaI, 178 mg (1.5 mmol, 6 eq), K2CO3, and 1 mL of methyl ethyl ketone. The reaction mixture was heated to 50 °C and allowed to stir under air for 96 hours. The reaction mixture was then quenched with water and extracted with ethyl acetate. The organic layer was then washed with brine, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oil was purified by flash column chromatography (0-20% MeOH in DCM), yielding 39 mg (44%) as an off-white solid.1H NMR (400 MHz, MeOD) δ 7.98 (dd, J = 8.3, 7.4 Hz, 1H), 7.95 (d, J = 0.9 Hz, 1H), 7.33 (dd, J = 7.4, 0.7 Hz, 1H), 7.19 (d, J = 0.9 Hz, 1H), 7.09 (dd, J = 8.3, 0.7 Hz, 1H), 6.89 (s, 1H), 6.80 – 6.75 (m, 2H), 4.57 (tt, J = 11.5, 4.2 Hz, 1H), 3.74 (s, 2H), 2.86 (d, J = 11.5 Hz, 2H), 2.42 (s, 3H), 2.37 – 2.27 (m, 6H), 2.16 (qd, J = 12.4, 3.9 Hz, 2H), 1.96 (t, J = 11.9 Hz, 2H), 1.77 (d, J = 12.7 Hz, 2H). Note: DCM solvent impurity observed at 5.51 ppm (s).13C NMR (101 MHz, MeOD) δ 165.1, 162.4, 155.3, 145.9, 142.7, 142.1, 141.5, 140.8, 133.4, 127.9, 127.8, 120.4, 120.2, 112.9, 57.7, 54.8, 53.4, 32.6, 21.5, 11.4.13C NMR (126 MHz, MeOD) δ 163.7, 153.8, 145.1, 144.5, 141.3, 140.7, 139.3, 132.0, 126.4, 119.0, 118.7, 111.4, 56.8, 54.6, 52.2, 31.6, 20.1, 10.1. Example 8: Preparation of A 20 mL vial was charged with 105 mg (0.2 mmol, 1 eq) of 2-(3,5-dimethylphenoxy)-6- (4-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-5-yl)pyridine (4HCl salt), 52mg (0.28 mmol, 1.4 eq) of 2-iodoacetamide 164 mg (1.2 mmol, 6 eq), K2CO3, and 1 mL of methyl ethyl ketone. The reaction mixture was heated to 50 °C and allowed to stir under air for 96 hours. The reaction mixture was then quenched with water and extracted with ethyl acetate. The organic layer was then washed with brine, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oil was purified by flash column chromatography (0-20% MeOH in DCM), yielding 66 mg (78%) as an off-white solid.1H NMR (400 MHz, MeOD) δ 7.98 (dd, J = 8.3, 7.4 Hz, 1H), 7.08 (dd, J = 8.3, 0.7 Hz, 1H), 6.89 (s, 1H), 6.80 – 6.75 (m, 2H), 4.59 (tq, J = 11.6, 4.0 Hz, 1H), 2.97 (s, 1H), 2.79 (dt, J = 12.3, 3.3 Hz, 2H), 2.42 (s, 3H), 2.32 (s, 6H), 2.18 (qd, J = 12.2, 3.9 Hz, 2H), 1.85 (td, J = 12.0, 2.3 Hz, 2H), 1.78 – 1.67 (m, 2H).13C NMR (101 MHz, MeOD) δ 176.0, 165.1, 155.3, 145.9, 142.7, 142.1, 140.7, 133.3, 127.8, 120.5, 120.1, 112.9, 62.1, 58.1, 54.0, 33.1, 21.5, 11.5. Example 9: Preparation of: To a 2 Dr vial was added sulfone (53 mg, 0.086 mmol, 1 eq), 3,5-dicyclopropylphenol (30 mg, 0.172 mmol, 2 eq), potassium carbonate (47 mg, 0.34 mmol, 4 eq), and anhydrous THF (2 mL). The resulting mixture was then sealed and stirred at 80 °C for 18 h before being diluted with EtOAc. The organic layer was then washed with 1 N NaOH until no phenol could be observed. The organic layer was dried over anhydrous magnesium sulfate and then purified by column chromatography (4 g, 0 to 100% EtOAc in Hexanes). This yielded the desired product as a white foam (40.6 mg).1H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 5.1 Hz, 1H), 7.81 (s, 1H), 7.59 (s, 4H), 6.83 (d, J = 5.1 Hz, 1H), 6.70 (d, J = 9.4 Hz, 2H), 4.94 (p, J = 7.9 Hz, 1H), 4.58 (d, J = 6.5 Hz, 1H), 3.88 (s, 1H), 2.35 (s, 1H), 2.08 – 1.54 (m, 6H), 1.45 (s, 9H), 1.04 – 0.91 (m, 4H), 0.70 (q, J = 4.9 Hz, 4H).13C NMR (101 MHz, CDCl3) δ 165.70, 159.94, 159.58, 155.29, 153.24, 146.12, 143.27, 137.99, 136.99, 130.04, 128.83, 125.57, 125.53, 125.29, 122.78, 120.36, 116.23, 116.11, 55.55, 50.63, 40.94, 31.74, 31.59, 28.41, 15.45, 9.56, 9.53.19F NMR (376 MHz, CDCl3) δ -62.53. To a 2 Dr vial was added boc-precursor (40 mg, 0.037 mmol, 1 eq) and dissolved in DCM (2 mL). To this solution was added excess trifluoroacetic acid (0.3 mL), resulting in a pale-yellow solution that was stirred for 1 h at ambient temperature. The reaction mixture was then blown dry under a stream of nitrogen and the desired was precipitated out with cold MTBE. The desired product was filtered and isolated as a white solid.1H NMR (400 MHz, MeOD) δ 8.66 (s, 1H), 8.54 (d, J = 5.3 Hz, 1H), 7.77 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H), 6.97 (d, J = 5.1 Hz, 1H), 6.77 (d, J = 23.6 Hz, 3H), 5.02 (s, 1H), 3.52 (d, J = 4.0 Hz, 1H), 2.51 (s, 1H), 2.24 – 1.72 (m, 7H), 1.11 – 0.94 (m, 4H), 0.76 – 0.68 (m, 4H).13C NMR (101 MHz, MeOD) δ 165.42, 160.61, 157.84, 153.40, 146.52, 139.47, 136.80, 135.37, 135.06, 134.76, 130.83, 130.50, 129.27, 125.76, 125.67, 125.63, 125.30, 119.83, 116.39, 115.47, 56.46, 49.27, 37.68, 30.49, 28.30, 14.77, 8.84, 8.79.19F NMR (376 MHz, MeOD) δ -64.24, -77.17. Example 10: Preparation of: The title compound (7i) was prepared as described by Divakaran, A., et al., ACS Med. Chem. Lett.2022, 13 (10), 1621–1627 and used as >95% purity. Example 11: Preparation of: The title compound was prepared using procedures similar to those described herein.1H NMR (500 MHz, MeOD) δ 8.62 (s, 1H), 8.55 (d, J = 5.1 Hz, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.39 – 7.33 (m, 2H), 7.30 (d, J = 7.8 Hz, 1H), 7.17 – 7.09 (m, 2H), 7.02 (d, J = 5.1 Hz, 1H), 4.75 (d, J = 5.6 Hz, 0H), 3.47 – 3.39 (m, 1H), 2.93 (s, 0H), 2.84 – 2.70 (m, 1H), 2.21 (s, 4H), 1.26 (d, J = 6.9 Hz, 6H).13C NMR (126 MHz, MeOD) δ 166.32, 162.10, 159.50, 152.58, 149.99, 138.04, 133.37, 132.51, 131.72, 131.46, 128.62, 125.07, 124.54, 121.41, 118.19, 53.60, 44.63, 34.81, 30.85, 24.39, 16.16. Example 12: Preparation of: To a round bottom flask was added 4-bromo-3-nitrobenzaldehyde (500 mg, 2.17 mmol, 1 eq), formamide (244 mg, 5.4 mmol, 2.5 eq), and TMSCl (257 mg, 2.3 mmol, 1.1 eq). The reaction mixture was purged under nitrogen and heated at 50 °C for 24 h. Then was added 4- methylbenzenesulfinic acid (523 mg, 3.04 mmol, 1.4 eq) and allowed to stir for an additional 24 h. The reaction mixture was allowed to cool before diluting with EtOAc (30 mL), where it was washed with water (50 mL) and saturated sodium bisulfate (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting mixture was purified through column chromatography (12 g, 0 to 100% EtOAc in Hexanes). This afforded the desired product as a white foam (143 mg, 16%).1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.95-7.94 (d, 1H, 2.12 Hz), 7.75 (m, 3H), 7.56 (dd, 1H, 8.35 Hz, 2.22 Hz), 7.36 (d, 2H, 8.02 Hz)6.45-6.43 (d, 1H, 10.42 Hz) 2.46 (s, 3H). Note: EtOAc Impurity noted at 4.13 ppm (q) and 1.26 ppm (t). 13C NMR (101 MHz, CDCl3) δ 169.84, 160.32, 149.63, 146.57, 135.52, 133.80, 131.97, 131.19, 130.22, 129.44, 125.89, 116.41, 69.37, 21.83. To a sealed tube was added the formamide (200 mg, 0.48 mmol) and DME (5 mL). Then, over ice was added phosphorous(V) oxychloride (185 mg, 1.21 mmol) and stirred for 10 min, followed by the addition of TEA (290 mg, 2.88 mmol). This resulted in the compound turning brown after 30 min, to which the reaction mixture was quenched with water. This was then extracted with EtOAc before drying over anhydrous magnesium sulfate. The organic layer was concentrated and the purified over a silica plug with 1:1 EtOAc in Hexanes. The resulting product was then added to a sealed vial with immine (80.6 mg, 0.24 mmol), potassium carbonate (110 mg, 0.8 mmol), and acetonitrile (5 mL) before being stirred at 40 C for 18 h. The reaction mixture was then quenched with EtOAc before being extracted with water. The organic layer was then concentrated and purified by column chromatography (4 g, 0 to 100% EtOAc in Hexanes). This yielded the product as a yellow foam (42 mg, 30% over two steps). Note: NMR contains EtOAc impurity.1H NMR (400 MHz, CDCl3) δ 8.48 (d, 1H, 5.14 Hz), 8.02 (s, 1H), 7.85 (s, 1H), 7.67 (d, 1H, 8.34 Hz), 7.50 (d, 1H, 7.68 Hz), 6.88 (d, 1H, 5.17 Hz), 4.70 (t, 1H, 11.48 Hz), 4.31 (b, 2H), 2.80 (b, 2H), 2.61(s, 3H), 2.18 (m, 2H), 1.93-1.83 (dd, 2H, 12.6 Hz, 4.36 Hz), 1.48 (s, 9H).13C NMR (101 MHz, CDCl3) δ 173.69, 171.15, 157.79, 156.86, 154.48, 150.06, 139.90, 136.77, 135.07, 134.78, 132.41, 125.43, 125.03, 116.85, 113.31, 80.21, 60.39, 54.57, 33.47, 28.40, 21.05, 14.20, 14.12. To a 2-dram vial was added the methyl sulfide (42 mg, 0.062 mmol), Oxone (45 mg, 0.148 mmol), and a 1:1 mixture of THF and Water (2 mL). The resulting reaction mixture was stirred at ambient temperature for 18 h before being diluted with EtOAc and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated. This was used crude for the next step. To a 2-dram vial was added the sulfone (36 mg, 0.062 mmol), carvacrol (18 mg, 0.12 mmol), potassium carbonate (33 mg, 0.24 mmol). The resulting reaction mixture was stirred at 80 °C for 18 h before being cooled and diluted with EtOAc. The organic layer was then washed with 1 N NaOH. The organic layer was separated and dried over anhydrous sodium sulfate and concentrated. The resulting product was purified through column chromatography (0 to 100% EtOAc in Hexanes, 4 g). This resulted in the desired product as a yellow foam (12.1 mg, 30%). The Boc-protected starting material (12 mg) was stirred in 4.0 N HCl in Dioxane (2 mL) overnight at ambient temperature. The resulting product was then concentrated and washed with diethyl ether. This resulted in the product as an HCl salt as a yellow solid (10.1 mg). Example 13: Preparation of: To a round-bottom flask was added tert-butyl ((1s,4s)-4-aminocyclohexyl)carbamate (500 mg, 2.3 mmol, 1 eq), 2-(methylthio)pyrimidine-4-carbaldehyde (354 mg, 1.6 mmol, 1 eq), and anhydrous magnesium sulfate (1.1 g, 9.6 mmol, 6 eq), which was dissolved in DCM (20 mL). The reaction mixture was stirred vigorously at ambient temperature for 18 h. The reaction mixture was then filtered and washed with water (10 mL) before volatiles were removed under vacuum. The resulting yellow oil was used without further purification (804.5 mg, quant.).1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 5.1 Hz, 1H), 8.25 (s, 1H), 7.58 (d, J = 5.1 Hz, 1H), 4.70 (s, 1H), 3.75 (s, 1H), 3.49 (t, J = 5.1 Hz, 1H), 2.61 (s, 3H), 1.90 – 1.69 (m, 8H), 1.47 (s, 9H).13C NMR (101 MHz, CDCl3) δ 172.96, 161.56, 158.71, 157.58, 155.25, 112.07, 79.15, 77.04, 66.34, 47.04, 30.25, 28.46, 28.37, 14.13, 0.00. To a round bottom flask was added Ca (455 mg, 1.3 mmol, 1.1 eq), isonitrile (400 mg, 1.17 mmol, 1 eq), potassium carbonate (488 mg, 3.5 mmol, 3 eq), and acetonitrile (10 mL). The reaction was stirred at 40 °C for 18 h before being filtered, diluted with EtOAc, and wasted with water. The organic layer was dried over anhydrous sodium sulfate before being concentrated and purified by column chromatography on a Teledyne CombiFlash (12 g, 0-100% EtOAc in Hexanes). The resulting produce was isolated as an orange foam (392 mg, 62%).1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 5.1 Hz, 1H), 7.86 (s, 1H), 7.60 (s, 4H), 6.82 (d, J = 5.1 Hz, 1H), 4.77 (d, J = 6.7 Hz, 1H), 4.63 (s, 0H), 3.91 (s, 1H), 2.62 (s, 3H), 2.16 – 1.99 (m, 5H), 1.93 – 1.80 (m, 2H), 1.68 (s, 3H), 1.50 (s, 9H). Note: EtOAc impurity noted at 1.28 (t) and 4.13 (q) ppm.13C NMR (101 MHz, CDCl3) δ 173.20, 157.64, 157.38, 155.32, 142.28, 137.78, 136.70, 129.83, 129.51, 128.61, 125.49, 125.45, 125.09, 122.80, 117.18, 77.05, 55.12, 44.43, 29.80, 28.92, 28.45, 14.06, -0.01.19F NMR (376 MHz, CDCl3) δ -62.52. To a round-bottom flask was added Cb (150 mg, 0.28 mmol, 1 eq), oxone (207 mg, 0.67 mmol, 2.4 eq), and a mixture of THF / Water (2:1 v / v, 12 mL). The reaction mixture was stirred for 18 h at ambient temperature before being diluted with THF and the organic layer was separated and washed with water. The organic layer was dried and then concentrated, giving the desired product as a yellow solid which was used without further purification (157 mg, 99%).1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 5.4 Hz, 1H), 7.96 (s, 1H), 7.64 (q, J = 8.3 Hz, 3H), 7.31 (d, J = 5.4 Hz, 1H), 4.95 – 4.76 (m, 2H), 3.41 (s, 3H), 2.14 (m, 2H), 2.02 (m, 2H), 1.76 (m, 4H), 1.49 (s, 9H).13C NMR (101 MHz, CDCl3) δ 166.30, 159.34, 157.62, 145.12, 138.37, 137.56, 130.69, 128.98, 125.92, 125.88, 125.34, 123.71, 123.10, 56.16, 39.04, 29.61, 29.03, 28.46.19F NMR (376 MHz, CDCl3) δ -62.62.

[0006] To a sealed tube was added Cc (157 mg, 0.28 mmol, 1 eq), carvacrol (82 mg, 0.55 mmol, 2 eq), potassium carbonate (153 mg, 1.1 mmol, 4 eq), and THF (3 mL, 0.1 M). The reaction mixture was stirred at 80 °C for 18 h before being diluted with ethyl acetate and washed with 1 N NaOH(aq) until excess carvacrol was no longer visible by TLC. The reaction mixture was concentrated by vacuum and purified through column chromatography on a Teledyne CombiFlash (0-100% EtOAc in Hexanes, 4 g). The resulting product was a white foam (71.4 mg, 40%). Note: EtOAc impurity visible in NMR spectra @ 2.06 and 4.13 ppm. 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 5.1 Hz, 1H), 7.82 (s, 1H), 7.63 (q, J = 9.9 Hz, 4H), 7.22 (d, J = 7.7 Hz, 1H), 7.13 – 7.04 (m, 2H), 6.86 (d, J = 5.1 Hz, 1H), 4.70 (d, J = 6.8 Hz, 1H), 4.59 (t, J = 11.6 Hz, 1H), 3.78 (s, 1H), 2.93 (hept, J = 6.9 Hz, 1H), 2.19 (s, 3H), 1.89 – 1.79 (m, 4H), 1.79 – 1.66 (m, 3H), 1.48 (s, 9H), 1.40 (d, J = 23.0 Hz, 2H), 1.27 (d, J = 7.0 Hz, 6H).13C NMR (101 MHz, CDCl3) δ 165.19, 160.05, 159.98, 155.26, 151.21, 148.35, 143.13, 138.02, 136.88, 131.17, 130.01, 129.69, 128.82, 127.48, 125.57, 125.53, 124.64, 123.94, 122.79, 120.20, 116.31, 79.67, 60.40, 54.65, 44.47, 33.58, 29.39, 28.67, 28.43, 23.95, 21.06, 16.14, 14.21.19F NMR (376 MHz, CDCl3) δ -62.53. To a 2-dram vial was added Cd (51.2 mg, 0.08 mmol, 1 eq) and 2.0 N HCl in Diethyl Ether (0.5 mL, 1.0 mmol, 12 eq). The reaction mixture was stirred at ambient temperature for 1 h resulting in the precipitation of a white solid. The solid was collected and washed with diethyl ether twice, yielding the product as a colorless solid. The HCl salt form was quantified through quantitative 19F NMR using 2,2,2-trifluoroethanol as an internal standard. Example 14: Preparation of: To a 20-mL vial was added tert-butyl ((1S,3R)-3-aminocyclopentyl)carbamate (400 mg, 2.0 mmol, 1 eq), 2-(methylthio)pyrimidine-4-carbaldehyde (308 mg, 2.0 mmol, 1 eq), anhydrous magnesium sulfate (962 mg, 8 mmol, 4 eq), and DCM (10 mL). The resulting mixture was stirred for 18 h at ambient temperature before filtering and concentrating. This yielded the desired product as a tan solid that was used without further purification (727 mg).1H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 4.5 Hz, 1H), 8.17 (s, 1H), 7.56 (d, J = 5.1 Hz, 1H), 5.27 (s, 1H), 4.24 (s, 1H), 3.99 (tt, J = 6.7, 3.6 Hz, 1H), 2.61 (s, 3H), 2.29 – 1.95 (m, 3H), 1.93 – 1.75 (m, 2H), 1.67 (dt, J = 13.6, 4.4 Hz, 2H), 1.48 (s, 9H). To a 20 mL vial was added the immine (197 mg, 0.88 mmol), isonitrile (166 mg, 0.489 mmol), potassium carbonate (324 mg, 2.3 mmol), and acetonitrile (10 mL). The reaction mixture was then sealed and stirred at 40 °C for 18 h. The reaction was then quenched with EtOAc and extracted with water before the organic layer was concentrated. The resulting oil was purified via column chromatography (0-100% EtOAc in Hexanes, 12 g), yielding the product as a yellow foam (28.5 mg, 47%).1H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 4.5 Hz, 1H), 8.17 (s, 1H), 7.58 (s, 4H), 5.27 (m, 1H), 4.24 (s, 1H), 3.99 (tt, J = 6.7, 3.6 Hz, 1H), 2.61 (s, 3H), 2.29 – 1.95 (m, 2H), 1.93 – 1.75 (m, 3H), 1.67 (dt, J = 13.6, 4.4 Hz, 2H), 1.48 (s, 9H).13C NMR (101 MHz, CDCl3) δ 173.34, 157.63, 157.44, 155.41, 142.33, 137.64, 136.64, 129.83, 128.48, 125.83, 125.50, 125.46, 117.24, 55.49, 31.90, 31.38, 28.39, 14.16.19F NMR (376 MHz, CDCl3) δ - 62.53. To a 2-dram vial was added the methyl sulfide (28 mg, 0.050 mmol), oxone (140 mg, 0.50 mmol), and a 1:1 mixture of THF and Water (3 mL). The resulting reaction mixture was stirred at ambient temperature for 18 h before being diluted with EtOAc and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated. This was used crude for the next step as a yellow foam (30.5 mg). To a 2-dram vial was added the sulfone (30.5 mg, 0.055 mmol), carvacrol (16 mg, 0.110 mmol), potassium carbonate (30.3 mg, 0.22 mmol). The resulting reaction mixture was stirred at 80 °C for 18 h before being cooled and diluted with EtOAc. The organic layer was then washed with 1 N NaOH. The organic layer was separated and dried over anhydrous sodium sulfate and concentrated. The resulting product was purified through column chromatography (0 to 100% EtOAc in Hexanes, 4 g). This resulted in the desired product as a yellow foam (15 mg, 43%).1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 5.1 Hz, 1H), 7.82 (s, 1H), 7.61 (d, J = 3.2 Hz, 4H), 7.29 – 7.23 (m, 1H), 7.11 (d, J = 9.6 Hz, 1H), 7.06 (s, 1H), 6.85 (d, J = 5.1 Hz, 1H), 4.89 (p, J = 7.9 Hz, 1H), 4.60 (d, J = 6.7 Hz, 1H), 3.88 – 3.82 (m, 1H), 2.94 (dt, J = 14.3, 7.2 Hz, 1H), 2.30 (dt, J = 13.0, 7.6 Hz, 1H), 2.18 (s, 3H), 2.02 – 1.83 (m, 2H), 1.63 (ddt, J = 12.2, 8.5, 4.8 Hz, 2H), 1.48 (s, 9H), 1.27 (d, J = 6.8 Hz, 6H).13C NMR (101 MHz, CDCl3) δ 165.33, 160.12, 159.64, 155.30, 151.37, 148.55, 143.26, 138.00, 137.00, 131.14, 128.82, 127.54, 125.62, 125.58, 125.54, 125.27, 124.00, 120.24, 116.11, 55.53, 40.84, 33.58, 31.67, 31.58, 28.41, 23.99, 23.95, 16.01.19F NMR (376 MHz, CDCl3) δ -62.54. To a vial containing the Boc-protected amine (15 mg, 1 eq) was added DCM (1 mL) and excess TFA (0.2 mL). The resulting solution was stirred at ambient temperature for 1 h before volatiles were removed under a stream of nitrogen. The product was then precipitated out under cold diethyl ether to give the title compound as a white solid.1H NMR (400 MHz, DMSO) δ 8.69 (d, J = 5.0 Hz, 1H),8.50 (s, 1H), 8.04 (d, J = 5.3 Hz, 3H), 7.72 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 7.7 Hz, 1H), 7.15 (d, J = 5.0 Hz, 1H), 7.12 – 6.99 (m, 2H), 4.65 (p, J = 8.2 Hz, 1H), 3.40 (m, 2H), 2.86 (p, J = 7.0 Hz, 1H), 2.37 – 2.26 (m, 2H), 2.06 (s, 4H), 1.82 (dddd, J = 22.2, 17.0, 11.3, 7.6 Hz, 4H), 1.17 (d, J = 6.9 Hz, 6H).13C NMR (101 MHz, CDCl3) δ 165.33, 160.12, 159.64, 155.30, 151.37, 148.55, 143.26, 138.00, 137.00, 131.14, 128.82, 127.54, 125.62, 125.58, 125.54, 125.27, 124.00, 120.24, 116.11, 55.53, 40.84, 33.58, 31.67, 31.58, 28.41, 23.99, 23.95, 16.01.19F NMR (376 MHz, DMSO) δ -61.03 (3F), -74.68 (9F).

[0007] Example 15: Preparation of: To a 20 mL vial was added tert-butyl ((1s,3s)-3-aminocyclobutyl)carbamate (595 mg, 3.2 mmol, 1.0 eq), 2-(methylthio)pyrimidine-4-carbaldehyde (500 mg, 3.2 mmol, 1.0 eq), anhydrous magnesium sulfate (1500 mg, 4.0 mmol, 4.0 eq), and DCM (20 mL). The resulting mixture was stirred overnight at ambient temperature. Once complete by TLC, the reaction mixture was filtered, and the organic layer was concentrated in vacuo. This yielded a white solid that was used without further purification. (1.346 g, 86%). Note: DCM impurity denoted in 13C NMR @ 53.44 ppm. Expected [M+H]: 323.15 Observed: 323.12.1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 5.1 Hz, 1H), 8.11 (d, J = 1.5 Hz, 1H), 7.55 (d, J = 5.0 Hz, 1H), 4.71 (s, 1H), 4.08 (s, 1H), 4.01 – 3.88 (m, 1H), 2.86 – 2.75 (m, 0H), 2.59 (s, 3H), 2.05 (s, 0H), 1.45 (s, 9H).13C NMR (101 MHz, CDCl3) δ 173.04, 161.23, 158.97, 157.71, 154.92, 112.01, 79.52, 77.37, 77.05, 76.73, 56.27, 53.44, 40.20, 39.00, 28.40, 14.13. To a 20 mL vial was added the desired immine (142 mg, 0.44 mmol, 1 eq), isonitrile (150 mg, 0.44 mmol, 1 eq), potassium carbonate (182 mg, 1.3 mmol, 3 eq), and acetonitrile (3 mL). The vial was capped and the resulting mixture was stirred at 40 °C for 18 h. The reaction was then diluted with EtOAc and washed with water. The organic layer was dried over anhydrous MgSO4 and concentrated. The resulting oil was purified through column chromatography on a Teledyne Combiflash (4 g, 0 to 100% EtOAc in Hexanes). This yielded the title compound as an orange foam (107.9 mg, 48%).1H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 5.1 Hz, 1H), 7.85 (s, 1H), 7.60 (s, 4H), 6.81 (d, J = 5.2 Hz, 1H), 4.89 – 4.76 (m, 2H), 3.99 (s, 1H), 2.99 – 2.86 (m, 2H), 2.62 (s, 3H), 2.28 (d, J = 9.7 Hz, 2H), 1.46 (s, 9H).19F NMR (376 MHz, CDCl3) δ -62.54. To a 6-dram vial was added starting imidazole (113 mg, 0.22 mmol, 1 eq), oxone (81 mg, 0.53 mmol, 2.4 eq), and a 1:1 v / v mixture of THF:Water (2 mL). The resulting solution was stirred at ambient temperature for 18 h before being diluted with EtOAc. The organic layer was then washed with water (30 mL) before being isolated and dried over anhydrous sodium sulfate. The organic layer was then concentrated in vacuo and purified via column chromatography on a Teledyne Combiflash (12 g, 0 to 100% EtOAc in Hexanes). This afforded the desired product as a white solid (64.2 mg, 53%).1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 5.3 Hz, 1H), 7.97 (s, 1H), 7.70 – 7.58 (m, 4H), 7.31 (d, J = 5.4 Hz, 1H), 4.94 (p, J = 8.3 Hz, 1H), 4.81 (s, 1H), 4.00 (dd, J = 15.4, 8.0 Hz, 1H), 3.44 (s, 3H), 3.08 (dddd, J = 8.9, 7.2, 4.7, 2.8 Hz, 2H), 2.41 (s, 2H), 1.47 (s, 9H).19F NMR (376 MHz, CDCl3) δ -62.65. To a sealed tube was added desired sulfone (64 mg, 0.119 mmol, 1 eq), carvacrol (53.5 mg, 0.357 mmol, 3 eq), anhydrous potassium carbonate (49 mg, 0.357 mmol, 3 eq), and THF (2 mL). The tube was then sealed and heated at 80 °C for 18 h behind a blast shield. Then, the reaction was let cool and diluted with EtOAc before being washed with water, followed by 1 N NaOH(aq). The organic layer was then separated and dried over anhydrous sodium sulfate before being concentrated. The resulting oil was then purified by column chromatography on a Teledyne CombiFlash (0 to 100% EtOAc in Hexanes, 4 g) to yield the desired product as a white foam (44.1 mg, 61%).1H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 5.2 Hz, 1H), 7.82 (s, 1H), 7.63 (s, 4H), 7.14 (d, J = 7.8 Hz, 1H), 7.06 (s, 1H), 6.85 (d, J = 5.2 Hz, 1H), 4.68 (s, 1H), 4.59 (tt, J = 9.4, 7.3 Hz, 1H), 3.75 (s, 1H), 2.96 (p, J = 6.9 Hz, 1H), 2.67 – 2.55 (m, 2H), 2.20 (s, 3H), 2.12 (s, 1H), 1.47 (s, 9H), 1.29 (d, J = 6.9 Hz, 6H).19F NMR (376 MHz, CDCl3) δ -62.56. To a 2-dram vial was added N-Boc Material (44 mg, 0.072 mmol, 1 eq) and THF (2 mL). To the solution was added 4 N HCl in Dioxane (0.2 mL, 0.8 mmol, 10 eq) dropwise. The solution was let stir for 1 h at ambient temperature. Then, to the stirring solution was added dropwise a solution of 2.0 N HCl in Et2O (0.5 mL, 1 mmol, 13.8 eq) and additional Et2O (2 mL). The resulting mixture was then evaporated under vacuum and washed with Et2O. This gave the deprotected product as a yellow solid, where the salt form was quantified by quantitative proton NMR. Example 16: Preparation of: The title compound was prepared as described by Cui, H., et al., Angew. Chem. Int. Ed. 2021, No.60, 1220–1226. Example 17: Preparation of: To a round-bottom flask was added Aa (1221 mg, 3.2 mmol, 1 eq), 2- (methylthio)pyrimidine-4-carbaldehyde (1010 mg, 3.2 mmol, 1 eq), and anhydrous magnesium sulfate (3100 mg, 26 mmol, 4 eq), which was dissolved in DCM (20 mL). The reaction mixture was stirred vigorously at ambient temperature for 18 h. The reaction mixture was then filtered and washed with water (10 mL) before volatiles were removed under vacuum and the reaction mixture. The resulting product was purified over column chromatography on a Teledyne Isco CombiFlash (24 g, 0-100% EtOAc in Hexanes) to yield the desired product, Ab, as a pink solid (1240 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 8.56 (d, 5.03 Hz, 1H) 8.27 (s, 1H), 7.54 (d, 5.07 Hz, 1H), 4.28 (m, 1H), 3.92-3.81 (m, 3H), 3.42 (m, 2H), 2.59 (s, 3H), 1.46 (s, 9H).13C NMR (101 MHz, CDCl3) δ 173.08, 161.69, 160.78, 157.76, 154.62, 112.26, 79.82, 75.27, 75.41 (d, 32.94 Hz), 74.90 (d, 14.14 Hz), 74.57, 52.02, 51.76 (d, 26.03 Hz), 50.45 (d, 54.83 Hz), 49.91, 28.50, 14.13. To a 20-mL vial was added isonitrile (200 mg, 0.58 mmol, 1 eq), Ab (215 mg.0.64 mmol, 1.2 eq), potassium carbonate (357 mg, 2.59 mmol, 4 eq), and acetonitrile (5 mL). The vial was then sealed and stirred at 40 °C for 18 h. The resulting mixture was then diluted with EtOAc and washed with water before being concentrated and purified via column chromatography on a TeledyneIsco CombiFlash (12 g, 0 to 100% EtOAc in Hexanes). This resulted in a yellow foam as the desired product (139.3 mg, 46%). 1H NMR (400 MHz, CDCl3) δ 8.44 (d, 5.25 Hz, 1H), 7.76 (s, 1H), 7.64 (s, 4H), 6.86 (d, 5.23 Hz, 1H), 4.93 (b, 1H), 4.68 (s, 1H), 4.02 (m, 1H), 3.85 (m, 2H), 3.52 (m, 3H), 2.96 (s, 3H) 1.51 (s, 9H). Residual water from CDCl3 noted at 1.64 ppm.19F NMR (376 MHz, CDCl3) δ -62.59 (3F). AcAdTo a sealed 20 mL vial was added Ac (100 mg, 0.19 mmol, 1.0 eq), Oxone (71 mg, 0.47 mmol, 2.5 eq), and a 1:1 v / v mixture of THF:Water (1 mL). The resulting mixture was stirred overnight at ambient temperature before being diluted with EtOAc and washed with water. The organic layer was dried over anhydrous sodium sulfate before being concentrated into a yellow foam. The resulting mixture of products was used crude without further purification. To a sealed tube was added the crude solid, Ad (155.8 mg), carvacrol (85 mg, 0.57 mmol, 3 eq), potassium carbonate (78 mg, 0.57 mmol, 3 eq), and THF (2 mL). The tube was sealed under nitrogen and stirred at 80 °C for 18 h before allowing to cool to ambient temperature. The reaction mixture was diluted with EtOAc and flittered before being run on silica gel (4 g, 100% EtOAc) to separate out the carvacrol. The product was then concentrated and resuspended in DCM (1 mL). Dropwise, TFA (0.2 mL) was added, and the reaction was allowed to stir at ambient temperature. After 1 h, volatiles were removed under a stream of nitrogen and the resulting crude oil was purified by semi-preparative HPLC (5-50%, 50 min, tR = 22 min). The fractions were lyophilized to yield a white fluffy solid, where the TFA salt was quantified by quantitative fluorine NMR.1H NMR (500 MHz, DMSO) δ 9.46-9.32 (d, 66.7 Hz, 2H), 8.72 (d, 5.0 Hz, 1H), 8.20 (s, 1H), 7.72 (d, 8.22 Hz, 2H), 7.65 (d, 8.28 Hz, 2H) 7.24 (m, 2H),7.06 (m, 2H), 6.05 (b, 1H), 4.86 (td, 6.39 and 3.88 Hz, 1H), 4.54 (m, 1H), 3.57 (m, 3H), 3.15 (b, 1H), 2.66 (p, 6.9 Hz, 1H), 2.07 (s, 3H), 1.17 (d, 6H).13C NMR (126 MHz, DMSO) δ 165.25, 161.77, 159.30, 151.42, 148.39, 140.56, 138.11, 137.76, 131.52, 128.40, 127.52, 126.42, 125.91, 123.98, 120.36, 117.95, 73.91, 61.48, 50.72, 48.73, 33.31, 24.27, 24.23, 16.00.19F NMR (376 MHz, DMSO) δ -60.99 (3F), -74.12 (6F). Expected Mass [M+H]: 524.2268. Observed Mass [M+H]: 524.2249. HPLC Purity by Area: 98.6%. Example 18: Preparation of: To a 2-dram vial equipped with a stir bar was added sulfide intermediate (76 mg, 0.145 mmol, 1 eq) and dissolved in THF (2 mL) before cooling over ice. To the vial was added NaH in a 60% oil dispersion (20 mg, 0.44 mmol, 3 eq) and stirred for 10 min before adding MeI (20 μL, 0.34 mmol, 2.5 eq). The reaction mixture was allowed to warm to ambient temperature and stirred for 2 h. Once the starting material was consumed by TLC (1:1 EtOAc:Hexanes), the reaction was quenched with water and diluted with EtOAc. The resulting organic layer was isolated and washed with brine before being dried over magnesium sulfate and concentrated. The reaction was purified through column chromatography on a Teledyne CombiFlash (4 h, 0 to 100% EtOAc in Hexanes) to yield the resulting product as a white foam (40.6 mg, 52%).1H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 5.2 Hz, 1H), 7.69 (s, 1H), 7.59 (s, 4H), 6.83 (d, J = 5.1 Hz, 1H), 5.30 (s, 1H), 4.17 – 3.86 (m, 3H), 3.80 – 3.45 (m, 2H), 3.33 (s, 3H), 2.62 (s, 3H), 1.50 (s, 9H).13C NMR (101 MHz, CDCl3) δ 173.54, 157.52, 157.17, 154.20, 142.70, 137.34, 136.59, 130.08, 129.77, 128.58, 126.83, 125.58, 125.54, 125.45, 122.74, 118.65, 117.20, 84.16, 83.13, 80.55, 59.63, 58.59, 57.49, 50.03, 49.27, 48.73, 28.45, 14.15.19F NMR (376 MHz, CDCl3) δ - 62.57. To a 2-dram vial equipped with a stir bar was added sulfide intermediate (31 mg, 0.057 mmol, 1 eq), Oxone (100 mg, 0.34 mmol, 6.0 eq), and 1:1 v / v Water:THF (5 mL). The reaction mixture was stirred at ambient temperature for 18 h. The reaction was quenched with water and washed with extracted with EtOAc before being concentrated in vacuo. The resulting yellow foam was then purified by column chromatography (4 g, 0 to 100% EtOAc in Hexanes). This resulted in the desired product as an orange solid (27 mg, 65%). 1H NMR (400 MHz, CDCl3) δ 8.71 (d, 5.28 Hz, 1H), 7.79 (d, 10.69 Hz, 1H), 7.65 (d, 8.2 Hz, 2H), 7.58 (d, 8.19 Hz, 2H), 7.34 (d, 5.26 Hz, 1H), 5.35 (s, 1H), 4.05 (m, 2H), 3.81 (m, 1H), 3.65 (m, 2H), 3.42 (s, 3H), 3.36 (d, 7.8 Hz, 3H), 1.51 (s, 9H). Residual water from CDCl3 noted @ 1.61 ppm.13C NMR (126 MHz, CDCl3) δ 166.44, 158.98, 158.10, 138.20, 136.99, 130.87, 130.61, 128.90, 127.07, 126.01, 125.98, 125.95, 125.01, 123.61, 122.84, 83.82, 82.82, 80.68, 60.39, 59.47, 57.38, 50.21, 49.49, 48.83, 48.30, 39.17, 28.44, -0.00.19F NMR (376 MHz, CDCl3) δ -62.68 (3F). To a 2-dram vial was added sulfone precursor (50 mg, 0.088 mmol, 1 eq), carvacrol (55 mg, 0.35 mmol, 4 eq), potassium carbonate (48 mg, 0.35 mmol, 4 eq), and THF (2 mL). The vial was then sealed, and the reaction was heated to 80 °C for 18 h. The reaction was then diluted with EtOAc and washed with 1N NaOH before purifying by column chromatography (4 g, 0 to 100% EtOAc in Hexanes). This resulted in the desired product as a colorless foam (49.3 mg, 88%).1H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 5.1 Hz, 1H), 7.68 (s, 1H), 7.61 (s, 3H), 7.22 (d, J = 7.8 Hz, 1H), 7.08 (dd, J = 7.7, 1.8 Hz, 1H), 7.01 (d, J = 1.9 Hz, 1H), 6.87 (d, J = 5.1 Hz, 1H), 5.31 (d, J = 4.4 Hz, 1H), 3.98 (s, 1H), 3.66 (d, J = 43.9 Hz, 1H), 3.32 (d, J = 9.6 Hz, 3H), 2.99 – 2.85 (m, 1H), 2.16 (s, 3H), 1.51 (s, 9H), 1.26 (d, J = 6.9 Hz, 6H).13C NMR (101 MHz, CDCl3) δ 165.32, 160.10, 159.59, 154.04, 151.18, 148.50, 137.58, 136.97, 131.19, 128.81, 127.45, 125.64, 125.60, 125.20, 124.12, 122.74, 119.89, 116.18, 83.87, 83.00, 80.44, 57.58, 49.81, 49.56, 49.14, 33.56, 28.46, 23.95, 23.90, 15.96.19F NMR (376 MHz, CDCl3) δ -62.58. To a 2 Dr vial was added boc-precursor (49 mg, 1 eq) and dissolved in DCM (2 mL). To this solution was added excess trifluoroacetic acid (0.3 mL), resulting in a pale-yellow solution that was stirred for 1 h at ambient temperature. The reaction mixture was then blown dry under a stream of nitrogen and the desired was precipitated out with cold MTBE. The desired product was filtered and isolated as a pale-yellow solid (34.2 mg).1H NMR (400 MHz, MeOD) δ 8.52 (d, J = 5.1 Hz, 1H), 8.40 (s, 1H), 7.76 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 7.8 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.06 (s, 1H), 7.02 (d, J = 5.1 Hz, 1H), 5.36 (s, 0H), 4.50 (s, 0H), 3.78 (dd, J = 13.3, 4.5 Hz, 1H), 3.65 (dd, J = 13.6, 3.7 Hz, 1H), 3.57 (d, J = 11.4 Hz, 1H), 3.47 (dd, J = 13.6, 7.5 Hz, 1H), 3.38 (s, 3H), 2.93 (hept, J = 6.9 Hz, 1H), 2.16 (s, 3H), 1.27 (d, J = 7.0 Hz, 6H).13C NMR (101 MHz, MeOD) δ 165.04, 160.67, 158.35, 151.22, 148.78, 141.44, 137.16, 135.89, 131.06, 130.61, 130.31, 129.92, 129.08, 127.48, 127.42, 125.66, 125.59, 125.55, 125.43, 123.91, 122.74, 119.56, 116.67, 82.68, 60.41, 56.72, 49.18, 48.88, 33.44, 22.97, 22.95, 14.61.19F NMR (376 MHz, MeOD) δ -64.21 (3F), -77.35 (9F). Example 19: Preparation of: To a sealed tube was added CS7110 (30 mg, 0.048 mmol, 1 eq), sulfuric diamide (15 mg, 0.132 mmol, 4 eq), triethylamine (0.2 mL), and 1,4-dioxane (2 mL). The reaction was then stirred at 110 °C for 18 h before being diluted with EtOAc. The mixture was washed with water and the organic layer was isolated and dried over anhydrous sodium sulfate. The resulting organic layer was removed of volatiles under vacuum and purified via column chromatography on a Teledyne CombiFlash (0-10% MeOH in DCM, 4 g). The desired product was isolated as a white solid (22.6 mg, 83%).1H NMR (400 MHz, DMSO) δ 8.67 (d, J = 5.0 Hz, 1H), 8.28 (s, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 8.2 Hz, 2H), 7.24 (s, 0H), 7.14 (d, J = 5.0 Hz, 1H), 7.08 (s, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.53 (s, 2H), 4.19 – 4.05 (m, 1H), 3.46 (s, 1H), 2.93 – 2.78 (m, 1H), 2.06 (s, 3H), 1.98 (dd, J = 12.3, 2.6 Hz, 2H), 1.80 (d, J = 13.5 Hz, 2H), 1.60 (d, J = 12.2 Hz, 2H), 1.35 (s, 2H), 1.17 (d, J = 6.9 Hz, 6H).19F NMR (376 MHz, DMSO) δ -60.94 (3F), -74.37 (3F).

[0008] Example 20: Preparation of: The title compound was prepared using procedures similar to those described herein.1H NMR (500 MHz, CDCl3) δ 8.43 (d, J = 5.2 Hz, 1H), 7.93 (s, 1H), 7.60 (d, J = 8.4 Hz, 4H), 7.21 (d, J = 7.8 Hz, 1H), 7.08 (dd, J = 7.7, 1.9 Hz, 1H), 7.02 (d, J = 1.8 Hz, 1H), 6.86 (d, J = 5.2 Hz, 1H), 6.58 (s, 1H), 5.46 (s, 1H), 5.14 – 5.06 (m, 1H), 3.14 (m, 3H), 2.97 – 2.85 (m, 2H), 2.39 – 2.25 (m, 2H), 2.15 (s, 3H), 2.12 – 2.01 (m, 1H), 1.94 (s, 1H), 1.25 (d, J = 6.9 Hz, 8H).13C NMR (126 MHz, CDCl3) δ 172.21, 165.11, 160.14, 159.22, 151.42, 148.53, 143.10, 137.82, 137.32, 131.06, 128.77, 127.73, 125.56, 125.53, 124.85, 123.92, 119.97, 115.84, 61.13, 58.31, 55.61, 53.42, 33.49, 33.13, 23.98, 23.95, 15.96.19F NMR (471 MHz, CDCl3) δ -62.57. Example 21: Preparation of: In a single neck 50 mL round bottom flask fitted with a magnetic stir bar and nitrogen inlet was charged methane sulfonyl chloride (5.6 mg, 0.049 mmol, 1 equiv.) in DCM at 0oC. To the aforementioned cooled reaction mixture was charged DCM solution of pyrrolidine.TFA (30 mg, 0.049 mmol) and Triethylamine (5.94 mg, 0.0578 mmol, 1.2 equiv.) dropwise. The reaction was stirred at room temperature for overnight (warmed to r.t. from 0oC). Upon completion of the reaction as indicated by TLC, 1N HCl was added to the reaction mixture. The organic layer was separated, dried over anhydrous Mg2SO4 and evaporated in vacuo to afford the crude product which was purified by Combiflash chromatography (0-10% MeOH in DCM) to afford the purified product (HPLC purity 90%). The pure product was further purified by prep. HPLC to afford purity > 95% (10 mg, 35%).1H-NMR (400 MHz, CDCl3): d 8.42 (d, J =4 Hz ,1H), 7.83 (s, 1H), 7.63 (m, 4H), 7.22 (d, 1H), 7.10-7.07 (m, 1H), 7.02-7.01 (s, J =4 Hz, 1H), 6.86 (d, J =4 Hz, 1H), 5.29 (m, 1H), 3.53 (m, 2H), 3.33 (m, 2H), 2.95-2.90 (m, 1H), 2.88 (s, 3H), 2.16 (s, 3H), 2.04-2.02 (m, 2H), 1.34 (d, J =8 Hz, 6H).19F-NMR (470 MHz, CDCl3) d -62.5 (3F).13C-NMR (125 MHz, CDCl3) d 165.1, 160.3, 159.0, 151.4, 148.6, 144.2, 137.1, 131.2, 130.4, 130.1, 129.0, 127.8, 125.7, 125.6, 124.5, 124.0, 120.0, 115.6, 55.9, 53.5, 45.9, 36.0, 33.6, 32.5, 24.0, 24.0, 16.0. HRMS: 586.2073 [M+H]+Example 22: Preparation of: To a sealed tube was added SG-0188 (30 mg, 0.048 mmol, 1 eq), sulfuric diamide (15 mg, 0.192 mmol, 4 eq), triethylamine (0.2 mL), and 1,4-dioxane (2 mL). The reaction was then stirred at 110 °C for 18 h before being diluted with EtOAc. The mixture was washed with water and the organic layer was isolated and dried over anhydrous sodium sulfate. The resulting organic layer was removed of volatiles under vacuum and purified via column chromatography on a Teledyne CombiFlash (0-10% MeOH in DCM, 4 g). The desired product was isolated as a white solid (11.3 mg, 40%).1H NMR (400 MHz, DMSO) δ 8.65 (d, J = 5.1 Hz, 1H), 8.10 (s, 1H), 7.72 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 7.7 Hz, 1H), 7.12 (d, J = 5.1 Hz, 1H), 7.10 – 7.05 (m, 2H), 6.95 (s, 2H), 5.02 – 4.92 (m, 1H), 3.41 – 3.31 (m, 2H), 3.26 (d, J = 5.2 Hz, 2H), 3.15 (dd, J = 5.9, 1.5 Hz, 1H), 2.94 – 2.80 (m, 1H), 2.11 – 1.95 (m, 5H), 1.18 (d, J = 6.9 Hz 6H)13C NMR (101 MHz DMSO) δ 16521 16155 15945 15155 14850 141.19, 138.58, 138.14, 131.53, 128.76, 127.64, 125.91, 125.88, 125.69, 123.98, 120.39, 117.44, 66.83, 55.57, 54.13, 46.45, 33.33, 32.03, 24.29, 24.27, 16.03.19F NMR (376 MHz, DMSO) δ - 60.95. Example 23: Preparation of: In a single neck 50 mL round bottom flask fitted with a magnetic stir bar and nitrogen inlet was charged TFA-deprotected amine (30-50 mg, 0.049-0.08 mmol, 1 equiv.) in DMF. To the aforementioned reaction mixture was charged K2CO3(0.19-0.32 mmol, 4 equiv.) followed by alkyl substituent (0.099-0.16 mmol, 2 equiv.). The reaction was heated to 80oC and allowed to stir overnight at that temperature under nitrogen atmosphere. Upon completion of the reaction as indicated by TLC, the reaction mixture was cooled to r.t. The reaction mixture was extracted with ethyl acetate and sequentially washed with 10-20% LiCl and water. The washed organic layer was dried over anhydrous Mg2SO4.The dried organic layer was evaporated in vacuo to afford the crude product which was purified by Combiflash chromatography (0-20% MeOH in DCM) to afford the pure product (35mg, 77%). (HPLC purity >95%).1H-NMR (500 MHz, CDCl3): d 8.42 (d, J =5 Hz,1H), 7.93 (s, 1H), 7.61-7.59 (m, 4H), 7.24 (d, J =10 Hz, 1H), 7.13- 7.11 (d, J =10 Hz, 1H), 7.02 (s,1H), 6.85 (d, J =5 Hz,1H), 5.14 (m, 1H), 3.73-3.64 (m, 2H), 3.07(m, 1H), 2.93 (m, 1H), 2.82 (d, J =10 Hz, 1H), 2.52-2.47(m,2H), 2.18 (s, 3H), 2.00 (m, 1H), 1.90 (m, 1H), 1.26 (d, J =5 Hz, 6H).13C-NMR (125 MHz, CDCl3) d 165.3, 160.3, 159.4, 151.6, 148.8, 143.2, 138.2, 138.1, 131.3, 129.0, 127.9, 125.7, 124.8, 124.3, 123.1, 120.1, 115.9, 114.3, 59.0, 55.5, 51.0, 41.3, 33.6, 33.6, 24.2, 24.1, 16.1.19F-NMR (470 MHz, CDCl3) d -62.5 (3F). HRMS: 547.2372 [M+H]+ Example 24: Preparation of: The title compound was prepared using procedures similar to those described herein.1H NMR (500 MHz, CDCl3) δ 8.40 (d, J = 5.2 Hz, 1H), 8.02 (s, 1H), 7.65 – 7.56 (m, 4H), 7.20 (d, J = 7.8 Hz, 1H), 7.07 (dd, J = 7.8, 1.9 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H), 6.84 (d, J = 5.2 Hz, 1H), 5.09 (t, J = 1.8 Hz, 1H), 3.72 – 3.48 (m, 8H), 3.31 (q, J = 13.4 Hz, 2H), 3.12 (td, J = 8.8, 3.2 Hz, 1H), 3.03 (d, J = 10.6 Hz, 1H), 2.35 – 2.21 (m, 2H), 2.15 (s, 3H), 1.88 – 1.76 (m, 1H), 1.25 (d, J = 6.9 Hz, 7H).13C NMR (126 MHz, CDCl3) δ 167.95, 165.21, 160.05, 159.51, 151.53, 148.57, 143.09, 138.15, 138.02, 131.12, 130.05, 129.79, 128.89, 127.80, 125.61, 125.58, 125.54, 125.21, 124.69, 123.94, 123.05, 120.08, 115.87, 66.93, 66.84, 60.70, 57.69, 55.59, 52.87, 46.05, 42.07, 33.59, 25.83, 25.66, 24.07, 24.04, 16.04.19F NMR (471 MHz, CDCl3) δ -62.54. Example 25: Preparation of: To a 2-Dr vial was added 7i (33.2 mg, 0.044 mmol, 1 eq), pyridine (14 μL, 0.177 mmol, 14 eq), and DCM (1.5 mL). Separately, acetyl chloride (6.2 μL, 0.088 mmol, 2 eq) was diluted with DCM (1.5 mL). To a stirring solution of 7i and was added acetyl chloride solution dropwise over 5 min. The reaction was stirred at ambient temperature over 2 h, turning a bright red. The reaction mixture was then concentrated and purified by reverse-phase semi-prep HPLC (10-60% MeCN in 0.1% TFA / Water, 45 min). The desired product as a TFA salt was then lyophilized to yield a white powder. 1H NMR (400 MHz, DMSO) δ 8.69 (d, 1H, 5.0 Hz), 8.41 (s, 1H), 7.74 (d, 2H, 8.2 Hz), 7.65 (d, 2H, 7.9 Hz), 7.25 (d, 1H, 9.0 Hz), 7.15 (d, 1H, 5.0 Hz), 7.09 (m, 2H), 4.39 (m, 2H), 3.81 (m, 1H), 2.86 (m, 2H), 2.28 (m, 1H), 2.09 (s, 3H), 2.02 (s, 3H), 1.78 (m, 4H), 1.17 (d, 6H, 6.97 Hz).13C NMR (101 MHz, DMSO) δ 168.49, 165.15, 161.83, 159.08, 151.42, 148.33, 138.05, 131.54, 128.78, 127.54, 125.98, 125.69, 123.87, 120.51, 117.92, 54.15, 45.32, 33.32, 32.80, 24.20, 21.71, 16.17.19F NMR (376 MHz, DMSO) δ -61.00, -74.79. Example 26: Preparation of: To a 2-dram vial was added 7i (30 mg, 0.040 mmol, 1 eq), iodoacetamide (28 mg, 0.16 mmol, 4 eq), cesium carbonate (52 mg, 0.16 mmol, 4 eq), and absolute ethanol (2 mL). The vial was sealed and stirred under reflux for 24 h. The resulting mixture was diluted with ethyl acetate (10 mL) before being washed with water (2x, 15 mL) and saturated sodium chloride (20 mL). The organic layer was dried over sodium sulfate and concentrated before being purified through column chromatography (0 to 30% MeOH in DCM, 4 g). This resulted in the desired product as a white solid (10.2 mg, 44%).1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 5.2 Hz, 1H), 7.81 (s, 1H), 7.62 (d, J = 2.1 Hz, 4H), 7.23 (d, J = 7.7 Hz, 1H), 7.14 – 7.04 (m, 2H), 6.96 (s, 1H), 6.87 (d, J = 5.1 Hz 1H) 564 (s 1H) 457 (dt J = 113 66 Hz 1H) 303 (s 2H) 292 (s 1H) 2.20 (s, 3H), 1.95 (s, 3H), 1.27 (d, J = 6.9 Hz, 6H).13C NMR (101 MHz, CDCl3) δ 172.83, 165.20, 160.14, 159.80, 151.18, 148.40, 143.08, 137.85, 136.75, 131.33, 130.09, 129.77, 128.78, 127.34, 127.28, 125.60, 125.56, 125.47, 124.80, 124.02, 123.96, 122.77, 120.21, 116.40, 61.29, 53.49, 53.20, 33.57, 33.54, 23.98, 16.18.19F NMR (376 MHz, CDCl3) δ -62.55. Example 27: Preparation of: In a round bottom flask was added iBRD4(D1) (50 mg, 0.133 mmol), 1-boc-3- formylazetidine (36 mg, 0.200 mmol), acetic acid (16 mg, 0.266 mmol), and absolute ethanol (0.75 mL). This mixture was stirred at ambient temperature for 2 h, where the disappearance of the starting material was observed by TLC. Then, sodium borohydride (42 mg, 1.1 mmol) was added, resulting in the evolution of gas. The reaction mixture was then heated to 75 ^C and stirred for 18h. The solution was diluted with EtOAc and concentrated before purifying through column chromatography with a Teledyne CombiFlash instrument (0 to 30% MeOH in DCM, 4 g silica, 20 min), yielding tert-butyl 3-((4-(5-(2-(5-isopropyl-2-methylphenoxy)pyrimidin-4-yl)-4- (4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)piperidin-1-yl)methyl)azetidine-1-carboxylate (13) as a white solid (90 mg, 90%).1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.86 (s, 1H), 7.64 (d, J = 1.0 Hz, 4H), 7.15 (dd, J = 7.8, 1.8 Hz, 1H), 6.86 (d, J = 5.2 Hz, 1H), 5.08 – 4.96 (m, 1H), 4.61 (s, 1H), 4.17 (d, J = 7.2 Hz, 1H), 2.98 (dq, J = 13.8, 6.9 Hz, 1H), 2.55 (dt, J = 14.1, 8.1 Hz, 2H), 2.23 (s, 3H), 2.16 – 2.04 (m, 2H), 1.50 (s, 9H), 1.30 (d, J = 6.9 Hz, 6H).13C NMR (101 MHz, CDCl3) δ 165.22, 160.05, 159.98, 156.36, 151.17, 148.33, 142.74, 137.88, 136.87, 131.28, 130.26, 129.94, 129.62, 129.29, 128.72, 127.26, 125.53, 125.49, 124.85, 123.83, 122.78, 120.93, 120.22, 116.51, 79.40, 77.39, 77.07, 76.75, 64.38, 62.14, 53.94, 52.80, 33.57, 33.29, 30.54, 28.41, 26.92, 23.98, 16.17.19F NMR (376 MHz, CDCl3) δ -62.56. To a 2-dram vial was added boc-protected amine (40 mg, 0.064 mmol) and DCM (1 mL). The resulting solution was stirred at ambient temperature while excess trifluoroacetic acid (0.5 mL) was added dropwise, and the solution was let stir for an additional 30 min. Volatiles were then removed under a stream of nitrogen before the desired product was crashed out with cold MTBE (5 mL) as a fluffy white solid. The resulting TFA-salt was then quantified through 19F NMR.1H NMR (400 MHz, DMSO) δ 8.96 (s, 1H), 8.79 – 8.64 (m, 1H), 8.14 (s, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.62 (d, J = 8.2 Hz, 2H), 7.23 (dd, J = 15.5, 6.5 Hz, 2H), 7.08 (d, J = 1.8 Hz, 2H), 4.47 – 4.34 (m, 1H), 4.05 (d, J = 8.9 Hz, 2H), 3.89 (s, 2H), 3.59 – 3.25 (m, 5H), 2.84 (s, 2H), 2.10 (s, 7H), 1.16 (d, J = 6.9 Hz, 6H).19F NMR (376 MHz, DMSO) δ -60.97 (3F), -74.28 (9F). Example 28: Preparation of: To a sealed tube was added 7i (50 mg, 0.06 mmol, 1 eq), urea (20 mg, 0.32 mmol, 5 eq), and dioxane (1 mL). A catalytic amount of triethylamine (2 drops) was added with stirring and the reaction mixture was sealed and heated to 120 °C for 18 h. The reaction mixture was then purified by reverse-phase HPLC (C18, 0-60% MeCN in 0.1% TFA / Water, product @ 20 min). The desired product was then lyophilized to yield a fluffy white solid as a 4x TFA salt (13.3 mg). 1H NMR (400 MHz, DMSO) δ 8.69-8.68 (s, 1H, 5.04 Hz), 8.51 (s, 1H), 7.75-7.73 (d, 2H, 8.2 Hz), 7.63-7.61 (d, 2H, 8.12 Hz), 7.25 (d, 1 H, 8.6 Hz), 7.15 (d, 1H, 8.6 Hz), 7.09 (m, 2H), 6.03 (b, 2H), 4.36 (m, 1H), 3.99 (d, 2H, 13.2 Hz), 2.88 (m, 1H), 2.45 (m, 2H), 2.08 (s, 3H), 1.75 (m, 4H), 1.18-1.16 (d, 6H, 6.8 Hz).13C NMR (101 MHz, DMSO) δ 165.16, 161.87, 158.93, 158.08, 151.40, 148.34, 137.99, 131.52, 128.87, 127.48, 126.02, 125.70, 123.93, 120.47, 117.92, 54.65, 43.12, 33.32, 33.05, 24.22, 16.16.19F NMR (376 MHz, DMSO) δ -61.04 (3F), -74.82 (6F). Example 29: Preparation of 2-(4-(5-(2-(5-isopropyl-2-methylphenoxy)pyrimidin-4-yl)-4-(4- (trifluoromethyl)phenyl)-1H-imidazol-1-yl)piperidin-1-yl)ethan-1-ol

[0009] 4-(1-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-4-yl)-4-(4- (trifluoromethyl)phenyl)-1H-imidazol-5-yl)-2-(5-isopropyl-2-methylphenoxy)pyrimidine ( In a single neck 50 mL round-bottom flask fitted with a magnetic stir bar and nitrogen inlet was charged 100 (60 mg, 0.094 mmol) in DMF. To the aforementioned reaction mixture was charged K2CO3(52 mg, 0.376 mmol) followed by TBDMS protected Bromoethanol (45 mg, 0.188 mmol). The reaction was heated to 80oC and allowed to stir overnight at that temperature under nitrogen atmosphere. Upon completion of the reaction as indicated by TLC, the reaction mixture was cooled to r.t. The reaction mixture was extracted with ethyl acetate and sequentially washed with 20% LiCl and water. The washed organic layer was dried over anhydrous Mg2SO4.The dried organic layer was evaporated in vacuo to afford the crude product which was purified by Combiflash chromatography (0-20% MeOH in DCM) to afford the pure product 1a as a colorless oil (36 mg, 38%).1H-NMR (500 MHz, CDCl3) d 8.41 (d, J =5 Hz,1H), 7.79 (s, 1H), 7.58 (s, 4H), 7.21 (d, J =10 Hz, 1H), 7.08-7.05 (m, 2H), 6.85 (d, J =5 Hz,1H), 4.48 (m, 1H), 3.74 (t, J =5Hz, 2H), 2.94(m, 3H), 2.51(t, J =10 Hz, J =5Hz, 2H), 2.18 (s, 3H), 1.88 (m, 6H), 1.26 (d, J =10 Hz, 6H), 0.90 (s, 9H), 0.07 (s, 6H).13C-NMR (125 MHz, CDCl3) d 165.1, 159.9, 151.0, 148.1, 142.6, 137.8, 136.7, 131.1, 129.7, 128.5, 127.1, 125.4, 125.3, 124.7, 123.7, 120.1, 116.3, 61.4, 60.0, 53.7, 53.2, 33.4, 25.8, 23.8, 18.1, 16.0, -.5.4.19F- NMR (470 MHz, CDCl3) d -62.5 (3F). HRMS: Expected [M+H]+: 680.3602 Observed: 680.3608. DCM impurity noted in proton NMR at 5.2 ppm. 2-(4-(5-(2-(5-isopropyl-2-methylphenoxy)pyrimidin-4-yl)-4-(4-(trifluoromethyl) phenyl)-1H-imidazol-1-yl)piperidin-1-yl)ethan-1-ol In a 20 mL glass vial fitted with a magnetic stir bar was charged 1a (36 mg, 0.0529 mmol) in 2M HCl in ether (5 mL). The reaction mixture was allowed to stir for 24 h at ambient temperature. Upon completion of the reaction as indicated by TLC, the reaction mixture was evaporated in vacuo to afford a white sticky solid, which was lyophilized to furnish the product 2 x2HCl as a fine white powder (26 mg, 77%) that was used without further purification.1H NMR (400 MHz, CDCl3) δ 8.34 (d, 5.25, 1H), 7.86 (s, 1H), 7.54 (q, 4.56, 4H), 7.19 (d, 1H, obscured by CDCl3), 7.02 (m, 2H), 6.80 (d, 5.22, 1H), 4.74 (b, 1H), 3.87 (b, 1H), 3.37 (b, 1H), 2.84 (m, 3H), 2.45 (b, 2H), 2.27 (m, 2H), 2.13 (s, 3H), 2.03 (d, J=2.7 Hz, 2H), 1.19 (d, J=6.94 Hz, 6H).13C-NMR (125 MHz, CDCl3) δ 166.5, 163.2, 157.0, 152.4, 149.9, 137.2, 134.9, 133.6, 132.5, 131.6, 128.6, 127.5, 126.2, 125.1, 124.0, 121.3, 118.7, 60.0, 56.7, 55.0, 53.0, 34.8, 31.1, 24.3, 16.1.19F NMR (376 MHz, CDCl3) δ -62.58 (s, 3F). HRMS [M+H]+Expected: 566.2737 Observed: 566.2743.95.1% via HPLC. Example 30: Preparation of: In a single neck 50 mL round bottom flask fitted with a magnetic stir bar and nitrogen inlet was charged piperidine intermediate (30 mg, 0.040-0.0484 mmol) in DMF. To the aforementioned reaction mixture was charged K2CO3(22-26 mg, 0.16-0.19 mmol, 4 equiv.) followed by alkyl substituent (0.080-0.0968 mmol, 2 equiv.). The reaction was heated to 80oC and allowed to stir overnight at that temperature under nitrogen atmosphere. Upon completion of the reaction as indicated by TLC, the reaction mixture was cooled to r.t. The reaction mixture was extracted with ethyl acetate and sequentially washed with 20% LiCl and water. The washed organic layer was dried over anhydrous Mg2SO4.The dried organic layer was evaporated in vacuo to afford the crude product which was purified by Combiflash chromatography (0-20% MeOH in DCM) to afford the pure product.1H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 5.1 Hz, 1H), 7.79 (s, 1H), 7.59 (s, 4H), 7.22 (d, J = 7.8 Hz, 1H), 7.07 (d, J = 15.1 Hz, 1H), 6.85 (d, J = 5.1 Hz, 1H), 4.52 (s, 1H), 4.18 (s, 1H), 3.57 (s, 6H), 3.48 – 3.40 (m, 14H), 3.27 – 3.17 (m, 1H), 2.98 – 2.86 (m, 1H), 2.17 (d, J = 2.6 Hz, 8H), 1.94 (t, J = 15.6 Hz, 7H), 1.48 (d, J = 1.1 Hz, 11H), 1.25 (d, J = 8.0 Hz, 6H).19F NMR (376 MHz, CDCl3) δ -62.54. Example 31: Preparation of: The title compound was prepared using procedures similar to those described in Example 31. Expected [M+H] 600.2256. Found: 600.2185. To an ACE sealed tube was added 7i (100 mg, 0.13 mmol, 1 eq), triethylamine (0.1 mL), sulfuric diamide (24 mg, 0.26 mmol, 2 eq), and dioxane (5 mL). The tube was sealed, and the reaction mixture was stirred at 90 °C for 18 h. The reaction mixture was diluted with EtOAc and washed with water before drying the organic layer over anhydrous Na2SO4and removed of volatiles. Purification was conducted by column chromatography on a Teledyne CombiFlash (0- 30% MeOH in DCM, 4 g) resulting in the product as a tan solid (56 mg, 71%).1H NMR (400 MHz, DMSO) δ 8.65 (d, 5.00 Hz, 1H), 8.22 (s, 1H), 7.70 (d, 8.25 Hz, 2H), 7.62 (d, 8.14 Hz, 2H), 7.28 (d, 7.72 Hz, 1H), 7.14 (d, 5.01 Hz, 1H), 7.10 (m, 2H), 6.87 (s, 2H), 4.24 (b, 1H), 3.50 (d, 11.7 Hz, 2H), 2.87 (hept, 9.60 Hz, 1H), 2.44 (td, 12.32 Hz, 2.72 Hz, 2H), 2.43 (s, 3H), 2.08 (m, 3H), 1.98 (m, 2H), 1.17 (d, 6.39 Hz, 6H).13C NMR (101 MHz, CDCl3) δ 165.22, 160.41, 151.13, 148.57, 136.94, 131.31, 128.92, 127.24, 125.71, 124.73, 124.05, 120.20, 116.36, 53.68, 45.76, 33.58, 32.30, 28.41, 23.97, 16.16.19F NMR (376 MHz, DMSO) δ -60.94. Expected Mass [M+H] = 601.2203 Observed Mass [M+H]: 601.2200 Purity by HPLC: 96.1%. Example 32: Preparation of: In a single neck 50 mL round bottom flask fitted with a magnetic stir bar and nitrogen inlet was charged piperidine intermediate (30 mg, 0.040-0.0484 mmol) in DMF. To the aforementioned reaction mixture was charged K2CO3(22-26 mg, 0.16-0.19 mmol, 4 equiv.) followed by alkyl substituent (0.080-0.0968 mmol, 2 equiv.). The reaction was heated to 80oC and allowed to stir overnight at that temperature under nitrogen atmosphere. Upon completion of the reaction as indicated by TLC, the reaction mixture was cooled to r.t. The reaction mixture was extracted with ethyl acetate and sequentially washed with 20% LiCl and water. The washed organic layer was dried over anhydrous Mg2SO4.The dried organic layer was evaporated in vacuo to afford the crude product which was purified by Combiflash chromatography (0-20% MeOH in DCM) to afford the pure product (19mg, 84%) (HPLC purity >95%).1H-NMR (500 MHz, MeOD): d 9.33 (s,1H), 8.64 (d, J =5 Hz, 1H), 7.84 (d, J =5 Hz, 2H), 7.66 (d, J =5 Hz, 2H), 7.34 (d, 1H), 7.14-7.12 (m,1H), 7.09 (m,1H), 7.06(d, J =5 Hz 1H), 4.55-4.53 (m, 1H), 3.80 (s, 2H), 2.92 (m, 3H), 2.28 (m, 2H), 2.20 (s, 3H), 2.06-2.03 (m, 4H), 1.25 (d, J =5 Hz, 6H).13C-NMR (125 MHz, CDCl3) d 166.5, 162.2, 159.6, 152.4, 149.8, 140.2, 138.3, 136.4, 132.9, 131.9, 131.7, 130.5, 128.3, 126.9, 126.9, 126.9, 126.5, 124.8, 124.4, 121.4, 118.3, 116.1, 56.6, 52.4, 45.9, 34.8, 33.6, 24.4, 16.2.19F-NMR (470 MHz, CDCl3) d -64.3 (3F). HRMS: 561.2590 [M+H]+Example 33: Preparation of: To a 2-dram vial was added iBRD4(D1) (30 mg), potassium carbonate (50 mg), chloroalkane (50 mg), and THF (5 mL). The vial was then sealed and stirred at 80 °C for 18 h before being washed with ethyl acetate. The organic layer was then dried and concentrated before purification by column chromatography (0-100% EtOAc and Hexanes, 4 g). The resulting product was then isolated as a yellow foam (15 mg).1H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 5.1 Hz, 1H), 7.81 (s, 1H), 7.61 (s, 4H), 7.23 (d, J = 7.7 Hz, 1H), 7.13 – 7.05 (m, 2H), 6.87 (d, J = 5.1 Hz, 1H), 4.51 (s, 1H), 3.46 (dt, J = 8.0, 4.8 Hz, 6H), 2.95 (q, J = 6.6 Hz, 3H), 2.54 (d, J = 4.7 Hz, 5H), 2.45 (d, J = 5.2 Hz, 5H), 2.20 (s, 3H), 1.91 (q, J = 7.3 Hz, 7H), 1.49 (s, 9H), 1.28 (d, J = 6.9 Hz, 6H).13C NMR (101 MHz, CDCl3) δ 165.26, 160.04, 154.73, 151.20, 148.34, 136.90, 131.29, 128.70, 127.28, 125.50, 124.86, 123.84, 120.23, 116.51, 53.96, 53.49, 53.21, 33.58, 33.39, 28.44, 23.99, 16.18, -0.00.19F NMR (376 MHz, CDCl3) δ -62.53. This was then deprotected in 1 mL of DCM with 0.2 mL of TFA for 18 h at room temperature. This was evaporated under nitrogen and precipitated out using MTBE to give the resulting product as a white solid. Example 34: Preparation of: To an ACE sealed tube was added 7i (100 mg, 0.13 mmol, 1 eq), triethylamine (0.1 mL), sulfuric diamide (24 mg, 0.26 mmol, 2 eq), and dioxane (5 mL). The tube was sealed, and the reaction mixture was stirred at 90 °C for 18 h. The reaction mixture was diluted with EtOAc and washed with water before drying the organic layer over anhydrous Na2SO4and removed of volatiles. Purification was conducted by column chromatography on a Teledyne CombiFlash (0- 30% MeOH in DCM, 4 g) resulting in the product as a tan solid (56 mg, 71%).1H NMR (400 MHz, DMSO) δ 8.65 (d, 5.00 Hz, 1H), 8.22 (s, 1H), 7.70 (d, 8.25 Hz, 2H), 7.62 (d, 8.14 Hz, 2H), 7.28 (d, 7.72 Hz, 1H), 7.14 (d, 5.01 Hz, 1H), 7.10 (m, 2H), 6.87 (s, 2H), 4.24 (b, 1H), 3.50 (d, 11.7 Hz, 2H), 2.87 (hept, 9.60 Hz, 1H), 2.44 (td, 12.32 Hz, 2.72 Hz, 2H), 2.43 (s, 3H), 2.08 (m, 3H), 1.98 (m, 2H), 1.17 (d, 6.39 Hz, 6H).13C NMR (101 MHz, CDCl3) δ 165.22, 160.41, 151.13, 148.57, 136.94, 131.31, 128.92, 127.24, 125.71, 124.73, 124.05, 120.20, 116.36, 53.68, 45.76, 33.58, 32.30, 28.41, 23.97, 16.16.19F NMR (376 MHz, DMSO) δ -60.94. Expected Mass [M+H] = 601.2203 Observed Mass [M+H]: 601.2200 Purity by HPLC: 96.1%. Example 35: Preparation of: (racemic) To a 2-dram vial was added Boc-iBRD4(D1)1(30 mg, 0.08 mmol, 1 eq) and a mixture of 1:1 v / v TFA:DCM (1 mL). The mixture was stirred until the complete disappearance of starting material was observed via TLC (10% MeOH in DCM). The reaction mixture was then blown dry under a stream of nitrogen and reconstituted in absolute EtOH (1 mL). To the reaction mixture was then added potassium carbonate (43 mg, 0.36 mmol, 4 eq) and 6-oxabicyclo[3.1.0]- hexane (20 mg, 0.24 mmol, 3 eq). The reaction was then stirred at 60 °C for 18 h before being concentrated in vacuo. The resulting oil was purified via column chromatography on a Teledyne CombiFlash (0-10% MeOH in DCM, 4 g). This yielded the product as a white solid (20.6 mg, 43%). Residual TFA salt was quantified through quantitative 19F-NMR.1H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 5.1 Hz, 1H), 7.87 (s, 1H), 7.62 (d, J = 2.6 Hz, 4H), 7.24 (d, J = 7.6 Hz, 1H), 7.10 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 5.1 Hz, 1H), 4.66 (s, 1H), 4.33 (q, J = 6.5 Hz, 1H), 3.49 (d, J = 10.0 Hz, 1H), 3.18 (dd, J = 21.5, 8.1 Hz, 1H), 2.94 (hept, J = 6.9 Hz, 1H), 2.82 (d, J = 7.4 Hz, 1H), 2.21 (m, 7H), 2.03 (m, 4H), 1.76 (s, 2H), 1.65 (s, 2H), 1.27 (d, J = 6.9 Hz, 6H).13C NMR (101 MHz, CDCl3) δ 165.15, 160.16, 159.70, 151.23, 148.53, 143.17, 137.81, 137.14, 131.25, 129.82, 128.85, 127.27, 125.61, 125.57, 124.56, 123.90, 120.35, 116.38, 77.05, 74.46, 52.82, 51.97, 49.77, 34.06, 33.57, 31.88, 26.92, 23.99, 23.98, 21.13, 16.14.19F NMR (376 MHz, CDCl3) δ -62.55 (3F), -75.64 (1.5F). Example 36: Preparation of: The title compound was prepared using procedures similar to those described herein.1H NMR (500 MHz, CDCl3) δ 8.41 (d, J = 5.1 Hz, 1H), 7.78 (s, 1H), 7.59 (d, J = 1.3 Hz, 4H), 7.22 (d, J = 7.8 Hz, 1H), 7.06 (dd, J = 18.2, 1.9 Hz, 2H), 6.85 (d, J = 5.1 Hz, 1H), 4.51 (s, 1H), 3.72 – 3.58 (m, 8H), 3.18 (s, 2H), 2.98 – 2.87 (m, 3H), 2.18 (s, 3H), 1.93 (d, J = 3.3 Hz, 7H), 1.25 (d, J = 6.9 Hz, 6H).13C NMR (126 MHz, CDCl3) δ 168.29, 165.64, 160.43, 160.37, 151.56, 148.74, 143.25, 138.28, 137.19, 131.70, 130.33, 130.07, 129.11, 127.70, 125.97, 125.94, 125.91, 125.88, 125.26, 124.31, 120.58, 116.84, 67.38, 67.34, 61.15, 54.13, 53.12, 46.53, 42.57, 33.95, 33.78, 24.37, 16.57.19F NMR (471 MHz, CDCl3) δ -62.53. Example 37: Preparation of: The title compound was prepared using procedures similar to those described by Divakaran, A., et al., ACS Med. Chem. Lett.2022, 13 (10), 1621–1627. Example 38: Preparation of: In a 20 mL glass vial fitted with a magnetic stir bar was charged TBDMS protected product (15 mg, 0.015 mmol) in 4N HCl / Dioxan (1 mL). The reaction mixture was allowed to stir for 24 h at r.t. Upon completion of the reaction as indicated by TLC, the reaction mixture was evaporated in by flushing nitrogen atmosphere leading to an oily material. The oily material was purified by Combiflash chromatography (0-10% MeOH in DCM) to afford pure product as a fine white powder (9 mg, 40%).1H-NMR (500 MHz, MeOD) d 8.49 (d, J =5 Hz,1H), 8.08 (s, 1H), 7.57 (d, J =5 Hz, 2H), 7.33 (d, J =5 Hz, 2H), 7.28 (d, J =10 Hz, 1H), 7.14 (d, 1H), 7.10 (s, 1H) 6.96 (d, J =5 Hz, 1H), 4.50 (m, 1H), 3.78 (t, J =5Hz, 2H), 3.23 (m 2H), 2.95-2.83 (m, 3H), 2.20(m, 5H), 1.99 (m, 4H), 1.31 (m, 2H), 1.26 (d, J =5 Hz, 6H).13C-NMR (125 MHz, MeOD): d 166.2, 161.4, 160.9, 152.6, 149.8, 144.0, 138.6, 134.1, 133.0, 132.6, 131.5, 128.5, 125.7, 125.0, 123.4, 121.4, 117.9, 53.6, 34.8, 24.4, 16.2. Example 39: Preparation of: The title compound was prepared using procedures similar to those described in Example 12.1H NMR (500 MHz, MeOD) δ 8.53 (d, J = 5.2 Hz, 1H), 8.32 (s, 1H), 7.67 (dd, J = 8.2, 7.3 Hz, 1H), 7.34 (dd, J = 9.6, 1.9 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.18 – 7.14 (m, 2H), 7.08 (d, J = 1.8 Hz, 1H), 7.04 (d, J = 5.1 Hz, 1H), 5.37 – 5.27 (m, 1H), 3.80 – 3.48 (m, 2H), 2.94 (p, J = 6.9 Hz, 1H), 2.40 (s, 0H), 2.35 – 2.24 (m, 1H), 2.17 (s, 3H), 1.27 (d, J = 6.9 Hz, 6H).13C NMR (126 MHz, MeOD) δ 166.40, 161.92, 161.52, 159.93, 159.56, 152.76, 150.21, 138.63, 135.83, 135.34, 132.41, 128.96, 126.99, 125.23, 121.26, 117.74, 117.56, 110.29, 57.00, 52.00, 46.07, 34.84, 32.09, 24.41, 15.98.19F NMR (471 MHz, MeOD) δ -77.25 (3F), -108.46 (1F). Example 40: Preparation of: The title compound was prepared with similar procedures to those reported herein.1H NMR (500 MHz, MeOD) δ 8.51 (d, J = 5.1 Hz, 1H), 8.13 (s, 1H), 7.71 (d, J = 5.7 Hz, 0H), 7.63 (d, J = 8.7 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.39 – 7.36 (m, 1H), 7.35 (t, J = 2.1 Hz, 1H), 4.73 – 4.63 (m, 1H), 3.36 (d, J = 3.1 Hz, 1H), 2.77 (d, J = 3.1 Hz, 1H), 2.25 – 2.05 (m, 2H), 1.34 (s, 9H).13C NMR (126 MHz, MeOD) δ 166.56, 163.21, 162.94, 161.73, 160.36, 154.96, 154.29, 143.17, 138.72, 138.54, 131.34, 131.09, 130.48, 130.32, 126.76, 126.73, 126.68, 126.51, 124.53, 123.74, 120.14, 119.65, 119.37, 118.40, 117.04, 52.73, 44.63, 35.77, 31.69, 31.12.19F NMR (471 MHz, MeOD) δ -64.10 (3F), -76.89 (3F). Example 41: Preparation of: The title compound was prepared using procedures similar to those described in Example 12.1H NMR (500 MHz, MeOD) δ 8.53 (d, J = 5.2 Hz, 1H), 8.32 (s, 1H), 7.67 (dd, J = 8.2, 7.3 Hz, 1H), 7.34 (dd, J = 9.6, 1.9 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.18 – 7.14 (m, 2H), 7.08 (d, J = 1.8 Hz, 1H), 7.04 (d, J = 5.1 Hz, 1H), 5.37 – 5.27 (m, 1H), 3.80 – 3.48 (m, 2H), 2.94 (p, J = 6.9 Hz, 1H), 2.40 (s, 0H), 2.35 – 2.24 (m, 1H), 2.17 (s, 3H), 1.27 (d, J = 6.9 Hz, 6H).13C NMR (126 MHz, MeOD) δ 166.40, 161.92, 161.52, 159.93, 159.56, 152.76, 150.21, 138.63, 135.83, 135.34, 132.41, 128.96, 126.99, 125.23, 121.26, 117.74, 117.56, 110.29, 57.00, 52.00, 46.07, 34.84, 32.09, 24.41, 15.98.19F NMR (471 MHz, MeOD) δ -77.25 (3F), -108.46 (1F). Example 42: Preparation of: In a single neck 50 mL round bottom flask fitted with a magnetic stir bar and nitrogen inlet was charged piperidine intermediate (30 mg, 0.040-0.0484 mmol) in DMF. To the aforementioned reaction mixture was charged K2CO3(22-26 mg, 0.16-0.19 mmol, 4 equiv.) followed by alkyl substituent (0.080-0.0968 mmol, 2 equiv.). The reaction was heated to 80oC and allowed to stir overnight at that temperature under nitrogen atmosphere. Upon completion of the reaction as indicated by TLC, the reaction mixture was cooled to r.t. The reaction mixture was extracted with ethyl acetate and sequentially washed with 20% LiCl and water. The washed organic layer was dried over anhydrous Mg2SO4.The dried organic layer was evaporated in vacuo to afford the crude product which was purified by Combiflash chromatography (0-20% MeOH in DCM) to afford the pure product.1H NMR (500 MHz, MeOD) δ 8.63 (d, J = 5.0 Hz, 1H), 7.83 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 8.1 Hz, 2H), 7.47 – 7.33 (m, 2H), 7.13 (ddd, J = 7.8, 2.4, 1.2 Hz, 1H), 7.08 (d, J = 5.0 Hz, 1H), 3.97 – 3.88 (m, 2H), 3.80 – 3.63 (m, 2H), 3.28 (s, 2H), 2.40 (d, J = 3.1 Hz, 4H), 1.35 (s, 9H).13C NMR (126 MHz, MeOD) δ 166.80, 162.87, 157.62, 155.03, 154.12, 137.49, 136.48, 133.20, 132.93, 130.88, 130.59, 127.87, 127.42, 126.33, 123.97, 120.09, 119.63, 118.81, 59.97, 56.66, 54.54, 53.05, 35.81, 31.70, 31.26.19F NMR (471 MHz, MeOD) δ -64.44. Example 43: Preparation of: The title compound was prepared using procedures similar to those described in Example 31. Expected [M+H] 600.2256. Found: 600.2185. Example 44: Preparation of: In a single neck 50 mL round bottom flask fitted with a magnetic stir bar and nitrogen inlet was charged piperidine intermediate (30 mg, 0.040-0.0484 mmol) in DMF. To the aforementioned reaction mixture was charged K2CO3(22-26 mg, 0.16-0.19 mmol, 4 equiv.) followed by alkyl substituent (0.080-0.0968 mmol, 2 equiv.). The reaction was heated to 80oC and allowed to stir overnight at that temperature under nitrogen atmosphere. Upon completion of the reaction as indicated by TLC, the reaction mixture was cooled to r.t. The reaction mixture was extracted with ethyl acetate and sequentially washed with 20% LiCl and water. The washed organic layer was dried over anhydrous Mg2SO4.The dried organic layer was evaporated in vacuo to afford the crude product which was purified by Combiflash chromatography (0-20% MeOH in DCM) to afford the pure product (37 mg, >90%) (HPLC purity >95%).1H-NMR (500 MHz, CDCl3): d 8.43 (d, J =5 Hz ,1H), 7.80 (s, 1H), 7.60 (m, 4H), 7.37-7.28 (m, 3H), 7.06 (m, 1H), 7.03(s, 2H), 6.87 (d, J =5 Hz ,1H), 4.58-4.56 (m, 1H), 3.74-3.70 (m, 2H), 2.86 (d, J =5 Hz, 2H), 2.01-1.98 (m, 6H), 1.34 (s, 9H).13C-NMR (125 MHz, CDCl3) d 165.5, 160.2, 159.8, 153.6, 152.7, 137.9, 136.9, 129.2, 128.9, 125.7, 124.9, 122.7, 119.0, 118.7, 116.8, 55.6, 52.8, 35.0, 33.3, 31.5, 31.5.19F-NMR (470 MHz, CDCl3) d -62.5 (3F). HRMS: 602.2784 [M+H]+Example 45: Preparation of: The title compound was prepared utilizing the compound of Example 41 and using procedures similar to those described in Example 26 which example is reproduced below. To a 2-dram vial was added 7i (30 mg, 0.040 mmol, 1 eq), iodoacetamide (28 mg, 0.16 mmol, 4 eq), cesium carbonate (52 mg, 0.16 mmol, 4 eq), and absolute ethanol (2 mL). The vial was sealed and stirred under reflux for 24 h. The resulting mixture was diluted with ethyl acetate (10 mL) before being washed with water (2x, 15 mL) and saturated sodium chloride (20 mL). The organic layer was dried over sodium sulfate and concentrated before being purified through column chromatography (0 to 30% MeOH in DCM 4 g) This resulted in the desired product as a white solid (10.2 mg, 44%).1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 5.2 Hz, 1H), 7.81 (s, 1H), 7.62 (d, J = 2.1 Hz, 4H), 7.23 (d, J = 7.7 Hz, 1H), 7.14 – 7.04 (m, 2H), 6.96 (s, 1H), 6.87 (d, J = 5.1 Hz, 1H), 5.64 (s, 1H), 4.57 (dt, J = 11.3, 6.6 Hz, 1H), 3.03 (s, 2H), 2.92 (s, 1H), 2.20 (s, 3H), 1.95 (s, 3H), 1.27 (d, J = 6.9 Hz, 6H).13C NMR (101 MHz, CDCl3) δ 172.83, 165.20, 160.14, 159.80, 151.18, 148.40, 143.08, 137.85, 136.75, 131.33, 130.09, 129.77, 128.78, 127.34, 127.28, 125.60, 125.56, 125.47, 124.80, 124.02, 123.96, 122.77, 120.21, 116.40, 61.29, 53.49, 53.20, 33.57, 33.54, 23.98, 16.18.19F NMR (376 MHz, CDCl3) δ -62.55. Example 46: Preparation of: To a 2 Dr vial was added sulfone (53 mg, 0.086 mmol, 1 eq), 3,5-dicyclopropylphenol (30 mg, 0.172 mmol, 2 eq), potassium carbonate (47 mg, 0.34 mmol, 4 eq), and anhydrous THF (2 mL). The resulting mixture was then sealed and stirred at 80 °C for 18 h before being diluted with EtOAc. The organic layer was then washed with 1 N NaOH until no phenol could be observed. The organic layer was dried over anhydrous magnesium sulfate and then purified by column chromatography (4 g, 0 to 100% EtOAc in Hexanes). This yielded the desired product as a white foam (58.6 mg, quant.).1H NMR (400 MHz, CDCl3) δ 8.42 (d, 5.1 Hz, 1H), 7.74 (s, 1H), 7.61 f(s, 4H), 6.85 (d, 5.14 Hz, 1H), 6.72 (s, 2H), 6.66 (s, 1H), 4.68 (tt, 12.3 Hz, 3.87 Hz, 1H), 4.10 (b, 2H), 2.43 (t, 12.8 Hz, 2H), 1.87 (m, 4H), 1.71 (m, 2H) 1.48 (s, 9H), 0.97 (m, 4H), 0.68 (m, 4H). Residual water from CDCl3 observed at 1.60 ppm.13C NMR (101 MHz, CDCl3) δ 165.45, 160.08, 159.52, 154.47, 153.00, 146.05, 143.39, 137.97, 136.89, 128.91, 125.57, 124.54, 120.10, 116.37, 116.28, 79.97, 54.06, 33.36, 28.43, 15.45, 9.46.19F NMR (376 MHz, CDCl3) δ - 62.54. To a 2 Dr vial was added boc-precursor (24 mg, 0.037 mmol, 1 eq) and dissolved in DCM (2 mL). To this solution was added excess trifluoroacetic acid (0.3 mL), resulting in a pale-yellow solution that was stirred for 1 h at ambient temperature. The reaction mixture was then blown dry under a stream of nitrogen and the desired was precipitated out with cold MTBE. The desired product was filtered and isolated as a white solid (30.0 mg, quant.).1H NMR (400 MHz, MeOD) δ 8.67 (s, 1H), 8.57 (d, J = 5.1 Hz, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.67 (d, J = 8.1 Hz, 3H), 7.01 (d, J = 5.1 Hz, 1H), 6.83 – 6.70 (m, 3H), 4.75 (s, 1H), 3.42 (d, J = 13.5 Hz, 2H), 2.80 (t, J = 11.1 Hz, 2H), 2.20 (s, 4H), 1.94 (s, 2H), 1.01 (s, 4H), 0.71 (s, 4H).13C NMR (101 MHz, MeOD) δ 165.24, 160.82, 160.67, 160.30, 157.58, 153.18, 146.44, 138.69, 136.77, 134.62, 131.12, 130.87, 130.55, 130.31, 129.24, 125.68, 125.64, 125.39, 122.67, 119.65, 119.51, 116.98, 112.76, 52.30, 43.17, 29.55, 25.81, 14.76, 8.77.19F NMR (376 MHz, MeOD) δ -64.25 (3F), -77.21 (6F). Examples 47-55 Chemistry Methods Unless otherwise noted, all materials were obtained from commercial suppliers and used without further purification. Anhydrous solvents were obtained from MilliporeSigma and ThermoScientific and used directly. Purification of intermediates and final products were carried out on a Teledyne ISCO CombiFlashTMinstrument using normal-phase chromatography. Purification was carried out using pre-packed silica cartridges (Silica RediSep Gold, 4 g, 12 g, etc) with either EtOAc / Hexanes or DCM / MeOH as mobile phases. The final purity of compounds was determined by peak area through reverse-phase UPLC with a VYDAC 4.6x250 mm, 5 μM C18 column (Cat# 201HS54) with 0.1% TFA in Water and Acetonitrile used as mobile phases (1 mL / min). Compounds were assessed with a 0-50% MeCN gradient over 50 min using 272 nm absorption after a DMSO-blank subtraction from HPLC traces. All compounds were determined to be >90% pure, unless otherwise noted, with cellular compounds being >95% pure. Chemical shifts of spectra reported in parts-per-million (ppm). The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad. Quantification of HCl salt forms were carried out using 2,2,2-trifluoroethanol as internal standard via quantitative NMR. Coupling constants shown in Hertz. General Procedure A: Immines A-F General Procedure B-C: Formation of Methyl Sulfide and Sulfone Products General Procedure D-E: Secondary Cycloalkyl Amines (e.g., piperidines and pyrrolidines): General Procedure D-E: Primary Cycloalkyl Amines (e.g., cyclohexyl, cyclopenyl, and cyclobutyl):

[0010] General Procedure A. To a round-bottom flask was added substituted cycloalkyl-amine (600 mg, 3.2 mmol, 1 eq), 2- (methylthio)pyrimidine-4-carbaldehyde (500 mg, 3.2 mmol, 1 eq), and anhydrous magnesium sulfate (1.5 g, 12.0 mmol, 4 eq), which was dissolved in DCM (20 mL). The reaction mixture was stirred vigorously at ambient temperature for 18 h. The reaction mixture was then filtered and washed with water (30 mL) before volatiles were removed under vacuum. The resulting yellow solid was used without further purification (1.346 g, 86%). Example given for ((1s,3s)-3- aminocyclobutyl)carbamate, yields ranged from 86% to quantitative. General Procedure B. To a 20 mL vial was added the substituted immine (0.5 mmol, 1.1 eq), isonitrile (0.44 mmol, 1 eq), potassium carbonate (1.3 mmol, 3 eq), and acetonitrile (5 mL). The vial was then capped, and the resulting mixture was stirred at 40 °C for 18 h. The reaction was then diluted with EtOAc and washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The resulting oil was purified through column chromatography on a Teledyne Combiflash (4 g, 0 to 100% EtOAc in Hexanes). This yielded the title compound as an orange foam (107.9 mg, 48%). General Procedure C. To a round-bottom flask was added methyl sulfide (150 mg, 0.28 mmol, 1 eq), Oxone (207 mg, 0.67 mmol, 2.4 eq), and a mixture of THF / Water (2:1 v / v, 12 mL). The reaction mixture was stirred for 18 h at ambient temperature before being diluted with THF and the organic layer was separated and washed with water. The organic layer was dried and then concentrated, giving the desired product as a yellow solid which was used without further purification (157 mg, 99%). Example given for CS-7110b; yields were consistently >95%. General Procedure D. To a sealed tube was added oxone product (0.10-0.28 mmol, 1 eq), substituted phenol (0.4-1.2 mmol, 4 eq), potassium carbonate (0.1-1.2 mmol, 4 eq), and THF (0.1 M). The reaction mixture was stirred at 80 °C for 18 h before being diluted with ethyl acetate and washed with 1 N NaOH(aq)until excess carvacrol was no longer visible by TLC (3:7 EtOAc:Hexanes, SiO2). The reaction mixture was concentrated by vacuum and purified through column chromatography on a Teledyne CombiFlash (0-100% EtOAc in Hexanes, 4 g). The resulting product was a white foam (71.4 mg, 40%). Example given for CS-7110c; yields ranged from 40-62% with carvacrol, or 73-81% with 3,5-dimethylphenol. General Procedure E. To a vial containing the Boc-protected amine (15-40 mg, 1 eq) was added DCM (1 mL) and excess TFA (0.2 mL). The resulting solution was stirred at ambient temperature for 1 h before volatiles were removed under a stream of nitrogen. The product was then precipitated out under cold diethyl ether to give the title compound as a white solid. Yields were consistently >95% for all products. Synthesis of Immine Precursors The following imines were synthesized using General Procedure A. Immine A. Synthesis of Immine A was reported in Cui, H., et al., J. Med. Chem.2022, 65 (3), 2342–2360 and was synthesized accordingly with similar yields (quant.). Immine B. Synthesis of Immine B was reported in Cui, H., et al., J. Med. Chem.2022, 65 (3), 2342–2360 and was synthesized accordingly with similar yields (quant.). Immine C. Synthesized from tert-butyl (3R,4R)-3-amino-4-hydroxypyrrolidine-1-carboxylate to give a pink solid (1240 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 8.56 (d, 5.03 Hz, 1H) 8.27 (s, 1H), 7.54 (d, 5.07 Hz, 1H), 4.28 (m, 1H), 3.92-3.81 (m, 3H), 3.42 (m, 2H), 2.59 (s, 3H), 1.46 (s, 9H).13C NMR (101 MHz, CDCl3) δ 173.08, 161.69, 160.78, 157.76, 154.62, 112.26, 79.82, 75.27, 75.41 (d, 32.94 Hz), 74.90 (d, 14.14 Hz), 74.57, 52.02, 51.76 (d, 26.03 Hz), 50.45 (d, 54.83 Hz), 49.91, 28.50, 14.13. Expected [M+H]: 339.4335 Observed: 339.4345. Immine D. Synthesized from tert-butyl cis-4-aminocyclohexyl)carbamate to give an off-white solid (804.5 mg, quant.). 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 5.1 Hz, 1H), 8.25 (s, 1H), 7.58 (d, J = 5.1 Hz, 1H), 4.70 (s, 1H), 3.75 (s, 1H), 3.49 (t, J = 5.1 Hz, 1H), 2.61 (s, 3H), 1.90 – 1.69 (m, 8H), 1.47 (s, 9H).13C NMR (101 MHz, CDCl3) δ 172.96, 161.56, 158.71, 157.58, 155.25, 112.07, 79.15, 66.34, 47.04, 30.25, 28.46, 28.37, 14.13. Expected [M+H]: 351.4885 Observed: 351.4891. Immine E. From tert-butyl ((1R,3S)-3-aminocyclopentyl)carbamate to give a yellow solid (857 mg, 95%). 1H NMR (500 MHz, CDCl3) δ 8.57 (d, J = 5.0 Hz, 1H), 8.16 (s, 1H), 7.54 (d, J = 5.2 Hz, 1H), 5.33 – 5.26 (m, 1H), 4.28 – 4.18 (m, 1H), 3.98 (dp, J = 6.9, 3.7 Hz, 1H), 2.60 (s, 3H), 2.22 (p, J = 6.7 Hz, 1H), 2.15 – 1.92 (m, 1H), 1.81 (pt, J = 5.8, 2.7 Hz, 2H), 1.65 (dt, J = 13.4, 4.3 Hz, 1H), 1.46 (s, 9H).13C NMR (126 MHz, CDCl3) δ 173.05, 161.27, 158.31, 157.62, 155.35, 112.05, 79.01, 70.33, 51.62, 41.81, 32.71, 32.43, 28.46, 14.13. Expected [M+H]: 337.4615 Observed: 337.4609. Immine F. Synthesized from tert-butyl ((1s,3s)-3-aminocyclobutyl)carbamate to give the title compound as a white solid (1.346 g, 86%). Note: DCM impurity denoted in 13C NMR @ 53.44 ppm. 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 5.1 Hz, 1H), 8.11 (d, J = 1.5 Hz, 1H), 7.55 (d, J = 5.0 Hz, 1H), 4.71 (s, 1H), 4.08 (s, 1H), 4.01 – 3.88 (m, 1H), 2.86 – 2.75 (m, 2H), 2.59 (s, 3H), 2.05 (qd, J = 9.0, 2.8 Hz, 2H), 1.45 (s, 9H).13C NMR (101 MHz, CDCl3) δ 173.04, 161.23, 158.97, 157.71, 154.92, 112.01, 79.52, 56.27, 40.20, 39.00, 28.40, 14.13. Expected [M+H]: 323.4345 Observed: 323.4377. Synthesis of Isonitrile A Precursor Isonitrile A. Characterization of Isonitrile A, along with synthesis and characterization of N- (tosyl(4-(trifluoromethyl)phenyl)methyl)formamide, was previously reported (Divakaran, A., et al., ACS Med. Chem. Lett.2022, 13 (10), 1621–1627; and Cui, H., et al., J. Med. Chem.2022, 65 3(3), 2342–2360). To an flame-dried and nitrogen-purged flask was added the starting formamide precursor (10 g, 28 mmol, 1 eq), which was dissolved in dry THF (70 mL) and cooled to -15 °C in a dry ice-ethanol bath. To the reaction mixture was added POCl3(7.8 mL, 84 mmol, 3 eq) dropwise over a period of 10 min. The reaction was maintained below -10 °C upon addition and for an additional 15 min. To the reaction mixture was then added 2,6-leutidine (39 mL, 336 mmol, 12 eq) before allowing to warm to room temperature and stirring overnight. The solution was then quenched with EtOAc (50 mL) and washed twice with 10% NaH2PO4(150 mL each). The organic layer was then separated and dried over anhydrous Na2SO4and filtered. The organic layer was then concentrated via rotary evaporation to half of the original volume, maintaining the temperature at 35 °C. Higher temperatures leads to degradation of product. The solution was then diluted with n-heptanes (100 mL) before being concentrated at 35 °C until half of the volume remained. The resulting tar was then scraped from the sides of the flask before being washed and concentrated three more times (400 mL heptane total), leading to a total volume ~400 mL. The resulting mixture was sonicated for 30 min before being stirred at room temperature with a recrystallization seed (20 mg) for 1 h, resulting in a tan slurry. The slurry was then filtered, affording the desired product as a tan solid (8.98 g, 94%). Example 47: Preparation of: a) The corresponding Boc protected amine was prepared using General Procedure D and was isolated product as a white foam (26.2 mg, 56%).1H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 5.1 Hz, 1H), 7.81 (s, 1H), 7.59 (s, 4H), 6.83 (d, J = 5.1 Hz, 1H), 6.74 – 6.66 (m, 2H), 4.94 (p, J = 7.9 Hz, 1H), 4.58 (d, J = 6.5 Hz, 1H), 3.88 (s, 1H), 2.35 (s, 1H), 1.89 (s, 6H), 1.63 (s, 2H), 1.45 (s, 9H), 1.04 – 0.91 (m, 4H), 0.70 (dt, J = 6.6, 4.5 Hz, 4H).13C NMR (101 MHz, CDCl3) δ 165.70, 159.94, 159.58, 155.29, 153.24, 146.12, 143.27, 137.99, 136.99, 130.04 (d, J = 15.9 Hz), 128.83, 125.55 (d, J = 3.7 Hz), 125.29, 122.78 (d, J = 258.1 Hz), 120.36, 116.23, 116.11, 55.55, 50.63, 40.94, 31.74, 31.59, 28.41, 15.45, 9.54 (d, J = 3.7 Hz).19F NMR (376 MHz, CDCl3) δ -62.53. Expected [M+H]: 646.3000 Observed [M+H]: 646.2997. b) The title compound was prepared from the corresponding Boc protected amine using General Procedure E and was isolated as a white solid (23.7 mg).1H NMR (400 MHz, MeOD) δ 8.66 (s, 1H), 8.54 (d, J = 5.3 Hz, 1H), 7.77 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H), 6.97 (d, J = 5.1 Hz, 1H), 6.80 (s, 1H), 6.74 (s, 2H), 5.02 (s, 1H), 3.52 (d, J = 4.0 Hz, 1H), 2.51 (s, 1H), 1.93 (s, 7H), 1.01 (s, 4H), 0.71 (s, 4H).13C NMR (101 MHz, MeOD) δ 165.42, 160.61, 157.84, 153.40, 146.52, 139.47, 136.80, 135.06, 130.83 (d, J = 38.2 Hz), 129.27, 125.77 – 125.49 (m), 123.19 (d, J = 226.7 Hz), 119.83, 116.39, 115.47, 56.46, 49.27, 37.68, 30.49, 28.30, 14.77, 8.82 (d, J = 5.0 Hz). 19F NMR (376 MHz, MeOD) δ -64.24, -77.17. Expected [M+H]: 546.2475 Observed [M+H]:546.2477. Example 48: Preparation of: NON F3C NH N N a) The corresponding Boc protected amine was prepared using General Procedure D and was isolated product as a white foam (49.6 mg, 59 %).1H NMR (500 MHz, CDCl3) δ 8.36 (d, J = 5.2 Hz, 1H), 7.66 (s, 1H), 7.57 – 7.49 (m, 4H), 7.25 (t, J = 7.9 Hz, 1H), 6.95 (dd, J = 8.0, 1.3 Hz, 1H), 6.93 – 6.86 (m, 2H), 6.79 (d, J = 5.2 Hz, 1H), 4.55 (tt, J = 12.1, 3.9 Hz, 1H), 4.04 (s, 2H), 2.39 (t, J = 13.4 Hz, 2H), 1.88 – 1.76 (m, 3H), 1.70 – 1.55 (m, 3H), 1.41 (s, 9H), 0.98 – 0.88 (m, 2H), 0.69 – 0.60 (m, 2H).13C NMR (126 MHz, CDCl3) δ 165.45, 160.16, 159.54, 154.45, 152.88, 146.49, 143.22, 137.85, 136.86, 130.07, 129.95 (q, J = 32.6 Hz), 125.57 (q, J = 3.7 Hz), 125.20 (q, J = 270.2 Hz), 129.45, 128.85, 127.35, 125.59, 125.56, 124.59, 123.03, 122.63, 121.23, 119.26, 118.87, 116.57, 80.03, 54.05, 33.30, 28.42, 15.42, 9.67.19F NMR (471 MHz, CDCl3) δ -62.54. Expected [M+H]: 606.2687 Observed [M+H]: 606.2689. b) The title compound was prepared from the corresponding Boc protected amine using General Procedure E and was isolated as a tan solid (88.2 mg, 2x TFA).1H NMR (500 MHz, CD3OD_SPE) δ 8.57 (d, J = 5.1 Hz, 1H), 8.46 (s, 1H), 7.75 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 8.1 Hz, 2H), 7.37 (t, J = 7.8 Hz, 1H), 7.11 – 6.99 (m, 4H), 4.71 (tt, J = 11.8, 4.2 Hz, 1H), 3.44 – 3.35 (m, 2H), 2.78 (td, J = 13.0, 3.2 Hz, 2H), 2.29 – 2.08 (m, 4H), 1.98 (tt, J = 8.3, 5.0 Hz, 1H), 1.10 – 1.00 (m, 2H), 0.80 – 0.71 (m, 2H).13C NMR (126 MHz, CD3OD_SPE) δ 165.21, 160.72, 158.03, 153.10, 146.78, 139.83, 136.87, 135.59, 130.78, 130.52, 130.39 (q, J = 32.6 Hz), 130.26, 129.99, 129.38, 129.12, 125.54 (q, J = 3.8 Hz), 125.52, 125.46, 125.17, 123.01, 123.02 (q, J = 272.9 Hz), 122.31, 118.68, 118.33, 117.03, 51.89, 43.20, 29.57, 14.71, 8.90.19F NMR (471 MHz, CD3OD_SPE) δ - 64.23 (3F), -77.24 (6F). Expected [M+H]: 506.2162 Observed [M+H]: 506.2161. Example 49: Preparation of: a) The corresponding Boc protected amine was prepared as follows. To a sealed 4-dram vial was added tert-butyl ((1R,3S)-3-(5-(2-(methylsulfonyl)pyrimidin-4-yl)-4-(4- (trifluoromethyl)phenyl)-1H-imidazol-1-yl)cyclopentyl)carbamate (42 mg, 0.076 mmol, 1 eq), 3-cyclopropylphenol (42 mg, 0.304 mmol, 4 eq), potassium carbonate (42 mg, 0.304 mmol, 4 eq), and THF (2 mL). The reaction mixture was stirred at 80 °C for 18 hours before letting cool and diluting with EtOAc. The organic layer was washed with 1 N NaOH(aq) and dried over anhydrous magnesium sulfate. The reaction mixture was purified via column chromatography, to provide a white solid (28.9 mg, 62%).1H NMR (500 MHz, CDCl3) δ 8.43 (d, J = 5.2 Hz, 1H), 7.82 (s, 1H), 7.65 – 7.57 (m, 4H), 7.35 (t, J = 7.9 Hz, 1H), 7.00 (d, J = 8.1 Hz, 2H), 6.96 (t, J = 2.0 Hz, 1H), 6.85 (d, J = 5.0 Hz, 1H), 4.92 (p, J = 7.9 Hz, 1H), 4.56 (s, 1H), 3.88 (d, J = 5.5 Hz, 1H), 2.35 (dt, J = 13.1, 7.4 Hz, 1H), 2.08 – 1.79 (m, 4H), 1.69 – 1.59 (m, 5H), 1.47 (s, 9H), 1.08 – 0.98 (m, 2H), 0.78 – 0.71 (m, 2H).13C NMR (126 MHz, CDCl3) δ 165.67, 160.04, 159.53, 155.28, 153.09, 146.56, 143.24, 136.95, 130.03, 129.90 (q, J = 31.8 Hz), 129.77, 129.50, 128.81, 125.65 – 125.44 (m), 125.60, 125.57 , 125.54, 125.27, 123.04, 122.78, 121.71 (q, J = 163.7 Hz), 119.28, 118.80, 116.35, 55.44, 40.90, 31.63, 31.50, 28.41, 15.43, 9.75, 9.73.19F NMR (471 MHz, CDCl3) δ -62.54. Expected [M+H]: 606.2687 Observed [M+H]: 606.2864. b) The title compound was prepared from the corresponding Boc protected amine using General Procedure E and was isolated as a white solid, 33.3 mg (2x TFA).1H NMR (500 MHz, CD3OD_SPE) δ 8.57 (s, 1H), 8.54 (d, J = 5.1 Hz, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.1 Hz, 2H), 7.38 (t, J = 7.9 Hz, 1H), 7.11 – 7.01 (m, 2H), 7.01 – 6.95 (m, 2H), 4.97 (ddd, J = 9.9, 8.2, 4.8 Hz, 1H), 3.51 (ddq, J = 7.2, 4.7, 2.5 Hz, 1H), 2.47 (d, J = 7.6 Hz, 1H), 2.15 – 1.81 (m, 6H), 1.10 – 1.00 (m, 2H), 0.79 – 0.72 (m, 2H).13C NMR (126 MHz, CD3OD_SPE) δ 165.42, 160.70, 160.61, 158.00, 153.28, 146.87, 139.82, 136.86, 135.42, 130.63, 130.50 (q, J = 32.5 Hz), 130.37, 130.11, 125.73, 125.67 – 125.44 (m), 125.59, 125.56, 125.53, 125.15, 123.00, 122.47, 118.63, 118.59, 118.52, 117.55 (d, J = 290.3 Hz)., 116.54, 115.24, 56.27, 49.24, 30.45, 28.26, 14.72, 8.99, 8.9319F NMR (471 MHz, CD3OD_SPE) δ -64.23 (3F), -77.12 (6F). [M+H] Expected [M+H]: 506.2162 Observed [M+H]: 506.2163. Example 50: Preparation of: a) The corresponding Boc protected amine was prepared as follows. To a 2-dram vial was added tert-butyl ((1R,3S)-3-(5-(2-(methylsulfonyl)pyrimidin-4-yl)-4-(4- (trifluoromethyl)phenyl)-1H-imidazol-1-yl)cyclobutyl)carbamate (56 mg, 0.11 mmol, 1 eq), potassium carbonate (61 mg, 0.44 mmol, 4 eq), 3,5-dicyclopropylphenol (38 mg, 0.22 mmol, 2 eq), and anhydrous THF (2 mL). The reaction mixture was stirred at 80 °C for 18 hours before being diluted with water and washed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate before being concentrated and purified through column chromatography (0-100% EtOAc in Hexanes, 4 g) to provide the product as a yellow foam (57 mg, 87%).1H NMR (500 MHz, CDCl3) δ 8.39 (d, J = 5.2 Hz, 1H), 7.83 (s, 1H), 7.61 (s, 4H), 6.83 (d, J = 5.2 Hz, 1H), 6.75 (t, J = 1.7 Hz, 1H), 6.71 (d, J = 1.7 Hz, 1H), 4.82 (d, J = 7.6 Hz, 1H), 4.62 (dh, J = 15.4, 7.6 Hz, 1H), 3.83 (d, J = 7.2 Hz, 1H), 2.65 (dtd, J = 10.1, 7.3, 2.9 Hz, 2H), 2.20 – 2.10 (m, 2H), 1.99 – 1.87 (m, 3H), 1.45 (s, 9H), 1.04 – 0.94 (m, 4H), 0.77 – 0.69 (m, 4H).13C NMR (126 MHz, CDCl3) δ 165.65, 159.79, 159.32, 154.73, 153.18, 146.15, 143.57, 137.95, 137.49, 129.94 (q, J = 32.5 Hz), 128.83, 125.56 (d, J = 3.6 Hz), 125.07, 121.95 (q, J = 272.5 Hz), 120.43, 116.14, 115.72, 79.65, 44.84, 39.30, 28.36, 15.48, 9.52.19F NMR (471 MHz, CDCl3) δ -62.54. Expected [M+H]: 632.2843 Observed [M+H]: 632.2840. b) The corresponding Boc protected amine (57 mg) was stirred in 20% TFA in DCM for 2 hours at ambient temperature. The volatiles were then removed under a stream of nitrogen before precipitating in cold diethyl ether to afford the desired product as a white solid (72 mg, 3x TFA, quant.).1H NMR (500 MHz, DMSO) δ 8.64 (d, J = 5.0 Hz, 1H), 8.31 (s, 1H), 8.05 (b, 3H), 7.74 – 7.68 (m, 2H), 7.65 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 5.0 Hz, 1H), 6.74 (d, J = 1.7 Hz, 2H), 6.68 (t, J = 1.7 Hz, 1H), 4.62 (p, J = 8.5 Hz, 1H), 3.47 – 3.41 (m, 1H), 2.51 (m, obscured by DMSO), 1.89 (tt, J = 8.4, 5.0 Hz, 2H), 0.99 – 0.89 (m, 4H), 0.74 – 0.63 (m, 4H).13C NMR (126 MHz, DMSO) δ 165.55, 161.59, 158.97 (q, J = 36.3 Hz), 158.39, 153.46, 146.30, 139.26, 138.49, 137.01, 128.92, 128.69 (q, J = 33.3 Hz), 125.97 (q, J = 3.6 Hz), 125.89, 124.65 (q, J = 272.0 Hz), 119.67, 117.40, 117.32, 116.09, 115.00, 112.69, 55.32, 44.42, 38.63, 36.55, 31.70, 28.82, 22.54, 15.50, 14.35, 10.07.19F NMR (471 MHz, DMSO) δ -61.16, -74.89. Expected [M+H]: 532.2319 Observed [M+H]: 532.2324. Example 51: Preparation of: N O N F3CNH2N N N OSO N OHO TFA, DCMN O N H N H N F3C NKCO , THF C N F C NH Boc2o3 F 3N80N Boc3 2C, 18 hN N N N a) The corresponding Boc protected amine was prepared as follows. To a 2-dram vial was added tert-butyl ((1R,3S)-3-(5-(2-(methylsulfonyl)pyrimidin-4-yl)-4-(4-(trifluoromethyl)- phenyl)-1H-imidazol-1-yl)cyclobutyl)carbamate (56 mg, 0.11 mmol, 1 eq), potassium carbonate (61 mg, 0.44 mmol, 4 eq), 3-cyclopropylphenol (44 mg, 0.33 mmol, 3 eq), and anhydrous THF (2 mL). The reaction mixture was then stirred at 80 °C for 18 hours before being diluted with water and washed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate before being concentrated and purified through column chromatography (0-100% EtOAc in Hexanes, 4 g) to provide the product as a yellow foam (48 mg, 80%).1H NMR (500 MHz, CDCl3) δ 8.41 (d, J = 5.2 Hz, 1H), 7.81 (s, 1H), 7.66 – 7.58 (m, 4H), 7.39 (t, J = 7.9 Hz, 1H), 7.03 (dt, J = 7.9, 2.0 Hz, 2H), 6.98 (t, J = 2.1 Hz, 1H), 6.85 (d, J = 5.0 Hz, 1H), 4.70 (b, 1H), 4.60 (tt, J = 9.5, 7.2 Hz, 1H), 3.81 (b, 1H), 2.69 – 2.60 (m, 2H), 2.16 – 2.11 (m, 2H), 1.98 (tt, J = 8.4, 5.0 Hz, 1H), 1.47 (s, 9H), 1.09 – 0.99 (m, 2H), 0.80 – 0.71 (m, 2H).13C NMR (126 MHz, CDCl3) δ 165.61, 159.87, 159.28, 154.78, 153.05, 146.61, 143.58, 137.91, 137.49, 130.07 (q, J = 32.5 Hz), 129.54, 128.82, 125.56 (q, J = 3.9 Hz), 125.01, 123.02 (q, J = 272.3 Hz), 122.86, 119.28, 118.80, 115.82, 79.68, 44.70, 39.30, 28.37, 15.44, 9.73.19F NMR (471 MHz, CDCl3) δ - 62.53. Expected [M+H]: 592.2530 Observed [M+H]: 592.2541 b) The corresponding Boc protected amine (48 mg) was stirred in 20% TFA in DCM for 2 hours at ambient temperature. The volatiles were then removed under a stream of nitrogen before precipitating in cold diethyl ether to afford the desired product as a white solid (45 mg, 2.5x TFA).1H NMR (500 MHz, DMSO) δ 8.65 (d, J = 5.2 Hz, 1H), 8.30 (s, 1H), 8.03 (b, 3H), 7.71 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.32 (t, J = 7.9 Hz, 1H), 7.11 (d, J = 5.0 Hz, 1H), 7.06 – 6.95 (m, 3H), 4.60 (p, J = 8.4 Hz, 1H), 3.41 (dd, J = 13.7, 5.5 Hz, 1H), 2.50 – 2.41 (m, obscured by DMSO), 1.94 (tt, J = 8.2, 5.1 Hz, 1H), 1.03 – 0.93 (m, 2H), 0.74 – 0.66 (m, 2H).13C NMR (126 MHz, DMSO) δ 165.49, 161.55, 159.05 (q, J = 36.9 Hz), 158.63, 153.35, 146.63, 140.06, 138.61, 137.66, 129.90, 128.88, 128.29 (d, J = 34.4 Hz), 126.04 – 125.76 (m), 123.61, 122.64, 119.22, 119.10, 117.44, 115.29 (q, J = 283.0 Hz), 49.16, 44.23, 38.64, 36.59, 31.71, 28.82, 27.25, 22.55, 15.45, 14.37, 10.27.19F NMR (471 MHz, DMSO) δ -61.06, -74.68. Expected [M+H]: 492.2006 Observed [M+H]: 492.2000. Example 52: Preparation of: a) The corresponding Boc protected amine was prepared as follows. To a 2-dram vial was added tert-butyl ((1R,3S)-3-(5-(2-(methylsulfonyl)pyrimidin-4-yl)-4-(4-(trifluoromethyl)-phenyl)- 1H-imidazol-1-yl)cyclobutyl)carbamate (56 mg, 0.11 mmol, 1 eq), potassium carbonate (61 mg, 0.44 mmol, 4 eq), 3,5-dimethylphenol (40 mg, 0.33 mmol, 3 eq), and anhydrous THF (2 mL). The reaction mixture was stirred at 80 °C for 18 hours before being diluted with water and washed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate before being concentrated and purified through column chromatography (0-100% EtOAc in Hexanes, 4 g) to provide the product as a colorless foam (49 mg, 82%).1H NMR (500 MHz, CDCl3) δ 8.40 (d, J = 5.2 Hz, 1H), 7.81 (s, 1H), 7.61 (s, 4H), 6.97 (s, 1H), 6.87 (s, 2H), 6.84 (d, J = 5.2 Hz, 1H), 4.83 – 4.78 (m, 1H), 4.64 (tt, J = 9.5, 7.3 Hz, 1H), 3.80 (s, 1H), 2.68 (d, J = 9.2 Hz, 2H), 2.39 (s, 6H), 2.21 – 2.11 (m, 2H), 1.46 (s, 9H).13C NMR (126 MHz, CDCl3) δ 165.69, 159.80, 159.43, 154.75, 152.84, 129.92 (q, J = 32.2 Hz), 128.76, 127.55, 125.55 (q, J = 3.9 Hz), 125.14, 121.95 (q, J = 272.0 Hz), 119.48, 115.82, 79.74, 44.77, 39.33, 28.36, 21.36.19F NMR (471 MHz, CDCl3) δ -62.54. Expected [M+H]: 580.2530 Observed [M+H]: 580.2533. b) The corresponding Boc protected amine (49 mg) was stirred in 20% TFA in DCM for 2 hours at ambient temperature. The volatiles were then removed under a stream of nitrogen before precipitating in cold diethyl ether to afford the product as a white solid (38.7 mg, 3x TFA).1H NMR (500 MHz, DMSO) δ 8.67 (d, J = 5.0 Hz, 1H), 8.37 (s, 1H), 8.19 (s, 3H), 7.71 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 5.0 Hz, 1H), 6.92 (s, 1H), 6.88 (s, 2H), 4.67 – 4.56 (m, 1H), 3.45 – 3.36 (m, 1H), 2.60 – 2.52 (m, obscured by DMSO), 2.29 (s, 6H).13C NMR (126 MHz, DMSO) δ 165.53, 161.61, 159.07 (q, J = 35.7 Hz), 158.63, 153.14, 139.61, 139.57, 138.49, 137.38, 128.77, 128.37 (q, J = 31.6 Hz), 127.37, 125.93 (q, J = 3.9 Hz), 125.76, 123.60, 119.70, 117.49, 116.23 (q, J = 292.0 Hz), 44.35, 38.71, 36.55, 31.71, 28.82, 22.55, 21.22, 14.37.19F NMR (471 MHz, DMSO) δ -61.08, -74.79. Expected [M+H]: 480.2006 Observed [M+H]: 480.2001. Example 53: Preparation of: To a vial was added sulfone (15.7 mg, 0.03 mmol, 1 eq), 3,5-dimethylphenol (57 mg, 0.4 mmol, 11 eq), potassium carbonate (0.61 mg, 0.44 mmol, 10 eq), and THF (2 mL). The vial was sealed and stirred at 80°C for 18 hours. The reaction mixture was diluted with EtOAc before washing with water (2x) and 1N NaOH(aq)until the presence of the phenol was not present by TLC. The organic layer was then concentrated into a yellow oil before being taken up in DCM (2 mL) and was added TFA (1 mL). This was stirred at ambient temperature for 2 hours before blowing dry under a stream of nitrogen and precipitating in cold diethyl ether. The crude solid was purified through column chromatography (4 g, 0-20% MeOH in DCM) to afford the product as an off-white solid (45%).1H NMR (500 MHz, CDCl3) δ 8.90 (d, J = 10.5 Hz, 1H), 8.69 (d, J = 5.0 Hz, 1H), 8.54 (d, J = 11.1 Hz, 1H), 8.17 (s, 1H), 7.72 (d, J = 8.7 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 5.0 Hz, 1H), 6.90 (s, 3H), 4.39 (td, J = 11.1, 4.6 Hz, 1H), 3.29 (d, J = 13.1 Hz, 2H), 2.77 (q, J = 11.7 Hz, 2H), 2.27 (s, 6H), 2.15 – 1.95 (m, 4H).13C NMR (126 MHz, CDCl3) δ 170.23, 166.42 (q, J = 22.3 Hz), 163.86, 163.64, 163.36, 157.82, 144.56, 144.24, 142.81, 142.23, 133.33, 132.93 (q, J = 31.8 Hz), 132.05, 130.65, 128.41 (q, J = 272.9 Hz), 124.42, 122.85, 122.81, 56.05, 47.83, 34.78, 26.03.19F NMR (471 MHz, CDCl3) δ -56.21 (3F), - 69.66 (6F). Expected [M+H]: 494.2162 Observed [M+H]: 494.2166. Example 54: Preparation of: To a 2-dram vial was added the compound of Example 49 (21 mg, 0.024 mmol, 1 eq), acetyl chloride (10 μL,5.4 eq), DIEA (0.1 mL, 0.28 mmol, 10 eq), and DCM (2 mL). This was stirred at ambient temperature for 18 hours, resulting in a yellow reaction mixture. The mixture was concentrated before being purified through column chromatography (4 g, 0-10% MeOH in DCM), to provide the product as a white foam (12.1 mg, 88%).1H NMR (500 MHz, DMSO) δ 8.65 (d, J = 5.1 Hz, 1H), 8.16 (s, 1H), 7.96 (dd, J = 14.3, 7.5 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.30 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 5.0 Hz, 1H), 7.01 (d, J = 6.4 Hz, 2H), 6.95 (d, J = 7.7 Hz, 1H), 4.60 (d, J = 8.2 Hz, 1H), 3.99 (h, J = 7.2 Hz, 1H), 2.50 (p, J = 1.8 Hz, 3H), 2.16 (dt, J = 12.9, 7.7 Hz, 1H), 1.93 (tt, J = 8.3, 4.9 Hz, 1H), 1.80 (s, 6H), 1.60 (dq, J = 12.6, 7.7 Hz, 2H), 1.24 (dd, J = 10.4, 5.6 Hz, 2H), 1.01 – 0.91 (m, 2H), 0.69 (dt, J = 5.0, 3.2 Hz, 2H).13C NMR (126 MHz, DMSO) δ 169.06, 165.58, 161.51, 153.34, 140.72, 138.69, 138.07, 129.89, 129.85, 127.99 (q, J = 31.4 Hz), 126.00, 125.82 (q, J = 3.9 Hz), 123.70 (q, J = 249.4 Hz), 122.47, 119.34, 119.12, 117.73, 71.56, 55.29, 48.71, 31.82, 31.13, 23.15, 15.47, 10.25 (d, J = 2.1 Hz).19F NMR (471 MHz, DMSO) δ -60.91. Expected [M+H]: 548.2268 Observed [M+H]: 548.2266.

[0011] Example 55: Preparation of: In a single neck 50 mL round bottom flask fitted with a magnetic stir bar and nitrogen inlet was charged piperidine intermediate (30 mg, 0.040-0.0484 mmol) in DMF. To the aforementioned reaction mixture was charged K2CO3(22-26 mg, 0.16-0.19 mmol, 4 equiv.) followed by alkyl substituent (0.080-0.0968 mmol, 2 equiv.). The reaction was heated to 80 °C and allowed to stir overnight at that temperature under nitrogen atmosphere. Upon completion of the reaction as indicated by TLC, the reaction mixture was cooled to room temperature. The reaction mixture was extracted with ethyl acetate and sequentially washed with 20% LiCl and water. The washed organic layer was dried over anhydrous Mg2SO4.The dried organic layer was evaporated in vacuo to afford the crude product which was purified by Combiflash chromatography (0-20% MeOH in DCM) to afford the pure product (39 mg, >90% - HPLC purity >95%).1H-NMR (500 MHz, CDCl3): d 8.43 (d, J =5 Hz ,1H), 7.79 (s, 1H), 7.60 (m, 4H), 7.36-7.34 (m, 1H), 7.30-7.28 (m, 2H), 7.08-7.06 (m, 1H), 6.94 (s, 1H), 6.87 (s, J =5 Hz, 1H), 5.55 (s, 1H), 4.57-4.52 (m, 1H), 3.00 (s, 2H), 2.87-2.84 (m, 2H), 2.04-1.86 (m, 6H), 1.34 (s, 9H).13C NMR (126 MHz, CDCl3) δ 173.09, 165.74, 160.48, 160.00, 153.90, 153.03, 143.47, 138.21, 137.16, 130.33 (d, J = 32.5 Hz), 129.47, 129.20, 125.97 (d, J = 3.8 Hz), 125.19, 123.42 (q, J = 271.9 Hz), 122.98, 119.28, 119.04, 117.05, 61.61, 53.84, 53.53, 35.29, 33.96, 31.74.19F- NMR (470 MHz, CDCl3) d -62.5 (3F). HRMS: 579.2619 [M+H]+.

[0012] Examples 56-76 Trifluoromethanesulfonyl Azide Solution: In a 20 mL vial, a solution of sodium azide (1.025 g, 15.8 mmol) was prepared in water (4 mL). The 20 mL vial was cooled in an ice bath. In a glovebox, trifluoromethanesulfonic anhydride (1.09 g, 3.87 mmol) was weighed into a 4 mL vial. The vial was sealed and removed from the glovebox. The trifluoromethanesulfonic anhydride was dissolved into DCM (3 mL) and the solution was added dropwise to the rapidly stirring solution of sodium azide in water. The vial of trifluoromethanesulfonic anhydride was rinsed with DCM (0.5 mL) and added to the 20 mL vial. The 20 mL vial was sealed under an atmosphere of air. After 10 minutes, the ice bath was removed and the reaction was allowed to warm to rt. After 2 hours the mixture was transferred to a separatory funnel and the DCM layer was collected. The aqueous layer was extracted with DCM (2 x 2.5 mL). The combined DCM layers (ca.8 mL), containing TfN3, were used without further purification. A quantitative formation of TfN3was assumed when calculating the molarity of TfN3in the DCM solution SAFETY NOTE: DO NOT ATTEMPT TO PURIFY OR CONCENTRATE THE SOLUTION OF TfN3. General Procedure 1: Diazo transfer and click reaction: Example given for (tert-butyl ((1r,3r)-3-(4-methyl-1H-1,2,3-triazol-1-yl)cyclobutyl)carbamate). A 20 mL vial was charged with solid tert-butyl ((1r,3r)-3-aminocyclobutyl)carbamate (167 mg, 0.9 mmol), potassium carbonate (208 mg, 1.5 mmol), and copper sulfate pentahydrate (11.9 mg, 47 µmol). To the vial, methanol (5 mL) and water (2 mL) were added. After the solids had dissolved, an aliquot of TfN3in DCM (4 mL) was added at room temperature and the vial was sealed under an atmosphere of air. After 18 hours, a second portion of copper sulfate pentahydrate (77 mg, 0.24 mmol) and sodium ascorbate (190 mg, 0.96 mmol) were added as solids. The vial was fit with an adaptor and a dry ice / acetone condenser. Propyne gas was slowly bubbled into the solution. The flow of propyne was maintained until a gentle reflux was evident. After 6 hours, the reaction was quenched by addition of potassium carbonate and ammonium chloride. The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. Final purification by column chromatography (gradient elution of 95:5 ethyl acetate:methanol in hexanes) afforded the cyclized product (155.4 mg, 68%).1H NMR (500 MHz, CDCl3) δ 7.35 (br, 1H), 5.46 (d, J = 6.8 Hz, 1H), 5.05 (s, 1H), 4.34 (br, 1H), 2.82 (ddd, J = 13.4, 8.2, 5.0 Hz, 2H), 2.62 (s, 2H), 2.27 (s, 3H), 1.38 (s, 9H).13C NMR (126 MHz, CDCl3) δ 155.1, 143.5, 120.2, 79.4, 51.1, 42.8, 37.2, 28.2, 10.6. HRMS (ESI-TOF) [M+Na]+Calculated for C12H20N4NaO2+275.1478; Found: 275.1471. General Procedure 2 was carried out as described by Cui, H., et al., J. Med. Chem.2021, 64 (14), 10497–10511. General Procedure 3 was carried out as described by Cui, H., et al., J. Med. Chem.2021, 64 (14), 10497–10511. Synthesis of tert-butyl 4-azidopiperidine-1-carboxylate (a). Compound a was synthesized using a the procedure described by Divakaran, A., et al., J. Med. Chem.2018, 61 (20), 9316– 9334. Synthesis of tert-butyl 4-(4-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (b). Compound b was synthesized using the procedure described by Carlson, A. S., et al., ACS Med. Chem. Lett.2019, 10 (9), 1296–1301. Synthesis of (3,5-dicyclopropylphenol) (c2). To a 25 mL round-bottom flask was added palladium (II) acetate (93 mg, 0.41 mmol), XPhos (348 mg, 0.72 mmol), potassium carbonate (5.00 g, 36.7 mmol), and potassium cyclopropyl trifluoroborate (2.20 g, 15 mmol). The flask was sealed, evacuated, and backfilled with nitrogen gas. To a separate vial, 3,5-dichlorophenol (1.07 g, 6.5 mmol) was added and dissolved in CPME (10 mL) and water (2 mL). The resulting solution was transferred via syringe to the flask containing the solid reagents and allowed to stir at 95 °C for 24 hours. The reaction mixture was allowed to come to room temperature, then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried with magnesium sulfate, filtered, and purified using flash column chromatography (0–15% ethyl acetate in hexanes). The desired compound c2 was isolated as a solid in 81% yield (841 mg).1H NMR (400 MHz, CDCl3) δ 6.44 (t, J = 1.6 Hz, 1H), 6.30 (d, J = 1.5 Hz, 2H), 4.61 (s, 1H), 1.80 (tt, J = 8.4, 5.1 Hz, 2H), 0.98 – 0.85 (m, 4H), 0.70 – 0.59 (m, 4H).13C NMR (101 MHz, MeOD) δ 158.38, 146.63, 115.91, 110.29, 16.09, 9.35. HRMS (ESI- TOF) [M+H]+Calculated for. Synthesis of 2-chloro-6-(3,5-dimethylphenoxy)pyridine (d1). To a solution of 3,5 dimethyl phenol (11.04 g, 90.4 mmol) and 2-chloro-6-fluoropyridine (10.7 g, 81.3 mmol) in DMF (200 mL) was added potassium carbonate (20.0 g, 144.64 mmol). The reaction was sealed under air and allowed to stir at 120 °C. After 18 hours, the reaction mixture was allowed to cool to room temperature and then quenched with water and extracted with ethyl acetate. The combined organic layers were washed with 1M KOH, and brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure to yield compound d1 as an off-white solid in 77% yield (14.6 g). HRMS (ESI-TOF) [M+H]+Calculated for. Synthesis of 2-chloro-6-(3,5-dicyclopropylphenoxy)pyridine (d2). To a solution of c2 (598 mg, 3.4 mmol) and 2-chloro-6-fluoropyridine (393 mg, 3.0 mmol) in DMF (5.6 mL) was added potassium carbonate (731 mg, 5.3 mmol). The reaction was sealed under air and allowed to stir at 100 °C for 18 hours. The reaction mixture was then allowed to cool to room temperature quenched with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried with magnesium sulfate, filtered, concentrated under reduced pressure, and purified using flash column chromatography (isocratic 100% hexanes for 5 minutes, followed by 0–15% ethyl acetate in hexanes for 15 minutes). The desired compound d2 was isolated as a solid in 52% yield (413 mg)1H NMR (400 MHz, CDCl3) δ 7.57 (t, J = 7.9 Hz, 1H), 7.01 (dd, J = 7.6, 0.7 Hz, 1H), 6.69 (t, J = 1.6 Hz, 1H), 6.66 (dd, J = 8.2, 0.7 Hz, 1H), 6.58 (d, J = 1.6 Hz, 2H), 1.85 (tt, J = 8.4, 5.1 Hz, 2H), 1.01 – 0.88 (m, 4H), 0.73 – 0.61 (m, 4H).13C NMR (101 MHz, CDCl3) δ 163.52, 154.11, 149.35, 146.18, 141.43, 118.40, 115.09, 108.90, 15.53, 9.47. HRMS (UPLC / QTOF-MS) [M+H]+Calculated for C17H16ClNO+:286.09931; found 286.099. Synthesis of tert-butyl 4-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3- triazol-1-yl)piperidine-1-carboxylate (e1). General procedure 4. To a flame-dried three-neck round bottom flask was added a solution of b (737 mg, 2.8 mmol) in anhydrous THF (28 mL), which was sealed under nitrogen and allowed to cool to –78 °C in a dry ice / acetone bath. To this solution, a solution of n-butyllithium (2.25 mL, 1.6 M in hexanes) was added dropwise via a syringe and allowed to stir for 10 minutes. Then, a freshly prepared solution of flame-dried ZnCl2in anhydrous THF (2 M, 1.8 mL, 3.6 mmol) was added to the reaction mixture via syringe, and the reaction was allowed to stir and warm to room temperature for 10 minutes. Next, a solution of d1 (838 mg, 3.6 mmol) and SPhosPdG3 (20 mg, 0.11 mmol) in THF (3.6 mL) was added and the reaction was heated to 60 °C and allowed to stir for 12 hours. The reaction was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried with magnesium sulfate, filtered, concentrated under reduced pressure, and purified using flash column chromatography (40–80% ethyl acetate in hexanes). The desired compound e1 was isolated as an off-white solid in 51% yield (660 mg). Synthesis of tert-butyl 4-(5-(6-(3,5-dicyclopropylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3- triazol-1-yl)piperidine-1-carboxylate (e2). General procedure 4 was modified using b (317 mg, 1.2 mmol) and d2 (394 mg, 1.4 mmol) to yield product e2 as an off-white solid in 67% yield (378 mg).1H NMR (400 MHz, MeOD) δ 7.99 (dd, J = 8.3, 7.5 Hz, 1H), 7.35 (dd, J = 7.4, 0.7 Hz, 1H), 7.09 (dd, J = 8.3, 0.7 Hz, 1H), 6.69 – 6.63 (m, 3H), 4.81 (td, J = 7.1, 3.6 Hz, 1H), 3.94 (d, J = 13.4 Hz, 2H), 2.45 (s, 4H), 1.88 (tt, J = 8.4, 5.1 Hz, 3H), 1.73 (dd, J = 12.9, 3.8 Hz, 2H), 1.50 (s, 10H), 1.02 – 0.90 (m, 4H), 0.72 – 0.60 (m, 4H).13C NMR (101 MHz, MeOD) δ 165.00, 156.29, 155.47, 147.53, 142.12, 120.07, 117.27, 112.89, 81.24, 58.08, 28.69, 16.15, 11.78, 10.01. HRMS (UPLC / QTOF-MS) [M+H]+Calculated for C30H37N5O3+: 516.29689; found 516.2958. Synthesis of 2-(3,5-dimethylphenoxy)-6-(4-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-5- yl)pyridine (1). General procedure 5. Compound e1 (104 mg, 0.22 mmol) was dissolved in a solution of 4N HCl in dioxane (1 mL) and was allowed to stir at room temp for two hours. The resulting semi- solid was dissolved in methanol and concentrated under reduced pressure. The desired compound 1 was isolated as an HCl salt in quantitative yield (102 mg). HRMS (UPLC / QTOF- MS) [M+H]+Calculated for C21H25N5O+: 364.21317; found 364.2122 Synthesis of 2-(3,5-dicyclopropylphenoxy)-6-(4-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol- 5-yl)pyridine (f2). General procedure 5 was used with compound e2 and desired compound f2 was isolated as an HCl salt in 92% yield (136 mg).1H NMR (400 MHz, MeOD) δ 8.04 (dd, J = 8.4, 7.4 Hz, 1H), 7.46 – 7.40 (m, 1H), 7.18 – 7.11 (m, 1H), 6.71 (t, J = 1.6 Hz, 1H), 6.64 (d, J = 1.6 Hz, 2H), 4.99 (tt, J = 10.8, 4.0 Hz, 1H), 3.37 (dt, J = 13.0, 3.5 Hz, 2H), 2.74 (td, J = 12.7, 3.0 Hz, 2H), 2.51 (s, 3H), 2.28 (tdd, J = 14.7, 11.5, 4.1 Hz, 2H), 2.07 (dd, J = 14.1, 3.7 Hz, 3H), 1.89 (tt, J = 8.4, 5.1 Hz, 2H), 1.04 – 0.91 (m, 4H), 0.72 – 0.62 (m, 4H).13C NMR (101 MHz, MeOD) δ 165.18, 155.56, 147.74, 144.32, 142.51, 120.68, 120.53, 116.71, 113.84, 56.15, 44.10, 29.85, 16.13, 11.02, 10.18. HRMS (UPLC / QTOF-MS) [M+H]+Calculated for C25H29N5O+: 416.24447; found 416.2427 Example 56: Preparation of: tert-Butyl (3R,4R)-3-amino-4-methoxypyrrolidine-1-carboxylate (tri-6). General procedure 1 was modified using amine tert-butyl (3R,4R)-3-amino-4-methoxypyrrolidine-1- carboxylate (237 mg, 1.10 mmol) and product tri-6 was isolated as a colorless oil in 96% (297 mg) yield.1H NMR (500 MHz, CDCl3) δ 7.29 (s, 1H), 4.89 (m, 1H), 4.10 (m, 1H), 3.86 (dd, J = 12.3, 7.1 Hz, 1H), 3.77 – 3.70 (m, 1H), 3.65 (m, 1H), 3.42 – 3.34 (m, 1H), 3.29 (s, 3H), 2.24 (s, 3H), 1.37 (s, 9H).13C NMR (126 MHz, CDCl3) δ 154.1, 143.4, 120.3, 83.4, 82.4, 80.1, 63.0, 62.1, 57.5, 49.6, 49.0, 48.9, 48.8, 28.4, 10.7. Note: the additional carbon resonances were assigned as being due to rotamers. HRMS (ESI-TOF) [M+Na]+Calculated for C13H22N4NaO3+305.1584; Found: 305.1597. tert-Butyl (3R,4R)-3-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1- yl)-4-methoxypyrrolidine-1-carboxylate (boc-6). General procedure 2 was modified using tri-6 (161 mg, 0.571 mmol) and product boc-6 was isolated as a colorless oil in 57% (156 mg) yield.1H NMR (500 MHz, CDCl3) for mixture of rotamers: δ 7.83 (m, 1H), 7.19 (m, 1H), 7.12 – 6.94 (m, 1H), 6.88 (m, 1H), 6.75 (s, 2H), 5.32 (m, 1H), 4.50 – 4.33 (m, 1H), 3.98 (m, 1H), 3.44 (m, 1H), 3.32 – 3.19 (m, 2H), 3.16 (m, 3H), 2.48 (s, 3H), 2.33 (s, 6H), 1.46 (s, 9H).13C NMR (126 MHz, CDCl3) δ 163.9, 154.0, 154.0, 153.6, 153.6, 144.8, 142.2, 142.0, 140.3, 140.3, 139.7, 139.7, 132.2, 132.0, 127.0, 126.9, 119.2, 119.2, 118.0, 111.2, 82.6, 82.1, 79.6, 79.5, 62.5, 61.7, 57.5, 57.4, 50.4, 50.0, 49.8, 49.1, 28.4, 21.2, 12.1, 12.1. Note: the additional carbon resonances were assigned as being due to rotamers. tert-Butyl 3-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1-yl)-2,5- dihydro-1H-pyrrole-1-carboxylate (boc-4). This molecule was isolated as a byproduct of reaction yielding boc-6 (vide infra). (54mg, 19%).1H NMR (500 MHz, CDCl3) δ 7.88 – 7.68 (m, 1H), 7.12 (m, 1H), 7.06 – 6.92 (m, 1H), 6.87 (s, 1H), 6.75 (m, 2H), 5.56 (m, 1H), 4.64 – 4.32 (m, 2H), 4.22 – 4.02 (m, 2H), 2.38 (s, 3H), 2.33 (s, 6H), 1.50 (s, 9H).13C NMR (126 MHz, CDCl3) δ 163.8, 153.8, 153.2, 144.7, 144.6, 143.0, 142.9, 140.0, 139.4, 139.3, 132.9, 132.7, 132.5, 126.9, 119.1, 119.1, 118.8, 117.4, 116.1, 111.8, 111.7, 80.0, 79.9, 52.1, 51.8, 28.4, 21.2, 10.9. Note: the additional carbon resonances were assigned as being due to rotamers. 2-(1-(2,5-Dihydro-1H-pyrrol-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl)-6-(3,5- dimethylphenoxy)pyridine (4). General procedure 3 was modified using boc-4 (38 mg, 0.085 mmol) and product 4 was isolated as a colorless oil in 46% (36 mg) yield. NMR analysis indicated that the isolated material contained 5 TFA molecules per triazole.1H NMR (500 MHz, MeOD) δ 7.99 (dd, J = 8.4, 7.4 Hz, 1H), 7.35 (d, J = 7.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.93 (s, 1H), 6.79 (s, 2H), 5.75 (s, 1H), 4.56 (s, 2H), 4.16 (s, 2H), 2.34 (s, 3H), 2.33 (s, 6H).13C NMR (126 MHz, MeOD) δ 164.2, 153.8, 143.7, 143.4, 141.0, 139.7, 133.0, 131.2, 126.5, 119.9, 118.7, 114.1, 112.1, 51.1, 49.9, 19.9, 9.2. Example 57: Preparation of: tert-Butyl (1R,5S,6s)-6-(4-methyl-1H-1,2,3-triazol-1-yl)-3-azabicyclo[3.1.0]hexane-3- carboxylate (tri-7). General procedure 1 was modified using amine tert-butyl (1R,5S,6s)-6- amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (268 mg, 1.35 mmol) and product tri-7 was isolated as a colorless oil in 88% (314 mg) yield.1H NMR (500 MHz, CDCl3) δ 7.30 (s, 1H), 3.79 (d, J = 11.4 Hz, 1H), 3.74 (d, J = 11.2 Hz, 1H), 3.48 – 3.40 (m, 3H), 2.34 – 2.26 (m, 2H), 2.25 (s, 3H), 1.32 (s, 9H).13C NMR (126 MHz, CDCl3) δ 154.4, 143.2, 122.0, 79.9, 47.6, 47.4, 39.9, 28.3, 24.7, 23.9, 10.7. HRMS (ESI-TOF) [M+Na]+Calculated for C13H20N4NaO2+ 287.1478; Found: 287.1476. tert-Butyl (1R,5S,6s)-6-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3- triazol-1-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (boc-7). General procedure 2 was modified using tri-7 (313 mg, 1.19 mmol) and product boc-7 was isolated as a colorless oil in 26% (143 mg) yield.1H NMR (500 MHz, CDCl3) δ 7.80 (dd, J = 8.3, 7.4 Hz, 1H), 7.17 (d, J = 7.4 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.84 (s, 1H), 6.75 (d, J = 1.7 Hz, 2H), 3.66 (d, J = 11.2 Hz, 2H), 3.53 (t, J = 2.4 Hz, 1H), 3.44 (bd, 2H), 2.35 (s, 3H), 3.34 – 2.24 (m, 2H), 2.30 (s, 6H), 1.43 (s, 9H).13C NMR (126 MHz, CDCl3) δ 163.9, 154.5, 153.6, 145.3, 142.6, 140.0, 139.5, 133.7, 126.8, 119.0, 118.1, 110.8, 79.8, 47.9, 47.7, 40.5, 28.4, 25.7, 24.9, 21.3, 11.4. HRMS (ESI-TOF) [M+Na]+Calculated for C26H31N5NaO3+484.2319; Found: 484.2320. (1R,5S,6s)-6-(5-(6-(3,5-Dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1-yl)-3- azabicyclo[3.1.0]hexane (7). General procedure 3 was modified using boc-7 (44 mg, 0.096 mmol) and product 7 was isolated as a colorless oil in 61% (41 mg) yield. NMR analysis indicated that the isolated material contained 3 TFA molecules per triazole.1H NMR (500 MHz, MeOD) δ 7.99 (dd, J = 8.4, 7.4 Hz, 1H), 7.44 (d, J = 7.4 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.93 – 6.92 (s, 1H), 6.82 (s, 1H), 3.91 (s, 1H), 3.57 (s, 4H), 2.68 (s, 2H), 2.38 (s, 3H), 2.33 (s, 6H).13C NMR (126 MHz, MeOD) δ 163.7, 153.9, 144.4, 142.4, 140.7, 139.7, 133.6, 126.3, 118.8, 118.2, 110.9, 47.1, 38.6, 24.9, 19.9, 10.0. HRMS (ESI-TOF) [M+H]+Calculated for C21H24N5O+362.1975; Found: 362.1979. Example 58: Preparation of: tert-Butyl 8-(4-methyl-1H-1,2,3-triazol-1-yl)-3-azabicyclo[3.2.1]octane-3-carboxylate (tri- 8). General procedure 1 was modified using tert-butyl 8-amino-3-azabicyclo[3.2.1]octane-3- carboxylate (250 mg, 1.10 mmol) and product tri-8 was isolated as a colorless oil in 43% (137 mg) yield.1H NMR (500 MHz, CDCl3) MAJOR DIASTEREOMER δ 7.35 (s, 1H), 4.26 (t, J = 4.7 Hz, 1H), 3.76 (d, J = 10.8 Hz, 1H), 3.63 (d, J = 10.8 Hz, 1H), 3.12 (d, J = 13.0 Hz, 1H), 2.96 (d, J = 13.3 Hz, 1H), 2.84 (m, 2H), 2.34 (s, 3H), 1.92 – 1.69 (m, 4H), 1.39 (s, 9H).13C NMR (126 MHz, CDCl3) FOR BOTH DIASTEREOMERS δ 156.0, 155.7, 143.3, 143.1, 121.6, 119.4, 80.0, 79.6, 69.0, 60.8, 50.6, 49.6, 44.8, 43.5, 39.9, 39.8, 36.2, 36.0, 28.4, 25.5, 25.4, 10.8. tert-Butyl 8-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1-yl)-3- azabicyclo[3.2.1]octane-3-carboxylate (boc-8). General procedure 2 was modified using tri-8 (135 mg, 0.46 mmol) and product boc-8 was isolated as a colorless oil in 55% (124 mg) yield. This compound was isolated as an apparent 9:1 mixture of diastereomers. Data are provided for the major isomer.1H NMR (500 MHz, CDCl3) δ 7.81 (dd, J = 8.3, 7.3 Hz, 1H), 7.10 (d, J = 7.2 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.90 – 6.85 (s, 1H), 6.78 – 6.69 (s, 2H), 4.47 (t, J = 4.4 Hz, 1H), 3.57 (dd, J = 13.2, 3.4 Hz, 1H), 3.52 – 3.40 (m, 2H), 3.07 (d, J = 13.4 Hz, 1H), 2.42 (s, 3H), 2.36 (bd, 1H), 2.31 (s, 6H), 2.25 – 2.14 (m, 1H), 1.76 – 1.51 (m, 4H), 1.42 (s, 9H).13C NMR (126 MHz, CDCl3) δ 163.7, 156.2, 153.3, 145.5, 142.2, 140.2, 139.4, 133.0, 126.9, 119.5, 118.4, 111.2, 79.2, 60.3, 45.7, 44.1, 36.0, 28.5, 25.4, 25.0, 21.3, 11.5. 8-(5-(6-(3,5-Dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1-yl)-3- azabicyclo[3.2.1]octane (8). General procedure 3 was modified using boc-8 (62 mg, 0.127 mmol) and product 8 was isolated as a colorless oil in 58% (62 mg) yield. NMR analysis indicated that the isolated material contained 4 TFA molecules per triazole. Note: This material was isolated as an apparent 10:1 mixture of isomers. Data is reported for the major isomer.1H NMR (500 MHz, MeOD) δ 7.99 (dd, J = 8.4, 7.4 Hz, 1H), 7.35 (dd, J = 7.4, 0.7 Hz, 1H), 7.09 (dd, J = 8.4, 0.7 Hz, 1H), 6.92 (s, 1H), 6.78 (s, 2H), 4.70 (t, J = 4.5 Hz, 1H), 3.67 (dd, J = 13.1, 1.7 Hz, 2H), 3.15 – 2.90 (dd, J = 13.1, 1.7 Hz, 2H), 2.45 (s, 3H), 2.41 (s, H), 2.31 (s, 6H), 1.75 (m, 4H).13C NMR (126 MHz, MeOD) δ 163.8, 153.5, 143.9, 141.9, 140.8, 139.4, 133.8, 126.4, 119.1, 119.0, 111.8, 58.6, 43.8, 34.8, 23.4, 19.8, 9.9.

[0013] Example 59: Preparation of: tert-Butyl 6-(4-methyl-1H-1,2,3-triazol-1-yl)-3-azabicyclo[3.1.1]heptane-3-carboxylate (tri- 9). General procedure 1 was modified using tert-butyl 4-(2-aminoethyl)piperazine-1- carboxylate (210.4 mg, 0.99 mmol) and product tri-9 was isolated as a colorless oil in 41% (113 mg) yield.1H NMR (500 MHz, CDCl3) δ1H NMR (500 MHz, CDCl3) δ 7.21 (s, 1H), 4.72 (t, J = 6.0 Hz, 1H), 3.69 (dt, J = 12.3, 1.8 Hz, 1H), 3.66 – 3.46 (m, 3H), 3.01 (td, J = 5.9, 2.6 Hz, 2H), 2.31 (s, 3H), 2.08 (ddd, J = 10.1, 6.6, 5.3 Hz, 1H), 1.56 (d, J = 9.9 Hz, 1H), 1.51 – 1.31 (m, 9H).13C NMR (126 MHz, CDCl3) δ 155.4, 143.1, 119.7, 79.8, 54.2, 45.2, 44.5, 36.8, 36.5, 28.4, 26.5, 10.8. tert-Butyl 6-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1-yl)-3- azabicyclo[3.1.1]heptane-3-carboxylate (boc-9). General procedure 2 was modified using tri- 9 (112 mg, 0.402 mmol) and product boc-9 was isolated as a colorless oil in 40% (77 mg) yield.1H NMR (500 MHz, CDCl3) δ 7.79 (dd, J = 8.3, 7.4 Hz, 1H), 7.15 (d, J = 7.3 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.91 – 6.88 (s, 1H), 6.80 – 6.69 (s, 2H), 4.50 (t, J = 5.8 Hz, 1H), 3.94 (ddd, J = 11.9, 2.4, 1.3 Hz, 1H), 3.40 (dd, J = 11.9, 2.8 Hz, 1H), 3.31 (dd, J = 12.4, 3.0 Hz, 1H), 3.16 (ddd, J = 12.3, 2.2, 1.2 Hz, 1H), 2.81 (dq, J = 5.8, 2.9 Hz, 1H), 2.42 (m, 4H), 2.34 (s, 6H), 1.65 (ddd, J = 6.1, 3.3, 1.5 Hz, 1H), 1.39 (s, 9H), 1.36 (d, J = 9.4 Hz, 1H).13C NMR (126 MHz, CDCl3) δ 163.6, 155.6, 153.5, 145.1, 141.5, 140.1, 139.4, 131.8, 126.9, 119.7, 118.0, 110.7, 79.3, 54.7, 46.1, 44.4, 37.0, 36.6, 28.4, 26.1, 21.3, 11.6. 6-(5-(6-(3,5-Dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1-yl)-3- azabicyclo[3.1.1]heptane (9). General procedure 3 was modified using boc-9 (77 mg, 0.162 mmol) and product 9 was isolated as a colorless oil in 49% (66 mg) yield. NMR analysis indicated that the isolated material contained 4 TFA molecules per triazole.1H NMR (500 MHz, MeOD) δ 7.99 (dd, J = 8.4, 7.4 Hz, 1H), 7.36 (dd, J = 7.3, 0.7 Hz, 1H), 7.10 (dd, J = 8.4, 0.7 Hz, 1H), 6.94 (s, 1H), 6.79 (s, 2H), 4.99 (t, J = 6.1 Hz, 1H), 3.72 (d, J = 12.7 Hz, 2H), 3.40 (dt, J = 12.6, 1.7 Hz, 2H), 2.57 (tt, J = 6.0, 1.5 Hz, 2H), 2.45 (s, 3H), 2.33 (s, 6H), 2.08 – 1.77 (m, 1H), 1.66 (d, J = 10.7 Hz, 1H).13C NMR (126 MHz, MeOD) δ 163.9, 153.7, 143.7, 141.7, 140.8, 139.6, 133.5, 126.4, 119.4, 118.7, 111.6, 53.3, 42.7, 37.7, 23.7, 19.9, 10.0. Example 60: Preparation of: tert-Butyl (1R,3s,5S)-3-(4-methyl-1H-1,2,3-triazol-1-yl)-8-azabicyclo[3.2.1]octane-8- carboxylate (tri-10). General procedure 1was modified using tert-butyl (1R,3s,5S)-3-(4- methyl-1H-1,2,3-triazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (223 mg, 0.99 mmol) and product tri-10 was isolated as a colorless oil in 3% (8.0 mg) yield.1H NMR (500 MHz, CDCl3) δ 7.40 (s, 1H), 4.51 (tt, J = 6.6, 3.3 Hz, 1H), 4.42 – 4.09 (m, 2H), 2.74 – 2.38 (m, 4H), 2.35 (s, 3H), 1.93 – 1.77 (m, 2H), 1.59 – 1.49 (m, 2H), 1.48 (s, 9H).13C NMR (126 MHz, CDCl3) 153.4, 143.4, 120.5, 79.6, 52.3, 52.0, 51.1, 34.1, 28.5, 28.3, 27.6, 10.9. tert-Butyl (1R,3s,5S)-3-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol- 1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (boc-10). General procedure 2 was modified using tri-10 (60 mg, 0.205 mmol) and product boc-10 was isolated as a colorless oil in 71% (71 mg) yield.1H NMR (500 MHz, CDCl3) δ 7.80 (dd, J = 8.3, 7.4 Hz, 1H), 7.17 – 6.65 (m, 5H), 5.14 – 4.71 (m, 1H), 4.44 – 4.01 (m, 2H), 2.36 (d, J = 34.6 Hz, 8H), 2.14 (s, 3H), 2.01 – 1.90 (m, 2H), 1.81 (ddd, J = 8.0, 5.5, 3.0 Hz, 2H), 1.47 (s, 9H).13C NMR (126 MHz, CDCl3) δ 164.0, 153.6, 153.0, 145.7, 142.7, 140.2, 139.5, 131.5, 126.9, 119.3, 118.1, 110.8, 79.2, 52.1, 50.9, 50.5, 34.9, 28.5, 28.4, 27.6, 21.4, 11.7. The final compound was prepared by removing the Boc group from (boc-10) as described in Example 59. Example 61: Preparation of: (rac – mixture of diastereomers) tert-Butyl 3-(4-methyl-1H-1,2,3-triazol-1-yl)-9-azabicyclo[3.3.1]nonane-9-carboxylate (tri- 11). General procedure 1 was modified using tert-butyl 3-amino-9-azabicyclo[3.3.1]nonane-9- carboxylate (232 mg, 0.97 mmol) and product tri-11 was isolated as a colorless oil in 82% (242 mg) yield.1H NMR (500 MHz, CDCl3) δ 7.28 (s, 1H), 5.45 (tt, J = 12.3, 6.3 Hz, 1H), 4.48 (s, 1H), 4.36 (s, 1H), 2.28 (s, 3H), 2.14 (m, 4H), 1.88 (m, 3H), 1.71 (m, 3H), 1.44 (s, 9H).13C NMR (126 MHz, CDCl3) δ 153.7, 143.5, 118.9, 80.0, 54.6, 46.9, 45.4, 37.2, 36.7, 28.7, 28.4, 28.3, 20.2, 10.9. HRMS (ESI-TOF) [M+Na]+Calculated for C16H26N4NaO2+329.1948; Found: 329.1951. tert-Butyl 3-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1-yl)-9- azabicyclo[3.3.1]nonane-9-carboxylate (boc-11, boc-12). General procedure 2 was modified using tri-11 (212 mg, 0.69 mmol) and products boc-11 and boc-12 was isolated as a colorless oil in 61% (214 mg) yield. Two fractions were collected. One fraction was a single diastereomer (boc-12). The other fraction was a ~1:1.8 mixture of diastereomers (boc-11).1H NMR (500 MHz, CDCl3) δ 7.83 (dd, J = 8.3, 7.4 Hz, 1H), 7.18 (d, J = 7.4 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.82 (s, 1H), 6.76 (s, 2H), 5.89 (dt, J = 12.4, 6.4 Hz, 1H), 4.39 (bd,1H), 4.30 (bd, 1H), 2.56 (td, J = 12.5, 5.2 Hz, 1H), 2.47 (s, 3H), 2.41 (td, J = 12.5, 5.9 Hz, 1H), 2.29 (s, 6H), 1.93 (ddd, J = 14.1, 5.8, 1.9 Hz, 2H), 1.75 (dt, J = 13.0, 6.4 Hz, 2H), 1.63 (m, 1H), 1.58 – 1.51 (m, 1H), 1.47 (s, 9H), 1.44 – 1.30 (m, 2H).13C NMR (126 MHz, CDCl3) δ 163.3, 153.6, 145.6, 141.6, 140.3, 139.5, 131.9, 126.4, 118.9, 118.2, 111.0, 79.4, 53.3, 47.1, 45.6, 36.5, 36.2, 28.7, 28.5, 28.2, 21.3, 20.3, 11.7. HRMS (ESI-TOF) [M+Na]+Calculated for C29H37N5NaO3+526.2789; Found: 526.2776. 3-(5-(6-(3,5-Dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1-yl)-9- azabicyclo[3.3.1]nonane (11). General procedure 3 was modified using boc-11 (15 mg, 0.030 mmol) and product 1 was isolated as a colorless oil in 98% (22 mg) yield. NMR analysis indicated that the isolated material contained 3 TFA molecules per triazole. Data is reported for the single isomer (12) below. Example 62: Preparation of: (major diastereomer – absolute stereochemistry not determined) tert-Butyl 3-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1-yl)-9- azabicyclo[3.3.1]nonane-9-carboxylate (boc-11, boc-12). General procedure 2 was modified using tri-11 (212 mg, 0.69 mmol) and products boc-11 and boc-12 was isolated as a colorless oil in 61% (214 mg) yield. Two fractions were collected. One fraction was a single diastereomer (boc-12). The other fraction was a ~1:1.8 mixture of diastereomers (boc-11).1H NMR (500 MHz, CDCl3) δ 7.83 (dd, J = 8.3, 7.4 Hz, 1H), 7.18 (d, J = 7.4 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.82 (s, 1H), 6.76 (s, 2H), 5.89 (dt, J = 12.4, 6.4 Hz, 1H), 4.39 (bd,1H), 4.30 (bd, 1H), 2.56 (td, J = 12.5, 5.2 Hz, 1H), 2.47 (s, 3H), 2.41 (td, J = 12.5, 5.9 Hz, 1H), 2.29 (s, 6H), 1.93 (ddd, J = 14.1, 5.8, 1.9 Hz, 2H), 1.75 (dt, J = 13.0, 6.4 Hz, 2H), 1.63 (m, 1H), 1.58 – 1.51 (m, 1H), 1.47 (s, 9H), 1.44 – 1.30 (m, 2H).13C NMR (126 MHz, CDCl3) δ 163.3, 153.6, 145.6, 141.6, 140.3, 139.5, 131.9, 126.4, 118.9, 118.2, 111.0, 79.4, 53.3, 47.1, 45.6, 36.5, 36.2, 28.7, 28.5, 28.2, 21.3, 20.3, 11.7. HRMS (ESI-TOF) [M+Na]+Calculated for C29H37N5NaO3+526.2789; Found: 526.2776. 3-(5-(6-(3,5-Dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1-yl)-9- azabicyclo[3.3.1]nonane (12). General procedure 3 was modified using triazole boc-12 (30 mg, 0.060 mmol) and product 12 was isolated as a colorless oil in 55% (51 mg) yield. NMR analysis indicated that the isolated material contained 4 TFA molecules per triazole.1H NMR (500 MHz MeOD) δ 803 (dd J = 84 75 Hz 1H) 744 (d J = 74 Hz 1H) 702 (d J = 83 Hz, 1H), 6.89 (s, 1H), 6.82 (s, 2H), 6.01 (tt, J = 12.1, 5.8 Hz, 1H), 3.76 (t, J = 5.3 Hz, 2H), 2.73 (tdd, J = 14.6, 5.4, 1.7 Hz, 2H), 2.49 (s, 3H), 2.31 (m, 8H), 2.14 – 1.92 (m, 2H), 1.88 – 1.59 (m, 4H).13C NMR (126 MHz, MeOD) δ 163.3, 153.8, 144.5, 141.7, 141.1, 139.6, 132.2, 125.9, 119.4, 117.6, 111.6, 50.9, 47.6, 33.7, 25.9, 19.9, 18.1, 10.1. HRMS (ESI-TOF) [M+H]+Calculated for C24H30N5O+404.2445; Found: 404.2443. Example 63: Preparation of: tert-Butyl 4-(2-(4-methyl-1H-1,2,3-triazol-1-yl)ethyl)piperazine-1-carboxylate (tri-13). General procedure 1 was modified using tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (235 mg, 1.02 mmol) and product tri-13 was isolated as a colorless oil in 56% (168 mg) yield.1H NMR (500 MHz, CDCl3) δ 7.35 (s, 1H), 4.37 (t, J = 6.4 Hz, 2H), 3.52 – 3.20 (m, 4H), 2.76 (t, J = 6.4 Hz, 2H), 2.38 (bd, 2H), 2.27 (s, 3H), 1.39 (s, 9H).13C NMR (126 MHz, CDCl3) δ.13C NMR (126 MHz, CDCl3) δ 154.6, 143.1, 121.7, 79.7, 57.6, 52.8, 47.4, 43.9, 43.0, 28.3, 10.8. HRMS (ESI-TOF) [M+Na]+Calculated for C14H25N5NaO2+318.1900; Found: 318.1903. tert-Butyl 4-(2-(5-(3-(3,5-dimethylphenoxy)phenyl)-4-methyl-1H-1,2,3-triazol-1- yl)ethyl)piperazine-1-carboxylate (boc-13). General procedure 2 was modified using tri-13 (168 mg, 0.569 mmol) and product boc-13 was isolated as a colorless oil in 56% (158 mg) yield.1H NMR (500 MHz, CDCl3) δ 7.87 – 7.74 (dd, J = 8.3, 7.4 Hz, 1H), 7.17 (d, J = 7.4 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.86 (s, 1H), 6.73 (s, 2H), 4.55 (t, J = 6.4 Hz, 2H), 3.37 – 3.15 (m, 4H), 2.52 (t, J = 6.4 Hz, 2H), 2.46 (s, 3H), 2.32 (s, 6H), 2.19 (t, J = 5.1 Hz, 4H), 1.43 (s, 9H).13C NMR (126 MHz, CDCl3) δ 163.7, 154.6, 153.7, 145.6, 141.9, 140.2, 139.5, 131.9, 126.7, 119.0, 118.0, 110.7, 79.5, 57.6, 52.7, 46.8, 43.8, 42.8, 28.4, 21.3, 12.1. HRMS (ESI-TOF) [M+Na]+Calculated for C27H36N6NaO3+515.2741; Found: 515.2718. 1-(2-(5-(6-(3,5-Dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1- yl)ethyl)piperazine (13). General procedure 3 was modified using boc-13 (78 mg, 0.158 mmol) and product 13 was isolated as a colorless oil in 48% (90 mg) yield. NMR analysis indicated that the isolated material contained 7 TFA molecules per triazole.1H NMR (500 MHz, MeOD) δ 8.00 (dd, J = 8.4, 7.5 Hz, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.97 (s, 1H), 6.82 (s, 2H), 4.89 – 4.70 (m, 2H), 3.42 (m, 4H), 3.37 – 3.27 (m, 4H), 3.07 (t, J = 5.6 Hz, 2H), 2.50 (s, 3H), 2.35 (s, 6H).13C NMR (126 MHz, MeOD) δ 164.0, 154.2, 144.1, 142.0, 140.9, 139.9, 132.5, 126.6, 119.0, 118.3, 111.2, 55.7, 44.6, 41.2, 19.8, 10.6. Example 64: Preparation of: tert-Butyl (3R,4R)-3-methoxy-4-(4-methyl-1H-1,2,3-triazol-1-yl)pyrrolidine-1-carboxylate (tri-14). General procedure 1 was modified using amine tert-butyl 4-(3-aminopropyl)- piperazine-1-carboxylate (266 mg, 1.09 mmol) and product tri-14 was isolated as a colorless oil in 58% (197 mg) yield.1H NMR (500 MHz, CDCl3) δ 7.26 (s, 1H), 4.36 (t, J = 6.9 Hz, 2H), 3.77 – 3.07 (m, 4H), 2.75 – 2.23 (m, 9H), 2.21 – 1.84 (m, 2H), 1.43 (s, 9H).13C NMR (126 MHz, CDCl3) δ 154.7, 143.2, 121.3, 79.6, 54.7, 52.9, 47.9, 43.9, 43.1, 28.4, 27.4, 10.8. tert-Butyl 4-(3-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1- yl)propyl)piperazine-1-carboxylate (boc-14). General procedure 2 was modified using tri-14 (309 mg, 0.637 mmol) and product boc-14 was isolated as a colorless oil in 43% (139 mg) yield.1H NMR (500 MHz, CDCl3) δ 7.81 (dd, J = 8.3, 7.5 Hz, 1H), 7.17 (d, J = 7.4 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.86 (s, 1H), 6.77 (s, 2H), 4.46 (t, J = 6.8 Hz, 2H), 3.35 (t, J = 5.1 Hz, 4H), 2.46 (s, 3H), 2.32 (s, 6H), 2.23 (t, J = 5.2 Hz, 4H), 2.13 (t, J = 6.8 Hz, 2H), 1.83 – 1.62 (m, 2H), 1.45 (s, 9H).13C NMR (126 MHz, CDCl3) δ 163.7, 154.6, 153.6, 145.4, 142.1, 140.1, 139.4, 131.6, 126.7, 119.2, 119.2, 117.9, 110.8, 79.6, 55.0, 52.8, 47.7, 43.9, 42.9, 28.4, 28.4, 26.9, 21.3, 12.2. 1-(3-(5-(6-(3,5-Dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1- yl)propyl)piperazine (14). General procedure 3 was modified using boc-14 (69 mg, 0.136 mmol) and product 14 was isolated as a colorless oil in 58% (105 mg) yield. NMR analysis indicated that the isolated material contained 8 TFA molecules per triazole.1H NMR (500 MHz, MeOD) δ 7.98 (dd, J = 8.4, 7.5 Hz, 1H), 7.39 (d, J = 7.4 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.95 (d, J = 1.4 Hz, 1H), 6.84 – 6.75 (d, J = 1.4 Hz, 2H), 4.56 (t, J = 6.3 Hz, 2H), 3.57 (t, J = 5.4 Hz, 4H), 3.50 – 3.40 (m, 4H), 3.15 – 3.01 (m, 2H), 2.48 (s, 3H), 2.34 (s, 6H), 2.15 – 1.94 (m, 2H).13C NMR (126 MHz, MeOD) δ 163.9, 154.1, 144.0, 141.9, 140.8, 139.7, 132.2, 126.4, 118.9, 118.3, 111.2, 53.9, 48.2, 46.6, 40.5, 23.6, 19.9, 10.4. Example 65: Preparation of: tert-Butyl (1R,2R,4S)-2-(4-methyl-1H-1,2,3-triazol-1-yl)-7-azabicyclo[2.2.1]heptane-7- carboxylate (tri-15). General procedure 1 was modified using amine tert-butyl (1R,2R,4S)-2- amino-7-azabicyclo[2.2.1]heptane-7-carboxylate (227 mg, 1.07 mmol) and product tri-15 was isolated as a colorless oil in 34% (102 mg) yield.1H NMR (500 MHz, CDCl3) δ 7.32 (s, 1H), 4.90 – 4.82 (m, 1H), 4.48 (t, J = 4.7 Hz, 1H), 4.33 (t, J = 4.8 Hz, 1H), 2.45 – 2.35 (M, 2H), 2.34 (s, 3H), 1.84 (ddd, J = 15.0, 10.0, 5.2 Hz, 1H), 1.75 – 1.54 (m, 2H), 1.45 (s, 9H), 1.25 (ddd, J = 13.3, 9.5, 4.8 Hz, 1H).13C NMR (126 MHz, CDCl3) δ 155.2, 143.5, 121.6, 80.4, 60.2, 60.1, 57.1, 33.8, 29.3, 28.2, 22.6, 10.8. HRMS (ESI-TOF) [M+Na]+Calculated for C14H22N4NaO2+301.1635; Found: 301.1633. tert-Butyl (1R,2R,4S)-2-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3- triazol-1-yl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (boc-15). General procedure 2 was modified using tri-15 (102 mg, 0.366 mmol) and product boc-15 was isolated as a colorless oil in 64% (113 mg) yield.1H NMR (500 MHz, CDCl3) δ 7.87 – 7.72 (dd, J = 8.3, 7.3 Hz, 1H), 7.09 (d, J = 7.3 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.87 (s, 1H), 6.78 (s, 2H), 5.34 – 5.21 (bd, 1H), 4.29 (bd, 1H), 3.97 (t, J = 4.7 Hz, 1H), 2.65 (dd, J = 12.7, 4.4 Hz, 1H), 2.41 (s, 3H), 2.33 (s, 6H), 2.13 (dt, J = 12.9, 6.5 Hz, 1H), 1.73 (bd, 2H), 1.44 (m, 10H), 1.08 (bd, 1H).13C NMR (126 MHz, CDCl3) δ 164.1, 155.1, 153.5, 144.9, 142.7, 140.2, 139.7, 133.1, 126.9, 119.3, 118.3, 111.1, 80.0, 59.4, 57.4, 33.0, 29.0, 28.3, 22.7, 21.2, 11.4. (1R,2R,4S)-2-(5-(6-(3,5-Dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1-yl)-7- azabicyclo[2.2.1]heptane (15). General procedure 3 was modified using boc-15 (54 mg, 0.114 mmol) and product 15 was isolated as a colorless oil in 60% (68 mg) yield. NMR analysis indicated that the isolated material contained 5.5 TFA molecules per triazole.1H NMR (500 MHz, MeOD) δ 8.00 (dd, J = 8.4, 7.4 Hz, 1H), 7.36 (dd, J = 7.4, 0.7 Hz, 1H), 7.13 – 7.06 (dd, J = 8.4, 0.7 Hz, 1H), 6.98 (s, 1H), 6.84 (s, 2H), 5.10 (m, 1H), 4.34 (t, J = 4.8 Hz, 1H), 3.53 (t, J = 4.6 Hz, 1H), 2.76 (dd, J = 13.9, 4.3 Hz, 1H), 2.45 (s, 3H), 2.42 (m, 1H), 2.34 (s, 6H), 2.19 – 2.00 (m, 2H), 1.61 – 1.45 (m, 2H).13C NMR (126 MHz, MeOD) δ 164.0, 153.5, 143.6, 142.4, 140.9, 139.9, 134.3, 126.7, 119.3, 119.0, 111.5, 61.1, 60.1, 57.6, 31.9, 25.7, 20.8, 19.8, 9.9. Example 66: Preparation of: tert-Butyl 7-(4-methyl-1H-1,2,3-triazol-1-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (tri- 16). General procedure 1 was modified using tert-butyl 7-amino-2-azabicyclo[2.2.1]heptane-2- carboxylate (250 mg, 1.18 mmol) and product tri-16 was isolated as a colorless oil in 80% (268 mg) yield.1H NMR (500 MHz, CDCl3) FOR MIXTURE OF DIASTEREOMERS δ 4.65 (s, 1H), 4.38 (m, 1H), 3.48 – 3.41 (m, 1H), 3.31 – 2.93 (m, 2H), 2.26 (s, 3H), 1.93 – 1.60 (m, 2H), 1.49 (m, 2H), 1.40 (s, 9H).13C NMR (126 MHz, CDCl3) FOR MIXTURE OF DIASTEREOMERS δ 154.1, 153.7, 143.1, 120.9, 79.9, 64.6, 64.4, 59.3, 58.3, 52.2, 51.4, 40.6, 40.1, 28.4, 28.2, 28.0, 25.5, 25.4, 10.7. HRMS (ESI-TOF) [M+Na]+Calculated for C14H22N4NaO2+301.1635; Found: 301.1633. tert-Butyl 7-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1-yl)-2- azabicyclo[2.2.1]heptane-2-carboxylate (boc-16). General procedure 2 was modified using tri-16 (265 mg, 0.922 mmol) and product boc-16 was isolated as a colorless oil in 89% (423 mg) yield. This material was isolated as an apparent 1.0:1.5 mixture of diastereomers. The data is reported for the mixture.1H NMR (500 MHz, CDCl3) δ 7.80 (m, 1H), 7.06 (m, 1H), 6.94 (m, 1H), 6.84 (s, 1H), 6.72 (m, 2H), 4.54 (m, 1H), 4.08 (s, 1H), 3.24 (m, 1H), 3.05 (m, 1H), 2.93 – 2.69 (m, 1H), 2.38 (s, 3H), 2.30 (m, 6H), 1.84 – 1.53 (m, 3H), 1.44 (m, 10H).13C NMR (126 MHz, CDCl3) δ 163.8, 153.8, 153.6, 153.3, 153.1, 145.1, 145.0, 141.8, 141.8, 140., 139.5, 139.3, 132.6, 127.1, 127.0, 119.6, 119.4, 118.1, 118.0, 111.3, 111.2, 79.6, 65.2, 65.0, 59.0, 58.3, 52.2, 51.2, 40.5, 40.2, 28.8, 28.5, 28.5, 28.2, 26.0, 25.8, 21.3, 21.3, 11.3, 11.2 7-(5-(6-(3,5-Dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1-yl)-2- azabicyclo[2.2.1]heptane (16). General procedure 3 was modified using boc-16 (106 mg, 0.242 mmol) and product 16 was isolated as a colorless oil in 35% (81 mg) yield. NMR analysis indicated that the isolated material contained 4 TFA molecules per triazole.1H NMR (500 MHz, MeOD) δ 8.00 (dd, J = 8.4, 7.4 Hz, 1H), 7.38 (dd, J = 7.4, 0.7 Hz, 1H), 7.19 – 7.02 (dd, J = 8.4, 0.7 Hz, 1H), 6.93 (s, 1H), 6.81 (s, 2H), 4.82 (d, J = 1.8 Hz, 1H), 4.33 (d, J = 2.6 Hz, 1H), 3.40 – 3.31 (m, 1H), 3.23 – 3.00 (m, 1H), 2.71 (s, 1H), 2.41 (s, 3H), 2.32 (s, 6H), 2.17 (m, 1H), 1.93 – 1.77 (m, 2H), 1.69 – 1.51 (m, 1H).13C NMR (126 MHz, MeOD) δ 163.9, 153.7, 144.0, 142.2, 140.9, 139.7, 133.5, 126.5, 119.3, 118.8, 111.7, 64.4, 58.8, 49.0, 39.4, 24.5, 24.4, 19.8, 9.8. Example 67: Preparation of: tert-Butyl (2-(4-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1- yl)piperidin-1-yl)ethyl)carbamate (boc-17). General procedure 6. To a solution of 1 (254 mg, 0.7 mmol) in methyl ethyl ketone (3.5 mL) was added tert-butyl (2-bromoethyl)carbamate (178 mg, 0.8 mmol), NaI (123 mg, 0.8 mmol), and potassium carbonate (398 mg 2.8 mmol). The reaction mixture was heated to 50 °C and allowed to stir under air for 96 hours. The reaction mixture was then quenched with water and extracted with ethyl acetate. The organic layer was then washed with brine, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oil was purified by flash column chromatography (0-20% MeOH in DCM), yielding 111 mg (31%) as an off-white solid.1H NMR (400 MHz, MeOD) δ 7.98 (dd, J = 8.3, 7.4 Hz, 1H), 7.33 (dd, J = 7.5, 0.7 Hz, 1H), 7.08 (dd, J = 8.3, 0.7 Hz, 1H), 6.91 (s, 1H), 6.78 (d, J = 1.5 Hz, 2H), 4.61 (tt, J = 11.5, 4.0 Hz, 1H), 3.19 (t, J = 6.8 Hz, 2H), 2.90 – 2.82 (m, 2H), 2.48 – 2.40 (m, 5H), 2.13 (qd, J = 12.9, 3.9 Hz, 2H), 1.81 – 1.69 (m, 5H), 1.47 (s, 9H).13C NMR (101 MHz, MeOD) δ 165.04, 155.25, 145.96, 142.72, 142.08, 140.72, 133.24, 127.86, 120.47, 120.11, 112.85, 58.54, 58.18, 53.61, 38.61, 32.76, 28.77, 21.51, 11.55. HRMS (UPLC / QTOF-MS) [M+H]+Calculated for C28H38N6O3+: 507.30779; found 507.3059 2-(4-(5-(6-(3,5-Dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1-yl)piperidin-1- yl)ethan-1-amine (17). General procedure 5 was used with boc-17, yielding the desired compound 17 as an off-white solid (113 mg, quant.) and the stoichiometry of the HCl salt was determined via NMR with 2 μL of 2,2,2-trifluoroethanol as an internal standard1H NMR (400 MHz, MeOD) δ 7.97 (dd, J = 8.4, 7.4 Hz, 1H), 7.32 (d, J = 7.4 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.88 (s, 1H), 6.77 (s, 2H), 4.59 (ddd, J = 11.7, 7.7, 4.1 Hz, 1H), 2.87 – 2.76 (m, 2H), 2.45 (t, J = 6.4 Hz, 2H), 2.41 (s, 3H), 2.31 (s, 6H), 2.10 (td, J = 12.4, 4.0 Hz, 2H), 1.79 – 1.69 (m, 4H). Note: TFE internal standard at 3.86 ppm (q).13C NMR (126 MHz, MeOD) δ 163.81, 153.87, 143.22, 141.08, 140.77, 139.64, 133.34, 126.47, 119.29, 119.06, 112.17, 66.74, 54.56, 53.22, 52.14, 48.92, 47.90, 33.91, 29.09, 26.49, 20.04, 9.63. HRMS (UPLC / QTOF-MS) [M+H]+Calculated for C23H30N6O+: 407.25537; found 407.254 Example 68: Preparation of: N N N NOHN O 2-(4-(5-(6-(3,5-Dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1-yl)piperidin-1- yl)ethan-1-ol (18). A modified version of general procedure 6, omitting NaI, was used with 1 and 2-iodoethanol, yielding the desired product 18 as an off-white solid in 28% yield (80 mg).1H NMR (400 MHz, MeOD) δ 7.99 (dd, J = 8.3, 7.4 Hz, 1H), 7.33 (dd, J = 7.5, 0.7 Hz, 1H), 7.09 (dd, J = 8.4, 0.7 Hz, 1H), 6.93 – 6.88 (m, 1H), 6.79 (d, J = 1.6 Hz, 2H), 4.61 (tt, J = 11.5, 4.2 Hz, 1H), 3.68 (t, J = 6.0 Hz, 2H), 2.92 (d, J = 11.7 Hz, 2H), 2.55 (t, J = 6.0 Hz, 2H), 2.43 (s, 3H), 2.36 – 2.30 (m, 7H), 2.23 – 2.08 (m, 2H), 1.89 – 1.81 (m, 2H). Example 69: Preparation of: tert-Butyl (3-(4-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1- yl)piperidin-1-yl)propyl)carbamate (boc-19). General procedure 6 was used with 1 and tert- butyl (3-bromopropyl) carbamate, yielding the desired compound boc-19 as an off-white solid in 47% yield (135 mg).1H NMR (400 MHz, MeOD) δ 7.99 (dd, J = 8.3, 7.5 Hz, 1H), 7.34 (d, J = 7.4 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 6.91 (s, 1H), 4.63 (dd, J = 14.6, 10.1 Hz, 1H), 3.11 (t, J = 6.7 Hz, 2H), 2.90 (d, J = 11.6 Hz, 2H), 2.44 (s, 4H), 2.34 (s, 6H), 2.15 (qd, J = 12.3, 3.6 Hz, 2H), 1.79 (d, J = 13.5 Hz, 4H), 1.47 (s, 10H).13C NMR (101 MHz, MeOD) δ 165.02, 155.27, 145.97, 142.69, 142.08, 133.22, 127.83, 120.12, 112.86, 79.90, 58.25, 56.97, 53.54, 39.77, 33.03, 32.77, 28.81, 28.14, 21.55, 14.43, 11.56. HRMS (UPLC / QTOF-MS) [M+H]+Calculated for C29H40N6O3+: 521.32344; found 521.3241 3-(4-(5-(6-(3,5-Dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1-yl)piperidin-1- yl)propan-1-amine (19). General procedure 5 was used with boc-19, yielding the desired product 19 as an HCl salt in quantitative yield (15 mg). Example 70: Preparation of: 2-(4-(5-(6-(3,5-Dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1-yl)piperidin-1- yl)acetamide (20). A modified version of general procedure 6, omitting NaI, was used with 1 and 2-iodoacetamide, yielding the desired product 20 as an off-white solid in 78% yield (66mg).1H NMR (400 MHz, MeOD) δ 7.98 (dd, J = 8.3, 7.4 Hz, 1H), 7.08 (dd, J = 8.3, 0.7 Hz, 1H), 6.89 (s, 1H), 6.80 – 6.75 (m, 2H), 4.59 (tq, J = 11.6, 4.0 Hz, 1H), 2.97 (s, 1H), 2.79 (dt, J = 12.3, 3.3 Hz, 2H), 2.42 (s, 3H), 2.32 (s, 6H), 2.18 (qd, J = 12.2, 3.9 Hz, 2H), 1.85 (td, J = 12.0, 2.3 Hz, 2H), 1.78 – 1.67 (m, 2H).13C NMR (101 MHz, MeOD) δ 176.0, 165.1, 155.3, 145.9, 142.7, 142.1, 140.7, 133.3, 127.8, 120.5, 120.1, 112.9, 62.1, 58.1, 54.0, 33.1, 21.5, 11.5. HRMS (UPLC / QTOF-MS) [M+H]+Calculated for C23H28N6O2+: 421.23463; found 421.2333 Example 71: Preparation of: 2-(3,5-Dimethylphenoxy)-6-(4-methyl-1-(1-(pyridin-2-ylmethyl)piperidin-4-yl)-1H-1,2,3- triazol-5-yl)pyridine (21). General procedure 6 was used with 1 and 2-chloromethyl-pyridine hydrochloride, yielding the desired compound 21 as an off-white solid in 86% yield (202 mg).13C NMR (126 MHz, MeOD) δ 165.0, 159.3, 155.1, 149.6, 145.9, 142.6, 142.0, 140.6, 138.6, 133.2, 127.8, 124.7, 123.8, 120.4, 120.1, 112.8, 64.5, 58.2, 53.7, 32.9, 21.6, 11.6. HRMS (UPLC / QTOF-MS) [M+H]+Calculated for C27H30N6O+: 455.25537; found 455.2553 Example 72: Preparation of: 2-(3,5-Dimethylphenoxy)-6-(4-methyl-1-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-1H-1,2,3- triazol-5-yl)pyridine (22). General procedure 6 was used with 1 and 3-picolyl chloride hydrochloride, yielding the desired compound 22 as an off-white solid in 21% yield (71mg).1H NMR (400 MHz, MeOD) δ 8.51 (d, J = 2.3 Hz, 1H), 8.48 (dd, J = 4.9, 1.7 Hz, 1H), 8.04 – 7.93 (m, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.45 (dd, J = 8.3, 5.4 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.87 (s, 1H), 6.78 (s, 2H), 4.65 – 4.53 (m, 1H), 3.54 (s, 2H), 2.77 (d, J = 12.2 Hz, 2H), 2.42 (s, 3H), 2.32 (s, 6H), 2.11 (td, J = 12.1, 3.5 Hz, 2H), 1.85 – 1.71 (m, 4H). Note: TFE internal standard at 3.88 ppm (q).13C NMR (126 MHz, MeOD) δ 163.6, 153.9, 149.4, 147.7, 144.6, 141.3, 140.7, 139.3, 137.8, 134.3, 131.9, 126.3, 123.8, 119.0, 118.8, 111.5, 59.2, 56.9, 53.4, 52.1, 31.5, 20.2, 10.1. HRMS (UPLC / QTOF-MS) [M+H]+Calculated for C27H30N6O+: 455.25537; found 455.2532. Example 73: Preparation of: 2-(3,5-Dimethylphenoxy)-6-(4-methyl-1-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-1H-1,2,3- triazol-5-yl)pyridine (23). General procedure 6 was used with 1 and 4-(chloromethyl)pyridine hydrochloride, yielding the desired compound 23 as an off-white solid in 33% yield (39 mg).1H NMR (400 MHz, MeOD) δ 8.54 – 8.47 (m, 2H), 7.98 (dd, J = 8.3, 7.4 Hz, 1H), 7.49 – 7.43 (m, 2H), 7.33 (dd, J = 7.4, 0.7 Hz, 1H), 7.09 (dd, J = 8.4, 0.7 Hz, 1H), 6.86 (s, 1H), 4.61 (ddt, J = 11.7, 7.7, 4.1 Hz, 1H), 3.55 (s, 2H), 2.77 (d, J = 11.9 Hz, 2H), 2.42 (s, 3H), 2.31 (s, 6H), 2.15 (qd, J = 12.6, 3.8 Hz, 2H), 1.85 – 1.72 (m, 4H). Note: TFE internal standard at 3.88 ppm (q).13C NMR (126 MHz, MeOD) δ 163.7, 153.9, 149.1, 148.7, 144.6, 141.3, 140.7, 139.3, 131.9, 126.4, 124.2, 119.0, 118.8, 111.5, 60.9, 56.9, 52.3, 31.6, 20.1, 10.1. HRMS (UPLC / QTOF-MS) [M+H]+Calculated for C27H30N6O+: 455.25537; found 455.2537 Example 74: Preparation of: 2-(1-(1-((1H-Imidazol-2-yl)methyl)piperidin-4-yl)-4-methyl-1H-1,2,3-triazol-5-yl)-6-(3,5- dimethylphenoxy)pyridine (24). General procedure 6 was used with 1 and 2-(chloromethyl)- 1H-imidazole hydrochloride, yielding the desired compound 24 as an off-white solid in 31% yield (35 mg).13C NMR (126 MHz, MeOD) δ 165.1, 155.2, 146.5, 145.9, 142.7, 142.1, 140.7, 133.4, 127.8, 120.4, 120.1, 112.8, 58.2, 55.9, 33.0, 21.5, 11.5. HRMS (UPLC / QTOF-MS) [M+H]+Calculated for C25H29N7O+: 444.25062; found 444.2512 Example 75: Preparation of: 2-((4-(5-(6-(3,5-Dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1-yl)piperidin-1- yl)methyl)oxazole (25). General procedure 6 was used with 1 and 2-chloromethyl-oxazole, yielding the desired compound 25 as an off-white solid in 31% yield (35 mg).1H NMR (400 MHz, MeOD) δ 7.97 (dd, J = 8.4, 7.4 Hz, 1H), 7.31 (dd, J = 7.4, 0.7 Hz, 1H), 7.22 – 7.13 (m, 1H), 6.88 (tt, J = 1.5, 0.8 Hz, 1H), 6.82 – 6.73 (m, 2H), 4.55 (tt, J = 11.5, 4.1 Hz, 1H), 3.68 (s, 2H), 2.81 (dt, J = 12.3, 3.5 Hz, 2H), 2.40 (s, 3H), 2.32 – 2.27 (m, 6H), 2.14 (qd, J = 12.2, 3.8 Hz, 2H), 1.89 (td, J = 12.1, 2.4 Hz, 2H), 1.75 (dp, J = 11.9, 2.4 Hz, 2H).13C NMR (101 MHz, MeOD) δ 165.08, 162.44, 155.26, 145.90, 142.68, 141.47, 140.75, 127.87, 127.76, 120.39, 120.18, 112.87, 57.73, 54.78, 53.40, 32.59, 21.48, 11.45. HRMS (UPLC / QTOF-MS) [M+H]+Calculated for C25H28N6O2+: 445.23463; found 445.2325 Example 76: Preparation of: tert-Butyl (2-(4-(5-(6-(3,5-dicyclopropylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1- yl)piperidin-1-yl)ethyl)carbamate (boc-26). General procedure 6 was used with f2 and tert- butyl (2-bromoethyl)carbamate, yielding the desired compound boc-26 as an off-white solid in 81% yield (202 mg).1H NMR (400 MHz, MeOD) δ 7.99 (dd, J = 8.3, 7.5 Hz, 1H), 7.34 (dd, J = 7.5, 0.7 Hz, 1H), 7.08 (dd, J = 8.3, 0.7 Hz, 1H), 6.72 (d, J = 1.6 Hz, 1H), 6.63 (d, J = 1.6 Hz, 2H), 4.63 (ddt, J = 12.2, 8.3, 4.3 Hz, 1H), 3.20 (t, J = 6.9 Hz, 2H), 2.86 (d, J = 11.5 Hz, 2H), 2.46 (d, J = 12.4 Hz, 5H), 2.12 (qd, J = 13.1, 4.0 Hz, 2H), 1.90 (tt, J = 8.4, 5.1 Hz, 2H), 1.77 (t, J = 10.7 Hz, 4H), 1.48 (s, 1H), 1.47 (s, 7H), 1.04 – 0.91 (m, 4H), 0.71 – 0.63 (m, 4H). HRMS (UPLC / QTOF-MS) [M+H]+Calculated for C32H42N6O3+: 559.33909; found 559.3383 2-(4-(5-(6-(3,5-Dicyclopropylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1- yl)piperidin-1-yl)ethan-1-amine (26). General procedure 5 was used with boc-26, yielding the desired product 26 as an HCl salt in quantitative yield (40 mg).1H NMR (400 MHz, MeOD) δ 8.02 (t, J = 7.9 Hz, 1H), 7.41 (d, J = 7.4 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 6.79 (s, 1H), 6.66 (s, 2H), 3.68 – 3.55 (m, 2H), 3.48 (s, 4H), 2.77 (s, 2H), 2.55 (d, J = 13.9 Hz, 2H), 2.48 (s, 3H), 2.13 (d, J = 14.7 Hz, 2H), 1.95 (dp, J = 8.5, 5.1 Hz, 2H), 1.06 – 0.93 (m, 4H), 0.75 – 0.67 (m, 4H).13C NMR (126 MHz, DMSO) δ 172.45, 163.00, 155.27, 153.64, 150.89, 150.63, 141.21, 135.93, 133.70, 128.62, 128.45, 124.88, 120.92, 69.06, 68.80, 68.53, 68.27, 62.95, 62.70, 60.81, 43.05, 38.41, 24.46, 20.82, 19.23. HRMS (UPLC / QTOF-MS) [M+H]+Calculated for C27H34N6O+: 459.28666; found 459.2875. Example 77: Preparation of: 2-(4-(5-(6-(3,5-Dicyclopropylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1- yl)piperidin-1-yl)acetamide (27). A modified version of general procedure 6, omitting NaI, was used with f2 and 2-iodoacetamide, yielding the desired product 27 as an off-white solid in 34% yield (21 mg).1H NMR (400 MHz, MeOD) δ 7.99 (dd, J = 8.3, 7.4 Hz, 1H), 7.34 (dd, J = 7.5, 0.7 Hz, 1H), 7.09 (dd, J = 8.3, 0.7 Hz, 1H), 6.69 (t, J = 1.6 Hz, 1H), 6.63 (d, J = 1.6 Hz, 1H), 4.64 – 4.54 (m, 2H), 2.99 (s, 2H), 2.79 (d, J = 11.7 Hz, 2H), 2.45 (s, 2H), 2.23 – 2.10 (m, 2H), 1.95 – 1.81 (m, 3H), 1.73 (d, J = 12.3 Hz, 2H), 1.03 – 0.94 (m, 3H), 0.71 – 0.62 (m, 3H). HRMS (UPLC / QTOF-MS) [M+H]+Calculated for C27H32N6O2+: 473.26593; found 473.2655 The biological activity of representative compounds was evaluated using the procedures described in Example 77. Example 78: Preparation of: tert-Butyl ((1r,3r)-3-(4-methyl-1H-1,2,3-triazol-1-yl)cyclobutyl)carbamate. A 20 mL vial was charged with solid tert-butyl ((1r,3r)-3-aminocyclobutyl)carbamate (167 mg, 0.9 mmol), potassium carbonate (208 mg, 1.5 mmol), and copper sulfate pentahydrate (11.9 mg, 47 µmol). To the vial, methanol (5 mL) and water (2 mL) were added. After the solids had dissolved, an aliquot of TfN3in DCM (4 mL) was added at rt and the vial was sealed under an atmosphere of air. After 18h, a second portion of copper sulfate pentahydrate (77 mg, 0.24 mmol) and sodium ascorbate (190 mg, 0.96 mmol) were added as solids. The vial was fit with an adaptor and a dry ice / acetone condenser. Propyne gas was slowly bubbled into the solution. The flow of propyne was maintained until a gentle reflux was evident. After 6 h, the reaction was quenched by addition of potassium carbonate and ammonium chloride. The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. Final purification by column chromatography (gradient elution of 95:5 ethyl acetate:methanol in hexanes) afforded tri-2 (155.4 mg, 68%).1H NMR (500 MHz, CDCl3) δ 7.35 (br, 1H), 5.46 (d, J = 6.8 Hz, 1H), 5.05 (s, 1H), 4.34 (br, 1H), 2.82 (ddd, J = 13.4, 8.2, 5.0 Hz, 2H), 2.62 (s, 2H), 2.27 (s, 3H), 1.38 (s, 9H).13C NMR (126 MHz, CDCl3) δ 155.1, 143.5, 120.2, 79.4, 51.1, 42.8, 37.2, 28.2, 10.6. HRMS (ESI-TOF) [M+Na]+Calculated for C12H20N4NaO2+275.1478; Found: 275.1471. tert-Butyl ((1r,3r)-3-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1- yl)cyclobutyl)carbamate (boc-2). General procedure 2 was modified by using 2.5 equiv of n- BuLi and using tri-2 (155 mg, 0.614 mmol) and product boc-2 was isolated as a colorless oil in 35% (96 mg) yield.1H NMR (500 MHz, CDCl3) δ 7.78 (t, J = 7.9 Hz, 1H), 7.11 (d, J = 7.4 Hz, 1H), 6.93 – 6.88 (m, 2H), 6.76 (s, 2H), 5.14 (td, J = 8.7, 4.3 Hz, 1H), 4.60 (br, 1H), 4.23 – 4.13 (m, 1H), 2.86 (br, 2H), 2.43 (s, 3H), 2.33 (d, J = 4.1 Hz, 6H), 2.01 (br, 2H), 1.44 (s, 9H).13C NMR (126 MHz, CDCl3) δ 163.5, 155.0, 153.8, 145.2, 142.3, 140.0, 139.5, 131.7, 130.3, 129.1, 126.6, 119.4, 117.9, 110.8, 79.4, 51.0, 36.7, 28.3, 21.2, 12.0. HRMS (ESI-TOF) [M+Na]+Calculated for C25H31N5NaO3+472.2319; Found: 472.2336. (1r,3r)-3-(5-(6-(3,5-Dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1- yl)cyclobutan-1-amine (2). General procedure 3 was modified using boc-2 (36 mg, 0.080 mmol) and product 2 was isolated as a colorless oil in 68% (50 mg) yield. NMR analysis indicated that the isolated material contained 5 TFA molecules per triazole. Note: This material was isolated as an apparent 5:1 mixture of isomers. Data is reported for the major isomer.1H NMR (500 MHz, MeOD) δ 7.96 (dd, J = 8.4, 7.4 Hz, 1H), 7.31 (dd, J = 7.5, 0.7 Hz, 1H), 7.00 (dd, J = 8.3, 0.7 Hz, 1H), 6.92 (d, J = 1.5, 1H), 6.78 (d, J = 1.5 Hz, 2H), 5.39 – 5.27 (m, 1H), 4.28 – 4.12 (m, 1H), 2.90 (ddt, J = 10.4, 8.4, 4.0 Hz, 2H), 2.75 – 2.50 (m, 2H), 2.41 (s, 3H), 2.33 (s, 6H).13C NMR (126 MHz, MeOD) δ 163.95, 153.89, 144.28, 142.04, 140.76, 139.56, 132.91, 126.33, 119.06, 118.64, 111.13, 50.52, 42.54, 33.85, 19.93, 9.87. Example 79: Preparation of: tert-Butyl 3-(4-methyl-1H-1,2,3-triazol-1-yl)pyrrolidine-1-carboxylate (tri-3). General procedure 1 was modified using tert-butyl 3-aminopyrrolidine-1-carboxylate (200 mg, 1.07 mmol) and product tert-butyl 3-(4-methyl-1H-1,2,3-triazol-1-yl)pyrrolidine-1-carboxylate was isolated as a colorless oil in 63% (170 mg) yield.1H NMR (500 MHz, CDCl3) δ 7.28 (s, 1H), 5.09 (bd, 1H), 3.83 (dd, J = 11.9, 6.5 Hz, 1H), 3.75 – 3.64 (m, 1H), 3.54 (m, 2H), 2.41 (m, 2H), 2.29 (s, 3H), 1.42 (s, 9H).13C NMR (126 MHz, CDCl3) δ 154.1, 143.6, 119.6, 80.0, 59.2, 58.5, 51.4, 51.1, 44.3, 43.9, 32.0, 31.2, 28.4, 27.9, 10.8. Note: the additional carbon resonances were assigned as being due to rotamers. HRMS (ESI-TOF) [M+Na]+Calculated for C12H20N4NaO2+275.1478; Found: 275.1483. tert-Butyl 3-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1- yl)pyrrolidine-1-carboxylate (boc-3). General procedure 2 was modified using tri-3 (170 mg, 0.674 mmol) and product boc-3 was isolated as a colorless oil in 23% (70.0 mg) yield.1H NMR (500 MHz, CDCl3) for mixture of rotamers: δ 7.83 (m, 1H), 7.18 (m, 1H), 6.97 (m, 1H), 6.88 (s, 1H), 6.74 (s, 2H), 5.34 (dt, J = 11.4, 6.2 Hz, 1H), 3.71 – 3.57 (m, 2H), 3.38 – 3.21 (m, 2H), 2.47 (s, 3H), 2.32 (s, 6H), 2.31 – 2.22 (m, 1H), 1.96 – 1.82 (m, 1H), 1.46 (s, 9H).13C NMR (126 MHz, CDCl3) δ 163.9, 154.2, 153.8, 145.0, 142.3, 142.1, 140.3, 139.6, 131.6, 131.5, 126.8, 119.5, 119.4, 117.9, 111.0, 110.9, 79.4, 58.3, 57.9, 51.3, 50.9, 44.9, 44.4, 31.3, 31.2, 28.5, 21.3, 12.2. Note: the additional carbon resonances were assigned as being due to rotamers. HRMS (ESI-TOF) [M+Na]+Calculated for C25H31N5NaO3+472.2319; Found: 472.2336. 2-(3,5-Dimethylphenoxy)-6-(4-methyl-1-(pyrrolidin-3-yl)-1H-1,2,3-triazol-5-yl)pyridine (3). General procedure 3 was modified using boc-3 (42 mg, 0.093 mmol) and product 3 was isolated as a colorless oil in 60% (45 mg) yield. NMR analysis indicated that the isolated material contained 4 TFA molecules per triazole.1H NMR (500 MHz, MeOD) δ 8.01 (dd, J = 8.4, 7.4 Hz, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.11 (d, J = 8.4, Hz, 1H), 6.96 (s, 1H), 6.81 (s, 2H), 5.60 (ddd, J = 6.7, 4.7, 2.0 Hz, 1H), 3.94 – 3.62 (m, 1H), 3.57 (ddd, J = 11.7, 10.2, 7.4 Hz, 1H), 3.48 – 3.39 (m, 1H), 3.17 (dd, J = 13.2, 6.6 Hz, 1H), 2.49 (s, 3H), 2.34 (s, 6H), 2.28 – 2.13 (m, 1H), 2.08 – 1.88 (m, 1H).13C NMR (126 MHz, MeOD) δ 163.9, 154.1, 143.9, 142.1, 140.9, 139.8, 132.0, 126.4, 119.2, 118.3, 111.3, 58.9, 50.4, 44.5, 31.5, 19.8, 10.5. HRMS (ESI-TOF) [M+H]+Calculated for C20H24N5O+350.1975; Found: 350.1985. Example 80: Preparation of: tert-Butyl (3R,4R)-3-hydroxy-4-(4-methyl-1H-1,2,3-triazol-1-yl)pyrrolidine-1-carboxylate (tri-5). General procedure 1 was modified using a commercially available azide. Tert-butyl (3R,4R)-3-azido-4-hydroxypyrrolidine-1-carboxylate (250 mg, 1.1 mmol) and product tri-5 was isolated as a colorless oil in 73% (215 mg) yield.1H NMR (500 MHz, CDCl3) δ 7.36 (s, 1H), 4.86 (s, 1H), 4.63 (dd, J = 32.8, 6.0 Hz, 1H), 4.04 – 3.95 (m, 1H), 3.79 – 3.67 (m, 2H), 3.39 (dd, J = 11.7, 4.6 Hz, 1H), 2.25 (s, 3H), 1.42 (s, 9H).13C NMR (126 MHz, CDCl3) δ 154.4, 154.2, 143.4, 121.0, 80.3, 74.1, 73.3, 65.4, 64.9, 51.4, 50.9, 48.7, 48.3, 28.3, 10.5. Note: the additional carbon resonances were assigned as being due to rotamers. HRMS (ESI-TOF) [M+Na]+Calculated for C12H20N4NaO3+291.1428; Found: 291.1438. tert-Butyl (3R,4R)-3-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1- yl)-4-hydroxypyrrolidine-1-carboxylate (boc-5). General procedure 2 was modified by using 2.5 equiv of n-BuLi and using tri-5 (200 mg, 0.78 mmol) and product boc-5 was isolated as a colorless oil in 37% (136 mg) yield.1H NMR (500 MHz, CDCl3) FOR MIXTURE OF ROTAMERS δ 7.80 (td, J = 8.0, 2.4 Hz, 1H), 7.13 (dd, J = 7.6, 4.0 Hz, 1H), 6.93 (dd, J = 8.3, 2.3 Hz, 1H), 6.87 (br, 1H), 6.74 (s, 2H), 5.10 (dq, J = 33.5, 7.1 Hz, 1H), 4.78 – 4.64 (m, 1H), 4.08 (dd, J = 144.2, 4.5 Hz, 1H), 3.83 (ddd, J = 25.2, 11.3, 6.7 Hz, 1H), 3.60 (ddd, J = 33.0, 11.3, 6.8 Hz, 1H), 3.41 (ddd, J = 44.2, 11.4, 8.0 Hz, 1H), 3.11 (td, J = 11.5, 6.1 Hz, 1H), 2.34 (s, 3H), 2.30 (s, 6H), 1.44 (d, J = 8.4 Hz, 9H).13C NMR (126 MHz, CDCl3) δ 163.8, 154.0, 153.6, 144.7, 140.5, 140.0, 127.1, 119.2, 119.1, 119.1, 118.3, 111.2, 79.7, 74.3, 74.0, 64.3, 63.9, 51.3, 50.7, 48.9, 48.7, 34.6, 31.5, 28.4, 21.2, 12.0. Note: the additional carbon resonances were assigned as being due to rotamers. (3R,4R)-4-(5-(6-(3,5-Dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1- yl)pyrrolidin-3-ol (5). General procedure 3 was modified using boc-5 (42 mg, 0.090 mmol) and product 5 was isolated as a colorless oil in 50% (47 mg) yield. NMR analysis indicated that the isolated material contained 6 TFA molecules per triazole.1H NMR (500 MHz, MeOD) δ 8.01 (dd, J = 8.4, 7.4 Hz, 1H), 7.40 (d, J = 7.4 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 7.01 – 6.90 (s, 1H), 6.80 (s, 2H), 5.45 (dd, J = 6.5, 1.4 Hz, 1H), 4.52 (d, J = 3.7 Hz, 1H), 3.82 (dd, J = 12.4, 4.0 Hz, 1H), 3.50 (d, J = 13.1 Hz, 1H), 3.36 (d, J = 12.4 Hz, 1H), 3.24 (dd, J = 13.1, 6.4 Hz, 1H), 2.46 (s, 3H), 2.35 (s, 6H).13C NMR (126 MHz, MeOD) δ 164.1, 153.9, 143.7, 140.9, 139.9, 126.6, 119.2, 118.4, 111.5, 73.9, 64.8, 52.6, 48.7, 19.9, 10.2. Example 81: Preparation of: tert-Butyl (3R,4R)-3-amino-4-methoxypyrrolidine-1-carboxylate (tri-6). General procedure 1 was modified using amine tert-butyl (3R,4R)-3-amino-4-methoxypyrrolidine-1-carboxylate (237 mg, 1.10 mmol) and product tri-6 was isolated as a colorless oil in 96% (297 mg) yield.1H NMR (500 MHz, CDCl3) δ 7.29 (s, 1H), 4.89 (m, 1H), 4.10 (m, 1H), 3.86 (dd, J = 12.3, 7.1 Hz, 1H), 3.77 – 3.70 (m, 1H), 3.65 (m, 1H), 3.42 – 3.34 (m, 1H), 3.29 (s, 3H), 2.24 (s, 3H), 1.37 (s, 9H).13C NMR (126 MHz, CDCl3) δ 154.1, 143.4, 120.3, 83.4, 82.4, 80.1, 63.0, 62.1, 57.5, 49.6, 49.0, 48.9 488 284 107 Note: the additional carbon resonances were assigned as being due to rotamers. HRMS (ESI-TOF) [M+Na]+Calculated for C13H22N4NaO3+305.1584; Found: 305.1597. tert-Butyl (3R,4R)-3-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1- yl)-4-methoxypyrrolidine-1-carboxylate (boc-6). General procedure 2 was modified using tri-6 (161 mg, 0.571 mmol) and product boc-6 was isolated as a colorless oil in 57% (156 mg) yield.1H NMR (500 MHz, CDCl3) for mixture of rotamers: δ 7.83 (m, 1H), 7.19 (m, 1H), 7.12 – 6.94 (m, 1H), 6.88 (m, 1H), 6.75 (s, 2H), 5.32 (m, 1H), 4.50 – 4.33 (m, 1H), 3.98 (m, 1H), 3.44 (m, 1H), 3.32 – 3.19 (m, 2H), 3.16 (m, 3H), 2.48 (s, 3H), 2.33 (s, 6H), 1.46 (s, 9H).13C NMR (126 MHz, CDCl3) δ 163.9, 154.0, 154.0, 153.6, 153.6, 144.8, 142.2, 142.0, 140.3, 140.3, 139.7, 139.7, 132.2, 132.0, 127.0, 126.9, 119.2, 119.2, 118.0, 111.2, 82.6, 82.1, 79.6, 79.5, 62.5, 61.7, 57.5, 57.4, 50.4, 50.0, 49.8, 49.1, 28.4, 21.2, 12.1, 12.1. Note: the additional carbon resonances were assigned as being due to rotamers. 2-(3,5-Dimethylphenoxy)-6-(1-((3R,4R)-4-methoxypyrrolidin-3-yl)-4-methyl-1H-1,2,3- triazol-5-yl)pyridine (6). General procedure 3 was modified using boc-6 (107 mg, 0.215 mmol) and product 6 was isolated as a colorless oil in 56% (180 mg) yield. NMR analysis indicated that the isolated material contained 4 TFA molecules per triazole.1H NMR (500 MHz, MeOD) δ 8.02 (dd, J = 8.4, 7.5 Hz, 1H), 7.44 (d, J = 7.4 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.96 (d, J = 1.7 Hz, 1H), 6.79 (d, J = 1.6 Hz, 2H), 5.67 (dt, J = 6.5, 1.2 Hz, 1H), 4.42 – 4.22 (m, 1H), 3.82 (dd, J = 12.9, 4.3 Hz, 1H), 3.58 (d, J = 13.2 Hz, 1H), 3.53 (d, J = 12.8 Hz, 1H), 3.33 (s, 3H), 3.21 (dd, J = 13.2, 6.5 Hz, 1H), 2.50 (s, 3H), 2.34 (s, 6H).13C NMR (126 MHz, MeOD) δ 163.9, 154.0, 143.8, 142.3, 141.1, 139.9, 132.2, 126.5, 118.8, 118.6, 111.4, 83.1, 61.8, 56.4, 49.9, 48.9, 19.9, 10.4. Example 82. Biological Evaluations Protein expression: His6BRD4 D1 are expressed and purified as reported by A. K. Urick, et al., ACS Chem. Biol.2015, 10, 2246–2256. His9BRD4 D1 expression. The His6BRD4 D1 insert is modified by addition of three histidines to the hexahistidine tag via site-directed mutagenesis by standard procedures (A. K. Urick, et al., ACS Chem. Biol.2015, 10, 2246–2256). The resulting gene is co-transformed with pRARE (Novagen) into BL21(DE3) E. coli (N. K. Mishra, et al.,, ACS Chem. Biol.2014, 9, 2755– 2760). Cells were grown on Luria-Bertani (LB) agar plates containing kanamycin (100 mg / mL) at 37 °C for 12 hours. Individual colonies are picked and grown for 12 hours in 5 mL of LB containing kanamycin (100mg / mL). The primary culture is used to inoculated 1 L of LB media containing kanamycin (100mg / mL) and the culture is grown by shaking at 220 RPM at 37 °C until an OD600 of 0.6-0.8 is reached. BRD4 D2 expression. The pET-28a(+) plasmid containing the second bromodomain of BRD4 (residues 333- 460) was purchased from GenScript. The E.coli strain BL21 Star (DE3) is transformed with the plasmid containing the desired insert and plated onto an agar plate containing the appropriate antibiotics. The plate is incubated overnight at 37°C. A 5 mL LB culture containing antibiotics, chloramphenicol (35 mg / L) and kanamycin (100 mg / L), is inoculated using a single colony form this plate and grown overnight at 37°C and shaking at 215 rpm. The primary culture is used to inoculate 1 L of LB media containing chloramphenicol (35 mg / L) and kanamycin (100 mg / L) at 37°C at 215 rpm until the optical density at 600 nm i reaches 0.6-0.8. An equilibration time of 30 minutes at 20°C and 215 rpm is followed by the addition of 1 mM IPTG to induce protein expression. The culture is shaken for 16-20 hours at 20°C and 220 rpm. Cells are pelleted by centrifugation at 8,000 g and stored at -20°C until purification. BRD2 D1 Expression. The pET28a(+) plasmid containing the first bromodomain of BRD2 (Residues 71-194) is purchased from GenScript. The E.coli strain BL21(DE3)-RIL are transformed with the BRD2 D1 plasmid and plated onto an agar plates containing kanamycin(100mg / L) and chloramphenicol (35mg / L). The plate is incubated overnight at 37°C. A 5 mL LB culture containing kanamycin(100mg / L) and chloramphenicol (35mg / L) is inoculated using a single colony from this plate and grown overnight at 25°C and shaking at 220 rpm. The primary culture is used to inoculate 1 L of LB media containing chloramphenicol (35 mg / L) and kanamycin (100 mg / L) until the optical density at 600 nm had reached 0.6-0.8. At this point, an equilibration time of 30 minutes at 20°C and 220 rpm is followed by the addition of 1 mM IPTG to induce protein expression. The culture is shaken for 16-20 hours at 20°C and 220 rpm. Cells are pelleted by centrifugation at 8,000 g and stored at -20°C until purification. Fluorescence Anisotropy: All fluorescence anisotropy (FA) experiments were run in a black 384 well plate in a buffer consisting of 50 mM HEPES, 100 mM NaCl, pH=7.4. Measurements were made using a Tecan Infinite 500 with an excitation frequency of 485 nm, an emission frequency of 535 nm, and a fluorescence polarization filter. All FA experiments (direct binding and competition) used a 10 mM stock of fluorescent tracer Fl-JQ1 diluted to a final concentration of 15 nM within each well (Divakaran, A., et al., J. Med. Chem.2018, 61 (20), 9316–9334) . For the direct binding experiment, the protein of interest was serially diluted across the plate (25 μM maximum protein concentration) and allowed to incubate in the presence of the fluorescent tracer for 30 minutes. After incubating, anisotropy values were recorded and fit using equation 1, where a is equal to the concentration of Fl-JQ1 (15 nM), b and c are the maximum and minimum anisotropy values, x is the concentration of the protein, and y is the observed concentration, allowing the Kdof the protein of interest to be calculated. The range of anisotropy values (b-c) measured in the direct binding experiment are then used to determine the concentration of protein at which the tracer is 80% bound. This is the protein concentration that will be used in the competition experiment. In the competition experiment, the concentration of Fl-JQ1 and protein are kept constant, and the inhibitors being tested are serially diluted across the plate with a maximum concentration of 50 μM. The anisotropy values were fit with Prism’s [inhibitor] versus response (four parameter) function to yield IC50values. These values can then be transformed into Kivalues using equation 2, a variant of the Cheng-Prusoff equation, where Lbis the concentration of bound tracer, IC50is the value obtained from the [inhibitor] versus response four parameter calculation, Kdis the value obtained from the direct binding experiment, L0is the total concentration of tracer, and R0is the initial concentration of the protein of interest (Pomerantz, W. C. K., et al., In Chemical Epigenetics; Mai, A., Ed.; Springer International Publishing: Cham, 2020; pp 287–337). Equation 2 Data for representative compounds is provided in the following table.

[0014] IC50values were determined by fluorescence anisotropy. Data represents the mean and standard deviation of three independent trials. Example 83. The following illustrate representative pharmaceutical dosage forms, containing a compound of formula I ('Compound X'), for therapeutic or prophylactic use in humans. (i) Tablet 1 mg / tablet Compound X= 100.0 Lactose 77.5 Povidone 15.0 Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesium stearate 3.0 300.0 (ii) Tablet 2 mg / tablet Compound X= 20.0 Microcrystalline cellulose 410.0 Starch 50.0 Sodium starch glycolate 15.0 Magnesium stearate 5.0 500.0 (iii) Capsule mg / capsule Compound X= 10.0 Colloidal silicon dioxide 1.5 Lactose 465.5 Pregelatinized starch 120.0 Magnesium stearate 3.0 600.0 (iv) Injection 1 (1 mg / ml) mg / ml Compound X= (free acid form) 1.0 Dibasic sodium phosphate 12.0 Monobasic sodium phosphate 0.7 Sodium chloride 4.5 1.0 N Sodium hydroxide solution (pH adjustment to 7.0-7.5) q.s. Water for injection q.s. ad 1 mL (v) Injection 2 (10 mg / ml) mg / ml Compound X= (free acid form) 10.0 Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 Polyethylene glycol 400 200.0 1.0 N Sodium hydroxide solution (pH adjustment to 7.0-7.5) q.s. Water for injection q.s. ad 1 mL (vi) Aerosol mg / can Compound X= 20.0 Oleic acid 10.0 Trichloromonofluoromethane 5,000.0 Dichlorodifluoromethane 10,000.0 Dichlorotetrafluoroethane 5,000.0 The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. All publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

Claims

2025-058 | VHPM 09531.605WO1 CLAIMS What is claimed is:

1. A compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein: R1is selected from H, halo, aryl, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2- C6)alkenyl, and (C2-C6)alkynyl, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, and (C2-C6)alkynyl, is optionally substituted with one or more groups independently selected from the group consisting of halo, oxo, −OH, cyano, (C3-C6)cycloalkyl, and (C1-C6)alkoxy; and wherein any aryl is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3- C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH; R2is aryl that is optionally substituted with one or more groups independently selected from the group consisting of selected from halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, and (C1-C6)alkoxy; X is Rm, (C3-C6)cycloalkyl, a 5-membered heterocycle, or a 6-10 membered bicyclic heterocycle, which (C3-C6)cycloalkyl 5-membered heterocycle, and 6-10 membered bicyclic heterocycle, is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C1-2025-058 | VHPM 09531.605WO1 C6)alkoxycarbonyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1- C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1- C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, 5-membered heteroaryl, 6- membered heteroaryl, and (C1-C6)alkoxy; or X is:and R3is (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyl, -C(=O)NRgRh, -S(O)2NRgRh, -S(O)2(C1- C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C3-C6)cycloalkyl, or (C1-C6)alkyl, which (C1- C6)alkoxycarbonyl, (C3-C6)cycloalkyl is optionally substituted with halo, −OH, cyano, (C3- C6)cycloalkyl, (C1-C6)alkoxy, −C(=N(Ra))NRaRb, −NRaRb, -C(=O)NRgRh, -S(O)2NRgRh, -NS(O)2NRgRh, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, a 5-membered heteroaryl, a 6- membered heteroaryl, a carbon-linked 4-6 membered heterocycle, -C(=O)NRgRh, or -(OCH2CH2)n-NRgRh, and which (C1-C6)alkyl is substituted with (C1-C6)alkoxycarbonyl, -C(=O)NRgRh, -S(O)2NRgRh, -NS(O)2NRgRh, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, a 5- membered heteroaryl, a 6-membered heteroaryl, a carbon-linked 4-6 membered heterocycle, -C(=O)NRgRh, or -(OCH2CH2)n-NRgRh; each Raand Rbis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Raand Rbtogether with the nitrogen to which they are attached form a 4-6 membered ring heterocycle; each Rcand Rdis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, -SO2NReRf, and (C3-C6)cycloalkyl; or Rcand Rdtogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; each Reand Rfis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Reand Rftogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; each Rgand Rhis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Rgand Rhtogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; Rmis (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-2025-058 | VHPM 09531.605WO1 C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3- C6)cycloalkyl, C1-C6)alkoxycarbonyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl , 5-10 membered heteroaryl, and a 5-10 membered heterocycle, which (C3-C6)cycloalkyl, 5-10 membered heteroaryl, and 5- 10 membered bicyclic heterocycle, is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3- C6)cycloalkyl, NRcRd, (C1-C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C1-C6)alkoxycarbonyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C1- C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, 5- membered heteroaryl, 6-membered heteroaryl, and (C1-C6)alkoxy; A, B, D and E are each independently selected from CH or N; provided that no more than two of A, B, D and E are N; F is O, S, or NRk; n is 1 or 2; G is CH or N; and Rkis H or (C1-C6)alkyl; or wherein R1is aryl that is substituted with one or more nitro and that is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1- C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH; R2is aryl that is optionally substituted with one or more groups independently selected from the group consisting of selected from halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, and (C1-C6)alkoxy;2025-058 | VHPM 09531.605WO1 X is:R3is selected from the group consisting of H, −C(=N(Ra))NRaRb, and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C3-C6)cycloalkyl, (C1-C6)alkoxy, −C(=N(Ra))NRaRb, and −NRaRb; each Raand Rbis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Raand Rbtogether with the nitrogen to which they are attached form a 4-6 membered ring heterocycle; A, B, D and E are each independently selected from CH or N; provided that no more than two of A, B, D and E are N; F is O, S, or NRk; G is CH or N; and Rkis H or (C1-C6)alkyl; or wherein R1is aryl that is substituted with one or more nitro and that is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1- C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH; R2is aryl that is optionally substituted with one or more groups independently selected from the group consisting of selected from halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, and (C1-C6)alkoxy; X is Rm, (C3-C6)cycloalkyl, a 5-membered heterocycle, or a 6-10 membered bicyclic heterocycle, which (C3-C6)cycloalkyl 5-membered heterocycle, and 6-10 membered bicyclic heterocycle, is optionally substituted with one or more groups independently selected from the2025-058 | VHPM 09531.605WO1 group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C1- C6)alkoxycarbonyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1- C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1- C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, 5-membered heteroaryl, 6- membered heteroaryl, and (C1-C6)alkoxy; or X is:and R3is (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyl, -C(=O)NRgRh, -S(O)2NRgRh, -S(O)2(C1- C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C3-C6)cycloalkyl, or (C1-C6)alkyl, which (C1- C6)alkoxycarbonyl, (C3-C6)cycloalkyl is optionally substituted with halo, −OH, cyano, (C3- C6)cycloalkyl, (C1-C6)alkoxy, −C(=N(Ra))NRaRb, −NRaRb, -C(=O)NRgRh, -S(O)2NRgRh, -NS(O)2NRgRh, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, a 5-membered heteroaryl, a 6- membered heteroaryl, a carbon-linked 4-6 membered heterocycle, -C(=O)NRgRh, or -(OCH2CH2)n-NRgRh, and which (C1-C6)alkyl is substituted with (C1-C6)alkoxycarbonyl, -C(=O)NRgRh, -S(O)2NRgRh, -NS(O)2NRgRh, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, a 5- membered heteroaryl, a 6-membered heteroaryl, a carbon-linked 4-6 membered heterocycle, -C(=O)NRgRh, or -(OCH2CH2)n-NRgRh; each Raand Rbis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Raand Rbtogether with the nitrogen to which they are attached form a 4-6 membered ring heterocycle; each Rcand Rdis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, -SO2NReRf, and (C3-C6)cycloalkyl; or Rcand Rdtogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; each Reand Rfis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Reand Rftogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; each Rgand Rhis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Rgand Rhtogether with the nitrogen to which they are attached form a 4-6 membered heterocycle;2025-058 | VHPM 09531.605WO1 Rmis (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1- C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3- C6)cycloalkyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl , 5-10 membered heteroaryl, and a 5-10 membered heterocycle, which (C3-C6)cycloalkyl, 5-10 membered heteroaryl, and 5- 10 membered bicyclic heterocycle, is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3- C6)cycloalkyl, NRcRd, (C1-C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C1-C6)alkoxycarbonyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C1- C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, 5- membered heteroaryl, 6-membered heteroaryl, and (C1-C6)alkoxy; A, B, D and E are each independently selected from CH or N; provided that no more than two of A, B, D and E are N; F is O, S, or NRk; n is 1 or 2; G is CH or N; and Rkis H or (C1-C6)alkyl; or wherein R1is selected from H, halo, aryl, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2- C6)alkenyl, and (C2-C6)alkynyl, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, and (C2-C6)alkynyl, is optionally substituted with one or more groups independently selected from the group consisting of halo, oxo, −OH, cyano, (C3-C6)cycloalkyl, and (C1-C6)alkoxy; and wherein any aryl is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3- C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with2025-058 | VHPM 09531.605WO1 one or more groups independently selected from the group consisting of halo and -OH; R2is aryl that is optionally substituted with one or more groups independently selected from the group consisting of selected from halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, and (C1-C6)alkoxy; X is selected from the group consisting of:; A, B, D and E are each independently selected from CH or N; provided that no more than two of A, B, D and E are N; F is O, S, or NRk; n is 1 or 2; G is CH or N; and Rkis H or (C1-C6)alkyl.

2. The compound or pharmaceutically acceptable salt of claim 1, wherein: R1is selected from H, halo, aryl, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2- C6)alkenyl, and (C2-C6)alkynyl, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, and (C2-C6)alkynyl, is optionally substituted with one or more groups independently selected from the group consisting of halo, oxo, −OH, cyano, (C3-C6)cycloalkyl, and (C1-C6)alkoxy; and wherein any aryl is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3- C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl (C1-C6)alkylthio and (C2-C6)alkanoyloxy wherein any (C1-C6)alkyl,2025-058 | VHPM 09531.605WO1 (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH; R2is aryl that is optionally substituted with one or more groups independently selected from the group consisting of selected from halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, and (C1-C6)alkoxy; X is Rm, (C3-C6)cycloalkyl, a 5-membered heterocycle, or a 6-10 membered bicyclic heterocycle, which (C3-C6)cycloalkyl 5-membered heterocycle, and 6-10 membered bicyclic heterocycle, is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C1- C6)alkoxycarbonyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1- C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1- C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, 5-membered heteroaryl, 6- membered heteroaryl, and (C1-C6)alkoxy; or X is:and R3is (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyl, -C(=O)NRgRh, -S(O)2NRgRh, -S(O)2(C1- C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C3-C6)cycloalkyl, or (C1-C6)alkyl, which (C1- C6)alkoxycarbonyl, (C3-C6)cycloalkyl is optionally substituted with halo, −OH, cyano, (C3- C6)cycloalkyl, (C1-C6)alkoxy, −C(=N(Ra))NRaRb, −NRaRb, -C(=O)NRgRh, -S(O)2NRgRh, -NS(O)2NRgRh, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, a 5-membered heteroaryl, a 6- membered heteroaryl, a carbon-linked 4-6 membered heterocycle, -C(=O)NRgRh, or -(OCH2CH2)n-NRgRh, and which (C1-C6)alkyl is substituted with (C1-C6)alkoxycarbonyl, -C(=O)NRgRh, -S(O)2NRgRh, -NS(O)2NRgRh, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, a 5- membered heteroaryl, a 6-membered heteroaryl, a carbon-linked 4-6 membered heterocycle, -C(=O)NRgRh, or -(OCH2CH2)n-NRgRh; each Raand Rbis independently selected from the group consisting of H, (C1-C6)alkyl,2025-058 | VHPM 09531.605WO1 (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Raand Rbtogether with the nitrogen to which they are attached form a 4-6 membered ring heterocycle; each Rcand Rdis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, -SO2NReRf, and (C3-C6)cycloalkyl; or Rcand Rdtogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; each Reand Rfis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Reand Rftogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; each Rgand Rhis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Rgand Rhtogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; Rmis (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1- C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3- C6)cycloalkyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl , 5-10 membered heteroaryl, and a 5-10 membered heterocycle, which (C3-C6)cycloalkyl, 5-10 membered heteroaryl, and 5- 10 membered bicyclic heterocycle, is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3- C6)cycloalkyl, NRcRd, (C1-C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C1-C6)alkoxycarbonyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C1- C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, 5- membered heteroaryl, 6-membered heteroaryl, and (C1-C6)alkoxy; A, B, D and E are each independently selected from CH or N; provided that no more than two of A, B, D and E are N; F is O, S, or NRk; n is 1 or 2; G is CH or N; and Rkis H or (C1-C6)alkyl.2025-058 | VHPM 09531.605WO1 3. The compound or pharmaceutically acceptable salt of claim 1, wherein: R1is aryl that is substituted with one or more nitro and that is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1- C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH; R2is aryl that is optionally substituted with one or more groups independently selected from the group consisting of selected from halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, and (C1-C6)alkoxy; X is:R3is selected from the group consisting of H, −C(=N(Ra))NRaRb, and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C3-C6)cycloalkyl, (C1-C6)alkoxy, −C(=N(Ra))NRaRb, and −NRaRb; each Raand Rbis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Raand Rbtogether with the nitrogen to which they are attached form a 4-6 membered ring heterocycle; A, B, D and E are each independently selected from CH or N; provided that no more than two of A, B, D and E are N; F is O, S, or NRk; G is CH or N; and Rkis H or (C1-C6)alkyl.

4. The compound or pharmaceutically acceptable salt of claim 1, wherein:2025-058 | VHPM 09531.605WO1 R1is aryl that is substituted with one or more nitro and that is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1- C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH; R2is aryl that is optionally substituted with one or more groups independently selected from the group consisting of selected from halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, and (C1-C6)alkoxy; X is Rm, (C3-C6)cycloalkyl, a 5-membered heterocycle, or a 6-10 membered bicyclic heterocycle, which (C3-C6)cycloalkyl 5-membered heterocycle, and 6-10 membered bicyclic heterocycle, is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C1- C6)alkoxycarbonyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1- C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1- C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C3-C6)cycloalkyl, 5-membered heteroaryl, 6-membered heteroaryl, and (C1-C6)alkoxy; or X is:and R3is (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyl, -C(=O)NRgRh, -S(O)2NRgRh, -S(O)2(C1- C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C3-C6)cycloalkyl, or (C1-C6)alkyl, which (C1- C6)alkoxycarbonyl, (C3-C6)cycloalkyl is optionally substituted with halo, −OH, cyano, (C3- C6)cycloalkyl, (C1-C6)alkoxy, −C(=N(Ra))NRaRb, −NRaRb, -C(=O)NRgRh, -S(O)2NRgRh, -NS(O)2NRgRh, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, a 5-membered heteroaryl, a 6- membered heteroaryl, a carbon-linked 4-6 membered heterocycle, -C(=O)NRgRh, or -(OCH2CH2)n-NRgRh, and which (C1-C6)alkyl is substituted with (C1-C6)alkoxycarbonyl,2025-058 | VHPM 09531.605WO1 -C(=O)NRgRh, -S(O)2NRgRh, -NS(O)2NRgRh, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, a 5- membered heteroaryl, a 6-membered heteroaryl, a carbon-linked 4-6 membered heterocycle, -C(=O)NRgRh, or -(OCH2CH2)n-NRgRh; each Raand Rbis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Raand Rbtogether with the nitrogen to which they are attached form a 4-6 membered ring heterocycle; each Rcand Rdis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, -SO2NReRf, and (C3-C6)cycloalkyl; or Rcand Rdtogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; each Reand Rfis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Reand Rftogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; each Rgand Rhis independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C3-C6)cycloalkyl; or Rgand Rhtogether with the nitrogen to which they are attached form a 4-6 membered heterocycle; Rmis (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1- C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3- C6)cycloalkyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl , 5-10 membered heteroaryl, and a 5-10 membered heterocycle, which (C3-C6)cycloalkyl, 5-10 membered heteroaryl, and 5- 10 membered bicyclic heterocycle, is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3- C6)cycloalkyl, NRcRd, (C1-C6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, (C1-C6)alkoxycarbonyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C1- C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, NRcRd, (C1-6)alkanoyl, -C(=O)NRcRd, -S(O)2NRcRd, -NS(O)2NRcRd, -S(O)2(C1-C6)alkyl, -S(O)2(C3-C6)cycloalkyl, 5- membered heteroaryl, 6-membered heteroaryl, and (C1-C6)alkoxy; A, B, D and E are each independently selected from CH or N; provided that no more than two of A, B, D and E are N; F is O, S, or NRk;2025-058 | VHPM 09531.605WO1 n is 1 or 2; G is CH or N; and Rkis H or (C1-C6)alkyl.

5. The compound or pharmaceutically acceptable salt of claim 1, wherein: R1is selected from H, halo, aryl, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2- C6)alkenyl, and (C2-C6)alkynyl, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, and (C2-C6)alkynyl, is optionally substituted with one or more groups independently selected from the group consisting of halo, oxo, −OH, cyano, (C3-C6)cycloalkyl, and (C1-C6)alkoxy; and wherein any aryl is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3- C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH; R2is aryl that is optionally substituted with one or more groups independently selected from the group consisting of selected from halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, and (C1-C6)alkoxy; X is selected from the group consisting of:; A, B D and E are each independently selected from CH or N; provided that no more2025-058 | VHPM 09531.605WO1 than two of A, B, D and E are N; F is O, S, or NRk; n is 1 or 2; G is CH or N; and Rkis H or (C1-C6)alkyl.

6. The compound or pharmaceutically acceptable salt of claim 1, wherein R1is (C1- C6)alkyl, wherein any (C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, oxo, −OH, cyano, (C3-C6)cycloalkyl, and (C1-C6)alkoxy.

7. The compound or pharmaceutically acceptable salt of claim 1, wherein R1is (C1- C6)alkyl.

8. The compound or pharmaceutically acceptable salt of claim 1, wherein R1is methyl.

9. The compound or pharmaceutically acceptable salt of claim 1, wherein R1is aryl and wherein any aryl is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2- C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2- C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH.

10. The compound or pharmaceutically acceptable salt of claim 1, wherein R1is aryl and wherein any aryl is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2- C6)alkanoyloxy.

11. The compound or pharmaceutically acceptable salt of claim 1, wherein R1is 4-2025-058 | VHPM 09531.605WO1 (trifluoromethyl)phenyl, 4-bromophenyl, 4-bromo-3-fluorophenyl, or 4-bromo-3-nitrophenyl.

12. The compound or pharmaceutically acceptable salt of claim 1, wherein R1is 4- (trifluoromethyl)phenyl, 4-bromophenyl, or 4-bromo-3-fluorophenyl.

13. The compound or pharmaceutically acceptable salt of claim 1, wherein R1is 4- (trifluoromethyl)phenyl.

14. The compound or pharmaceutically acceptable salt of claim 1, wherein R1is aryl that is substituted with one or more nitro and that is optionally substituted with one or more groups independently selected from the group consisting of halo, −OH, cyano, (C1-C6)alkyl, (C3- C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH.

15. The compound or pharmaceutically acceptable salt of claim 1, wherein R1is 4-bromo-3- nitrophenyl. 16 The compound or pharmaceutically acceptable salt of any one of claims 1-15, wherein F is O.

17. The compound or pharmaceutically acceptable salt of any one of claims 1-16, wherein R2is aryl that is optionally substituted with one or more groups independently selected from the group consisting of selected from halo, −OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1- C6)alkoxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C1-C6)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo, and (C1-C6)alkoxy.

18. The compound or pharmaceutically acceptable salt of any one of claims 1-16, wherein R2is 3,5-dimethylphenyl, 3-isopropyl-6-methylphenyl, 3-tertbutylphenyl, 3,5-dicyclopropylphenyl,2025-058 | VHPM 09531.605WO1 or 3-propylphenyl.

19. The compound or pharmaceutically acceptable salt of claim 1, wherein X is:.

20. The compound or pharmaceutically acceptable salt of claim 1, wherein X is:.

21. The compound or pharmaceutically acceptable salt of claim 1, wherein X is:2025-058 | VHPM 09531.605WO1.

22. The compound or pharmaceutically acceptable salt of claim 1, wherein X is:.

23. The compound or pharmaceutically acceptable salt of claim 1, wherein X is:.

24. The compound or pharmaceutically acceptable salt of claim 1, wherein X is:2025-058 | VHPM 09531.605WO1pharmaceutically acceptable salt of claim 1, wherein X is:.

26. The compound or pharmaceutically acceptable salt of claim 1, wherein X is:2025-058 | VHPM 09531.605WO1.

27. A compound selected from the group consisting of:or a pharmaceutically acceptable salt thereof.

28. A compound selected from the group consisting of:2025-058 | VHPM 09531.605WO1 N N N N N N N N N N N N N N N N N N O O O N N N N N N N N NH O N N and N N O O or a pharmaceutically acceptable salt thereof.

29. A compound selected from the group consisting of: NO N ON ON N O2NF3C NH Br NHN NBr NHN N N N N NO N ON NH2 N ON C NH2F3C (R) N F3NH NNN(S) F3C 2N N N2025-058 | VHPM 09531.605WO1 NO N O N ON NOH NOMe FCF3C(R)F3C(R) 3(R) (R)N NH N(S)NN NHNN NH ON O N ONNO NN H F FC OF3CN O3C SNN NH2 3NNNO NH2(S)N(S)SO NNN O N O N ON N N O F3C ONH F3CN CNF3C 2N NO NN(SNS) (S) NN ON N(S)NO N O N ONO NN FF C N F3C NNH2 3C N3N N N O NH N N N NON ON OF3C NNN ONH N2 F3C N OH NN N NF3C NN H N N N O2025-058 | VHPM 09531.605WO12025-058 | VHPM 09531.605WO1or a pharmaceutically acceptable salt thereof.

30. A compound selected from the group consisting of: NO N O N OO2NNNN NH2Br NHFNH2(R) 3CF3CN NNN NN(S)NO N ON ON N OH FC F3C(R) N3N NH NHN (R)F3C2N(S)N NH N N2025-058 | VHPM 09531.605WO12025-058 | VHPM 09531.605WO1or a pharmaceutically acceptable salt thereof.

31. A compound selected from the group consisting of:2025-058 | VHPM 09531.605WO1or a pharmaceutically acceptable salt thereof.

32. A compound selected from the group consisting of:2025-058 | VHPM 09531.605WO1or a pharmaceutically acceptable salt thereof.

33. A compound selected from the group consisting of: 2-(4-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1-yl)piperidin- 1-yl)ethan-1-amine, 2-(4-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1-yl)piperidin- 1-yl)ethan-1-ol, 3-(4-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1-yl)piperidin- 1-yl)propan-1-amine, 2-(4-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1-yl)piperidin- 1-yl)acetamide, 2-(3,5-dimethylphenoxy)-6-(4-methyl-1-(1-(pyridin-2-ylmethyl)piperidin-4-yl)-1H- 1,2,3-triazol-5-yl)pyridine, 2-(3,5-dimethylphenoxy)-6-(4-methyl-1-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-1H- 1,2,3-triazol-5-yl)pyridine, 2-(3,5-dimethylphenoxy)-6-(4-methyl-1-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-1H- 1,2,3-triazol-5-yl)pyridine, 2-(1-(1-((1H-imidazol-2-yl)methyl)piperidin-4-yl)-4-methyl-1H-1,2,3-triazol-5-yl)-6- (3,5-dimethylphenoxy)pyridine, 2-((4-(5-(6-(3,5-dimethylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1- yl)piperidin-1-yl)methyl)oxazole, 2-(4-(5-(6-(3,5-dicyclopropylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1- yl)piperidin-1-yl)ethan-1-amine, and 2-(4-(5-(6-(3,5-dicyclopropylphenoxy)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-1- yl)piperidin-1-yl)acetamide2025-058 | VHPM 09531.605WO1 or a pharmaceutically acceptable salt thereof.

34. A compound selected from the group consisting of:or a pharmaceutically acceptable salt thereof.

35. A pharmaceutical composition comprising a compound as described in any one of claims 1-34 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

36. A method for treating cancer, an inflammatory condition, or heart disease in an animal comprising administering to the animal a compound as described in any one of claims 1-34 or a pharmaceutically acceptable salt thereof.

37. A compound as described in any one of claims 1-34 or a pharmaceutically acceptable salt thereof for use in medical therapy.

38. A compound as described in any one of claims 1-34 or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment of cancer, heart disease, or an inflammatory condition.

39. The use of a compound as described in any one of claims 1-34 or a pharmaceutically acceptable salt thereof to prepare a medicament for treating cancer, heart disease, or an inflammatory condition in an animal (e.g. a mammal such as a human).

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