WO2024182380A2 - Substituted thiadiazolyl compounds - Google Patents

Abstract

This application is directed to inhibitors of DNA Polymerase Theta (Polθ) activity represented by the following structural formula, (I), and methods for their use, such as to treat cancer.

Description

SUBSTITUTED THIADIAZOLYL COMPOUNDS CROSS-REFERENCE TO RELATED APPLICATION This application claims priority to, and the benefit of, U.S. Provisional Application No.63/448,768, filed on February 28, 2023, the entire contents of which are incorporated herein by reference. BACKGROUND DNA lesions can occur as a result of exogenous and endogenous DNA-damaging agents. To maintain genomic stability and to limit the progression of DNA lesions, cells evolved DNA damage response (DDR) mechanisms. Double-strand breaks (DSBs) are repaired by two major pathways: homologous recombination (HR) and non-homologous end- joining (NHEJ). When NHEJ or HR are compromised, alternative end-joining (alt-EJ), also known as microhomology-mediated end-joining (MMEJ) pathway, can serve as a backup repair pathway. DNA polymerase theta (Polθ) is an A-family polymerase encoded by the POLQ gene. It is a multi-functional protein that exhibits a C-terminal DNA polymerase domain (Polθ-pol), a central domain, and an N-terminal helicase domain (Polθ-hel). It is an error-prone polymerase that promotes MMEJ in higher organisms. The Polθ-hel domain is a member of the SF2 helicases. While it has single-stranded DNA-dependent ATPase activity that can strip Replication Protein A (RPA) from single stranded DNA, it can suppress HR pathway by disrupting Rad51 nucleoprotein complex formation after radiation exposure. This anti- recombinase activity of Polθ promotes the alt-EJ pathway. The helicase domain of Polθ can bridge two single stranded DNA sequences resulting in microhomology-mediated strand annealing. Specifically, Polθ promotes end-joining in alt- EJ pathway by employing this annealing activity even when single stranded DNA overhangs possess limited homology. The Rad51 interaction is followed by ATPase-mediated displacement of Rad51 from DSB damage sites during the reannealing process. Once annealed, the primer strand of DNA is extended by the polymerase domain of Polθ. It has been shown that cancer cells with deficiency in HR, NHEJ or ataxia telangiectasia-mutated (ATM) are highly dependent on Polθ expression. Polθ has limited expression in normal cells, but is overexpressed in a variety of cancer cells. Depletion of Polθ can impair cell-viability and can lead to synthetic lethality of cancer cells. As such, Polθ is an attractive target for novel synthetic lethal therapy of cancers containing DNA repair defects. In view of the connection between the overexpression of Polθ in cancer cells, there is a need for compounds that inhibit Polθ helicase activity. The present application addresses the need. SUMMARY Disclosed herein are certain substituted thiadiazolyl compounds that inhibit DNA Polymerase Theta (Polθ) activity, in particular inhibit the activity of the helicase domain of Polθ. In one aspect, described herein is a compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein ring A, Ar, R_A, m, R_N, L₁, L₂, and T are described herein. Also, disclosed are pharmaceutical compositions comprising such compounds and methods of treating and/or preventing diseases treatable by inhibition of Polθ such as cancer, including homologous recombination (HR) deficient cancers. Also disclosed are pharmaceutical compositions comprising such compounds and methods of treating and/or preventing diseases, e.g., diseases such as cancer treatable by inhibition of Polθ, including homologous recombination (HR) deficient cancers. In another aspect, described herein is a method for treating and/or preventing a disease in a subject, such as cancer characterized by overexpression/overactivity of Polθ helicase, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof. In another aspect, described herein is a method for treating and/or preventing a cancer in a subject, such as cancer characterized by a deficiency in homologous recombinant (HR) or by a reduction or absence of BRCA gene expression, the absence of the BRAC gene, or reduced function of BRCA protein, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof. In another aspect, described herein is a method for inhibiting DNA repair by Polθ in a cell, comprising contacting the cell with an effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cell is HR deficient.

In another aspect, provided herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for inhibiting DNA repair by Pol9 in a cell. In some embodiments, the cell is HR deficient.

In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for treating and/or preventing a disease in a subject, e.g., a disease such as cancer treatable by inhibition of Pol0, including homologous recombination (HR) deficient cancers.

In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for treating and/or preventing a disease in a subject, such as cancer characterized by overexpression/overactivity of Polθ helicase, by a deficiency in homologous recombinant (HR), or by a reduction or absence of BRAC gene expression, the absence of the BRAC gene, or reduced function of BRAC protein.

In another aspect, provided herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for inhibiting DNA repair by Polθ in a cell. In some embodiments, the cell is HR deficient.

In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for treating and/or preventing a disease in a subject, e.g., a disease such as cancer treatable by inhibition of Pol0, including homologous recombination (HR) deficient cancers.

In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for treating and/or preventing a disease in a subject, such as cancer characterized by overexpression/overactivity of Polθ helicase, by a deficiency in homologous recombinant (HR), or by a reduction or absence of BRAC gene expression, the absence of the BRAC gene, or reduced function of BRAC protein.

In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for treating and/or preventing a cancer that is resistant to poly(ADP-ribose) polymerase (PARP) inhibitor therapy in a subject. Examples of cancers resistant to PARP-inhibitors include, but are not limited to, breast cancer, ovarian cancer, lung cancer, bladder cancer, liver cancer, head and neck cancer, pancreatic cancer, gastrointestinal cancer, and colorectal cancer. The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties. DETAILED DESCRIPTION Compounds of the Disclosure The present disclosure relates to a compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein: ring A is C₆-C₁₀ aryl or heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S; each R_A is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NR_a3R_a4, -CN, halogen, oxo, -C(X)R_a1, -C(X)OR_a1, - C(X)NR_a3R_a4, -NR_a2C(X)R_a1, -NR_a2C(X)OR_a1, or -NR_a2C(X)NR_a3R_a4; X is NR_N, O, or S; m is 0, 1, 2, 3, 4, 5, or 6; Ar is C₆-C₁₀ aryl or heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with 1-4 R_Ar; each R_Ar is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -O(CR_C1R_C2)_1-3R_O, -NR_a3R_a4, -CN, halogen, oxo, -C(X)R_a1, - C(X)OR_a1, -C(X)NR_a3R_a4, -NR_a2C(X)R_a1, -NR_a2C(X)OR_a1, or -NR_a2C(X)NR_a3R_a4; R_C1 and R_C2 are each independently H or -CH₃; R_O is -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), C₃-C₈ cycloalkyl, heterocyclyl comprising one 3- to 6-membered ring and 1-2 heteroatoms selected from N, O, and S, C₆ aryl, or heteroaryl comprising one 5- or 6-membered ring and 1-2 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, and oxo; R_N is H or C₁-C₆ alkyl; L₁ is absent, -O-, -N(R_N)-, -S-, -S(=O)₂-, or -N(S(=O)₂R_N)-; L₂ is absent, C₁-C₆ alkylenyl, C₂-C₆ alkenylenyl, or C₂-C₆ alkynylenyl; T is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, -C(X)R_a1, -C(X)OR_a1, - C(X)NR_a3R_a4, R_T, or -XR_T; provided that when L₁ is -O-, and L₂ is C₁-C₆ alkylenyl, then T is not R_T, when L₁ is -O-, and L₂ is absent or C₁-C₆ alkylenyl, then T is not C₁- C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₃-C₈ cycloalkyl, or heterocyclyl comprising one 3- to 6-membered ring and 1-2 heteroatoms selected from N, O, and S; R_T is C₃-C₈ cycloalkyl, heterocyclyl comprising one 3- to 6-membered ring and 1-2 heteroatoms selected from N, O, and S, C₆ aryl, or heteroaryl comprising one 5- or 6- membered ring and 1-2 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R_t; each R_t is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NR_a3R_a4, -CN, halogen, oxo, -C(X)R_a1, -C(X)OR_a1, - C(X)NR_a3R_a4, -NR_a2C(X)R_a1, -NR_a2C(X)OR_a1, -NR_a2C(X)NR_a3R_a4, C₃-C₈ cycloalkyl, heterocyclyl comprising one 3- to 6-membered ring and 1-2 heteroatoms selected from N, O, and S, C₆ aryl, or heteroaryl comprising one 5- or 6-membered ring and 1-2 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁- C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, and oxo; each R_a1 is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkyl-C₆-C₁₀ aryl, or C₁-C₆ alkyl-heteroaryl wherein the heteroaryl comprises a 5- or 6-membered ring and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, oxo, -C(X)R_a1, -C(X)OR_a1, -C(X)NR_a1R_a2, -NR_a2C(X)R_a1, -NR_a2C(X)OR_a1, and - NR_a2C(X)NR_a1R_a2; each R_a2 is independently H or C₁-C₆ alkyl; and R_a3 and R_a4 are each independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₃-C₈ cycloalkyl, heterocyclyl comprising one 3- to 6-membered ring and 1-2 heteroatoms selected from N, O, and S, C₆ aryl, or heteroaryl comprising one 5- or 6- membered ring and 1-2 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, and oxo; or R_a3 and R_a4, together with the nitrogen atom to which they are bonded, form a 5- or 6- membered heterocyclyl ring optionally comprising 1-2 additional heteroatoms selected from N, O, and S and optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, - NH₂, -NR_a2(C₁-C₆ alkyl), -CN, and halogen, wherein the cycloalkyl or heterocyclyl ring may be a non-bridged and non-spiro, spirocyclic, or bridged ring system. Various embodiments of the compounds of the present disclosure, including embodiments of the various groups defined for any of ring A, R_A, m, Ar, R_Ar, X, L₁, L₂, T, R_N, R_O, R_T, R_C1, R_C2, R_t, R_a1, R_a2, R_a3, and R_a4 are described herein, such as below. It is understood that any group or embodiment described herein for any of ring A, R_A, m, Ar, R_Ar, X, L₁, L₂, T, R_N, R_O, R_T, R_C1, R_C2, R_t, R_a1, R_a2, R_a3, and R_a4 can be combined with one or more groups or embodiments described herein for one or more of the remainder of ring A, R_A, m, Ar, R_Ar, X, L₁, L₂, T, R_N, R_O, R_T, R_C1, R_C2, R_t, R_a1, R_a2, R_a3, and R_a4. Embodiments of the Disclosure Embodiment 1. A compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof, as described above. Embodiment 2. The compound of Embodiment 1, wherein ring A is C₆-C₁₀ aryl. Embodiment 3. The compound of Embodiment 1 or 2, wherein ring A is phenyl. Embodiment 4. The compound of Embodiment 1, wherein ring A is heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S. Embodiment 5. The compound of any of previous Embodiments to the extent applicable, wherein ring A is heteroaryl comprising one 5- or 6-membered ring and 1-4 heteroatoms selected from N, O, and S. Embodiment 6. The compound of any of previous Embodiments to the extent applicable, wherein ring A is heteroaryl comprising one 5- or 6-membered ring and 1-2 heteroatoms selected from N, O, and S. Embodiment 6a. The compound of any of previous Embodiments to the extent applicable, wherein ring A is heteroaryl comprising one 5-membered ring and 1-2 heteroatoms selected from N, O, and S. Embodiment 6b. The compound of any of previous Embodiments to the extent applicable, wherein ring A is heteroaryl comprising one 6-membered ring and 1-2 heteroatoms selected from N, O, and S. Embodiment 7. The compound of any of previous Embodiments to the extent applicable, wherein ring A is heteroaryl comprising one 5- or 6-membered ring and 1-2 nitrogen atoms. Embodiment 8. The compound of any of previous Embodiments to the extent applicable, wherein ring A is heteroaryl comprising one 6-membered ring and 1-2 nitrogen atoms. Embodiment 8’. The compound of any of previous Embodiments to the extent applicable, wherein ring A is heteroaryl comprising one 5-membered ring and 1-2 nitrogen atoms. Embodiment 9. The compound of Embodiment 1, of Formula II:

or a pharmaceutically acceptable salt or solvate thereof, wherein A₁, A₂, A₃, A₄, and A₅ are each independently N, CH, or CR_A, or when A₁, A₂, A₃, A₄, or A₅ is bonded to Ar, C. Embodiment 10. The compound of Embodiment 9, wherein A₁ is bonded with Ar. Embodiment 11. The compound of Embodiment 9, wherein A₂ is bonded with Ar. Embodiment 12. The compound of Embodiment 9, wherein A₃ is bonded with Ar. Embodiment 13. The compound of Embodiment 9, wherein A₄ is bonded with Ar. Embodiment 14. The compound of Embodiment 9, wherein A₅ is bonded with Ar. Embodiment 15. The compound of any of previous Embodiments to the extent applicable, of Formula IIa:

or a pharmaceutically acceptable salt or solvate thereof, wherein A₂, A₃, A₄, and A₅ are each independently N, CH, or CR_A. Embodiment 16. The compound of any of previous Embodiments to the extent applicable, wherein Ar is C₆-C₁₀ aryl optionally substituted with 1-4 R_Ar. Embodiment 17. The compound of any of previous Embodiments to the extent applicable, wherein Ar is phenyl optionally substituted with 1-4 R_Ar. Embodiment 18. The compound of any of previous Embodiments to the extent applicable, wherein Ar is heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted with 1-4 R_Ar. Embodiment 19. The compound of any of previous Embodiments to the extent applicable, wherein Ar is heteroaryl comprising one 5- or 6-membered ring and 1-4 heteroatoms selected from N, O, and S, optionally substituted with 1-4 R_Ar. Embodiment 19’. The compound of any of previous Embodiments to the extent applicable, wherein Ar is heteroaryl comprising two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted with 1-4 R_Ar. Embodiment 20. The compound of any of previous Embodiments to the extent applicable, wherein Ar is heteroaryl comprising one 5- or 6-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with 1-4 R_Ar. Embodiment 21. The compound of any of previous Embodiments to the extent applicable, wherein Ar is heteroaryl comprising one 5- or 6-membered ring and 1-2 nitrogen atoms, optionally substituted with 1-4 R_Ar. Embodiment 21a. The compound of any of previous Embodiments to the extent applicable, wherein Ar is heteroaryl comprising one 5-membered ring and 1-2 nitrogen atoms, optionally substituted with 1-4 R_Ar. Embodiment 21b. The compound of any of previous Embodiments to the extent applicable, wherein Ar is heteroaryl comprising one 6-membered ring and 1-2 nitrogen atoms, optionally substituted with 1-4 R_Ar. Embodiment 22. The compound of any of previous Embodiments to the extent applicable, of Formula III:

or a pharmaceutically acceptable salt or solvate thereof, wherein: A₂, A₃, A₄, and A₅ are each independently N, CH, or CR_A; and A₆, A₇, A₈, A₉, and A₁₀ are each independently N, CH, or CR_Ar. Embodiment 23. The compound of any of previous Embodiments to the extent applicable, of Formula IIIa or IIIb:

or a pharmaceutically acceptable salt or solvate thereof, wherein A₂, A₃, A₄, and A₅ are each independently N, CH, or CR_A. Embodiment 24. The compound of any of previous Embodiments to the extent applicable, of Formula IV:

or a pharmaceutically acceptable salt or solvate thereof, wherein: A₂, A₃, A₄, and A₅ are each independently N, CH, or CR_A; and A₈, A₉, A₁₀, A₁₁, A₁₂, A₁₃, and A₁₄ are each independently N, CH, or CR_Ar. Embodiment 25. The compound of any of previous Embodiments to the extent applicable, of Formula IVa, IVb, or IVc:

or a pharmaceutically acceptable salt or solvate thereof, wherein: A₂, A₃, A₄, and A₅ are each independently N, CH, or CR_A; and A₈, A₉, and A₁₀ are each independently N, CH, or CR_Ar. Embodiment 26. The compound of any of previous Embodiments to the extent applicable, wherein one of A₁, A₂, A₃, A₄, and A₅ is N. Embodiment 27. The compound of any of previous Embodiments to the extent applicable, wherein A₁ is N. Embodiment 28. The compound of any of previous Embodiments to the extent applicable, wherein A₂ is N. Embodiment 29. The compound of any of previous Embodiments to the extent applicable, wherein A₃ is N. Embodiment 30. The compound of any of previous Embodiments to the extent applicable, wherein A₄ is N. Embodiment 31. The compound of any of previous Embodiments to the extent applicable, wherein A₅ is N. Embodiment 32. The compound of any of previous Embodiments to the extent applicable, wherein two of A₁, A₂, A₃, A₄, and A₅ are N. Embodiment 33. The compound of any of previous Embodiments to the extent applicable, wherein A₁ and A₂ are N. Embodiment 34. The compound of any of previous Embodiments to the extent applicable, wherein A₁ and A₃ are N. Embodiment 35. The compound of any of previous Embodiments to the extent applicable, wherein A₁ and A₄ are N. Embodiment 36. The compound of any of previous Embodiments to the extent applicable, wherein A1 and A₅ are N. Embodiment 37. The compound of any of previous Embodiments to the extent applicable, wherein A₂ and A₃ are N. Embodiment 38. The compound of any of previous Embodiments to the extent applicable, wherein A₂ and A₄ are N. Embodiment 39. The compound of any of previous Embodiments to the extent applicable, wherein A₂ and A₅ are N. Embodiment 40. The compound of any of previous Embodiments to the extent applicable, wherein A₃ and A₄ are N. Embodiment 41. The compound of any of previous Embodiments to the extent applicable, wherein A₃ and A₅ are N. Embodiment 42. The compound of any of previous Embodiments to the extent applicable, wherein A₄ and A₅ are N. Embodiment 43. The compound of any of previous Embodiments to the extent applicable, wherein three of A₁, A₂, A₃, A₄, and A₅ are N. Embodiment 44. The compound of any of previous Embodiments to the extent applicable, wherein four of A₁, A₂, A₃, A₄, and A₅ are N. Embodiment 45. The compound of any of previous Embodiments to the extent applicable, wherein one of A₆, A₇, A₈, A₉, A₁₀, A₁₁, A₁₂, A₁₃, and A₁₄ is N. Embodiment 46. The compound of any of previous Embodiments to the extent applicable, wherein two of A₆, A₇, A₈, A₉, A₁₀, A₁₁, A₁₂, A₁₃, and A₁₄ are N. Embodiment 47. The compound of any of previous Embodiments to the extent applicable, wherein three of A₆, A₇, A₈, A₉, A₁₀, A₁₁, A₁₂, A₁₃, and A₁₄ are N. Embodiment 48. The compound of any of previous Embodiments to the extent applicable, wherein L₁ is absent, and L₂ is absent. Embodiment 49. The compound of any of previous Embodiments to the extent applicable, wherein L₁ is absent, and L₂ is C₁-C₆ alkylenyl, C₂-C₆ alkenylenyl, or C₂-C₆ alkynylenyl. Embodiment 50. The compound of any of previous Embodiments to the extent applicable, wherein L₁ is -O-, and L₂ is absent. Embodiment 51. The compound of any of previous Embodiments to the extent applicable, wherein L₁ is -O-, and L₂ is C₁-C₆ alkylenyl, C₂-C₆ alkenylenyl, or C₂-C₆ alkynylenyl. Embodiment 52. The compound of any of previous Embodiments to the extent applicable, wherein L₁ is -N(R_N)-, and L₂ is absent. Embodiment 53. The compound of any of previous Embodiments to the extent applicable, wherein L₁ is -N(R_N)-, and L₂ is C₁-C₆ alkylenyl, C₂-C₆ alkenylenyl, or C₂-C₆ alkynylenyl. Embodiment 54. The compound of any of previous Embodiments to the extent applicable, wherein L₁ is -S-, and L₂ is absent. Embodiment 55. The compound of any of previous Embodiments to the extent applicable, wherein L₁ is -S-, and L₂ is C₁-C₆ alkylenyl, C₂-C₆ alkenylenyl, or C₂-C₆ alkynylenyl. Embodiment 56. The compound of any of previous Embodiments to the extent applicable, wherein L₁ is -S(=O)₂-, and L₂ is absent. Embodiment 57. The compound of any of previous Embodiments to the extent applicable, wherein L₁ is -S(=O)₂-, and L₂ is C₁-C₆ alkylenyl, C₂-C₆ alkenylenyl, or C₂-C₆ alkynylenyl. Embodiment 58. The compound of any of previous Embodiments to the extent applicable, wherein L₁ is -N(S(=O)₂R_N)-, and L₂ is absent. Embodiment 59. The compound of any of previous Embodiments to the extent applicable, wherein L₁ is -N(S(=O)₂R_N)-, and L₂ is C₁-C₆ alkylenyl, C₂-C₆ alkenylenyl, or C₂- C₆ alkynylenyl. Embodiment 60. The compound of any of previous Embodiments to the extent applicable, wherein L₂ is C₁-C₆ alkylenyl. Embodiment 61. The compound of any of previous Embodiments to the extent applicable, wherein R_N is H. Embodiment 62. The compound of any of previous Embodiments to the extent applicable, wherein R_N is C₁-C₆ alkyl. Embodiment 63. The compound of any of previous Embodiments to the extent applicable, wherein T is C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ hydroxyalkyl. Embodiment 64. The compound of any of previous Embodiments to the extent applicable, wherein T is -C(X)R_a1, -C(X)OR_a1, or -C(X)NR_a3R_a4. Embodiment 65. The compound of any of previous Embodiments to the extent applicable, wherein T is R_T, or -XR_T. Embodiment 65a. The compound of any of previous Embodiments to the extent applicable, wherein T is R_T. Embodiment 65b. The compound of any of previous Embodiments to the extent applicable, wherein T is -XR_T. Embodiment 66. The compound of any of previous Embodiments to the extent applicable, wherein R_T is C₃-C₈ cycloalkyl, optionally substituted with one or more R_t. Embodiment 66a. The compound of any of previous Embodiments to the extent applicable, wherein R_T is C₃-C₈ cycloalkyl comprising a non-bridged and non-spiro ring, optionally substituted with one or more R_t. Embodiment 66b. The compound of any of previous Embodiments to the extent applicable, wherein R_T is C₃-C₈ cycloalkyl comprising a bridged ring, optionally substituted with one or more R_t. Embodiment 66c. The compound of any of previous Embodiments to the extent applicable, wherein R_T is C₃-C₈ cycloalkyl comprising a spiro ring, optionally substituted with one or more R_t. Embodiment 67. The compound of any of previous Embodiments to the extent applicable, wherein R_T is heterocyclyl comprising one 3- to 6-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more R_t. Embodiment 67a. The compound of any of previous Embodiments to the extent applicable, wherein R_T is heterocyclyl comprising one 3- to 6-membered ring and 1-2 heteroatoms selected from N, O, and S and comprising a non-bridged and non-spiro ring, optionally substituted with one or more R_t. Embodiment 67b. The compound of any of previous Embodiments to the extent applicable, wherein R_T is heterocyclyl comprising one 3- to 6-membered ring and 1-2 heteroatoms selected from N, O, and S and comprising a bridged ring, optionally substituted with one or more R_t. Embodiment 67c. The compound of any of previous Embodiments to the extent applicable, wherein R_T is heterocyclyl comprising one 3- to 6-membered ring and 1-2 heteroatoms selected from N, O, and S and comprising a spiro ring, optionally substituted with one or more R_t. Embodiment 68. The compound of any of previous Embodiments to the extent applicable, wherein R_T is C₆ aryl, optionally substituted with one or more R_t. Embodiment 69. The compound of any of previous Embodiments to the extent applicable, wherein R_T is heteroaryl comprising one 5- or 6-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more R_t. Embodiment 69a. The compound of any of previous Embodiments to the extent applicable, wherein R_T is heteroaryl comprising one 5-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more R_t. Embodiment 69b. The compound of any of previous Embodiments to the extent applicable, wherein R_T is heteroaryl comprising one 5-membered ring and 1-2 heteroatoms selected from N and O, optionally substituted with one or more R_t. Embodiment 69c. The compound of any of previous Embodiments to the extent applicable, wherein R_T is heteroaryl comprising one 6-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more R_t. Embodiment 69d. The compound of any of previous Embodiments to the extent applicable, wherein R_T is heteroaryl comprising one 6-membered ring and 1-2 heteroatoms selected from N and O, optionally substituted with one or more R_t. Embodiment 70. The compound of any of previous Embodiments to the extent applicable, wherein at least one R_A is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁- C₆ alkoxy, or C₁-C₆ haloalkoxy. Embodiment 71. The compound of any of previous Embodiments to the extent applicable, wherein at least one R_A is -OH, -NR_a3R_a4, -CN, halogen, or oxo. Embodiment 72. The compound of any of previous Embodiments to the extent applicable, wherein at least one R_A is -C(X)R_a1, -C(X)OR_a1, -C(X)NR_a3R_a4, -NR_a2C(X)R_a1, - NR_a2C(X)OR_a1, or -NR_a2C(X)NR_a3R_a4. Embodiment 73. The compound of any of previous Embodiments to the extent applicable, wherein at least one R_Ar is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁- C₆ alkoxy, or C₁-C₆ haloalkoxy. Embodiment 74. The compound of any of previous Embodiments to the extent applicable, wherein at least one R_Ar is -OH, -NR_a3R_a4, -CN, halogen, or oxo. Embodiment 75. The compound of any of previous Embodiments to the extent applicable, wherein at least one R_Ar is -C(X)R_a1, -C(X)OR_a1, -C(X)NR_a3R_a4, -NR_a2C(X)R_a1, - NR_a2C(X)OR_a1, or -NR_a2C(X)NR_a3R_a4. Embodiment 76. The compound of any of previous Embodiments to the extent applicable, wherein R_C1 and R_C2 are each H. Embodiment 77. The compound of any of previous Embodiments to the extent applicable, wherein R_C1 and R_C2 are each -CH₃. Embodiment 78. The compound of any of previous Embodiments to the extent applicable, wherein one of R_C1 and R_C2 is H, and the other is -CH₃. Embodiment 79. The compound of any of previous Embodiments to the extent applicable, wherein R_O is -OH, -NH₂, or -NR_a2(C₁-C₆ alkyl). Embodiment 80. The compound of any of previous Embodiments to the extent applicable, wherein R_O is C₃-C₈ cycloalkyl, optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, and oxo. Embodiment 81. The compound of any of previous Embodiments to the extent applicable, wherein R_O is heterocyclyl comprising one 3- to 6-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, and oxo. Embodiment 82. The compound of any of previous Embodiments to the extent applicable, wherein R_O is C₆ aryl, optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, and oxo. Embodiment 83. The compound of any of previous Embodiments to the extent applicable, wherein R_O is heteroaryl comprising one 5- or 6-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, and oxo. Embodiment 84. The compound of any of previous Embodiments to the extent applicable, wherein at least one R_t is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. Embodiment 85. The compound of any of previous Embodiments to the extent applicable, wherein at least one R_t is -OH, -NR_a3R_a4, -CN, halogen, or oxo. Embodiment 86. The compound of any of previous Embodiments to the extent applicable, wherein at least one R_t is -C(X)R_a1, -C(X)OR_a1, -C(X)NR_a3R_a4, -NR_a2C(X)R_a1, - NR_a2C(X)OR_a1, or -NR_a2C(X)NR_a3R_a4. Embodiment 87. The compound of any of previous Embodiments to the extent applicable, wherein at least one R_t is C₃-C₈ cycloalkyl, heterocyclyl comprising one 3- to 6- membered ring and 1-2 heteroatoms selected from N, O, and S, C₆ aryl, or heteroaryl comprising one 5- or 6-membered ring and 1-2 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, and oxo. Embodiment 87a. The compound of any of previous Embodiments to the extent applicable, wherein at least one R_t is C₃-C₈ cycloalkyl, optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, and oxo. Embodiment 87a1. The compound of any of previous Embodiments to the extent applicable, wherein at least one R_t is C₃-C₈ cycloalkyl comprising a non-bridged and non- spiro ring, optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, - NR_a2(C₁-C₆ alkyl), -CN, halogen, and oxo. Embodiment 87a2. The compound of any of previous Embodiments to the extent applicable, wherein at least one R_t is C₃-C₈ cycloalkyl comprising a bridged ring, optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, and oxo. Embodiment 87a3. The compound of any of previous Embodiments to the extent applicable, wherein at least one R_t is C₃-C₈ cycloalkyl comprising a spiro ring, optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, and oxo. Embodiment 87b. The compound of any of previous Embodiments to the extent applicable, wherein at least one R_t is heterocyclyl comprising one 3- to 6-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, and oxo. Embodiment 87b1. The compound of any of previous Embodiments to the extent applicable, wherein at least one R_t is heterocyclyl comprising one 3- to 6-membered ring and 1-2 heteroatoms selected from N, O, and S and comprising a non-bridged and non-spiro ring, optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁- C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, and oxo. Embodiment 87b2. The compound of any of previous Embodiments to the extent applicable, wherein at least one R_t is heterocyclyl comprising one 3- to 6-membered ring and 1-2 heteroatoms selected from N, O, and S and comprising a bridged ring, optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, and oxo. Embodiment 87b3. The compound of any of previous Embodiments to the extent applicable, wherein at least one R_t is heterocyclyl comprising one 3- to 6-membered ring and 1-2 heteroatoms selected from N, O, and S and comprising a spiro ring, optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, and oxo. Embodiment 87c. The compound of any of previous Embodiments to the extent applicable, wherein at least one R_t is C₆ aryl, optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, and oxo. Embodiment 87d. The compound of any of previous Embodiments to the extent applicable, wherein at least one R_t is heteroaryl comprising one 5- or 6-membered ring and 1- 2 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, and oxo. Embodiment 88. The compound of any of previous Embodiments to the extent applicable, wherein R_a1 is H. Embodiment 89. The compound of any of previous Embodiments to the extent applicable, wherein R_a1 is C₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s- butyl, t-butyl, pentyl, or hexyl), or C₁-C₆ haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n- butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, substituted with one or more halogen (e.g., F, Cl, Br, or I). Embodiment 90. The compound of any of previous Embodiments to the extent applicable, wherein R_a1 is C₁-C₆ alkyl-C₆-C₁₀ aryl, or C₁-C₆ alkyl-heteroaryl wherein the heteroaryl comprises a 5- or 6-membered ring and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, - OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, oxo, -C(X)R_a1, -C(X)OR_a1, -C(X)NR_a1R_a2, - NR_a2C(X)R_a1, -NR_a2C(X)OR_a1, and -NR_a2C(X)NR_a1R_a2. Embodiment 90a. The compound of any of previous Embodiments to the extent applicable, wherein R_a1 is C₁-C₆ alkyl-C₆-C₁₀ aryl, wherein the aryl is optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, oxo, -C(X)R_a1, - C(X)OR_a1, -C(X)NR_a1R_a2, -NR_a2C(X)R_a1, -NR_a2C(X)OR_a1, and -NR_a2C(X)NR_a1R_a2. Embodiment 90b. The compound of any of previous Embodiments to the extent applicable, wherein R_a1 is C₁-C₆ alkyl-heteroaryl wherein the heteroaryl comprises a 5- or 6- membered ring and 1-4 heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁- C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, oxo, -C(X)R_a1, -C(X)OR_a1, -C(X)NR_a1R_a2, -NR_a2C(X)R_a1, -NR_a2C(X)OR_a1, and - NR_a2C(X)NR_a1R_a2. Embodiment 91. The compound of any of previous Embodiments to the extent applicable, wherein R_a2 is H. Embodiment 92. The compound of any of previous Embodiments to the extent applicable, wherein at least one R_a2 is C₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl, n- butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl). Embodiment 93. The compound of any of previous Embodiments to the extent applicable, wherein R_a3 and R_a4 are each H. Embodiment 94. The compound of any of previous Embodiments to the extent applicable, wherein at least one of R_a3 and R_a4 is C₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i- propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), C₁-C₆ hydroxyalkyl, or C₁-C₆ haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, substituted with one or more halogen (e.g., F, Cl, Br, or I). Embodiment 95. The compound of any of previous Embodiments to the extent applicable, wherein at least one of R_a3 and R_a4 is C₃-C₈ cycloalkyl, heterocyclyl comprising one 3- to 6-membered ring and 1-2 heteroatoms selected from N, O, and S, C₆ aryl, or heteroaryl comprising one 5- or 6-membered ring and 1-2 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, and oxo. Embodiment 95a. The compound of any of previous Embodiments to the extent applicable, wherein at least one of R_a3 and R_a4 is C₃-C₈ cycloalkyl, optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NRa2(C₁-C₆ alkyl), -CN, halogen, and oxo. Embodiment 95b. The compound of any of previous Embodiments to the extent applicable, wherein at least one of R_a3 and R_a4 is heterocyclyl comprising one 3- to 6- membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, and oxo. Embodiment 95c. The compound of any of previous Embodiments to the extent applicable, wherein at least one of R_a3 and R_a4 is C₆ aryl, optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, and oxo. Embodiment 95d. The compound of any of previous Embodiments to the extent applicable, wherein at least one of R_a3 and R_a4 is heteroaryl comprising one 5- or 6-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, and oxo. Embodiment 96. The compound of any of previous Embodiments to the extent applicable, wherein R_a3 and R_a4, together with the nitrogen atom to which they are bonded, form a 5- or 6-membered heterocyclyl ring optionally comprising 1-2 additional heteroatoms selected from N, O, and S and optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, and halogen. Embodiment 96a. The compound of any of previous Embodiments to the extent applicable, wherein R_a3 and R_a4, together with the nitrogen atom to which they are bonded, form a 5-membered heterocyclyl ring optionally comprising 1-2 additional heteroatoms selected from N, O, and S and optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, and halogen. Embodiment 96b. The compound of any of previous Embodiments to the extent applicable, wherein R_a3 and R_a4, together with the nitrogen atom to which they are bonded, form a 6-membered heterocyclyl ring optionally comprising 1-2 additional heteroatoms selected from N, O, and S and optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, and halogen. Embodiment 97. The compound of any of previous Embodiments to the extent applicable, wherein X is O. Embodiment 98. The compound of any of previous Embodiments to the extent applicable, wherein X is S. Embodiment 99. The compound of any of previous Embodiments to the extent applicable, wherein X is NR_N. Embodiment 100. The compound of any of previous Embodiments to the extent applicable, wherein R_N is H. Embodiment 101. The compound of any of previous Embodiments to the extent applicable, wherein R_N is C₁-C₆ alkyl. Embodiment 102. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C₁-C₆ alkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl. Embodiment 102a. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C₁-C₆ alkyl is methyl, ethyl, or propyl, or i-propyl. Embodiment 103. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C₁-C₆ haloalkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, substituted with one or more halogen (e.g., F, Cl, Br, or I). Embodiment 103a. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C₁-C₆ haloalkyl is methyl, ethyl, propyl, or i-propyl, substituted with one or more halogen (e.g., F, Cl, Br, or I). Embodiment 104. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C₁-C₆ alkoxy is methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexoxy. Embodiment 104a. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C₁-C₆ alkoxy is methoxy, ethoxy, propoxy, or i-propoxy. Embodiment 105. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C₁-C₆ haloalkoxy is methoxy, ethoxy, propoxy, or i-propoxy, n-butoxy, i-butoxy, s-butoxy, t- butoxy, pentoxy, or hexoxy, substituted with one or more halogen (e.g., F, Cl, Br, or I). Embodiment 105a. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C₁-C₆ haloalkoxy is methoxy, ethoxy, propoxy, or i-propoxy, substituted with one or more halogen (e.g., F, Cl, Br, or I). Embodiment 106. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, halogen is F, Cl, Br, or I. Embodiment 106a. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, halogen is F. Embodiment 106b. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, halogen is Cl. Embodiment 107. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C₃-C₈ cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. Embodiment 108. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C₃-C₈ cycloalkyl comprises a non-bridged and non-spiro ring system, a bridged ring system, or a spiro ring system. Embodiment 108a. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C₃-C₈ cycloalkyl comprises a non-bridged and non-spiro ring system. Embodiment 108b. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C₃-C₈ cycloalkyl comprises a bridged ring system. Embodiment 108c. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C₃-C₈ cycloalkyl comprises a spiro ring system. Embodiment 109. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, heterocyclyl comprises a non-bridged and non-spiro ring system, a bridged ring system, or a spiro ring system. Embodiment 109a. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, heterocyclyl comprises a non-bridged and non-spiro ring system. Embodiment 109b. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, heterocyclyl comprises a bridged ring system.

Embodiment 109c. The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, heterocyclyl comprises a spiro ring system.

In some embodiments, non-limiting illustrative compounds of the present disclosure are listed in Table 1.

Table 1: Compounds of the Present Disclosure

In some embodiments, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a pharmaceutically acceptable salt. In some embodiments, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a solvate. In some embodiments, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a hydrate.

The compounds of the present disclosure may form salts which are also within the scope of this disclosure. Reference to a compound of the formulae herein is understood to include reference to salts thereof, unless otherwise indicated.

Representative "pharmaceutically acceptable salts" include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumerate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3- naphthoate, einbonate), pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

“Solvate” means solvent addition forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds or salts have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H₂O.

Compounds having one or more chiral centers can exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric, enantiomeric, and epimeric forms as well as racemates and mixtures thereof.

The term “geometric isomer” refers to cyclic compounds having at least two substituents, wherein the two substituents are both on the same side of the ring (cis) or wherein the substituents are each on opposite sides of the ring (trans). When a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or the structure encompasses one or more of the possible stereoisomers, or geometric isomers, or a mixture of the encompassed stereoisomers or geometric isomers. When a geometric isomer is depicted by name or structure, it is to be understood that the named or depicted isomer exists to a greater degree than another isomer, that is that the geometric isomeric purity of the named or depicted geometric isomer is greater than 50%, such as at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Geometric isomeric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all of the geometric isomers in the mixture. “Chiral isomer” means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture”. When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

In some embodiments, the compounds of the disclosure are diastereomers. In some embodiments, the compounds are the syn diastereomer. In some embodiments, the compounds are the anti diastereomer.

Racemic mixture means 50% of one enantiomer and 50% of is corresponding enantiomer. When a compound with one chiral center is named or depicted without indicating the stereochemistry of the chiral center, it is understood that the name or structure encompasses both possible enantiomeric forms (e.g., both enantiomerically-pure, enantiomerically-enriched or racemic) of the compound. When a compound with two or more chiral centers is named or depicted without indicating the stereochemistry of the chiral centers, it is understood that the name or structure encompasses all possible diastereomeric forms (e.g., diastereomerically pure, diastereomerically enriched and equimolar mixtures of one or more diastereomers (e.g., racemic mixtures) of the compound.

Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers also can be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

When a compound is designated by a name or structure that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as “enantiomerically pure”). Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers. When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers. It is also possible that the compounds of the disclosure may exist in different tautomeric forms, and all such forms are embraced within the scope of the disclosure. “Tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solid form, usually one tautomer predominates. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertable by tautomerizations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose. Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam- lactim, amide-imidic acid tautomerism in heterocyclic rings (e.g., in nucleobases such as guanine, thymine and cytosine), amine-enamine and enamine-imine. The disclosure also comprehends isotopically-labeled compounds, which are identical to those recited in the each of the formulae described herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, fluorine, such as ³H, ¹¹C, ¹⁴C, ²H and ¹⁸F. Compounds of the disclosure that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present disclosure. Isotopically-labeled compounds of the present disclosure, for example those into which radioactive isotopes such as ³H, ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are useful for their ease of preparation and detectability.¹¹C and ¹⁸F isotopes are useful in PET (positron emission tomography). PET is useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the disclosure, can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. In some embodiments, the compounds of the disclosure are not isotopically labelled. Methods for Preparing the Compounds The compounds of the present disclosure may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below. The compounds may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the scheme described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of the compounds of the present disclosure. Those skilled in the art will recognize if a stereocenter exists in the compounds of the present disclosure. Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compound but the individual enantiomers and/or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes. The compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, the compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. The compounds of the present disclosure (i.e., a compound of Formula I) can be synthesized by following the steps outlined in General Schemes and/or General Methods below, such as in the Examples. It is understood that the experimental conditions and starting materials and/or intermediates illustrated in the General Methods in the Examples may be adjusted according to techniques and knowledge available in the art. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated.

General methods for synthesis are identified below for reference.

The ability of compounds of the disclosure to inhibit Polq can be measured as described in Example 56 below, or according to methods known in the art. Definitions The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. The term "and/or" is used in this disclosure to mean either "and" or "or" unless indicated otherwise. The term "alkyl" as used herein, refers to saturated, straight or branched-chain hydrocarbon radicals containing, In some embodiments, between one and six carbon atoms. Examples of C₁-C₈ alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, n-heptyl, and n-octyl radicals. Examples of C₁-C₆ alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, and n-hexyl radicals. The term “alkylsulfonyl” means a -SO₂R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, 2-propylsulfonyl, and the like. The term “alkoxy” means an alkyl radical attached through an oxygen linking atom, represented by –O-alkyl. For example, “(C₁-C₄) alkoxy” includes methoxy, ethoxy, propoxy, and butoxy. The term “alkoxycarbonyl” means a -COOR radical where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, propoxy, or 2-propoxycarbonyl, or tertbutoxycarbonyl, and the like. The term “alkoxyalkyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one alkoxy group, as defined above, e.g., 2-methoxyethyl, 1-, 2-, or 3- methoxypropyl, 2-ethoxyethyl, and the like. The term “acyl” means a -C(O)R radical where R is alkyl as defined herein, e.g., methylcarbonyl, ethylcarbonyl, and the like. The term “acylamino” means a -NHC(O)R radical where R is alkyl as defined herein, e.g., methylcarbonylamino, ethylcarbonylamino, and the like. The term “amino” means a -NH₂. The terms “haloalkyl” and “haloalkoxy” mean alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term “alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated e.g., methylene, ethylene, propylene, 1-methylpropylene, 2- methylpropylene, butylene, pentylene, and the like. An “alkylene group” is a saturated aliphatic branched or straight-chain divalent hydrocarbon radical. Unless otherwise specified, an alkylene group typically has 1-6 carbon atoms, e.g., (C₁-C₆) alkylene. The term “aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl or naphthyl. The term “Bicyclic heterocyclyl” means a saturated monocyclic ring having 4 to 7 ring carbon ring atoms wherein one or two ring carbon atoms is(are) replaced by a heteroatom selected from N, O, or S(O) n, (where n is an integer from 0 to 2) that is fused to phenyl, five or six-membered heteroaryl or heterocyclyl, each as defined herein. Exemplary bicyclic heterocyclyl groups include, but are not limited to,

and the like. The term “cycloalkyl” means a monocyclic saturated hydrocarbon ring system. For example, C₃-C₇ cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, cycloheptyl. A bridged cycloalkyl means a bicyclic hydrocarbon ring system in which the two rings share at least three adjacent ring carbon atoms. For example, a bridged cycloalkyl has 6- 12 ring carbon atoms. Examples include, but are not limited to, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[4.3.1]decyl, bicyclo[3.3.1]nonyl, bornyl, bornenyl, norbornyl, norbornenyl, 6,6-dimethylbicyclo [3.1.1]heptyl, and adamantyl. The terms “heterocyclyl”, “heterocyclic ring”, and “heterocyclic group”, are used interchangeably herein, and means saturated or unsaturated non-aromatic 4-10 membered ring radical containing from 1 to 4 ring heteroatoms, which may be the same or different, selected from N, O, or S. It can be monocyclic, bicyclic or tricyclic (e.g., a fused or bridged bicyclic or tricyclic ring). Examples of include, but are not limited to, azetidinyl, morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dihydroimidazole, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, dihydropyrimidinyl, dihydrothienyl, dihydrothiophenyl, dihydrothiopyranyl, tetrahydroimidazole, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl. A heterocyclic ring optionally contains one or more double bonds and/or is optionally fused with one or more aromatic rings (for example, tetrahydronaphthyridine, indolinone, dihydropyrrolotriazole, imidazopyrimidine, quinolinone, dioxaspirodecane). Examples of 3-7 membered monocyclic heterocyclic ring include, but are not limited to, azetidinyl, morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dihydroimidazole, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, dihydropyrimidinyl, dihydrothienyl, dihydrothiophenyl, dihydrothiopyranyl, tetrahydroimidazole, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl. The term “bridged heterocyclyl” means a saturated monocyclic ring having 5 to 7 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CRR’)n group where n is 1 to 3 and each R and R’ is independently H or methyl (also may be referred to herein as “bridging” group) and further wherein one or two ring carbon atoms, including an atom in the bridging group, is replaced by a heteroatom selected from N, O, or S(O)n, where n is an integer from 0 to 2. Bridged heterocyclyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, or cyano. Examples include, but are not limited to, 2-azabicyclo[2.2.2]octane, quinuclidine, 7-oxabicyclo[2.2.1]heptane, and the like. A bridged heterocyclyl means a bicyclic ring system containing from 1 to 4 ring heteroatoms in which the two rings share at least three adjacent ring atoms. For example, a bridged heterocyclyl has 6-12 ring atoms. Examples include, but are not limited to, azanorbornyl, quinuclidinyl, isoquinuclidinyl, tropanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.2.1]heptany1, 2-azabicyclo[3.2.1]octanyl, azabicyclo[3.2.1]octanyl, azabicyclo[3.2.2]nonanyl, azabicyclo[3.3.0]nonanyl, and azabicyclo [3.3.1]nonanyl. The term “deuteroalkyl” means an alkyl radical as defined above wherein one to six hydrogen atoms in the alkyl radical are replaced by deuterium, e.g., -CD₃, -CH₂CD₃, and the like. The term “dialkylamino” means -NRR’ radical where R and R’ are independently alkyl as defined herein. The term “halo” means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro. The term “oxo,” as used herein, alone or in combination, refers to =(O). The terms “heteroaryl”, “heteroaromatic”, “heteroaryl ring”, “heteroaryl group”, “heteroaromatic ring”, and “heteroaromatic group”, are used interchangeably herein. “Heteroaryl”, when used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy”, refers to aromatic ring groups having five to ten ring atoms selected from carbon and at least one (typically 1 to 4, more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen, or sulfur). “Heteroaryl” includes monocyclic rings and polycyclic rings in which a monocyclic heteroaromatic ring is fused to one or more other aromatic or heteroaromatic rings. “Heteroaryl” includes monocyclic and bicyclic ring systems. “Monocyclic 5-6 membered heteroaromatic ring (or heteroaryl)” means a monocyclic heteroaromatic ring having five or six ring atoms selected from carbon and at least one (typically 1 to 3, more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen, or sulfur). Examples of monocyclic 5-6 membered heteroaromatic ring groups include furanyl (e.g., 2- furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5- oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3- pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl, triazolyl (e.g., 2-triazolyl, 5-triazolyl), tetrazolyl (e.g., tetrazolyl), and thienyl (e.g., 2-thienyl, 3-thienyl). If a group is described as being “substituted,” a non-hydrogen substituent replaces a hydrogen atom on a carbon or nitrogen. Thus, for example, a substituted alkyl is an alkyl wherein at least one non-hydrogen substituent is in the place of a hydrogen atom on the alkyl substituent. To illustrate, monofluoroalkyl is alkyl substituted with a fluoro substituent, and difluoroalkyl is alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen substituent can be identical or different (unless otherwise stated). As used herein, many moieties (e.g., alkyl, cycloalkyl, or a heterocyclic ring) are referred to as being either “substituted” or “optionally substituted”. It will be appreciated that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." When a moiety is modified by one of these terms, unless otherwise noted, it denotes that any portion of the moiety that is known to one skilled in the art as being available for substitution can be substituted, which includes one or more substituents. If more than one substituent is present, then each substituent is independently selected. Such means for substitution are well-known in the art and/or taught by the instant disclosure. The optional substituents can be any substituents that are suitable to attach to the moiety. A person of ordinary skill in the art will recognize that the compounds and definitions provided do not include impermissible substituent patterns (e.g., methyl substituted with 5 different groups, and the like). Such impermissible substitution patterns are clearly recognized by a person of ordinary skill in the art. When a group is described as being optionally substituted by “one or more” substituents, it denotes that the group is optionally substituted by one, two, three, four, five or six substituents. In some embodiments, a group is optionally substituted by 1-3 substituents. In some embodiments, a group is optionally substituted by 1-2 substituents. In some embodiments, a group is optionally substituted by one substituent. Suitable substituents are those which do not have a significant adverse effect on the ability of the compound. Where suitable substituents are not specifically enumerated, exemplary substituents include, but are not limited to, halo, CN, alkyl, alkoxy, halomethyl, halomethoxy, (C₁-C₅)alkyl, halo(C₁-C₅)alkyl, (C₁-C₅)alkoxy, NO₂, OR^c’, NR^a’R^b’, S(O)_iR^a’, NR^aS(O)_iR^b’, S(O)_iNR^a’R^b’, C(=O)OR^a’, OC(=O)OR^a’, C(=S)OR^a’, O(C=S)R^a’, C(=O)NR^a’R^b’, NR^a’C(=O)R^b’, C(=S)NR^a’R^b’, NR^a’C(=S)R^b’, NR^a’(C=O)OR^b’, O(C=O)NR^a’R^b’, NR^a’(C=S)OR^b’, O(C=S)NR^a’R^b’, NR^a’(C=O)NR^a’R^b’, NR^a’(C=S)NR^a’R^b’, C(=S)R^a’, C(=O)R^a’, (C₃-C₆) cycloalkyl, monocyclic heteroaryl, and phenyl, wherein the (C₃- C₆) cycloalkyl, monocyclic heteroaryl, and phenyl substituents are optionally and independently substituted, for example, with CH₃, halomethyl, halo, methoxy, or halomethoxy. Each R^a’ and each R^b’ are independently H or (C₁ -C₆) alkyl, wherein the (C₁ -C₆) alkyl group represented by R^a’ or R^b’ is optionally substituted, for example, with hydroxyl or (C₁ -C₃) alkoxy; R^c’ is H, halo(C₁ -C₆) alkyl, or (C₁ -C₆) alkyl, wherein the (C₁ -C₆) alkyl group represented by R^c is optionally substituted, for example with hydroxyl or (C₁-C₃) alkoxy; and i is 0, 1, or 2. =O is also a suitable substituent for alkyl, cycloalkyl, and a heterocyclic ring. Suitable substituents may also include: -F, -Cl, -Br, -I, -OH, protected hydroxy, -NO₂, -CN, -NH₂, protected amino, -NH-C₁-C₁₂-alkyl, -NH-C₂-C₁₂-alkenyl, -NH-C₂-C₁₂-alkenyl, - NH -C₃-C₁₂-cycloalkyl, -NH-aryl, -NH -heteroaryl, -NH -heterocycloalkyl, -dialkylamino, - diarylamino, -diheteroarylamino, -O-C₁-C₁₂-alkyl, -O-C₂-C₁₂-alkenyl, -O-C₂-C₁₂-alkenyl, -O-C3-C₁₂-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(O)-C₁-C₁₂-alkyl, - C(O)- C₂-C₁₂-alkenyl, -C(O)-C₂-C₁₂-alkenyl, -C(O)-C₃-C₁₂-cycloalkyl, -C(O)-aryl, -C(O)- heteroaryl, -C(O)-heterocycloalkyl, -CONH₂, -CONH-C₁-C₁₂-alkyl, -CONH-C₂-C₁₂-alkenyl, -CONH-C₂-C₁₂-alkenyl, -CONH-C₃-C₁₂-cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl,-OCO₂-C₁-C₁₂-alkyl, -OCO₂-C₂-C₁₂-alkenyl, -OCO₂-C₂-C₁₂- alkenyl, -OCO₂-C₃-C₁₂-cycloalkyl, -OCO₂-aryl, -OCO₂-heteroaryl, -OCO₂-heterocycloalkyl, -OCONH₂, -OCONH-C₁-C₁₂-alkyl, -OCONH- C₂-C₁₂-alkenyl, -OCONH- C₂-C₁₂-alkenyl, -OCONH-C₃-C₁₂-cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH- heterocycloalkyl, -NHC(O)-C₁-C₁₂-alkyl, -NHC(O)-C₂-C₁₂-alkenyl, -NHC(O)-C₂-C₁₂- alkenyl, -NHC(O)-C₃-C₁₂-cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)- heterocycloalkyl, -NHCO₂-C₁-C₁₂-alkyl, -NHCO₂-C₂-C₁₂-alkenyl, -NHCO₂-C₂-C₁₂-alkenyl, -NHCO₂-C₃-C₁₂-cycloalkyl, -NHCO₂-aryl, -NHCO₂-heteroaryl, -NHCO₂- heterocycloalkyl, -NHC(O)NH₂, -NHC(O)NH-C₁-C₁₂-alkyl, -NHC(O)NH-C₂-C₁₂-alkenyl, -NHC(O)NH-C₂-C₁₂-alkenyl, -NHC(O)NH-C₃-C₁₂-cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, NHC(O)NH-heterocycloalkyl, -NHC(S)NH₂, -NHC(S)NH-C₁-C₁₂-alkyl, -NHC(S)NH-C₂-C₁₂-alkenyl, -NHC(S)NH-C₂-C₁₂-alkenyl, -NHC(S)NH-C₃-C₁₂-cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocycloalkyl, -NHC(NH)NH₂, -NHC(NH)NH- C₁-C₁₂-alkyl, -NHC(NH)NH-C₂-C₁₂-alkenyl, -NHC(NH)NH-C₂-C₁₂-alkenyl, -NHC(NH)NH-C₃-C₁₂-cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NHheterocycloalkyl, -NHC(NH)-C₁-C₁₂-alkyl, -NHC(NH)-C₂-C₁₂-alkenyl, -NHC(NH)-C₂-C₁₂-alkenyl, -NHC(NH)-C₃-C₁₂-cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocycloalkyl, -C(NH)NH-C₁-C₁₂-alkyl, -C(NH)NH-C₂-C₁₂-alkenyl, -C(NH)NH-C₂-C₁₂-alkenyl, C(NH)NH-C₃-C₁₂-cycloalkyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NHheterocycloalkyl, -S(O)-C₁-C₁₂-alkyl,- S(O)-C₂-C₁₂-alkenyl,- S(O)-C₂-C₁₂-alkenyl, -S(O)-C₃-C₁₂-cycloalkyl,- S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocycloalkyl -SO₂NH₂, -SO₂NH-C₁-C₁₂-alkyl, -SO₂NH-C₂-C₁₂-alkenyl, -SO₂NH-C₂-C₁₂-alkenyl, -SO₂NH-C₃-C₁₂-cycloalkyl, -SO₂NH-aryl, -SO₂NH-heteroaryl, -SO₂NH-heterocycloalkyl, -NHSO₂-C₁-C₁₂-alkyl, -NHSO₂-C₂-C₁₂-alkenyl,- NHSO₂-C₂-C₁₂-alkenyl, -NHSO₂-C₃-C₁₂-cycloalkyl, -NHSO₂-aryl, -NHSO₂-heteroaryl, -NHSO₂-heterocycloalkyl, -CH₂NH₂, -CH₂SO₂CH₃, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C₃-C₁₂-cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-C₁-C₁₂-alkyl, -S-C₂-C₁₂-alkenyl, -S-C₂-C₁₂-alkenyl, -S-C₃-C₁₂-cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl, or methylthiomethyl. A "patient" or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus. An "effective amount" or “therapeutically effective amount” when used in connection with a compound or pharmaceutical composition is an amount effective for treating or preventing a disease in a subject as described herein. The term "treating" with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder. The compounds of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, can also be used to prevent a disease, condition or disorder. As used herein, “preventing” or “prevent” describes reducing or eliminating the onset of the symptoms or complications of the disease, condition or disorder. The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated. As used herein, the term diseases or disorders in which Polθ helicase plays a role means any disease or other deleterious condition in which Polθ helicase is known to play a role. Accordingly, another embodiment of the present application relates to treating or lessening the severity of one or more diseases in which Polθ helicase is known to play a role. Pharmaceutical Compositions The compounds disclosed therein are Polθ helicase inhibitors. The pharmaceutical composition of the present application comprises one or more Polθ helicase inhibitors, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent. A “pharmaceutical composition” is a formulation containing the compound of the present disclosure in a form suitable for administration to a subject. In some embodiments, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or a pharmaceutically acceptable salt or solvate thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In some embodiments, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers or propellants that are required.

As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

“Pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent” refer to a substance that aids the formulation and/or administration of an active agent to and/or absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the subject. Non-limiting examples of pharmaceutically acceptable carriers and/or diluents include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein. One of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with disclosed compounds.

The term "carrier", as used in this disclosure, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.

The pharmaceutical compositions of the present teachings optionally include one or more pharmaceutically acceptable carriers and/or diluents therefor, such as lactose, starch, cellulose and dextrose. Other excipients, such as flavoring agents; sweeteners; and preservatives, such as methyl, ethyl, propyl and butyl parabens, can also be included. More complete listings of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5^th Ed., Pharmaceutical Press (2005)). A person skilled in the art would know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington’s Pharmaceutical Sciences (2003 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999. The carriers, diluents and/or excipients are “acceptable” in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.

Pharmaceutical compositions of the disclosure are formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous disclosure can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. A compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment. For example, for treatment of cancers, a compound of the disclosure may be injected directly into tumors, injected into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not as high as to cause unacceptable side effects. The state of the disease condition (e.g., cancer, precancer, and the like) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment. The term “therapeutically effective amount”, as used herein, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician. For any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED₅₀ (the dose therapeutically effective in 50% of the population) and LD₅₀ (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD₅₀/ED₅₀. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration. Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

The pharmaceutical compositions containing active compound (i.e., a compound of Formula (I)) of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the active compound into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compound is delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compound is formulated into ointments, salves, gels, or creams as generally known in the art.

The active compound can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

In therapeutic disclosures, the dosages of the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in slowing, and preferably regressing, the growth of the tumors and also preferably causing complete regression of the cancer. Dosages can range from about 0.01 mg/kg per day to about 5000 mg/kg per day. An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. For example, regression of a tumor in a subject may be measured with reference to the diameter of a tumor. Decrease in the diameter of a tumor indicates regression. Regression is also indicated by failure of tumors to reoccur after treatment has stopped. As used herein, the term “dosage effective manner” refers to amount of an active compound to produce the desired biological effect in a subject or cell.

The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

The dosage regimen utilizing the compound is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or pharmaceutically acceptable salt or solvate thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

Techniques for formulation and administration of the disclosed compound of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19^th edition, Mack Publishing Co., Easton, PA (1995). In some embodiments, the compound described herein, and the pharmaceutically acceptable salts or solvates thereof, are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compound or pharmaceutically acceptable salts or solvates thereof will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.

All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure.

Methods of Using the Compounds

The present application provides a method of treating a subject with a disease or disorder which can be ameliorated by inhibition of Polθ helicase, by administering to the subject an effective amount of one or more disclosed compounds, or a pharmaceutically acceptable salt or solvate thereof, or the corresponding pharmaceutical composition. Diseases which can be ameliorated by inhibition of Polθ helicase include treating cancer.

The present application further relates to a method of treating a disease or disorder in which Polθ helicase plays a role, for example, cancer. The method comprises administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition disclosed herein.

In one aspect, described herein is a method for treating and/or preventing a disease in a subject, such as cancer characterized by overexpression/overactivity of Pol 9 helicase, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, described herein is a method for treating and/or preventing a cancer in a subject, such as cancer characterized by a deficiency in homologous recombinant (HR) or by a reduction or absence of BRCA gene expression, the absence of the BRAC gene, or reduced function of BRCA protein, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, described herein is a method for inhibiting DNA repair by Polθ in a cell, comprising contacting the cell with an effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cell is HR deficient.

In another aspect, provided herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for inhibiting DNA repair by Polθ in a cell. In some embodiments, the cell is HR deficient.

In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for treating and/or preventing a disease in a subject, e.g., a disease such as cancer treatable by inhibition of Polθ, including homologous recombination (HR) deficient cancers.

In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for treating and/or preventing a disease in a subject, such as cancer characterized by overexpression/overactivity of Pol 0 helicase, by a deficiency in homologous recombinant (HR), or by a reduction or absence of BRAC gene expression, the absence of the BRAC gene, or reduced function of BRAC protein.

In another aspect, provided herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for inhibiting DNA repair by Polθ in a cell. In some embodiments, the cell is HR deficient.

In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for treating and/or preventing a disease in a subject, e.g., a disease such as cancer treatable by inhibition of Polθ, including homologous recombination (HR) deficient cancers. In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for treating and/or preventing a disease in a subject, such as cancer characterized by overexpression/overactivity of Polθ helicase, by a deficiency in homologous recombinant (HR), or by a reduction or absence of BRAC gene expression, the absence of the BRAC gene, or reduced function of BRAC protein.

In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for treating and/or preventing a cancer that is resistant to poly(ADP-ribose) polymerase (PARP) inhibitor therapy in a subject. Examples of cancers resistant to PARP-inhibitors include, but are not limited to, breast cancer, ovarian cancer, lung cancer, bladder cancer, liver cancer, head and neck cancer, pancreatic cancer, gastrointestinal cancer, and colorectal cancer.

In one aspect, described herein is a method of treating cancer, the method comprising administering a therapeutically effective dose of a composition as described herein, e.g., a composition comprising a compound of the present disclosure, to a subject in need of treatment for cancer.

The present disclosure further relates to use of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein, in the manufacture of a medicament for the treatment of a disease or disorder in which Polθ helicase plays a role, for example, a cancer.

The present disclosure provides use of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein, in the manufacture of a medicament for the treatment of a disease or disorder which can be ameliorated by inhibition of Polθ helicase.

In one aspect, described herein is use of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein, in the manufacture of a medicament for the treatment of a cancer.

The present disclosure further relates to a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein, for use in treating a disease or disorder in which Pol9 helicase plays a role, for example, a cancer. The present disclosure provides a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein, for use in treating a disease or disorder which can be ameliorated by inhibition of Polθ helicase.

In another aspect, described herein is a method for treating and/or preventing a disease, such as cancer, characterized by overexpression of Polθ helicase in a patient comprising administering to the patient a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, described herein is a method for treating and/or preventing a homologous recombinant (HR) deficient cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, described herein is a method for inhibiting DNA repair by Pol9 in a cancer cell comprising contacting the cell with an effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cancer is HR deficient cancer.

In some embodiments, described herein is a method for treating and/or preventing a cancer in a patient, wherein the cancer is characterized by a reduction or absence of BRCA gene expression, the absence of the BRAC gene, or reduced function of BRCA protein, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof, optionally in a pharmaceutical composition.

In some embodiments, the cancer is lymphoma, leukemia, multiple myeloma, soft tissue cancer, rhabdoid tumor, rhabdomyosarcoma, central nervous system cancer, peripheral nervous system cancer, bone cancer, uterine cancer, ovarian cancer, upper aerodigestive cancer, esophagus cancer, gastric cancer, gastrointestinal cancer, colorectal cancer, mesothelioma, breast cancer, lung cancer, bladder cancer, liver cancer, head and neck cancer, fibroblast cancer, urinary tract cancer, kidney cancer, skin cancer, prostate cancer, and pancreatic cancer.

In some embodiments, an HR-deficient cancer is breast cancer. Breast cancer includes, but is not limited to, lobular carcinoma in situ (LCIS), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC), inflammatory breast cancer, Paget disease of the nipple, Phyllodes tumor, angiosarcoma, adenoid cystic carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapillary carcinoma, mixed carcinoma, and other breast cancer, including but not limited to, breast cancer that is triple negative, HER positive, estrogen receptor positive, progesterone receptor positive, HER and estrogen receptor positive, HER and progesterone receptor positive, estrogen and progesterone receptor positive, and/or HER and estrogen and progesterone receptor positive.

In some embodiments, an HR-deficient cancer is ovarian cancer, including, but not limited to, epithelial ovarian carcinomas (EOC), maturing teratomas, dysgerminomas, endodermal sinus tumors, granulosa-theca tumors, Sertoli-Leydig cell tumors, and primary peritoneal carcinoma.

In some embodiments, cancers that can be treated by the disclosed methods include cancer of the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestine, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue, or uterus. In addition, the cancer may specifically be of the following histological type, though it is not limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; sarcomas; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant; branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma; acidophil carcinoma; oxyphilic adenocarcinoma; basophil carcinoma; clear cell adenocarcinoma; granular cell carcinoma; follicular adenocarcinoma; papillary and follicular adenocarcinoma; nonencapsulating sclerosing carcinoma; adrenal cortical carcinoma; endometroid carcinoma; skin appendage carcinoma; apocrine adenocarcinoma; sebaceous adenocarcinoma; ceruminous adenocarcinoma; mucoepidermoid carcinoma; cystadenocarcinoma; papillary cystadenocarcinoma; papillary serous cystadenocarcinoma; mucinous cystadenocarcinoma; mucinous adenocarcinoma; signet ring cell carcinoma; infiltrating duct carcinoma; medullary carcinoma; lobular carcinoma; inflammatory carcinoma; Paget’s disease, mammary; acinar cell carcinoma; adenosquamous carcinoma; adenocarcinoma w/squam ous metaplasia; thymoma, malignant; ovarian stromal tumor, malignant; thecoma, malignant; granulosa cell tumor, malignant; androblastoma, malignant; sertoli cell carcinoma; leydig cell tumor, malignant; lipid cell tumor, malignant; paraganglioma, malignant; extra-mammary paraganglioma, malignant; pheochromocytoma; glomangiosarcoma; malignant melanoma; amelanotic melanoma; superficial spreading melanoma; malig melanoma in giant pigmented nevus; epithelioid cell melanoma; blue nevus, malignant; sarcoma; fibrosarcoma; fibrous histiocytoma, malignant; myxosarcoma; liposarcoma; leiomyosarcoma; rhabdomyosarcoma; embryonal rhabdomyosarcoma; alveolar rhabdomyosarcoma; stromal sarcoma; mixed tumor, malignant; mullerian mixed tumor; nephroblastoma; hepatoblastoma; carcinosarcoma; mesenchymoma, malignant; Brenner tumor, malignant; phyllodes tumor, malignant; synovial sarcoma; mesothelioma, malignant; dysgerminoma; embryonal carcinoma; teratoma, malignant; struma ovarii, malignant; choriocarcinoma; mesonephroma, malignant; hemangiosarcoma; hemangioendothelioma, malignant; Kaposi’s sarcoma; hemangiopericytoma, malignant; lymphangiosarcoma; osteosarcoma; juxtacortical osteosarcoma; chondrosarcoma; chondroblastoma, malignant; mesenchymal chondrosarcoma; giant cell tumor of bone; Ewing’s sarcoma; odontogenic tumor, malignant; ameloblastic odontosarcoma; ameloblastoma, malignant; ameloblastic fibrosarcoma; pinealoma, malignant; chordoma; glioma, malignant; ependymoma; astrocytoma; protoplasmic astrocytoma; fibrillary astrocytoma; astroblastoma; glioblastoma; oligodendroglioma; oligodendroblastoma; primitive neuroectodermal; cerebellar sarcoma; ganglioneuroblastoma; neuroblastoma; retinoblastoma; olfactory neurogenic tumor; meningioma, malignant; neurofibrosarcoma; neurilemmoma, malignant; granular cell tumor, malignant; malignant lymphoma; Hodgkin’s disease; hodgkin’s; paragranuloma; malignant lymphoma, small lymphocytic; malignant lymphoma, large cell, diffuse; malignant lymphoma, follicular; mycosis fungoides; other specified non-Hodgkin’s lymphomas; malignant histiocytosis; multiple myeloma; mast cell sarcoma; immunoproliferative small intestinal disease; leukemia; lymphoid leukemia; plasma cell leukemia; erythroleukemia; lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryoblastic leukemia; myeloid sarcoma; and hairy cell leukemia.

The term “treating” or “treatment” of a disease includes inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

The terms “inhibiting”, “reducing”, or any variation of these terms in relation of Pol0, includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, reduction of Polθ activity compared to its normal activity. The term “preventing” refers to causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease. The term “homologous recombination” refers to the cellular process of genetic recombination in which nucleotide sequences are exchanged between two similar or identical DNA. The term “homologous recombination (HR) deficient cancer” refers to a cancer that is characterized by a reduction or absence of a functional HR repair pathway. HR deficiency may arise from absence of one or more HR-associated genes or presence of one or more mutations in one or more HR-associated genes. Examples of HR-associated genes include BRCA1, BRCA2, RAD54, RAD51B, CtlP (Choline Transporter-Like Protein), PALB2 (Partner and Localizer of BRCA2), XRCC2 (X-ray repair complementing defective repair in Chinese hamster cells 2), RECQL4 (RecQ Protein-Like 4), BLM (Bloom syndrome, RecQ helicase-like), WRN (Werner syndrome , one or more HR-associated genes) Nbs 1 (Nibrin), and genes encoding Fanconi anemia (FA) proteins or FA-like genes e.g., FANCA, FANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANJ (BRIP1), FANCL, FANCM, FANCN (RALB2), FANCP (SLX4), FANCS (BRCA1), RAD51C, and XPF. The term “Polθ overexpression” refers to the increased expression or activity of Polθ in disease cells e.g., cancerous cell, relative to expression or activity of Polθ in a normal cell (e.g., non-diseased cell of the same kind). The amount of Polθ can be at least 2-fold, at least 3-fold, at least 4- fold, at least 5- fold, at least 10-fold, or more relative to the Polθ expression in a normal cell. Examples of Polθ cancers include, but are not limited to, breast, ovarian, cervical, lung, colorectal, gastric, bladder and prostate cancers. In addition, the compounds of the present disclosure can be co-administered with other therapeutic agents. In some embodiments, other therapeutic agents include chemotherapeutic agents known in the art, such as inhibitors of the DNA repair pathways (e.g., HR and NHEJ) and immunomodulatory agents. As used herein, the terms “co- administration”, “administered in combination with”, and their grammatical equivalents, are meant to encompass administration of two or more therapeutic agents to a single subject, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different times. These terms encompass administration of two or more agents to the subject so that both agents and/or their metabolites are present in the subject at the same time. They include simultaneous administration in separate compositions, administration at different times in separate compositions, and/or administration in a composition in which both agents are present. Thus, in some embodiments, the compounds described herein and the other agent(s) are administered in a single composition. In some embodiments, the compounds described herein and the other agent(s) are admixed in the composition. EXAMPLES Compounds Preparation Reagent grade chemicals and anhydrous solvents were purchased from commercial sources and, unless otherwise mentioned, were used without further purification. The preparation of compounds is either commercially available or known in the literature, as reported in the references. ChemDraw (PerkinElmer) was used to determine the names of the products. In cases where compounds are described as being prepared analogously to earlier examples or intermediates, reaction time, reagent equivalents, temperature, work-up, and purification techniques may vary slightly. Purifications Chromatographic separations were performed on: - Teledyne ISCO CombiFlash flash chromatography systems, using pre-packaged SiO₂ or C18 columns - Teledyne ISCO ACCQPrep high pressure preparative liquid chromatography system; Column: Gemini 5 um C18110 Å, 150 x 30 mm - Biotage Isolera flash chromatography systems, using pre-packaged SiO₂ or C18 columns. - Waters Mass Trigger Semi-Prep HPLC; Column: Gemini 5 um NX-C18110 Å, 100 x 30 mm Analytical Methods - LC-MS were performed on Waters UPLC-MS; Column: Acquity UPLC, CSH C18, 1.7 um, 2.1 × 30 mm; Methods: from 5% to 95% of CH₃CN in H₂O with 0.1% (v/v) formic acid in 2 min or from 5% to 95% of CH₃CN in 10 mM ammonium bicarbonate in 2 min. - NMR spectroscopy was carried out using a Varian NMR (AS 400) 400 MHz Spectrometer with Inova interface. In all cases, NMR data were consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts-per-million using conventional abbreviations for designation of peaks: e.g. s, singlet; d, doublet; t; triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; b, broad; etc. Abbreviations used: 9-BBN 9-Borabicyclo[3.3.1]nonane δ Chemical shift Å Angström Ac Acetyl ACN Acetonitrile Bn Benzyl Boc tert-Butoxycarbonyl b Broad singlet Bu Butyl Calcd Calculated d Doublet DAST (Diethylamino)sulfur trifluoride dd Doublet of doublets dt Doublet of triplets DCM Dichloromethane DDQ 2,3-Dichloro-5,6-dicyano-p-benzoquinone DIBALH Diisobutylaluminium hydride DIPA N,N-Diisopropyl amine DIPEA N,N-Diisopropylethylamine DMAP 4-Dimethylaminopyridine DMF N,N-Dimethylformamide DMP Dess-Martin periodinane DMSO Dimethyl sulfoxide Dppf 1,1′-Ferrocenediyl-bis(diphenylphosphine) EA Ethyl acetate ee Enantiomeric excess Et Ethyl EtOH Ethanol Et₃N Triethylamine eq Equivalents g Gram Hour h HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate Hz Hertz HPLC High performance liquid chromatography i-Pr Isopropyl J Coupling constant L Liter LC-MS Liquid chromatography-mass spectroscopy LDA Lithium diisopropylamide LiHMDS Lithium bis(trimethylsilyl)amide M Molar m Multiplet mCPBA meta-chloroperoxybenzoic acid Me Methyl MeTHF 2-Methyltetrahydrofuran MeOH Methanol mg Milligram MHz Megahertz min Minutes mL Milliliter mm Millimeter mmol Millimole mol Mole MS Mass spectroscopy N Normal NBS N-bromosuccinimide PCC Pyridinium chlorochromate Pd₂(dba)₃ Tris(dibenzylideneacetone)dipalladium(0) Pd(PPh₃)₄ Tetrakis(triphenylphosphine)palladium(0) Pd(dppf)Cl₂.DCM [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane Pd(dppf)Cl₂ [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) pH Potential of hydrogen Ph Phenyl PPh3 Triphenylphosphine ppm Parts per million PyBOP Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate q Quadruplet RT Room temperature NMR Nuclear magnetic resonance s Singlet sat Saturated sxt Sextuplet t tert t Triplet tt Triplet of triplet t-Bu tert-Butyl TCFH Chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate TMS Trimethylsilyl TFA Trifluoroacetic acid THF Tetrahydrofuran Ts Tosyl mol Micromole v/v Volume/volume XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene ° Degree % Percentage General methods for synthesis are identified below for reference.

Example 1. Preparation of N-(5-((4-chlorobenzyl)thio)-1,3,4-thiadiazol-2-yl)-3-(2- methoxyphenyl)isonicotinamide (Compound 1)

Step 1: Synthesis of 5-((4-chlorobenzyl)thio)-1,3,4-thiadiazol-2-amine A solution of 0.1 N sodium hydroxide (38 mL, 3.75 mmol) was added, at 0 °C, to a mixture of 5-amino-1,3,4-thiadiazole-2-thiol (1 g, 7.51 mmol) and 4-chlorobenzyl bromide (1.57 g, 7.51 mmol) in EtOH (100 mL). After stirring for 15 min, the reaction mixture was allowed to warm to room temperature and stirred for 24 h. The resulting precipitate was collected by vacuum filtration and washed with water and EtOH to afford 5-((4- chlorobenzyl)thio)-1,3,4-thiadiazol-2-amine (1.4 g, 72% yield) as a white solid. MS (ESI): m/z 257.0 (calcd), 258.0 (M+H⁺, found). Step2: Synthesis of N-(5-((4-chlorobenzyl)thio)-1,3,4-thiadiazol-2-yl)-3-(2- methoxyphenyl) isonicotinamide (Compound 1) – General method A To a stirring solution of 5-((4-chlorobenzyl)thio)-1,3,4-thiadiazol-2-amine (100 mg, 0.39 mmol) and 3-(2-methoxyphenyl)isonicotinic acid (89 mg, 0.39 mmol, WO 2020/243459, p.84) in dry DMF (5 mL), were added HATU (226 mg, 0.58 mmol) and DIPEA (203 mL, 1.16 mmol). The reaction mixture was stirred for 3 h at room temperature under argon atmosphere. The reaction mixture was diluted with water and extracted with EA (3×10 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexanes). The isolated product was dissolved in ACN (1 mL), diluted with water (4 mL), and lyophilized to afford N-(5-((4-chlorobenzyl)thio)-1,3,4- thiadiazol-2-yl)-3-(2-methoxyphenyl) isonicotinamide (Compound 1) (105 mg, 58% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.42 (3H, s), 4.47 (2H, s), 6.96 (1H, d, J = 8.1 Hz), 7.06 (1H, td, J = 7.5, 1.0 Hz), 7.41-7.34 (6H, m), 7.64 (1H, d, J = 4.9 Hz), 8.61 (1H, s), 8.71 (1H, d, J = 4.9 Hz), 13.17 (1H, s). MS (ESI): m/z 468.0 (calcd), 469.1 (M+H⁺, found). Example 2. Preparation of N-(5-((4-chlorobenzyl)amino)-1,3,4-thiadiazol-2-yl)-3-(2- methoxyphenyl)isonicotinamide (Compound 2)

Step 1: Synthesis of N²-(4-chlorobenzyl)-1,3,4-thiadiazole-2,5-diamine – General method B To a suspension of 2-amino-5-bromo-1,3,4-thiadiazole (1 g, 5.55 mmol) in dry THF (15 mL), Et₃N (2 mL, 13.9 mmol) and 4-chlorobenzylamine (676 mL, 5.55 mmol) were added. The reaction mixture was refluxed for 2 h, cooled to room temperature and the volatiles were removed under reduced pressure. EtOH (10 mL) was added, and the resulting precipitate was collected by vacuum filtration and washed with DCM (2×10 mL) to afford N²-(4-chlorobenzyl)-1,3,4-thiadiazole-2,5-diamine (1.34 g, 82% yield) as a grey solid. MS (ESI): m/z 240.0 (calcd), 241.1 (M+H⁺, found). Step 2: Synthesis of N-(5-((4-chlorobenzyl)amino)-1,3,4-thiadiazol-2-yl)-3-(2- methoxyphenyl) isonicotinamide (Compound 2) The title compound was obtained from N²-(4-chlorobenzyl)-1,3,4-thiadiazole-2,5- diamine (100 mg, 0.42 mmol), 3-(2-methoxyphenyl)isonicotinic acid (95 mg, 0.42 mmol), HATU (237 mg, 0.62 mmol) and DIPEA (217 mL, 1.25 mmol) in DMF (5 mL) following General method A. The crude product was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexanes). The isolated product was dissolved in ACN (1 mL), diluted with water (4 mL), and lyophilized to afford N-(5-((4-chlorobenzyl)amino)- 1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl) isonicotinamide (Compound 2) (37 mg, 20% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.52 (3H, s), 4.44 (2H, d, J = 5.8 Hz), 6.99 (1H, d, J = 8.2 Hz), 7.05 (1H, t, J = 7.5 Hz), 7.39-7.32 (6H, m), 7.58 (1H, d, J = 5.0 Hz), 7.88 (1H, t, J = 5.8 Hz), 8.58 (1H, s), 8.68 (1H, d, J = 5.0 Hz), 12.43 (1H, s). MS (ESI): m/z 451.1 (calcd), 452.2 (M+H⁺, found). Example 3. Preparation of (E)-N-(5-(4-chlorostyryl)-1,3,4-thiadiazol-2-yl)-3-(2- methoxyphenyl)isonicotinamide (Compound 3)

Step 1: Synthesis of (E)-5-(4-chlorostyryl)-1,3,4-thiadiazol-2-amine A stirring mixture of thiosemicarbazide (500 mg, 5.48 mmol), 4-chlorocinnamic acid (1 g, 5.48 mmol) and POCl₃ (3 mL, 31.9 mmol) was refluxed for 0.5 h. After cooling to room temperature, water (4 mL, 222 mmol) was added, and the resulting mixture was refluxed for 4 h. After cooling to room temperature, the reaction mixture was basified to pH = 8-9 by addition of 50% NaOH aqueous solution under stirring. The resulting precipitate was filtered and washed twice with EtOH to afford (E)-5-(4-chlorostyryl)-1,3,4-thiadiazol-2-amine (1.15 g, 88% yield) as a pale-yellow solid. MS (ESI): m/z 237.0.0 (calcd), 238.1 (M+H⁺, found). Step 2: Synthesis of (E)-N-(5-(4-chlorostyryl)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl) isonicotinamide (Compound 3) - General method C To a stirring solution of (E)-5-(4-chlorostyryl)-1,3,4-thiadiazol-2-amine (50 mg, 0.21 mmol) and 3-(2-methoxyphenyl)isonicotinic acid (48 mg, 0.21 mmol) in dry DMF (2 mL) was added 1-methylimidazole (61 mL, 0.74 mmol). After 5 min, a solution of TCFH (60.2 mg, 0.21 mmol) in dry DMF (1 mL) was added dropwise. The reaction mixture was stirred for 3 h at room temperature under argon atmosphere. Water (5 mL) was added, and the resulting white precipitate was then collected by vacuum filtration, washed with water (2×10 mL), MeOH (2×10 mL) and ACN (2×10 mL) to afford (E)-N-(5-(4-chlorostyryl)-1,3,4-thiadiazol- 2-yl)-3-(2-methoxyphenyl) isonicotinamide (Compound 3) (53 mg, 56% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.49 (3H, s), 6.98 (1H, d, J = 8.2 Hz), 7.08 (1H, t, J = 7.5 Hz), 7.40-7.36 (2H, m), 7.50-7.45 (3H, m), 7.58-7.54 (1H, m), 7.69 (1H, d, J = 4.9 Hz), 7.74 (2H, d, J = 8.4 Hz), 8.63 (1H, s), 8.74 (1H, d, J = 5.0 Hz), 13.18 (1H, br s). MS (ESI): m/z 448.1 (calcd), 449.1 (M+H⁺, found). Example 4. Preparation of N-(5-(4-chlorophenethyl)-1,3,4-thiadiazol-2-yl)-3-(2- methoxyphenyl)isonicotinamide (Compound 4)

To a stirring solution of (E)-N-(5-(4-chlorostyryl)-1,3,4-thiadiazol-2-yl)-3-(2- methoxyphenyl) isonicotinamide (3, 20 mg, 0.05 mmol) in DMA (1 mL), was added Pd (10 wt.%) on carbon (5 mg, 0.005 mmol). The reaction mixture was degassed under reduced pressure with a backflow of hydrogen (3 times) and stirred for 18 h under standard hydrogen atmosphere. The catalyst was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexanes). The isolated product was dissolved in ACN (1 mL), diluted with water (4 mL), and lyophilized to afford N-(5-(4- chlorophenethyl)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide (Compound 4) (15 mg, 75% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.03 (2H, t, J = 7.5 Hz), 3.30 (2H, t, J = 7.5 Hz), 3.41 (3H, s), 6.96 (1H, d, J = 8.1 Hz), 7.06 (1H, t, J = 7.4 Hz), 7.27-2.25 (2H, m), 7.39-7.31 (4H, m), 7.63 (1H, d, J = 5.0 Hz), 8.61 (1H, s), 8.71 (1H, d, J = 5.0 Hz), 12.92 (1H, s). MS (ESI): m/z 450.1 (calcd), 451.2 (M+H⁺, found). Example 5. Preparation of N-(5-((4-chlorobenzyl)sulfonyl)-1,3,4-thiadiazol-2-yl)-3-(2- methoxyphenyl)isonicotinamide (Compound 5)

An aqueous solution of 4% KMnO₄ (67 mg, 0.43 mmol) was added dropwise to a stirred solution of N-(5-((4-chlorobenzyl)thio)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl) isonicotinamide (1, 100 mg, 0.21 mmol) in acetic acid (4 mL) at room temperature. The addition of KMnO₄ was continued till the purple color persisted and the reaction mixture was stirred for 30 min. The reaction mixture was cooled to 5 °C and saturated sodium sulfite solution was added until the brown color disappeared. The precipitate was collected by vacuum filtration, washed with water (3×10 mL) and dried. The dry solid was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexanes). The isolated product was dissolved in ACN (1 mL), diluted with water (4 mL), and lyophilized to afford N-(5-((4-chlorobenzyl) sulfonyl)-1,3,4-thiadiazol-2-yl)-3-(2- methoxyphenyl)isonicotinamide (Compound 5) (75 mg, 70% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.37 (3H, s), 5.11 (2H, s), 6.96 (1H, d, J = 8.6 Hz), 7.09 (1H, t, J = 7.5 Hz), 7.30-7.28 (2H, m), 7.45-7.38 (4H, m), 7.70 (1H, d, J = 5.0 Hz), 8.66 (1H, s), 8.76 (1H, d, J = 5.0 Hz), 13.88 (1H, s). MS (ESI): m/z 500.0 (calcd), 501.1 (M+H⁺, found). Example 6. Preparation of N-(5-((4-chlorobenzyl)(methyl)amino)-1,3,4-thiadiazol-2-yl)- 3-(2 methoxyphenyl) isonicotinamide (Compound 6)

Step 1: Synthesis of N²-(4-chlorobenzyl)-N²-methyl-1,3,4-thiadiazole-2,5-diamine The title compound was prepared from 2-amino-5-bromo-1,3,4-thiadiazole (100 mg, 0.56 mmol), 1-(4-chlorophenyl)-N-methylmethanamine (74 mL, 0.56 mmol) and Et₃N (194 mL, 1.39 mmol) in THF (5 mL) following General method B. Sequential trituration of the crude product with EtOH (5 mL) and DCM (5 mL) afforded N²-(4-chlorobenzyl)-N²-methyl- 1,3,4-thiadiazole-2,5-diamine (63 mg, 45% yield) as a brown solid. MS (ESI): m/z 254.0 (calcd), 255.2 (M+H⁺, found). Step 2: Synthesis of N-(5-((4-chlorobenzyl)(methyl)amino)-1,3,4-thiadiazol-2-yl)-3-(2- methoxyphenyl)isonicotinamide (Compound 6) The title compound was obtained from N²-(4-chlorobenzyl)-N²-methyl-1,3,4- thiadiazole-2,5-diamine (60 mg, 0.24 mmol), 3-(2-methoxyphenyl)isonicotinic acid (54 mg, 0.24 mmol), 1-methylimidazole (66 mL, 0.82 mmol) and TCFH (79 mg, 0.28 mmol) in DMF (2 mL) following General method C. The crude product was purified by flash column chromatography (eluent gradient from 0% to 5% of MeOH in DCM), then by Prep-HPLC (Column: Gemini® 5 um NX-C18110 Å, 100 x 30 mm) (eluent gradient from 40% to 100% of ACN in ammonium formate 10 mM). The isolated product was dissolved in ACN (1 mL), diluted with water (4 mL), and lyophilized to afford N-(5-((4-chlorobenzyl)(methyl)amino)- 1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide (Compound 6) (52 mg, 47% yield) as an off-white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.04 (3H, s), 3.52 (3H, s), 4.63 (2H, s), 6.98 (1H, d, J = 8.3 Hz), 7.04 (1H, t, J = 7.5 Hz), 7.39-7.29 (4H, m), 7.42-7.39 (2H, m), 7.59 (1H, d, J = 5.0 Hz), 8.57 (1H, s), 8.68 (1H, d, J = 4.9 Hz), 12.52 (1H, br s). MS (ESI): m/z 465.1 (calcd), 466.2 (M+H⁺, found). Example 7. Preparation of N-(5-((4-chlorobenzyl)(ethyl)amino)-1,3,4-thiadiazol-2-yl)-3- (2-methoxyphenyl)isonicotinamide (Compound 7)

Step 1: Synthesis of N²-(4-chlorobenzyl)-N²-ethyl-1,3,4-thiadiazole-2,5-diamine The title compound was obtained from 2-amino-5-bromo-1,3,4-thiadiazole (200 mg, 1.11 mmol), N-(4-chlorobenzyl)ethanamine (207 mL, 1.11 mmol) and Et₃N (389 mL, 2.78 mmol) in THF (10 mL) following General method B. The residue was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexanes) to afford N²- (4-chlorobenzyl)-N²-ethyl-1,3,4-thiadiazole-2,5-diamine (290 mg, 97% yield) as an off-withe solid. MS (ESI): m/z 268.1 (calcd), 269.2 (M+H⁺, found). Step 2: Synthesis of N-(5-((4-chlorobenzyl)(ethyl)amino)-1,3,4-thiadiazol-2-yl)-3-(2- methoxyphenyl) isonicotinamide (Compound 7) The title compound was prepared from N²-(4-chlorobenzyl)-N²-ethyl-1,3,4- thiadiazole-2,5-diamine (20, 70 mg, 0.26 mmol), 3-(2-methoxyphenyl)isonicotinic acid (4, 60 mg, 0.26 mmol), 1-methylimidazole (73 mL, 0.91 mmol) and TCFH (82 mg, 0.29 mmol) in DMF (3 mL) following General method C. The crude product was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexanes). The isolated material was dissolved in ACN (1 mL), diluted with water (4 mL), and lyophilized to afford N-(5-((4- chlorobenzyl) (ethyl)amino)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl) isonicotinamide (Compound 7) (80 mg, 64% yield) as an off-white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12 (3H, t, J = 7.0 Hz), 3.46 (2H, q, J = 7.1 Hz), 3.52 (3H, s), 4.63 (2H, s), 6.98 (1H, d, J = 8.3 Hz), 7.05 (1H, td, J = 7.5, 1.0 Hz), 7.37-7.31 (4H, m), 7.41-7.38 (2H, m), 7.59 (1H, d, J = 5.0 Hz), 8.58 (1H, s), 8.68 (1H, d, J = 5.0 Hz), 12.50 (1H, br s). MS (ESI): m/z 479.1 (calcd), 480.3 (M+H⁺, found). Example 8. Preparation of ethyl 2-((5-(3-(2-methoxyphenyl)isonicotinamido)-1,3,4- thiadiazol-2-yl)oxy)acetate (Compound 8)

Step 1: Synthesis of ethyl 2-((5-amino-1,3,4-thiadiazol-2-yl)oxy)acetate To a stirring solution of 2-amino-5-bromo-1,3,4-thiadiazole (1 g, 5.55 mmol) in DMF (10 mL) cooled to 0 °C, ethyl 2-hydroxyacetate (2 mL, 22.2 mmol) and Et₃N (2 mL, 13.9 mmol) were added. The reaction mixture was warmed to room temperature, stirred for 6 h diluted with water (20 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with brine (30 mL), dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (eluent gradient from 70% to 100% EA in hexanes) to provide ethyl 2-((5-amino-1,3,4-thiadiazol-2- yl)oxy)acetate (668 mg, 59% yield) as a tan solid. MS (ESI): m/z 203.0 (calcd), 204.1 (M+H⁺, found). Step 2: Synthesis of ethyl 2-((5-(3-(2-methoxyphenyl)isonicotinamido)-1,3,4-thiadiazol- 2-yl)oxy)acetate (Compound 8) The title compound was prepared from of ethyl 2-((5-amino-1,3,4-thiadiazol-2- yl)oxy)acetate (500 mg, 2.46 mmol), 3-(2-methoxyphenyl)isonicotinic acid (564 mg, 2.46 mmol), 1-methylimidazole (715 µL, 8.61 mmol), and TCFH (704 mg, 2.46 mmol) in DMF (24 mL) following General method C. The crude product was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexanes) to afford ethyl 2-((5- (3-(2-methoxyphenyl)isonicotinamido)-1,3,4-thiadiazol-2-yl)oxy)acetate (Compound 8) (1 g, 99% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.24 (3H, t, J = 7.1 Hz), 3.55 (3H, s), 4.21 (2H, q, J = 7.1 Hz), 5.12 (2H, s), 7.03 (1H, d, J = 8.1 Hz), 7.11 (1H, td, J = 7.5, 1.0 Hz), 7.44-7.40 (2H, m), 7.67 (1H, d, J = 5.0 Hz), 8.65 (1H, s), 8.75 (1H, d, J = 5.0 Hz), 12.96 (1H, s). MS (ESI): m/z 414.1 (calcd), 415.2 (M+H⁺, found). Example 9. Preparation of 2-((5-(3-(2-methoxyphenyl)isonicotinamido)-1,3,4-thiadiazol- 2-yl)oxy)acetic acid (Compound 9)

To a stirring solution of ethyl 2-((5-(3-(2-methoxyphenyl)isonicotinamido)-1,3,4- thiadiazol-2-yl)oxy)acetate (8, 750 mg, 1.81 mmol) in a mixture of water (9 mL) and THF (9 mL) cooled to 0 °C, NaOH (74 mg, 1.81 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 30 min, concentrated under reduced pressure, and acidified to pH = 2. The resulting precipitate was collected by vacuum filtration, washed with water, and dried to provide 2-((5-(3-(2-methoxyphenyl)isonicotinamido)-1,3,4- thiadiazol-2-yl)oxy)acetic acid (Compound 9) (581 mg, 83% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.52 (3H, s), 4.96 (2H, s), 7.00 (1H, d, J = 8.2 Hz), 7.07 (1H, td, J = 7.5, 1.0 Hz), 7.40-7.35 (2H, m), 7.64 (1H, d, J = 5.0 Hz), 8.61 (1H, s), 8.72 (1H, d, J = 5.0 Hz), 12.93 (1H, br, s), 13.15 (1H, br, s). MS (ESI): m/z 386.1 (calcd), 387.1 (M+H⁺, found). Example 10. Preparation of 3-(2-methoxyphenyl)-N-(5-(2-morpholino-2-oxoethoxy)- 1,3,4-thiadiazol-2-yl)isonicotinamide (Compound 10)

The title compound was obtained from 2-((5-(3-(2-methoxyphenyl)isonicotinamido)- 1,3,4-thiadiazol-2-yl)oxy)acetic acid (9, 50 mg, 0.13 mmol), morpholine (11 µL, 0.13 mmol), 1-methylimidazole (38 µL, 0.45 mmol) ), and TCFH (37 mg, 0.13 mmol) in DMF (1.3 mL) following General method C. The crude product was purified by flash column chromatography (eluent gradient from 0% to 10% MeOH in DCM). The isolated material was dissolved in ACN (1 mL), diluted with water (4 mL), and lyophilized to afford 3-(2- methoxyphenyl)-N-(5-(2-morpholino-2-oxoethoxy)-1,3,4-thiadiazol-2-yl)isonicotinamide (Compound 10) (15 mg, 25% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.43-3.39 (4H, m), 3.53 (3H, s), 3.58 (4H, dt, J = 13.5, 4.7 Hz), 5.21-5.21 (2H, m), 7.07-6.99 (2H, m), 7.39-7.33 (2H, m), 7.64-7.61 (1H, m), 8.77-8.46 (2H, m), 12.91 (1H, s). MS (ESI): m/z 455.1 (calcd), 456.2 (M+H⁺, found). Compounds 11-15 (examples 11-15) were synthesized starting from compound 9 by following the procedure described above for the synthesis of compound 10, using corresponding amines instead of morpholine. Characterization of compounds 11-15 (examples 11-15) is provided in the Table 2. Table 2: Characterization of compounds 11-15 (Examples 11-15).

Example 16. Preparation of 3-(2-methoxyphenyl)-N-(5-(oxetan-3-yloxy)-l,3,4- thiadiazol-2-yl)isonicotinamide (Compound 16)

Step 1: Synthesis of 5-(oxetan-3-yloxy)-1,3,4-thiadiazol-2-amine (General method D) To a stirring solution of 3-hydroxyoxetane (82 mg, 1.11 mmol) in dry DMF (3 mL) cooled to 0 °C, was slowly added NaH (67 mg, 1.67 mmol) (60% dispersion in mineral oil). After stirring for 15 min at 0° C, 2-amino-5-bromo-1,3,4-thiadiazole (200 mg, 1.11 mmol) in dry DMF (1 mL) was added dropwise and the reaction mixture was warmed to room temperature and stirred for 1 h. Water (5 mL) was added, and the mixture was extracted with a chloroform /isopropanol mixture (3/1) (10 ml × 3). The combined organic layers were washed with brine, dried over anhydrous MgSO₄, filtered, and concentrated to dryness to afford 5-(oxetan-3-yloxy)-1,3,4-thiadiazol-2-amine (80 mg, 42% yield) as a pale-yellow oil. MS (ESI): m/z 173.0 (calcd), 174.1 (M+H⁺, found). Step 2: Synthesis of 3-(2-methoxyphenyl)-N-(5-(oxetan-3-yloxy)-1,3,4-thiadiazol-2- yl)isonicotinamide (Compound 16) The title compound was prepared from 5-(oxetan-3-yloxy)-1,3,4-thiadiazol-2-amine (40 mg, 0.23 mmol), 3-(2-methoxyphenyl)isonicotinic acid (53 mg, 0.23 mmol), 1- methylimidazole (77 mL, 0.92 mmol) and TCFH (73 mg, 0.25 mmol) in DMF (3 mL) following General method C. The residue was purified by flash column chromatography (eluent gradient from 0% to 5% of MeOH in DCM), then by Prep-HPLC (Column: Gemini® 5 um NX-C18110 Å, 100 x 30 mm) (eluent gradient from 40% to 100% of ACN in ammonium formate 10 mM). The isolated product was dissolved in ACN (1 mL), diluted with water (4 mL), and lyophilized to afford 3-(2-methoxyphenyl)-N-(5-(oxetan-3-yloxy)- 1,3,4-thiadiazol-2-yl)isonicotinamide (Compound 16) (21 mg, 24% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.51 (3H, s), 4.63 (2H, dd, J = 8.0, 4.8 Hz), 4.91-4.87 (2H, m), 5.68-5.63 (1H, m), 6.99 (1H, d, J = 8.2 Hz), 7.07 (1H, dd, J = 7.8, 6.9 Hz), 7.39- 7.34 (2H, m), 7.62 (1H, d, J = 5.0 Hz), 8.61 (1H, s), 8.71 (1H, d, J = 5.0 Hz), 12.94 (1H, s). MS (ESI): m/z 384.1 (calcd), 385.2 (M+H⁺, found). Example 17. Preparation of N-(5-(N-(4-Chlorobenzyl)methylsulfonamido)-1,3,4- thiadiazol-2-yl)-3-(2-methoxyphenyl) isonicotinamide (Compound 17)

Step 1: Synthesis of N-(4-chlorobenzyl)methanesulfonamide To a stirring solution of 4-chlorobenzylamine (430 mL, 3.53 mmol) and Et₃N (594 mL, 4.24 mmol) in dry DCM (8 mL) cooled to 0 °C, was slowly added methanesulfonyl chloride (307 mL, 3.88 mmol). After stirring for 15 min at 0 °C, the reaction mixture was warmed to room temperature and stirred for 1 h under argon atmosphere. The mixture was then diluted with DCM (20 mL) and sequentially washed with 10% citric acid aqueous solution (20 ml × 2) and brine, and finally, dried over anhydrous MgSO₄, filtered, and concentrated to dryness. Trituration of the crude product with EA (20 mL) afforded N-(4- chlorobenzyl)methanesulfonamide (700 mg, 90% yield) as a white solid. MS (ESI): m/z 219.0 (calcd), 218.0 (-ESI, [M-H]-, found). Step 2: Synthesis of N-(5-amino-1,3,4-thiadiazol-2-yl)-N-(4- chlorobenzyl)methanesulfonamide The title compound was prepared from N-(4-chlorobenzyl)methanesulfonamide (200 mg, 0.91 mmol), 2-amino-5-bromo-1,3,4-thiadiazole (164 mg, 0.91 mmol) and NaH (54.6 mg, 1.37 mmol) (60% dispersion in mineral oil) in DMF (5 mL) following General method D to afford N-(5-amino-1,3,4-thiadiazol-2-yl)-N-(4-chlorobenzyl)methanesulfonamide (224 mg, 77% yield) as a brown solid. MS (ESI): m/z 318.0 (calcd), 319.1 (M+H⁺, found). The crude product was used directly in the next step without further purification. Step 3: Synthesis of N-(5-(N-(4-chlorobenzyl)methylsulfonamido)-1,3,4-thiadiazol-2-yl)- 3-(2-methoxyphenyl) isonicotinamide (Compound 17) The title compound was obtained from N-(5-amino-1,3,4-thiadiazol-2-yl)-N-(4- chlorobenzyl)methanesulfonamide (35, 80 mg, 0.25 mmol), 3-(2-methoxyphenyl)isonicotinic acid (4, 58 mg, 0.25 mmol), 1-methylimidazole (83 mL, 1.00 mmol) and TCFH (79 mg, 0.28 mmol) in DMF (3 mL) following General method C. The crude product was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexanes), then by Prep-HPLC (Column: Gemini® 5 um NX-C18110 Å, 100 x 30 mm) (eluent gradient from 40% to 100% of ACN in ammonium formate 10 mM). The isolated product was dissolved in ACN (1 mL), diluted with water (4 mL), and lyophilized to afford N-(5-(N-(4- chlorobenzyl)methyl sulfonamido)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl) isonicotinamide (Compound 17) (11 mg, 8% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.34 (3H, s), 3.45 (3H, s), 5.09 (2H, s), 6.97 (1H, d, J = 8.3 Hz), 7.05 (1H, t, J = 7.4 Hz), 7.31-7.42 (6H, m), 7.61 (1H, d, J = 4.9 Hz), 8.58 (1H, s), 8.69 (1H, s), 12.96 (1H, s). MS (ESI): m/z 529.1 (calcd), 530.2 (M+H⁺, found). Example 18. Preparation of N-(5-(3,3-difluorocyclobutoxy)-1,3,4-thiadiazol-2-yl)-3-(2- methoxyphenyl)isonicotinamide (Compound 18)

Step 1: Synthesis of 3-(2-methoxyphenyl)isonicotinonitrile To a stirring solution of 3-bromo-4-cyanopyridine (1 g, 5.36 mmol) in a mixture of dioxane (10 mL) and water (5 mL), 2-methoxyphenylboronic acid (1 mL, 6.43 mmol), K₂CO₃ (2 g, 16.1 mmol), and Pd(PPh₃)₄ (0.63 g, 0.54 mmol) were added. The reaction mixture was degassed under reduced pressure with a backflow of argon three times, warmed to 100 ℃, and stirred for 2 h. The reaction mixture was then cooled to room temperature and diluted with water and EA. The layers were separated, and the organic layer was washed with brine, dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent gradient from 0% to 60% EA in hexanes) to provide 3-(2-methoxyphenyl)isonicotinonitrile (1 g, 89 % yield) as a white solid. MS (ESI): m/z 210.1 (calcd), 211.2 (M+H⁺, found). Step 2: Synthesis of 3-(2-methoxyphenyl)isonicotinamide To a stirring solution of 3-(2-methoxyphenyl)isonicotinonitrile (180 mg, 0.86 mmol) in a mixture of EtOH (6 mL) and H₂O (2 mL), Ghaffar-Parkins catalyst (37 mg, 86 µmol) was added. The reaction mixture was warmed to 80 ℃, stirred for 2.5 h, then cooled to room temperature, filtered over Celite, and concentrated under reduced pressure to provide 3-(2- methoxyphenyl) isonicotinamide (195 mg, 99 % yield) as an off-white solid. The crude product was used directly in the next step without further purification.¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.69 (3H, s), 7.07-6.99 (2H, m), 7.26 (1H, dd, J = 7.5, 1.7 Hz), 7.36 (2H, t, J = 7.0 Hz), 7.43 (1H, d, J = 5.0 Hz), 7.62 (1H, s), 8.48 (1H, s), 8.59 (1H, d, J = 5.0 Hz). MS (ESI): m/z 228.1 (calcd), 229.2 (M+H⁺, found). Step 3: Synthesis of 2-bromo-5-(3,3-difluorocyclobutoxy)-1,3,4-thiadiazole The title compound was obtained from 2,5-dibromo-1,3,4-thiadiazole (200 mg, 0.82 mmol), 3,3-difluorocyclobutanol (89 mg, 0.82 mmol), NaH (49 mg, 1.23 mmol) (60% dispersion in mineral oil) in DMF (3 mL) following General method D. The residue was purified by flash column chromatography (eluent gradient from 0% to 30% of EA in hexanes) to afford 2-bromo-5-(3,3-difluorocyclobutoxy)-1,3,4-thiadiazole (200 mg, 90% yield) as a colorless oil. MS (ESI): m/z 270.0 (calcd), 272.9 (M+H⁺, found). Step 4: Synthesis of N-(5-(3,3-difluorocyclobutoxy)-1,3,4-thiadiazol-2-yl)-3-(2 methoxyphenyl) isonicotinamide (Compound 18) A stirring solution of 2-bromo-5-(3,3-difluorocyclobutoxy)-1,3,4-thiadiazole (80 mg, 0.29 mmol), 3-(2-methoxyphenyl)isonicotinamide (67 mg, 0.29 mmol), Cs₂CO₃ (192 mg, 0.59 mmol) and H₂O (3 mL, 0.17 mmol) in dioxane (3 mL) was degassed under reduced pressure with a backflow of argon for 15 min. Then, Pd2(dba)3 (27 mg, 0.03 mmol), and XantPhos (34 mg, 0.06 mmol) were added. The reaction mixture was flushed with argon, warmed to 100 ℃, and stirred for 4 h. The reaction mixture was then cooled to room temperature, filtered through a Celite pad, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexanes), then by Prep-HPLC (Column: Gemini® 5 um NX-C18110 Å, 100 x 30 mm) (eluent gradient from 40% to 100% of ACN in ammonium formate 10 mM). The isolated product was dissolved in ACN (1 mL), diluted with water (4 mL), and lyophilized to afford N-(5-(3,3-difluorocyclobutoxy)-1,3,4-thiadiazol-2-yl)-3-(2 methoxyphenyl) isonicotinamide (Compound 18) (12 mg, 10% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.92-2.80 (2H, m), 3.23-3.12 (2H, m), 3.52 (3H, s), 5.19-5.14 (1H, m), 6.99 (1H, d, J = 8.2 Hz), 7.05 (1H, t, J = 7.5 Hz), 7.38-7.32 (2H, m), 7.62 (1H, d, J = 4.9 Hz), 8.57 (1H, s), 8.68 (1H, d, J = 5.0 Hz). MS (ESI): m/z 418.1 (calcd), 419.1 (M+H⁺, found). Example 19. Preparation of N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(2- methoxyphenyl)isonicotinamide (Compound 19)

Step 1: Synthesis of tert-butyl (5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2- yl)carbamate – General method E Dry DMF (3 mL) was added to a mixture of N-boc-2-amino-5- bromo[1,3,4]thiadiazole (300 mg, 1.05 mmol), 1-chloro-4-ethynylbenzene (146 mg, 1.05 mmol), copper iodide (20 mg, 0.10 mmol) and tetrakis(triphenylphosphine)palladium (122 mg, 0.11 mmol) followed by addition of dry DIPA (147 µL, 1.05 mmol). The reaction mixture was degassed three times and filled with argon after each degassing, stirred at 60 °C for 6 h, cooled to room temperature, diluted with water, and extracted with EA (15 mL × 3). The combined organic extracts were dried over anhydrous Na₂SO₄, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (eluent gradient from 20% to 90% of EA in hexanes) to afford tert-butyl (5- ((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)carbamate (300 mg, 85 % yield). MS (ESI): m/z 335.1 (calcd), 336.1 (M+H⁺, found). Step 2: Synthesis of 5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-amine – General method F Trifluoroacetic acid (684 µL, 8.93 mmol) was added to a solution of tert-butyl (5-((4- chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)carbamate (300 mg, 0.893 mmol) in DCM (6 mL) at room temperature. The mixture was stirred for 18 h and concentrated to dryness to afford 5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-amine (211 mg, quantitative yield) as an orange solid. The crude material was used in the next step without further purification. MS (ESI): m/z 235.0 (calcd), 236.1 (M+H⁺, found). Step 3: Synthesis of N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(2- methoxyphenyl)isonicotinamide (Compound 19) The title compound was prepared from 5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol- 2-amine (50 mg, 0.21 mmol), 3-(2-methoxyphenyl)isonicotinic acid (49 mg, 0.21 mmol), 1- methylimidazole (62 µL, 0.74 mmol) and TCFH (61 mg, 0.21 mmol) in DMF (2 mL) following General method C. The crude product was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexanes). The isolated material was dissolved in ACN (1 mL), diluted with water (4 mL) and lyophilized to afford N-(5-((4- chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide (Compound 19) (25 mg, 26% yield) as a white solid. MS (ESI): m/z 446.1 (calcd), 447.1 (M+H⁺, found).¹H NMR ( 400 MHz, DMSO-d₆) δ ppm 3.46 (3H, s), 6.98 (1H, d, J = 8.1 Hz), 7.08 (1H, t, J = 7.5 Hz), 7.40-7.36 (2H, m), 7.61-7.55 (2H, m), 7.72-7.70 (3H, m), 8.65 (1H, s), 8.75 (1H, d, J = 5.0 Hz), 13.52 (1H, s). MS (ESI): m/z 446.1 (calcd), 447.1 (M+H⁺, found). Example 20. Preparation of 3-(2-methoxyphenyl)-N-(5-(4-phenylbut-1-yn-1-yl)-1,3,4-

thiadiazol-2-yl)isonicotinamide (Compound 20)

Step 1: Synthesis of tert-butyl (5-(4-phenylbut-1-yn-1-yl)-1,3,4-thiadiazol-2- yl)carbamate The title compound was obtained from N-boc-2-amino-5-bromo[1,3,4]thiadiazole (300 mg, 1.05 mmol,), 4-phenyl-1-butyne (137 mg, 1.05 mmol), copper iodide (20 mg, 0.10 mmol), tetrakis(triphenylphosphine)palladium (122 mg, 0.11 mmol), DIPA (147 µL, 1.05 mmol) in DMF (3 mL) following General method E. The crude product was purified by flash column chromatography (eluent gradient from 20% to 90% of EA in hexane) to afford tert-butyl (5-(4-phenylbut-1-yn-1-yl)-1,3,4-thiadiazol-2-yl)carbamate (300 mg, 87 % yield). MS (ESI): m/z 329.4 (calcd), 330.1 (M+H⁺, found). Step 2: Synthesis of 5-(4-phenylbut-1-yn-1-yl)-1,3,4-thiadiazol-2-amine The title compound was prepared from tert-butyl (5-(4-phenylbut-1-yn-1-yl)-1,3,4- thiadiazol-2-yl)carbamate (200 mg, 0.61 mmol), trifluoroacetic acid (465 µL, 6.07 mmol) in DCM (6 mL) following General method F. The reaction mixture was concentrated to dryness to afford 5-(4-phenylbut-1-yn-1-yl)-1,3,4-thiadiazol-2-amine (139 mg, quantitative yield) as an orange solid. The crude material was used in the next step without further purification MS (ESI): m/z 229.3 (calcd), 230.1 (M+H⁺, found). Step 3: Synthesis of 3-(2-methoxyphenyl)-N-(5-(4-phenylbut-1-yn-1-yl)-1,3,4-thiadiazol- 2-yl)isonicotinamide (Compound 20) The title compound was obtained from 5-(4-phenylbut-1-yn-1-yl)-1,3,4-thiadiazol-2- amine (100 mg, 0.44 mmol), 3-(2-methoxyphenyl)isonicotinic acid (100 mg, 0.44 mmol), 1- methylimidazole (290 µL, 3.50 mmol) and TCFH (125 mg, 0.44 mmol) in DMF (2 mL), following General method C. The crude product was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexanes). The isolated product was dissolved in ACN (1 mL), diluted with water (4 mL) and lyophilized to afford 3-(2- methoxyphenyl)-N-(5-(4-phenylbut-1-yn-1-yl)-1,3,4-thiadiazol-2-yl)isonicotinamide (50 mg, 26% yield) as a white solid.¹H NMR (400 MHz, DMSO- d₆) δppm 2.91-2.82 (4H, m), 3.45 (3H, s), 6.97 (1H, d, J = 8.4 Hz), 7.07 (1H, t, J = 7.4 Hz), 7.24-7.19 (1H, m), 7.31 (4H, m), 7.39-7.36 (2H, m), 7.72-7.63 (1H, s), 8.80-8.61 (2H, br, s), 13.36 (1H, s). MS (ESI): m/z 440.5 (calcd), 441.3 (M+H⁺, found). Example 21. Preparation of 3-(2-methoxyphenyl)-N-(5-(3-phenoxyprop-1-yn-1-yl)-1,3,4- thiadiazol-2-yl)isonicotinamide (Compound 21)

Step 1: Synthesis of tert-butyl (5-(3-phenoxyprop-1-yn-1-yl)-1,3,4-thiadiazol-2- yl)carbamate The title compound was prepared from N-boc-2-amino-5-bromo[1,3,4]thiadiazole (300 mg, 1.05 mmol), phenyl propargyl ether (137 mg, 1.05 mmol), copper iodide (20 mg, 0.10 mmol) and tetrakis(triphenylphosphine)palladium (122 mg, 0.11 mmol), DIPA (147 µL, 1.05 mmol) in DMF (3 mL) following General method E. The crude product was purified by flash column chromatography (eluent gradient from 20% to 90% of EA in hexanes) to afford tert-butyl (5-(3-phenoxyprop-1-yn-1-yl)-1,3,4-thiadiazol-2-yl)carbamate (310 mg, 89 % yield). MS (ESI): m/z 331.4 (calcd), 332.1 (M+H⁺, found). Step 2: Synthesis of 5-(3-phenoxyprop-1-yn-1-yl)-1,3,4-thiadiazol-2-amine The title compound was prepared from tert-butyl (5-(3-phenoxyprop-1-yn-1-yl)-1,3,4- thiadiazol-2-yl)carbamate (200 mg, 0.60 mmol), trifluoroacetic acid (462 µL, 6.04 mmol) in DCM (6 mL) following General method F. The reaction mixture was concentrated to dryness to afford 5-(3-phenoxyprop-1-yn-1-yl)-1,3,4-thiadiazol-2-amine (139 mg, quantitative yield) as an orange solid. The crude product was used in the next step without further purification MS (ESI): m/z 231.3 (calcd), 232.1 (M+H⁺, found). Step 3: Synthesis of 3-(2-methoxyphenyl)-N-(5-(3-phenoxyprop-1-yn-1-yl)-1,3,4- thiadiazol-2-yl)isonicotinamide (Compound 21) The title compound was prepared from 5-(3-phenoxyprop-1-yn-1-yl)-1,3,4-thiadiazol- 2-amine (20 mg, 0.09 mmol), 3-(2-methoxyphenyl)isonicotinic acid (20 mg, 0.09 mmol), 1- methylimidazole (57 µL, 0.69 mmol) and TCFH (25 mg, 0.09 mmol) in DMF (1 mL) following General method C. The crude product was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexanes). The isolated material was dissolved in ACN (1 mL), diluted with water (4 mL) and lyophilized to afford 3-(2- methoxyphenyl)-N-(5-(3-phenoxyprop-1-yn-1-yl)-1,3,4-thiadiazol-2-yl)isonicotinamide (Compound 21) (10 mg, 26% yield) as a white solid.¹H NMR (400 MHz, DMSO- d₆) δ ppm 3.44 (3H, s), 5.17 (2H, s), 7.13- 6.91 (5H, m), 7.40-7.32 (4H, m), 7.68 (1H, d, J = 5.0 Hz), 8.62 (1H, s), 8.72 (1H, d, J = 5.0 Hz), 13.54-13.46 (1H, s). MS (ESI): m/z 442.5 (calcd), 443.3 (M+H⁺, found). Example 22. Preparation of tert-butyl 4-((5-(3-(2-methoxyphenyl)isonicotinamido)-1,3,4- thiadiazol-2-yl)oxy)piperidine-1-carboxylate (Compound 22)

Step 1: Synthesis of tert-butyl 4-((5-bromo-1,3,4-thiadiazol-2-yl)oxy)piperidine-1- carboxylate The title compound was prepared from 2,5-dibromo-1,3,4-thiadiazole (100 mg, 0.41 mmol), tert-butyl 4-hydroxy-1-piperidinecarboxylate (165 mg, 0.82 mmol) and sodium hydride (60% dispersion in mineral oil) (49.20 mg, 1.23 mmol) in DMF (2 mL) following General method D. The crude product was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexanes) to obtain tert-butyl 4-((5-bromo-1,3,4- thiadiazol-2-yl)oxy)piperidine-1-carboxylate (140 mg, 94 % yield) as a white solid. Step 2: Synthesis of tert-butyl 4-((5-(3-(2-methoxyphenyl)isonicotinamido)-1,3,4- thiadiazol-2-yl)oxy)piperidine-1-carboxylate (Compound 22) – General method G To a stirring solution of tert-butyl 4-((5-bromo-1,3,4-thiadiazol-2-yl)oxy)piperidine- 1-carboxylate (20 mg, 0.06 mmol) in DMF (1 mL), 3-(2-methoxyphenyl)isonicotinamide (15 mg, 0.07 mmol) was added. The reaction mixture was degassed under flow of argon for 5 min before cesium carbonate (36 mg, 0.11 mmol), tris(dibenzylideneacetone)dipalladium (5 mg, 0.01 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7 mg, 0.01 mmol) were added. The reaction mixture was flushed with argon under reduced pressure before being warmed to 100 ℃. The reaction mixture was stirred for 3 h cooled to room temperature, filtered through a Celite pad and concentrated under reduced pressure. The crude product was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexanes) to obtain tert-butyl 4-((5-(3-(2-methoxyphenyl)isonicotinamido)- 1,3,4-thiadiazol-2-yl)oxy)piperidine-1-carboxylate (Compound 22) (20 mg, 71 % yield) as a white solid.¹H NMR (400 MHz, DMSO- d₆) δppm 1.40 (9H, s), 1.68-1.59 (2H, m), 2.05- 1.98 (2H, m), 3.24- 3.14 (2H, m), 3.52 (3H, s), 3.68-3.62 (2H, m), 5.10-5.06 (1H, m), 6.99 (1H, d, J = 8.2 Hz), 7.08- 7.04 (1H, m), 7.39-7.34 (2H, m), 7.62 (1H, d, J = 5.0 Hz), 8.61 (1H, s), 8.71 (1H, d, J = 5.0 Hz), 12.85 (1H, s). MS (ESI): m/z 511.6 (calcd), 512.3 (M+H⁺, found). Example 23. Preparation of 3-(2-methoxyphenyl)-N-(5-(piperidin-4-yloxy)-1,3,4- thiadiazol-2-yl)isonicotinamide (Compound 23)

The title compound was prepared from tert-butyl 4-((5-(3-(2-methoxyphenyl) isonicotinamido)-1,3,4-thiadiazol-2-yl)oxy)piperidine-1-carboxylate (Compound 22) (7 mg, 0.014 mmol) and trifluoroacetic acid (53 µL, 0.68 mmol) in DCM (1 mL) following General method F. The crude product was purified by Prep-HPLC (Column: Gemini® 5 um NX-C18 110 Å, 100 x 30 mm) (eluent gradient from 25% to 100% of MeOH in ammonium formate 10 mM) to provide 3-(2-methoxyphenyl)-N-(5-(piperidin-4-yloxy)-1,3,4-thiadiazol-2-yl) isonicotinamide (Compound 23) (2.3 mg, 41 % yield) as a white solid.¹H NMR (400 MHz, DMSO- d₆) δ ppm 1.86 (2H, br, s), 2.17 (2H, br, s), 2.97 (2H, br, s), 3.17 (2H, br, s), 3.53 (3H, s), 5.06 (1H, s), 7.03-6.97 (2H, m), 7.37-7.29 (2H, m), 7.62 (1H, t, J = 4.4 Hz), 8.57 (1H, s), 8.68 (1H, s). MS (ESI): m/z 411.5 (calcd), 412.2 (M+H⁺, found). Example 24. Preparation of N-(5-((1-acetylpiperidin-4-yl)oxy)-1,3,4-thiadiazol-2-yl)-3- (2-methoxyphenyl)isonicotinamide (Compound 24)

Step 1: Synthesis of 1-(4-((5-amino-1,3,4-thiadiazol-2-yl)oxy)piperidin-1-yl)ethan-1-one The title compound was prepared from 2-amino-5-bromo-1,3,4-thiadiazole (50 mg, 0.28 mmol), 1-(4-hydroxypiperidin-1-yl)ethanone (81 mg, 0.56 mmol) and sodium hydride (60% dispersion in mineral oil) (33 mg, 0.83 mmol) in DMF (2 mL) following General method D. The crude product was purified by flash column chromatography (eluent gradient from 0% to 10% of MeOH (0.1% NH₄OH) in DCM) to obtain 1-(4-((5-amino-1,3,4- thiadiazol-2-yl)oxy)piperidin-1-yl)ethan-1-one (13 mg, 19 % yield) as a colorless oil. MS (ESI): m/z 242.3 (calcd), 243.1 (M+H⁺, found). Step 2: Synthesis of N-(5-((1-acetylpiperidin-4-yl)oxy)-1,3,4-thiadiazol-2-yl)-3-(2- methoxyphenyl)isonicotinamide (Compound 24) The title compound was obtained from 1-(4-((5-amino-1,3,4-thiadiazol-2- yl)oxy)piperidin-1-yl)ethan-1-one (13 mg, 0.05 mmol), 3-(2-methoxyphenyl)isonicotic acid (12 mg, 0.05 mmol), 1-methylimidazole (16 µL, 0.19 mmol) and TCFH (15 mg, 0.05 mmol) in DMF (1 mL) following General method C. The crude product was purified by Prep- HPLC (Column: Gemini® 5 um NX-C18110 Å, 100 x 30 mm) (eluent gradient from 25% to 100% of MeOH in ammonium bicarbonate 10 mM). The isolated product was dissolved in ACN (1 mL), diluted with water (4 mL) and lyophilized to afford N-(5-((1-acetylpiperidin-4- yl)oxy)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide (Compound 24) (10 mg, 41% yield) as a white solid.¹H NMR (400 MHz, DMSO- d₆) δ ppm 1.78-1.58 (2H, m), 2.09- 2.00 (5H, m), 3.25-3.16 (1H, m), 3.36-3.33 (1H, m), 3.53 (3H, s), 3.69-3.62 (1H, m), 3.86- 3.79 (1H, m), 5.11-5.05 (1H, m), 6.99 (1H, d, J = 8.9 Hz), 7.03 (1H, td, J = 7.5, 0.8 Hz), 7.36-7.29 (2H, m), 7.62 (1H, d, J = 4.8 Hz), 8.59-8.53 (1H, m), 8.69-8.63 (1H, m), 12.86 (1H, s). MS (ESI): m/z 453.5 (calcd), 454.2 (M+H⁺, found). Example 25. Preparation of N-(5-(2-(4-bromophenoxy)ethoxy)-1,3,4-thiadiazol-2-yl)-3- (2-methoxyphenyl)isonicotinamide (Compound 25)

Step 1: Synthesis of 2-bromo-5-(2-(4-bromophenoxy)ethoxy)-1,3,4-thiadiazole The title compound was obtained from 2-amino-5-bromo-1,3,4-thiadiazole (100 mg, 0.56 mmol), 2-(4-bromophenoxy)ethanol (181 mg, 0.83 mmol) and sodium hydride (60% dispersion in mineral oil) (29 mg, 0.72 mmol) in DMF (2 mL) following General method D. The crude product was purified by flash column chromatography (eluent gradient from 0% to 10% of MeOH (0.1%NH₄OH) in DCM) to obtain 2-bromo-5-(2-(4-bromophenoxy)ethoxy)- 1,3,4-thiadiazole (150 mg, 85 % yield) as a colorless oil. MS (ESI): m/z 316.1 (calcd), 318.0 (M+H⁺, found). Step 2: Synthesis of N-(5-(2-(4-bromophenoxy)ethoxy)-1,3,4-thiadiazol-2-yl)-3-(2- methoxyphenyl)isonicotinamide (Compound 25) The title compound was obtained from 2-bromo-5-(2-(4-bromophenoxy)ethoxy)- 1,3,4-thiadiazole (100 mg, 0.32 mmol), 3-(2-methoxyphenyl)isonicotinic acid (73 mg, 0.32 mmol), 1-methylimidazole (92 µL, 1.11 mmol) and TCFH (91 mg, 0.32 mmol) in DMF (1.50 mL) following General method C. The crude product was purified by Prep-HPLC (Column: Gemini® 5 um NX-C18110 Å, 100 x 30 mm) (eluent gradient from 25% to 100% of ACN in ammonium bicarbonate 10 mM). The isolated product was dissolved in ACN (1 mL), diluted with water (4 mL) and lyophilized to afford N-(5-(2-(4-bromophenoxy)ethoxy)-1,3,4- thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide (Compound 25) (20 mg, 12% yield) as a white solid.¹H NMR (400 MHz, DMSO- d₆) δ ppm 3.51 (3H, s), 4.35-4.33 (2H, m), 4.70- 4.67 (2H, m), 7.05-6.95 (4H, m), 7.37-7.30 (2H, m), 7.46-7.43 (2H, m), 7.63 (1H, d, J = 5.0 Hz), 8.55 (1H, s), 8.65 (1H, d, J = 4.9 Hz), 12.87 (1H, s). MS (ESI): m/z 527.4 (calcd), 529.0 (M+H⁺, found). Example 26. Preparation of N-(5-(2-(4-chlorophenoxy)ethoxy)-1,3,4-thiadiazol-2-yl)-3- (2-methoxyphenyl)isonicotinamide (Compound 26)

Step 1: Synthesis of 2-amino-5-(2-(4-chlorophenoxy)ethoxy)-1,3,4-thiadiazole The title compound was obtained from 2-amino-5-bromo-1,3,4-thiadiazole (300 mg, 1.67 mmol), 2-(4-chlorophenoxy)ethanol (431 mg, 2.50 mmol) and sodium hydride (87 mg, 2.17 mmol) in DMF (3 mL) following General method D. The crude product was purified by flash column chromatography (eluent gradient from 0% to 10% of MeOH (0.1%NH₄OH) in DCM) to obtain 2-amino-5-(2-(4-chlorophenoxy)ethoxy)-1,3,4-thiadiazole (400 mg, 88 % yield) as a colorless oil. MS (ESI): m/z 271.7 (calcd), 272.1 (M+H⁺, found). Step 2: Synthesis of N-(5-(2-(4-chlorophenoxy)ethoxy)-1,3,4-thiadiazol-2-yl)-3-(2- methoxyphenyl)isonicotinamide (Compound 26) The title compound was obtained from 2-amino-5-(2-(4-chlorophenoxy)ethoxy)- 1,3,4-thiadiazole (100 mg, 0.32 mmol), 3-(2-methoxyphenyl)isonicotinic acid (84 mg, 0.37 mmol), 1-methylimidazole (107 µL, 1.29 mmol) and TCFH (105 mg, 0.37 mmol) in DMF (1.5 mL) following General method C. The crude product was purified by Prep-HPLC (Column: Gemini® 5 um NX-C18110 Å, 100 x 30 mm) (eluent gradient from 25% to 100% of ACN in ammonium bicarbonate 10 mM). The isolated material was dissolved in ACN (1 mL), diluted with water (4 mL) and lyophilized to afford N-(5-(2-(4-chlorophenoxy)ethoxy)- 1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide (Compound 26) (82 mg, 46% yield) as a white solid.¹H NMR (400 MHz, DMSO- d6) δ ppm 3.51 (3H, s), 4.37-4.35 (2H, m), 4.74- 4.72 (2H, m), 7.08-6.97 (4H, m), 7.39-7.32 (4H, m), 7.63 (1H, d, J = 5.0 Hz), 8.60 (1H, s), 8.71 (1H, d, J = 4.9 Hz), 12.86 (1H, s). MS (ESI): m/z 482.9 (calcd), 483.2 (M+H⁺, found). Example 27. Preparation of 3-(2-methoxyphenyl)-N-(5-(2-phenoxyethoxy)-1,3,4- thiadiazol-2-yl)isonicotinamide (Compound 27)

Step 1: Synthesis of 2-bromo-5-(2-phenoxyethoxy)-1,3,4-thiadiazole The title compound was obtained from 2-amino-5-bromo-1,3,4-thiadiazole (300 mg, 1.67 mmol), 2-phenoxyethanol (345 mg, 1.5 mmol) and sodium hydride (87 mg, 2.17 mmol) in DMF (3 mL) following General method D. The crude product was purified by flash column chromatography (eluent gradient from 0% to 10% of MeOH (0.1%NH₄OH) in DCM) to obtain 2-bromo-5-(2-phenoxyethoxy)-1,3,4-thiadiazole (300 mg, 76 % yield) as a colorless oil. MS (ESI): m/z 237.3 (calcd), 238.1 (M+H⁺, found). Step 2: Synthesis of 3-(2-methoxyphenyl)-N-(5-(2-phenoxyethoxy)-1,3,4-thiadiazol-2- yl)isonicotinamide (Compound 27) The title compound was obtained from 2-bromo-5-(2-phenoxyethoxy)-1,3,4- thiadiazole (100 mg, 0.32 mmol), 3-(2-methoxyphenyl)isonicotinic acid (97 mg, 0.42 mmol), 1-methylimidazole (122 µL, 1.48 mmol) and TCFH (121 mg, 0.42 mmol) in DMF (1.5 mL) following General method C. The crude product was purified by Prep-HPLC (Column: Gemini® 5 um NX-C18110 Å, 100 x 30 mm) (eluent gradient from 25% to 100% of ACN in ammonium bicarbonate 10 mM). The isolated material was dissolved in ACN (1 mL), diluted with water (4 mL) and lyophilized to afford 3-(2-methoxyphenyl)-N-(5-(2-phenoxyethoxy)- 1,3,4-thiadiazol-2-yl)isonicotinamide (Compound 27) (110 mg, 58% yield) as a white solid. ¹H NMR (400 MHz, DMSO- d₆) δ ppm 3.52 (3H, s), 4.35 (2H, m), 4.74 (2H, m), 7.00-6.94 (4H, m), 7.07 (1H, t, J = 7.5 Hz), 7.37-7.28 (4H, m), 7.63 (1H, d, J = 5.0 Hz), 8.61 (1H, s), 8.71 (1H, d, J = 5.0 Hz), 12.86 (1H, s). MS (ESI): m/z 448.5 (calcd), 449.2 (M+H⁺, found). Example 28. Preparation of 3-(2-methoxyphenyl)-N-(5-((1-phenylcyclopropyl)ethynyl)- 1,3,4-thiadiazol-2-yl)isonicotinamide (Compound 28)

Step 1: Synthesis of tert-butyl (5-((1-phenylcyclopropyl)ethynyl)-1,3,4-thiadiazol-2- yl)carbamate The title compound was prepared from N-boc-2-amino-5-bromo[1,3,4]thiadiazole (300 mg, 1.05 mmol,), (1-ethynylcyclopropyl)benzene (142 mg, 1.05 mmol), copper iodide (20 mg, 0.10 mmol), tetrakis(triphenylphosphine)palladium (122 mg, 0.11 mmol) and DIPA (147 µL, 1.05 mmol) in DMF (3 mL) following General method E. The crude product was purified by flash column chromatography (eluent gradient from 20% to 90% of EA in hexanes) to afford tert-butyl (5-((1-phenylcyclopropyl)ethynyl)-1,3,4-thiadiazol-2- yl)carbamate (280 mg, 78 % yield). MS (ESI): m/z 341.43 (calcd), 342.1 (M+H⁺, found). Step 2: Synthesis of 5-((1-phenylcyclopropyl)ethynyl)-1,3,4-thiadiazol-2-amine The title compound was obtained from tert-butyl (5-((1-phenylcyclopropyl)ethynyl)- 1,3,4-thiadiazol-2-yl)carbamate (280 mg, 0.82 mmol) and trifluoroacetic acid (628 µL, 8.20 mmol) in DCM (6 mL) following General method F. The reaction mixture was concentrated to dryness to afford 5-((1-phenylcyclopropyl)ethynyl)-1,3,4-thiadiazol-2-amine (198 mg, quantitative yield) as an orange solid. The crude material was used in the next step without further purification MS (ESI): m/z 241.3 (calcd), 242.1 (M+H⁺, found). Step 3: Synthesis of 3-(2-methoxyphenyl)-N-(5-((1-phenylcyclopropyl)ethynyl)-1,3,4- thiadiazol-2-yl)isonicotinamide (Compound 28) The title compound was obtained from 5-((1-phenylcyclopropyl)ethynyl)-1,3,4- thiadiazol-2-amine (50 mg, 0.21 mmol), 3-(2-methoxyphenyl)isonicotinic acid (48 mg, 0.21 mmol), 1-methylimidazole (60 µL, 0.73 mmol) and TCFH (59 mg, 0.21 mmol) in DMF (1.5 mL) following General method C. The crude product was purified by Prep-HPLC (Column: Gemini® 5 um NX-C18110 Å, 100 x 30 mm) (eluent gradient from 25% to 100% of ACN in ammonium bicarbonate 10 mM). The purified material was dissolved in ACN (1 mL), diluted with water (4 mL) and lyophilized to afford 3-(2-methoxyphenyl)-N-(5-((1- phenylcyclopropyl) ethynyl)-1,3,4-thiadiazol-2-yl)isonicotinamide (Compound 28) (45 mg, 48% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.49-1.46 (2H, m), 1.65- 1.62 (2H, m), 3.46 (3H, s), 6.97 (1H, d, J = 8.5 Hz), 7.07 (1H, t, J = 7.5 Hz), 7.27-7.23 (1H, m), 7.40-7.33 (6H, m), 7.68 (1H, d, J = 4.9 Hz), 8.62 (1H, s), 8.73 (1H, s), 13.39 (1H, s). MS (ESI): m/z 452.5 (calcd), 453.2 (M+H⁺, found). Example 29. Preparation of (rac)-3-(2-methoxyphenyl)-N-(5-((1-phenoxypropan-2- yl)oxy)-1,3,4-thiadiazol-2-yl)isonicotinamide (Compound 29)

Step 1: Synthesis of 5-((1-phenoxypropan-2-yl)oxy)-1,3,4-thiadiazol-2-amine The title compound was obtained from 2-amino-5-bromo-1,3,4-thiadiazole (300 mg, 1.67 mmol), 1-phenoxy-2-propanol (380 mg, 2.5 mmol) and sodium hydride (87 mg, 2.17 mmol) in DMF (3 mL) following General method D. The crude product was purified by flash column chromatography (eluent gradient from 0% to 10% of MeOH (0.1%NH₄OH) in DCM) to obtain 5-((1-phenoxypropan-2-yl)oxy)-1,3,4-thiadiazol-2-amine (100 mg, 24 %) as a colorless oil. MS (ESI): m/z 251.3 (calcd), 252.2 (M+H⁺, found). Step 2: Synthesis of 3-(2-methoxyphenyl)-N-(5-((1-phenoxypropan-2-yl)oxy)-1,3,4- thiadiazol-2-yl)isonicotinamide (Compound 29) The title compound was obtained from 5-((1-phenoxypropan-2-yl)oxy)-1,3,4- thiadiazol-2-amine (50 mg, 0.19 mmol), 3-(2-methoxyphenyl)isonicotinic acid (46 mg, 0.20 mmol), 1-methylimidazole (58 µL, 0.70 mmol) and TCFH (57 mg, 0.20 mmol) in DMF (1 mL) following General method C. The crude product was purified by reverse phase C18 column chromatography (eluent gradient from 0% to 100% of ACN in water containing 0.1% of FA). The isolated product was dissolved in ACN (1 mL), diluted with water (4 mL) and lyophilized to afford 3-(2-methoxyphenyl)-N-(5-((1-phenoxypropan-2-yl)oxy)-1,3,4- thiadiazol-2-yl)isonicotinamide (Compound 29) (50 mg, 54% yield) as a white solid.¹H NMR (400 MHz, DMSO- d₆) δ ppm 1.31 (1H, d, J = 6.3 Hz), 1.47 (3H, d, J = 6.4 Hz), 3.50 (1H, s), 3.52 (3H, s), 4.24-4.18 (1H, m), 5.38-5.31 (1H, m), 7.00-6.92 (7H, m), 7.06 (1H, t, J = 7.5 Hz), 7.30- 7.25 (3H, m), 7.40-7.34 (2H, m), 7.63 (2H, t, J = 4.8 Hz), 8.60 (1H, s), 8.70 (1H, d, J = 5.0 Hz), 12.49 (1H, br s). MS (ESI): m/z 462.5 (calcd), 463.4 (M+H⁺, found). Example 30. Preparation of N-(5-(3-hydroxy-3-methylbut-1-yn-1-yl)-1,3,4-thiadiazol-2- yl)-3-(2-methoxyphenyl)isonicotinamide (Compound 30)

Step 1: Synthesis of tert-butyl (5-(3-hydroxy-3-methylbut-1-yn-1-yl)-1,3,4-thiadiazol-2- yl)carbamate Dry benzene (1 mL) was added to a mixture of N-boc-2-amino-5- bromo[1,3,4]thiadiazole (300 mg, 1.05 mmol,), 2-methyl-3-butyn-2-ol (88 mg, 1.05 mmol), copper iodide (20 mg, 0.10 mmol), dichlorobis-(triphenylphosphine)palladium(II) (15 mg, 0.02 mmol) and triphenylphosphine (11 mg, 0.04 mmol) followed by addition of Et₃N (2 mL, 15.70 mmol). The mixture was degassed three times and filled with argon. The reaction mixture was stirred at 80 °C for 6 h, cooled to room temperature, diluted with water, and extracted with EA (15 mL × 3). The combined organic extracts were dried over anhydrous Na₂SO₄, filtered, and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (eluent gradient from 20% to 90% of EA in hexanes) to afford tert-butyl (5-(3-hydroxy-3-methylbut-1-yn-1-yl)-1,3,4-thiadiazol-2- yl)carbamate (113 mg, 38 % yield). MS (ESI): m/z 283.3 (calcd), 284.1 (M+H⁺, found). Step 2: Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-2-methylbut-3-yn-2-ol The title compound was obtained from tert-butyl (5-(3-hydroxy-3-methylbut-1-yn-1- yl)-1,3,4-thiadiazol-2-yl)carbamate (112 mg, 0.39 mmol), trifluoroacetic acid (605 µL, 7.91 mmol) in DCM (2 mL) following General method F. The reaction mixture was concentrated to dryness to afford 4-(5-amino-1,3,4-thiadiazol-2-yl)-2-methylbut-3-yn-2-ol (73 mg, 100 % yield) as an orange solid. The crude material was used in the next step without further purification MS (ESI): m/z 183.2 (calcd), 184.1 (M+H⁺, found). Step 3: Synthesis of N-(5-(3-hydroxy-3-methylbut-1-yn-1-yl)-1,3,4-thiadiazol-2-yl)-3-(2- methoxyphenyl)isonicotinamide (Compound 30) The title compound was obtained from 4-(5-amino-1,3,4-thiadiazol-2-yl)-2- methylbut-3-yn-2-ol (50 mg, 0.27 mmol), 3-(2-methoxyphenyl)isonicotinic acid (63 mg, 0.27 mmol), 1-methylimidazole (79 µL, 0.96 mmol) and TCFH (78 mg, 0.27 mmol) in DMF (1 mL) following General method C. The crude product was purified by reverse phase C18 column chromatography (eluent gradient from 0% to 100% of ACN in 0.1% of FA). The isolated material was dissolved in ACN (1 mL), diluted with water (4 mL) and lyophilized to afford N-(5-(3-hydroxy-3-methylbut-1-yn-1-yl)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl) isonicotinamide (Compound 30) (40 mg, 37% yield) as a white solid.¹H NMR (400 MHz, DMSO- d₆) δ ppm 1.48 (6H, s), 3.45 (3H, s), 5.76 (1H, s), 6.97 (1H, d, J = 8.5 Hz), 7.07 (1H, t, J = 7.5 Hz), 7.40-7.36 (2H, m), 7.68 (1H, d, J = 5.0 Hz), 8.63 (1H, s), 8.74 (1H, d, J = 4.9 Hz), 13.40 (1H, s). MS (ESI): m/z 394.4 (calcd), 395.2 (M+H⁺, found). Example 31. Preparation of N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(2- methoxyphenyl)isonicotinamide (Compound 31)

Step 1: Synthesis of (5-bromo-1,3,4-thiadiazol-2-yl)methanol To a stirring solution of ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate (1 g, 4.01 mmol) in MeOH (16 mL) cooled to 0 ºC, sodium borohydride was added portion wise. Once gas evolution subsided, the reaction mixture was warmed to room temperature and stirred for 18 h. The reaction mixture was then diluted with EA and water was added. The layers were separated, and the organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to provide (5-bromo-1,3,4-thiadiazol-2-yl)methanol (607 mg, 78 % yield) as a yellow solid. The crude material was used in the next step without further purification. MS (ESI): m/z 193.9 (calcd), 195.1 (M+H⁺, found). Step 2: Synthesis of (5-bromo-1,3,4-thiadiazol-2-yl)methyl methanesulfonate To a stirring solution of (5-bromo-1,3,4-thiadiazol-2-yl)methanol (0.30 g, 1.54 mmol) in DCM (8 mL), methanesulfonyl chloride (0.16 mL, 2.00 mmol) and Et₃N (0.32 mL, 2.31 mmol) were added. The reaction mixture was stirred for 1 h and diluted with water. The layers were separated, and the organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent gradient from 10% to 50% EA in hexanes) to provide (5-bromo- 1,3,4-thiadiazol-2-yl)methyl methanesulfonate (400 mg, 95 % yield) as a yellow solid. MS (ESI): m/z 271.9 (calcd), 273.1-275-1 (M+H⁺, found). Step 3: Synthesis of 2-bromo-5-((4-chlorophenoxy)methyl)-1,3,4-thiadiazole To a stirring solution of 5-bromo-1,3,4-thiadiazol-2-yl)methyl methanesulfonate (0.20 g, 0.73 mmol) in DMF (3 mL), 4-chlorophenol (86 mg, 0.67 mmol) and K₂CO₃ (0.18 g, 1.33 mmol) were added. The reaction mixture was stirred for 4.5 h before water and EA were added. The layers were separated, and the aqueous layer was extracted with EA (x3). The combined organic layers were washed with brine (×3) and co-evaporated with heptanes (×2) to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent gradient from 5% to 100% EA in hexanes) to provide 2-bromo-5-((4- chlorophenoxy)methyl)-1,3,4-thiadiazole (168 mg, 83 % yield) as a white solid. MS (ESI): m/z 303.9 (calcd), 306.9 (M+H⁺, found). Step 4: Synthesis of N-(5-((4-chlorophenoxy)methyl)-1,3,4-thiadiazol-2-yl)-3-(2 methoxyphenyl)isonicotinamide (Compound 31) The title compound was obtained from benzyl 2-bromo-5-((4-chlorophenoxy)methyl)- 1,3,4-thiadiazole (0.26 g, 0.67 mmol), 3-(2-methoxyphenyl)isonicotinamide (56 µL, 0.24 mmol), Cs₂CO₃ (130 mg, 0.39 mmol), Pd₂(dba)₃ (19 mg, 0.02 mmol), XantPhos (23 mg, 0.04 mmol), and dioxane (0.98 mL) following General method G. Purification by Prep-HPLC (Column: Gemini® 5 um NX-C18110 Å, 100 x 30 mm) (eluent gradient from 50% to 100% of MeOH in ammonium bicarbonate) provided N-(5-((4-chlorophenoxy)methyl)-1,3,4- thiadiazol-2-yl)-3-(2 methoxyphenyl)isonicotinamide (Compound 31) (13 mg, 15 % yield) as a white solid.¹H NMR (400 MHz DMSO-d₆) δ ppm 3.40 (3H, s), 5.47 (2H, s), 6.93-6.91 (1H, m), 7.07-7.01 (3H, m), 7.36-7.32 (4H, m), 7.62 (1H, d, J = 5.0 Hz), 8.58 (1H, s), 8.68 (1H, d, J = 5.0 Hz), 13.14-13.11 (1H, br s). MS (ESI): m/z 452.1 (calcd), 453.3 (M+H⁺, found). Example 32. Preparation of N-(5-((4-chlorobenzyl)amino)-1,3,4-thiadiazol-2-yl)-3- (naphthalen-1-yl)isonicotinamide (Compound 32)

Step 1: Synthesis of ethyl 3-(naphthalen-1-yl)isonicotinate – General method H To a stirring solution of methyl 3-bromoisonicotinate (0.51 mL, 2.31 mmol) in dioxane (12 mL) sparged with argon, naphthalene-1-boronic acid (400 mg, 2.31 mmol), Pd(PPh₃)₄ (140 mg, 0.11 mmol), and K₂CO₃ (0.80 g, 5.79 mmol) were added. The reaction mixture was degassed under reduced pressure with backflow of argon three times, warmed to 100 ℃, and stirred for 2 h. The reaction mixture was cooled to room temperature and diluted with water and EA. The layers were separated, and the organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent gradient from 0% to 40% EA in hexanes) to provide ethyl 3-(naphthalen-1-yl)isonicotinate (0.55 g, 90 % yield) as a yellow oil. MS (ESI): m/z 263.1 (calcd), 264.1 (M+H⁺, found). Step 2: Synthesis of 3-(naphthalen-1-yl)isonicotinic acid To a solution of ethyl 3-(naphthalen-1-yl)isonicotinate (450 mg, 1.71 mmol) in THF (4.30 mL) was added a solution of lithium hydroxide (144 mg, 3.42 mmol) in water (4.30 mL). The reaction mixture was stirred for 2 h. The organic phase was separated, and the slightly yellow aqueous phase (pH 8-9) was collected and acidified with HCl 1M until a yellow precipitate was formed (pH 5-4). The precipitate was collected by filtration and dried to afford 3-(naphthalen-1-yl)isonicotinic acid as a yellow solid (350 mg, 82% yield). MS (ESI): m/z 249.08 (calcd), 250.2 (M+H⁺, found). Step 3: Synthesis of N-(5-((4-chlorobenzyl)amino)-1,3,4-thiadiazol-2-yl)-3-(naphthalen- 1-yl)isonicotinamide (Compound 32) The title compound was obtained from N²-(4-chlorobenzyl)-1,3,4-thiadiazole-2,5- diamine (48 mg, 0.20 mmol) in DMF (2 mL), 3-(naphthalen-1-yl)isonicotinic acid (50 mg, 0.20 mmol), 1-methylimidazole (58 µL, 0.70 mmol), and TCFH (57 mg, 0.20 mmol) following General method C. The residue was purified by flash column chromatography (eluent gradient from 30% to 100% EA in hexanes) to provide N-(5-((4- chlorobenzyl)amino)-1,3,4-thiadiazol-2-yl)-3-(naphthalen-1-yl)isonicotinamide (Compound 32) (41 mg, 43 % yield) as a white solid.¹H NMR (400 MHz DMSO-d₆) δ ppm 4.34 (2H, d, J = 5.8 Hz), 7.34-7.26 (4H, m), 7.40 (2H, m), 7.53-7.46 (3H, m), 7.71 (1H, d, J = 4.9 Hz), 7.94 (2H, t, J = 6.9 Hz), 8.61 (1H, s), 8.77 (1H, d, J = 5.0 Hz), 12.58 (1H, br, s). MS (ESI): m/z 471.1 (calcd), 472.3 (M+H⁺, found). Example 33. Preparation of N-(5-((4-chlorobenzyl)thio)-1,3,4-thiadiazol-2-yl)-3- (naphthalen-1-yl)isonicotinamide (Compound 33)

The title compound was obtained from 5-((4-chlorobenzyl)thio)-1,3,4-thiadiazol-2- amine (53 mg, 0.20 mmol) in DMF (2 mL), 3-(naphthalen-1-yl)isonicotinic acid (50 mg, 0.20 mmol), 1-methylimidazole (57 µL, 0.70 mmol), and TCFH (57 mg, 0.20 mmol) following General method C. The residue was purified by flash column chromatography (eluent gradient from 30% to 100% EA in hexanes) to provide N-(5-((4-chlorobenzyl)thio)-1,3,4- thiadiazol-2-yl)-3-(naphthalen-1-yl)isonicotinamide (Compound 33) (60 mg, 61 % yield) as a white solid.¹H NMR (400 MHz DMSO-d₆) δ ppm 4.38 (2H, s), 7.42-7.37 (2H, m), 7.53- 7.46 (3H, m), 7.79 (1H, dd, J = 5.0, 0.8 Hz), 7.95-7.92 (2H, m), 8.66 (1H, s), 8.82 (1H, d, J = 5.0 Hz), 13.30 (1H, br, s). MS (ESI): m/z 488.1 (calcd), 489.2 (M+H⁺, found). Example 34. Preparation of (E)-N-(5-(4-chlorostyryl)-1,3,4-thiadiazol-2-yl)-3- (naphthalen-1-yl)isonicotinamide (Compound 34)

The title compound was obtained from (E)-5-(4-chlorostyryl)-1,3,4-thiadiazol-2- amine (48 mg, 0.20 µmol) in DMF (2 mL), 3-(naphthalen-1-yl)isonicotinic acid (50 mg, 0.20 mmol), 1-methylimidazole (58 µL, 0.70 mmol), and TCFH (57 mg, 0.20 mmol) following General method C. The residue was purified by flash column chromatography (eluent gradient from 30% to 100% EA in hexanes) to provide (E)-N-(5-(4-chlorostyryl)-1,3,4- thiadiazol-2-yl)-3-(naphthalen-1-yl)isonicotinamide (Compound 34) (86 mg, 91 % yield) as a white solid.¹H NMR (400 MHz DMSO-d₆) δ ppm 7.47-7.37 (6H, m), 7.55-7.46 (3H, m), 7.67-7.64 (2H, m), 7.86 (1H, d, J = 5.0 Hz), 7.96 (2H, d, J = 8.2 Hz), 8.69 (1H, s), 8.86 (1H, d, J = 5.0 Hz), 13.34-13.31 (1H, br, s). MS (ESI): m/z 468.1 (calcd), 469.2 (M+H⁺, found). Example 35. Preparation of N-(5-(4-chlorophenethyl)-1,3,4-thiadiazol-2-yl)-3- (naphthalen-1-yl)isonicotinamide (Compound 35)

To a stirring solution of (E)-N-(5-(4-chlorostyryl)-1,3,4-thiadiazol-2-yl)-3- (naphthalen-1-yl)isonicotinamide (34, 86 mg, 0.18 mmol) in DMA (4 mL), palladium (10 wt. %) on carbon (20 mg, 18 µmol) was added. The reaction mixture was degassed under reduced pressure with backflow of hydrogen three times and stirred for 36 h under standard hydrogen atmosphere. The reaction mixture was filtered through a Celite pad and concentrated under reduced pressure. Purification by Prep-HPLC (Column: Gemini® 5 um NX-C18 110 Å, 100 x 30 mm) (eluent gradient from 50% to 100% of ACN in ammonium formate 10 mM) provided N-(5-(4-chlorophenethyl)-1,3,4-thiadiazol-2-yl)-3-(naphthalen-1- yl)isonicotinamide (Compound 35) (16.5 mg, 19 % yield) as a white solid.¹H NMR (400 MHz DMSO-d₆) δ ppm 2.90 (2H, t, J = 7.6 Hz), 3.15 (2H, t, J = 7.6 Hz), 7.18 (2H, d, J = 8.1 Hz), 7.26 (2H, d, J = 8.1 Hz), 7.39 (2H, t, J = 7.3 Hz), 7.52-7.45 (3H, m), 7.78 (1H, d, J = 5.0 Hz), 7.93 (2H, dd, J = 8.2, 4.5 Hz), 8.64 (1H, s), 8.80 (1H, d, J = 4.9 Hz), 13.10-13.05 (1H, br, s). MS (ESI): m/z 470.1 (calcd), 471.3 (M+H⁺, found). Example 36. Preparation of N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3- (naphthalen-1-yl)isonicotinamide (Compound 36)

The title compound was obtained from 5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol- 2-amine (47 mg, 0.20 mmol) in DMF (2 mL), 3-(naphthalen-1-yl)isonicotinic acid (50 mg, 0.20 mmol), 1-methylimidazole (58 µL, 0.70 mmol), and TCFH (57 mg, 0.20 mmol) following General method C. The crude product was purified by flash column chromatography (eluent gradient from 50% to 100% EA in hexanes) to provide N-(5-((4- chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(naphthalen-1-yl)isonicotinamide (Compound 36) (12.7 mg, 14 % yield) as a white solid.¹H NMR (400 MHz DMSO-d₆) δ ppm 7.43-7.39 (2H, m), 7.55-7.47 (5H, m), 7.62 (2H, d, J = 8.3 Hz), 7.85 (1H, d, J = 5.0 Hz), 7.94 (2H, d, J = 8.2 Hz), 8.69 (1H, s), 8.85 (1H, d, J = 5.0 Hz), 13.63 (1H, br, s). MS (ESI): m/z 466.1 (calcd), 467.2 (M+H⁺, found). Example 37. Preparation of N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3- (quinolin-4-yl)isonicotinamide (Compound 37)

Step 1: Synthesis of ethyl 3-(quinolin-4-yl)isonicotinate The title compound was prepared from methyl 3-bromoisonicotinate (0.51 mL, 2.31 mmol) in dioxane (12 mL) sparged with argon, quinoline-4-boronic acid (0.4 g, 2.31 mmol), Pd(PPh3)4 (0.14 g, 0.12 mmol), and K₂CO₃ (0.8 g, 5.79 mmol) following General method H, except that the reaction mixture was stirred for 18 h at 100 ºC. The residue was purified by flash column chromatography (eluent gradient from 30% to 100% EA in hexanes) to provide ethyl 3-(quinolin-4-yl)isonicotinate (167 mg, 27 % yield) as a colorless oil. MS (ESI): m/z 264.1 (calcd), 265.2 (M+H⁺, found). Step 2: Synthesis of 3-(quinolin-4-yl)isonicotinic acid To a solution of ethyl 3-(quinolin-4-yl)isonicotinate (80 mg, 0.30 mmol) in THF (1.30 mL) is added a solution of lithium hydroxide (37 mg, 1.51 mmol) in water (1.30 mL). The mixture was stirred for 18 h, the solvents were evaporated under reduce pressure and the resulting yellowish solid was used without further purification. MS (ESI): m/z 250.07 (calcd), 251.2 (M+H⁺, found). Step 3: Synthesis of N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(quinolin-4- yl)isonicotinamide (Compound 37) The title compound was obtained from 5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol- 2-amine (47 mg, 0.20 mmol) in DMF (2 mL), 3-(quinolin-4-yl)isonicotinic acid (50 mg, 0.20 mmol), 1-methylimidazole (58 µL, 0.70 mmol), and TCFH (57 mg, 0.20 mmol) following General method C. The residue was purified by flash column chromatography (eluent gradient from 0% to 20% MeOH in DCM) to provide N-(5-((4-chlorophenyl)ethynyl)-1,3,4- thiadiazol-2-yl)-3-(quinolin-4-yl)isonicotinamide (Compound 37) (15 mg, 16 % yield) as a yellow solid.¹H NMR (400 MHz DMSO-d₆) δ ppm 7.54-7.44 (5H, m), 7.62-7.59 (2H, m), 7.74-7.70 (1H, m), 7.95 (1H, d, J = 5.1 Hz), 8.04 (1H, d, J = 8.5 Hz), 8.73 (1H, s), 8.93-8.91 (2H, m), 13.78-13.73 (1H, br, s). MS (ESI): m/z 467.1 (calcd), 468.2 (M+H⁺, found). Example 38. Preparation of N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3- (isoquinolin-4-yl)isonicotinamide (Compound 38)

Step 1: Synthesis of (ethyl 3-(isoquinolin-4-yl)isonicotinate The title compound was obtained from methyl 3-bromoisonicotinate (62 mg, 0.29 mmol) in dioxane (1.54 mL) sparged with argon, 4-isoquinolineboronic acid (31 µL, 0.29 mmol), Pd(PPh₃)₄ (17 mg, 15 µmol), and a solution of K₂CO₃ (0.10 g, 0.72 mmol) in water (0.39 mL) following General method H, except that the reaction mixture was stirred for 4 h at 90 ºC. The crude product was purified by flash column chromatography (eluent gradient from 50% to 100% EA in hexanes) to provide (ethyl 3-(isoquinolin-4-yl)isonicotinate (57 mg, 75 % yield) as a white solid. MS (ESI): m/z 264.1 (calcd), 265.2 (M+H⁺, found). Step 2: Synthesis of 3-(isoquinolin-4-yl)isonicotinic acid To a stirring solution of ethyl 3-(isoquinolin-4-yl)isonicotinate (57 mg, 0.22 mmol) in THF (0.98 mL), a solution of LiOH (27 mg, 1.08 mmol) in water (0.98 mL) was added. The reaction mixture was stirred for 18 h before the volatiles were removed under reduced pressure to provide 3-(isoquinolin-4-yl)isonicotinic acid (53 mg, quant. yield) as a yellow solid. The crude material was used in the next step without further purification. MS (ESI): m/z 250.1 (calcd), 251.2 (M+H⁺, found). Step 3: Synthesis of N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(isoquinolin- 4-yl)isonicotinamide (Compound 38) The title compound was obtained from 5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol- 2-amine (48 mg, 0.20 mmol) in DMF (2 mL), 3-(isoquinolin-4-yl)isonicotinic acid (50 mg, 0.20 mmol), 1-methylimidazole (58 µL, 0.70 mmol), and TCFH (57 mg, 0.20 mmol) following General method C. The crude product was purified by flash column chromatography (eluent gradient from 1% to 10% MeOH in DCM) to provide N-(5-((4- chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(isoquinolin-4-yl)isonicotinamide (Compound 38) (13 mg, 14 % yield) as a white solid.¹H NMR (400 MHz DMSO-d₆) δ ppm 7.50 (3H, d, J = 8.1 Hz), 7.71-7.61 (4H, m), 7.92 (1H, d, J = 5.0 Hz), 8.16 (1H, d, J = 7.7 Hz), 8.39 (1H, s), 8.75 (1H, s), 8.89 (1H, s), 9.33 (1H, s), 13.73 (1H, br, s). MS (ESI): m/z 467.1 (calcd), 468.2 (M+H⁺, found). Example 39. Preparation of N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3- (isoquinolin-4-yl)isonicotinamide (Compound 39) – General Method I

To a stirring solution of 3-(2-methoxyphenyl)-N-(5-(4-phenylbut-1-yn-1-yl)-1,3,4- thiadiazol-2-yl)isonicotinamide (20, 5 mg, 11 µmol) in DMA (0.11 mL), palladium (10 wt. %) on carbon (1.21 mg, 1.14 µmol) was added. The reaction mixture was degassed under reduced pressure with backflow of hydrogen three times and stirred for 3 h under standard hydrogen atmosphere. The reaction mixture was diluted with EA and water was added. The layers were separated, and the organic layer was collected, washed with brine, dried over Na₂SO₄, filtered through a pad of Celite, and concentrated under reduced pressure to provide N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(isoquinolin-4-yl)isonicotinamide (Compound 39) (5 mg, quant. yield) as a white solid.¹H NMR (400 MHz DMSO-d₆) δ ppm 1.63-1.58 (2H, m), 1.74-1.65 (2H, m), 2.60 (2H, t, J = 1.1 Hz), 2.99 (2H, t, J = 7.4 Hz), 3.46 (3H, s), 6.96 (1H, d, J = 8.3 Hz), 7.05 (1H, t, J = 7.4 Hz), 7.19-7.15 (3H, m), 7.28-7.24 (2H, m), 7.38-7.34 (2H, m), 7.64 (1H, d, J = 5.0 Hz), 8.59-8.58 (1H, s), 8.70 (1H, d, J = 4.8 Hz), 12.92 (1H, br, s). MS (ESI): m/z 444.2 (calcd), 445.2 (M+H⁺, found). Example 40. Preparation of N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3- (isoquinolin-4-yl)isonicotinamide (Compound 40)

The title compound was obtained from 3-(2-methoxyphenyl)-N-(5-(4-phenylbut-1- yn-1-yl)-1,3,4-thiadiazol-2-yl)isonicotinamide (21, 5 mg, 11 µmol) and palladium (10 wt. %) on carbon (1.21 mg, 1.14 µmol) in DMA (0.11 mL) following General method I to provide N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(isoquinolin-4-yl)isonicotinamide (Compound 40) (5 mg, quant. yield) as a white solid.¹H NMR (400 MHz DMSO-d₆) δ ppm 2.19-2.12 (2H, m), 3.17-3.13 (2H, m), 3.46 (3H, s), 4.04-4.01 (2H, m), 6.96-6.90 (4H, m), 7.06 (1H, td, J = 7.5, 1.0 Hz), 7.30-7.26 (2H, m), 7.39-7.35 (2H, m), 7.64 (1H, d, J = 5.0 Hz), 8.61 (1H, s), 8.71 (1H, d, J = 5.0 Hz), 12.96-12.94 (1H, br, s). MS (ESI): m/z 446.1 (calcd), 447.3 (M+H⁺, found). Example 41. Preparation of N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-1-(2- methoxyphenyl)-1H-imidazole-5-carboxamide (Compound 41)

Step 1: Synthesis of ethyl (2-methoxyphenyl)glycinate To a stirring solution of ethyl bromoacetate (2 mL, 15.40 mmol) in DMF (46 mL), o- anisidine (2 mL, 16.20 mmol) and K₂CO₃ (4.48 g, 32.50 mmol) were added. The reaction mixture was heated to 90 ºC and stirred for 1.5 h. The reaction mixture was then cooled to room temperature, diluted with EA, and water was added. The layers were separated, and the organic layer was collected, washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent gradient from 0% to 50% EA in hexanes) to provide ethyl (2-methoxyphenyl)glycinate (2.42 g, 72 % yield) as a colorless oil. MS (ESI): m/z 209.1 (calcd), 210.2 (M+H⁺, found). Step 2: Synthesis of ethyl N-acetyl-N-(2-methoxyphenyl)glycinate To a stirring solution of ethyl (2-methoxyphenyl)glycinate (2.42 g, 11.60 mmol) in dry THF (29 mL) cooled to 0 ºC, acetyl chloride (0.99 mL, 13.9 mmol) was added dropwise. The reaction mixture was stirred for 15 min before Et₃N (1.62 mL, 11.6 mmol) was added dropwise. The reaction mixture was then warmed to room temperature and stirred for 2 h before being diluted with EA and water. The layers were separated, and the organic layer was collected, washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent gradient from 5% to 40% EA in hexanes) to provide ethyl N-acetyl-N-(2-methoxyphenyl)glycinate (2.57 g, 88 % yield) as a yellow oil. MS (ESI): m/z 251.1 (calcd), 252.3 (M+H⁺, found). Step 3: Synthesis of ethyl 2-mercapto-1-(2-methoxyphenyl)-1H-imidazole-5-carboxylate To a stirring solution of ethyl N-acetyl-N-(2-methoxyphenyl)glycinate (0.10 g, 0.40 mmol) in benzene (0.19 mL) cooled to 0 ºC, ethyl formate (0.11 mL, 1.33 mmol) and KOtBu (45 mg, 0.40 mmol) were added. The reaction mixture was let stand at 0 ºC for 18 h before water was added. The layers were separated, and the aqueous layer was treated with potassium thiocyanate (39 µL, 0.40 mmol) and conc. HCl (0.13 mL, 1.59 mmol) before warming to 60 ºC and stirring for 2 h. The reaction mixture was then cooled to room temperature and extracted with EA. The organic extract was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent gradient from 10% to 100% EA in hexanes) to provide ethyl 2-mercapto-1-(2-methoxyphenyl)-1H- imidazole-5-carboxylate (37 mg, 34 % yield) as a yellow solid. MS (ESI): m/z 278.1 (calcd), 279.1 (M+H⁺, found). Step 4: Synthesis of ethyl 1-(2-methoxyphenyl)-1H-imidazole-5-carboxylate To a solution of H₂WO₄ (2.54 mg, 10.8 µmol) in a mixture of water (2 mL) and ethanol (2 mL) at 0 ºC, hydrogen peroxide (0.19 mL, 1.89 mmol) and ethyl 2-mercapto-1-(2- methoxyphenyl)-1H-imidazole-5-carboxylate (0.15 g, 0.54 mmol) were added. The reaction mixture was warmed to room temperature and stirred for 4.5 h before a saturated solution of NaHCO₃ was added. The reaction mixture was then concentrated under reduced pressure and the aqueous layer was extracted with EA. The organic extract was concentrated under reduced pressure to provide ethyl 1-(2-methoxyphenyl)-1H-imidazole-5-carboxylate (0.13 g, 96 %) as a yellow oil. The crude material was used in the next step without further purification. MS (ESI): m/z 246.1 (calcd), 247.1 (M+H⁺, found). Step 5: Synthesis of 1-(2-methoxyphenyl)-1H-imidazole-5-carboxylic acid To a stirring solution of ethyl 1-(2-methoxyphenyl)-1H-imidazole-5-carboxylate (0.13 g, 0.52 mmol) in THF (1.30 mL), a solution of LiOH (37 mg, 1.56 mmol) in water (1.30 mL) was added. The reaction mixture was stirred for 18 h before conc. HCl was added, and the volatiles were removed under reduced pressure to provide 1-(2-methoxyphenyl)-1H- imidazole-5-carboxylic acid (112 mg, quant. yield) as a white solid. The crude material was used in the next step without further purification. MS (ESI): m/z 218.1 (calcd), 219.2 (M+H⁺, found). Step 6: Synthesis of N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-1-(2- methoxyphenyl)-1H-imidazole-5-carboxamide (Compound 41) The title compound was obtained from 5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol- 2-amine (14 mg, 64.2 µmol) in DMF (0.60 mL), 1-(2-methoxyphenyl)-1H-imidazole-5- carboxylic acid (15 mg, 64.20 µmol), 1-methylimidazole (20 µL, 0.23 mmol), and TCFH (18 mg, 64.20 µmol) following General method C. Purification by Prep-HPLC (Column: Gemini® 5 um NX-C18110 Å, 100 x 30 mm) (eluent gradient from 70% to 100% of ACN in ammonium bicarbonate) provided N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-1- (2-methoxy phenyl)-1H-imidazole-5-carboxamide (Compound 41) (13 mg, 14 % yield) as a white solid.¹H NMR (400 MHz DMSO-d₆) δ ppm 3.61 (3H, s), 7.00 (1H, td, J = 7.6, 1.2 Hz), 7.12 (1H, dd, J = 8.3, 1.2 Hz), 7.27 (1H, dd, J = 7.8, 1.7 Hz), 7.41-7.37 (1H, m), 7.49- 7.46 (2H, m), 7.58-7.55 (2H, m), 7.71 (2H, s). MS (ESI): m/z 435.1 (calcd), 436.1 (M+H⁺, found). Example 42. Preparation of 3-(2-methoxyphenyl)-N-(5-methyl-1,3,4-thiadiazol-2- yl)isonicotinamide (Compound 42)

The title compound was obtained from 2-amino-5-methyl-1,3,4-thiadiazole (50 mg, 0.44 mmol) in DMF (2 mL), 3-(2-methoxyphenyl)isonicotinic acid (0.10 g, 0.44 mmol), 1- methylimidazole (0.13 mL, 1.53 mmol), and TCFH (0.13 g, 0.44 mmol) following General method C. The residue was purified by flash column chromatography (eluent gradient from 1% to 10% MeOH in DCM) to provide 3-(2-methoxyphenyl)-N-(5-methyl-1,3,4-thiadiazol-2- yl)isonicotinamide (Compound 42) (99 mg, 70 % yield) as a white solid.¹H NMR (400 MHz DMSO-d₆) δ ppm 2.59 (3H, s), 3.46 (3H, s), 6.96 (1H, d, J = 8.6 Hz), 7.06-7.02 (1H, m), 7.37-7.33 (2H, m), 7.63 (1H, d, J = 5.0 Hz), 8.60 (1H, s), 8.70 (1H, d, J = 5.0 Hz), 12.88 (1H, s). MS (ESI): m/z 326.1 (calcd), 327.1 (M+H⁺, found). Example 43. Preparation of N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(2- fluoro-6-(2-morpholinoethoxy)phenyl)isonicotinamide (Compound 43)

Step 1: Synthesis of 3-(2-fluoro-6-hydroxyphenyl)isonicotinic acid To a stirring solution of methyl 3-bromoisonicotinate (0.25 mL, 1.81 mmol) in dioxane (9.68 mL) sparged with argon, (2-fluoro-6-hydroxyphenyl)boronic acid (0.38 g, 2.36 mmol), XPhos Pd G4 (78 mg, 0.09 mmol), and a solution of K₃PO₄ (0.78 g, 3.63 mmol) in water (2.42 mL) were added. The reaction mixture was degassed under reduced pressure with backflow of argon three times, warmed to 80 ℃, and stirred for 1 h. The reaction mixture was then cooled to room temperature, diluted with MeOH, and filtered through a Celite pad. The filtrate was evaporated, and the residue was triturated with DCM to provide 3-(2-fluoro- 6-hydroxyphenyl) isonicotinic acid (308 mg, 73 % yield) as a tan solid. MS (ESI): m/z 233.0 (calcd), 234.1 (M+H⁺, found). Step 2: Synthesis of 3-(2-fluoro-6-(2-morpholinoethoxy)phenyl)isonicotinic acid To a stirring solution of 3-(2-fluoro-6-hydroxyphenyl)isonicotinic acid (0.18 g, 0.66 mmol) in DMF (2.00 mL), K₂CO₃ (0.20 g, 1.46 mmol) and 4-(2-chloroethyl)morpholine (0.38 mL, 2.65 mmol) were added. The reaction mixture was warmed to 95 ℃, stirred for 3 hrs, cooled to room temperature and diluted with water (10 mL) and EA (10 mL). The layers were separated, and the aqueous layer was extracted with EA (2 × 10 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was dissolved in a mixture of water (0.65 mL) and THF (2.35 mL), and LiOH (47 mg, 1.96 mmol) was added. The reaction mixture was stirred at room temperature for 1 h before the volatiles were removed under reduced pressure. Purification of the residue by reverse phase C18 column chromatography (eluent gradient from 0% to 40% of ACN in ammonium bicarbonate 10 mM, pH=10) provided 3-(2-fluoro-6- (2-morpholinoethoxy)phenyl) isonicotinic acid (41 mg, 18 % yield) as a brown oil. MS (ESI): m/z 346.1 (calcd), 347.1 (M+H⁺, found). Step 3: Synthesis of N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-6- (2-morpholinoethoxy)phenyl)isonicotinamide (Compound 43) To a stirring solution of 5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-amine (48, 26 mg, 0.11 mmol) in DMF (0.55 mL), 3-(2-fluoro-6-(2-morpholinoethoxy)phenyl)isonicotinic acid (40 mg, 0.11 mmol) and 1-methylimidazole (32 µL, 0.38 mmol) were added. Then, a solution of TCFH (32 mg, 0.11 mmol) in DMF (0.52 mL) was added dropwise. The reaction mixture was stirred for 1 h at room temperature, diluted with water (10 mL), and extracted with a mixture of chloroform/isopropanol (3/1) (2 × 10 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated under reduced pressure. Purification of the residue by Prep-HPLC (Column: Gemini® 5 um NX-C18110 Å, 100 x 30 mm) (eluent gradient from 50% to 100% of MeOH in ammonium formate 10 mM) provided N-(5-((4- chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-6-(2- morpholinoethoxy)phenyl)isonicotinamide (Compound 43) (4 mg, 6.4 % yield) as a pale- yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.16 (4H, m), 2.37 (2H, m), 3.39 (4H, m), 3.79 (1H, m), 4.02 (1H, m), 6.85 (2H, br s), 7.29 (1H, s), 7.51 (2H, d, J = 8.3 Hz), 7.60 (2H, d, J = 8.2 Hz), 8.04 (1H, br s), 8.51 (2H, br s).¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm - 115.0 (1F, s). MS (ESI): m/z 563.1 (calcd), 564.3 (M+H⁺, found). Example 44. Preparation of N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(3- (2-morpholinoethoxy)phenyl)isonicotinamide (Compound 44)

Step 1: Synthesis of methyl 3-(3-hydroxyphenyl)isonicotinate The title compound was obtained from methyl 3-bromoisonicotinate (0.25 mL, 1.81 mmol) in dioxane (10 mL), 3-hydroxyphenylboronic acid (0.33 g, 2.36 mmol), XPhos Pd G4 (78 mg, 0.09 mmol), and a solution of K₃PO₄ (0.78 g, 3.63 mmol) in water (2 mL) following General method H to provide methyl 3-(3-hydroxyphenyl)isonicotinate (416 mg, 99 % yield) as a clear oil. MS (ESI): m/z 229.1 (calcd), 230.1 (M+H⁺, found). Step 2: Synthesis of methyl 3-(3-(2-morpholinoethoxy)phenyl)isonicotinate To a stirring solution of methyl 3-(3-hydroxyphenyl)isonicotinate (0.20 g, 0.91 mmol) in DMF (5 mL), K₂CO₃ (0.15 g, 1.09 mmol) and 4-(2-chloroethyl)morpholine (0.17 g, 1.09 mmol) were added. The reaction mixture was warmed to 95 ℃ and stirred for 3 h, cooled to room temperature and diluted with water (10 mL) and DCM (10 mL). The layers were separated, and the aqueous layer was extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent gradient from 0% to 10% MeOH in DCM (0.1% Et3N)) to provide methyl 3-(3-(2- morpholinoethoxy)phenyl) isonicotinate (0.30 g, 97 % yield) as a pale-yellow oil. MS (ESI): m/z 342.2 (calcd), 343.1 (M+H⁺, found). Step 3: Synthesis of 3-(3-(2-morpholinoethoxy)phenyl)isonicotinic acid To a stirring solution of methyl 3-(3-(2-morpholinoethoxy)phenyl)isonicotinate (0.20 g, 0.58 mmol) in a mixture of water (0.58 mL) and THF (2 mL), LiOH (28 mg, 1.17 mmol) was added. The reaction mixture was stirred at room temperature for 2 h before the volatiles were removed under reduced pressure to provide 3-(3-(2- morpholinoethoxy)phenyl)isonicotinic acid (0.19 g, 99 % yield) as an off-white solid. The crude material was used in the next step without further purification. MS (ESI): m/z 328.1 (calcd), 329.1 (M+H⁺, found). Step 4: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-3-(3-(2- morpholinoethoxy)phenyl)isonicotinamide (Compound 44) The title compound was obtained from 5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol- 2-amine (30 mg, 0.13 mmol) in DMF (0.64 mL), 3-(3-(2- morpholinoethoxy)phenyl)isonicotinic acid (42 mg, 0.13 mmol), 1-methylimidazole (37 µL, 0.45 mmol), and TCFH (36 mg, 0.13 mmol) in DMF (0.60 mL) following General method C. Purification of the crude product by reverse phase C18 column chromatography (eluent gradient from 5% to 38% of ACN in ammonium bicarbonate 10 mM, pH=10) provided N-(5- ((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-3-(3-(2- morpholinoethoxy)phenyl)isonicotinamide (Compound 44) (11.6 mg, 17 % yield) as an off- white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.46 (4H, m), 2.70 (2H, appt, J = 5.5 Hz), 3.56 (4H, m), 4.03 (2H, appt, J = 5.6 Hz), 6.95-7.00 (3H, m), 7.33 (1H, t, J = 7.7 Hz), 7.57 (2H, d, J = 8.3 Hz), 7.70 (3H, m), 8.74 (1H, d, J = 5.0 Hz), 8.77 (1H, s), 13.32 (1H, br s). MS (ESI): m/z 545.1 (calcd), 546.3 (M+H⁺, found). Example 45. Preparation of N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(3- (2-(dimethylamino)ethoxy)phenyl)isonicotinamide (Compound 45)

Step 1: Synthesis of 3-(3-(2-(dimethylamino)ethoxy)phenyl)isonicotinic acid To a stirring solution of methyl 3-(3-hydroxyphenyl)isonicotinate (0.21 g, 0.91 mmol) in DMF (4.54 mL), 2-chloro-N,N-dimethylethylamine hydrochloride (0.16 g, 1.09 mmol) and K₂CO₃ (0.28 g, 2.00 mmol) were added. The reaction mixture was warmed to 95 ℃ and stirred for 24 h, cooled to room temperature and diluted with water (10 mL) and DCM (10 mL). The layers were separated, and the aqueous layer was extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was dissolved in a mixture of water (0.52 mL) and THF (2 mL), and LiOH (25 mg, 1.05 mmol) was added. The reaction mixture was stirred at room temperature for 2 h before the volatiles were removed under reduced pressure to provide 3-(3-(2-(dimethylamino)ethoxy)phenyl)isonicotinic acid (0.15 g, 57 % yield) as an off-white solid. The crude material was used in the next step without further purification. MS (ESI): m/z 286.1 (calcd), 287.2 (M+H⁺, found). Step 2: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-3-(3-(2- (dimethylamino) ethoxy)phenyl)isonicotinamide (Compound 45) The title compound was obtained from 5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol- 2-amine (40 mg, 0.17 mmol) in DMF (1 mL), 3-(3-(2-(dimethylamino)- ethoxy)phenyl)isonicotinic acid (49 mg, 0.17 mmol), 1-methylimidazole (49 µL, 0.59 mmol), and TCFH (49 mg, 0.17 mmol) in DMF (0.50 mL) following General method C. The crude product was purified by reverse phase C18 column chromatography (eluent gradient from 5% to 40% of ACN in ammonium bicarbonate 10 mM) provided N-(5-((4-chlorobenzyl)oxy)- 1,3,4-thiadiazol-2-yl)-3-(3-(2-(dimethylamino)ethoxy)phenyl)isonicotinamide (Compound 45) (11 mg, 13 % yield) as a pale-yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.51 (6H, s), 3.06 (2H, t, J = 4.9 Hz), 4.12 (2H, t, J = 5.3 Hz), 6.94 (1H, dd, J = 8.3, 2.4 Hz), 7.01- 7.05 (2H, m), 7.31 (1H, t, J = 7.9 Hz), 7.53-7.58 (3H, m), 7.65 (2H, d, J = 8.4 Hz), 8.63-8.65 (2H, m). MS (ESI): m/z 503.1 (calcd), 504.2 (M+H⁺, found). Example 46. Preparation of benzyl 3-((5-(3-(2-methoxyphenyl)isonicotinamido)-1,3,4- thiadiazol-2-yl)oxy)pyrrolidine-1-carboxylate (Compound 46)

Step 1: Synthesis of benzyl 3-((5-bromo-1,3,4-thiadiazol-2-yl)oxy)pyrrolidine-1- carboxylate To a stirring solution of 2,5-dibromo-1,3,4-thiadiazole (0.30 g, 1.23 mmol) and benzyl 3-hydroxypyrrolidine-1-carboxylate (0.33 mL, 1.35 mmol) in DMF (4 mL) at 0 ℃, NaH (0.10 g, 2.46 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 10 min. Water (10 mL) was added and the aqueous layer was extracted with EA (2 × 10 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over MgSO₄, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluent gradient from 0% to 40% EA in hexanes) to provide benzyl 3-((5- bromo-1,3,4-thiadiazol-2-yl)oxy)pyrrolidine-1-carboxylate (254 mg, 54 % yield) as an opaque oil. MS (ESI): m/z 383.0 (calcd), 384.1 (M+H⁺, found). Step 2: Synthesis of benzyl 3-((5-(3-(2-methoxyphenyl)isonicotinamido)-1,3,4-thiadiazol- 2-yl)oxy)pyrrolidine-1-carboxylate (Compound 46) The title compound was obtained from benzyl 3-((5-bromo-1,3,4-thiadiazol-2- yl)oxy)pyrrolidine-1-carboxylate (0.26 g, 0.67 mmol), 3-(2-methoxyphenyl)isonicotinamide (0.18 g, 0.80 mmol), Cs₂CO₃ (0.44 g, 1.33 mmol), Pd2(dba)3 (63 mg, 0.07 mmol), and XantPhos (79 mg, 0.13 mmol) following General method G. Purification by reverse phase C18 column chromatography (eluent gradient from 5% to 40% of ACN in ammonium bicarbonate 10 mM, pH=10) provided benzyl 3-((5-(3-(2-methoxyphenyl)isonicotinamido)- 1,3,4-thiadiazol-2-yl)oxy)pyrrolidine-1-carboxylate (Compound 46) (55 mg, 16 % yield) as an off-white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.21 (2H, br s), 3.38-3.67 (7H, m), 5.08 (2H, s), 5.45 (1H, s), 6.98 (1H, d, J = 8.3 Hz), 7.03 (1H, t, J = 7.4 Hz), 7.31-7.37 (7H, m), 7.62 (1H, d, J = 5.0 Hz), 8.56 (1H, s), 8.66 (1H, d, J = 4.9 Hz), 12.87 (1H, br s). MS (ESI): m/z 531.2 (calcd), 532.2 (M+H⁺, found). Example 47. Preparation of 3-(2-methoxyphenyl)-N-(5-(pyrrolidin-3-yloxy)-1,3,4- thiadiazol-2-yl)isonicotinamide (Compound 47)

To a stirring solution of benzyl 3-((5-(3-(2-methoxyphenyl)isonicotinamido)-1,3,4- thiadiazol-2-yl)oxy)pyrrolidine-1-carboxylate (22 mg, 0.04 mmol) in DCM (0.83 mL) sparged with argon, Pd(OAc)₂ (11 mg, 0.05 mmol), Et₃N (14 µL, 0.10 mmol), and triethylsilane (67 µL, 0.41 mmol) were added. The reaction mixture was warmed to 45 ℃, stirred for 2 h, cooled to room temperature, filtered over a Celite pad, and concentrated under reduced pressure. Purification of the crude product by Prep-HPLC (Column: Gemini® 5 um NX-C18 110 Å, 100 x 30 mm) (eluent gradient from 5% to 100% of ACN in ammonium formate 10 mM) provided 3-(2-methoxyphenyl)-N-(5-(pyrrolidin-3-yloxy)-1,3,4-thiadiazol- 2-yl)isonicotinamide (Compound 47) (3 mg, 18 % yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.05 (2H, m), 3.14 (4H, br m), 3.53 (3H, s), 5.38 (1H, s), 6.96-7.00 (2H, m), 7.27 (1H, dd, J = 7.4, 1.7 Hz), 7.32 (1H, td, J = 7.8, 1.6 Hz), 7.62 (1H, d, J = 4.8 Hz), 8.26 (1H, br s), 8.48 (1H, s), 8.59 (1H, s). MS (ESI): m/z 397.1 (calcd), 398.2 (M+H⁺, found). Example 48. Preparation of 3-(2-methoxyphenyl)-N-(5-(piperidin-3-yloxy)-1,3,4- thiadiazol-2-yl)isonicotinamide (Compound 48)

Step 1: Synthesis of tert-butyl 3-((5-amino-1,3,4-thiadiazol-2-yl)oxy)piperidine-1- carboxylate The title compound was obtained from tert-butyl 3-hydroxypiperidine-1-carboxylate (0.43 g, 2.16 mmol), NaH (0.11 g, 2.80 mmol), DMF (6.16 mL), and 5-bromo-1,3,4- thiadiazol-2-amine (0.40 g, 2.16 mmol) following General method D. The crude product was purified by flash column chromatography (eluent gradient from 0% to 100% EA in hexanes) to provide tert-butyl 3-((5-amino-1,3,4-thiadiazol-2-yl)oxy)piperidine-1-carboxylate (30 mg, 4.6 % yield) as a yellow oil. MS (ESI): m/z 300.1 (calcd), 301.2 (M+H⁺, found). Step 2: Synthesis of tert-butyl 3-((5-(3-(2-methoxyphenyl)isonicotinamido)-1,3,4-thiadiazol- 2-yl)oxy)piperidine-1-carboxylate The title compound was obtained from tert-butyl 3-((5-amino-1,3,4-thiadiazol-2- yl)oxy)piperidine-1-carboxylate (35 mg, 0.11 mmol) in DMF (1.00 mL), 3-(2- methoxyphenyl)isonicotinic acid (29 mg, 0.13 mmol), 1-methylimidazole (34 µL, 0.41 mmol), and TCFH (37 mg, 0.13 mmol) in DMF (0.50 mL) following General method C. The resulting precipitate was collected by vacuum filtration to provide tert-butyl 3-((5-(3-(2- methoxyphenyl) isonicotinamido)-1,3,4-thiadiazol-2-yl)oxy)piperidine-1-carboxylate (36 mg, 53 % yield) as a tan solid. MS (ESI): m/z 511.2 (calcd), 512.3 (M+H⁺, found). Step 3: Synthesis of 3-(2-methoxyphenyl)-N-(5-(piperidin-3-yloxy)-1,3,4-thiadiazol-2- yl)isonicotinamide (Compound 48) To a stirring solution of tert-butyl 3-((5-(3-(2-methoxyphenyl)isonicotinamido)-1,3,4- thiadiazol-2-yl)oxy)piperidine-1-carboxylate (36 mg, 0.06 mmol) in DCM (0.31 mL), TFA (47 µL, 0.62 mmol) was added. The reaction mixture was stirred for 30 min before Et₃N (0.10 mL) was added and the volatiles were removed under reduced pressure. Purification of the residue by reverse phase C18 column chromatography (eluent gradient from 5% to 55% of MeOH in ammonium bicarbonate 10 mM) provided 3-(2-methoxyphenyl)-N-(5-(piperidin- 3-yloxy)-1,3,4-thiadiazol-2-yl)isonicotinamide (Compound 48) (16 mg, 62 % yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.44-1.51 (1H, m), 1.65-1.73 (2H, m), 2.01-2.07 (1H, m), 2.61-2.67 (1H, m), 2.77-2.84 (2H, m), 3.16-3.21 (1H, m), 3.53 (3H, s), 4.83-4.88 (1H, m), 6.97-7.04 (2H, m), 7.29-7.36 (2H, m), 7.61 (1H, d, J = 5.0 Hz), 8.53-8.54 (1H, m), 8.64 (1H, d, J = 5.0 Hz). MS (ESI): m/z 411.1 (calcd), 412.3 (M+H⁺, found). Example 49. Preparation of 3-(2-methoxyphenyl)-N-(5-(3-(trifluoromethyl)bicyclo[1.1.1] pentan-1-yl)-1,3,4-thiadiazol-2-yl)isonicotinamide (Compound 49)

Step 1: Synthesis of 5-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1,3,4-thiadiazol-2- amine – General method J To a flask charged with 3-(trifluoromethyl)-bicyclo[1.1.1]pentane-1-carboxylic acid (0.10 g, 0.56 mmol) and hydrazinecarbothioamide (54 mg, 0.58 mmol), POCl₃ (0.55 mL, 5.83 mmol) was added. The reaction mixture was warmed to 75 ℃, stirred for 3 h, cooled to 0 ℃ and quenched with water (10 mL). The solution was rendered basic with a solution of NaOH (2M), and the resulting precipitate was collected by vacuum filtration and dried to provide 5-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1,3,4-thiadiazol-2-amine (116 mg, 89 % yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.34 (6H, s), 7.24 (2H, s).¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -71.3 (3F, S). MS (ESI): m/z 235.0 (calcd), 236.1 (M+H⁺, found). Step 2: Synthesis of 3-(2-methoxyphenyl)-N-(5-(3-(trifluoromethyl)bicyclo[1.1.1]pentan- 1-yl)-1,3,4-thiadiazol-2-yl)isonicotinamide (Compound 49) The title compound was obtained from 5-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1- yl)-1,3,4-thiadiazol-2-amine (60 mg, 0.26 mmol) in DMF (1.54 mL), 3-(2- methoxyphenyl)isonicotinic acid (70 mg, 0.31 mmol), 1-methylimidazole (74 µL, 0.89 mmol), and TCFH (80 mg, 0.28 mmol) in DMF (0.77 mL) following General method C. Purification of the crude product by reverse phase C18 column chromatography (eluent gradient from 5% to 80% of ACN in H₂O (0.1% FA) provided 3-(2-methoxyphenyl)-N-(5-(3- (trifluoromethyl)bicyclo [1.1.1]pentan-1-yl)-1,3,4-thiadiazol-2-yl)isonicotinamide (Compound 49) (15.8 mg, 62 % yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.45 (6H, s), 3.47 (3H, s), 6.98 (1H, d, J = 8.5 Hz), 7.06 (1H, t, J = 7.5 Hz), 7.37 (2H, t, J = 7.3 Hz), 7.64 (1H, d, J = 5.0 Hz), 8.62 (1H, s), 8.72 (1H, d, J = 5.0 Hz), 13.15 (1H, s).¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -71.3 (3F, S). MS (ESI): m/z 446.1 (calcd), 447.2 (M+H⁺, found). Example 50. Preparation of 3-(2-methoxyphenyl)-N-(5-(3-phenylbicyclo[1.1.1]pentan-1- yl)-1,3,4-thiadiazol-2-yl)isonicotinamide (Compound 50)

Step 1: Synthesis of methyl 3-phenylbicyclo[1.1.1]pentane-1-carboxylate To an Ace pressure vessel charged with a stirring solution of [1.1.1]propellane (3.00 mL, 1.47 mmol, Angew. Chem., Int. Ed.2017, 56, 12774−12777) in diethyl ether (0.49 M), a solution of phenylmagnesium bromide (0.98 mL, 2.94 mmol) in diethyl ether (3 M) was added. The vessel was sealed, and the reaction mixture was warmed to 100 ℃ and stirred for 18 h. The reaction mixture was then slowly cooled to -78 ℃ and methylchloroformate (0.45 mL, 5.88 mmol) was added in one portion. The reaction mixture was warmed to room temperature over 30 min, stirred for 1 h, and diluted with diethyl ether (20 mL) and a saturated solution of NH₄Cl (30 mL). The layers were separated, and the aqueous layer was extracted with diethyl ether (2 × 30 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent gradient from 0% to 5% diethyl ether in hexanes) to provide methyl 3-phenylbicyclo[1.1.1]pentane-1-carboxylate (100 mg, 34 % yield) as a pale-yellow oil.¹H NMR (400 MHz, CHCl₃-d) δ ppm 2.20 (6H, s), 3.58 (3H, s), 7.06-7.12 (3H, m), 7.18 (2H, m). Step 2: Synthesis of 3-phenylbicyclo[1.1.1]pentane-1-carboxylic acid To a stirring solution of methyl 3-phenylbicyclo[1.1.1]pentane-1-carboxylate (95 mg, 0.47 mmol) in a mixture of water (0.47 mL), and THF (2 mL), lithium hydroxide (23 mg, 0.94 mmol) was added. The reaction mixture was stirred for 2 h before the volatiles were removed under reduced pressure and the residue was dissolved in water and acidified with HCl (2N). The resulting precipitate was collected by vacuum filtration and washed with hexanes to provide 3-phenylbicyclo[1.1.1]pentane-1-carboxylic acid (57 mg, 64 % yield) as a white solid.¹H NMR (400 MHz, CHCl₃-d) δ ppm 2.37 (6H, s), 7.22-7.26 (3H, m), 7.31-7.35 (2H, m). Step 3: Synthesis of 5-(3-phenylbicyclo[1.1.1]pentan-1-yl)-1,3,4-thiadiazol-2-amine The title compound was obtained from 3-phenylbicyclo[1.1.1]pentane-1-carboxylic acid (55 mg, 0.29 mmol), hydrazinecarbothioamide (28 mg, 0.31 mmol), and POCl₃ (0.50 mL, 5.32 mmol) following General method J. The resulting precipitate was collected by vacuum filtration to provide 5-(3-phenylbicyclo[1.1.1]pentan-1-yl)-1,3,4-thiadiazol-2-amine (63 mg, 89 % yield) as a white solid. MS (ESI): m/z 243.1 (calcd), 244.2 (M+H⁺, found). Step 4: Synthesis of 3-(2-methoxyphenyl)-N-(5-(3-phenylbicyclo[1.1.1]pentan-1-yl)-1,3,4- thiadiazol-2-yl)isonicotinamide (Compound 50) The title compound was obtained from 5-(3-phenylbicyclo[1.1.1]pentan-1-yl)-1,3,4- thiadiazol-2-amine (63 mg, 0.26 mmol) in DMF (1.56 mL), 3-(2-methoxyphenyl)isonicotinic acid (65 mg, 0.29 mmol), 1-methylimidazole (75 µL, 0.91 mmol), and TCFH (82 mg, 0.29 mmol) in DMF (0.78 mL) following General method C. The crude product was purified by flash column chromatography (eluent gradient from 0% to 3% MeOH in DCM) to provide 3- (2-methoxyphenyl)-N-(5-(3-phenylbicyclo[1.1.1]pentan-1-yl)-1,3,4-thiadiazol-2- yl)isonicotinamide (Compound 50) (74 mg, 63 % yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.45 (6H, s), 3.48 (3H, s), 6.99 (1H, d, J = 8.6 Hz), 7.07 (1H, t, J = 7.5 Hz), 7.27-7.42 (7H, m), 7.65 (1H, d, J = 5.0 Hz), 8.62 (1H, s), 8.73 (1H, d, J = 5.0 Hz), 13.10 (1H, s). MS (ESI): m/z 454.1 (calcd), 455.3 (M+H⁺, found). Example 51. Preparation of N-(5-(3-(4-chlorophenyl)bicyclo[1.1.1]pentan-1-yl)-1,3,4- thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide (Compound 51)

Step 1: Synthesis of 3-(4-chlorophenyl)bicyclo[1.1.1]pentane-1-carboxylic acid To an Ace pressure vessel charged with a stirring solution of [1.1.1]propellane (3.00 mL, 1.47 mmol, Angew. Chem., Int. Ed.2017, 56, 12774−12777) in diethyl ether (0.49 M), a solution of 4-chlorophenylmagnesium bromide (2.94 mL, 2.94 mmol) in MeTHF (1.0 M) was added. The vessel was sealed, the reaction mixture was warmed to 100 ℃ and stirred for 18 h. The reaction mixture was then slowly cooled to 0 ℃ and CO₂ (dried over anhydrous CaSO₄) was bubbled through the reaction mixture for 5 min. The reaction mixture was warmed to room temperature and stirred for 15 min before EA (20 mL) and 2N HCl (20 mL) were added. The layers were separated, and the aqueous layer was extracted with EA (2 × 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent gradient from 0% to 30% EA in hexanes) to provide 3-(4-chlorophenyl)bicyclo[1.1.1]pentane-1- carboxylic acid (112 mg, 34 % yield) as an off-white solid.¹H NMR (400 MHz, CHCl₃-d) δ ppm 2.35 (6H, s), 7.14 (2H, d, J = 8.3 Hz), 7.28 (1H, d, J = 8.2 Hz). Step 2: Synthesis of 5-(3-(4-chlorophenyl)bicyclo[1.1.1]pentan-1-yl)-1,3,4-thiadiazol-2- amine The title compound was obtained from 3-(4-chlorophenyl)bicyclo[1.1.1]pentane-1- carboxylic acid (0.10 g, 449 µmol), hydrazinecarbothioamide (43 mg, 0.47 mmol), and POCl₃ (1.10 mL, 11.7 mmol) following General method J. The resulting precipitate was collected by vacuum filtration to provide 5-(3-(4-chlorophenyl)bicyclo[1.1.1]pentan-1-yl)- 1,3,4-thiadiazol-2-amine (114 mg, 92 % yield) as a pale-yellow solid. MS (ESI): m/z 277.0 (calcd), 278.1 (M+H⁺, found). Step 3: Synthesis of N-(5-(3-(4-chlorophenyl)bicyclo[1.1.1]pentan-1-yl)-1,3,4-thiadiazol- 2-yl)-3-(2-methoxyphenyl)isonicotinamide (Compound 51) The title compound was obtained from 5-(3-(4-chlorophenyl)bicyclo[1.1.1]pentan-1- yl)-1,3,4-thiadiazol-2-amine (75 mg, 0.27 mmol) in DMF (2 mL), 3-(2- methoxyphenyl)isonicotinic acid (68 mg, 0.30 mmol), 1-methylimidazole (79 µL, 0.95 mmol), and TCFH (85 mg, 0.30 mmol) in DMF (0.50 mL) following General method C. The crude product was purified by flash column chromatography (eluent gradient from 0% to 3% MeOH in DCM) to provide N-(5-(3-(4-chlorophenyl)bicyclo[1.1.1]pentan-1-yl)-1,3,4- thiadiazol-2-yl)-3-(2-methoxyphenyl) isonicotinamide (Compound 51) (68 mg, 52 % yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.46 (6H, s), 3.48 (3H, s), 6.99 (1H, d, J = 8.6 Hz), 7.07 (1H, t, J = 7.5 Hz), 7.30-7.41 (6H, m), 7.65 (1H, d, J = 5.0 Hz), 8.62 (1H, s), 8.72 (1H, d, J = 5.0 Hz), 13.08 (1H, s). MS (ESI): m/z 488.1 (calcd), 489.3 (M+H⁺, found). Example 52. Preparation of N-(5-(3-(4-chlorophenyl)bicyclo[1.1.1]pentan-1-yl)-1,3,4- thiadiazol-2-yl)-3-(2-fluoro-5-(2-morpholinoethoxy)phenyl)isonicotinamide (Compound 52)

Step 1: Synthesis of methyl 3-(2-fluoro-5-hydroxyphenyl)isonicotinate The title compound was obtained from methyl 3-bromoisonicotinate (0.25 mL, 1.81 mmol) in dioxane (10 mL), (2-fluoro-5-hydroxyphenyl)boronic acid (0.38 g, 2.36 mmol), XPhos Pd G4 (0.12 g, 0.14 mmol), and a solution of K₃PO₄ (0.78 g, 3.63 mmol) in water (2.42 mL) following General method H to provide methyl 3-(2-fluoro-5- hydroxyphenyl)isonicotinate (361 mg, 80 % yield) as a tan solid. MS (ESI): m/z 247.1 (calcd), 248.1 (M+H⁺, found). Step 2: Synthesis of methyl 3-(2-fluoro-5-(2-morpholinoethoxy)phenyl)isonicotinate To a stirring solution of methyl 3-(2-fluoro-5-hydroxyphenyl)isonicotinate (0.25 g, 1.01 mmol) in DMF (3.37 mL), K₂CO₃ (0.17 g, 1.21 mmol) and 4-(2-chloroethyl)morpholine (0.19 g, 1.21 mmol) were added. The reaction mixture was warmed to 95 ℃ and stirred for 3 h. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with DCM (2 × 10 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO₄, filtered, and concentrated under reduced pressure to provide methyl 3-(2-fluoro-5-(2-morpholinoethoxy)phenyl)isonicotinate (364 mg, 99 % yield) as a pale- yellow oil. The crude material was used in the next step without further purification. MS (ESI): m/z 360.1 (calcd), 361.1 (M+H⁺, found). Step 3: Synthesis of 3-(2-fluoro-5-(2-morpholinoethoxy)phenyl)isonicotinic acid To a stirring solution of methyl 3-(2-fluoro-5-(2- morpholinoethoxy)phenyl)isonicotinate (0.36 g, 1.00 mmol) in a mixture of water (1 mL), and THF (4 mL), LiOH (48 mg, 2.00 mmol) was added. The reaction mixture was stirred at room temperature for 2 h before the volatiles were removed under reduced pressure to provide 3-(2-fluoro-5-(2-morpholinoethoxy)phenyl) isonicotinic acid (346 mg, 99 % yield) as an off-white solid. The crude material was used in the next step without further purification. MS (ESI): m/z 346.1 (calcd), 347.2 (M+H⁺, found). Step 4: Synthesis of N-(5-(3-(4-chlorophenyl)bicyclo[1.1.1]pentan-1-yl)-1,3,4-thiadiazol- 2-yl)-3-(2-fluoro-5-(2-morpholinoethoxy)phenyl)isonicotinamide (Compound 52) The title compound was obtained from 5-(3-(4-chlorophenyl)bicyclo[1.1.1]pentan-1- yl)-1,3,4-thiadiazol-2-amine (34 mg, 0.12 mmol) in DMF (0.73 mL), 3-(2-fluoro-5-(2- morpholinoethoxy)phenyl)isonicotinic acid (51 mg, 0.15 mmol), 1-methylimidazole (35 µL, 0.43 mmol), and TCFH (35 mg, 0.12 mmol) in DMF (0.37 mL) following General method C. The crude product was purified by flash column chromatography (eluent gradient from 0% to 6% MeOH in DCM) to provide N-(5-(3-(4-chlorophenyl)bicyclo[1.1.1]pentan-1-yl)-1,3,4- thiadiazol-2-yl)-3-(2-fluoro-5-(2-morpholinoethoxy)phenyl)isonicotinamide (Compound 52) (17 mg, 23 % yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.46 (10H, m), 2.66 (2H, t, J = 5.7 Hz), 3.56 (4H, t, J = 4.6 Hz), 4.08 (2H, t, J = 5.7 Hz), 6.98-7.04 (2H, m), 7.16 (1H, t, J = 9.4 Hz), 7.32 (2H, d, J = 8.3 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.75 (1H, d, J = 5.0 Hz), 8.75 (1H, s), 8.80 (1H, d, J = 5.0 Hz), 13.28 (1H, br s).¹⁹F NMR (376 MHz, DMSO- d₆) δ ppm -127.5 (1F, S). MS (ESI): m/z 605.2 (calcd), 606.3 (M+H⁺, found). Example 53. Preparation of 3-(2-methoxyphenyl)-N-(5-((tetrahydro-2H-pyran-4- yl)oxy)-1,3,4-thiadiazol-2-yl)isonicotinamide (Compound 53)

Step 1: Synthesis of 5-((tetrahydro-2H-pyran-4-yl)oxy)-1,3,4-thiadiazol-2-amine To a stirring solution of 2-amino-5-bromo-1,3,4-thiadiazole (1 g, 5.55 mmol) in DMF (20 mL) cooled to 0 °C, tetrahydro-4H-pyran-4-ol (1 g, 11.1 mmol) and Et₃N (2 mL, 13.9 mmol) were added. The reaction mixture was warmed to room temperature, stirred for 6 h diluted with water (20 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with brine (30 mL), dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (eluent gradient from 0% to 20% MeOH (0.1% NH₄OH) in DCM) to provide 5-((tetrahydro-2H-pyran-4- yl)oxy)-1,3,4-thiadiazol-2-amine (157 mg, 14 % yield) as a pink solid. MS (ESI): m/z 201.1 (calcd), 202.2 (M+H⁺, found). Step 2: Synthesis of 3-(2-methoxyphenyl)-N-(5-((tetrahydro-2H-pyran-4-yl)oxy)-1,3,4- thiadiazol-2-yl)isonicotinamide (Compound 53) The title compound was obtained from 5-((tetrahydro-2H-pyran-4-yl)oxy)-1,3,4- thiadiazol-2-amine (105 mg, 0.52 mmol), 3-(2-methoxyphenyl)isonicotinic acid (60 mg, 0.26 mmol), HATU (142 mg, 0.37 mmol) and DIPEA (136 mL, 0.78 mmol) in DMF (5 mL) following General method A. The crude product was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexanes). The isolated material was dissolved in ACN (1 mL), diluted with water (4 mL), and lyophilized to afford 3-(2- methoxyphenyl)-N-(5-((tetrahydro-2H-pyran-4-yl)oxy)-1,3,4-thiadiazol-2-yl)isonicotinamide (Compound 53) (35 mg, 16% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.72-1.69 (2H, m), 2.11-2.07 (2H, m), 3.52-3.46 (5H, m), 3.86-3.83 (2H, m), 5.09 (1H, s), 6.99 (1H, d, J = 8.2 Hz), 7.07 (1H, dd, J = 7.9, 6.9 Hz), 7.40-7.36 (2H, m), 7.62 (1H, d, J = 5.0 Hz), 8.61 (1H, s), 8.71 (1H, d, J = 5.0 Hz), 12.85 (1H, s). MS (ESI): m/z 412.1 (calcd), 413.2 (M+H⁺, found). Example 54. Preparation of N-(5-(4-chlorophenoxy)-1,3,4-thiadiazol-2-yl)-3-(2- methoxyphenyl)isonicotinamide (Compound 54)

To a stirring solution of 2-amino-5-bromo-1,3,4-thiadiazole (100 mg, 0.54 mmol) in DMF (3 mL) cooled to 0 °C, 4-chlorophenol (63 mL, 0.65 mmol) and DIPEA (188 mL, 1.08 mmol) were added. The reaction mixture was warmed to room temperature and stirred for 48 h. Then, 3-(2-methoxyphenyl)isonicotinic acid (123 mg, 0.54 mmol), HATU (251 mg, 0.65 mmol) and DIPEA (188 mL, 1.08 mmol) were added at room temperature under argon atmosphere. The reaction mixture was stirred for 1h, diluted with water and extracted with EA (3×10 mL). The combined extracts were dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. The crude product was purified by Prep-HPLC (Column: Gemini® 5 um NX-C18110 Å, 100 x 30 mm) (eluent gradient from 40% to 100% of ACN in ammonium formate 10 mM). The isolated material was dissolved in ACN (1 mL), diluted with water (4 mL), and lyophilized to afford N-(5-(4-chlorophenoxy)-1,3,4-thiadiazol-2-yl)-3-(2- methoxyphenyl)isonicotinamide (Compound 54) (6 mg, 2.5% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.52 (3H, s), 7.04-6.97 (2H, m), 7.38-7.31 (4H, m), 7.52 (2H, d, J = 8.7 Hz), 7.65 (1H, d, J = 4.8 Hz), 8.69-8.51 (2H, m), 13.10 (1H, s). MS (ESI): m/z 438.1 (calcd), 439.2 (M+H⁺, found). Example 55. Preparation of 3-(naphthalen-1-yl)-N-(5-((tetrahydro-2H-pyran-4-yl)oxy)- 1,3,4-thiadiazol-2-yl)isonicotinamide (Compound 55)

The title compound was obtained from 5-((tetrahydro-2H-pyran-4-yl)oxy)-1,3,4- thiadiazol-2-amine (154, 40 mg, 0.20 mmol), 3-(naphthalen-1-yl)isonicotinic acid (50 mg, 0.20 mmol), 1-methylimidazole (58 µL, 0.70 mmol) and TCFH (57 mg, 0.20 mmol) in DMF (2 mL) following General method C. The crude product was purified by flash column chromatography (eluent gradient from 50% to 100% EA in hexanes) to provide 3- (naphthalen-1-yl)-N-(5-((tetrahydro-2H-pyran-4-yl)oxy)-1,3,4-thiadiazol-2- yl)isonicotinamide (Compound 55) (64 mg, 55 % yield) as a white solid.¹H NMR (400 MHz DMSO-d₆) δ ppm 1.61 (2H, d, J = 11.4 Hz), 1.98 (2H, d, J = 12.4 Hz), 3.40 (2H, t, J = 10.5 Hz), 3.77-3.74 (2H, m), 4.98 (1H, dd, J = 8.0, 6.5 Hz), 7.41 (2H, dd, J = 14.3, 6.9 Hz), 7.54-7.47 (3H, m), 7.76 (1H, d, J = 5.0 Hz), 7.94 (2H, dd, J = 8.2, 3.7 Hz), 8.64 (1H, s), 8.81 (1H, d, J = 5.0 Hz), 12.99 (1H, br, s). MS (ESI): m/z 432.1 (calcd), 433.2 (M+H⁺, found). Example 56. Biochemical Assay to Determine the Ability of the Compounds of Formula (I) to Inhibit ATPase Activity of Pol theta (1-894) Polymerase theta helicase domain (amino acid residues 1 to 894) was expressed in insect cells as a hexahistidine fusion protein and purified by metal affinity chromatography. Helicase catalyzed ATPase activity was measured in an assay buffer containing 40 mM Tris•HCL 7.5, 20 mM MgCl₂, 0.1 mg/ml BSA, 1mM dithiothreitol. A combination of 10 mM test compound dissolved in DMSO and DMSO were added to test wells to create a 9-point dilution series of test compound, no activity control wells, full activity control wells and a final DMSO volume of 50 nl. A substrate solution comprised of 2.5 µl 300 nM single stranded DNA (5’-CCAGTGAATTGTTGCTCGGTACCTGCTAAC -3’) and 62.5 µM ATP in assay buffer was added to all test wells. 2.5 µl of assay buffer containing 40 nM polymerase domain was added to all wells except for the no activity control wells, to which 2.5 µl of assay buffer was added. The wells were covered and incubated at ambient temperature for 40 minutes. ADP was measured using the ADP-glo system (Promega, Madison WI).5 µl ADP-glo reagent was added to all wells which were then covered and incubated at ambient temperature for 40 minutes. 10 µl Kinase Detection Solution was added to all wells which were then covered and incubated for 30 minutes prior to measurement of chemiluminescence. Inhibition of polymerase activity in test wells was calculated using no activity control well chemiluminescence as 100 % inhibition and full activity control wells as 0% inhibition. Non-linear least squares fitting of inhibition as a function of inhibitor concentration was performed to determine maximum inhibition, minimum inhibition, IC₅₀ and Hill slope. The biological activities of the compounds of the present application are listed in Table 3 below. Table 3: IC₅₀ of the Compounds of the Present Disclosure IC₅₀: A: ≤ 0.1 μM, B: 0.1 μM – 0.5 μM, C: 0.5 μM – 1 μM, D: > 1 μM

EQUIVALENTS

The details of one or more embodiments of the disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated by reference.

The foregoing description has been presented only for the purposes of illustration and is not intended to limit the disclosure to the precise form disclosed, but by the claims appended hereto.

Claims

CLAIMS 1. A compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein: ring A is C₆-C₁₀ aryl or heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S; each R_A is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NR_a3R_a4, -CN, halogen, oxo, -C(X)R_a1, -C(X)OR_a1, - C(X)NR_a3R_a4, -NR_a2C(X)R_a1, -NR_a2C(X)OR_a1, or -NR_a2C(X)NR_a3R_a4; X is NR_N, O, or S; m is 0, 1, 2, 3, 4, 5, or 6; Ar is C₆-C₁₀ aryl or heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with 1-4 R_Ar; each R_Ar is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -O(CR_C1R_C2)_1-3R_O, -NR_a3R_a4, -CN, halogen, oxo, -C(X)R_a1, - C(X)OR_a1, -C(X)NR_a3R_a4, -NR_a2C(X)R_a1, -NR_a2C(X)OR_a1, or -NR_a2C(X)NR_a3R_a4; R_C1 and R_C2 are each independently H or -CH₃; R_O is -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), C₃-C₈ cycloalkyl, heterocyclyl comprising one 3- to 6-membered ring and 1-2 heteroatoms selected from N, O, and S, C₆ aryl, or heteroaryl comprising one 5- or 6-membered ring and 1-2 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, and oxo; R_N is H or C₁-C₆ alkyl; L₁ is absent, -O-, -N(R_N)-, -S-, -S(=O)₂-, or -N(S(=O)₂R_N)-; L₂ is absent, C₁-C₆ alkylenyl, C₂-C₆ alkenylenyl, or C₂-C₆ alkynylenyl; T is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, -C(X)R_a1, -C(X)OR_a1, - C(X)NR_a3R_a4, R_T, or -XR_T; provided that when L₁ is -O-, and L₂ is C₁-C₆ alkylenyl, then T is not R_T, when L₁ is -O-, and L₂ is absent or C₁-C₆ alkylenyl, then T is not C₁- C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₃-C₈ cycloalkyl, or heterocyclyl comprising one 3- to 6-membered ring and 1-2 heteroatoms selected from N, O, and S; R_T is C₃-C₈ cycloalkyl, heterocyclyl comprising one 3- to 6-membered ring and 1-2 heteroatoms selected from N, O, and S, C₆ aryl, or heteroaryl comprising one 5- or 6- membered ring and 1-2 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R_t; each R_t is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NR_a3R_a4, -CN, halogen, oxo, -C(X)R_a1, -C(X)OR_a1, - C(X)NR_a3R_a4, -NR_a2C(X)R_a1, -NR_a2C(X)OR_a1, -NR_a2C(X)NR_a3R_a4, C₃-C₈ cycloalkyl, heterocyclyl comprising one 3- to 6-membered ring and 1-2 heteroatoms selected from N, O, and S, C₆ aryl, or heteroaryl comprising one 5- or 6-membered ring and 1-2 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁- C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, and oxo; each R_a1 is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkyl-C₆-C₁₀ aryl, or C₁-C₆ alkyl-heteroaryl wherein the heteroaryl comprises a 5- or 6-membered ring and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, oxo, -C(X)R_a1, -C(X)OR_a1, -C(X)NR_a1R_a2, -NR_a2C(X)R_a1, -NR_a2C(X)OR_a1, and - NR_a2C(X)NR_a1R_a2; each R_a2 is independently H or C₁-C₆ alkyl; and R_a3 and R_a4 are each independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₃-C₈ cycloalkyl, heterocyclyl comprising one 3- to 6-membered ring and 1-2 heteroatoms selected from N, O, and S, C₆ aryl, or heteroaryl comprising one 5- or 6- membered ring and 1-2 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, -NH₂, -NR_a2(C₁-C₆ alkyl), -CN, halogen, and oxo; or R_a3 and R_a4, together with the nitrogen atom to which they are bonded, form a 5- or 6- membered heterocyclyl ring optionally comprising 1-2 additional heteroatoms selected from N, O, and S and optionally substituted with one or more groups independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -OH, - NH₂, -NR_a2(C₁-C₆ alkyl), -CN, and halogen, wherein the cycloalkyl or heterocyclyl ring may be a non-bridged and non-spiro, spirocyclic, or bridged ring system.

2. The compound of claim 1, wherein ring A is C₆-C₁₀ aryl.

3. The compound of claim 1 or 2, wherein ring A is phenyl.

4. The compound of claim 1, wherein ring A is heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S.

5. The compound of claim 1 or 4, wherein ring A is heteroaryl comprising one 5- or 6- membered ring and 1-4 heteroatoms selected from N, O, and S.

6. The compound of claim 1, 4, or 5, wherein ring A is heteroaryl comprising one 5- or 6-membered ring and 1-2 heteroatoms selected from N, O, and S.

7. The compound of any one of claims 1 and 4-6, wherein ring A is heteroaryl comprising one 5- or 6-membered ring and 1-2 nitrogen atoms.

8. The compound of any one of claims 1 and 4-7, wherein ring A is heteroaryl comprising one 6-membered ring and 1-2 nitrogen atoms.

9. The compound of claim 1, of Formula II:

or a pharmaceutically acceptable salt or solvate thereof, wherein A₁, A₂, A₃, A₄, and A₅ are each independently N, CH, or CR_A, or when A₁, A₂, A₃, A₄, or A₅ is bonded to Ar, C.

10. The compound of claim 9, wherein A₁ is bonded with Ar.

11. The compound of claim 9, wherein A₂ is bonded with Ar.

12. The compound of claim 9, wherein A₃ is bonded with Ar.

13. The compound of claim 9, wherein A₄ is bonded with Ar.

14. The compound of claim 9, wherein A₅ is bonded with Ar.

15. The compound of claim 1 or 9, of Formula IIa:

or a pharmaceutically acceptable salt or solvate thereof, wherein A₂, A₃, A₄, and A₅ are each independently N, CH, or CR_A.

16. The compound of any one of claims 1-15, wherein Ar is C₆-C₁₀ aryl optionally substituted with 1-4 R_Ar.

17. The compound of any one of claims 1-16, wherein Ar is phenyl optionally substituted with 1-4 R_Ar.

18. The compound of any one of claims 1-15, wherein Ar is heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted with 1-4 R_Ar.

19. The compound of any one of claims 1-15 and 18, wherein Ar is heteroaryl comprising one 5- or 6-membered ring and 1-4 heteroatoms selected from N, O, and S, optionally substituted with 1-4 R_Ar.

20. The compound of any one of claims 1-15, 18, and 19, wherein Ar is heteroaryl comprising one 5- or 6-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with 1-4 R_Ar.

21. The compound of any one of claims 1-15 and 18-20, wherein Ar is heteroaryl comprising one 5- or 6-membered ring and 1-2 nitrogen atoms, optionally substituted with 1- 4 R_Ar.

22. The compound of claim 1, 9, or 15, of Formula III:

or a pharmaceutically acceptable salt or solvate thereof, wherein: A₂, A₃, A₄, and A₅ are each independently N, CH, or CR_A; and A₆, A₇, A₈, A₉, and A₁₀ are each independently N, CH, or CR_Ar.

23. The compound of claim 1, 9, 15, or 22, of Formula IIIa or IIIb:

or a pharmaceutically acceptable salt or solvate thereof, wherein A₂, A₃, A₄, and A₅ are each independently N, CH, or CR_A.

24. The compound of claim 1, 9, or 15, of Formula IV:

or a pharmaceutically acceptable salt or solvate thereof, wherein: A₂, A₃, A₄, and A₅ are each independently N, CH, or CR_A; and A₈, A₉, A₁₀, A₁₁, A₁₂, A₁₃, and A₁₄ are each independently N, CH, or CR_Ar.

25. The compound of claim 1, 9, 15, or 24, of Formula IVa, IVb, or IVc:

or a pharmaceutically acceptable salt or solvate thereof, wherein: A₂, A₃, A₄, and A₅ are each independently N, CH, or CR_A; and A₈, A₉, and A₁₀ are each independently N, CH, or CR_Ar.

26. The compound of any one of claims 9, 15, and 22-25, wherein one of A₁, A₂, A₃, A₄, and A₅ is N.

27. The compound of any one of claims 9, 15, and 22-25, wherein two of A₁, A₂, A₃, A₄, and A₅ are N.

28. The compound of any one of claims 9, 15, and 22-25, wherein three of A₁, A₂, A₃, A₄, and A₅ are N.

29. The compound of any one of claims 9, 15, and 22-25, wherein four of A₁, A₂, A₃, A₄, and A₅ are N.

30. The compound of claim 22, 24, or 25, wherein one of A₆, A₇, A₈, A₉, A₁₀, A₁₁, A₁₂, A₁₃, and A₁₄ is N.

31. The compound of claim 22, 24, or 25, wherein two of A₆, A₇, A₈, A₉, A₁₀, A₁₁, A₁₂, A₁₃, and A₁₄ are N.

32. The compound of claim 22, 24, or 25, wherein three of A₆, A₇, A₈, A₉, A₁₀, A₁₁, A₁₂, A₁₃, and A₁₄ are N.

33. The compound of any one of claims 1-32, wherein L₁ is absent, and L₂ is absent.

34. The compound of any one of claims 1-32, wherein L₁ is absent, and L₂ is C₁-C₆ alkylenyl, C₂-C₆ alkenylenyl, or C₂-C₆ alkynylenyl.

35. The compound of any one of claims 1-32, wherein L₁ is -O-, and L₂ is absent.

36. The compound of any one of claims 1-32, wherein L₁ is -O-, and L₂ is C₁-C₆ alkylenyl, C₂-C₆ alkenylenyl, or C₂-C₆ alkynylenyl.

37. The compound of any one of claims 1-32, wherein L₁ is -N(R_N)-, and L₂ is absent.

38. The compound of any one of claims 1-32, wherein L₁ is -N(R_N)-, and L₂ is C₁-C₆ alkylenyl, C₂-C₆ alkenylenyl, or C₂-C₆ alkynylenyl.

39. The compound of any one of claims 1-32, wherein L₁ is -S-, and L₂ is absent.

40. The compound of any one of claims 1-32, wherein L₁ is -S-, and L₂ is C₁-C₆ alkylenyl, C₂-C₆ alkenylenyl, or C₂-C₆ alkynylenyl.

41. The compound of any one of claims 1-32, wherein L₁ is -S(=O)₂-, and L₂ is absent.

42. The compound of any one of claims 1-32, wherein L₁ is -S(=O)₂-, and L₂ is C₁-C₆ alkylenyl, C₂-C₆ alkenylenyl, or C₂-C₆ alkynylenyl.

43. The compound of any one of claims 1-32, wherein L₁ is -N(S(=O)₂R_N)-, and L₂ is absent.

44. The compound of any one of claims 1-32, wherein L₁ is -N(S(=O)₂R_N)-, and L₂ is C₁- C₆ alkylenyl, C₂-C₆ alkenylenyl, or C₂-C₆ alkynylenyl.

45. The compound of claim 34, 36, 38, 40, 42, or 44, wherein L₂ is C₁-C₆ alkylenyl.

46. The compound of any one of claims 1-45, wherein R_N is H.

47. The compound of any one of claims 1-45, wherein R_N is C₁-C₆ alkyl.

48. The compound of any one of claims 1-47, wherein T is C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ hydroxyalkyl.

49. The compound of any one of claims 1-47, wherein T is -C(X)R_a1, -C(X)OR_a1, or - C(X)NR_a3R_a4.

50. The compound of any one of claims 1-47, wherein T is R_T, or -XR_T.

51. The compound of any one of claims 1-50, wherein R_T is C₃-C₈ cycloalkyl, optionally substituted with one or more R_t.

52. The compound of any one of claims 1-50, wherein R_T is heterocyclyl comprising one 3- to 6-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more R_t.

53. The compound of any one of claims 1-50, wherein R_T is C₆ aryl, optionally substituted with one or more R_t.

54. The compound of any one of claims 1-50, wherein R_T is heteroaryl comprising one 5- or 6-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more R_t.

55. A pharmaceutical composition comprising a compound of any one of claims 1-54 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

56. A method of treating or preventing a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-54 or a pharmaceutically acceptable salt or solvate thereof.

57. Use of a compound of any one of claims 1-54 or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for treating or preventing a disease.

58. A compound of any one of claims 1-54 or a pharmaceutically acceptable salt or solvate thereof for treating or preventing a disease.