TW202448435A - Substituted thiadiazolyl compounds - Google Patents

Abstract

This application is directed to inhibitors of DNA Polymerase Theta (Polθ) activity represented by the following structural formula,

Description

Substituted thiadiazole compounds

Disclosed herein are specific substituted thiadiazolyl compounds that inhibit DNA polymerase θ (Polθ) activity, particularly the activity of the helicase domain of Polθ. Cross-reference to related applications 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 hereby incorporated by reference.

DNA damage can occur as a result of exogenous and endogenous DNA damaging agents. To maintain genome stability and limit the progression of DNA damage, cells have developed 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 is impaired, the alternative end-joining (alt-EJ), also known as microhomology-mediated end-joining (MMEJ) pathway can serve as a backup repair pathway. DNA polymerase θ (Polθ) is an A-family polymerase encoded by the POLQ gene. It is a multifunctional protein that exhibits a C-terminal DNA polymerase domain (Polθ-pol), an intermediate 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 helicase. While it has single-strand DNA-dependent ATPase activity that can remove replication protein A (RPA) from single-stranded DNA, it can inhibit the HR pathway by interfering with the formation of the Rad51 nucleoprotein complex after radiation exposure. This anti-recombinase activity of Polθ promotes the alt-EJ pathway. The helicase domain of Polθ is able to bridge two single-stranded DNA sequences resulting in microhomology-mediated strand adhesion. Specifically, Polθ promotes end joining in the alt-EJ pathway by employing this adhesion activity even when the single-stranded DNA overhangs have limited homology. During the re-adhesion process, Rad51 interaction is followed by ATPase-mediated displacement of Rad51 from the DSB damage site. Once annealed, the primer strand of the DNA is extended by the polymerase domain of Polθ. Cancer cells with HR, NHEJ deficiency, or ataxia telangiectasia-mutated (ATM) have been shown to be highly dependent on Polθ expression. Polθ has limited expression in normal cells but is overexpressed in a variety of cancer cells. Loss of Polθ can impair cell viability and can lead to synthetic lethality in cancer cells. Therefore, Polθ is an interesting target for novel synthetic lethal therapies for cancers with DNA repair defects. Based on the association between overexpression of Polθ in cancer cells, there is a need for compounds that inhibit Polθ helicase activity. This application addresses this need.

Disclosed herein are specific substituted thiadiazolyl compounds that inhibit DNA polymerase θ (Polθ) activity, particularly 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 solvent complex thereof, wherein Ring A, Ar, _RA , m, _RN , _L1 , _L2 , and T as described herein. Also disclosed are pharmaceutical compositions comprising the compound and methods for treating and/or preventing diseases that can be treated by inhibiting Polθ, such as cancer, including homologous recombination (HR)-deficient cancers. Also disclosed are pharmaceutical compositions comprising the compound and methods for treating and/or preventing diseases, such as diseases that can be treated by inhibiting Polθ, such as cancer, including homologous recombination (HR)-deficient cancers. In another aspect, described herein is a method for treating and/or preventing a disease in an individual, such as a cancer characterized by overexpression/overactivity of Polθ helicase, comprising administering a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvent complex thereof to the individual. In another aspect, described herein is a method for treating and/or preventing cancer in an individual (e.g., a cancer characterized by homologous recombination (HR) deficiency or by reduced or absent expression of BRCA genes, absent BRAC genes, or reduced function of BRCA proteins), comprising administering a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvent complex thereof to the individual. In another aspect, described herein is a method for inhibiting DNA repair by Pol θ in a cell, comprising contacting the cell with an effective amount of a compound described herein or a pharmaceutically acceptable salt or solvent complex 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 solvent complex thereof for inhibiting DNA repair by Pol θ 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 solvent complex thereof for treating and/or preventing a disease in an individual, such as a disease treatable by inhibiting Pol θ, such as cancer, including homologous recombination (HR) deficient cancer. In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvent complex thereof for treating and/or preventing a disease in an individual, such as a cancer characterized by overexpression/overactivity of Pol θ helicase, by homologous recombination (HR) deficiency, or by reduced or absent expression of BRAC genes, absence of BRAC genes, or reduced function of BRAC proteins. In another aspect, provided herein is a compound described herein or a pharmaceutically acceptable salt or solvent complex thereof for use in the manufacture of a medicament for inhibiting DNA repair by Pol θ 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 solvent complex thereof for use in the manufacture of a medicament for treating and/or preventing a disease in an individual, such as a disease treatable by inhibiting Pol θ, such as cancer, including homologous recombination (HR) deficient cancer. In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvent combination thereof for use in the manufacture of a medicament for treating and/or preventing a disease in an individual, such as a cancer characterized by overexpression/overactivity of Pol θ helicase, by homologous recombination (HR) deficiency, or by reduced or absent expression of BRAC genes, absent BRAC genes, or reduced function of BRAC proteins. In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvent combination thereof for use in treating and/or preventing a cancer resistant to poly (ADP-ribose) polymerase (PARP) inhibitor therapy in an individual. Examples of cancers that are 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 present disclosure are set forth in the accompanying description below. Exemplary methods and materials are now described, although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure. Other features, objects, and advantages of the present disclosure will become more apparent from the specification and the appended claims. In the specification and the appended claims, the singular also includes the plural unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art to which the present disclosure belongs. All patents and publications mentioned in this specification are hereby incorporated by reference in their entirety. Specific embodiments of the present disclosure The present disclosure relates to a compound of formula I: or a pharmaceutically acceptable salt or solvent thereof, wherein: Ring A is a C ₆ -C ₁₀ aryl or heteroaryl group comprising one or two 5-membered or 6-membered rings and 1 to 4 heteroatoms selected from N, O, and S; each _RA is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl, C 1 -C _{6 hydroxyalkyl, C 1 -C 6 alkoxy ,} C _{1 -C 6} halogenalkoxy, -OH, -NR _a3 R _a4 , -CN, halogen, oxo, -C(X)R _a1 , -C(X)OR _a1 , -C(X)NR _a3 R _a4 , -NR _a2 C(X)R _a1 , -NR _a2 C(X)OR _a1 , or -NR _a2 C(X)NR _a3 R _a4 ; X is NR _N , O, or S; m is 0, 1, 2, 3, 4, 5, or 6; Ar is a C ₆ -C ₁₀ aryl or heteroaryl group comprising one or two 5-membered or 6-membered rings and 1 to 4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl group is optionally substituted by 1 to 4 R _Ar ; each R _Ar is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ halogenalkoxy, -OH, -O(CR _C1 R _C2 ) _1-3 R _O , -NR _a3 R _a4 , -CN, halogen, oxo, -C(X)R _a1 , -C(X)OR _a1 , -C(X)NR _a3 R _a4 , -NR _a2 C(X)R _a1 , -NR _a2 C(X)OR _a1 , or -NR _a2 C(X)NR _a3 R _a4 ; _RC1 and _RC2 are each independently H or -CH ₃ ; _RO is -OH, -NH ₂ , -NR _a2 (C ₁ -C ₆ alkyl), C ₃ -C ₈ cycloalkyl, a heterocyclic group containing a 3- to 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, a C ₆ aryl, or a heteroaryl group containing a 5- or 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocyclic group, aryl, or heteroaryl group is optionally independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl, C ₁ -C ₆ hydroxyalkyl, C 3 -C 8 The group is substituted by one or more of: _-1 -C ₆ alkoxy, -1 _- C ₆ halogen alkoxy, -OH, -NH ₂ , -NR _a2 (C ₁ -C ₆ alkyl), -CN, halogen, and pendoxy; _RN is H or C ₁ -C ₆ alkyl; L ₁ is absent, -O-, -N( _RN )-, -S-, -S(=O) ₂ -, or -N(S(=O) ₂ R _N )-; L ₂ is absent, C ₁ -C ₆ alkylenyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynylenyl; T is C ₁ -C ₆ alkyl, C 1 -C ₆ halogen alkyl, C _{1 -C 6} hydroxyalkyl, -C(X)R _a1 , -C(X)OR _a1 , -C(X)NR _a3 R _a4 , _RT , or _-XRT ; provided that when L ₁ is -O- and L ₂ is C ₁ -C ₆ alkylene, then T is not _RT ; when L ₁ is -O- and L ₂ is absent or C ₁ -C ₆ alkylene, then T is not C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl, C ₁ -C ₆ hydroxyalkyl, C ₃ -C ₈ cycloalkyl, or a heterocyclic group containing a 3- to 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S; _RT is C ₃ -C ₈ cycloalkyl, a heterocyclic group containing a 3- to 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, C ₆ aryl, or a heteroaryl group comprising a 5-membered or 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally substituted by one or more R _t ; each R _t is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ halogenalkoxy, -OH, -NR _a3 R _a4 , -CN, halogen, oxo, -C(X)R _a1 , -C(X)OR _a1 , -C(X)NR _a3 R _a4 , -NR _a2 C(X)R _a1 , -NR _a2 C(X)OR _a1 , -NR _a2 C(X)NR _a3 R _a4 , C wherein the cycloalkyl, heterocyclic group, aryl, or heteroaryl group is optionally substituted with one or more groups independently selected from C ₁ -C ₆ alkyl, C 1 -C ₆ halogenalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C _{6 alkoxy, C 1 -C 6} halogenalkoxy, -OH, -NH 2 , -NR a2 (C ₁ -C 6 alkyl), -CN, halogen, and pendoxy; and each R a1 is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C _{1 -C 6} alkoxy, C ₁ -C ₆ halogenalkoxy, -OH, -NH ₂ , -NR _a2 (C ₁ -C ₆ alkyl), _-CN , halogen, and pendoxy; C ₁ -C ₆ alkyl, C 1 -C ₆ halogenalkyl, C ₁ -C ₆ alkyl- _{C 6} -C ₁₀ aryl, or C ₁ -C ₆ alkyl-heteroaryl, wherein the heteroaryl comprises a 5-membered or 6-membered ring and 1 to 4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ halogenalkoxy, -OH, -NH ₂ , -NR _a2 (C ₁ -C ₆ alkyl), -CN, halogen, oxo, -C(X)R _a1 , -C(X)OR _a1 , -C(X)NR _a1 R _a2 , -NR _a2 C(X)R _a1 , -NR _a2 C(X)OR _a1 , and one or more of -NR _a2 C(X)NR _a1 R _a2 ; each R _a2 is independently H or C ₁ -C ₆ alkyl; and R _a3 and R _a4 are each independently H, C ₁ -C 6 alkyl, C ₁ -C ₆ halogenalkyl, C 1 -C ₆ hydroxyalkyl, C ₃ -C ₈ cycloalkyl, a heterocyclic group containing a 3- to 6-membered ring and 1 to ₂ heteroatoms selected from N, O, and S, a C ₆ aryl, or a heteroaryl group containing a 5- or 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocyclic group, aryl, or heteroaryl group is optionally independently selected from C _{1 -C 6} alkyl, C 1 -C 6 halogenalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, a heterocyclic group containing a 3- to 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocyclic group, aryl, or heteroaryl group is optionally independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl, C ₁ -C or _R a3 and R _a4 together _with the nitrogen atom to which they are bound form a _5- or ₆ -membered heterocyclic ring which optionally comprises ₁ to ₂ additional heteroatoms selected from N, O, and _S and which is optionally substituted by _one or more groups independently selected from C _{1 -C 6 alkyl, C 1 -C 6 halogenalkyl ,} C ₁ -C ₆ hydroxyalkyl, C _{1 -C 6} alkoxy, C ₁ -C ₆ halogenalkoxy, -OH, -NH ₂ , -NR _a2 (C _{1 -C 6} alkyl), -CN, and halogen, Wherein the cycloalkyl or heterocyclic ring can be non-bridged and non-spiro, spirocyclic, or bridged ring system. Various embodiments of the compounds of the present disclosure described herein include various embodiments of groups defined for any one of Ring A, _RA , m, Ar, _RAr , X, _L1 , _L2 , _T , RN, _RO , _RT , _RC1 , _RC2 , _Rt , _Ra1 , _Ra2 , _Ra3 , and _Ra4 , such as the following. It is understood that any group or embodiment described herein for any of Ring A, _RA , _m , Ar, _RAr , X, _L1 , L2, _T , RN, _{RO, RT , RC1} , RC2, _Rt , _Ra1 , _Ra2 , _{Ra3 ,} and _Ra4 can be combined with one or more groups or embodiments described herein for one or more of the rest of Ring A, _RA , m, _Ar , _RAr , X, _L1 , _L2 , _T , _RN , RO, _RT , _RC1 , _RC2 , Rt, _Ra1 , _Ra2 , _Ra3 , and _Ra4 .

Implementation of the present disclosure Implementation 1. A compound of formula I: Or a pharmaceutically acceptable salt or solvent thereof, as described above. Implementation 2. A compound as in Implementation 1, wherein Ring A is C ₆-C ₁₀Aryl. 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 a heteroaryl group comprising one or two 5-membered or 6-membered rings and 1 to 4 heteroatoms selected from N, O, and S. Embodiment 5. Within the scope of application of the compound of any of the preceding embodiments, wherein Ring A is a heteroaryl group comprising a 5-membered or 6-membered ring and 1 to 4 heteroatoms selected from N, O, and S. Embodiment 6. Within the scope of application of the compound of any of the preceding embodiments, wherein Ring A is a heteroaryl group comprising a 5-membered or 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S. Embodiment 6a. Within the scope of application of the compound of any of the preceding embodiments, wherein ring A is a heteroaryl group comprising a 5-membered ring and 1 to 2 heteroatoms selected from N, O, and S. Embodiment 6b. Within the scope of application of the compound of any of the preceding embodiments, wherein ring A is a heteroaryl group comprising a 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S. Embodiment 7. Within the scope of application of the compound of any of the preceding embodiments, wherein ring A is a heteroaryl group comprising a 5-membered or 6-membered ring and 1 to 2 nitrogen atoms. Embodiment 8. Within the scope of application of the compound of any of the preceding embodiments, wherein ring A is a heteroaryl group comprising a 6-membered ring and 1 to 2 nitrogen atoms. Embodiment 8'. Within the scope of application of any of the above embodiments, the ring A is a heteroaryl group comprising a 5-membered ring and 1 to 2 nitrogen atoms. Embodiment 9. The compound of embodiment 1, which is of formula II: or a pharmaceutically acceptable salt or solvent thereof, wherein A ₁、A ₂、A ₃、A ₄, and A ₅Each independently is N, CH, or CR _A, or when A ₁、A ₂、A ₃、A ₄, or A ₅When it is bonded to Ar, they are C. Implementation method 10. The compound as described in implementation method 9, wherein A ₁is bonded to Ar. Implementation method 11. A compound as described in Implementation method 9, wherein A ₂is bonded to Ar. Implementation method 12. A compound as in Implementation method 9, wherein A ₃is bonded to Ar. Implementation method 13. A compound as in Implementation method 9, wherein A ₄is bonded to Ar. Implementation method 14. A compound as described in Implementation method 9, wherein A ₅It is bonded to Ar. Implementation 15. Within the scope of application of any of the compounds of the aforementioned implementations, it is of formula IIa: or a pharmaceutically acceptable salt or solvent thereof, wherein A ₂、A ₃、A ₄, and A ₅Each independently is N, CH, or CR _A. Embodiment 16. Within the scope of application of any of the compounds of the preceding embodiments, wherein Ar is optionally substituted with 1 to 4 R _ArSubstituted C ₆-C ₁₀Aryl. Embodiment 17. Within the scope of application of any of the compounds of the preceding embodiments, wherein Ar is optionally substituted with 1 to 4 R_ArSubstituted phenyl. Embodiment 18. Within the scope of application of the compound of any of the preceding embodiments, wherein Ar is a heteroaryl group comprising one or two 5-membered or 6-membered rings and 1 to 4 heteroatoms selected from N, O, and S, which is optionally substituted by 1 to 4 R _Arsubstituted. Embodiment 19. Within the scope of application of the compound of any of the preceding embodiments, wherein Ar is a heteroaryl group comprising a 5-membered or 6-membered ring and 1 to 4 heteroatoms selected from N, O, and S, which is optionally substituted by 1 to 4 R _Arsubstituted. Embodiment 19'. Within the scope of application of the compound of any of the aforementioned embodiments, wherein Ar is a heteroaryl group comprising two 5-membered or 6-membered rings and 1 to 4 heteroatoms selected from N, O, and S, which is optionally substituted by 1 to 4 R _Arsubstituted. Embodiment 20. Within the scope of application of the compound of any of the preceding embodiments, wherein Ar is a heteroaryl group comprising a 5-membered or 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, which is optionally substituted by 1 to 4 R _Arsubstituted. Embodiment 21. Within the scope of application of the compound of any of the preceding embodiments, wherein Ar is a heteroaryl group comprising a 5-membered or 6-membered ring and 1 to 2 nitrogen atoms, which is optionally substituted by 1 to 4 R _Arsubstituted. Embodiment 21a. Within the scope of application of the compound of any of the preceding embodiments, wherein Ar is a heteroaryl group comprising a 5-membered ring and 1 to 2 nitrogen atoms, which is optionally substituted by 1 to 4 R _Arsubstituted. Embodiment 21b. Within the scope of application of the compound of any of the preceding embodiments, wherein Ar is a heteroaryl group comprising a 6-membered ring and 1 to 2 nitrogen atoms, which is optionally substituted by 1 to 4 R _ArReplacement. Implementation 22. Within the scope of application of the compound of any of the preceding implementations, it is of formula III: or a pharmaceutically acceptable salt or solvent thereof, wherein: A ₂、A ₃、A ₄, and A ₅Each independently is N, CH, or CR _A; and A ₆、A ₇、A ₈、A ₉, and A ₁₀Each independently is N, CH, or CR _Ar. Implementation 23. Within the scope of application of the compound of any of the preceding implementations, it is of formula IIIa or IIIb: or a pharmaceutically acceptable salt or solvent thereof, wherein A ₂、A ₃、A ₄, and A ₅Each independently is N, CH, or CR _A. Implementation 24. Within the scope of application of the compound of any of the preceding implementations, it is of formula IV: or a pharmaceutically acceptable salt or solvent thereof, wherein: A ₂、A ₃、A ₄, and A ₅Each independently is N, CH, or CR _A; and A ₈、A ₉、A ₁₀、A ₁₁、A ₁₂、A ₁₃, and A ₁₄Each independently is N, CH, or CR _Ar. Embodiment 25. Within the scope of application of the compound of any of the preceding embodiments, it is of formula IVa, IVb, or IVc: or a pharmaceutically acceptable salt or solvent thereof, wherein: A ₂、A ₃、A ₄, and A ₅Each independently is N, CH, or CR _A; and A ₈、A ₉, and A ₁₀Each independently is N, CH, or CR _Ar. Implementation method 26. Within the scope of application of the compound of any of the aforementioned implementation methods, wherein A ₁、A ₂、A ₃、A ₄, and A ₅One of them is N. Implementation 27. Within the scope of application of the compound of any of the aforementioned implementations, wherein A ₁is N. Implementation 28. Within the scope of application of the compound of any of the aforementioned implementations, wherein A ₂is N. Implementation 29. Within the scope of application of the compound of any of the aforementioned implementations, wherein A ₃is N. Implementation method 30. Within the scope of application of the compound of any of the aforementioned implementation methods, wherein A ₄is N. Implementation 31. Within the scope of application of the compound of any of the aforementioned implementations, wherein A ₅is N. Implementation 32. Within the scope of application of the compound of any of the aforementioned implementations, wherein A ₁、A ₂、A ₃、A ₄, and A ₅Both of them are N. Implementation method 33. Within the scope of application of the compound of any of the aforementioned implementation methods, wherein A ₁with A ₂is N. Implementation 34. Within the scope of application of the compound of any of the aforementioned implementations, wherein A ₁with A ₃is N. Implementation 35. Within the scope of application of the compound of any of the aforementioned implementations, wherein A ₁with A ₄is N. Implementation 36. Within the scope of application of the compound of any of the aforementioned implementations, wherein A ₁with A ₅is N. Implementation 37. Within the scope of application of the compound of any of the aforementioned implementations, wherein A ₂with A ₃is N. Implementation 38. Within the scope of application of the compound of any of the aforementioned implementations, wherein A ₂with A ₄is N. Implementation 39. Within the scope of application of the compound of any of the aforementioned implementations, wherein A ₂with A ₅is N. Implementation method 40. Within the scope of application of the compound of any of the aforementioned implementation methods, wherein A ₃with A ₄is N. Implementation method 41. Within the scope of application of the compound of any of the aforementioned implementation methods, wherein A ₃with A ₅is N. Implementation 42. Within the scope of application of the compound of any of the aforementioned implementations, wherein A ₄with A ₅is N. Implementation 43. Within the scope of application of the compound of any of the aforementioned implementations, wherein A ₁、A ₂、A ₃、A ₄, and A ₅The three of them are N. Implementation method 44. Within the scope of application of the compound of any of the aforementioned implementation methods, wherein A ₁、A ₂、A ₃、A ₄, and A ₅Four of them are N. Implementation method 45. Within the scope of application of the compound of any of the aforementioned implementation methods, wherein A ₆、A ₇、A ₈、A ₉、A ₁₀、A ₁₁、A ₁₂、A ₁₃, and A ₁₄One of them is N. Implementation method 46. Within the scope of application of the compound of any of the aforementioned implementation methods, wherein A ₆、A ₇、A ₈、A ₉、A ₁₀、A ₁₁、A ₁₂、A ₁₃, and A ₁₄Both of them are N. Implementation method 47. Within the scope of application of the compound of any of the aforementioned implementation methods, wherein A ₆、A ₇、A ₈、A ₉、A ₁₀、A ₁₁、A ₁₂、A ₁₃, and A ₁₄The three of them are N. Implementation method 48. Within the scope of application of the compound of any of the aforementioned implementation methods, wherein L ₁is non-existent, and L ₂is absent. Implementation method 49. Within the scope of application of the compound of any of the aforementioned implementation methods, wherein L ₁is non-existent, and L ₂For C₁-C ₆Alkylene, C ₂-C ₆Alkenyl, or C ₂-C ₆Alkyne. Embodiment 50. Within the scope of application of the compound of any of the above embodiments, wherein L ₁is -O-, and L ₂is absent. Implementation 51. Within the scope of application of the compound of any of the aforementioned implementations, wherein L ₁is -O-, and L ₂For C₁-C ₆Alkylene, C ₂-C ₆Alkenyl, or C ₂-C ₆Alkyne. Embodiment 52. Within the scope of application of the compound of any of the preceding embodiments, wherein L ₁For-N(R _N)-, and L ₂is absent. Implementation 53. Within the scope of application of the compound of any of the aforementioned implementations, wherein L ₁For-N(R _N)-, and L ₂For C₁-C ₆Alkylene, C ₂-C ₆Alkenyl, or C ₂-C ₆Alkyne. Embodiment 54. Within the scope of application of the compound of any of the above embodiments, wherein L ₁is -S-, and L ₂is absent. Implementation method 55. Within the scope of application of the compound of any of the aforementioned implementation methods, wherein L ₁is -S-, and L ₂For C₁-C ₆Alkylene, C ₂-C ₆Alkenyl, or C ₂-C ₆Alkyne. Embodiment 56. Within the scope of application of the compound of any of the preceding embodiments, wherein L ₁=-S(=O) ₂-, and L ₂is absent. Implementation 57. Within the scope of application of the compound of any of the aforementioned implementations, wherein L ₁=-S(=O) ₂-, and L ₂For C₁-C ₆Alkylene, C ₂-C ₆Alkenyl, or C ₂-C ₆Alkyne. Embodiment 58. Within the scope of application of the compound of any of the preceding embodiments, wherein L ₁is -N(S(=O) ₂R _N)-, and L ₂is absent. Implementation method 59. Within the scope of application of the compound of any of the aforementioned implementation methods, wherein L ₁is -N(S(=O) ₂R _N)-, and L ₂For C₁-C ₆Alkylene, C ₂-C ₆Alkenyl, or C ₂-C ₆Alkyne. Embodiment 60. Within the scope of application of the compound of any of the above embodiments, wherein L ₂for C ₁-C ₆Alkylene. Implementation method 61. Within the scope of application of the compound of any of the aforementioned implementation methods, wherein R _Nis H. Implementation 62. Within the scope of application of the compound of any of the aforementioned implementations, wherein R _Nfor C ₁-C ₆Alkyl. Embodiment 63. Within the scope of application of the compound of any of the preceding embodiments, wherein T is C ₁-C ₆Alkyl, C ₁-C ₆Halogen alkyl, or C ₁-C ₆Hydroxylalkyl. Embodiment 64. Within the scope of application of the compound of any of the preceding embodiments, wherein T is -C(X)R _a1、-C(X)OR _a1, or -C(X)NR _a3R _a4. Implementation 65. Within the scope of application of the compound of any of the preceding implementations, wherein T is R _T, or -XR _T. Embodiment 65a. Within the scope of application of the compound of any of the preceding embodiments, wherein T is R _T. Embodiment 65b. Within the scope of application of the compound of any of the preceding embodiments, wherein T is -XR _T. Implementation method 66. Within the scope of application of the compound of any of the aforementioned implementation methods, wherein R _Tfor C ₃-C ₈Cycloalkyl, which is optionally substituted by one or more R_tReplacement. Embodiment 66a. Within the scope of application of the compound of any of the preceding embodiments, wherein R _TContains non-bridged and non-spirocyclic C ₃-C ₈Cycloalkyl, which is optionally substituted by one or more R_tReplacement. Embodiment 66b. Within the scope of application of the compound of any of the preceding embodiments, wherein R _TFor C containing the bridge ring ₃-C ₈Cycloalkyl, which is optionally substituted by one or more R_tReplacement. Embodiment 66c. Within the scope of application of the compound of any of the preceding embodiments, wherein R _TC containing a spiro ring ₃-C ₈Cycloalkyl, which is optionally substituted by one or more R_tReplacement. Implementation 67. Within the scope of application of the compound of any of the preceding implementations, wherein R _TA heterocyclic group comprising a 3- to 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, which is optionally terminated by one or more R_tReplacement. Embodiment 67a. Within the scope of application of the compound of any of the preceding embodiments, wherein R _TA heterocyclic group containing a 3- to 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S and containing non-bridged and non-spirocyclic rings, which is optionally connected through one or more R_tReplacement. Embodiment 67b. Within the scope of application of the compound of any of the preceding embodiments, wherein R _TA heterocyclic group comprising a 3- to 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S and comprising a bridged ring, which is optionally connected via one or more R _tReplacement. Embodiment 67c. Within the scope of application of the compound of any of the preceding embodiments, wherein R _TA heterocyclic group containing a 3- to 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S and containing a spirocycle, which is optionally terminated by one or more R_tReplacement. Implementation 68. Within the scope of application of the compound of any of the preceding implementations, wherein R _TFor C₆Aryl, which may optionally be substituted with one or more R_tReplacement. Implementation 69. Within the scope of application of any of the compounds of the aforementioned implementations, wherein R _TA heteroaryl group comprising a 5-membered or 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, which is optionally substituted by one or more R_tReplacement. Embodiment 69a. Within the scope of application of the compound of any of the preceding embodiments, wherein R _TA heteroaryl group comprising a 5-membered ring and 1 to 2 heteroatoms selected from N, O, and S, which is optionally substituted by one or more R_tReplacement. Embodiment 69b. Within the scope of application of the compound of any of the preceding embodiments, wherein R _TA heteroaryl group comprising a 5-membered ring and 1 to 2 heteroatoms selected from N and O, which is optionally substituted by one or more R_tReplacement. Embodiment 69c. Within the scope of application of the compound of any of the preceding embodiments, wherein R _TA heteroaryl group comprising a 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, which is optionally substituted by one or more R_tReplacement. Embodiment 69d. Within the scope of application of the compound of any of the preceding embodiments, wherein R _TA heteroaryl group comprising a 6-membered ring and 1 to 2 heteroatoms selected from N and O, which is optionally substituted by one or more R_tsubstituted. Implementation 70. Within the scope of application of the compound of any of the preceding implementations, at least one R _AFor C₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Hydroxyl, C ₁-C ₆Alkoxy, or C ₁-C ₆Halogen alkoxy. Implementation 71. Within the scope of application of any of the above implementations, at least one R _A-OH, -NR _a3R _a4, -CN, halogen, or pendoxy. Implementation 72. Within the scope of application of the compound of any of the preceding implementations, at least one R _Ais -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. Implementation method 73. Within the scope of application of any of the above-mentioned implementation methods, at least one R _ArFor C₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Hydroxyl, C ₁-C ₆Alkoxy, or C ₁-C ₆Halogen alkoxy. Implementation 74. Within the scope of application of any of the above implementations, at least one R _Ar-OH, -NR _a3R _a4, -CN, halogen, or pendoxy. Implementation 75. Within the scope of application of the compound of any of the aforementioned implementations, at least one R _Aris -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. Implementation method 76. Within the scope of application of the compound of any of the aforementioned implementation methods, wherein R _C1with R _C2Each is H. Implementation 77. Within the scope of application of the compound of any of the aforementioned implementations, wherein R _C1with R _C2Each is -CH ₃. Implementation method 78. Within the scope of application of the compound of any of the aforementioned implementation methods, wherein R _C1with R _C2One of them is H and the other is -CH ₃. Implementation method 79. Within the scope of application of the compound of any of the aforementioned implementation methods, wherein R _O-OH, -NH ₂, or -NR _a2(C ₁-C ₆Alkyl). Embodiment 80. Within the scope of application of the compound of any of the aforementioned embodiments, wherein R _OFor C₃-C ₈Cycloalkyl, which is optionally independently selected from C ₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Hydroxyl, C ₁-C ₆Alkoxy, C ₁-C ₆Halogen alkoxy, -OH, -NH ₂、-NR _a2(C ₁-C ₆alkyl), -CN, halogen, and one or more groups of pendoxyl groups. Implementation 81. Within the scope of application of any of the compounds of the aforementioned implementations, wherein R _OA heterocyclic group comprising a 3- to 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, which are optionally independently selected from C₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Hydroxyl, C ₁-C ₆Alkoxy, C ₁-C ₆Halogen alkoxy, -OH, -NH ₂、-NR _a2(C ₁-C ₆alkyl), -CN, halogen, and one or more groups of pendoxyl groups. Implementation 82. Within the scope of application of any of the compounds of the aforementioned implementations, wherein R _OFor C₆Aryl, which is optionally independently selected from C ₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Hydroxyl, C ₁-C ₆Alkoxy, C ₁-C ₆Halogen alkoxy, -OH, -NH ₂、-NR _a2(C ₁-C ₆alkyl), -CN, halogen, and one or more groups of pendoxyl groups. Implementation 83. Within the scope of application of any of the compounds of the aforementioned implementations, wherein R _OA heteroaryl group comprising a 5-membered or 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, which are optionally independently selected from C₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Hydroxyl, C ₁-C ₆Alkoxy, C ₁-C ₆Halogen alkoxy, -OH, -NH ₂、-NR _a2(C ₁-C ₆alkyl), -CN, halogen, and one or more groups of pendoxyl groups. Implementation 84. Within the scope of application of any of the compounds of the aforementioned implementations, at least one R _tFor C₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Hydroxyl, C ₁-C ₆Alkoxy, or C ₁-C ₆Halogen alkoxy. Implementation 85. Within the scope of application of any of the above implementations, at least one R _t-OH, -NR _a3R _a4, -CN, halogen, or pendoxy. Implementation 86. Within the scope of application of the compound of any of the aforementioned implementations, at least one R _tis -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. Implementation 87. Within the scope of application of the compound of any of the aforementioned implementations, at least one R _tFor C₃-C ₈Cycloalkyl, a heterocyclic group containing a 3- to 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, C ₆Aryl, or heteroaryl comprising a 5-membered or 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally independently selected from C₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Hydroxyl, C ₁-C ₆Alkoxy, C ₁-C ₆Halogen alkoxy, -OH, -NH ₂、 -NR _a2(C ₁-C ₆alkyl), -CN, halogen, and one or more groups of pendoxyl groups. Implementation 87a. Within the scope of application of any of the compounds of the aforementioned implementations, at least one R _tFor C₃-C ₈Cycloalkyl, which is optionally independently selected from C ₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Hydroxyl, C ₁-C ₆Alkoxy, C ₁-C ₆Halogen alkoxy, -OH, -NH ₂、-NR _a2(C ₁-C ₆alkyl), -CN, halogen, and one or more groups of pendoxyl groups. Implementation 87a1. Within the scope of application of any of the compounds of the aforementioned implementations, at least one R _tContains non-bridged and non-spirocyclic C ₃-C ₈Cycloalkyl, which is optionally independently selected from C ₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Hydroxyl, C ₁-C ₆Alkoxy, C ₁-C ₆Halogen alkoxy, -OH, -NH ₂、-NR _a2(C ₁-C ₆alkyl), -CN, halogen, and one or more groups of pendoxyl groups. Implementation 87a2. Within the scope of application of any of the compounds of the aforementioned implementations, at least one R _tFor C containing the bridge ring ₃-C ₈Cycloalkyl, which is optionally independently selected from C ₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Hydroxyl, C ₁-C ₆Alkoxy, C ₁-C ₆Halogen alkoxy, -OH, -NH ₂、 -NR _a2(C ₁-C ₆alkyl), -CN, halogen, and one or more groups of pendoxyl groups. Implementation 87a3. Within the scope of application of any of the compounds of the aforementioned implementations, at least one R _tC containing a spiro ring ₃-C ₈Cycloalkyl, which is optionally independently selected from C ₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Hydroxyl, C ₁-C ₆Alkoxy, C ₁-C ₆Halogen alkoxy, -OH, -NH ₂、 -NR _a2(C ₁-C ₆alkyl), -CN, halogen, and one or more groups of pendoxyl groups. Implementation 87b. Within the scope of application of any of the compounds of the aforementioned implementations, at least one R _tA heterocyclic group comprising a 3- to 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, which are optionally independently selected from C₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Hydroxyl, C ₁-C ₆Alkoxy, C ₁-C ₆Halogen alkoxy, -OH, -NH ₂、-NR _a2(C ₁-C ₆alkyl), -CN, halogen, and one or more groups of pendoxyl groups. Implementation 87b1. Within the scope of application of any of the compounds of the aforementioned implementations, at least one R _tA heterocyclic group comprising a 3- to 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S and comprising a non-bridged and non-spirocyclic ring, which is optionally independently selected from C₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Hydroxyl, C ₁-C ₆Alkoxy, C ₁-C ₆Halogen alkoxy, -OH, -NH ₂、-NR _a2(C ₁-C ₆alkyl), -CN, halogen, and one or more groups of pendoxyl groups. Implementation 87b2. Within the scope of application of any of the compounds of the aforementioned implementations, at least one R _tA heterocyclic group comprising a 3- to 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S and comprising a bridged ring, which is optionally independently selected from C ₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Hydroxyl, C ₁-C ₆Alkoxy, C ₁-C ₆Halogen alkoxy, -OH, -NH ₂、 -NR _a2(C ₁-C ₆alkyl), -CN, halogen, and one or more groups of pendoxyl groups. Implementation 87b3. Within the scope of application of any of the compounds of the aforementioned implementations, at least one R _tA heterocyclic group comprising a 3- to 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S and comprising a spirocycle, which is optionally independently selected from C₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Hydroxyl, C ₁-C ₆Alkoxy, C ₁-C ₆Halogen alkoxy, -OH, -NH ₂、 -NR _a2(C ₁-C ₆alkyl), -CN, halogen, and one or more groups of pendoxyl groups. Implementation 87c. Within the scope of application of any of the compounds of the aforementioned implementations, at least one R _tFor C₆Aryl, which is optionally independently selected from C ₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Hydroxyl, C ₁-C ₆Alkoxy, C ₁-C ₆Halogen alkoxy, -OH, -NH ₂、-NR _a2(C ₁-C ₆alkyl), -CN, halogen, and one or more groups of pendoxyl groups. Implementation 87d. Within the scope of application of any of the compounds of the aforementioned implementations, at least one R _tA heteroaryl group comprising a 5-membered or 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, which are optionally independently selected from C₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Hydroxyl, C ₁-C ₆Alkoxy, C ₁-C ₆Halogen alkoxy, -OH, -NH ₂、-NR _a2(C ₁-C ₆alkyl), -CN, halogen, and one or more groups of pendoxyl groups. Implementation 88. Within the scope of application of any of the compounds of the aforementioned implementations, wherein R _a1is H. Implementation 89. Within the scope of application of the compound of any of the aforementioned implementations, wherein R _a1For C₁-C ₆Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, dibutyl, tertiary butyl, pentyl, or hexyl) or C ₁-C ₆A halogen alkyl group (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, dibutyl, tertiary butyl, pentyl, or hexyl, which is substituted with one or more halogens (e.g., F, Cl, Br, or I). Embodiment 90. Within the scope of application of the compound of any of the preceding embodiments, wherein R _a1For C₁-C ₆Alkyl-C ₆-C ₁₀Aryl, or C ₁-C ₆Alkyl-heteroaryl, wherein the heteroaryl comprises a 5-membered or 6-membered ring and 1 to 4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally independently selected from C₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Alkoxy, C ₁-C ₆Halogen alkoxy, -OH, -NH ₂、-NR _a2(C ₁-C ₆Alkyl), -CN, halogen, pendoxy, -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 _a2One or more groups are substituted. Implementation method 90a. Within the scope of application of the compound of any of the aforementioned implementation methods, wherein R _a1For C₁-C ₆Alkyl-C ₆-C ₁₀Aryl, wherein the aryl groups are optionally independently selected from C ₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Alkoxy, C ₁-C ₆Halogen alkoxy, -OH, -NH ₂、-NR _a2(C ₁-C ₆Alkyl), -CN, halogen, pendoxy, -C(X)R _a1、-C(X)OR _a1、 -C(X)NR _a1R _a2、-NR _a2C(X)R _a1、-NR _a2C(X)OR _a1、with -NR _a2C(X)NR _a1R _a2One or more groups are substituted. Implementation method 90b. Within the scope of application of the compound of any of the aforementioned implementation methods, wherein R _a1For C₁-C ₆Alkyl-heteroaryl, wherein the heteroaryl comprises a 5-membered or 6-membered ring and 1 to 4 heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally independently selected from C₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Alkoxy, C ₁-C ₆Halogen alkoxy, -OH, -NH ₂、-NR _a2(C ₁-C ₆Alkyl), -CN, halogen, pendoxy, -C(X)R _a1、-C(X)OR _a1、 -C(X)NR _a1R _a2、-NR _a2C(X)R _a1、-NR _a2C(X)OR _a1、with -NR _a2C(X)NR _a1R _a2One or more groups are substituted. Implementation 91. Within the scope of application of the compound of any of the aforementioned implementations, wherein R _a2is H. Implementation 92. Within the scope of application of the compound of any of the aforementioned implementations, at least one R _a2For C₁-C ₆Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, dibutyl, tertiary butyl, pentyl, or hexyl). Embodiment 93. Within the scope of application of the compound of any of the preceding embodiments, wherein R _a3with R _a4Each is H. Implementation 94. Within the scope of application of the compound of any of the aforementioned implementations, wherein R _a3with R _a4At least one of them is C ₁-C ₆Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, dibutyl, tertiary butyl, pentyl, or hexyl), C ₁-C ₆Hydroxyl, or C ₁-C ₆A halogen alkyl group (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, dibutyl, tertiary butyl, pentyl, or hexyl, which is substituted with one or more halogens (e.g., F, Cl, Br, or I). Embodiment 95. Within the scope of application of the compound of any of the preceding embodiments, wherein R _a3with R _a4At least one of them is C ₃-C ₈Cycloalkyl, heterocyclic group containing a 3- to 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, C ₆Aryl, or heteroaryl comprising a 5-membered or 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally independently selected from C₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Hydroxyl, C ₁-C ₆Alkoxy, C ₁-C ₆Halogen alkoxy, -OH, -NH ₂、-NR _a2(C ₁-C ₆alkyl), -CN, halogen, and one or more groups of pendoxyl groups. Implementation 95a. Within the scope of application of any of the compounds of the aforementioned implementations, wherein R _a3with R _a4At least one of them is C ₃-C ₈Cycloalkyl, which is optionally independently selected from C ₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Hydroxyl, C ₁-C ₆Alkoxy, C ₁-C ₆Halogen alkoxy, -OH, -NH ₂、 -NR _a2(C ₁-C ₆alkyl), -CN, halogen, and one or more groups of pendoxyl groups. Implementation 95b. Within the scope of application of any of the compounds of the aforementioned implementations, wherein R _a3with R _a4At least one of the is a heterocyclic group comprising a 3- to 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, which are optionally independently selected from C ₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Hydroxyl, C ₁-C ₆Alkoxy, C ₁-C ₆Halogen alkoxy, -OH, -NH ₂、-NR _a2(C ₁-C ₆alkyl), -CN, halogen, and one or more groups of pendoxyl groups. Implementation 95c. Within the scope of application of any of the compounds of the aforementioned implementations, wherein R _a3with R _a4At least one of them is C ₆Aryl, which is optionally independently selected from C ₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Hydroxyl, C ₁-C ₆Alkoxy, C ₁-C ₆Halogen alkoxy, -OH, -NH ₂、-NR _a2(C ₁-C ₆alkyl), -CN, halogen, and one or more groups of pendoxyl groups. Implementation 95d. Within the scope of application of any of the compounds of the aforementioned implementations, wherein R _a3with R _a4At least one of them is a heteroaryl group comprising a 5-membered or 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, which are optionally independently selected from C ₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Hydroxyl, C ₁-C ₆Alkoxy, C ₁-C ₆Halogen alkoxy, -OH, -NH ₂、-NR _a2(C ₁-C ₆alkyl), -CN, halogen, and one or more groups of pendoxyl groups. Implementation 96. Within the scope of application of any of the compounds of the aforementioned implementations, wherein R _a3with R _a4Together with the nitrogen atoms to which they are bonded, they form a group which optionally includes 1 to 2 additional impurity atoms selected from N, O, and S and optionally independently selected from C₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Hydroxyl, C ₁-C ₆Alkoxy, C ₁-C ₆Halogen alkoxy, -OH, -NH ₂、 -NR _a2(C ₁-C ₆alkyl), -CN, and a 5-membered or 6-membered heterocyclic ring substituted with one or more halogen groups. Implementation 96a. Within the scope of application of any of the compounds of the aforementioned implementations, wherein R _a3with R _a4Together with the nitrogen atoms to which they are bonded, they form a group which optionally includes 1 to 2 additional impurity atoms selected from N, O, and S and optionally independently selected from C₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Hydroxyl, C ₁-C ₆Alkoxy, C ₁-C ₆Halogen alkoxy, -OH, -NH ₂、 -NR _a2(C ₁-C ₆alkyl), -CN, and a 5-membered heterocyclic ring substituted with one or more halogen groups. Implementation 96b. Within the scope of application of any of the compounds of the aforementioned implementations, wherein R _a3with R _a4Together with the nitrogen atoms to which they are bonded, they form a group which optionally includes 1 to 2 additional impurity atoms selected from N, O, and S and optionally independently selected from C₁-C ₆Alkyl, C ₁-C ₆Halogenated, C ₁-C ₆Hydroxyl, C ₁-C ₆Alkoxy, C ₁-C ₆Halogen alkoxy, -OH, -NH ₂、 -NR _a2(C ₁-C ₆alkyl), -CN, and a 6-membered heterocyclic ring substituted with one or more halogen groups. Embodiment 97. Within the scope of application of the compound of any of the preceding embodiments, wherein X is O. Embodiment 98. Within the scope of application of the compound of any of the preceding embodiments, wherein X is S. Embodiment 99. Within the scope of application of the compound of any of the preceding embodiments, wherein X is NR _N. Implementation 100. Within the scope of application of the compound of any of the aforementioned implementations, wherein R _Nis H. Implementation 101. Within the scope of application of the compound of any of the aforementioned implementations, wherein R _NFor C₁-C ₆Alkyl. Embodiment 102. Within the scope of the compound of any of the preceding embodiments, wherein in any group defined for any variable herein, C ₁-C ₆Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, dibutyl, tertiary butyl, pentyl, or hexyl. Embodiment 102a. Within the scope of the compound of any of the preceding embodiments, wherein in any group defined for any variable herein, C₁-C ₆Alkyl is methyl, ethyl, or propyl, or isopropyl. Embodiment 103. Within the scope of application of the compound of any of the preceding embodiments, wherein in any group defined for any variable herein, C ₁-C ₆The halogen alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, dibutyl, tertiary butyl, pentyl, or hexyl, which is substituted with one or more halogens (e.g., F, Cl, Br, or I). Embodiment 103a. Within the scope of the compound of any of the preceding embodiments, wherein in any group defined for any variable herein, C₁-C ₆The halogen alkyl group is methyl, ethyl, propyl, or isopropyl, which is substituted with one or more halogens (e.g., F, Cl, Br, or I). Embodiment 104. Within the scope of the compound of any of the preceding embodiments, wherein in any group defined for any variable herein, C₁-C ₆Alkoxy is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, di-butoxy, tertiary-butoxy, pentyloxy, or hexyloxy. Embodiment 104a. Within the scope of the compound of any of the preceding embodiments, wherein in any group defined for any variable herein, C₁-C ₆Alkoxy is methoxy, ethoxy, propoxy, or isopropoxy. Embodiment 105. Within the scope of the compound of any of the preceding embodiments, wherein in any group defined for any variable herein, C₁-C ₆Halogen alkoxy is methoxy, ethoxy, propoxy, or isopropoxy, n-butoxy, isobutoxy, di-butoxy, tertiary-butoxy, pentyloxy, or hexyloxy, which is substituted with one or more halogens (e.g., F, Cl, Br, or I). Embodiment 105a. Within the scope of the compounds of any of the preceding embodiments, wherein in any group defined for any variable herein, C₁-C ₆Halogen alkoxy is methoxy, ethoxy, propoxy, or isopropoxy, which is substituted with one or more halogens (e.g., F, Cl, Br, or I). Embodiment 106. Within the scope of the compound of any of the preceding embodiments, wherein the halogen is F, Cl, Br, or I in any group defined for any variable herein as applicable. Embodiment 106a. Within the scope of the compound of any of the preceding embodiments, wherein the halogen is F in any group defined for any variable herein as applicable. Embodiment 106b. Within the scope of the compound of any of the preceding embodiments, wherein the halogen is Cl in any group defined for any variable herein as applicable. Embodiment 107. Within the scope of the compound of any of the preceding embodiments, wherein in any group defined for any variable herein, C₃-C ₈Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. Embodiment 108. Within the scope of the compound of any of the preceding embodiments, wherein in any group defined for any variable herein, C₃-C ₈Cycloalkyl groups include non-bridged and non-spiro ring systems, bridged ring systems, or spiro ring systems. Embodiment 108a. Within the scope of the compounds of any of the preceding embodiments, wherein in any group defined for any variable herein, C₃-C ₈Cycloalkyl groups include non-bridged and non-spirocyclic systems. Embodiment 108b. Within the scope of the compounds of any of the preceding embodiments, wherein in any group defined for any variable herein, C₃-C ₈Cycloalkyl groups contain bridged ring systems. Embodiment 108c. Within the scope of the compounds of any of the preceding embodiments, wherein in any group defined for any variable herein, C ₃-C ₈The cycloalkyl group comprises a spiro ring system. Embodiment 109. Within the scope of the compound of any of the preceding embodiments, wherein in any group defined for any variable herein as applicable, the heterocyclic group comprises a non-bridged and non-spiro ring system, a bridged ring system, or a spiro ring system. Embodiment 109a. Within the scope of the compound of any of the preceding embodiments, wherein in any group defined for any variable herein as applicable, the heterocyclic group comprises a non-bridged and non-spiro ring system. Embodiment 109b. Within the scope of the compound of any of the preceding embodiments, wherein in any group defined for any variable herein as applicable, the heterocyclic group comprises a bridged ring system. Embodiment 109c. Within the scope of the compounds of any of the preceding embodiments, wherein in any group defined for any variable herein as applicable, the heterocyclic group comprises a spiro ring system. In some embodiments, non-limiting exemplary compounds of the present disclosure are listed in Table 1. surface 1：Compounds of the present disclosure Compound# Structure Name 1 N-(5-((4-chlorobenzyl)thio)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide 2 N-(5-((4-chlorobenzyl)amino)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide 3 (E)-N-(5-(4-chlorophenylvinyl)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isosonicotinamide 4 N-(5-(4-chlorophenethyl)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide 5 N-(5-((4-chlorobenzyl)sulfonyl)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide 6 N-(5-((4-chlorobenzyl)(methyl)amino)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide 7 N-(5-((4-chlorobenzyl)(ethyl)amino)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide 8 Ethyl 2-((5-(3-(2-methoxyphenyl)isonicotinoyl)-1,3,4-thiadiazol-2-yl)oxy)acetate 9 2-((5-(3-(2-methoxyphenyl)isonicotinoylamino)-1,3,4-thiadiazol-2-yl)oxy)acetic acid 10 3-(2-methoxyphenyl)-N-(5-(2- (2-( ... 11 3-(2-methoxyphenyl)-N-(5-(2-oxo-2-((tetrahydro-2H-pyran-4-yl)amino)ethoxy)-1,3,4-thiadiazol-2-yl)isonicotinamide 12 3-(2-methoxyphenyl)-N-(5-(2-(methyl(phenyl)amino)-2-oxoethoxy)-1,3,4-thiadiazol-2-yl)isonicotinamide 13 3-(2-methoxyphenyl)-N-(5-(2-oxo-2-(pyridin-3-ylamino)ethoxy)-1,3,4-thiadiazol-2-yl)isonicotinamide 14 N-(5-(2-(cyclopropylamino)-2-oxoethoxy)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide 15 N-(5-(2-(cyclopropyl(methyl)amino)-2-oxoethoxy)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide 16 3-(2-methoxyphenyl)-N-(5-(cyclohexane-3-yloxy)-1,3,4-thiadiazol-2-yl)isonicotinamide 17 N-(5-(N-(4-chlorobenzyl)methylsulfonamido)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isosonicotinamide 18 N-(5-(3,3-difluorocyclobutoxy)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide 19 N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide 20 3-(2-methoxyphenyl)-N-(5-(4-phenylbut-1-yn-1-yl)-1,3,4-thiadiazol-2-yl)isonicotinamide twenty one 3-(2-methoxyphenyl)-N-(5-(3-phenoxyprop-1-yn-1-yl)-1,3,4-thiadiazol-2-yl)isonicotinamide twenty two Tributyl 4-((5-(3-(2-methoxyphenyl)isonicotinoyl)-1,3,4-thiadiazol-2-yl)oxy)piperidine-1-carboxylate twenty three 3-(2-methoxyphenyl)-N-(5-(piperidin-4-yloxy)-1,3,4-thiadiazol-2-yl)isonicotinamide twenty four N-(5-((1-acetylpiperidin-4-yl)oxy)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide 25 N-(5-(2-(4-bromophenoxy)ethoxy)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide 26 N-(5-(2-(4-chlorophenoxy)ethoxy)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide 27 3-(2-methoxyphenyl)-N-(5-(2-phenoxyethoxy)-1,3,4-thiadiazol-2-yl)isonicotinamide 28 3-(2-methoxyphenyl)-N-(5-((1-phenylcyclopropyl)ethynyl)-1,3,4-thiadiazol-2-yl)isonicotinate 29 (rac)-3-(2-methoxyphenyl)-N-(5-((1-phenoxypropane-2-yl)oxy)-1,3,4-thiadiazol-2-yl)isonicotinamide 30 N-(5-(3-hydroxy-3-methylbut-1-yn-1-yl)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide 31 N-(5-((4-chlorophenoxy)methyl)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide 32 N-(5-((4-chlorobenzyl)amino)-1,3,4-thiadiazol-2-yl)-3-(naphthyl-1-yl)isosonicotinamide 33 N-(5-((4-chlorobenzyl)thio)-1,3,4-thiadiazol-2-yl)-3-(naphthyl-1-yl)isosonicotinamide 34 (E)-N-(5-(4-chlorophenylvinyl)-1,3,4-thiadiazol-2-yl)-3-(naphthyl-1-yl)isosonicotinamide 35 N-(5-(4-chlorophenethyl)-1,3,4-thiadiazol-2-yl)-3-(naphthyl-1-yl)isonicotinamide 36 N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(naphthyl-1-yl)isonicotinamide 37 N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(quinolin-4-yl)isonicotinamide 38 N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(isoquinolin-4-yl)isonicotinamide 39 3-(2-methoxyphenyl)-N-(5-(4-phenylbutyl)-1,3,4-thiadiazol-2-yl)isonicotinamide 40 3-(2-methoxyphenyl)-N-(5-(3-phenoxypropyl)-1,3,4-thiadiazol-2-yl)isonicotinamide 41 N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-1-(2-methoxyphenyl)-1H-imidazole-5-carboxamide 42 3-(2-methoxyphenyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)isonicotinamide 43 N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-6-(2- (1-(2-(4-(2-(4-phenyl)ethoxy)-1-(2-(4-phenyl)isonicotinamide) 44 N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(3-(2- (1-(2-(4-(2-(4-(2-(4-ethoxy)phenyl)isonicotinate)) 45 N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(3-(2-(dimethylamino)ethoxy)phenyl)isonicotinamide 46 (rac)-Benzyl 3-((5-(3-(2-methoxyphenyl)isonicotinamide)-1,3,4-thiadiazol-2-yl)oxy)pyrrolidine-1-carboxylate 47 (rac)-3-(2-methoxyphenyl)-N-(5-(pyrrolidin-3-yloxy)-1,3,4-thiadiazol-2-yl)isonicotinamide 48 (rac)-3-(2-methoxyphenyl)-N-(5-(piperidin-3-yloxy)-1,3,4-thiadiazol-2-yl)isonicotinamide 49 3-(2-methoxyphenyl)-N-(5-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1,3,4-thiadiazol-2-yl)isonicotinamide 50 3-(2-methoxyphenyl)-N-(5-(3-phenylbicyclo[1.1.1]pentan-1-yl)-1,3,4-thiadiazol-2-yl)isonicotinamide 51 N-(5-(3-(4-chlorophenyl)bicyclo[1.1.1]pentan-1-yl)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide 52 N-(5-(3-(4-chlorophenyl)bicyclo[1.1.1]pentan-1-yl)-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-5-(2- (1-(2-(4-(2-(4-(2-(4-ethoxy)phenyl)isonicotinate)) 53 3-(2-methoxyphenyl)-N-(5-((tetrahydro-2H-pyran-4-yl)oxy)-1,3,4-thiadiazol-2-yl)isonicotinamide 54 N-(5-(4-chlorophenoxy)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide 55 3-(Naphthyl-1-yl)-N-(5-((tetrahydro-2H-pyran-4-yl)oxy)-1,3,4-thiadiazol-2-yl)isonicotinamide In some embodiments, the compounds of the present disclosure (e.g., compounds of any formula disclosed herein or any independent compound) are pharmaceutically acceptable salts. In some embodiments, the compounds of the present disclosure (e.g., compounds of any formula disclosed herein or any independent compound) are solvates. In some embodiments, the compounds of the present disclosure (e.g., compounds of any formula disclosed herein or any independent compound) are hydrates. The compounds of the present disclosure may form salts, which are also within the scope of this disclosure. References to compounds of the formula herein are understood to include references to their salts unless otherwise indicated. Representative "pharmaceutically acceptable salts" include, for example, water-soluble and water-insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, and the like. edetate), camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, fiunarate, Gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactose Acid salt, laurate, magnesium, apple acid salt, maleate, mandelate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucate, naphthalenesulfonate, nitrate, N-methylglucosamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methylene-bis-2-hydroxy-3-naphthoate, einbonate) ), pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, toluenesulfonate, triethiodide, and valerate. "Solvate" means a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds or salts have a tendency to capture a fixed molar ratio of solvent molecules in the crystalline solid state, thereby 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 water molecules with a molecule of a substance, in which the water maintains its molecular state as H ₂O. Compounds with one or more chiral centers can exist in multiple stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial configuration. Stereoisomers include all non-image-wise, image-wise, and epimeric forms as well as racemates and mixtures thereof. The term "geoisomeric" refers to cyclic compounds with at least two substituents, wherein the two substituents are simultaneously located on the same side of the ring (cis) or wherein the substituents are each located on opposite sides of the ring (trans). When a disclosed compound is named or depicted by structure without specifying stereochemistry, it is understood that the name or structure encompasses one or more possible stereoisomers, or geometric isomers, or mixtures of the encompassed stereoisomers or geometric isomers. When geometric isomers are depicted by name or structure, it is understood that the named or depicted isomer is present in a greater degree than another isomer, meaning that the geometric isomer purity of the named or depicted geometric isomer is greater than 50% by weight, such as at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure. The geometric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all geometric isomers in the mixture. "Chiral isomer" means a compound having at least one chiral center. Compounds having more than one chiral center may exist as individual non-mirror image isomers or as a mixture of non-mirror image isomers (referred to as a "non-mirror image isomer mixture"). When one chiral center is present, the stereoisomers may be characterized by the absolute configuration (R or S) of the chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center in question. Substituents attached to the chiral center in question are ranked according to the order rules 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., Experientia1956, 12, 81; Cahn, J. Chem. Educ.1964, 41, 116). In some embodiments, the compounds of the present disclosure are non-mirror isomers. In some embodiments, the compounds are syn non-mirror isomers. In some embodiments, the compounds are anti non-mirror isomers. A racemic mixture means 50% of one mirror image isomer and 50% of its corresponding mirror image isomer. When a compound having a 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 mirror image isomer forms of the compound (e.g., both mirror image pure, mirror image enriched, or racemic). When a compound having two or more chiral centers is named or depicted without specifying the stereochemistry of the chiral centers, it is understood that the name or structure encompasses all possible non-imagerally isomeric forms (e.g., non-imagerally pure, non-imagerally enriched, and equimolar mixtures of one or more non-imagerally isomers of the compound (e.g., racemic mixtures). Mirror isomers and non-mirror isomer mixtures can be separated into their component mirror isomers or stereoisomers by known methods, such as chiral phase gas chromatography, chiral phase high performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Mirror isomers and non-mirror isomers can also be obtained from non-mirror isomer-pure or mirror isomer-pure intermediates, reagents, and catalysts by known asymmetric synthesis methods. When a compound is designated by a name or structure that refers to a single mirror image isomer, the compound is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure (also referred to as "mirror image pure") unless otherwise indicated. Optical purity is the weight of the named or depicted mirror image in a mixture divided by the total weight of the two mirror image isomers in the mixture. When the stereochemistry of a disclosed compound is named or depicted as a structure, when the named or depicted structure encompasses more than one stereoisomer (e.g., as in a non-mirror isomer pair), it is understood to include one of the encompassed stereoisomers or any mixture of encompassed stereoisomers. It is further understood that the stereoisomeric purity of the named or depicted stereoisomer is 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 stereoisomers encompassed by the name or structure by the total weight in the mixture of all stereoisomers. It is also possible that the compounds of the present disclosure may exist in different tautomeric forms (tautomeric isomers). form), and all such forms are included within the scope of the present disclosure. A "tautomer" is one of two or more structural isomers that exist in equilibrium and readily convert from one isomeric form to another. This conversion results in a formal migration of hydrogen atoms accompanied by a switch of adjacent conjugated double bonds. In solution, tautomers exist as a mixture of tautomeric groups. In solid form, usually one tautomer is predominant. In solutions in which tautomerism is possible, a chemical equilibrium of the tautomers will be reached. Tautomerism The exact ratio of the compounds depends on several factors, including temperature, solvent, and pH. The concept of tautomers being interconvertible by tautomerism is called tautomerism. Of the multiple tautomerisms possible, two are usually observed. In keto-enol tautomerism, a simultaneous displacement of electrons and hydrogen atoms occurs. Cyclochain tautomerism is the result of the reaction of an aldehyde group (-CHO) in a sugar chain molecule with a hydroxyl group (-OH) in the same molecule to give a cyclic (ring-shaped) form as seen in glucose. Common tautomeric pairs are: keto-enol, amide-nitrile, lactam-lactam, amide-imidic acid tautomerism in heterocyclic rings, such as in nucleobases (e.g., guanine, thymine, and cytosine), amine-enamine and enamine-imine. The present disclosure also contemplates isotopically labeled compounds, which are identical to the formulae described herein except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that may be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, fluorine, such as ³H. ¹¹C. ¹⁴C. ²H and ¹⁸F. Compounds of the present disclosure containing the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present disclosure. Isotope-labeled compounds of the present disclosure, for example, compounds in which radioactive isotopes are incorporated, such as ³H. ¹⁴C, which can be used in drug and/or substrate tissue distribution analysis. Tritiation, for example ³H and carbon 14, for example ¹⁴C isotopes are useful because of their ease of preparation and detectability. ¹¹C and ¹⁸F analysis isotopes are useful in PET (positron tomography). PET is useful in brain imaging. In addition, heavier isotopes such as deuterium, such as ²H substitution may confer certain therapeutic advantages derived from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some circumstances. Isotopically labeled compounds of the present disclosure can generally be prepared by carrying out the procedures disclosed in the schemes and/or examples described herein, by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents. In some embodiments, the compounds of the present disclosure are not isotopically labeled. Methods for preparing compoundsThe compounds of the present disclosure may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are illustrated in the schemes given below. The compounds may be prepared by methods known in the art of organic synthesis as illustrated in some of the following synthetic schemes. In the schemes illustrated below, it is understood that protecting groups for sensitive or reactive groups are used as necessary according to 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", 3rd edition, Wiley, New York 1999). These groups are removed at appropriate stages of the synthesis of the compound using methods readily known to those having ordinary knowledge in the art. The selection of processes, as well as the reaction conditions and the order in which they are performed should be consistent with the preparation of the compounds of the present disclosure. Those of ordinary skill in the art will understand whether stereocenters exist in the compounds of the present disclosure. Therefore, the present disclosure includes two possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but also independent mirror isomers and/or non-mirror isomers. When a compound is intended to be a single mirror isomer or non-mirror isomer, it can be obtained by stereospecific synthesis or by resolution of the final product or any appropriate intermediate. Resolution of the final product, intermediate, or starting material can be achieved by any appropriate method known in the art. For example, refer to "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994). The compounds described herein can 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 variety of ways known to those skilled in the art for organic synthesis. For example, the compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the field of synthetic organic chemistry, or variations thereof as understood by those skilled in the art. Preferred methods include but are not limited to those described below. The compounds of the present disclosure (i.e., compounds of formula I) can be synthesized by following the steps summarized in the following general schemes and/or general methods, such as those described in the embodiments. It is understood that the experimental conditions and starting materials and/or intermediates shown in the general methods of the embodiments can be adjusted according to the techniques and knowledge available in the art. Starting materials are either commercially available or can be made by known procedures as described in the literature or as shown. General methods for synthesis are indicated below for reference. General approach Reaction Name A Amide coupling reaction (HATU) B Amination C Amidide coupling reaction (TCFH) D Williamson ether synthesis E Sonogashira cross coupling F BOC deprotection G Buchwald amide cross coupling H Suzuki Marionette I Hydrogenation J Condensation reaction The ability of the disclosed compounds to inhibit Polq can be measured as described in Example 56 below or according to methods known in the art. DefinitionThe articles "a" and "an" are used in this disclosure to indicate one or more than one (i.e., at least one) grammatical object of the article. For example, "an element" means one element or more than one element. Unless otherwise indicated, the term "and/or" is used in this disclosure to mean "and" or "or". As used herein, the term "alkyl" refers to a saturated, straight-chain or branched hydrocarbon group containing between one and six carbon atoms in some embodiments. C ₁-C ₈Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, n-heptyl, and n-octyl groups. C ₁-C ₆Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, and n-hexyl groups. The term "alkylsulfonyl" means -SO ₂R group, where R is an alkyl group as defined above, such as methylsulfonyl, ethylsulfonyl, 2-propylsulfonyl, etc. The term "alkoxy" refers to an alkyl group connected through an oxygen linking atom, represented by -O-alkyl. For example, "(C ₁-C ₄)alkoxy" includes methoxy, ethoxy, propoxy, and butoxy. The term "alkoxycarbonyl" refers to a -COOR group, wherein R is an alkyl group as defined above, for example, methoxycarbonyl, ethoxycarbonyl, propoxy, or 2-propoxycarbonyl, or tertiary butoxycarbonyl, etc. The term "alkoxyalkyl" refers to a linear monovalent hydrocarbon group of one to six carbon atoms or a branched monovalent hydrocarbon group of three to six carbon atoms substituted by an alkoxy group as defined above, for example, 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, etc. The term "acyl" refers to a -C(O)R group, wherein R is an alkyl group as defined herein, for example, methylcarbonyl, ethylcarbonyl, etc. The term "acylamino" refers to a -NHC(O)R group, where R is an alkyl group as defined herein, for example, methylcarbonylamino, ethylcarbonylamino, etc. The term "amino" refers to -NH ₂. The terms "haloalkyl" and "haloalkoxy" refer to alkyl or alkoxy groups, as appropriate, substituted with one or more halogen atoms. Unless otherwise specified, the term "alkylene" refers to a linear saturated divalent hydrocarbon group of one to six carbon atoms or a branched saturated divalent hydrocarbon group of three to six carbon atoms, for example, methylene, ethyl, propyl, 1-methylpropyl, 2-methylpropyl, butyl, pentyl, etc. "Alkylene group" is a saturated aliphatic branched or straight chain divalent hydrocarbon group. Unless otherwise specified, an alkylene group typically has 1 to 6 carbon atoms, for example (C ₁-C ₆)alkylene. The term "aryl" refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon group of 6 to 10 ring atoms, such as phenyl or naphthyl. The term "bicyclic heterocyclic" refers to a saturated monocyclic ring having 4 to 7 ring carbon ring atoms fused to phenyl, a five-membered or six-membered heteroaryl or heterocyclic group, wherein one or two ring carbon atoms are replaced by a heteroatom selected from N, O, or S(O)n (where n is an integer from 0 to 2), each as defined herein. Exemplary bicyclic heterocyclic groups include, but are not limited to etc. The term "cycloalkyl" refers to a monocyclic saturated hydrocarbon ring system. For example, C ₃-C ₇Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Bridged cycloalkyl groups represent bicyclic hydrocarbon ring systems in which the two rings share at least three adjacent ring carbon atoms. For example, bridged cycloalkyl groups have 6 to 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, Alkenyl, norbornenyl, norbornenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, and adamantyl. The terms "heterocyclyl", "heterocyclic ring", and "heterocylic group" are used interchangeably herein and refer to a saturated or unsaturated non-aromatic 4- to 10-membered cyclic group containing 1 to 4 ring heteroatoms which may be the same or different and selected from N, O, or S. It may be monocyclic, bicyclic or tricyclic (e.g., fused or bridged bicyclic or tricyclic rings). Examples include, but are not limited to, azathiocarboxyl, oxafolyl, thiothiocarboxyl, pyrrolidonyl, pyrrolidinyl, piperidinyl, piperonyl, hydantoinyl, valerolactamyl, oxafolyl, oxafolyl, dihydroimidazole, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, dihydropyrimidinyl, dihydrothiophenyl, dihydrothiopyranyl, tetrahydroimidazole, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl. The heterocyclic ring optionally contains one or more double bonds and/or is optionally fused to one or more aromatic rings (eg, tetrahydronaphthyridine, indolinone, dihydropyrrolotriazole, imidazopyrimidine, quinolinone, dioxaspirodecane). Examples of 3-7 membered monocyclic heterocyclic rings include, but are not limited to, azathiocarboxyl, oxothiocarboxyl, thiothiothiocarboxyl, pyrrolidone, pyrrolidyl, piperidinyl, piperidine, hydantoin, valerolactamyl, oxothiocarboxyl, oxothiocarboxyl, dihydroimidazole, dihydrofuranyl, dihydropyranyl, dihydropyridyl, dihydropyrimidinyl, dihydrothienyl, dihydrothiophenyl, dihydrothiopyranyl, tetrahydroimidazole, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl. The term "bridged heterocyclic group" refers to a saturated monocyclic ring having 5 to 7 ring carbon atoms, wherein 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 referred to herein as a "bridged" group), and further wherein one or two ring carbon atoms (including atoms in the bridged group) are replaced by a heteroatom selected from N, O, or S(O)n (where n is an integer from 0 to 2). Bridged heterocyclic groups are optionally substituted by one or two substituents independently selected from alkyl, halogen, alkoxy, hydroxyl, or cyano. Examples include, but are not limited to, 2-azabicyclo[2.2.2]octane, quinuclidine, 7-oxahedralbicyclo[2.2.1]heptane, etc. A bridged heterocyclic group refers to a bicyclic ring system containing 1 to 4 ring heteroatoms, wherein the two rings share at least three adjacent ring atoms. For example, a bridged heterocyclic group has 6 to 12 ring atoms. Examples include, but are not limited to, aza-heterocyclic groups, Pyridyl, isocyanate Pidinyl, tropanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.2.1]heptyl, 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" refers to an alkyl group as defined above wherein one to six hydrogen atoms in the alkyl group are replaced by deuterium, e.g. -CD ₃、-CH ₂CD ₃etc. The term "dialkylamino" refers to a -NRR' group, wherein R and R' are independently alkyl as defined herein. The term "halogen" refers to fluorine, chlorine, bromine, or iodine, preferably fluorine or chlorine. As used herein, the term "pendooxy" refers alone or in combination 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 (such as "heteroaralkyl" or "heteroaralkoxy"), refers to an aromatic cyclic radical having five to ten ring atoms selected from carbon and at least one (typically 1 to 4, more typically 1 or 2) heteroatom (e.g., oxygen, nitrogen, or sulfur). "Heteroaryl" includes monocyclic and polycyclic rings, wherein the 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)" refers to 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) heteroatom (e.g., oxygen, nitrogen, or sulfur). Examples of monocyclic 5-6 membered heteroaryl 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-oxadiazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., For example, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridinyl (for example, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyrimidinyl (for example, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), thiazolyl (for example, 3-thiazolyl), thiazolyl (for example, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl, triazolyl (for example, 2-triazolyl, 5-triazolyl), tetrazolyl (for example, tetrazolyl), and thienyl (for example, 2-thienyl, 3-thienyl). If a group is described as "substituted", a non-hydrogen substituent replaces a hydrogen atom on a carbon or nitrogen. Thus, for example, a substituted alkyl group is an alkyl group in which at least one non-hydrogen substituent is located in the position where a hydrogen atom on the alkyl substituent would be located. For purposes of illustration, a monofluoroalkyl group is an alkyl group substituted with one fluorine substituent, and a difluoroalkyl group is an alkyl group substituted with two fluorine substituents. It will be understood that if there is more than one substitution on a substituent, each non-hydrogen substituent may be the same or different (unless otherwise specified). As used herein, many moieties (e.g., alkyl, cycloalkyl, or heterocyclic ring) are referred to as "substituted" or "optionally substituted." It will be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." When a moiety is modified by one of these terms, unless otherwise specified, it means that any portion of the moiety known to those skilled in the art to be available for substitution may be substituted, including one or more substituents. If more than one substituent is present, each substituent is independently selected. Such substitution methods are known in the art and/or taught by the present disclosure. An optional substituent can be any substituent suitable for attachment to the moiety. One of ordinary skill in the art will appreciate that the compounds and the definitions provided do not include impermissible substitution patterns (e.g., a methyl group substituted with 5 different groups, etc.). One of ordinary skill in the art clearly understands this impermissible substitution pattern. When a group is recorded as optionally substituted with "one or more" substituents, it means that the group is optionally substituted with one, two, three, four, five, or six substituents. In some embodiments, the group is optionally substituted with 1 to 3 substituents. In some embodiments, the group is optionally substituted with 1 to 2 substituents. In some embodiments, the group is optionally substituted with one substituent. Suitable substituents are those that do not have a significant negative effect on the ability of the compound. When suitable substituents are not specifically listed, exemplary substituents include, but are not limited to, halogen, CN, alkyl, alkoxy, halogenmethyl, halogenmethoxy, (C₁-C ₅) alkyl, halogen (C ₁-C ₅)alkyl, (C ₁-C ₅)Alkoxy, NO ₂、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'、(C ₃-C ₆) cycloalkyl, monocyclic heteroaryl, and phenyl, among which (C ₃-C ₆) Cycloalkyl, monocyclic heteroaryl, and phenyl substituents are optionally and independently substituted by, for example, CH₃, halogenmethyl, halogen, methoxy, or halogenmethoxy. Each R ^a'With each R ^b'Independently H or (C ₁-C ₆) alkyl, where R ^a'or R ^b'What is represented (C ₁-C ₆) The alkyl group may be optionally substituted with, for example, a hydroxyl group or (C₁-C ₃) Alkoxy substitution; R ^c'For H, halogen (C ₁-C ₆) alkyl, or (C ₁-C ₆) alkyl, where R ^cRepresented by (C ₁-C ₆) The alkyl group may be optionally substituted with, for example, a hydroxyl group or (C₁-C ₃) alkoxy substituted; and i is 0, 1, or 2. =O is also a suitable substituent for alkyl, cycloalkyl, and heterocyclic rings. Suitable substituents may also include: -F, -Cl, -Br, -I, -OH, protected hydroxyl, -NO ₂、-CN、-NH ₂, protected amine groups, -NH-C ₁-C ₁₂-alkyl, -NH-C ₂-C ₁₂-Alkenyl, -NH-C ₂-C ₁₂-alkenyl, -NH-C ₃-C ₁₂-cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamine, -diarylamine, -diheteroarylamine, -O-C ₁-C ₁₂-Alkyl, -O-C ₂-C ₁₂-Alkenyl, -O-C ₂-C ₁₂-Alkenyl, -O-C ₃-C ₁₂-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(O)-C ₁-C ₁₂-alkyl, -C(O)-C ₂-C ₁₂-Alkenyl, -C(O)-C ₂-C ₁₂-Alkenyl, -C(O)-C ₃-C ₁₂-cycloalkyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocycloalkyl, -CONH ₂、-CONH-C ₁-C ₁₂-alkyl, -CONH-C ₂-C ₁₂-Alkenyl, -CONH-C ₂-C ₁₂-alkenyl, -CONH-C ₃-C ₁₂-cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO ₂-C ₁-C ₁₂-Alkyl, -OCO ₂-C ₂-C ₁₂-Alkenyl, -OCO ₂-C ₂-C ₁₂-Alkenyl, -OCO ₂-C ₃-C ₁₂-cycloalkyl, -OCO ₂-Aryl, -OCO ₂-Heteroaryl, -OCO ₂-heterocycloalkyl, -OCONH ₂、-OCONH-C ₁-C ₁₂-alkyl, -OCONH-C ₂-C ₁₂-Alkenyl, -OCONH- C ₂-C ₁₂-Alkenyl, -OCONH-C ₃-C ₁₂-cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocycloalkyl, -NHC(O)-C ₁-C ₁₂-alkyl, -NHC(O)-C ₂-C ₁₂-alkenyl, -NHC(O)-C ₂-C ₁₂-Alkenyl, -NHC(O)-C ₃-C ₁₂-cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocycloalkyl, -NHCO ₂-C ₁-C ₁₂-Alkyl, -NHCO ₂-C ₂-C ₁₂-alkenyl, -NHCO ₂-C ₂-C ₁₂-Alkenyl, -NHCO ₂-C ₃-C ₁₂-cycloalkyl, -NHCO ₂-Aryl, -NHCO ₂-Heteroaryl, -NHCO ₂-heterocycloalkyl, -NHC(O)NH ₂、-NHC(O)NH-C ₁-C ₁₂-alkyl, -NHC(O)NH-C ₂-C ₁₂-Alkenyl, -NHC(O)NH-C ₂-C ₁₂-alkenyl, -NHC(O)NH-C ₃-C ₁₂-cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, NHC(O)NH-heterocycloalkyl, -NHC(S)NH ₂、-NHC(S)NH-C ₁-C ₁₂-alkyl, -NHC(S)NH-C ₂-C ₁₂-Alkenyl, -NHC(S)NH-C ₂-C ₁₂-alkenyl, -NHC(S)NH-C ₃-C ₁₂-cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocycloalkyl, -NHC(NH)NH ₂、-NHC(NH)NH-C ₁-C ₁₂-alkyl, -NHC(NH)NH-C ₂-C ₁₂-Alkenyl, -NHC(NH)NH-C ₂-C ₁₂-alkenyl, -NHC(NH)NH-C ₃-C ₁₂-cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH heterocycloalkyl, -NHC(NH)-C ₁-C ₁₂-alkyl, -NHC(NH)-C ₂-C ₁₂-alkenyl, -NHC(NH)-C ₂-C ₁₂-Alkenyl, -NHC(NH)-C ₃-C ₁₂-cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocycloalkyl, -C(NH)NH-C ₁-C ₁₂-alkyl, -C(NH)NH-C ₂-C ₁₂-alkenyl, -C(NH)NH-C ₂-C ₁₂-Alkenyl, C(NH)NH-C ₃-C ₁₂-cycloalkyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NH-heterocycloalkyl, -S(O)-C ₁-C ₁₂-alkyl, -S(O)-C ₂-C ₁₂-alkenyl, -S(O)-C ₂-C ₁₂-Alkenyl, -S(O)-C ₃-C ₁₂-cycloalkyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocycloalkyl-SO ₂NH ₂、 -SO ₂NH-C ₁-C ₁₂-Alkyl, -SO ₂NH-C ₂-C ₁₂-Alkenyl, -SO ₂NH-C ₂-C ₁₂-Alkenyl, -SO ₂NH-C ₃-C ₁₂-cycloalkyl, -SO ₂NH-aryl, -SO ₂NH-heteroaryl, -SO ₂NH-heterocycloalkyl, -NHSO ₂-C ₁-C ₁₂-Alkyl, -NHSO ₂-C ₂-C ₁₂-alkenyl, -NHSO ₂-C ₂-C ₁₂-Alkenyl, -NHSO ₂-C ₃-C ₁₂-cycloalkyl, -NHSO ₂-Aryl, -NHSO ₂-Heteroaryl, -NHSO ₂-heterocycloalkyl, -CH ₂NH ₂、-CH ₂SO ₂CH ₃, -aryl, -aralkyl, -heteroaryl, -heteroaralkyl, -heterocycloalkyl, -C ₃-C ₁₂-cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-C ₁-C ₁₂-alkyl, -S-C ₂-C ₁₂-Alkenyl, -S-C ₂-C ₁₂-alkenyl, -S-C ₃-C ₁₂-cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl, or methylthiomethyl. "Patient" or "subject" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or Gangetic monkey. "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 respect to a subject refers to ameliorating at least one symptom of a disease in the subject. Treatment includes curing, ameliorating, or at least partially ameliorating a disease. The compounds of the present disclosure or their pharmaceutically acceptable salts or solvent compositions can also be used to prevent a disease, condition or disorder. As used herein, "preventing" or "preventing" refers to reducing or eliminating the onset of symptoms or complications of a disease, condition or disorder. The term "disorder" is used in this disclosure to refer to and is used interchangeably with the term disease, condition, or illness unless otherwise indicated. As used herein, the term disease or disorder in which Polθ helicase plays a role refers to any disease or other harmful condition in which Polθ helicase is known to play a role. Therefore, another embodiment of the present application relates to treating or reducing the severity of one or more diseases in which Polθ helicase is known to play a role. Pharmaceutical ingredientsThe compounds disclosed herein are Polθ helicase inhibitors. The pharmaceutical composition of the present application comprises one or more Polθ helicase inhibitors or pharmaceutically acceptable salts or solvents thereof, and a pharmaceutically acceptable carrier or diluent. A "pharmaceutical composition" is a formulation containing a compound of the present disclosure in a form suitable for administration to an individual. In some embodiments, the pharmaceutical composition is in bulk form 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 amount of active ingredient in a unit dosage form of the composition (e.g., a formulation of a disclosed compound or a pharmaceutically acceptable salt or solvent thereof) is an effective amount and varies depending on the specific treatment involved. Those of ordinary skill in the art will appreciate that it is sometimes necessary to routinely vary 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, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration of the compounds of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In some embodiments, the active compound is mixed with a pharmaceutically acceptable carrier and any preservatives, buffers or propellants required under sterile conditions. As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, carriers, and/or dosage forms that are suitable for contact with human and animal tissues within the scope of reasonable medical judgment without excessive toxicity, irritation, allergic reaction, or other problems or complications, and have a reasonable benefit/risk ratio. "Pharmaceutically acceptable carrier" and "pharmaceutically acceptable diluent" refer to those that facilitate the formulation and/or administration of the active agent to an individual and/or absorption by an individual, and can be included in the composition of the present disclosure without causing significant adverse toxicological effects to the individual. Non-limiting examples of pharmaceutically acceptable carriers and/or diluents include water, NaCl, physiological saline solution, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrators, lubricants, coatings, sweeteners, flavorings, saline solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates (such as lactose, linear starch or starch), fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine and pigments, etc. Such preparations may be sterilized and, if desired, may be mixed with auxiliary agents (such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts affecting osmotic pressure, buffers, colorants and/or aromatic substances, etc.) that do not react adversely with the compounds provided herein or interfere with their activity. A person of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with the disclosed compounds. The term "carrier" as used in this disclosure encompasses carriers, excipients, and diluents and refers to materials, compositions, or vehicles involved in carrying or transporting a pharmaceutical agent from one organ or body part of an individual to another organ or body part, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. The pharmaceutical composition of the present teachings may optionally include one or more pharmaceutically acceptable carriers and/or diluents therefor, such as lactose, starch, cellulose, and dextrose. Other excipients may also be included, such as flavorings; sweeteners; and preservatives, such as methyl, ethyl, propyl, and butyl hydroxybenzoate. A more complete list of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5th edition, Pharmaceutical Press (2005)). One of ordinary skill in the art will know how to prepare formulations suitable for a variety of routes of administration. Traditional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003-20th edition) and The United States Pharmacopeia: The National Formulary (USP 24 NF19), published in 1999. 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. The pharmaceutical compositions of the present disclosure are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, eg, intravenous, intradermal, subcutaneous, oral (eg, inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions for parenteral, intradermal, or subcutaneous administration may include the following components: a sterile diluent (e.g., water for injection, aqueous saline solution, nonvolatile oils, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents); antibacterial agents (e.g., benzyl alcohol or methyl paraben); antioxidants (e.g., ascorbic acid or sodium bisulfite); chelating agents (e.g., ethylenediaminetetraacetic acid); buffers (e.g., acetate, citrate or phosphate), and agents for adjusting tonicity (e.g., sodium chloride or dextrose). pH may be adjusted with acids or bases (e.g., hydrochloric acid or sodium hydroxide). Parenteral formulations may be enclosed in ampoules, disposable syringes, or multi-dose vials made of glass or plastic. The compounds or pharmaceutical compositions of the present disclosure may be administered to an individual by any of a number of known methods currently used for chemotherapy. For example, in the treatment of cancer, the compounds of the present disclosure may be injected directly into a tumor, injected into the bloodstream or body cavity, or orally, or applied through the skin as a patch. The dose selected should be sufficient to constitute an effective treatment, but not so high as to cause unacceptable side effects. The status of the disease state (e.g., cancer, precancer, etc.) and the patient's health should preferably be closely monitored during treatment or for a reasonable period of time after treatment. The term "therapeutically effective amount," as used herein, refers to the amount of a pharmaceutical agent that is effective to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect may be detected by any analytical method known in the art. The precise effective amount for an individual will depend on the individual's weight, size, and health; the nature and extent of the condition; and the therapy or combination of therapies selected for administration. The therapeutically effective amount for a given situation may be determined by routine experimentation within the expertise and judgment of the clinician. For any compound, the therapeutically effective amount may be initially assessed, for example, in a cell culture assay of tumor cells, or in an animal model (usually rats, mice, rabbits, dogs, or pigs). Animal models can also be used to determine appropriate concentration ranges and routes of administration. This information can then be used to determine useful doses and routes of administration in humans. Therapeutic/prophylactic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell culture or experimental animals, e.g., ED ₅₀(the therapeutically effective dose in 50% of the total) and LD ₅₀(The dose that causes 50% of the total lethality). The dose ratio between toxicity and therapeutic effect is the therapeutic index, and it can be expressed as the ratio LD ₅₀/ED ₅₀Indicates. Pharmaceutical compositions that exhibit a large therapeutic index are preferred. Dosages may vary within this range depending on the dose used, patient sensitivity, and route of administration. Dosage and administration are adjusted to provide adequate levels of active agent or to maintain the desired effect. Factors that may be considered include the severity of the disease state, the general health of the individual, the age, weight and sex of the individual, diet, time and frequency of administration, drug combination, reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, weekly, or biweekly, depending on the half-life and clearance rate of the particular formulation. Pharmaceutical compositions containing the active compounds of the present disclosure (i.e., compounds of formula (I)) can be prepared in a generally known manner, for example, using known mixing, dissolving, granulating, sugar-coating, grinding, emulsifying, encapsulating, entrapping, or lyophilizing methods. Pharmaceutical compositions can be formulated in a known manner using one or more pharmaceutically acceptable carriers (which include excipients and/or adjuvants that facilitate processing of the active compounds into pharmaceutically usable preparations). Of course, the appropriate formulation depends on the chosen route of administration. Pharmaceutical compositions suitable for injection include sterile aqueous solutions (where water soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile injection solutions or dispersions. 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 it can be easily injected. It must be stable under the conditions of manufacture and storage and must resist the contaminating action of microorganisms (such as bacteria and fungi). The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycol, etc.) and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of coatings such as lecithin, by the maintenance of the required particle size in the case of dispersions, 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, sodium thiomersalate, and the like. In many cases, it will be advantageous to include in the composition an isotonic agent, for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride. Prolonged absorption of the injectable composition 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 combining the active compound in the required amount in an appropriate solvent with one or a combination of the ingredients listed above, if necessary, followed by filtering and sterilizing. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation are vacuum drying and freeze drying, which produce a powder of the active ingredient plus any additional desired ingredients from its previous sterile filtered solution. 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 may be mixed with a formulation and used in the form of tablets, troches, or capsules. Oral compositions may 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 binders and/or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, tablets, etc. may contain any of the following ingredients, or compounds of similar nature: binders such as microcrystalline cellulose, tragacanth, or gelatin; formulators such as starch or lactose; disintegrants such as alginic acid, sodium carboxymethyl starch (Primogel), or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as mint, methyl salicylate, or orange flavor. For administration by inhalation, the compound is delivered as an aerosol spray from a pressurized container or dispenser containing a suitable propellant (e.g., a gas such as carbon dioxide), or a nebulizer. Systemic administration may also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate for the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art and include, for example, for mucosal administration, detergents, bile salts, and fusidic acid derivatives for transmucosal administration. Transmucosal administration may be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compound is formulated into an ointment, salves, gel, or cream as is generally known in the art. The active compound may be prepared with a pharmaceutically acceptable carrier that prevents rapid elimination of the compound from the body, for example, a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers may be used, for example, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparing such formulations will be apparent to those skilled in the art. Such materials may also be commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) may also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art (e.g., as described in U.S. Patent No. 4,522,811). For ease of administration and dosage consistency, oral or parenteral compositions in dosage unit form are particularly advantageous. As used herein, dosage unit form refers to physically discrete units suitable as unit doses for individuals to be treated; each unit contains a calculated predetermined amount of active compound combined with a pharmaceutical carrier required to produce the desired therapeutic effect. The dosage unit form of the present disclosure is specified by or directly depends on the unique properties of the active compound and the specific therapeutic effect to be achieved. In the treatment disclosure, the dosage of the pharmaceutical composition used according to the present disclosure varies depending on the dosage, the age, weight, and clinical condition of the patient receiving it, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors that affect the dosage selected. Generally, the dosage should be sufficient to cause a slowing down, and preferably regression of the growth of the tumor, and also preferably to cause complete regression of the cancer. The dosage range may be from about 0.01 mg/kg per day to about 5000 mg/kg per day. The effective amount of a pharmaceutical agent is the amount that provides an objectively identifiable improvement noted by a clinician or other qualified observer. For example, the regression of a tumor in an individual can be measured with reference to the diameter of the tumor. Reduction in tumor size indicates regression. Regression is also indicated by the absence of tumor recurrence after cessation of treatment. As used herein, the term "dosage effective manner" refers to the amount of active compound that produces the desired biological effect in an individual or cell. The pharmaceutical composition may be included in a container, package, or dispenser along with instructions for administration. The dosage regimen for utilizing the compound is selected based on a variety of factors, including the type, race, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the patient's renal and liver function; and the specific compound or its pharmaceutically acceptable salt or solvent complex employed. A physician or veterinarian of ordinary skill can readily determine and prescribe an effective amount of the necessary medication to prevent, counter, or arrest the progression of the condition. Techniques for the formulation and administration of the compounds disclosed in this disclosure can be found in Remington: the Science and Practice of Pharmacy, 19 ^thedition, Mack Publishing Co., Easton, PA (1995). In some embodiments, the compounds described herein and their pharmaceutically acceptable salts or solvents are combined with pharmaceutically acceptable carriers or diluents for use in pharmaceutical preparations. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compound or its pharmaceutically acceptable salt or solvent will be present in the pharmaceutical composition in an amount sufficient to provide the desired dosage within the range described herein. Unless otherwise indicated, all percentages and ratios used herein are by weight. Other features and advantages of the present disclosure are apparent from different examples. The examples provided show different components and methods that can be used to practice the present disclosure. The examples do not limit the claimed disclosure. Those skilled in the art will be able to identify and adopt other components and methods useful for practicing the present disclosure based on the present disclosure. Methods of using the compoundThe present application provides a method for treating an individual suffering from a disease or condition that can be improved by inhibiting Polθ helicase, by administering an effective amount of one or more disclosed compounds, or a pharmaceutically acceptable salt or solvent thereof, or a corresponding pharmaceutical composition to the individual. Diseases that can be improved by inhibiting Polθ helicase include the treatment of cancer. The present application further relates to a method for treating a disease or condition (e.g., cancer) in which Polθ helicase plays a role. The method comprises administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvent thereof, or a pharmaceutical composition disclosed herein to an individual in need thereof. In one aspect, described herein is a method for treating and/or preventing a disease in an individual, such as a cancer characterized by overexpression/overactivity of Polθ helicase, comprising administering a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvent thereof to the individual. In another aspect, described herein is a method for treating and/or preventing a cancer in an individual, such as a cancer characterized by homologous recombination (HR) deficiency or by reduced or absent expression of a BRCA gene, absent BRAC gene, or reduced function of a BRCA protein, comprising administering a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvent thereof to the individual. 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 solvent complex 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 solvent complex 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 solvent complex thereof for treating and/or preventing a disease in an individual, such as a disease treatable by inhibiting Polθ, such as cancer, including homologous recombination (HR)-deficient cancer. In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvent complex thereof for treating and/or preventing a disease in an individual, such as a cancer characterized by overexpression/overactivity of Polθ helicase, by homologous recombination (HR) deficiency, or by reduced or absent expression of BRAC genes, absent BRAC genes, or reduced function of BRAC proteins. In another aspect, provided herein is a compound described herein or a pharmaceutically acceptable salt or solvent complex thereof for use in the manufacture of an agent 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 solvent complex thereof for use in the manufacture of a medicament for treating and/or preventing a disease in an individual, such as a disease treatable by inhibiting Polθ, such as cancer, including homologous recombination (HR) deficient cancer. In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvent complex thereof for use in the manufacture of a medicament for treating and/or preventing a disease in an individual, such as a cancer characterized by overexpression/overactivity of Polθ helicase, by homologous recombination (HR) deficiency, or by reduced or absent expression of BRAC genes, absence of BRAC genes, or reduced function of BRAC proteins. In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvent thereof for treating and/or preventing cancer resistant to poly (ADP-ribose) polymerase (PARP) inhibitor therapy in an individual. 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 for treating cancer, comprising administering a therapeutically effective amount of a composition as described herein (e.g., a composition comprising a compound of the present disclosure) to an individual in need of treating cancer. The present disclosure further relates to the use of a compound disclosed herein, or a pharmaceutically acceptable salt or solvent complex thereof, or a pharmaceutical composition disclosed herein, in the manufacture of a medicament for treating a disease or condition in which Polθ helicase plays a role (e.g., cancer). The present disclosure provides the use of a compound disclosed herein, or a pharmaceutically acceptable salt or solvent complex thereof, or a pharmaceutical composition disclosed herein, in the manufacture of a medicament for treating a disease or condition that can be improved by inhibiting Polθ helicase. In one embodiment, described herein is the use of a compound disclosed herein, or a pharmaceutically acceptable salt or solvent complex thereof, or a pharmaceutical composition disclosed herein, in the manufacture of a medicament for the treatment of cancer. The present disclosure further relates to a compound disclosed herein, or a pharmaceutically acceptable salt or solvent complex thereof, or a pharmaceutical composition disclosed herein, for treating a disease or condition in which Polθ helicase plays a role, such as cancer. The present disclosure provides a compound disclosed herein, or a pharmaceutically acceptable salt or solvent complex thereof, or a pharmaceutical composition disclosed herein, for treating a disease or condition that can be improved by inhibiting Polθ helicase. In another aspect, described herein is a method for treating and/or preventing a disease characterized by overexpression of Polθ helicase in a patient, such as cancer, comprising administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvent complex thereof, to the patient. In some embodiments, described herein is a method for treating and/or preventing homologous recombination (HR)-deficient cancer in a patient, comprising administering a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvent complex thereof to the patient. In some embodiments, described herein is a method for inhibiting DNA repair by Polθ in cancer cells, comprising contacting the cells with an effective amount of a compound described herein or a pharmaceutically acceptable salt or solvent complex thereof. In some embodiments, the cancer is a HR-deficient cancer. In some embodiments, described herein is a method for treating and/or preventing cancer in a patient, wherein the cancer is characterized by reduced or absent expression of a BRCA gene, absent a BRAC gene, or reduced function of a BRCA protein, comprising administering a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvent thereof (optionally in a pharmaceutical composition) to the individual. In some embodiments, the cancer is lymphoma, leukemia, multiple myeloma, soft tissue cancer, rhabdomyosarcoma, rhabdomyosarcoma, central nervous system cancer, peripheral nervous system cancer, bone cancer, uterine cancer, ovarian cancer, upper aerodigestive tract cancer, esophageal cancer, gastric cancer, gastrointestinal cancer, colorectal cancer, malignant mesothelioma, breast cancer, lung cancer, bladder cancer, liver cancer, head and neck cancer, fibroblastic carcinoma, urinary tract cancer, kidney cancer, skin cancer, prostate cancer, and pancreatic cancer. In some embodiments, the HR-deficient cancer is breast cancer. Breast cancer includes but is not limited to lobular carcinoma in situ (lobular carcinoma in situ) in situ,LCIS), ductal carcinoma in situin situ,DCIS), invasive ductal carcinoma (IDC), inflammatory breast cancer, Paget’s disease of the nipple, phyllodes tumor, angiosarcoma, adenoid cystic carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous adenocarcinoma, papillary carcinoma, tubular carcinoma, metaplastic breast cancer, micropapillary carcinoma, mixed carcinoma, and other breast cancers, including but not limited to 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 breast cancers. In some embodiments, the HR-deficient cancer is an ovarian cancer, including but not limited to epithelial ovarian carcinomas (EOC), mature teratomas, dysgerminomas, endodermal sinus tumors, ovarian granulomas, Sertoli-stromal cell tumors, and primary peritoneal carcinomas. In some embodiments, cancers that can be treated by the disclosed methods include cancers of the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestinal, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, testicle, tongue, or uterus. Furthermore, the cancer may specifically be of the following histological types, although not limited thereto: malignant neoplasm; tumor; carcinoma; undifferentiated carcinoma; giant cell and spindle cell carcinoma; sarcoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; malignant gastrinoma; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyps; adenocarcinoma, familial colon polyps; solid carcinoma; malignant carcinoid tumor; bronchopulmonary Alveolar carcinoma; Papillary adenocarcinoma; Chromophobe cell carcinoma; Oncocytic carcinoma; Oncocytic adenocarcinoma; Alkaline glomerulosa carcinoma; Clear cell adenocarcinoma; Granular cell carcinoma; Follicular adenocarcinoma; Papillary and follicular adenocarcinoma; Sclerosing adenocarcinoma without capsule formation; Adrenal cortical carcinoma; Endometrioid carcinoma; Carcinoma of skin appendages; Apocrine adenocarcinoma; Sebaceous gland carcinoma; Cerumen gland carcinoma; Mucoepidermoid carcinoma; Cystadenocarcinoma; Papillary cystadenocarcinoma; Papillary serous cystadenocarcinoma; Mucinous cystadenocarcinoma; Mucinous adenocarcinoma; Ring cell carcinoma; Infiltrating ductal carcinoma; Medullary carcinoma; Lobular carcinoma; Inflammatory carcinoma; Paget’s disease of the breast disease); acinar cell carcinoma; adenosquamous carcinoma; adenocarcinoma with squamous metaplasia; malignant thymoma; malignant ovarian stromal tumor; malignant sarcoma; malignant granulocytoma; androgenic tumor; sertoli cell carcinoma; malignant leydig cell tumor; malignant lipocytoma; malignant paraganglioma; malignant extramammary paraganglioma; pheochromocytoma; glomus sarcoma; malignant melanoma; amelanoma; superficial diffuse melanoma; malignant melanoma in giant pigmented nevus; epithelioid cell melanoma; malignant blue nevus; sarcoma; fibrosarcoma; malignant fibrosarcoma Histiocytic tumor; myxosarcoma; liposarcoma; leiomyosarcoma; rhabdomyosarcoma; embryonal rhabdomyosarcoma; alveolar rhabdomyosarcoma; stromal sarcoma; malignant mixed tumor; Mullerian mixed tumor; nephroblastoma; hepatoblastoma; carcinosarcoma; malignant stromal tumor; malignant Brenner tumor; malignant phyllodes tumor; synovial sarcoma; malignant mesothelioma; asexual embryonal tumor; embryonal carcinoma; malignant teratoma; malignant thyrodermatoid ovarian tumor; choriocarcinoma; malignant mesenchymal tumor; angiosarcoma; malignant hemangioendothelioma; Kaposi's sarcoma sarcoma); malignant hemangiopericytoma; lymphangiosarcoma; osteosarcoma; juxtacortical osteosarcoma; chondrosarcoma; malignant chondroblastoma; mesenchymal chondrosarcoma; giant cell tumor of bone; Ewing's sarcoma; malignant odontogenic tumor; ameloblastic odontosarcoma; malignant amelanoblastoma; amelanoblastic fibrosarcoma; malignant pinealoma; chordoma; malignant glioma; ependymoma; astrocytoma; protoplasmic astrocytoma; protofibromatous astrocytoma; astroblastoma; neuroglioblastoma; oligodendroglioma Glioblastoma; Oligodendritic neuroglioblastoma; Primitive neuroectoderm; Cerebellar sarcoma; Ganglioneuroblastoma; Neuroblastoma; Retinoblastoma; Olfactory neurogenic tumor; Malignant meningioma; Neurofibrosarcoma; Malignant schwannoma; Malignant granulocytoma; Malignant lymphoma; Hodgkin's disease ; Hodgkin's; paragranuloma; small lymphocytic malignant lymphoma; large cell diffuse malignant lymphoma; follicular malignant lymphoma; 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 terms "treatment" or "treating" of a disease include inhibiting the disease, e.g., arresting or reducing the development of the disease or its clinical symptoms; or relieving the disease, e.g., causing regression of the disease or its clinical symptoms. The terms "inhibiting," "reducing," or any variation of these terms with respect to Polθ include any measurable reduction or complete inhibition to achieve the desired result. For example, the reduction in Polθ activity may be reduced by about, up to 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, compared to its normal activity. The term "prevention" refers to the absence of clinical symptoms of a disease in a mammal that may be exposed to or predisposed to the disease but has not yet experienced or displayed 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 DNAs. The term "homologous recombination (HR)-deficient cancer" refers to cancers characterized by a reduction or absence of functional HR repair pathways. HR deficiency can result from the absence of one or more HR-related genes or the presence of one or more mutations in one or more HR-related genes. Examples of HR-related genes include BRCA1, BRCA2, RAD54, RAD51B, CtlP (Choline Transporter-Like Protein), PALB2 (Partner and Localizer of BRCA2), XRCC2 (X-ray repair complement defect in Chinese hamster cells 2), RECQL4 (RecQ protein-like 4), BLM (Bloom syndrome, RecQ helicase-like), WRN (Werner syndrome, one or more HR-related genes) Nbs 1 (Nibrin), and the gene encoding Fanconi anemia, FA) protein genes or FA-like genes, for example, 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 "Pol θ overexpression" refers to an increase in the expression or activity of Pol θ in disease cells (e.g., cancerous cells) relative to the expression or activity of Pol θ in normal cells (e.g., non-disease cells of the same type). The amount of Pol θ can be at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 10 times, or more relative to the expression of Pol θ in normal cells. 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, the other therapeutic agents include chemotherapeutics known in the art, such as inhibitors of DNA repair pathways (e.g., HR and NHEJ) and immunomodulators. As used herein, the terms "co-administration," "combination administration," and their grammatical equivalents are intended to cover the administration of two or more therapeutic agents to a single individual, and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration or the same or different times. These terms encompass administration of two or more agents to a subject such that both agents and/or their metabolites are present in the subject at the same time. These 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 agents are administered in a single composition. In some embodiments, the compounds described herein and the other agents are mixed in a composition. Embodiment Compound preparationReagent grade chemicals and anhydrous solvents were purchased from commercial sources and used without further purification unless otherwise mentioned. Preparations of compounds are either commercially available or known in the literature, as presented in the references. ChemDraw (PerkinElmer) was used to determine product names. In cases where compounds were prepared similarly to previous examples or intermediates, reaction times, reagent equivalents, temperatures, work-ups, and purification techniques may vary slightly. PurificationAnalytical separation was performed on: -   Teledyne ISCO CombiFlash flash chromatography system using pre-filled SiO₂or C18 column -   Teledyne ISCO ACCQPrep high pressure preparative liquid chromatography system; column: Gemini 5 um C18 110 Å, 150×30 mm -   Biotage Isolera rapid chromatography system, using pre-packed SiO₂Or C18 column. -   Waters Mass Trigger Semi-Prep HPLC; column: Gemini 5 um NX-C18 110Å, 100×30 mm Analytical methods-LC-MS on Waters UPLC-MS; column: Acquity UPLC, CSH C ₁₈, 1.7 um, 2.1×30 mm; Method: In 2 minutes in H containing 0.1% (v/v) formic acid₂From 5% to 95% CH in O ₃CN or CH from 5% to 95% in 10 mM ammonium bicarbonate within 2 minutes ₃CN. -NMR spectroscopy was performed using a Varian NMR (AS 400) 400 MHz spectrometer with an Inova interface. In all cases, the NMR data were consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts per million using conventional peak nomenclature abbreviations: 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                      Butylcarbonyl b                      Broad peak singlet Bu                       Butyl Calcd                 Calculated value d                      Peak DAST                (Diethylamino)sulfur trifluoride dd                     Doublet of doublet dt                     Doublet of triplet DCM                     Dichloromethane DDQ                2,3-Dichloro-5,6-dicyano-p-benzoquinone DIBALH            Diisobutylaluminum hydroxide DIPA N, N-Diisopropylamine DIPEA N,N-Diisopropylethylamine DMAP              4-Dimethylaminopyridine DMF N,N-Dimethylformamide DMP                  Dess-Martin periodinane DMSO                Dimethylsulfoxide Dppf                      1,1’-ferrocenediyl-bis(diphenylphosphine) EA                        Ethyl acetate ee                     Excess of mirror image isomer Et                        Ethyl EtOH                 Ethanol Et ₃N                  Triethylamine eq                     Equivalent g                    Gram Hour                  Hour(h) HATU         1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazole[4,5- b]Pyridinium 3-oxide hexafluorophosphate Hz                     Hertz HPLC             High performance liquid chromatography i-Pr                  Isopropyl JCoupling constant L                         Liter LC-MS                   Liquid chromatography-mass spectrometry LDA                  Lithium diisopropylamide LiHMDS                 Lithium bis(trimethylsilyl)amide M                      Mole m                      Multiplet mCPBA                  m-Chloroperbenzoic acid Me                   Methyl MeTHF                   2-Methyltetrahydrofuran MeOH                Methanol mg                   Milligram MHz                     Millihertz min                      Minute mL                      Milliliter mm                    Millimeter mmol                    Millimole mol                     Mole MS                    Mass spectrum N                      Normal NBS N-Succinimidyl bromide PCC                         Pyridine chlorochromate Pd ₂(dba) ₃Tris(dibenzylindeneacetone)dipalladium(0) Pd(PPh ₃) ₄Tetrakis(triphenylphosphine)palladium(0) Pd(dppf)Cl ₂.DCM [1,1’-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexed with dichloromethane Pd(dppf)Cl ₂[1,1’-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) pH                        Potential of hydrogen Ph                         Phenyl PPh ₃triphenylphosphine ppm                parts per million PyBOP               Benzotriazolyl-1-yloxytripyrrolidinylphosphonium hexafluorophosphate q                      quartet RT                    room temperature NMR                 nuclear magnetic resonance s                       singlet sat                    saturated sxt                    sextuplet tLevel 3 t                       Triplet tt                      Triplet of triplet t-Bu                Tertiary butyl TCFH                Chloro- N, N, N', N'-Tetramethylformamidine hexafluorophosphate TMS                      trimethylsilyl TFA                 trifluoroacetic acid THF                 tetrahydrofuran Ts                     tosyl mol                       micromolar v/v                    volume/volume XantPhos            4,5-bis(diphenylphosphino)-9,9-dimethyl °                       Degree %                      Percentage The general method used for synthesis is indicated below for reference. General approach Reaction Name A Amide coupling reaction (HATU) B Amination C Amidide coupling reaction (TCFH) D Williamson ether synthesis E Sonogashira cross coupling F BOC deprotection G Buchwald amide cross coupling H Suzuki Marionette I Hydrogenation J Condensation reaction Embodiment 1. N-(5-((4- Benzyl chloride ) Sulfur )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound 1) Preparation Steps 1 : 5-((4- Benzyl chloride ) Sulfur )-1,3,4- Thiadiazole -2- Synthesis of aminesA solution of 0.1 N sodium hydroxide (38 mL, 3.75 mmol) was added to a mixture of 5-amino-1,3,4-thiadiazol-2-thiol (1 g, 7.51 mmol) and 4-chlorobenzyl bromide (1.57 g, 7.51 mmol) in EtOH (100 mL) at 0°C. 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 provide 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 ⁺, actual value). Steps 2 : N-(5-((4- Benzyl chloride ) Sulfur )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound 1 ) Synthesis – General approach AHATU (226 mg, 0.58 mmol) and DIPEA (203 mL, 1.16 mmol) were added to a stirred solution of 5-((4-chlorobenzyl)thio)-1,3,4-thiadiazolyl-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). The reaction mixture was stirred at room temperature under an argon atmosphere for 3 h. The reaction mixture was diluted with water and extracted with EA (3×10 mL). The combined organic layers were heated in anhydrous Na ₂SO ₄Dry on ice, filter, and concentrate to dryness. Purify the residue by flash chromatography (elution gradient from 0% to 50% EA in hexanes). The isolated product was dissolved in ACN (1 mL), diluted with water (4 mL), and freeze-dried to provide N-(5-((4-chlorobenzyl)thio)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide ( Compound 1)(105 mg, 58% yield), white solid. ¹H NMR (400 MHz, DMSO- d ₆) 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(calculated), 469.1(M+H ⁺, actual value). Embodiment 2. N-(5-((4- Benzyl chloride ) Amine )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound 2) Preparation Steps 1 : N ² -(4- Benzyl chloride )-1,3,4- Thiadiazole -2,5- Synthesis of diamines – General approach BTo a suspension of 2-amino-5-bromo-1,3,4-thiadiazole (1 g, 5.55 mmol) in dry THF (15 mL), add Et ₃N (2 mL, 13.9 mmol) and 4-chlorobenzylamine (676 mL, 5.55 mmol). 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 provide N ²-(4-Chlorobenzyl)-1,3,4-thiadiazole-2,5-diamine (1.34 g, 82% yield) as a gray solid. MS (ESI): m/z 240.0 (calculated), 241.1 (M+H ⁺, actual value). Steps 2 : N-(5-((4- Benzyl chloride ) Amine )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound 2 ) SynthesisAccording to the general method Afrom N ²-(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) gave the title compound. The crude product was purified by flash chromatography (gradient of eluent 0% to 50% EA in hexanes). The isolated product was dissolved in ACN (1 mL), diluted with water (4 mL), and freeze-dried to provide N-(5-((4-chlorobenzyl)amino)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinate ( Compound 2)(37 mg, 20% yield), white solid. ¹H NMR (400 MHz, DMSO- d ₆) 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 = MS (ESI): m/z 451.1(calculated value), 452.2(M+H ⁺, actual value). Embodiment 3. ( E )-N-(5-(4- Chlorothenyl )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound 3) Preparation Steps 1 : ( E )-5-(4- Chlorothenyl )-1,3,4- Thiadiazole -2- Synthesis of aminesThiosemicarbazide (500 mg, 5.48 mmol), 4-chlorocinnamic acid (1 g, 5.48 mmol) and POCl ₃(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 adding 50% aqueous NaOH solution with stirring. The resulting precipitate was filtered and washed twice with EtOH to provide ( E)-5-(4-chlorophenylvinyl)-1,3,4-thiadiazolyl-2-amine (1.15 g, 88% yield) as a light yellow solid. MS (ESI): m/z 237.0.0 (calculated), 238.1 (M+H ⁺, actual value). Steps 2 : ( E )-N-(5-(4- Chlorothenyl )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound 3 ) Synthesis - General approach Cright( E)-5-(4-chlorophenylvinyl)-1,3,4-thiadiazolyl-2-amine (50 mg, 0.21 mmol) and 3-(2-methoxyphenyl) isonicotinic acid (48 mg, 0.21 mmol) in dry DMF (2 mL) were stirred and 1-methylimidazole (61 mL, 0.74 mmol) was added. After 5 minutes, a solution of TCFH (60.2 mg, 0.21 mmol) in dry DMF (1 mL) was added dropwise. The reaction mixture was stirred at room temperature under an atmosphere of argon for 3 h. Water (5 mL) was added and the resulting white precipitate was collected by vacuum filtration and washed with water (2×10 mL), MeOH (2×10 mL) and ACN (2×10 mL) to provide ( E)- N-(5-(4-chlorophenylvinyl)-1,3,4-thiadiazole-2-yl)-3-(2-methoxyphenyl)isonicotinamide( Compound 3)(53 mg, 56% yield), white solid. ¹H NMR (400 MHz, DMSO- d ₆) 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 (calculated), 449.1(M+H ⁺, actual value). Embodiment 4. N-(5-(4- Chlorophenethyl )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound 4) Preparation right( E)-N-(5-(4-chlorophenylvinyl)-1,3,4-thiadiazole-2-yl)-3-(2-methoxyphenyl)isosonicotinamide( 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 with hydrogen countercurrent under reduced pressure (3 times) and stirred under normal hydrogen atmosphere for 18 h. The catalyst was removed by filtration through celite and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (eluent gradient from 0% to 100% EA in hexanes). The isolated product was dissolved in ACN (1 mL), diluted with water (4 mL), and freeze-dried to provide N-(5-(4-chlorophenethyl)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinate ( Compound 4)(15 mg, 75% yield), white solid. ¹H NMR (400 MHz, DMSO- d ₆) 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 (calculated), 451.2(M+H ⁺, actual value). Embodiment 5. N-(5-((4- Benzyl chloride ) Sulfonyl )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound 5) Preparation 4% KMnO at room temperature₄(67 mg, 0.43 mmol) aqueous solution was added dropwise to 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). KMnO ₄The reaction mixture was stirred for 30 minutes until the purple color persisted. 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 dried solid was purified by flash chromatography (elution gradient from 0% to 100% EA in hexanes). The isolated product was dissolved in ACN (1 mL), diluted with water (4 mL), and freeze-dried to provide N-(5-((4-chlorobenzyl)sulfonyl)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide ( Compound 5)(75 mg, 70% yield), white solid. ¹H NMR (400 MHz, DMSO- d ₆) 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(calculated), 501.1(M+H ⁺, actual value). Embodiment 6. N-(5-((4- Benzyl chloride )( methyl ) Amine )-1,3,4- Thiadiazole -2- base )-3-(2 Methoxyphenyl ) Iononia ( Compound 6) Preparation Steps 1 : N ² -(4- Benzyl chloride )-N ² - methyl -1,3,4- Thiadiazole -2,5- Synthesis of diaminesAccording to the general method BFrom 2-amino-5-bromo-1,3,4-thiadiazole (100 mg, 0.56 mmol), 1-(4-chlorophenyl)-N-methylmethanamine (74 mL, 0.56 mmol) and Et ₃N (194 mL, 1.39 mmol) was used to prepare the title compound in THF (5 mL). The crude product was triturated with EtOH (5 mL) and DCM (5 mL) to give N²-(4-chlorobenzyl)-N ²-methyl-1,3,4-thiadiazole-2,5-diamine (63 mg, 45% yield) as a brown solid. MS (ESI): m/z 254.0 (calculated), 255.2 (M+H ⁺, actual value). Steps 2 : N-(5-((4- Benzyl chloride )( methyl ) Amine )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound 6 ) SynthesisAccording to the general method CFrom N ²-(4-chlorobenzyl)-N ²1-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) gave the title compound. The crude product was purified by flash chromatography (eluent gradient from 0% to 5% MeOH in DCM) followed by Prep-HPLC (column: Gemini® 5 um NX-C18 110Å, 100×30 mm) (eluent gradient from 40% to 100% ACN in 10 mM ammonium formate). The isolated product was dissolved in ACN (1 mL), diluted with water (4 mL), and freeze-dried to provide N-(5-((4-chlorobenzyl)(methyl)amino)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide ( Compound 6)(52 mg, 47% yield), off-white solid. ¹H NMR (400 MHz, DMSO- d ₆) 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 (calculated), 466.2 (M+H ⁺, actual value). Embodiment 7. N-(5-((4- Benzyl chloride )( Ethyl ) Amine )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound 7) Preparation Steps 1 : N ² -(4- Benzyl chloride )-N ² - Ethyl -1,3,4- Thiadiazole -2,5- Synthesis of diaminesAccording to the general method BFrom 2-amino-5-bromo-1,3,4-thiadiazole (200 mg, 1.11 mmol), N-(4-Chlorobenzyl)ethylamine (207 mL, 1.11 mmol) and Et ₃N (389 mL, 2.78 mmol) in THF (10 mL) gave the title compound. The residue was purified by flash chromatography (gradient of eluent from 0% to 100% EA in hexanes) to provide N ²-(4-chlorobenzyl)-N ²-ethyl-1,3,4-thiadiazole-2,5-diamine (290 mg, 97% yield) as an off-white solid. MS (ESI): m/z 268.1 (calculated), 269.2 (M+H ⁺, actual value). Steps 2 : N-(5-((4- Benzyl chloride )( Ethyl ) Amine )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound 7 ) SynthesisAccording to the general method Cfrom N ²-(4-chlorobenzyl)- N ²-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) to prepare the title compound. The crude product was purified by flash chromatography (elution gradient from 0% to 100% EA in hexanes). The isolated material was dissolved in ACN (1 mL), diluted with water (4 mL), and freeze-dried to provide N-(5-((4-chlorobenzyl)(ethyl)amino)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinate ( Compound 7)(80 mg, 64% yield), off-white solid. ¹H NMR (400 MHz, DMSO- d ₆) 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 (calculated), 480.3(M+H ⁺, actual value). Embodiment 8. 2-((5-(3-(2- Methoxyphenyl ) Isonicotinamide )-1,3,4- Thiadiazole -2- base ) Oxygen ) Ethyl acetate ( Compound 8) Preparation Steps 1 : 2-((5- Amine -1,3,4- Thiadiazole -2- base ) Oxygen ) Synthesis of Ethyl AcetateTo a stirred 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 Et ₃N (2 mL, 13.9 mmol). The reaction mixture was heated to room temperature, stirred for 6 h, diluted with water (20 mL) and extracted with EA (50 mL × 3). The combined organic layer was washed with brine (30 mL) and precipitated with MgSO ₄Dry over medium, filter, and concentrate under reduced pressure. The crude product was purified by flash chromatography (elution 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 light brown solid. MS (ESI): m/z 203.0 (calcd), 204.1 (M+H ⁺, actual value). Steps 2 : 2-((5-(3-(2- Methoxyphenyl ) Isonicotinamide )-1,3,4- Thiadiazole -2- base ) Oxygen ) Ethyl acetate ( Compound 8 ) SynthesisAccording to the general method CThe title compound was prepared from ethyl 2-((5-amino-1,3,4-thiadiazol-2-yl)oxy)acetate (500 mg, 2.46 mmol), 3-(2-methoxyphenyl)isonicotinate (564 mg, 2.46 mmol), 1-methylimidazole (715 µL, 8.61 mmol), and TCFH (704 mg, 2.46 mmol) in DMF (24 mL). The crude product was purified by flash chromatography (gradient of eluent from 0% to 100% EA in hexanes) to provide ethyl 2-((5-(3-(2-methoxyphenyl)isonicotinateamido)-1,3,4-thiadiazol-2-yl)oxy)acetate ( Compound 8)(1 g, 99% yield), white solid. ¹H NMR (400 MHz, DMSO- d ₆) 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(calculated), 415.2(M+H ⁺, actual value). Embodiment 9. 2-((5-(3-(2- Methoxyphenyl ) Isonicotinamide )-1,3,4- Thiadiazole -2- base ) Oxygen ) Acetic acid ( Compound 9) Preparation Ethyl 2-((5-(3-(2-methoxyphenyl)isonicotinoylamino)-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 minutes, 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)isonicotinoylamino)-1,3,4-thiadiazol-2-yl)oxy)acetic acid ( Compound 9)(581 mg, 83% yield), white solid. ¹H NMR (400 MHz, DMSO- d ₆) 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 (calculated), 387.1 (M+H ⁺, actual value). Embodiment 10. 3-(2- Methoxyphenyl )- N -(5-(2- Phyl -2- Pentoxyethoxy )-1,3,4- Thiadiazole -2- base ) Iononia ( Compound 10) Preparation According to the general method CFrom 2-((5-(3-(2-methoxyphenyl)isonicotinoylamino)-1,3,4-thiadiazol-2-yl)oxy)acetic acid ( 9, 50 mg, 0.13 mmol) The title compound was obtained by mixing 1-(2-methoxyphenyl)-1-nitropropene (11 µL, 0.13 mmol), 1-methylimidazole (38 µL, 0.45 mmol), and TCFH (37 mg, 0.13 mmol) in DMF (1.3 mL). The crude product was purified by flash chromatography (gradient eluent from 0% to 10% MeOH in DCM). The isolated material was dissolved in ACN (1 mL), diluted with water (4 mL), and freeze-dried to provide 3-(2-methoxyphenyl)- N-(5-(2- Phenyl-2-oxoethoxy)-1,3,4-thiadiazol-2-yl)isonicotinamide ( Compound 10)(15 mg, 25% yield), white solid. ¹H NMR (400 MHz, DMSO- d ₆) 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 (calculated), 456.2 (M+H ⁺, actual value). By following the above method for the compound 10The procedure described for the synthesis of Phenylidene, from compounds 9Start synthesizing compounds 11-15(Examples 11-15). The compounds are provided in Table 2 11-15( Embodiment 11-15) characteristics. Embodiment 16. 3-(2- Methoxyphenyl )-N-(5-( Cyclobutane -3- Oxy )-1,3,4- Thiadiazole -2- base ) Iononia ( Compound 16) Preparation Steps 1 : 5-( Cyclobutane -3- Oxy )-1,3,4- Thiadiazole -2- amine ( General approach D ) SynthesisTo a stirred solution of 3-hydroxycyclohexane (82 mg, 1.11 mmol) in dry DMF (3 mL) cooled to 0°C, NaH (67 mg, 1.67 mmol) (60% dispersion in mineral oil) was slowly added. After stirring at 0°C for 15 minutes, 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 heated to room temperature and stirred for 1 h. Water (5 mL) was added and the mixture was extracted with a mixture of chloroform/isopropanol (3/1) (10 ml×3). The combined organic layer was washed with brine and precipitated on anhydrous MgSO ₄Dry on ice, filter, and concentrate to dryness to provide 5-(cyclohexane-3-yloxy)-1,3,4-thiadiazolyl-2-amine (80 mg, 42% yield) as a light yellow oil. MS (ESI): m/z 173.0 (calcd), 174.1 (M+H ⁺, actual value). Steps 2 : 3-(2- Methoxyphenyl )-N-(5-( Cyclobutane -3- Oxy )-1,3,4- Thiadiazole -2- base ) Iononia ( Compound 16 ) SynthesisAccording to the general method CThe title compound was prepared from 5-(cyclohexane-3-yloxy)-1,3,4-thiadiazolyl-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). The residue was purified by flash chromatography (eluent gradient from 0% to 5% MeOH in DCM) followed by Prep-HPLC (column: Gemini® 5 um NX-C18 110 Å, 100×30 mm) (eluent gradient from 40% to 100% ACN in 10 mM ammonium formate). The isolated product was dissolved in ACN (1 mL), diluted with water (4 mL), and freeze-dried to provide 3-(2-methoxyphenyl)-N-(5-(cyclohexane-3-yloxy)-1,3,4-thiadiazol-2-yl)isonicotinate ( Compound 16)(21 mg, 24% yield), white solid. ¹H NMR (400 MHz, DMSO- d ₆) 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 (calculated), 385.2 (M+H ⁺, actual value). Embodiment 17. N-(5-(N-(4- Benzyl chloride ) Methylsulfonamide )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound 17) Preparation Steps 1 : N-(4- Benzyl chloride ) Synthesis of methanesulfonamide4-Chlorobenzylamine (430 mL, 3.53 mmol) and Et ₃To a stirred solution of N (594 mL, 4.24 mmol) in dry DCM (8 mL) cooled to 0°C, methanesulfonyl chloride (307 mL, 3.88 mmol) was slowly added. After stirring at 0°C for 15 minutes, the reaction mixture was warmed to room temperature and stirred under an argon atmosphere for 1 h. The mixture was then diluted with DCM (20 mL) and washed with 10% aqueous citric acid (20 ml×2) and brine in sequence, and finally washed with anhydrous MgSO₄Dry on ice, filter, and concentrate to dryness. Trituration of the crude product with EA (20 mL) gave N-(4-chlorobenzyl)methanesulfonamide (700 mg, 90% yield) as a white solid. MS (ESI): m/z 219.0 (calculated), 218.0 (-ESI, [M-H] ^-, actual value). Steps 2 : N-(5- Amine -1,3,4- Thiadiazole -2- base )-N-(4- Benzyl chloride ) Methanesulfonamide SynthesisAccording to the general method Dfrom NThe title compound was prepared from 2-(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) to provide 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 (calculated), 319.1 (M+H ⁺, actual value). The crude product was used directly in the next step without further purification. Steps 3 : N -(5-(N-(4- Benzyl chloride ) Methylsulfonamide )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound 17 ) SynthesisAccording to the general method CFrom N-(5-amino-1,3,4-thiadiazole-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) gave the title compound. The crude product was purified by flash chromatography (gradient of eluent from 0% to 100% EA in hexanes) followed by Prep-HPLC (column: Gemini® 5 um NX-C18 110 Å, 100×30 mm) (gradient of eluent from 40% to 100% ACN in 10 mM ammonium formate). The isolated product was dissolved in ACN (1 mL), diluted with water (4 mL), and freeze-dried to provide N-(5-(N-(4-chlorobenzyl)methylsulfonamido)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinate ( Compound 17)(11 mg, 8% yield), white solid. ¹H NMR (400 MHz, DMSO- d ₆) 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 (calculated), 530.2 (M+H ⁺, actual value). Embodiment 18. N-(5-(3,3- Difluorocyclobutoxy )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound 18) Preparation Steps 1 : 3-(2- Methoxyphenyl ) Synthesis of isonicotinic acid nitrileTo a stirred 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), K ₂CO ₃(2 g, 16.1 mmol), and Pd(PPh ₃) ₄(0.63 g, 0.54 mmol). The reaction mixture was degassed three times with argon countercurrent under reduced pressure, heated to 100 °C, 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 and precipitated in MgSO₄Dry on ice, filter, and concentrate under reduced pressure. The residue was purified by flash chromatography (elution gradient from 0% to 60% EA in hexanes) to provide 3-(2-methoxyphenyl)isonicotinatecarbonitrile (1 g, 89% yield) as a white solid. MS (ESI): m/z 210.1 (calcd), 211.2 (M+H ⁺, actual value). Steps 2 : 3-(2- Methoxyphenyl ) Synthesis of isonicotinamide3-(2-Methoxyphenyl)isonicotinecarbonitrile (180 mg, 0.86 mmol) in EtOH (6 mL) and H ₂To the stirred solution in a mixture of 4% CO (2 mL), Ghaffar-Parkins catalyst (37 mg, 86 µmol) was added. The reaction mixture was heated to 80 °C, stirred for 2.5 h, then cooled to room temperature, filtered on celite, and concentrated under reduced pressure to provide 3-(2-methoxyphenyl)isonicotinate (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- d ₆) 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(calculated), 229.2(M+H ⁺, actual value). Steps 3 : 2- bromine -5-(3,3- Difluorocyclobutoxy )-1,3,4- Synthesis of ThiadiazoleAccording to the general method DThe 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). The residue was purified by flash chromatography (elution gradient from 0% to 30% EA in hexanes) to provide 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 ⁺, actual value). Steps 4 : N-(5-(3,3- Difluorocyclobutoxy )-1,3,4- Thiadiazole -2- base )-3-(2 Methoxyphenyl ) Iononia ( Compound 18) Synthesis2-Bromo-5-(3,3-difluorocyclobutoxy)-1,3,4-thiadiazole (80 mg, 0.29 mmol), 3-(2-methoxyphenyl)isonicotinate (67 mg, 0.29 mmol), Cs ₂CO ₃(192 mg, 0.59 mmol) and H ₂A stirred solution of 2-nitropropene (3 mL, 0.17 mmol) in dioxane (3 mL) was degassed for 15 min. Then, Pd was added.₂(dba) ₃(27 mg, 0.03 mmol) and XantPhos (34 mg, 0.06 mmol). The reaction mixture was flushed with argon, heated to 100 °C, 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 chromatography (eluent gradient from 0% to 100% EA in hexanes) followed by Prep-HPLC (column: Gemini® 5 um NX-C18 110 Å, 100×30 mm) (eluent gradient from 40% to 100% ACN in 10 mM ammonium formate). The isolated product was dissolved in ACN (1 mL), diluted with water (4 mL), and freeze-dried to provide N-(5-(3,3-difluorocyclobutoxy)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinate ( Compound 18)(12 mg, 10% yield), white solid. ¹H NMR (400 MHz, DMSO- d ₆) 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 (calculated), 419.1 (M+H ⁺, actual value). Embodiment 19. N-(5-((4- Chlorophenyl ) Ethylene )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound 19) Preparation Steps 1 ： Tributyl (5-((4- Chlorophenyl ) Ethylene )-1,3,4- Thiadiazole -2- base ) Synthesis of carbamate – General approach EAdd dry DMF (3 mL) to 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) were added, followed by the 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 heated in anhydrous Na ₂SO ₄Dry on ice, filter, and remove the solvent under reduced pressure. The residue was purified by flash chromatography (elution gradient from 20% to 90% EA in hexanes) to provide Tertiary Butyl(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)carbamate (300 mg, 85% yield). MS (ESI): m/z 335.1 (calculated), 336.1 (M+H ⁺, actual value). Steps 2 : 5-((4- Chlorophenyl ) Ethylene )-1,3,4- Thiadiazole -2- Synthesis of amines – General approach FTrifluoroacetic 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 provide 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 ⁺, actual value). Steps 3 : N-(5-((4- Chlorophenyl ) Ethylene )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound 19 ) SynthesisAccording to the general method CThe title compound was prepared from 5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazolyl-2-amine (50 mg, 0.21 mmol), 3-(2-methoxyphenyl)isosonicotinic acid (49 mg, 0.21 mmol), 1-methylimidazole (62 µL, 0.74 mmol) and TCFH (61 mg, 0.21 mmol) in DMF (2 mL). The crude product was purified by flash chromatography (eluent gradient from 0% to 100% EA in hexanes). The isolated material was dissolved in ACN (1 mL), diluted with water (4 mL) and freeze-dried to provide N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinate ( Compound 19)(25 mg, 26% yield), white solid. MS (ESI): m/z 446.1(calculated), 447.1(M+H ⁺, actual value). ¹H NMR (400 MHz, DMSO- d ₆ ) 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(calculated), 447.1(M+H ⁺, actual value). Embodiment 20. 3-(2- Methoxyphenyl )-N-(5-(4- Phenylbutyl -1- Alkyne -1- base )-1,3,4- Thiadiazole -2- base ) Iononia ( Compound 20) Preparation Steps 1 ： Tributyl (5-(4- Phenylbutyl -1- Alkyne -1- base )-1,3,4- Thiadiazole -2- base ) Synthesis of carbamateAccording to the general method Efrom 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) to obtain the title compound. The crude product was purified by flash chromatography (gradient of eluent from 20% to 90% EA in hexanes) to provide Tertiary 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 ⁺, actual value). Steps 2 : 5-(4- Phenylbutyl -1- Alkyne -1- base )-1,3,4- Thiadiazole -2- Synthesis of aminesAccording to the general method Ffrom Tertiary ButylThe title compound was prepared from (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). The reaction mixture was concentrated to dryness to provide 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 ⁺, actual value). Steps 3 : 3-(2- Methoxyphenyl )-N-(5-(4- Phenylbutyl -1- Alkyne -1- base )-1,3,4- Thiadiazole -2- base ) Iononia ( Compound 20 ) SynthesisAccording to the general method CThe title compound was obtained from 5-(4-phenylbut-1-yn-1-yl)-1,3,4-thiadiazolyl-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). The crude product was purified by flash chromatography (eluent gradient from 0% to 100% EA in hexanes). The isolated product was dissolved in ACN (1 mL), diluted with water (4 mL) and freeze-dried to provide 3-(2-methoxyphenyl)-N-(5-(4-phenylbut-1-yn-1-yl)-1,3,4-thiadiazol-2-yl)isonicotinate (50 mg, 26% yield) as a white solid. ¹H NMR (400 MHz, DMSO- d ₆ ) 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 (calculated), 441.3 (M+H ⁺, actual value). Embodiment 21. 3-(2- Methoxyphenyl )-N-(5-(3- Phenoxypropyl -1- Alkyne -1- base )-1,3,4- Thiadiazole -2- base ) Iononia ( Compound twenty one) Preparation Steps 1 ： Tributyl (5-(3- Phenoxypropyl -1- Alkyne -1- base )-1,3,4- Thiadiazole -2- base ) Synthesis of carbamateAccording to the general method Efrom 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) to prepare the title compound. The crude product was purified by flash chromatography (gradient of eluent from 20% to 90% EA in hexanes) to provide Tertiary 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 (calculated), 332.1 (M+H ⁺, actual value). Steps 2 : 5-(3- Phenoxypropyl -1- Alkyne -1- base )-1,3,4- Thiadiazole -2- Synthesis of aminesAccording to the general method Ffrom Tertiary ButylThe title compound was prepared from (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). The reaction mixture was concentrated to dryness to provide 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 ⁺, actual value). Steps 3 : 3-(2- Methoxyphenyl )-N-(5-(3- Phenoxypropyl -1- Alkyne -1- base )-1,3,4- Thiadiazole -2- base ) Iononia ( Compound twenty one ) SynthesisAccording to the general method CThe title compound was prepared from 5-(3-phenoxyprop-1-yn-1-yl)-1,3,4-thiadiazolyl-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). The crude product was purified by flash chromatography (eluent gradient from 0% to 100% EA in hexanes). The isolated material was dissolved in ACN (1 mL), diluted with water (4 mL) and freeze-dried to provide 3-(2-methoxyphenyl)-N-(5-(3-phenoxyprop-1-yn-1-yl)-1,3,4-thiadiazol-2-yl)isonicotinamide ( Compound twenty one)(10 mg, 26% yield), white solid. ¹H NMR (400 MHz, DMSO- d ₆ ) 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(calculated), 443.3(M+H ⁺, actual value). Embodiment twenty two. Tertiary Butyl 4-((5-(3-(2- Methoxyphenyl ) Isonicotinamide )-1,3,4- Thiadiazole -2- base ) Oxygen ) Piperidine -1- Formate ( Compound twenty two) Preparation Steps 1 ： Tributyl 4-((5- bromine -1,3,4- Thiadiazole -2- base ) Oxygen ) Piperidine -1- Synthesis of formate estersAccording to the general method DFrom 2,5-dibromo-1,3,4-thiadiazole (100 mg, 0.41 mmol), Tertiary ButylThe title compound was prepared from 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). The crude product was purified by flash chromatography (gradient of eluent from 0% to 100% EA in hexanes) to give Tertiary Butyl4-((5-Bromo-1,3,4-thiadiazol-2-yl)oxy)piperidine-1-carboxylate (140 mg, 94% yield) as a white solid. Steps 2 ： Tributyl 4-((5-(3-(2- Methoxyphenyl ) Isonicotinamide )-1,3,4- Thiadiazole -2- base ) Oxygen ) Piperidine -1- Formate ( Compound twenty two ) Synthesis - General approach Gright Tertiary ButylTo a stirred solution of 4-((5-bromo-1,3,4-thiadiazol-2-yl)oxy)piperidine-1-carboxylate (20 mg, 0.06 mmol) in DMF (1 mL), add 3-(2-methoxyphenyl)isonicotinate (15 mg, 0.07 mmol). Then add cesium carbonate (36 mg, 0.11 mmol), three(Dibenzylidenacetone) dipalladium (5 mg, 0.01 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyl (7 mg, 0.01 mmol) before the reaction mixture was degassed under a stream of argon for 5 min. The reaction mixture was flushed with argon under reduced pressure before heating to 100 °C. 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 chromatography (gradient of eluent from 0% to 100% EA in hexanes) to obtain Tertiary Butyl4-((5-(3-(2-methoxyphenyl)isonicotinoylamino)-1,3,4-thiadiazol-2-yl)oxy)piperidine-1-carboxylate ( Compound twenty two)(20 mg, 71% yield), white solid. ¹H NMR (400 MHz, DMSO- d ₆ ) 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 (calculated), 512.3 (M+H ⁺, actual value). Embodiment 23. 3-(2- Methoxyphenyl )-N-(5-( Piperidine -4- Oxy )-1,3,4- Thiadiazole -2- base ) Iononia ( Compound twenty three) Preparation According to the general method Ffrom Tertiary Butyl4-((5-(3-(2-methoxyphenyl)isonicotinoylamino)-1,3,4-thiadiazol-2-yl)oxy)piperidine-1-carboxylate ( Compound twenty two) (7 mg, 0.014 mmol) and trifluoroacetic acid (53 µL, 0.68 mmol) in DCM (1 mL) to prepare the title compound. The crude product was purified by Prep-HPLC (column: Gemini® 5 um NX-C18 110 Å, 100×30 mm) (gradient of eluent from 25% to 100% MeOH in 10 mM ammonium formate) to provide 3-(2-methoxyphenyl)-N-(5-(piperidin-4-yloxy)-1,3,4-thiadiazol-2-yl)isonicotinate ( Compound twenty three)(2.3 mg, 41% yield), white solid. ¹H NMR (400 MHz, DMSO- d ₆ ) 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 (calculated), 412.2 (M+H ⁺, actual value). Embodiment twenty four. N-(5-((1- Acetylpiperidine -4- base ) Oxygen )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound twenty four) Preparation Steps 1 : 1-(4-((5- Amine -1,3,4- Thiadiazole -2- base ) Oxygen ) Piperidine -1- base )1- Synthesis of Ethyl KetoneAccording to the general method DThe 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). The product was purified by flash chromatography (0% to 10% MeOH (0.1% NH₄The crude product was purified by elution gradient of 5% 4-nitropropene (5-nitropropene) (4-((5-amino-1,3,4-thiadiazol-2-yl)oxy)piperidin-1-yl)-1-ethanone (13 mg, 19% yield) as a colorless oil. MS (ESI): m/z 242.3 (calculated), 243.1 (M+H ⁺, actual value). Steps 2 : N-(5-((1- Acetylpiperidine -4- base ) Oxygen )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound twenty four ) SynthesisAccording to the general method CThe title compound was obtained from 1-(4-((5-amino-1,3,4-thiadiazol-2-yl)oxy)piperidin-1-yl)ethyl 1-ol (13 mg, 0.05 mmol), 3-(2-methoxyphenyl)isosonicotinic acid (12 mg, 0.05 mmol), 1-methylimidazole (16 µL, 0.19 mmol) and TCFH (15 mg, 0.05 mmol) in DMF (1 mL). The crude product was purified by Prep-HPLC (column: Gemini® 5 um NX-C18 110 Å, 100×30 mm) (eluent gradient from 25% to 100% MeOH in 10 mM ammonium bicarbonate). The isolated product was dissolved in ACN (1 mL), diluted with water (4 mL) and freeze-dried to provide N-(5-((1-acetylpiperidin-4-yl)oxy)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinate ( Compound twenty four)(10 mg, 41% yield), white solid. ¹H NMR (400 MHz, DMSO- d ₆ ) 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 (calculated), 454.2 (M+H ⁺, actual value). Embodiment 25. N-(5-(2-(4- Bromophenoxy ) Ethoxy )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound 25) Preparation Steps 1 : 2- bromine -5-(2-(4- Bromophenoxy ) Ethoxy )-1,3,4- Synthesis of ThiadiazoleAccording to the general method DThe 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). The product was purified by flash chromatography (0% to 10% MeOH (0.1% NH₄The crude product was purified by elution gradient of 4-(4-bromophenoxy)ethoxy)-1,3,4-thiadiazole (150 mg, 85% yield) as a colorless oil. MS (ESI): m/z 316.1 (calculated), 318.0 (M+H ⁺, actual value). Steps 2 : N-(5-(2-(4- Bromophenoxy ) Ethoxy )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound 25 ) SynthesisAccording to the general method CThe 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). The crude product was purified by Prep-HPLC (column: Gemini® 5 um NX-C18 110 Å, 100×30 mm) (eluent gradient from 25% to 100% ACN in 10 mM ammonium bicarbonate). The isolated product was dissolved in ACN (1 mL), diluted with water (4 mL) and freeze-dried to provide N-(5-(2-(4-bromophenoxy)ethoxy)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinate ( Compound 25)(20 mg, 12% yield), white solid. ¹H NMR (400 MHz, DMSO- d ₆ ) 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 (calculated), 529.0(M+H ⁺, actual value). Embodiment 26. N-(5-(2-(4- Chlorophenoxy ) Ethoxy )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound 26) Preparation Steps 1 : 2- Amine -5-(2-(4- Chlorophenoxy ) Ethoxy )-1,3,4- Synthesis of ThiadiazoleAccording to the general method DThe 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). The product was purified by flash chromatography (0% to 10% MeOH (0.1% NH₄The crude product was purified by elution gradient of 5-(4-chlorophenoxy)ethoxy)-1,3,4-thiadiazole (400 mg, 88% yield) as a colorless oil. MS (ESI): m/z 271.7 (calculated), 272.1 (M+H ⁺, actual value). Steps 2 : N-(5-(2-(4- Chlorophenoxy ) Ethoxy )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound 26 ) SynthesisAccording to the general method CThe 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). The crude product was purified by Prep-HPLC (column: Gemini® 5 um NX-C18 110 Å, 100×30 mm) (eluent gradient from 25% to 100% ACN in 10 mM ammonium bicarbonate). The isolated material was dissolved in ACN (1 mL), diluted with water (4 mL) and freeze-dried to provide N-(5-(2-(4-chlorophenoxy)ethoxy)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinate ( Compound 26)(82 mg, 46% yield), 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 (calculated), 483.2 (M+H ⁺, actual value). Embodiment 27. 3-(2- Methoxyphenyl )-N-(5-(2- Phenoxyethoxy )-1,3,4- Thiadiazole -2- base ) Iononia ( Compound 27) Preparation Steps 1 : 2- bromine -5-(2- Phenoxyethoxy )-1,3,4- Synthesis of ThiadiazoleAccording to the general method DThe 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). The product was purified by flash chromatography (0% to 10% MeOH (0.1% NH₄The crude product was purified by elution gradient of 5-(4-(2-phenoxyethoxy)-1,3,4-thiadiazole (300 mg, 76% yield) as a colorless oil. MS (ESI): m/z 237.3 (calculated), 238.1 (M+H ⁺, actual value). Steps 2 : 3-(2- Methoxyphenyl )-N-(5-(2- Phenoxyethoxy )-1,3,4- Thiadiazole -2- base ) Iononia ( Compound 27 ) SynthesisAccording to the general method CThe title compound was obtained from 2-bromo-5-(2-phenoxyethoxy)-1,3,4-thiadiazole (100 mg, 0.32 mmol), 3-(2-methoxyphenyl)isonicotinate (97 mg, 0.42 mmol), 1-methylimidazole (122 µL, 1.48 mmol) and TCFH (121 mg, 0.42 mmol) in DMF (1.5 mL). The crude product was purified by Prep-HPLC (column: Gemini® 5 um NX-C18 110 Å, 100×30 mm) (eluent gradient from 25% to 100% ACN in 10 mM ammonium bicarbonate). The isolated material was dissolved in ACN (1 mL), diluted with water (4 mL) and freeze-dried to provide 3-(2-methoxyphenyl)-N-(5-(2-phenoxyethoxy)-1,3,4-thiadiazol-2-yl)isonicotinate ( Compound 27) (110 mg, 58% yield) as a white solid. ¹H NMR (400 MHz, DMSO- d ₆ ) 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 (calculated), 449.2 (M+H ⁺, actual value). Embodiment 28. 3-(2- Methoxyphenyl )-N-(5-((1- Phenylcyclopropyl ) Ethylene )-1,3,4- Thiadiazole -2- base ) Iononia ( Compound 28) Preparation Steps 1 ： Tributyl (5-((1- Phenylcyclopropyl ) Ethylene )-1,3,4- Thiadiazole -2- base ) Synthesis of carbamateAccording to the general method Efrom 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) to prepare the title compound. The crude product was purified by flash chromatography (elution gradient from 20% to 90% EA in hexanes) to provide Tertiary Butyl(5-((1-phenylcyclopropyl)ethynyl)-1,3,4-thiadiazol-2-yl)carbamate (280 mg, 78% yield). MS (ESI): m/z 341.43 (calculated), 342.1 (M+H ⁺, actual value). Steps 2 : 5-((1- Phenylcyclopropyl ) Ethylene )-1,3,4- Thiadiazole -2- Synthesis of aminesAccording to the general method Ffrom Tertiary 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) gave the title compound. The reaction mixture was concentrated to dryness to provide 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 ⁺, actual value). Steps 3 : 3-(2- Methoxyphenyl )-N-(5-((1- Phenylcyclopropyl ) Ethylene )-1,3,4- Thiadiazole -2- base ) Iononia ( Compound 28 ) SynthesisAccording to the general method CThe title compound was obtained from 5-((1-phenylcyclopropyl)ethynyl)-1,3,4-thiadiazolyl-2-amine (50 mg, 0.21 mmol), 3-(2-methoxyphenyl)isonicotinate (48 mg, 0.21 mmol), 1-methylimidazole (60 µL, 0.73 mmol) and TCFH (59 mg, 0.21 mmol) in DMF (1.5 mL). The crude product was purified by Prep-HPLC (column: Gemini® 5 um NX-C18 110 Å, 100×30 mm) (eluent gradient from 25% to 100% ACN in 10 mM ammonium bicarbonate). The purified material was dissolved in ACN (1 mL), diluted with water (4 mL) and freeze-dried to provide 3-(2-methoxyphenyl)-N-(5-((1-phenylcyclopropyl)ethynyl)-1,3,4-thiadiazol-2-yl)isonicotinate ( Compound 28)(45 mg, 48% yield), white solid. ¹H NMR (400 MHz, DMSO- d ₆) 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 (calculated), 453.2 (M+H ⁺, actual value). Embodiment 29. ( rac )-3-(2- Methoxyphenyl )-N-(5-((1- Phenoxypropane -2- base ) Oxygen )-1,3,4- Thiadiazole -2- base ) Iononia ( Compound 29) Preparation Steps 1 : 5-((1- Phenoxypropane -2- base ) Oxygen )-1,3,4- Thiadiazole -2- Synthesis of aminesAccording to the general method DThe 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). The product was purified by flash chromatography (0% to 10% MeOH (0.1% NH₄The crude product was purified by elution gradient of 4-(4-(4-(2-phenoxypropane-2-yl)oxy)-1,3,4-thiadiazolyl-2-amine (100 mg, 24%) as a colorless oil. MS (ESI): m/z 251.3 (calculated), 252.2 (M+H ⁺, actual value). Steps 2 : 3-(2- Methoxyphenyl )-N-(5-((1- Phenoxypropane -2- base ) Oxygen )-1,3,4- Thiadiazole -2- base ) Iononia ( Compound 29 ) SynthesisAccording to the general method CThe title compound was obtained from 5-((1-phenoxypropan-2-yl)oxy)-1,3,4-thiadiazolyl-2-amine (50 mg, 0.19 mmol), 3-(2-methoxyphenyl)isosonicotinic acid (46 mg, 0.20 mmol), 1-methylimidazole (58 µL, 0.70 mmol) and TCFH (57 mg, 0.20 mmol) in DMF (1 mL). The crude product was purified by reverse phase C18 column chromatography (eluent gradient from 0% to 100% ACN in water containing 0.1% FA). The isolated product was dissolved in ACN (1 mL), diluted with water (4 mL) and freeze-dried to provide 3-(2-methoxyphenyl)-N-(5-((1-phenoxypropane-2-yl)oxy)-1,3,4-thiadiazol-2-yl)isonicotinamide ( Compound 29)(50 mg, 54% yield), white solid. ¹H NMR (400 MHz, DMSO- d ₆ ) 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 (calculated), 463.4 (M+H ⁺, actual value). Embodiment 30. N-(5-(3- Hydroxyl -3- Methylbutyl -1- Alkyne -1- base )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound 30) Preparation Steps 1 ： Tributyl (5-(3- Hydroxyl -3- Methylbutyl -1- Alkyne -1- base )-1,3,4- Thiadiazole -2- base ) Synthesis of carbamateAdd dry benzene (1 mL) to 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 the addition of Et ₃N (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 heated in anhydrous Na ₂SO ₄Dry on ice, filter, and remove the solvent under reduced pressure. The crude product was purified by flash chromatography (elution gradient from 20% to 90% EA in hexanes) to provide Tertiary 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 (calculated), 284.1 (M+H ⁺, actual value). Steps 2 : 4-(5- Amine -1,3,4- Thiadiazole -2- base )-2- Methylbutyl -3- Alkyne -2- Synthesis of alcoholAccording to the general method Ffrom Tertiary 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) gave the title compound. The reaction mixture was concentrated to dryness to provide 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 ⁺, actual value). Steps 3 : N -(5-(3- Hydroxyl -3- Methylbutyl -1- Alkyne -1- base )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound 30 ) SynthesisAccording to the general method CThe 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). The crude product was purified by reverse phase C18 column chromatography (eluent gradient from 0% to 100% ACN in 0.1% FA). The isolated material was dissolved in ACN (1 mL), diluted with water (4 mL) and freeze-dried to provide N-(5-(3-hydroxy-3-methylbut-1-yn-1-yl)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinate ( Compound 30)(40 mg, 37% yield), white solid. ¹H NMR (400 MHz, DMSO- d ₆ ) 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 (calculated), 395.2 (M+H ⁺, actual value). Embodiment 31. N-(5-((4- Chlorophenyl ) Ethylene )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound 31) Preparation Steps 1 : (5- bromine -1,3,4- Thiadiazole -2- base ) Methanol SynthesisTo a stirred solution of ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate (1 g, 4.01 mmol) in MeOH (16 mL) cooled to 0°C, sodium borohydride was added portionwise. Once the 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 and concentrated in Na ₂SO ₄Dry on ice, filter, and concentrate 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 ⁺, actual value). Steps 2 : (5- bromine -1,3,4- Thiadiazole -2- base ) Synthesis of Methyl MethanesulfonateTo a stirred solution of (5-bromo-1,3,4-thiadiazol-2-yl)methanol (0.30 g, 1.54 mmol) in DCM (8 mL) was added methanesulfonyl chloride (0.16 mL, 2.00 mmol) and Et ₃N (0.32 mL, 2.31 mmol). The reaction mixture was stirred for 1 h and diluted with water. The layers were separated and the organic layer was washed with brine and precipitated in Na ₂SO ₄Dry on ice, filter, and concentrate under reduced pressure. The residue was purified by flash chromatography (elution gradient from 10% to 50% EA in hexanes) to provide methyl (5-bromo-1,3,4-thiadiazol-2-yl)methanesulfonate (400 mg, 95% yield) as a yellow solid. MS (ESI): m/z 271.9 (calcd), 273.1-275-1 (M+H ⁺, actual value). Steps 3 : 2- bromine -5-((4- Chlorophenoxy ) methyl )-1,3,4- Synthesis of ThiadiazoleTo a stirred solution of methyl 5-bromo-1,3,4-thiadiazol-2-yl)methanesulfonate (0.20 g, 0.73 mmol) in DMF (3 mL), 4-chlorophenol (86 mg, 0.67 mmol) and K ₂CO ₃(0.18 g, 1.33 mmol). 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 (x3) and co-evaporated to dryness under reduced pressure with heptanes (x2). The residue was purified by flash chromatography (elution 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 ⁺, actual value). Steps 4 : N-(5-((4- Chlorophenoxy ) methyl )-1,3,4- Thiadiazole -2- base )-3-(2 Methoxyphenyl ) Iononia ( Compound 31 ) SynthesisAccording to the general method GFrom benzyl 2-bromo-5-((4-chlorophenoxy)methyl)-1,3,4-thiadiazole (0.26 g, 0.67 mmol), 3-(2-methoxyphenyl)isonicotinate (56 µL, 0.24 mmol), Cs ₂CO ₃(130 mg, 0.39 mmol), Pd ₂(dba) ₃(19 mg, 0.02 mmol), XantPhos (23 mg, 0.04 mmol), and dioxane (0.98 mL) to obtain the title compound. Purification by Prep-HPLC (column: Gemini® 5 um NX-C18 110 Å, 100×30 mm) (gradient of eluent from 50% to 100% MeOH in ammonium bicarbonate) provided N-(5-((4-chlorophenoxy)methyl)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinate ( Compound 31)(13 mg, 15% yield), white solid. ¹H NMR (400 MHz DMSO- d ₆) 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(calculated), 453.3(M+H ⁺, actual value). Embodiment 32. N-(5-((4- Benzyl chloride ) Amine )-1,3,4- Thiadiazole -2- base )-3-( Naphthyl -1- base ) Iononia ( Compound 32) Preparation Steps 1 : 3-( Naphthyl -1- base ) Synthesis of Ethyl Isonicotinate - General approach HTo a stirred solution of methyl 3-bromoisonicotinate (0.51 mL, 2.31 mmol) in dioxane (12 mL) under hydrogen, naphthalene-1-boric acid (400 mg, 2.31 mmol), Pd(PPh ₃) ₄(140 mg, 0.11 mmol), and K ₂CO ₃(0.80 g, 5.79 mmol). The reaction mixture was degassed three times with argon countercurrent under reduced pressure, heated to 100 °C, 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 and precipitated in Na ₂SO ₄Dry on ice, filter, and concentrate under reduced pressure. The residue was purified by flash chromatography (elution gradient from 0% to 40% EA in hexanes) to provide ethyl 3-(naphthyl-1-yl)isonicotinate (0.55 g, 90% yield) as a yellow oil. MS (ESI): m/z 263.1 (calcd), 264.1 (M+H ⁺, actual value). Steps 2 : 3-( Naphthyl -1- base ) Synthesis of isonicotinic acidTo a solution of ethyl 3-(naphthyl-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 provide 3-(naphthyl-1-yl) isonicotinate as a yellow solid (350 mg, 82% yield). MS (ESI): m/z 249.08 (calculated), 250.2 (M+H ⁺, actual value). Steps 3 : N-(5-((4- Benzyl chloride ) Amine )-1,3,4- Thiadiazole -2- base )-3-( Naphthyl -1- base ) Iononia ( Compound 32 ) SynthesisAccording to the general method CFrom DMF (2 mL) N ²-(4-chlorobenzyl)-1,3,4-thiadiazole-2,5-diamine (48 mg, 0.20 mmol), 3-(naphthyl-1-yl)isonicotinic acid (50 mg, 0.20 mmol), 1-methylimidazole (58 µL, 0.70 mmol), and TCFH (57 mg, 0.20 mmol) to obtain the title compound. The residue was purified by flash chromatography (gradient of eluent from 30% to 100% EA in hexanes) to provide N-(5-((4-chlorobenzyl)amino)-1,3,4-thiadiazole-2-yl)-3-(naphthyl-1-yl)isonicotinamide ( Compound 32)(41 mg, 43% yield), white solid. ¹H NMR (400 MHz DMSO- d ₆) 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(calculated), 472.3(M+H ⁺, actual value). Embodiment 33. N-(5-((4- Benzyl chloride ) Sulfur )-1,3,4- Thiadiazole -2- base )-3-( Naphthyl -1- base ) Iononia ( Compound 33) Preparation According to the general method CThe title compound was obtained from 5-((4-chlorobenzyl)thio)-1,3,4-thiadiazol-2-yl)-3-(naphthyl-1-yl)isonicotinic acid (50 mg, 0.20 mmol), 1-methylimidazole (57 µL, 0.70 mmol), and TCFH (57 mg, 0.20 mmol) in DMF (2 mL). The residue was purified by flash chromatography (gradient of eluent from 30% to 100% EA in hexanes) to provide N-(5-((4-chlorobenzyl)thio)-1,3,4-thiadiazol-2-yl)-3-(naphthyl-1-yl)isonicotinamide ( Compound 33)(60 mg, 61% yield), white solid. ¹H NMR (400 MHz DMSO- d ₆) 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 (calculated), 489.2(M+H ⁺, actual value). Embodiment 34. (E)-N-(5-(4- Chlorothenyl )-1,3,4- Thiadiazole -2- base )-3-( Naphthyl -1- base ) Iononia ( Compound 34) Preparation According to the general method CThe title compound was obtained from (E)-5-(4-chlorostyryl)-1,3,4-thiadiazol-2-amine (48 mg, 0.20 µmol), 3-(naphthyl-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). The residue was purified by flash chromatography (gradient of eluent from 30% to 100% EA in hexanes) to provide (E)-N-(5-(4-chlorostyryl)-1,3,4-thiadiazol-2-yl)-3-(naphthyl-1-yl)isonicotinamide ( Compound 34)(86 mg, 91% yield), white solid. ¹H NMR (400 MHz DMSO- d ₆) 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(calculated), 469.2(M+H ⁺, actual value). Embodiment 35. N-(5-(4- Chlorophenethyl )-1,3,4- Thiadiazole -2- base )-3-( Naphthyl -1- base ) Iononia ( Compound 35) Preparation p-(E)-N-(5-(4-chlorophenylvinyl)-1,3,4-thiadiazole-2-yl)-3-(naphthyl-1-yl)isosonicotinamide ( 34, 86 mg, 0.18 mmol) in DMA (4 mL) was added palladium (10 wt.%) on carbon (20 mg, 18 µmol). The reaction mixture was degassed three times with hydrogen countercurrent under reduced pressure 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 110Å, 100×30 mm) (elution gradient from 50% to 100% ACN in 10 mM ammonium formate) provided N-(5-(4-chlorophenethyl)-1,3,4-thiadiazol-2-yl)-3-(naphthyl-1-yl)isonicotinamide ( Compound 35) (16.5 mg, 19% yield) as a white solid. ¹H NMR (400 MHz DMSO- d ₆) 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(calculated), 471.3(M+H ⁺, actual value). Embodiment 36. N-(5-((4- Chlorophenyl ) Ethylene )-1,3,4- Thiadiazole -2- base )-3-( Naphthyl -1- base ) Iononia ( Compound 36) Preparation According to the general method CThe title compound was obtained from 5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(naphthyl-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). The crude product was purified by flash chromatography (gradient of eluent from 50% to 100% EA in hexanes) to provide N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(naphthyl-1-yl)isonicotinamide ( Compound 36)(12.7 mg, 14% yield), white solid. ¹H NMR (400 MHz DMSO- d ₆) 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 (calculated), 467.2 (M+H ⁺, actual value). Embodiment 37. N-(5-((4- Chlorophenyl ) Ethylene )-1,3,4- Thiadiazole -2- base )-3-( Quinoline -4- base ) Iononia ( Compound 37) Preparation Steps 1 : 3-( Quinoline -4- base ) Synthesis of Ethyl IsonicotinateAccording to the general method HFrom methyl 3-bromoisonicotinate (0.51 mL, 2.31 mmol), quinoline-4-boronic acid (0.4 g, 2.31 mmol), Pd(PPh ₃) ₄(0.14 g, 0.12 mmol), and K ₂CO ₃(0.8 g, 5.79 mmol) was used to prepare the title compound, except that the reaction mixture was stirred at 100 °C for 18 h. The residue was purified by flash chromatography (elution 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 ⁺, actual value). Steps 2 : 3-( Quinoline -4- base ) Synthesis of isonicotinic acidTo a solution of ethyl 3-(quinolin-4-yl)isonicotinate (80 mg, 0.30 mmol) in THF (1.30 mL) was added a solution of lithium hydroxide (37 mg, 1.51 mmol) in water (1.30 mL). The mixture was stirred for 18 h, the solvent was evaporated under reduced pressure and the resulting light yellow solid was used without further purification. MS (ESI): m/z 250.07 (calculated), 251.2 (M+H ⁺, actual value). Steps 3 : N-(5-((4- Chlorophenyl ) Ethylene )-1,3,4- Thiadiazole -2- base )-3-( Quinoline -4- base ) Iononia ( Compound 37 ) SynthesisAccording to the general method CThe title compound was obtained from 5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-amine (47 mg, 0.20 mmol), 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) in DMF (2 mL). The residue was purified by flash chromatography (gradient of eluent 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), yellow solid. ¹H NMR (400 MHz DMSO- d ₆) 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(calculated), 468.2(M+H ⁺, actual value). Embodiment 38.N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(isoquinolin-4-yl)isonicotinamide ( Compound 38) Preparation Steps 1 : (3-( Isoquinoline -4- base ) Synthesis of Ethyl IsonicotinateAccording to the general method HMethyl 3-bromoisonicotinate (62 mg, 0.29 mmol), 4-isoquinolineboronic acid (31 µL, 0.29 mmol), Pd(PPh ₃) ₄(17 mg, 15 µmol), and K ₂CO ₃(0.10 g, 0.72 mmol) in water (0.39 mL) gave the title compound except that the reaction mixture was stirred at 90 °C for 4 h. The crude product was purified by flash 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 ⁺, actual value). Steps 2 : 3-( Isoquinoline -4- base ) Synthesis of isonicotinic acidTo a stirred solution of ethyl 3-(isoquinolin-4-yl)isonicotinate (57 mg, 0.22 mmol) in THF (0.98 mL) was added a solution of LiOH (27 mg, 1.08 mmol) in water (0.98 mL). The reaction mixture was stirred for 18 h before the volatiles were removed under reduced pressure to provide 3-(isoquinolin-4-yl)isonicotinate (53 mg, quantitative 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 ⁺, actual value). Steps 3 : N-(5-((4- Chlorophenyl ) Ethylene )-1,3,4- Thiadiazole -2- base )-3-( Isoquinoline -4- base ) Iononia ( Compound 38 ) SynthesisAccording to the general method CThe title compound was obtained from 5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-amine (48 mg, 0.20 mmol), 3-(isoquinolin-4-yl)isonicotinate (50 mg, 0.20 mmol), 1-methylimidazole (58 µL, 0.70 mmol), and TCFH (57 mg, 0.20 mmol) in DMF (2 mL). The crude product was purified by flash chromatography (elution 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)isonicotinate ( Compound 38)(13 mg, 14% yield), white solid. ¹H NMR (400 MHz DMSO- d ₆) 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(calculated), 468.2(M+H ⁺, actual value). Embodiment 39.N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(isoquinolin-4-yl)isonicotinamide ( Compound 39) Preparation - General approach I 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) was added palladium (10 wt.%) on carbon (1.21 mg, 1.14 µmol). The reaction mixture was degassed three times with hydrogen countercurrent under reduced pressure 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, and precipitated in Na ₂SO ₄The mixture was dried on ice, filtered through a diatomaceous earth pad, and concentrated under reduced pressure to provide N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(isoquinolin-4-yl)isonicotinate ( Compound 39)(5 mg, quantitative yield), white solid. ¹H NMR (400 MHz DMSO- d ₆) 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 (calculated), 445.2(M+H ⁺, actual value). Embodiment 40.N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(isoquinolin-4-yl)isonicotinamide ( Compound 40) Preparation According to the general method IFrom 3-(2-methoxyphenyl)-N-(5-(4-phenylbut-1-yn-1-yl)-1,3,4-thiadiazol-2-yl) isonicotinoylamide ( twenty one, 5 mg, 11 µmol) and palladium on carbon (10 wt.%) (1.21 mg, 1.14 µmol) in DMA (0.11 mL) to give the title compound to provide N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(isoquinolin-4-yl)isonicotinoylamide ( Compound 40)(5 mg, quantitative yield), white solid. ¹H NMR (400 MHz DMSO- d ₆) 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(calculated), 447.3 (M+H ⁺, actual value). Embodiment 41. N-(5-((4- Chlorophenyl ) Ethylene )-1,3,4- Thiadiazole -2- base )-1-(2- Methoxyphenyl )-1 H - Imidazole -5- Carboxamide ( Compound 41) Preparation Steps 1 : (2- Methoxyphenyl ) Synthesis of ethyl glycineTo a stirred solution of ethyl bromoacetate (2 mL, 15.40 mmol) in DMF (46 mL), o-anisidine (2 mL, 16.20 mmol) and K ₂CO ₃(4.48 g, 32.50 mmol). Heat the reaction mixture to 90 °C and stir for 1.5 h. The reaction mixture is then cooled to room temperature, diluted with EA, and water is added. The layers are separated, and the organic layer is collected, washed with brine, and precipitated in Na ₂SO ₄Dry over medium, filter, and concentrate under reduced pressure. The residue was purified by flash chromatography (elution gradient from 0% to 50% EA in hexanes) to provide ethyl (2-methoxyphenyl)glycine (2.42 g, 72% yield) as a colorless oil. MS (ESI): m/z 209.1 (calcd), 210.2 (M+H ⁺, actual value). Steps 2 : N- Acetyl -N-(2- Methoxyphenyl ) Synthesis of ethyl glycineTo a stirred solution of ethyl (2-methoxyphenyl)glycine (2.42 g, 11.60 mmol) in dry THF (29 mL) cooled to 0°C, add acetyl chloride (0.99 mL, 13.9 mmol) dropwise. Then add Et ₃The reaction mixture was stirred for 15 min before adding N (1.62 mL, 11.6 mmol). The reaction mixture was then warmed to room temperature and stirred for 2 h before diluting with EA and water. The layers were separated and the organic layer was collected, washed with brine, and precipitated at 4 °C in Na ₂SO ₄Dry on ice, filter, and concentrate under reduced pressure. The residue was purified by flash chromatography (elution gradient from 5% to 40% EA in hexanes) to provide ethyl N-acetyl-N-(2-methoxyphenyl)glycine (2.57 g, 88% yield) as a yellow oil. MS (ESI): m/z 251.1 (calculated), 252.3 (M+H ⁺, actual value). Steps 3 : 2- XIANGJI -1-(2- Methoxyphenyl )-1 H - Imidazole -5- Synthesis of Ethyl CarboxylateTo a stirred solution of ethyl N-acetyl-N-(2-methoxyphenyl)glycine (0.10 g, 0.40 mmol) in benzene (0.19 mL) cooled to 0 °C, ethyl formate (0.11 mL, 1.33 mmol) and KOtBu (45 mg, 0.40 mmol) were added. The reaction mixture was allowed to stand at 0 °C 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 concentrated. HCl (0.13 mL, 1.59 mmol) was added and stirred for 2 h before heating to 60 °C. The reaction mixture was then cooled to room temperature and extracted with EA. The organic extracts were concentrated under reduced pressure. The residue was purified by flash chromatography (elution gradient from 10% to 100% EA in hexanes) to provide 2-hydroxy-1-(2-methoxyphenyl)-1 H-imidazole-5-carboxylic acid ethyl ester (37 mg, 34% yield) as a yellow solid. MS (ESI): m/z 278.1 (calculated), 279.1 (M+H ⁺, actual value). Steps 4 : 1-(2- Methoxyphenyl )-1 H - Imidazole -5- Synthesis of Ethyl CarboxylateFor H ₂WO ₄(2.54 mg, 10.8 µmol) in a mixture of water (2 mL) and ethanol (2 mL) at 0°C, add hydrogen peroxide (0.19 mL, 1.89 mmol) and ethyl 2-hydroxy-1-(2-methoxyphenyl)-1H-imidazole-5-carboxylate (0.15 g, 0.54 mmol). The reaction mixture was warmed to room temperature and NaHCO was added.₃The solution was stirred for 4.5 h before saturation. 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 1-(2-methoxyphenyl)-1 H-Ethyl 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 ⁺, actual value). Steps 5 : 1-(2- Methoxyphenyl )-1 H - Imidazole -5- Synthesis of Carboxylic Acids1-(2-methoxyphenyl)-1 HTo a stirred solution of ethyl imidazole-5-carboxylate (0.13 g, 0.52 mmol) in THF (1.30 mL) was added a solution of LiOH (37 mg, 1.56 mmol) in water (1.30 mL). The reaction mixture was stirred for 18 h before concentration. HCl was added and the volatiles were removed under reduced pressure to provide 1-(2-methoxyphenyl)-1 H-imidazole-5-carboxylic acid (112 mg, quantitative 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 ⁺, actual value). Steps 6 : N-(5-((4- Chlorophenyl ) Ethylene )-1,3,4- Thiadiazole -2- base )-1-(2- Methoxyphenyl )-1 H - Imidazole -5- Carboxamide ( Compound 41 ) SynthesisAccording to the general method CFrom 5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazolyl-2-amine (14 mg, 64.2 µmol), 1-(2-methoxyphenyl)-1 H-imidazole-5-carboxylic acid (15 mg, 64.20 µmol), 1-methylimidazole (20 µL, 0.23 mmol), and TCFH (18 mg, 64.20 µmol) to obtain the title compound. Purification by Prep-HPLC (column: Gemini® 5 um NX-C18 110 Å, 100×30 mm) (gradient of eluent from 70% to 100% ACN in ammonium bicarbonate) provided N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-1-(2-methoxyphenyl)-1 H-Imidazole-5-carboxylic acid amide ( Compound 41)(13 mg, 14% yield), white solid. ¹H NMR (400 MHz DMSO- d ₆) 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 (calculated), 436.1 (M+H ⁺, actual value). Embodiment 42. 3-(2- Methoxyphenyl )-N-(5- methyl -1,3,4- Thiadiazole -2- base ) Iononia ( Compound 42) Preparation According to the general method CThe title compound was obtained from 2-amino-5-methyl-1,3,4-thiadiazole (50 mg, 0.44 mmol), 3-(2-methoxyphenyl) isonicotinoic acid (0.10 g, 0.44 mmol), 1-methylimidazole (0.13 mL, 1.53 mmol), and TCFH (0.13 g, 0.44 mmol) in DMF (2 mL). The residue was purified by flash chromatography (elution gradient from 1% to 10% MeOH in DCM) to provide 3-(2-methoxyphenyl)-N-(5-methyl-1,3,4-thiadiazole-2-yl) isonicotinoic acid amide ( Compound 42)(99 mg, 70% yield), white solid. ¹H NMR (400 MHz DMSO- d ₆) 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(calculated), 327.1(M+H ⁺, actual value). Embodiment 43. N-(5-((4- Chlorophenyl ) Ethylene )-1,3,4- Thiadiazole -2- base )-3-(2- fluorine -6-(2- Linoethoxy ) Phenyl ) Iononia ( Compound 43) Preparation Steps 1 : 3-(2- fluorine -6- Hydroxyphenyl ) Synthesis of isonicotinic acidTo a stirred solution of methyl 3-bromoisonicotinate (0.25 mL, 1.81 mmol) in dioxane (9.68 mL) with hydrogen gas, (2-fluoro-6-hydroxyphenyl)boronic acid (0.38 g, 2.36 mmol), XPhos Pd G4 (78 mg, 0.09 mmol), and K ₃PO ₄(0.78 g, 3.63 mmol) in water (2.42 mL). The reaction mixture was degassed three times with argon countercurrent under reduced pressure, heated to 80 °C, 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 purified by trituration with DCM to provide 3-(2-fluoro-6-hydroxyphenyl)isonicotinate (308 mg, 73% yield) as a light brown solid. MS (ESI): m/z 233.0 (calculated), 234.1 (M+H ⁺, actual value). Steps 2 : 3-(2- fluorine -6-(2- Phytophenone Ethoxy ) Phenyl ) Synthesis of isonicotinic acidTo a stirred solution of 3-(2-fluoro-6-hydroxyphenyl)isonicotinate (0.18 g, 0.66 mmol) in DMF (2.00 mL), add K ₂CO ₃(0.20 g, 1.46 mmol) and 4-(2-chloroethyl) Phenylpyridinium (0.38 mL, 2.65 mmol). Heat the reaction mixture to 95°C, stir for 3 h, cool to room temperature and dilute with water (10 mL) and EA (10 mL). Separate the layers and extract the aqueous layer with EA (2×10 mL). Wash the combined organic layer with brine (30 mL) and precipitate in MgSO ₄The residue was dried over 400 °C, 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. The residue was purified by reverse phase C18 column chromatography (eluent gradient from 0% to 40% ACN in ammonium bicarbonate 10 mM, pH=10) to provide 3-(2-fluoro-6-(2- (1-(4-( ...⁺, actual value). Steps 3 : N-(5-((4- Chlorophenyl ) Ethylene )-1,3,4- Thiadiazole -2- base )-3-(2- fluorine -6-(2- Linoethoxy ) Phenyl ) Iononia ( Compound 43 ) Synthesis5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazolyl-2-amine ( 48, 26 mg, 0.11 mmol) in DMF (0.55 mL) was stirred and 3-(2-fluoro-6-(2- Phenylethoxy)phenyl)isonicotinic acid (40 mg, 0.11 mmol) and 1-methylimidazole (32 µL, 0.38 mmol). Then, a solution of TCFH (32 mg, 0.11 mmol) in DMF (0.52 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 h, diluted with water (10 mL), and extracted with a mixture of chloroform/isopropanol (3/1) (2×10 mL). The combined organic layer was precipitated on MgSO ₄The residue was purified by Prep-HPLC (column: Gemini® 5 um NX-C18 110 Å, 100×30 mm) (eluent gradient from 50% to 100% MeOH in 10 mM ammonium formate) to provide N-(5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-6-(2- Phenylethoxy)phenyl)isonicotinamide ( Compound 43)(4 mg, 6.4% yield), light yellow solid. ¹H NMR (400 MHz, DMSO- d ₆ ) 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- d ₆ ) δ ppm -115.0 (1F, s). MS (ESI): m/z 563.1(calculated), 564.3(M+H ⁺, actual value). Embodiment 44. N-(5-((4- Chlorophenyl ) Ethylene )-1,3,4- Thiadiazole -2- base )-3-(3-(2- Phytophenone Ethoxy ) Phenyl ) Iononia ( Compound 44) Preparation Steps 1 : 3-(3- Hydroxyphenyl ) Synthesis of Methyl IsonicotinateAccording to the general method HFrom methyl 3-bromoisonicotinate (0.25 mL, 1.81 mmol), 3-hydroxyphenylboronic acid (0.33 g, 2.36 mmol), XPhos Pd G4 (78 mg, 0.09 mmol), and K ₃PO ₄(0.78 g, 3.63 mmol) in water (2 mL) to obtain the title compound to provide methyl 3-(3-hydroxyphenyl)isonicotinate (416 mg, 99% yield) as a clear oil. MS (ESI): m/z 229.1 (calculated), 230.1 (M+H ⁺, actual value). Steps 2 : 3-(3-(2- Linoethoxy ) Phenyl ) Synthesis of Methyl IsonicotinateTo a stirred solution of methyl 3-(3-hydroxyphenyl)isonicotinate (0.20 g, 0.91 mmol) in DMF (5 mL), add K ₂CO ₃(0.15 g, 1.09 mmol) and 4-(2-chloroethyl) Phenyline (0.17 g, 1.09 mmol). The reaction mixture was heated to 95 °C 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) and precipitated in MgSO ₄The residue was purified by flash chromatography (eluent gradient from 0% to 10% MeOH in DCM (0.1% Et3N)) to provide 3-(3-(2- Methyl (1,2-(2-((1-( ...⁺, actual value). Steps 3 : 3-(3-(2- Linoethoxy ) Phenyl ) Synthesis of isonicotinic acid3-(3-(2- To a stirred solution of methyl 1-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2- (Phenylethoxy)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 ⁺, actual value). Steps 4 : N-(5-((4- Benzyl chloride ) Oxygen )-1,3,4- Thiadiazole -2- base )-3-(3-(2- Linoethoxy ) Phenyl ) Iononia ( Compound 44 ) SynthesisAccording to the general method CFrom 5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazolyl-2-amine (30 mg, 0.13 mmol), 3-(3-(2- The title compound was obtained by mixing 1-(4-( ... Phenylethoxy)phenyl)isonicotinamide ( Compound 44) (11.6 mg, 17% yield), off-white solid. ¹H NMR (400 MHz, DMSO- d ₆ ) 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(calculated), 546.3(M+H ⁺, actual value). Embodiment 45. N-(5-((4- Chlorophenyl ) Ethylene )-1,3,4- Thiadiazole -2- base )-3-(3-(2-( Dimethylamino ) Ethoxy ) Phenyl ) Iononia ( Compound 45 ) Preparation Steps 1 : 3-(3-(2-( Dimethylamino ) Ethoxy ) Phenyl ) Synthesis of isonicotinic acidTo a stirred solution of methyl 3-(3-hydroxyphenyl)isonicotinate (0.21 g, 0.91 mmol) in DMF (4.54 mL), add 2-chloro- N, N-Dimethylethylamine hydrochloride (0.16 g, 1.09 mmol) and K ₂CO ₃(0.28 g, 2.00 mmol). The reaction mixture was heated to 95 °C 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) and precipitated in MgSO₄The mixture was dried over 400 °C, 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)isonicotinate (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 ⁺, actual value). Steps 2 : N-(5-((4- Benzyl chloride ) Oxygen )-1,3,4- Thiadiazole -2- base )-3-(3-(2-( Dimethylamino ) Ethoxy ) Phenyl ) Iononia ( Compound 45 ) SynthesisAccording to the general method CThe title compound was obtained from 5-((4-chlorophenyl)ethynyl)-1,3,4-thiadiazolyl-2-amine (40 mg, 0.17 mmol), 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). The crude product was purified by reverse phase C18 column chromatography (eluent gradient from 5% to 40% ACN in 10 mM ammonium bicarbonate) to provide N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-3-(3-(2-(dimethylamino)ethoxy)phenyl)isonicotinate ( Compound 45)(11 mg, 13% yield), light yellow solid. ¹H NMR (400 MHz, DMSO- d ₆ ) 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(calculated), 504.2(M+H ⁺, actual value). Embodiment 46. Benzyl 3-((5-(3-(2- Methoxyphenyl ) Isonicotinamide )-1,3,4- Thiadiazole -2- base ) Oxygen ) Pyrrolidine -1- Formate ( Compound 46) Preparation Steps 1 : Benzyl 3-((5- bromine -1,3,4- Thiadiazole -2- base ) Oxygen ) Pyrrolidine -1- Synthesis of formate estersTo a stirred 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°C, add NaH (0.10 g, 2.46 mmol). Warm the reaction mixture to room temperature and stir for 10 min. Add water (10 mL) and extract the aqueous layer with EA (2×10 mL). Wash the combined organic layers with brine (2×20 mL) and precipitate over MgSO ₄Dry on ice, filter, and concentrate to dryness. The residue was purified by flash chromatography (elution 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 ⁺, actual value). Steps 2 : Benzyl 3-((5-(3-(2- Methoxyphenyl ) Isonicotinamide )-1,3,4- Thiadiazole -2- base ) Oxygen ) Pyrrolidine -1- Formate ( Compound 46 ) SynthesisAccording to the general method GFrom benzyl 3-((5-bromo-1,3,4-thiadiazol-2-yl)oxy)pyrrolidine-1-carboxylate (0.26 g, 0.67 mmol), 3-(2-methoxyphenyl)isonicotinate (0.18 g, 0.80 mmol), Cs ₂CO ₃(0.44 g, 1.33 mmol), Pd ₂(dba) ₃(63 mg, 0.07 mmol), and XantPhos (79 mg, 0.13 mmol) to obtain the title compound. Purification by reverse phase C18 column chromatography (gradient of eluent from 5% to 40% ACN in 10 mM ammonium bicarbonate, pH=10) provided benzyl 3-((5-(3-(2-methoxyphenyl)isonicotinoylamino)-1,3,4-thiadiazol-2-yl)oxy)pyrrolidine-1-carboxylate ( Compound 46)(55 mg, 16% yield), off-white solid. ¹H NMR (400 MHz, DMSO- d ₆ ) 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 (calculated), 532.2 (M+H ⁺, actual value). Embodiment 47. 3-(2- Methoxyphenyl )-N-(5-( Pyrrolidine -3- Oxy )-1,3,4- Thiadiazole -2- base ) Iononia ( Compound 47) Preparation Pd(OAc) was added to a stirred solution of benzyl 3-((5-(3-(2-methoxyphenyl)isonicotinoylamino)-1,3,4-thiadiazol-2-yl)oxy)pyrrolidine-1-carboxylate (22 mg, 0.04 mmol) in DCM (0.83 mL) under hydrogen.₂(11 mg, 0.05 mmol), Et ₃N (14 µL, 0.10 mmol), and triethylsilane (67 µL, 0.41 mmol). The reaction mixture was heated to 45 °C, stirred for 2 h, cooled to room temperature, filtered on a celite pad, and concentrated under reduced pressure. The crude product was purified by Prep-HPLC (column: Gemini® 5 um NX-C18 110 Å, 100 × 30 mm) (elution gradient from 5% to 100% ACN in 10 mM ammonium formate) to provide 3-(2-methoxyphenyl)-N-(5-(pyrrolidin-3-yloxy)-1,3,4-thiadiazol-2-yl)isonicotinate ( Compound 47)(3 mg, 18% yield), white solid. ¹H NMR (400 MHz, DMSO- d ₆ ) 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 (calculated), 398.2 (M+H ⁺, actual value). Embodiment 48. 3-(2- Methoxyphenyl )- N -(5-( Piperidine -3- Oxy )-1,3,4- Thiadiazole -2- base ) Iononia ( Compound 48) Preparation Steps 1 ： Tributyl 3-((5- Amine -1,3,4- Thiadiazole -2- base ) Oxygen ) Piperidine -1- Synthesis of formate estersAccording to the general method Dfrom Tertiary Butyl3-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-thiadiazolyl-2-amine (0.40 g, 2.16 mmol) gave the title compound. The crude product was purified by flash chromatography (gradient of eluent from 0% to 100% EA in hexanes) to provide Tertiary Butyl3-((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 (calculated), 301.2 (M+H ⁺, actual value). Steps 2 ： Tributyl 3-((5-(3-(2- Methoxyphenyl ) Isonicotinamide )-1,3,4- Thiadiazole -2- base ) Oxygen ) Piperidine -1- Synthesis of formate estersAccording to the general method CFrom DMF (1.00 mL) Tertiary Butyl3-((5-amino-1,3,4-thiadiazol-2-yl)oxy)piperidine-1-carboxylate (35 mg, 0.11 mmol), 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) gave the title compound. The resulting precipitate was collected by vacuum filtration to provide Tertiary Butyl3-((5-(3-(2-methoxyphenyl)isonicotinoylamino)-1,3,4-thiadiazol-2-yl)oxy)piperidine-1-carboxylate (36 mg, 53% yield) as a light brown solid. MS (ESI): m/z 511.2 (calculated), 512.3 (M+H ⁺, actual value). Steps 3 : 3-(2- Methoxyphenyl )-N-(5-( Piperidine -3- Oxy )-1,3,4- Thiadiazole -2- base ) Iononia ( Compound 48 ) Synthesisright Tertiary ButylTo a stirred solution of 3-((5-(3-(2-methoxyphenyl)isonicotinoylamino)-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. Et ₃The reaction mixture was stirred for 30 min before addition of N (0.10 mL) and the volatiles were removed under reduced pressure. The residue was purified by reverse phase C18 column chromatography (eluent gradient from 5% to 55% MeOH in 10 mM ammonium bicarbonate) to provide 3-(2-methoxyphenyl)-N-(5-(piperidin-3-yloxy)-1,3,4-thiadiazol-2-yl)isonicotinate ( Compound 48)(16 mg, 62% yield), white solid. ¹H NMR (400 MHz, DMSO- d ₆ ) 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(calculated), 412.3(M+H ⁺, actual value). Embodiment 49. 3-(2- Methoxyphenyl )-N-(5-(3-( Trifluoromethyl ) Double ring [1.1.1] Pentane -1- base )-1,3,4- Thiadiazole -2- base ) Iononia ( Compound 49) Preparation Steps 1 : 5-(3-( Trifluoromethyl ) Double ring [1.1.1] Pentane -1- base )-1,3,4- Thiadiazole -2- Synthesis of amines - General approach JTo a flask containing 3-(trifluoromethyl)-bicyclo[1.1.1]pentane-1-carboxylic acid (0.10 g, 0.56 mmol) and hydrazinecarbosulfamide (54 mg, 0.58 mmol), add POCl ₃(0.55 mL, 5.83 mmol). The reaction mixture was heated to 75 °C, stirred for 3 h, cooled to 0 °C and quenched with water (10 mL). The solution was made alkaline with NaOH (2M) solution, 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-thiadiazolyl-2-amine (116 mg, 89% yield) as a white solid. ¹H NMR (400 MHz, DMSO- d ₆) δ ppm 2.34 (6H, s), 7.24 (2H, s). ¹⁹F NMR (376 MHz, DMSO- d ₆) δ ppm -71.3 (3F, S). MS (ESI): m/z 235.0(calculated), 236.1(M+H ⁺, actual value). Steps 2 : 3-(2- Methoxyphenyl )-N-(5-(3-( Trifluoromethyl ) Double ring [1.1.1] Pentane -1- base )-1,3,4- Thiadiazole -2- base ) Iononia ( Compound 49 ) SynthesisAccording to the general method CThe title compound was obtained from 5-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1,3,4-thiadiazolyl-2-amine (60 mg, 0.26 mmol), 3-(2-methoxyphenyl)isosonicotinic 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). The product was purified by reverse phase C18 column chromatography (in H ₂Purification of the crude product by elution with 5% to 80% ACN in 0.1% FA) provided 3-(2-methoxyphenyl)-N-(5-(3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-yl)-1,3,4-thiadiazol-2-yl)isonicotinate ( Compound 49)(15.8 mg, 62% yield), white solid. ¹H NMR (400 MHz, DMSO- d ₆ ) 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- d ₆) δ ppm -71.3 (3F, S). MS (ESI): m/z 446.1(calculated), 447.2 (M+H ⁺, actual value). Embodiment 50. 3-(2- Methoxyphenyl )-N-(5-(3- Phenyl bicyclic [1.1.1] Pentane -1- base )-1,3,4- Thiadiazole -2- base ) Iononia ( Compound 50) Preparation Steps 1 : 3- Phenyl bicyclic [1.1.1] Pentane -1- Synthesis of methyl carboxylateFor f[1.1.1]spiropropane (3.00 mL, 1.47 mmol, Angew. Chem., Int. Ed. 2017, 56, 12774-12777) in diethyl ether (0.49 M) was added to an Ace pressure vessel with a solution of phenylmagnesium bromide (0.98 mL, 2.94 mmol) in diethyl ether (3 M). The vessel was sealed and the reaction mixture was heated to 100 °C and stirred for 18 h. The reaction mixture was then slowly cooled to -78 °C and a portion of methyl chloroformate (0.45 mL, 5.88 mmol) was added. The reaction mixture was heated to room temperature for more than 30 min, stirred for 1 h, and treated with diethyl ether (20 mL) and NH ₄Dilute with a saturated solution of Cl (30 mL). Separate the layers and extract the aqueous layer with diethyl ether (2×30 mL). The combined organic layers are in MgSO₄Dry over medium, filter, and concentrate under reduced pressure. The residue was purified by flash chromatography (elution 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 light yellow oil. ¹H NMR (400 MHz, CHCl ₃- d) δ ppm 2.20 (6H, s), 3.58 (3H, s), 7.06-7.12 (3H, m), 7.18 (2H, m). Steps 2 : 3- Phenyl bicyclic [1.1.1] Pentane -1- Synthesis of Carboxylic AcidsTo a stirred 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) was added lithium hydroxide (23 mg, 0.94 mmol). 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, CHCl ₃- d) δ ppm 2.37 (6H, s), 7.22-7.26 (3H, m), 7.31-7.35 (2H, m). Steps 3 : 5-(3- Phenyl bicyclic [1.1.1] Pentane -1- base )-1,3,4- Thiadiazole -2- Synthesis of aminesAccording to the general method JFrom 3-phenylbicyclo[1.1.1]pentane-1-carboxylic acid (55 mg, 0.29 mmol), hydrazinecarbosulfamide (28 mg, 0.31 mmol), and POCl ₃(0.50 mL, 5.32 mmol) to obtain the title compound. The resulting precipitate was collected by vacuum filtration to provide 5-(3-phenylbicyclo[1.1.1]pentan-1-yl)-1,3,4-thiadiazolyl-2-amine (63 mg, 89% yield) as a white solid. MS (ESI): m/z 243.1 (calculated), 244.2 (M+H ⁺, actual value). Steps 4 : 3-(2- Methoxyphenyl )-N-(5-(3- Phenyl bicyclic [1.1.1] Pentane -1- base )-1,3,4- Thiadiazole -2- base ) Iononia ( Compound 50 ) SynthesisAccording to the general method CThe title compound was obtained from 5-(3-phenylbicyclo[1.1.1]pentan-1-yl)-1,3,4-thiadiazolyl-2-amine (63 mg, 0.26 mmol), 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). The crude product was purified by flash chromatography (eluent gradient from 0% to 3% MeOH in DCM) to provide 3-(2-methoxyphenyl)- N-(5-(3-phenylbicyclo[1.1.1]pentane-1-yl)-1,3,4-thiadiazole-2-yl)isonicotinamide ( Compound 50)(74 mg, 63% yield), white solid. ¹H NMR (400 MHz, DMSO- d ₆ ) 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 (calculated), 455.3 (M+H ⁺, actual value). Embodiment 51. N-(5-(3-(4- Chlorophenyl ) Double ring [1.1.1] Pentane -1- base )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound 51) Preparation Steps 1 : 3-(4- Chlorophenyl ) Double ring [1.1.1] Pentane -1- Synthesis of Carboxylic AcidsFor [1.1.1]spiropropane (3.00 mL, 1.47 mmol, Angew. Chem., Int. Ed. 2017, 56, 12774-12777) in diethyl ether (0.49 M) was added to an Ace pressure vessel. A solution of 4-chlorophenylmagnesium bromide (2.94 mL, 2.94 mmol) in MeTHF (1.0 M) was added. The vessel was sealed and the reaction mixture was heated to 100 °C and stirred for 18 h. The reaction mixture was then slowly cooled to 0 °C and CO ₂(in anhydrous CaSO ₄Dry on ice) 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 concentrated under reduced pressure in MgSO₄Dry on ice, filter, and concentrate under reduced pressure. The residue was purified by flash chromatography (elution 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, CHCl ₃- d) δ ppm 2.35 (6H, s), 7.14 (2H, d, J= 8.3 Hz), 7.28 (1H, d, J = 8.2 Hz). Steps 2 : 5-(3-(4- Chlorophenyl ) Double ring [1.1.1] Pentane -1- base )-1,3,4- Thiadiazole -2- Synthesis of aminesAccording to the general method JFrom 3-(4-chlorophenyl)bicyclo[1.1.1]pentane-1-carboxylic acid (0.10 g, 449 µmol), hydrazinecarbosulfamide (43 mg, 0.47 mmol), and POCl ₃(1.10 mL, 11.7 mmol) to obtain the title compound. The resulting precipitate was collected by vacuum filtration to provide 5-(3-(4-chlorophenyl)bicyclo[1.1.1]pentan-1-yl)-1,3,4-thiadiazolyl-2-amine (114 mg, 92% yield) as a light yellow solid. MS (ESI): m/z 277.0 (calculated), 278.1 (M+H ⁺, actual value). Steps 3 : N-(5-(3-(4- Chlorophenyl ) Double ring [1.1.1] Pentane -1- base )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound 51) SynthesisAccording to the general method CThe title compound was obtained from 5-(3-(4-chlorophenyl)bicyclo[1.1.1]pentan-1-yl)-1,3,4-thiadiazolyl-2-amine (75 mg, 0.27 mmol), 3-(2-methoxyphenyl)isosonicotinic acid (68 mg, 0.30 mmol), 1-methylimidazole (79 µL, 0.95 mmol) in DMF (2 mL) and TCFH (85 mg, 0.30 mmol) in DMF (0.50 mL). The crude product was purified by flash 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)isonicotinate ( Compound 51)(68 mg, 52% yield), white solid. ¹H NMR (400 MHz, DMSO- d ₆ ) 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(calculated), 489.3(M+H ⁺, actual value). Embodiment 52. N-(5-(3-(4- Chlorophenyl ) Double ring [1.1.1] Pentane -1- base )-1,3,4- Thiadiazole -2- base )-3-(2- fluorine -5-(2- Phytophenone Ethoxy ) Phenyl ) Iononia ( Compound 52) Preparation Steps 1 : 3-(2- fluorine -5- Hydroxyphenyl ) Isonicotinic acid First Synthesis of estersAccording to the general method HFrom methyl 3-bromoisonicotinate (0.25 mL, 1.81 mmol), (2-fluoro-5-hydroxyphenyl)boronic acid (0.38 g, 2.36 mmol), XPhos Pd G4 (0.12 g, 0.14 mmol), and K ₃PO ₄(0.78 g, 3.63 mmol) in water (2.42 mL) to obtain the title compound to provide methyl 3-(2-fluoro-5-hydroxyphenyl) isonicotinate (361 mg, 80% yield) as a light brown solid. MS (ESI): m/z 247.1 (calculated), 248.1 (M+H ⁺, actual value). Steps 2 : 3-(2- fluorine -5-(2- Phytophenone Ethoxy ) Phenyl ) Isonicotinic acid First Synthesis of estersTo a stirred solution of methyl 3-(2-fluoro-5-hydroxyphenyl) isonicotinate (0.25 g, 1.01 mmol) in DMF (3.37 mL), add K ₂CO ₃(0.17 g, 1.21 mmol) and 4-(2-chloroethyl) Phenylpyridinium (0.19 g, 1.21 mmol). The reaction mixture was heated to 95 °C 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) and precipitated in MgSO ₄dried, filtered, and concentrated under reduced pressure to provide 3-(2-fluoro-5-(2- Methyl (1,2-dimethoxy)phenyl)isonicotinate (364 mg, 99% yield) as a light 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 ⁺, actual value). Steps 3 : 3-(2- fluorine -5-(2- Linoethoxy ) Phenyl ) Synthesis of isonicotinic acid3-(2-fluoro-5-(2- To a stirred solution of methyl 1-(2-(2-(2-fluoro-5-(2-nitro-1-yl)ethoxy)phenyl)isonicotinate (0.36 g, 1.00 mmol) in a mixture of water (1 mL) and THF (4 mL) was added LiOH (48 mg, 2.00 mmol). 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-nitro-1-yl)ethoxy)phenyl)isonicotinate. (Phenylethoxy)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 ⁺, actual value). Steps 4 : N-(5-(3-(4- Chlorophenyl ) Double ring [1.1.1] Pentane -1- base )-1,3,4- Thiadiazole -2- base )-3-(2- fluorine -5-(2- Linoethoxy ) Phenyl ) Iononia ( Compound 52) SynthesisAccording to the general method CFrom 5-(3-(4-chlorophenyl)bicyclo[1.1.1]pentan-1-yl)-1,3,4-thiadiazolyl-2-amine (34 mg, 0.12 mmol), 3-(2-fluoro-5-(2- (1-(4-(5-((4-chlorophenyl)bicyclo[1.1.1]pentan-1-yl)-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-5-(2- Phenylethoxy)phenyl)isonicotinamide ( Compound 52)(17 mg, 23% yield), white solid. ¹H NMR (400 MHz, DMSO- d ₆ ) 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- d ₆) δ ppm -127.5 (1F, S). MS (ESI): m/z 605.2(calculated), 606.3(M+H ⁺, actual value). Embodiment 53. 3-(2- Methoxyphenyl )-N-(5-(( Tetrahydrogen -2H- Pyran -4- base ) Oxygen )-1,3,4- Thiadiazole -2- base ) Iononia ( Compound 53) Preparation Steps 1 : 5-(( Tetrahydrogen -2H- Pyran -4- base ) Oxygen )-1,3,4- Thiadiazole -2- Synthesis of aminesTo a stirred solution of 2-amino-5-bromo-1,3,4-thiadiazole (1 g, 5.55 mmol) in DMF (20 mL) cooled to 0°C, add tetrahydro-4 H-pyran-4-yl (1 g, 11.1 mmol) and Et ₃N (2 mL, 13.9 mmol). The reaction mixture was heated to room temperature, stirred for 6 h, diluted with water (20 mL) and extracted with EA (50 mL×3). The combined organic layer was washed with brine (30 mL) and precipitated with MgSO ₄Dry on ice, filter, and concentrate under reduced pressure. Purify by flash chromatography (0% to 20% MeOH (0.1% NH ₄The crude product was purified by elution gradient of 4-(4-(4-(4-pyran-4-yl)oxy)-1,3,4-thiadiazolyl-2-amine (157 mg, 14% yield) as a pink solid. MS (ESI): m/z 201.1 (calculated), 202.2 (M+H ⁺, actual value). Steps 2 : 3-(2- Methoxyphenyl )-N-(5-(( Tetrahydrogen -2H- Pyran -4- base ) Oxygen )-1,3,4- Thiadiazole -2- base ) Iononia ( Compound 53 ) SynthesisAccording to the general method AThe title compound was obtained from 5-((tetrahydro-2H-pyran-4-yl)oxy)-1,3,4-thiadiazolyl-2-amine (105 mg, 0.52 mmol), 3-(2-methoxyphenyl)isonicotinate (60 mg, 0.26 mmol), HATU (142 mg, 0.37 mmol) and DIPEA (136 mL, 0.78 mmol) in DMF (5 mL). The crude product was purified by flash chromatography (eluent gradient from 0% to 100% EA in hexanes). The isolated material was dissolved in ACN (1 mL), diluted with water (4 mL), and freeze-dried to provide 3-(2-methoxyphenyl)-N-(5-((tetrahydro-2H-pyran-4-yl)oxy)-1,3,4-thiadiazol-2-yl)isonicotinate ( Compound 53)(35 mg, 16% yield), white solid. ¹H NMR (400 MHz, DMSO- d ₆) 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(calculated value), 413.2(M+H ⁺, actual value). Embodiment 54. N-(5-(4- Chlorophenoxy )-1,3,4- Thiadiazole -2- base )-3-(2- Methoxyphenyl ) Iononia ( Compound 54) Preparation To a stirred 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)isonicotinate (123 mg, 0.54 mmol), HATU (251 mg, 0.65 mmol) and DIPEA (188 mL, 1.08 mmol) were added at room temperature under an argon atmosphere. The reaction mixture was stirred for 1 h, diluted with water and extracted with EA (3×10 mL). The combined extracts were heated in anhydrous Na ₂SO ₄Dry on ice, filter, and concentrate to dryness. The crude product was purified by Prep-HPLC (column: Gemini® 5 um NX-C18 110 Å, 100×30 mm) (elution gradient from 40% to 100% ACN in 10 mM ammonium formate). The isolated material was dissolved in ACN (1 mL), diluted with water (4 mL), and freeze-dried to provide N-(5-(4-chlorophenoxy)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinate ( Compound 54)(6 mg, 2.5% yield), white solid. ¹H NMR (400 MHz, DMSO- d ₆) 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(calculated), 439.2(M+H ⁺, actual value). Embodiment 55. 3-( Naphthyl -1- base )-N-(5-(( Tetrahydrogen -2H- Pyran -4- base ) Oxygen )-1,3,4- Thiadiazole -2- base ) Iononia ( Compound 55) Preparation According to the general method CThe title compound was obtained from 5-((tetrahydro-2H-pyran-4-yl)oxy)-1,3,4-thiadiazolyl-2-amine (154, 40 mg, 0.20 mmol), 3-(naphthyl-1-yl)isosonicotinic acid (50 mg, 0.20 mmol), 1-methylimidazole (58 µL, 0.70 mmol) and TCFH (57 mg, 0.20 mmol) in DMF (2 mL). The crude product was purified by flash chromatography (eluent gradient from 50% to 100% EA in hexanes) to provide 3-(naphthyl-1-yl)-N-(5-((tetrahydro-2H-pyran-4-yl)oxy)-1,3,4-thiadiazol-2-yl)isonicotinate ( Compound 55) (64 mg, 55% yield) as a white solid. ¹H NMR (400 MHz DMSO- d ₆ ) 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(calculated), 433.2(M+H ⁺, actual value). Embodiment 56. Test type (I) Compound inhibition Polθ (1-894) Of ATP Biochemical analysis of enzyme activityThe polymerase θ helicase domain (amino acid residues 1 to 894) was expressed as a hexahistidine fusion protein in insect cells and purified by metal affinity chromatography. In a medium containing 40 mM Tris•HCL 7.5, 20 mM MgCl ₂Helicase catalytic ATPase activity was measured in assay buffer containing 10 mM test compound dissolved in DMSO and 1 mM dithiothreitol. A combination of 10 mM test compound dissolved in DMSO and DMSO was added to the assay wells to generate a 9-point dilution series of test compound, inactive control wells, fully active control wells, and a final DMSO volume of 50 nl. A substrate solution containing 2.5 µl of 300 nM single-stranded DNA (5’- CCAGTGAATTGTTGCTCGGTACCTGCTAAC-3’) and 62.5 µM ATP in assay buffer was added to all assay wells. 2.5 µl of assay buffer containing 40 nM polymerase domain was added to all wells except the inactive 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 of ADP-glo reagent was added to all wells, which were then covered and incubated at ambient temperature for 40 minutes. Prior to measuring chemiluminescence, 10 µl of kinase assay solution was added to all wells, which were then covered and incubated for 30 minutes. Inhibition of polymerase activity in the assay wells was calculated using the chemiluminescence of the inactive control wells as 100% inhibition and the fully active 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, IC ₅₀and Hill slope. The biological activities of the compounds in this application are listed in Table 3 below. EquivalentThe details of one or more embodiments of the present disclosure are described in the description attached above. Although any methods and materials similar to 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, purposes, and advantages of the present disclosure will be apparent from the specification and the patent application. In the specification and the attached patent application, the singular form includes plural references unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those with ordinary knowledge in the field to which the present disclosure belongs. All patents and publications mentioned in this specification are incorporated by reference. The foregoing description has been presented for exemplary purposes only and is not intended to limit the present disclosure to the precise form disclosed, except as defined by the appended claims.

Claims (58)

A compound of formula I: or a pharmaceutically acceptable salt or solvent thereof, wherein: Ring A is a C ₆ -C ₁₀ aryl or heteroaryl group comprising one or two 5-membered or 6-membered rings and 1 to 4 heteroatoms selected from N, O, and S; each _RA is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl, C 1 -C _{6 hydroxyalkyl, C 1 -C 6 alkoxy ,} C _{1 -C 6} halogenalkoxy, -OH, -NR _a3 R _a4 , -CN, halogen, oxo, -C(X)R _a1 , -C(X)OR _a1 , -C(X)NR _a3 R _a4 , -NR _a2 C(X)R _a1 , -NR _a2 C(X)OR _a1 , or -NR _a2 C(X)NR _a3 R _a4 ; X is NR _N , O, or S; m is 0, 1, 2, 3, 4, 5, or 6; Ar is a C ₆ -C ₁₀ aryl or heteroaryl group comprising one or two 5-membered or 6-membered rings and 1 to 4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl group is optionally substituted by 1 to 4 R _Ar ; each R _Ar is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ halogenalkoxy, -OH, -O(CR _C1 R _C2 ) _1-3 R _O , -NR _a3 R _a4 , -CN, halogen, oxo, -C(X)R _a1 , -C(X)OR _a1 , -C(X)NR _a3 R _a4 , -NR _a2 C(X)R _a1 , -NR _a2 C(X)OR _a1 , or -NR _a2 C(X)NR _a3 R _a4 ; _RC1 and _RC2 are each independently H or -CH ₃ ; _RO is -OH, -NH ₂ , -NR _a2 (C ₁ -C ₆ alkyl), C ₃ -C ₈ cycloalkyl, a heterocyclic group containing a 3- to 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, a C ₆ aryl, or a heteroaryl group containing a 5- or 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocyclic group, aryl, or heteroaryl group is optionally independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl, C ₁ -C ₆ hydroxyalkyl, C 3 -C 8 The group is substituted by one or more of: _-1 -C ₆ alkoxy, -1 _- C ₆ halogen alkoxy, -OH, -NH ₂ , -NR _a2 (C ₁ -C ₆ alkyl), -CN, halogen, and pendoxy; _RN is H or C ₁ -C ₆ alkyl; L ₁ is absent, -O-, -N( _RN )-, -S-, -S(=O) ₂ -, or -N(S(=O) _2RN )-; L ₂ is absent, C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene, or C ₂ -C _{6 alkynylene} ; T is C ₁ -C ₆ alkyl, C ₁ -C ₆ halogen alkyl, C ₁ -C ₆ hydroxyalkyl, -C(X)R _a1 , -C(X)OR _a1 , -C(X)NR _a3 R _a4 , _RT , or -XR _T ; provided that when L ₁ is -O- and L ₂ is C ₁ -C ₆ alkylene, then T is not _RT ; when L ₁ is -O- and L ₂ is absent or C ₁ -C ₆ alkylene, then T is not C ₁ -C ₆ alkyl, C ₁ -C 6 halogenalkyl, C ₁ -C ₆ hydroxyalkyl, C ₃ -C ₈ cycloalkyl, or a heterocyclic group containing _{a 3- to 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S; RT is C 3 -C 8 cycloalkyl , a} heterocyclic group containing a 3- to 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, C ₆ aryl, or a heteroaryl comprising a 5-membered or 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted by one or more R _t ; each R _t is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ halogenalkoxy, -OH, -NR _a3 R _a4 , -CN, halogen, oxo, -C(X)R _a1 , -C(X)OR _a1 , -C(X)NR _a3 R _a4 , -NR _a2 C(X)R _a1 , -NR _a2 C(X)OR _a1 , -NR _a2 C(X)NR _a3 R _a4 , C ₃ -C ₈ cycloalkyl, a heterocyclic group containing a 3- to 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, a C ₆ aryl group, or a heteroaryl group containing a 5- or 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocyclic group, aryl group, or heteroaryl group is optionally substituted with one or more groups independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ halogenalkoxy, -OH, -NH ₂ , -NR _a2 (C ₁ -C ₆ alkyl), -CN, halogen, and pendoxy; each R _a1 is independently H, C ₁ -C 6 C ₁ -C ₆ alkyl, C 1 -C ₆ halogenalkyl, C ₁ -C ₆ alkyl- _{C 6} -C ₁₀ aryl, or C ₁ -C ₆ alkyl-heteroaryl, wherein the heteroaryl comprises a 5-membered or 6-membered ring and 1 to 4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ halogenalkoxy, -OH, -NH ₂ , -NR _a2 (C ₁ -C ₆ alkyl), -CN, halogen, oxo, -C(X)R _a1 , -C(X)OR _a1 , -C(X)NR _a1 R _a2 , -NR _a2 C(X)R _a1 , -NR _a2 C(X)OR _a1 , and one or more of -NR _a2 C(X)NR _a1 R _a2 ; each R _a2 is independently H or C ₁ -C ₆ alkyl; and R _a3 and R _a4 are each independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl, C ₁ -C ₆ hydroxyalkyl, C ₃ -C ₈ cycloalkyl, a heterocyclic group containing a 3- to 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, a C ₆ aryl, or a heteroaryl group containing a 5- or 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocyclic group, aryl, or heteroaryl group is optionally independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ halogenalkyl, -OH, -NH ₂ , -NR _a2 (C ₁ -C ₆ alkyl), -CN, halogen, and pendoxy group; or R _a3 and R _a4 together with the nitrogen atom to which they are bound form a group which optionally comprises 1 to 2 additional heteroatoms selected from N, O, and S and is optionally independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl, C 1 -C 6 hydroxyalkyl, C ₁ -C ₆ alkoxy, C _{1 -C 6} halogenalkyl, -OH, -NH ₂ , -NR _a2 (C ₁ -C ₆ alkyl), -CN, halogen, and _pendoxy group. -CN, and a 5- or 6-membered heterocyclic ring substituted with one or more halogen groups, wherein the cycloalkyl or heterocyclic ring can be a non-bridged and non-spiro, spirocyclic, or bridged ring system. The compound of claim 1, wherein ring A is a C ₆ -C ₁₀ aryl group. The compound of claim 1 or 2, wherein ring A is phenyl. The compound of claim 1, wherein ring A is a heteroaryl group comprising one or two 5-membered or 6-membered rings and 1 to 4 heteroatoms selected from N, O, and S. The compound of claim 1 or 4, wherein ring A is a heteroaryl group comprising a 5-membered or 6-membered ring and 1 to 4 heteroatoms selected from N, O, and S. The compound of claim 1, 4, or 5, wherein ring A is a heteroaryl group comprising a 5-membered or 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S. The compound of any one of claims 1 and 4 to 6, wherein Ring A is a heteroaryl group comprising a 5- or 6-membered ring and 1 to 2 nitrogen atoms. The compound of any one of claims 1 and 4 to 7, wherein Ring A is a heteroaryl group comprising a 6-membered ring and 1 to 2 nitrogen atoms. The compound of claim 1 is of formula II: or a pharmaceutically acceptable salt or solvent thereof, wherein _A1 , _A2 , _A3 , _A4 , and _A5 are each independently N, CH, or CR _A , or are C when _A1 , _A2 , _A3 , _A4 , or _A5 is bonded to Ar. The compound of claim 9, wherein _A1 is bonded to Ar. The compound of claim 9, wherein _A2 is bonded to Ar. The compound of claim 9, wherein _A3 is bonded to Ar. The compound of claim 9, wherein _A4 is bonded to Ar. The compound of claim 9, wherein _A5 is bonded to Ar. The compound of claim 1 or 9, which is of formula IIa: or a pharmaceutically acceptable salt or solvent thereof, wherein A ₂ , A ₃ , A ₄ , and A ₅ are each independently N, CH, or CR _A . The compound of any one of claims 1 to 15, wherein Ar is C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R _Ar . The compound of any one of claims 1 to 16, wherein Ar is phenyl optionally substituted with 1 to 4 R _Ar . The compound of any one of claims 1 to 15, wherein Ar is a heteroaryl group comprising one or two 5- or 6-membered rings and 1 to 4 heteroatoms selected from N, O, and S, which is optionally substituted with 1 to 4 R _Ar . The compound of any one of claims 1 to 15 and 18, wherein Ar is a heteroaryl group comprising a 5- or 6-membered ring and 1 to 4 heteroatoms selected from N, O, and S, which is optionally substituted with 1 to 4 R _Ar . The compound of any one of claims 1 to 15, 18, and 19, wherein Ar is a heteroaryl group comprising a 5-membered or 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, which is optionally substituted with 1 to 4 R _Ar . The compound of any one of claims 1 to 15 and 18 to 20, wherein Ar is a heteroaryl group comprising a 5- or 6-membered ring and 1 to 2 nitrogen atoms, which is optionally substituted with 1 to 4 R _Ar . The compound of claim 1, 9, or 15, which is of formula III: or a pharmaceutically acceptable salt or solvent thereof, wherein: A ₂ , A ₃ , A ₄ , and A ₅ are each independently N, CH, or CR _A ; and A ₆ , A ₇ , A ₈ , A ₉ , and A ₁₀ are each independently N, CH, or CR _Ar . The compound of claim 1, 9, 15, or 22, which is of formula IIIa or IIIb: or a pharmaceutically acceptable salt or solvent thereof, wherein A ₂ , A ₃ , A ₄ , and A ₅ are each independently N, CH, or CR _A . The compound of claim 1, 9, or 15, which is of formula IV: or a pharmaceutically acceptable salt or solvent 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 . The compound of claim 1, 9, 15, or 24, which is of formula IVa, IVb, or IVc: or a pharmaceutically acceptable salt or solvent thereof, wherein: A ₂ , A ₃ , A ₄ , and A ₅ are each independently N, CH, or CR _A ; and A ₈ , A ₉ , and A ₁₀ are each independently N, CH, or CR _Ar . The compound of any one of claims 9, 15, and 22 to 25, wherein one of A ₁ , A ₂ , A ₃ , A ₄ , and A ₅ is N. The compound of any one of claims 9, 15, and 22 to 25, wherein two of A ₁ , A ₂ , A ₃ , A ₄ , and A ₅ are N. The compound of any one of claims 9, 15, and 22-25, wherein three of A ₁ , A ₂ , A ₃ , A ₄ , and A ₅ are N. The compound of any one of claims 9, 15, and 22 to 25, wherein four of A ₁ , A ₂ , A ₃ , A ₄ , and A ₅ are N. The compound of claim 22, 24, or 25, wherein one of A ₆ , A ₇ , A ₈ , A ₉ , A ₁₀ , A ₁₁ , A ₁₂ , A ₁₃ , and A ₁₄ is N. The compound of claim 22, 24, or 25, wherein two of A ₆ , A ₇ , A ₈ , A ₉ , A ₁₀ , A ₁₁ , A ₁₂ , A ₁₃ , and A ₁₄ are N. The compound of claim 22, 24, or 25, wherein three of A ₆ , A ₇ , A ₈ , A ₉ , A ₁₀ , A ₁₁ , A ₁₂ , A ₁₃ , and A ₁₄ are N. The compound of any one of claims 1 to 32, wherein _L1 is absent, and _L2 is absent. The compound of any one of claims 1 to 32, wherein L ₁ is absent, and L ₂ is C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene, or C ₂ -C ₆ alkynylene. The compound of any one of claims 1 to 32, wherein L ₁ is -O-, and L ₂ is absent. The compound of any one of claims 1 to 32, wherein L ₁ is -O-, and L ₂ is C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene, or C ₂ -C ₆ alkynylene. The compound of any one of claims 1 to 32, wherein L ₁ is -N( _RN )-, and L ₂ is absent. The compound of any one of claims 1 to 32, wherein L ₁ is -N( _RN )-, and L ₂ is C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene, or C ₂ -C ₆ alkynylene. The compound of any one of claims 1 to 32, wherein L ₁ is -S-, and L ₂ is absent. The compound of any one of claims 1 to 32, wherein L ₁ is -S-, and L ₂ is C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene, or C ₂ -C ₆ alkynylene. The compound of any one of claims 1 to 32, wherein L ₁ is -S(=O) ₂ -, and L ₂ is absent. The compound of any one of claims 1 to 32, wherein L ₁ is -S(=O) ₂ -, and L ₂ is C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene, or C ₂ -C ₆ alkynylene. The compound of any one of claims 1 to 32, wherein L ₁ is -N(S(=O) _{2 RN} )-, and L ₂ is absent. The compound of any one of claims 1 to 32, wherein L ₁ is -N(S(=O) ₂ R _N )-, and L ₂ is C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene, or C ₂ -C ₆ alkynylene. The compound of claim 34, 36, 38, 40, 42, or 44, wherein L ₂ is C ₁ -C ₆ alkylene. A compound as claimed in any one of claims 1 to 45, wherein _RN is H. The compound of any one of claims 1 to 45, wherein _RN is C ₁ -C ₆ alkyl. The compound of any one of claims 1 to 47, wherein T is C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl, or C ₁ -C ₆ hydroxyalkyl. The compound of any one of claims 1 to 47, wherein T is -C(X)R _a1 , -C(X)OR _a1 , or -C(X)NR _a3 R _a4 . The compound of any one of claims 1 to 47, wherein T is _RT , or _-XRT . The compound of any one of claims 1 to 50, wherein _RT is _C3 - _C8 cycloalkyl, which is optionally substituted with one or more _Rt . The compound of any one of claims 1 to 50, wherein _RT is a heterocyclic group comprising a 3- to 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, which is optionally substituted with one or more _Rt . A compound as claimed in any one of claims 1 to 50, wherein _RT is _C6 aryl, which is optionally substituted with one or more _Rt . The compound of any one of claims 1 to 50, wherein _RT is a heteroaryl group comprising a 5-membered or 6-membered ring and 1 to 2 heteroatoms selected from N, O, and S, which is optionally substituted by one or more _Rt . A pharmaceutical composition comprising a compound according to any one of claims 1 to 54 or a pharmaceutically acceptable salt or solvent thereof, and a pharmaceutically acceptable carrier or excipient. A method for treating or preventing a disease in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 54 or a pharmaceutically acceptable salt or solvent thereof to the subject. Use of a compound according to any one of claims 1 to 54 or a pharmaceutically acceptable salt or solvent thereof in the manufacture of a medicament for treating or preventing a disease. A compound according to any one of claims 1 to 54 or a pharmaceutically acceptable salt or solvent thereof for use in treating or preventing a disease.