PROTEIN SECRETION INHIBITORS

Abstract

The present invention features compounds useful in the inhibition of the secretion of proteins. The compounds of the invention can be used in methods for treating diseases associated with protein secretion, and in methods for inhibiting protein secretion.

Claims

1. A compound, or pharmaceutically acceptable salt thereof, having the structure of Formula 1: ##STR00384## wherein R.sub.1 is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.7 cycloalkyl, optionally substituted C.sub.2-C.sub.9 heterocycle, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.2-C.sub.9 heteroaryl, C.sub.2-C.sub.9 heteroaryl C.sub.1-C.sub.6 alkyl, or R.sub.a-R.sub.b-R.sub.c, wherein R.sub.a is optionally substituted C.sub.6-C.sub.10 arylene or optionally substituted C.sub.2-C.sub.9 heteroarylene; R.sub.b is O or optionally substituted C.sub.1-C.sub.6 alkylene, and R.sub.c is optionally substituted C.sub.6-C.sub.10 aryl; Z is absent, optionally substituted C.sub.3-C.sub.10 cycloalkylene, optionally substituted C.sub.2-C.sub.9 heterocyclylene, C.sub.6-C.sub.10 arylene, or optionally substituted C.sub.2-C.sub.9 heteroarylene; Y is absent, O, or NR.sub.3; X is absent or optionally substituted C.sub.1-C.sub.6 alkylene; W is absent, S, O or NR.sub.3; n is 0 or 1; A is S, O, NH, or CH.sub.2; B is CH or N; R.sub.2 is optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.3-7 cycloalkyl, optionally substituted C.sub.2-9 heterocycle, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.2-9 heteroaryl; optionally substituted C.sub.2-C.sub.9 heteroaryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.7 cycloalkyl C.sub.1-C.sub.6 aryl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, cyano, or has the structure X.sub.1OY.sub.1; wherein X.sub.1 is optionally substituted C.sub.1-C.sub.6 alkylene, and Y.sub.1 is optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.8 cycloalkyl, or optionally substituted C.sub.6-C.sub.10 aryl; and each R.sub.3 is, independently, H or C.sub.1-C.sub.6 alkyl.

2. The compound, or pharmaceutically acceptable salt thereof, of claim 1, wherein n is 1.

3. The compound, or pharmaceutically acceptable salt thereof, of claim 1, wherein the compound has the structure of Formula II: ##STR00385##

4. The compound, or pharmaceutically acceptable salt thereof, of claim 1, wherein the compound has the structure of Formula III: ##STR00386##

5. The compound, or pharmaceutically acceptable salt thereof, of claim 1, wherein the compound has the structure of Formula IV: ##STR00387##

6. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 3 to 5, wherein Z is optionally substituted C.sub.6-C.sub.10 aryl, or optionally substituted C.sub.2-C.sub.9 heteroaryl.

7. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 to 6, wherein Y is O or NR.sub.3.

8. The compound, or pharmaceutically acceptable salt thereof, of claim 7, wherein Y is O.

9. The compound, or pharmaceutically acceptable salt thereof, of claim 7, wherein Y is NR.sub.3.

10. The compound, or pharmaceutically acceptable salt thereof, of claim 7, wherein Y is NH.

11. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 3 to 10 wherein X is optionally substituted C.sub.1-C.sub.6 alkylene.

12. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 to 11, wherein W is S, O or NR.sub.3.

13. The compound, or pharmaceutically acceptable salt thereof, of claim 12, wherein W is S.

14. The compound, or pharmaceutically acceptable salt thereof, of claim 12, wherein W is O.

15. The compound, or pharmaceutically acceptable salt thereof, of claim 12, wherein W is NR.sub.3.

16. The compound, or pharmaceutically acceptable salt thereof, of claim 15, wherein W is NH.

17. The compound, or pharmaceutically acceptable salt thereof, of claim 1 or 2 wherein A is S and B is C.

18. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1, 2, or 17, wherein the compound has the structure of Formula IV: ##STR00388## wherein Y is O or NR.sub.3.

19. The compound, or pharmaceutically acceptable salt thereof, of claim 18, wherein X is optionally substituted C.sub.1-C.sub.6 alkylene.

20. The compound, or pharmaceutically acceptable salt thereof, of claim 19, wherein Y is O.

21. The compound, or pharmaceutically acceptable salt thereof, of claim 19, wherein Y is NR.sub.3

22. The compound, or pharmaceutically acceptable salt thereof, of claim 22, wherein Y is NH.

23. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1, 2, or 17, wherein the compound has the structure of Formula V: ##STR00389## wherein W is NR.sub.3.

24. The compound, or pharmaceutically acceptable salt thereof, of claim 22, wherein X is optionally substituted C.sub.1-C.sub.6 alkylene.

25. The compound, or pharmaceutically acceptable salt thereof, of claim 23 or 24, wherein W is NH.

26. The compound, or pharmaceutically acceptable salt thereof, of claim 1, wherein n is 0.

27. The compound, or pharmaceutically acceptable salt thereof, of claims 1 to 5, 7 to 17, or 26, wherein Z is optionally substituted phenylene, optionally substituted pyridinylene, optionally substituted pyrimidinylene, optionally substituted pyridazinylene, optionally substituted pyrazinylene, optionally substituted triazinylene, optionally substituted tetrazinylene, optionally substituted thiophenylene, optionally substituted pyrrolylene, optionally substituted furanylene, optionally substituted pyrazolylene, optionally substituted thiazolylene, optionally substituted oxadiazolylene, optionally substituted thiadiazolylene, optionally substituted isoxazolylene, optionally substituted isothiazolylene, optionally substituted thiazolylene, optionally substituted oxazolylene, optionally substituted imidazolylene, optionally substituted cyclohexylene, optionally substituted cyclopentylene, optionally substituted cyclobutylene, optionally substituted cyclopropylene, optionally substituted cycloheptylene, optionally substituted cyclooctylene, optionally substituted indolylene, or optionally substituted azaindolylene.

28. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 to 17, 26, or 27, wherein Z has the structure of Formula VIi: ##STR00390## wherein A, B, C and D are, each, independently, N, CH, or CR.sub.4; and each R.sub.4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol.

29. The compound, or pharmaceutically acceptable salt thereof, of claim 28, wherein Z has the structure of Formula VIIi: ##STR00391## wherein B, C, and D are each, independently, CH or CR.sub.4.

30. The compound, or pharmaceutically acceptable salt thereof, of claim 28, wherein Z has the structure of formula VIIIi: ##STR00392## wherein A, C, and D are each, independently, CH or CR.sub.4.

31. The compound, or pharmaceutically acceptable salt thereof, of claim 28, wherein Z has the structure of formula IXi: ##STR00393## wherein A, B, and D are each, independently, CH or CR.sub.4.

32. The compound, or pharmaceutically acceptable salt thereof, of claim 28, wherein Z has the structure of Formula Xi: ##STR00394## wherein A, B, and C are each, independently, CH or CR.sub.4.

33. The compound, or pharmaceutically acceptable salt thereof, of claim 28, wherein Z has the structure of Formula Xli: ##STR00395## wherein A and B are each, independently, CH or CR.sub.4.

34. The compound, or pharmaceutically acceptable salt thereof, of claim 28, wherein Z has the structure of Formula XIIi: ##STR00396## wherein A and D are each, independently, CH or CR.sub.4.

35. The compound, or pharmaceutically acceptable salt thereof, of claim 28, wherein Z has the structure of Formula XIIIi: ##STR00397## wherein C and D are each, independently, CH or CR.sub.4.

36. The compound, or pharmaceutically acceptable salt thereof, of claim 28, wherein Z has the structure of Formula XIVi: ##STR00398## wherein B and D are each, independently, CH or CR.sub.4.

37. The compound, or pharmaceutically acceptable salt thereof, of claim 28, wherein Z has the structure of Formula XVi: ##STR00399## wherein B and C are each, independently, CH or CR.sub.4.

38. The compound, or pharmaceutically acceptable salt thereof, of claim 28, wherein Z has the structure of Formula XVIi: ##STR00400## wherein A and C are each, independently, CH or CR.sub.4.

39. The compound, or pharmaceutically acceptable salt thereof, of claim 28, wherein Z has the structure of Formula XVIIi: ##STR00401## wherein A is CH or CR.sub.4.

40. The compound, or pharmaceutically acceptable salt thereof, of claim 28, wherein Z has the structure of Formula XVIIIi: ##STR00402## wherein D Is CH or CR.sub.4.

41. The compound, or pharmaceutically acceptable salt thereof, of claim 28, wherein Z has the structure of Formula XIXi: ##STR00403## wherein B is CH or CR.sub.4.

42. The compound, or pharmaceutically acceptable salt thereof, of claim 28, wherein Z has the structure of Formula XXi: ##STR00404## wherein C is CH or CR.sub.4.

43. The compound, or pharmaceutically acceptable salt thereof, of claim 28, wherein Z has the structure of Formula XXIi: ##STR00405## wherein A, B, C, and D are each, independently, CH or CR.sub.4

44. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 to 5, 7 to 17, 26, or 27, wherein Z has the structure of Formula XXIIi: ##STR00406## wherein o is 0, 1, 2, 3, or 4; and each R.sub.4 is, independently, optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol.

45. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 to 5, 7 to 17, 26, or 27, wherein Z has the structure of Formula XXIIIi: ##STR00407## wherein o is 0, 1, 2, or 3; and each R.sub.4 is, independently, optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol.

46. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 to 17, 26, or 27, wherein Z has the structure of Formula XXIVi: ##STR00408## wherein E is NH, O, or S; F and G are each, independently, N, CH, or CR.sub.4; and each R.sub.4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol.

47. The compound, or pharmaceutically acceptable salt thereof, of claim 46, wherein Z has the structure of Formula XXVi: ##STR00409## wherein F and G are each, independently, CH or CR.sub.4.

48. The compound, or pharmaceutically acceptable salt thereof, of claim 46, wherein Z has the structure of Formula XXVIi: ##STR00410## wherein F and G are each, independently, CH or CR.sub.4

49. The compound, or pharmaceutically acceptable salt thereof, of claim 46, wherein Z has the structure of Formula XXVIIi: ##STR00411## wherein F and G are each, independently, CH or CR.sub.4.

50. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 to 17, 26, or 27, wherein Z has the structure of Formula XXVIIIi: ##STR00412## wherein E is NH, O, or S; F and G are each, independently, N, CH, or CR.sub.4; and each R.sub.4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol.

51. The compound, or pharmaceutically acceptable salt thereof, of claim 50, wherein Z has the structure of Formula XXIXi: ##STR00413## wherein F and G are each, independently, CH or CR.sub.4.

52. The compound, or pharmaceutically acceptable salt thereof, of claim 50, wherein Z has the structure of Formula XXXi: ##STR00414## wherein F and G are each, independently, CH or CR.sub.4.

53. The compound, or pharmaceutically acceptable salt thereof, of claim 50, wherein Z has the structure of Formula XXXIi: ##STR00415## wherein F and G are each, independently, CH or CR.sub.4.

54. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 to 17, 26, or 27, wherein Z has the structure of Formula XXXIIi: ##STR00416## wherein E is NH, O, or S; F and G are each, independently, N, CH, or CR.sub.4; and each R.sub.4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol.

55. The compound, or pharmaceutically acceptable salt thereof, of claim 54, wherein Z has the structure of Formula XXXIIIi: ##STR00417## wherein F and G are each, independently, CH or CR.sub.4.

56. The compound, or pharmaceutically acceptable salt thereof, of claim 54, wherein Z has the structure of Formula XXXIVi: ##STR00418## wherein F and G are each, independently, CH or CR.sub.4.

57. The compound, or pharmaceutically acceptable salt thereof, of claim 54, wherein Z has the structure of Formula XXXVi: ##STR00419## wherein F and G are each, independently, CH or CR.sub.4.

58. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 to 17, 26, or 27, wherein Z has the structure of Formula XXXVIi: ##STR00420## wherein E is N or CH; F, G, and H are each, independently, N, CH, or CR.sub.4; and each R.sub.4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol.

59. The compound, or pharmaceutically acceptable salt thereof, of claim 58, wherein Z has the structure of Formula XXXVIIi: ##STR00421##

60. The compound, or pharmaceutically acceptable salt thereof, of claim 58, wherein Z has the structure of Formula XXXVIIii: ##STR00422##

60. The compound, or pharmaceutically acceptable salt thereof, of claim 58, wherein Z has the structure of Formula XXXVIIIi: ##STR00423##

61. The compound, or pharmaceutically acceptable salt thereof, of claim 58, wherein Z has the structure of Formula XXXIXi: ##STR00424##

62. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 to 17, 26, or 27, wherein Z has the structure of Formula XXXXIIi: ##STR00425## wherein A, B, C, and D are each, independently, CH, CR.sub.4, or N; and each R.sub.4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol.

63. The compound, or pharmaceutically acceptable salt thereof, of claim 62, wherein Z has the structure of Formula XXXX: ##STR00426##

64. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 17 or 26 to 63 wherein X is C.sub.1-C.sub.6 alkylene.

65. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 17 or 26 to 64, wherein Y is O or NR.sub.3.

66. The compound, or pharmaceutically acceptable salt thereof, of claim 64, wherein Y is O.

67. The compound, or pharmaceutically acceptable salt thereof, of claim 64, wherein Y is NR.sub.3.

68. The compound, or pharmaceutically acceptable salt thereof, of claim 66, wherein Y is NH.

69. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 17 or 26 to 68, wherein W is S, O, or NR.sub.3.

70. The compound, or pharmaceutically acceptable salt thereof, of claim 69, wherein W is S.

71. The compound, or pharmaceutically acceptable salt thereof, of claim 69, wherein W is O.

72. The compound, or pharmaceutically acceptable salt thereof, of claim 69, wherein W is NR.sub.3.

73. The compound, or pharmaceutically acceptable salt thereof, of claim 69, wherein W is NH.

74. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 to 73, wherein R.sub.2 is optionally substituted C.sub.1-C.sub.6 alkyl.

75. The compound, or pharmaceutically acceptable salt thereof, of claim 74, wherein R.sub.2 is ##STR00427##

76. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 to 73, wherein R.sub.2 is optionally substituted C.sub.2-C.sub.9 heterocyclyl.

77. The compound, or pharmaceutically acceptable salt thereof, of claim 73, wherein R.sub.2 ##STR00428##

78. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 to 73, wherein R.sub.2 is optionally substituted C.sub.2-C.sub.9 heteroaryl.

79. The compound, or pharmaceutically acceptable salt thereof, of claim 78, wherein R.sub.2 is ##STR00429##

80. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 to 73, wherein R.sub.2 has the structure X.sub.1OY.sub.1.

81. The compound, or pharmaceutically acceptable salt thereof, of claim 80, wherein X.sub.1 is optionally substituted with one or two methyl groups.

82. The compound, or pharmaceutically acceptable salt thereof, of claim 80 or 81, wherein Y.sub.1 is optionally substituted phenyl or optionally substituted cyclopropyl.

83. The compound, or pharmaceutically acceptable salt thereof, of claim any one of claims 80 to 82, wherein R.sub.2 is ##STR00430##

84. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 to 73, wherein R.sub.2 is optionally substituted C.sub.6-C.sub.10 aryl.

85. The compound, or pharmaceutically acceptable salt thereof, of claim 84, wherein R.sub.2 is phenyl.

86. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 to 85, wherein R.sub.1 is optionally substituted C.sub.2-C.sub.9 heteroaryl.

87. The compound, or pharmaceutically acceptable salt thereof, of claim 86, wherein R.sub.1 is ##STR00431##

88. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 to 85, wherein R.sub.1 is R.sub.a-R.sub.b-R.sub.c.

89. The compound, or pharmaceutically acceptable salt thereof, of claim 88, wherein R.sub.b is O.

90. The compound, or pharmaceutically acceptable salt thereof, of claim 88 or 89, wherein R.sub.1 is ##STR00432##

91. The compound, or pharmaceutically acceptable salt thereof, of claim 88, wherein R.sub.b is optionally substituted C.sub.1-C.sub.6 alkylene.

92. The compound, or pharmaceutically acceptable salt thereof, of claim 88 or 91, wherein R.sub.1 is ##STR00433##

93. The compound, or pharmaceutically salt thereof, of any one of claims 1 to 85, wherein R.sub.1 is an optionally substituted C.sub.2-C.sub.9 heteroaryl C.sub.1-C.sub.6 alkyl.

94. The compound, or pharmaceutically acceptable salt thereof, of claim 93, wherein R.sub.1 is or ##STR00434##

95. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 to 85, wherein R.sub.1 is an optionally substituted C.sub.6-C.sub.10 aryl. ##STR00435##

96. The compound, or pharmaceutically acceptable salt thereof, of claim 95, wherein R.sub.1 is.

97. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 to 96, wherein X is ##STR00436##

98. A compound having the structure of any one of compounds 1 to 50 in Table 1, or a pharmaceutically acceptable salt thereof.

99. A pharmaceutical composition comprising a compound of any one of claims 1 to 98, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

100. A method of treating a Sec61-associated disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 to 98 or a pharmaceutical composition of claim 99.

101. The method of claim 100, wherein the disease or disorder is selected from amyloidosis, light chain amyloidosis, autoantibody diseases, chronic kidney disease, fibrosis, neurodegeneration, autoimmune disease, genetically-defined kidney disease, viral disease, influenza, dengue virus, zika virus, hepatitis B virus, hepatitis C virus, SARS-CoV-2, human immunodeficiency virus, malaria, cancer, glioma, myeloma, multiple types of cancer with solid tumors, autoimmune diseases, rheumatoid arthritis, ankylosing spondylitis, celiac disease, multiple sclerosis, atopic dermatitis, Crohn's disease, psoriasis, allergic asthma, autoimmune antibody diseases, myasthenia gravis, neuromyelitis optica, warm antibody hemolytic anemia, prion disease, immune thrombocytopenic purpura, chronic inflammatory demyelinating polyradiculoneuropathy, fibrotic diseases, idiopathic pulmonary fibrosis, endometriosis, nonalcoholic steatohepatitis, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, hypercholesterolemia, Creutzfeldt-Jakob disease, Gerstmann-Strsussler-Scheinker syndrome, high cholesterol, metabolic syndrome, and fatal familial insomnia.

102. The method of claim 101, wherein the disease is viral diseases.

103. The method of claim 101, wherein the disease is cancer.

104. The method of claim 101, wherein the disease is prion disease.

105. The method of claim 101, wherein the disorder is light chain amyloidosis.

106. The method of claim 101, wherein the disease is autoimmune antibody disease.

107. The method of claim 101, wherein the disease is genetically-defined kidney disease.

108. The method of claim 101, wherein the disease is malaria.

109. A method of inhibiting the translocation of a target protein through Sec61, the method comprising contacting a cell with an effective amount of a compound of any one of claims 1 to 98, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 99.

110. The method of claim 109, wherein inhibition of translocation is selective for a target protein over a non-target protein.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0276] The invention features compounds useful for the selective inhibition of protein secretion, e.g., by selectively inhibiting the Sec61 protein secretion complex. Exemplary compounds described herein include compounds having a structure according to formula I:

##STR00097##

[0277] Or pharmaceutically acceptable salts thereof.

[0278] Other embodiments, as well as exemplary compounds, methods for the synthesis or production of these compounds, the use of these compounds in the treatment of a disease and/or disorder associated with Sec61, and the use of these compounds in the selective inhibition of Sec61 are described herein.

Sec61 Inhibitors

[0279] Exemplary Sec61 inhibitors disclosed herein include a compound of Formula 1:

##STR00098## [0280] wherein [0281] R.sub.1 is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.7 cycloalkyl, optionally substituted C.sub.2-C.sub.9 heterocycle, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.2-C.sub.9 heteroaryl, C.sub.2-C.sub.9 heteroaryl C.sub.1-C.sub.6 alkyl, or R.sub.a-R.sub.b-R.sub.c, [0282] wherein R.sub.a is C.sub.6-C.sub.10 arylene [0283] R.sub.b is O or optionally substituted C.sub.1-C.sub.6 alkylene, and [0284] R.sub.c is C.sub.6-C.sub.10 aryl; [0285] Z is absent, optionally substituted C.sub.3-C.sub.10 cycloalkylene, optionally substituted C.sub.2-C.sub.9 heterocyclylene, C.sub.6-C.sub.10 arylene, or optionally substituted C.sub.2-C.sub.9 heteroarylene; [0286] Y is absent, O, or NR.sub.3; [0287] X is absent or optionally substituted C.sub.1-C.sub.6 alkylene; [0288] W is absent, S, O or NR.sub.3; [0289] n is 0 or 1; [0290] A is S, O, or CH; [0291] B is C or N; [0292] R.sub.2 is optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.3-7 cycloalkyl, optionally substituted C.sub.2-9 heterocycle, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.2-9 heteroaryl; optionally substituted C.sub.2-C.sub.9 heteroaryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.7 cycloalkyl C.sub.1-C.sub.6 aryl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, or cyano; and [0293] each R.sub.3 is, independently, H or C.sub.1-C.sub.6 alkyl.

[0294] Exemplary Sec61 inhibitors described herein include a compound of Formula II:

##STR00099##

[0295] Exemplary Sec61 inhibitors described herein include a compound of Formula III:

##STR00100##

[0296] Exemplary Sec61 inhibitors described herein include a compound of Formula IV:

##STR00101##

[0297] Exemplary Sec61 inhibitors described herein include a compound of Formula V:

##STR00102## [0298] wherein Y is O or NR.sub.3.

[0299] Exemplary Sec61 inhibitors described herein include a compound of Formula VI:

##STR00103## [0300] wherein W is NR.sub.3.

[0301] Exemplary Sec61 inhibitors described herein include a compound of Formula VII:

##STR00104## [0302] wherein A, B, C and D are, each, independently, N, CH, or CR.sub.4; and [0303] each R.sub.4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol.

[0304] Exemplary Sec61 inhibitors described herein include a compound of Formula VIII:

##STR00105## [0305] wherein B, C, and D are each, independently, CH or CR.sub.4

[0306] Exemplary Sec61 inhibitors described herein include a compound of Formula IX:

##STR00106## [0307] wherein A, C, and D are each, independently, CH or CR.sub.4.

[0308] Exemplary Sec61 inhibitors described herein include a compound of Formula X:

##STR00107## [0309] wherein A, B, and D are each, independently, CH or CR.sub.4

[0310] Exemplary Sec61 inhibitors described herein include a compound of Formula XI:

##STR00108## [0311] wherein A, B, and C are each, independently, CH or CR.sub.4.

[0312] Exemplary Sec61 inhibitors described herein include a compound of Formula XII:

##STR00109## [0313] wherein A and B are each, independently, CH or CR.sub.4.

[0314] Exemplary Sec61 inhibitors described herein include a compound of Formula XIII:

##STR00110## [0315] wherein A and D are each, independently, CH or CR.sub.4.

[0316] Exemplary Sec61 inhibitors described herein include a compound of Formula XIV:

##STR00111## [0317] wherein C and D are each, independently, CH or CR.sub.4.

[0318] Exemplary Sec61 inhibitors described herein include a compound of Formula XV:

##STR00112## [0319] wherein B and D are each, independently, CH or CR.sub.4.

[0320] Exemplary Sec61 inhibitors described herein include a compound of Formula XVI:

##STR00113## [0321] wherein B and C are each, independently, CH or CR.sub.4.

[0322] Exemplary Sec61 inhibitors described herein include a compound of Formula XVII:

##STR00114## [0323] wherein A and C are each, independently, CH or CR.sub.4.

[0324] Exemplary Sec61 inhibitors described herein include a compound of Formula XVIII:

##STR00115## [0325] wherein A is CH or CR.sub.4.

[0326] Exemplary Sec61 inhibitors described herein include a compound of Formula XIX:

##STR00116## [0327] wherein D Is CH or CR.sub.4.

[0328] Exemplary Sec61 inhibitors described herein include a compound of Formula XX:

##STR00117## [0329] wherein B is CH or CR.sub.4.

[0330] Exemplary Sec61 inhibitors described herein include a compound of Formula XXI:

##STR00118## [0331] wherein C is CH or CR.sub.4.

[0332] Exemplary Sec61 inhibitors described herein include a compound of Formula XXII:

##STR00119## [0333] wherein A, B, C, and D are each, independently, CH or CR.sub.4

[0334] Exemplary Sec61 inhibitors described herein include a compound of Formula XXIII:

##STR00120## [0335] wherein o is 0, 1, 2, 3, or 4; and [0336] each R.sub.4 is, independently, optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol.

[0337] Exemplary Sec61 inhibitors described herein include a compound of Formula XXIV:

##STR00121## [0338] wherein o is 0, 1, 2, or 3; and [0339] each R.sub.4 is, independently, optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol.

[0340] Exemplary Sec61 inhibitors described herein include a compound of Formula XXV:

##STR00122## [0341] wherein E is NH, O, or S; [0342] F and G are each, independently, N, CH, or CR.sub.4; and [0343] each R.sub.4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol.

[0344] Exemplary Sec61 inhibitors described herein include a compound of Formula XXVI:

##STR00123## [0345] wherein F and G are each, independently, CH or CR.sub.4.

[0346] Exemplary Sec61 inhibitors described herein include a compound of Formula XXVII:

##STR00124## [0347] wherein F and G are each, independently, CH or CR.sub.4

[0348] Exemplary Sec61 inhibitors described herein include a compound of Formula XXVIII:

##STR00125## [0349] wherein F and G are each, independently, CH or CR.sub.4.

[0350] Exemplary Sec61 inhibitors described herein include a compound of Formula XXIX:

##STR00126## [0351] wherein E is NH, O, or S; [0352] F and G are each, independently, N, CH, or CR.sub.4; and [0353] each R.sub.4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol.

[0354] Exemplary Sec61 inhibitors described herein include a compound of Formula XXX:

##STR00127## [0355] wherein F and G are each, independently, CH or CR.sub.4.

[0356] Exemplary Sec61 inhibitors described herein include a compound of Formula XXXI:

##STR00128## [0357] wherein F and G are each, independently, CH or CR.sub.4.

[0358] Exemplary Sec61 inhibitors described herein include compounds of Formula XXXII:

##STR00129## [0359] wherein F and G are each, independently, CH or CR.sub.4.

[0360] Exemplary Sec61 inhibitors described herein include compounds of Formula XXXIII:

##STR00130## [0361] wherein [0362] E is NH, O, or S; [0363] F and G are each, independently, N, CH, or CR.sub.4; and [0364] each R.sub.4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol.

[0365] Exemplary Sec61 inhibitors described herein include compounds of Formula XXXIV:

##STR00131## [0366] wherein F and G are each, independently, CH or CR.sub.4.

[0367] Exemplary Sec61 inhibitors described herein include compounds of Formula XXXV:

##STR00132## [0368] wherein F and G are each, independently, CH or CR.sub.4.

[0369] Exemplary Sec61 inhibitors described herein include compounds of Formula XXXVI:

##STR00133## [0370] wherein F and G are each, independently, CH or CR.sub.4.

[0371] Exemplary Sec61 inhibitors described herein include compounds of Formula XXXVII:

##STR00134## [0372] wherein E is N or CH; [0373] F, G, and H are each, independently, N, CH, or CR.sub.4; and [0374] each R.sub.4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol.

[0375] Exemplary Sec61 inhibitors described herein include compounds of Formula XXXVIII:

##STR00135##

[0376] Exemplary Sec61 inhibitors described herein include compounds of Formula XXXIX:

##STR00136##

[0377] Exemplary Sec61 inhibitors described herein include compounds of Formula XXXX:

##STR00137##

[0378] Exemplary Sec61 inhibitors described herein include compounds of Formula XXXXI:

##STR00138##

[0379] Exemplary Sec61 inhibitors described herein include compounds of Formula XXXXII:

##STR00139## [0380] wherein A, B, C, and D are each, independently, CH, CR.sub.4, or N; and [0381] each R.sub.4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol.

[0382] Exemplary Sec61 inhibitors described herein include compounds of Formula XXXXIII:

##STR00140##

[0383] Sec61 inhibitors described here in include any one of the compounds in Table 1.

TABLE-US-00001 TABLE 1 Compounds of the Invention # Structure 1 [00141] 2 [00142] 3 [00143] 4 [00144] 5 [00145] 6 [00146] 7 [00147] 8 [00148] 9 [00149] 10 [00150] 11 [00151] 12 [00152] 13 [00153] 14 [00154] 15 [00155] 16 [00156] 17 [00157] 18 [00158] 19 [00159] 20 [00160] 21 [00161] 22 [00162] 23 [00163] 24 [00164] 25 [00165] 26 [00166] 27 [00167] 28 [00168] 29 [00169] 30 [00170] 31 [00171] 32 [00172] 33 [00173] 35 [00174] 36 [00175] 37 [00176] 38 [00177] 39 [00178] 43 [00179] 44 [00180] 45 [00181] 46 [00182] 47 [00183] 48 [00184] 49 [00185] 50 [00186]

Pharmaceutical Compositions

[0384] The compounds of the invention are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo.

[0385] Accordingly, in another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention in admixture with a suitable diluent, carrier, or excipient.

[0386] The compounds of the invention may be used in the form of the free base, in the form of salts, solvates, and as prodrugs. All forms are within the scope of the invention. In accordance with the methods of the invention, the described compounds or salts, solvates, or prodrugs thereof may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The compounds of the invention may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0387] A compound of the invention may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutic administration, a compound of the invention may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers.

[0388] A compound of the invention may also be administered parenterally. Solutions of a compound of the invention can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003, 20.sup.th ed.) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19), published in 1999.

[0389] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that may be easily administered via syringe.

[0390] Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels, and powders. Aerosol formulations typically include a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant, which can be a compressed gas, such as compressed air or an organic propellant, such as fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomizer.

Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, where the active ingredient is formulated with a carrier, such as sugar, acacia, tragacanth, gelatin, and glycerine.

[0391] Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter.

[0392] The compounds of the invention may be administered to an animal, e.g., a human, alone or in combination with pharmaceutically acceptable carriers, as noted herein, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice.

Dosages

[0393] The dosage of the compounds of the invention, and/or compositions comprising a compound of the invention, can vary depending on many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the clearance rate of the compound in the animal to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. The compounds of the invention may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response.

Protein Secretion

[0394] Myriad proteins are secreted from cells. In humans, secreted proteins are trafficked from the cytosol to outside the cell by the protein secretory pathway. The proteins secretory pathway comprises the endoplasmic reticulum, Golgi bodies, secretory or transport vesicles, and the cell membrane. In order to be secreted from cells, proteins must pass through the biological membranes that divide cells into compartments. The passage of proteins from the cytosol into the membrane of the endoplasmic reticulum is facilitated by the translocon, a complex of proteins comprising at least Sec61. Polypeptides which are secreted from cells may comprise a signal peptide. The signal peptide is a sequence of amino acids located at the N-terminus of the polypeptide to be secreted. The signal peptide facilitates targeting of the polypeptide to the translocon, e.g., targeting to Sec61. In some instances, after translocation through the translocon, e.g., through Sec61, the signal peptide is cleaved from the polypeptide, generating a free signal peptide and a mature polypeptide.

Inhibition of Sec61

[0395] Sec61 is a membrane protein complex that, in humans, translocates nascent proteins from the cytosol into the endoplasmic reticulum. Sec61 is a hetero-trimeric complex comprising three subunits: SecY, SecE, and SecG. Newly synthesized polypeptides pass from the ribosome, which associates with Sec61, through Sec61 and into the membrane of the endoplasmic reticulum. Sec61 comprises a channel through which polypeptides pass, and a luminal plug, which, when closed, blocks passage through the channel. The luminal plug is displaced, opening the channel, when polypeptides interact with other portions of Sec61.

[0396] The present inventors have discovered small molecules that selectively inhibit the translocation of specific polypeptides through Sec61. The following description of the Sec61 inhibitors described herein is provided without wishing to be bound by theory. In some embodiments, the Sec61 inhibitors of the present disclosure bind to the luminal plug region of Sec61. In some embodiments, a conserved portion of the Sec61 inhibitors binds to Sec61. In some embodiments, a variable portion of the Sec61 inhibitors makes contacts with the signal peptide of a nascent polypeptide that is in the process of translocating through Sec61. In some embodiments, the contacts between the variable portion of the Sec61 inhibitor and the signal peptide of the nascent polypeptide prevent the translocation of the polypeptide. In some embodiments, selectivity can be achieved for different signal peptides by chemical modification of the variable portion of the Sec61 inhibitor.

[0397] In some embodiments, the signal peptide is orthogonal and independent of the mature protein sequence. In some embodiments, targeting the signal portion of the polypeptide allows for the inhibition of targets that lack druggable handles.

[0398] In some embodiments, components of the body, e.g., the immune system, recognize cells by the proteins that are expressed on the cell surface. In some embodiments, cell identity is determined by the proteins expressed on the cell surface. In some embodiments, selectively targeting the translocation through Sec61 of proteins that are expressed on the cell surface allows for selective editing of the proteins expressed on the cell surface. In some embodiments, selectively targeting the translocation through Sec61 of proteins that are expressed on the cell surface allows for the non-destructive changes to cell identity. In some embodiments, selectively targeting the translocation through Sec61 of proteins that are expressed on the cell surface allows for the removal of surface proteins without harming the cell.

[0399] In some embodiments, selective targeting of the translocation through Sec61 of proteins allows for the targeting of tissue types that are inaccessible to other modalities, e.g., the brain (mABS) and non-liver (siRNA).

[0400] In some embodiments, selectively targeting the translocation through Sec61 of newly made proteins and cells that actively synthesize proteins allows for the targeting of dynamically-regulated targets and synthesis-sensitive cells.

[0401] In some embodiments, selectively targeting the translocation of irreversibly pathogenic proteins through Sec61 allows for targeting the aggregation of irreversibly pathogenic proteins and cascades of irreversibly pathogenic proteins.

[0402] In some embodiments, selectively targeting the translocation of viral proteins thorough Sec61 blocks viral protein secretion and inhibits viral replication.

Methods of Treatment

[0403] The compounds described herein may be used to treat diseases and/or disorders associated with secreted proteins that are translocated through Sec61. In some embodiments, the compounds described herein selectively inhibit the translocation of a disease-associated protein through Sec61. Sec6l-associated diseases and/or disorders that may be treated by a compound described herein include, amyloidosis, light chain amyloidosis, autoantibody diseases, chronic kidney disease, fibrosis, neurodegeneration, autoimmune disease, genetically-defined kidney disease, viral disease, influenza, dengue virus, zika virus, hepatitis B virus, hepatitis C virus, SARS-CoV-2, and human immunodeficiency virus, malaria, cancer, glioma, myeloma, multiple types of cancer with solid tumors, autoimmune diseases, rheumatoid arthritis, ankylosing spondylitis, celiac disease, multiple sclerosis, atopic dermatitis, Crohn's disease, psoriasis, allergic asthma, autoimmune antibody diseases, myasthenia gravis, neuromyelitis optica, warm antibody hemolytic anemia, prion disease, immune thrombocytopenic purpura, chronic inflammatory demyelinating polyradiculoneuropathy, fibrotic diseases, idiopathic pulmonary fibrosis, endometriosis, nonalcoholic steatohepatitis, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and hypercholesterolemia, Creutzfeldt-Jakob disease, Gerstmann-Strsussler-Scheinker syndrome, high cholesterol, metabolic syndrome, and fatal familial insomnia.

Light Chain Amyloidosis

[0404] Amyloidosis is a group of diseases characterized by the harmful and undesired buildup of misfolded amyloid protein in various tissues. Nonlimiting examples of tissues that may suffer from buildup of misfolded amyloid protein include the kidneys, the heart, the brain, the liver, the thyroid glands, the adrenal glands, the musculoskeletal system, the eyes, and the oral cavity. Light chain amyloidosis is a form of amyloidosis characterized by the buildup of amyloid protein formed from the light chains (AL) of antibodies produced in bone marrow by plasma cells. The secretion of light chain in plasma cells is facilitated by Sec61. In light chain amyloidosis, amyloid protein is deposited in tissues throughout the body including but not limited to the kidneys, the heart, the digestive system, the liver, and the nervous system. Without wishing to be bound by theory, inhibition of light chain translocation by Sec61 may reduce the levels of amyloid derived from light chains present in tissues including but not limited to the kidneys, the heart, the digestive system, the liver, and the nervous system.

Prion Disease

[0405] Prion disease is a fatal neurodegenerative disease caused by the elevated levels of misfolded prion protein (PrP). Individuals suffering from prion disease may experience impaired brain function causing changes in memory, personality and behavior, dementia, and ataxia. PrP is translocated from the cytosol to the endoplasmic reticulum by Sec61. Without wishing to bound by theory, inhibition of PrP translocation via Sec61 may reduce circulating PrP levels, e.g., in the brain.

Autoimmune Antibody Disease

[0406] Autoimmune Antibody Disease is characterized by the failure of the immune system to differentiate between host antigens and foreign antigens. In some instances, Autoimmune Antibody Disease comprises immunoglobulin G (IgG) having pathogenic effects on the body. The neonatal crystallizable fragment receptor (FcRn) is a protective IgG receptor and is positively correlated with the level of circulating IgG. FcRn is translocated into the endoplasmic reticulum via Sec61. Without wishing to be bound by theory, inhibition of FcRn translocation may reduce IgG levels.

Genetically Defined Kidney Disease

[0407] Genetically defined kidney disease comprises a group of kidney disease that have a genetic origin. Nonlimiting examples of genetically-defined kidney diseases include End-stage kidney disease (ESKD) and

[0408] Focal segmental glomerulosclerosis (FSGS). APOL1 is a protein associated with genetically defined kidney diseases. APOL1 is translocated into the endoplasmic reticulum via Sec61. Without wishing to be bound by theory, inhibition of APOL1 translocation by Sec61 may reduce the levels of APOL1 in the kidney and thus preserve podocytes and slow the progression of kidney disease.

Malaria

[0409] Malaria is a disease caused by the parasite Plasmodium falciparum. P. falciparum utilizes Sec61 to export proteins that are important for its survival and replication into host erythrocytes. Without wishing to be bound by theory, inhibition of translocation of P. falciparum proteins via Sec61 may inhibit the replication of P. falciparum.

Viral Diseases

[0410] All viruses co-opt the cellular machinery of their host cell in order to replicate. Nonlimiting examples of viruses whose ability to replicate inside host cells may be Sec61-dependent include influenza, dengue virus, zika virus, hepatitis B virus, hepatitis C virus, SARS-CoV-2, and human immunodeficiency virus (HIV). Without wishing to be bound by theory, Sec61 may contribute to the transportation of viral proteins into biological membranes, e.g., into the endoplasmic reticulum. Without wishing to be bound by theory, inhibition of the translocation of viral proteins through Sec61 may prevent the replication of viruses in host cells.

Cancer

[0411] Cancer is a group of diseases characterized by the harmful, abnormal, uncontrolled, and undesirable growth of cells. Cancer occurs in multiple tissues and organs, including the lungs, the breasts, the bladder, the colon, the rectum, the uterus, the testes, the kidneys, the blood, the lymphatic system, the liver, the bile ducts, the skin, the pancreas, the prostate, the thyroid gland, the brain, the spinal cord, and the stomach. Cancer cells differ from healthy cells in their protein expression profiles. For example, cancer cells may express proteins which are involved in tumor metastasis, such as CD74, at higher levels than healthy cells.

[0412] Without wishing to be bound by theory, the proteins translocated through Sec61 in cancer cells may differ from the proteins translocated through Sec61 in healthy cells. Additionally, proteins that are translocated through Sec61 in both cancer cells and healthy cells may be translocated through Sec61 at a higher rate in cancer cells than in healthy cells. Furthermore, cancer cells may rely on proteins translocated through Sec61 for survival, such as increased proliferation or evasion from immune recognition. Inhibiting the translocation of proteins that are translocated through Sec61 in cancer cells but not in healthy cells, and/or inhibiting the translocation of proteins that are translocated through Sec61 at higher levels in cancer cells than in healthy cells, and/or inhibiting the translocation of proteins that cancer cells rely on for increased proliferation or evasion from immune recognition, may inhibit the proliferation of cancer cells.

Equivalents and Scope

[0413] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments in accordance with the invention described herein. The scope of the present invention is not intended to be limited to the above Description.

[0414] The following Examples are illustrative only and not intended to limit the invention in any way.

EXAMPLES

Example 1. Synthesis of Compounds

[0415] Compounds of the invention can be synthesized according to one or more of the exemplary syntheses shown below.

Materials and Methods

[0416] NMR Equipment: NMR spectra were recorded at 400 MHz using a QOne AS400 400 MHz spectrometer.

LC-MS (Aglient-P2):

[0417] LC: Agilent Technologies 1290 series, Binary Pump, Diode Array Detector. Agilent EclipsePlus RRHD C18, 1.8 ?m, 3.0?50 mm. Mobile phase: A: 0.05% Formate in water (v/v), B: 0.05% Formate in MeCN(v/v). Flow Rate: 0.8 mL/min at 25? C. Detector: 214 nm, 254 nm.

Timetable:

[0418]

TABLE-US-00002 T (min) A (%) B (%) 0.00 90 10 0.50 90 10 4.00 10 90 4.50 0 100 4.51 90 10 5.00 90 10

LC-MS (SHIMADZU-2020-P2):

[0419] LC: Shimadzu LC-20 AD series, Binary Pump, Diode Array Detector. Waters Sunfire, 3.5 ?m, 4.6?50 mm column. Mobile phase: A: 0.05% Formate in water (v/v), B: 0.05% Formate in MeCN(v/v). Flow Rate: 1 mL/min at 25? C. Detector: 214 nm, 254 nm. Gradient stop time, 5 min. Timetable:

TABLE-US-00003 T (min) A (%) B (%) 0.00 85 15 0.50 85 15 4.00 0 100 4.50 0 100 4.51 85 15 5.00 85 15 [0420] 1. MS: 2020, Quadrupole LC/MS, Ion Source: API-ESI, TIC: 100-900 m/z, Drying gas flow: 15 L/min, Nebulizer pressure: 1.5 L/min, Drying gas temperature: 250? C., Vcap: 4500V. [0421] 2. Sample preparation: samples were dissolved in methanol at 1-10 ?g/mL, then filtered through a 0.22 ?m filter membrane. Injection volume: 1-10 ?L.

HPLC (Agilent-1200-A2):

[0422] LC: Agilent Technologies 1200 series, Binary Pump, Diode Array Detector. Column Temperature: 35? C.; Acquisition wavelength: 214 nm, 254 nm; Mobile Phase A: 0.1% TFA in water (v/v); Mobile Phase B: CAN; Run time: 18.01 min; Post time: 2 min; Flow rate: 1.0 ml/min HPLC-01-A2: Gradient stop time, 18 min.

Timetable:

[0423]

TABLE-US-00004 Time(min) A B 0 90 10 1 90 10 17 0 100 18 0 100

Synthesis of Intermediate 1

Step 1: Synthesis of methyl (2R)-4,4-difluoro-1-[phenyl]pyrrolidine-2-carboxylate

[0424] ##STR00187##

[0425] A 100 mL round bottom flask with stir bar was charged with methyl (2R)-4,4-difluoropyrrolidine-2-carboxylate (2.00 g, 4.4 mmol, 1.00 equiv), phenyl boronic acid (1.59 g, 13.0 mmol, 3 equiv), Cu(OAc).sub.2 (2.37 g, 13.0 mmol, 3 equiv), TEA (2.20 g, 21.8 mmol, 5 equiv) and DCM (30 mL, 0.15 M) under nitrogen atmosphere. The reaction flask was then vacuumed and flushed with oxygen, and the sequence was repeated twice. The vial was capped and placed in a 25? C. bath. The reaction mixture was stirred at 25? C. for 48 h under oxygen atmosphere using an oxygen balloon. The reaction mixture was poured into DCM (150 mL) and quenched by the addition of NH.sub.3.Math.H.sub.2O (20 mL), washed with H.sub.2O (1?50 mL) and brine (3?50 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The resulting crude material was purified via silica gel chromatography to yield the desired product. LCMS (+ESI): calc. [M+H]+=242; found 242.

Step 2: synthesis of 2-(2-chloroacetyl)-4,4-difluoro-1-[phenyl]pyrrolidine

[0426] ##STR00188##

[0427] A 20 mL vial with stir bar was charged with methyl (2R)-4,4-difluoro-1-[phenyl]pyrrolidine-2-carboxylate (182 g, 0.887 mmol, 1.0 equiv), sodium 2-chloroacetate (155 mg, 1.33 mmol, 1.5 equiv), triethylamine (0.124 mL, 0.887 mmol, 1.0 equiv) and THE (1.0 mL, 0.2 M). The reaction mixture was cooled to 0? C., and tert-butylmagnesium chloride (1.0 M in THF, 2.7 mL, 2.70 mmol, 3.0 equiv) was added. The reaction mixture was allowed to warm to room temperature overnight. The next morning, the reaction mixture was poured into EtOAc (50 mL). The organic layer was washed with saturated NaHCO.sub.3 (2?50 mL). The combined aqueous layers were extracted with EtOAc (1?50 mL), and the combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The resulting crude material was used in the next step without further purification.

[0428] LCMS (+ESI): calc. [M+H]+=260; found 260.

Step 3: Synthesis of (R)-4-(1-phenyl-4,4-difluoropyrrolidin-2-yl)thiazol-2-amine (intermediate 1)

[0429] ##STR00189##

[0430] A 20 mL vial with stir bar was charged with 2-(2-chloroacetyl)-4,4-difluoro-1-[phenyl]pyrrolidine (307 mg, 1.28 mmol, 1.0 equiv), thiourea (108 mg, 1.41 mmol, 1.1 equiv) and EtOH (7 mL). The resulting solution was stirred at 80? C. overnight. The next morning, the resulting solution was cooled and poured into EtOAc (100 ml). The mixture was washed with saturated NaHCO.sub.3 (2?100 ml), and the combined aqueous layers were extracted with EtOAc (1?100 ml). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The resulting crude material was purified via silica gel chromatography to yield the desired product.

[0431] LCMS (+ESI): calc. [M+H]+=282; found 282.

[0432] Intermediate 1 may be used in the preparation of compounds of the invention. For example, the following procedure describes the synthesis of a compound of the invention that contains an amide using intermediate 1 and a carboxylic acid.

[0433] Synthesis of amides using intermediate 1 and carboxylic acids Intermediate 1 is added to a solution of carboxylic acid and EDCI in DMF followed by DIPEA. After 24 hours the mixture was diluted with EtOAc, washed with water (4?), then the organic fraction was concentrated under reduced pressure and purified using silica gel chromatography.

Synthesis of 2-(pyridin-4-yl)ethyl (R)-(4-(1-phenylpyrrolidin-2-yl)thiazol-2-yl)carbamate (Compound 1)

[0434] ##STR00190##

[0435] To a solution of 2-(pyridin-4-yl)ethan-1-ol (29 mg, 0.24 mmol) and triphosgene (35 mg, 0.12 mmol) in DCM (2 mL) was added a solution of DMAP (99 mg, 0.84 mmol) in DCM (1 mL) dropwise at OoC. The reaction mixture was stirred at 0? C. for 30 mins, then (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (51 mg, 0.24 mmol) was added. The reaction mixture was warmed to RT and stirred at RT overnight. After completion, the reaction mixture was poured into water (10 mL) and extracted with DCM (10 mL?3). The combined organic layers were washed with brine (10 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was purified by prep-TLC (DCM/MeOH=10/1, v/v) to provide the title compound (15 mg, 16% yield) as a pink solid.

[0436] LCMS (Agilent-S12): Rt=2.65 min; m/z [M+H]+ 395.2.

[0437] 1H NMR (400 MHz, DMSO-d6) ? 11.71 (s, 1H), 8.49-8.47 (m, 2H), 7.34-7.32 (m, 2H), 7.09 (t, J=8.4 Hz, 2H), 6.66 (s, 1H), 6.55 (t, J=7.2 Hz, 1H), 6.47 (d, J=8.0 Hz, 2H), 4.69 (d, J=7.6 Hz, 1H), 4.40 (t, J=6.4 Hz, 2H), 3.56 (t, J=8.0 Hz, 1H), 3.26-3.16 (m, 1H), 2.97 (t, J=6.4 Hz, 2H), 2.24-2.17 (m, 1H), 1.99-1.92 (m, 3H).

Synthesis of amide (R)-(4-(4,4-difluoro-1-phenylpyrrolidin-2-yl)thiazol-2-yl) 3-(4-pyridyloxy)propenamide (Compound 35)

[0438] ##STR00191##

[0439] A vial with stir bar is charged with 3-(4-pyridyloxy)propionic acid (1.00 equiv), 2-(2-aminothiazolyl)-4,4-difluoro-1-[phenyl]pyrrolidine (1.30 equiv), NMI (3.50 equiv) and ACN. TCFH (1.21 equiv) is added, and the vial is capped and placed in a 25? C. bath. The reaction mixture is stirred at 25? C. overnight. The next morning, the reaction mixture is poured into EtOAc and washed with brine. The combined aqueous layers are extracted with EtOAc, and the combined organic layers are dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The resulting crude material was purified via silica gel chromatography & Prep-HPLC or RP column to yield the desired product.

Synthesis of 3-((4-pyridyl)methoxy)pyridinyl (R)-(4-(4,4-difluoro-1-phenylpyrrolidin-2-yl)thiazol-2-yl)amine (Compound 36)

[0440] ##STR00192##

[0441] A vial with stir bar is charged with 2-chloro-3-((4-pyridyl)methoxy)pyridine (1.00 equiv), (R)-4-(1-phenyl-4,4-difluoropyrrolidin-2-yl)thiazol-2-amine (1.30 equiv), Cesium carbonate (3.50 equiv) and DMF. The vial was capped and placed in a 100? C. bath. The reaction mixture was stirred at 100? C. overnight. The next morning, the reaction mixture was poured into EtOAc and washed with brine. The combined aqueous layers were extracted with EtOAc, and the combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The resulting crude material was purified via silica gel chromatography & Prep-HPLC or RP column to yield the desired product.

Synthesis of Compound 2

[0442] ##STR00193##

Step 1: Synthesis of ethyl 3-(pyridin-4-yloxy)propanoate

[0443] ##STR00194##

[0444] To a solution of pyridin-4-ol (500 mg, 5.26 mmol, 1 eq) in DMF (8 mL) was added NaH (316 g, 7.89 mmol, 1.5 eq) at 0? C. The solution was stirred at 0? C. for 0.5 h. ethyl 3-bromopropanoate (1.42 g, 7.89 mmol, 1.5 eq) was added to the solution. After stirring at room temperature for 4 h. The solution was extracted with EtOAc (10 mL?3), washed with water (10 mL?3), brine (10 mL), dried over Na.sub.2SO.sub.4 and concentrated to give a crude, the crude was purification by silica gel column (PE/EtOAc=2:1, v/v) to give the desired product (650 mg, 3.33 mmol, 63%) as a white oil.

[0445] LCMS (Waters-QDa-02): Rt 1.01 min; [M+1].sup.+=196.09

Step 2: Synthesis of 3-(pyridin-4-yloxy)propanoic acid

[0446] ##STR00195##

[0447] To a solution of ethyl 3-(pyridin-4-yloxy)propanoate (650 mg, 3.33 mmol, 1 eq) in THE (9 mL) and H.sub.2 (3 mL) was added LiOH (240 mg, 9.99 mmol, 3 eq). After stirring at room temperature for 2 h, the reaction mixture was adjusted PH to 2 by HCl aqueous solution (1 M) and concentrated to give the crude (550 mg) as a yellow solid.

[0448] LCMS (Waters-QDa-02): Rt 0.27 min; [M+1].sup.+=168.05

Step 3: Synthesis of (R)N-(4-(1-phenylpyrrolidin-2-yl)thiazol-2-yl)-3-(pyridin-4-yloxy)propanamide

[0449] ##STR00196##

To a solution of 3-(pyridin-4-yloxy)propanoic acid (380 mg, 2.27 mmol, 2 eq) in DMA (3 mL) were added (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (100 mg, 1.13 mmol, 1 eq), EDCI (117 mg, 0.61 mmol, 1.5 eq) and DMAP (100 mg, 0.81 mmol, 2 eq). After stirring at 100? C. for 1 h in microwave. The solution was extracted with EtOAc (3 mL?3), washed with water (5 mL?3), brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated to give a crude, the crude was purification by prep.TLC (DCM/MeOH=10:1, v/v) to give the desired product (6 mg, 0.015 mmol, 1%) as a white solid.

[0450] LCMS (Agilent-1290): Rt: 2.61 min, m/z [M+1]+=395.1/396.2

[0451] HNMR (400 MHz, DMSO-d6): ? ppm: 12.23 (s, 1H), 7.93 (s, 2H), 7.72 (s, 1H), 7.19 (s, 1H), 7.13-7.06 (m, 2H), 6.73 (s, 1H), 6.56-6.52 (m, 1H), 6.47-6.45 (d, J=8 Hz, 1H), 6.41 (s, 1H), 4.74-4.72 (m, 1H), 4.28 (s, 2H), 3.58-3.54 (m, 2H), 2.98-2.94 (m, 2H), 2.26-2.19 (m, 1H), 2.01-1.93 (m, 3H).

[0452] HPLC (Agilent-1200-A2): Rt: 10.47 min, 96% purity.

Synthesis of Compound 3

[0453] ##STR00197##

Step 1: Synthesis of 3-((tert-butoxycarbonyl)amino)propanoic acid

[0454] ##STR00198##

[0455] To a solution of 3-aminopropanoic acid (1 g, 11.23 mmol, 1 eq) in MeOH (15 mL) were added Boc.sub.2O (2.7 g, 12.35 mmol, 1.1 eq) and TEA (2.3 g, 22.46 mmol, 2.0 eq). After stirring at room temperature for 16 h, the reaction adjusted PH to 2 by HCl aqueous solution (1M) and extracted with DCM (30 mL?3), washed with water (20 mL?3), brine (20 mL), dried over Na.sub.2SO.sub.4 and concentrated to give the desired product (2.11 g, 11.23 mmol, 99%) as a white solid.

[0456] HNMR: (400 MHz, DMSO-d.sub.6) ? ppm: 6.77 (s, 1H), 3.13-3.08 (m, 2H), 2.35-2.31 (m, 2H), 1.36 (s, 9H).

Step 2: Synthesis of tert-butyl (R)-(3-oxo-3-((4-(1-phenylpyrrolidin-2-yl)thiazol-2-yl)amino)propyl)carbamate

[0457] ##STR00199##

[0458] To a solution of 3-((tert-butoxycarbonyl)amino)propanoic acid (300 m, 1.58 mmol, 2 eq) in DMF (6 mL) were added (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (200 mg, 0.79 mmol, 1 eq), DIEA (369 mg, 1.58 mmol, 2 eq) and HATU (621 mg, 1.63 mmol, 2 eq) at 0? C. After stirring at room temperature for 16 h. The solution was extracted with EtOAc (6 mL?3), washed with water (6 mL?3), brine (6 mL), dried over Na.sub.2SO.sub.4 and concentrated to give a crude. The crude was purified by silica gel column (PE/EtOAc=2/1, v/v) to give the desired product (300 g, 0.72 mmol, 45%) as a white oil.

[0459] LCMS (Waters-QDa-02): Rt 1.89 min; [M+1].sup.+=417.19/418.34

Step 3: (R)-3-amino-n-(4-(1-phenylpyrrolidin-2-yl)thiazol-2-yl)propanamide

[0460] ##STR00200##

[0461] To a solution of tert-butyl (R)-(3-oxo-3-((4-(1-phenylpyrrolidin-2-yl)thiazol-2-yl)amino)propyl)carbamate (280 mg, 0.67 mmol, 1 eq) in dioxane (3 mL) was added HCl/dioxanne (4 M) (6 ml). After stirring at room temperature for 2 h, the reaction mixture was concentrated under reduced pressure to give the desired product (210 mg, 0.67 mmol, 99%) as a yellow oil.

[0462] LCMS (Waters-QDa-02): Rt 0.67 min; [M+1].sup.+=317.19/418.20

Step 4: Synthesis of (R)N-(4-(1-phenylpyrrolidin-2-yl)thiazol-2-yl)-3-(pyridin-4-ylamino)propanamide

[0463] ##STR00201##

[0464] To a solution of (R)-3-amino-N-(4-(1-phenylpyrrolidin-2-yl)thiazol-2-yl)propanamide (300 mg, 0.94 mmol, 1 eq) in DMF (5 mL) at were added 4-fluoropyridine (125 mg, 0.94 mmol, 1 eq) and Cs2CO3 (924 mg, 2.85 mmol, 3 eq). The solution was stirred at 100? C. for 16 h. The reaction was extracted with ethyl acetate (6 mL?3), washed with water (6 mL?3), brine (6 mL), dried over Na.sub.2SO.sub.4 and concentrated to give a crude, the crude was purified by prep.TLC (DCM/MeOH=10/1, v/v) to give the desired product (80 mg, 0.94 mmol, 21%) as a yellow solid.

[0465] LCMS (SHIMADZU-2020-P2): Rt: 3.45 min, m/z [M+1]+=394.2/385.1

[0466] HNMR (400 MHz, DMSO-d6): ? ppm: 11.99 (s, 1H), 8.01-8.00 (d, J=4 Hz, 2H), 7.10-7.08 (m, 2H), 7.06 (s, 1H), 6.70-6.46 (m, 6H), 4.75-4.72 (m, 1H), 3.60-3.55 (m, 1H), 3.41-3.36 (m, 2H), 3.25-3.17 (m, 1H), 2.69-2.65 (m, 2H), 2.27-2.22 (m, 1H), 2.02-1.92 (m, 3H).

[0467] HPLC (Agilent-1200-A2): Rt: 10.40 min, 98% purity.

Synthesis of Compound 4

[0468] ##STR00202##

[0469] Step 1: Synthesis of (R)N-(4-((R)-1-phenylpyrrolidin-2-yl)thiazol-2-yl)-2-(pyridin-4-ylmethoxy)propanamide

##STR00203##

[0470] To a solution of (S)-2-(pyridin-4-ylmethoxy)propanoic acid (210 mg, 1.16 mmol, 2 eq) in DMA (3 mL) were added (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (142 mg, 0.58 mmol, 1 eq), EDCI (111 mg, 0.57 mmol, 1.5 eq) and DMAP (141 mg, 1.16 mmol, 2 eq). After stirring at 130? C. for 5 h in microwave. The solution was extracted with EtOAc (3 mL?3), washed with water (5 mL?3), brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated to give a crude, the crude was purification by prep.TLC (DCM/MeOH=10:1, v/v) to give the desired product (18 mg, 0.04 mmol, 7%) as a white solid.

[0471] LCMS (Agilent-1290): Rt: 2.74 min, m/z [M+1]+=409.2/410.2

[0472] HNMR (400 MHz, DMSO-d6): ? ppm: 12.18 (s, 1H), 8.53-8.51 (m, 2H), 7.37-7.36 (m, 2H), 7.10-7.07 (m, 2H), 6.76 (s, 1H), 6.57-6.53 (m, 1H), 6.49-6.47 (m, 2H), 4.76-4.74 (m, 1H), 4.62-4.58 (m, 1H), 4.52-4.47 (m, 1H), 4.29-4.24 (m, 1H), 3.60-3.56 (m, 1H), 3.27-3.23 (m, 1H), 2.29-2.20 (m, 1H), 2.04-1.98 (m, 3H), 1.40-1.38 (m, 3H).

[0473] HPLC (Agilent-1200-A2): Rt: 10.77 min, 98% purity.

Synthesis of Compound 5

[0474] ##STR00204##

Step 1: Synthesis of (S)N-(4-((R)-1-phenylpyrrolidin-2-yl)thiazol-2-yl)-2-(pyridin-4-ylmethoxy)propanamide

[0475] ##STR00205##

[0476] To a solution of (S)-2-(pyridin-4-ylmethoxy)propanoic acid (50 mg, 0.3 mmol, 1.5 eq) in DMA (2 mL) were added (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (50 mg, 0.25 mmol, 1 eq), EDCI (58 mg, 0.3 mmol, 1.5 eq) and DMAP (49 mg, 0.4 mmol, 2 eq). After stirring at 100? C. for 2 h in microwave. The solution was extracted with EtOAc (3 mL?3), washed with water (5 mL?3), brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated to give a crude, the crude was purification by prep.TLC (DCM/MeOH=10:1, v/v) to give the desired product (20 mg, 0.04 mmol, 4%) as a white solid.

[0477] LCMS (Agilent-1290): Rt: 2.77 min, m/z [M+1]+=409.2/410.2

[0478] HNMR (400 MHz, DMSO-d6): ? ppm: 12.18 (s, 1H), 8.54-8.52 (m, 2H), 7.37-7.36 (m, 2H), 7.11-7.07 (m, 2H), 6.76 (s, 1H), 6.57-6.53 (m, 1H), 6.49-6.47 (m, 2H), 4.76-4.74 (d, J=8 Hz, 1H), 4.63-4.58 (m, 1H), 4.52-4.48 (m, 1H), 4.47-4.24 (m, 1H), 3.60-3.56 (m, 1H), 3.26-3.16 (m, 1H), 2.27-2.20 (m, 1H), 2.11-1.95 (m, 3H), 1.40-1.37 (m, 3H).

[0479] HPLC (Agilent-1200-A2): Rt: 10.71 min, 98% purity.

Synthesis of Compound 6

[0480] ##STR00206##

Step 1: Synthesis of (R)-1-methyl-3-(4-(1-phenylpyrrolidin-2-yl)thiazol-2-yl)-1-(2-(pyridin-4-yl)ethyl)urea

[0481] ##STR00207##

[0482] To a solution of (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (100 mg, 0.4 mmol, 1 eq) in DCM (4 mL) were added Triphosgene (60 mg, 0.2 mmol, 0.5 eq), DMAP (159 mg, 1.3 mmol, 3.2 eq) at 0? C. The solution was stirred at 0? C. for 2 h. N-methyl-2-(pyridin-4-yl)ethan-1-amine (111 mg, 0.81 mmol, 2 eq) was added to the solution. After stirring at room temperature for 16 h. The solution was extracted with DCM (5 mL?3), washed with water (5 mL?3), brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated to give a crude, the crude was purification by prep.TLC (DCM/MeOH=20:1, v/v) to give the desired product (56 mg, 0.13 mmol, 33%) as a white solid.

[0483] LCMS (Agilent): Rt: 2.53 min, m/z [M+1].sup.+=408.4/409.3

[0484] HNMR (400 MHz, DMSO-d6): ? ppm: 10.71 (s, 1H), 8.46-8.44 (m, 2.5H), 7.30-7.28 (m, 2H), 7.21-7.20 (m, 0.5H), 7.11-7.07 (m, 2H), 6.57-6.53 (m, 1H), 6.49-6.46 (m, 3H), 4.68-4.66 (d, J=8 Hz, 1H), 3.62-3.56 (m, 3H), 3.27-3.22 (m, 1H), 2.93 (s, 3H), 2.84-2.80 (m, 2H), 2.24-2.17 (m, 1H), 2.02-1.95 (m, 3H).

[0485] HPLC (Agilent-1200-A2): Rt: 9.51 min, 97% purity.

Synthesis of Compound 7

[0486] ##STR00208##

Step 1: Synthesis of 3-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid

[0487] ##STR00209##

[0488] To a solution of 3-amino-2-methylpropanoic acid (500 mg, 4.85 mmol, 1 eq) in MeOH (25 mL) were added Boc.sub.2O (1.16 g, 5.33 mmol, 1.1 eq) and TEA (982 mg, 9.7 mmol, 2.0 eq). After stirring at room temperature for 16 h, the reaction adjusted PH to 2 by HCl aqueous solution (1M) and extracted with DCM (30 mL?3), washed with water (20 mL?3), brine (20 mL), dried over Na.sub.2SO.sub.4 and concentrated to give the desired product (900 mg, 4.85 mmol, 91%) as a white solid.

[0489] HNMR (400 MHz, DMSO-d6): ? ppm: 6.80 (s, 1H), 3.18-3.08 (m, 1H), 2.94-2.88 (m, 1H), 2.46-2.41 (m, 1H), 1.36 (s, 9H), 1.01-0.99 (d, J=8 Hz, 3H).

Step 2: Synthesis of tert-butyl (2-methyl-3-oxo-3-((4-((R)-1-phenylpyrrolidin-2-yl)thiazol-2-yl)amino)propyl)carbamate

[0490] ##STR00210##

[0491] To a solution of 3-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (414 mg, 2.03 mmol, 2.5 eq) in DMF (6 mL) were added (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (200 mg, 0.82 mmol, 1 eq), DIEA (369 mg, 2.04 mmol, 2.5 eq) and HATU (369 mg, 2.86 mmol, 3.5 eq) at 0? C. After stirring at room temperature for 16 h. The solution was extracted with EtOAc (6 mL?3), washed with water (6 mL?3), brine (6 mL), dried over Na.sub.2SO.sub.4 and concentrated to give a crude. The crude was purified by silica gel column (PE/EtOAc=2/1, v/v) to give the desired product (280 mg, 0.82 mmol, 80%) as a white solid.

[0492] LCMS (Waters-QDa-02): Rt 1.98 min; [M+1].sup.+=431.1/432.2

Step 3: Synthesis of 3-amino-2-methyl-N-(4-((R)-1-phenylpyrrolidin-2-yl)thiazol-2-yl)propanamide

[0493] ##STR00211##

[0494] To a solution of tert-butyl (2-methyl-3-oxo-3-((4-((R)-1-phenylpyrrolidin-2-yl)thiazol-2-yl)amino)propyl)carbamate (140 mg, 0.32 mmol, 1 eq) in dioxane (2 mL) was added HCl/dioxanne (4 M) (4 ml). After stirring at room temperature for 2 h, the reaction mixture was concentrated under reduced pressure to give the desired product (170 mg crude) as a yellow oil.

[0495] LCMS (Waters-QDa-02): Rt 0.93 min; [M+1].sup.+=331.1/332.2

Step 4: Synthesis of 2-methyl-N-(4-((R)-1-phenylpyrrolidin-2-yl)thiazol-2-yl)-3-(pyridin-4-ylamino)propanamide

[0496] ##STR00212##

[0497] To a solution of 3-amino-2-methyl-N-(4-((R)-1-phenylpyrrolidin-2-yl)thiazol-2-yl)propanamide (50 mg, 0.15 mmol, 1 eq) in DMF (5 mL) were added 4-fluoropyridine (21 mg, 0.15 mmol, 1 eq) and Cs.sub.2CO.sub.3 (155 mg, 0.45 mmol, 3 eq). The solution was stirred at 100? C. for 16 h. The reaction was extracted with ethyl acetate (6 mL?3), washed with water (6 mL?3), brine (6 mL), dried over Na.sub.2SO.sub.4 and concentrated to give a crude, the crude was purified by prep.TLC (DCM/MeOH=10/1, v/v) to give the desired product (7 mg, 0.15 mmol, 11%) as a yellow solid.

[0498] LCMS (Agilent-1290): Rt: 2.65 min, m/z [M+1].sup.+=408.2/409.3

[0499] HNMR (400 MHz, DMSO-d6): ? ppm: 12.14 (s, 1H), 8.00-7.98 (m, 2H), 7.10-7.16 (m, 2H), 6.71-6.46 (m, 7H), 4.74-4.72 (d, J=8 Hz, 1H), 3.57-3.55 (m, 1H), 3.24-3.16 (m, 2H), 3.09 (m, 1H), 2.94-2.90 (m, 1H), 2.24-2.21 (m, 1H), 1.97-1.93 (m, 3H), 1.14-1.12 (m, 3H).

[0500] HPLC (Agilent-1200-A2): Rt: 13.86 min, 100% purity.

Synthesis of Compound 8

[0501] ##STR00213##

Step 1: Synthesis of 2-chloro-3-(pyridin-4-ylmethoxy)pyridine

[0502] ##STR00214##

[0503] To a mixture of 2-chloropyridin-3-ol (500 mg, 3.8 mmol, 1 eq) in DMF (15 mL) was added NaH (310 mg, 7.7 mmol, 2 eq) at 0? C. After stirring at 0? C. for 0.5 h, 4-(chloromethyl)pyridine (947 mg, 5.8 mmol, 1.5 eq) was added to the solution. The solution was stirred at room temperature for 16 h. The solution was quenched with NH.sub.4Cl solution (20 ml), extracted with EtOAc (20 mL?3), washed with water (30 mL?3), brine (30 mL), dried over Na.sub.2SO.sub.4 and concentrated to give a crude, the residue was purified by silica gel column (PE/EtOAc=2/1, v/v) to give the desired product (50 mg, 0.22 mmol, 6%) as a yellow oil.

[0504] LCMS (Waters-QDa-02): Rt 1.34 min; [M+1].sup.+=221.1/222.1

Step 2: Synthesis of (R)-4-(1-phenylpyrrolidin-2-yl)-N-(3-(pyridin-4-ylmethoxy)pyridin-2-yl)thiazol-2-amine

[0505] ##STR00215##

[0506] To a solution of (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (96 mg, 0.4 mmol, 1 eq) in dioxane (5 mL) were added 2-chloro-3-(pyridin-4-ylmethoxy)pyridine (86 mg, 0.4 mmol, 1 eq), Pd2(dba).sub.3 (40 mg, 0.03 mmol, 0.1 eq), xantphos (45 mg, 0.07 mmol, 0.2 eq) and Cs2CO3 (385 mg, 1.18 mmol, 3 eq). The solution was stirred at 100? C. for 16 h. The reaction was concentrated to give a crude, the crude was purified by prep.TLC (DCM/MeOH=10/1, v/v) to give the desired product (60 mg, 0.13 mmol, 35%) as a yellow solid.

[0507] LCMS (Agilent-1290): Rt: 3.24 min, m/z [M+1]+=430.2/432.2

[0508] HNMR (400 MHz, DMSO-d6): ? ppm: 10.29 (s, 1H), 8.60-8.59 (m, 2H), 7.87-7.86 (m, 1H), 7.62-7.61 (m, 2H), 7.37-7.35 (m, 1H), 7.11-7.07 (m, 2H), 6.91-6.89 (m, 1H), 6.57-6.48 (m, 4H), 5.31 (s, 2H), 4.74-4.72 (m, 1H), 3.60 (s, 1H), 3.25-3.16 (m, 1H), 2.24-2.22 (m, 3H).

[0509] HPLC (Agilent-1200-A2): Rt: 11.01 min, 98% purity.

Synthesis of Compound 9

[0510] ##STR00216##

Step 1: Synthesis of (R)-1-(4-(1-phenylpyrrolidin-2-yl)thiazol-2-yl)-3-(2-(pyridin-4-yl)ethyl)urea

[0511] ##STR00217##

[0512] To a solution of (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (100 mg, 0.4 mmol, 1 eq) in DCM (4 mL) were added Triphosgene (61 mg, 0.4 mmol, 0.5 eq), DMAP (160 mg, 1.3 mmol, 3.2 eq) at 0? C. The solution was stirred at 0? C. for 2 h. 2-(pyridin-4-yl)ethan-1-amine (47 mg, 0.4 mmol, 1 eq) was added to the solution. After stirring at room temperature for 16 h. The solution was extracted with DCM (5 mL?3), washed with water (5 mL?3), brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated to give a crude, the crude was purification by prep.TLC (DCM/MeOH=20:1, v/v) to give the desired product (10 mg, 0.02 mmol, 6%) as a white solid.

[0513] LCMS (Agilent-1290): Rt: 2.42 min, m/z [M+1]+=394.1/395.2

[0514] HNMR (400 MHz, DMSO-d6): ? ppm: 10.38 (s, 1H), 8.48-8.46 (m, 2H), 7.26-7.25 (m, 2H), 7.10-7.06 (m, 2H), 6.56-6.46 (m, 5H), 4.67-4.65 (m, 1H), 3.55-3.51 (m, 1H), 3.43-3.38 (m, 2H), 3.27-3.20 (m, 1H), 2.79-2.76 (m, 2H), 2.21-2.17 (m, 1H), 2.01-1.94 (m, 3H).

[0515] HPLC (Agilent-1200-A2): Rt: 9.91 min, 95% purity.

Synthesis of Compound 10

[0516] ##STR00218##

Step 1: Synthesis of (R)-1-methyl-3-(4-(1-phenylpyrrolidin-2-yl)thiazol-2-yl)-1-(pyridin-4-ylmethyl)urea

[0517] ##STR00219##

[0518] To a solution of (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (100 mg, 0.4 mmol, 1 eq) in DCM (4 mL) were added Triphosgene (61 mg, 0.2 mmol, 0.5 eq), DMAP (160 mg, 1.3 mmol, 3.2 eq) at 0? C. The solution was stirred at 0? C. for 2 h. N-methyl-1-(pyridin-4-yl)methanamine (50 mg, 0.4 mmol, 1 eq) was added to the solution. After stirring at room temperature for 16 h. The solution was extracted with DCM (5 mL?3), washed with water (5 mL?3), brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated to give a crude, the crude was purification by prep.TLC (DCM/MeOH=20:1, v/v) to give the desired product (40 mg, 0.1 mmol, 25%) as a white solid.

[0519] LCMS (Agilent-1290): Rt: 2.53 min, m/z [M+1]+=394.1/395.2

[0520] HNMR (400 MHz, DMSO-d6): ? ppm: 10.88 (s, 1H), 8.52-8.51 (m, 2H), 7.21-7.20 (m, 2H), 7.11-7.07 (m, 2H), 6.57-6.65 (m, 2H), 6.48-6.46 (m, 2H), 4.69-4.67 (d, J=8 Hz, 1H), 4.61 (s, 1H), 3.60-3.56 (m, 1H), 3.26-3.20 (m, 1H), 2.99 (s, 3H), 2.24-2.07 (m, 1H), 1.98-1.90 (m, 3H).

[0521] HPLC (Agilent-1200-A2): Rt: 9.82 min, 99% purity.

Synthesis of Compound 11

[0522] ##STR00220##

Step 1: Synthesis of (R)-1-(4-(1-phenylpyrrolidin-2-yl)thiazol-2-yl)-3-(pyridin-4-ylmethyl)urea

[0523] ##STR00221##

[0524] To a solution of (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (100 mg, 0.4 mmol, 1 eq) in DCM (4 mL) were added Triphosgene (61 mg, 0.2 mmol, 0.5 eq), DMAP (160 mg, 1.3 mmol, 3.2 eq) at 0? C. The solution was stirred at 0? C. for 2 h. pyridin-4-ylmethanamine (44 mg, 0.4 mmol, 1 eq) was added to the solution. After stirring at room temperature for 16 h. The solution was extracted with DCM (5 mL?3), washed with water (5 mL?3), brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated to give a crude, the crude was purification by prep.TLC (DCM/MeOH=20:1, v/v) to give the desired product (25 mg, 0.06 mmol, 16%) as a white solid.

[0525] LCMS (Agilent-1290): Rt: 2.45 min, m/z [M+1]+=380.1/381.2

[0526] HNMR (400 MHz, DMSO-d6): ? ppm: 10.68 (s, 1H), 8.50-8.49 (m, 2H), 7.27-7.25 (m, 2H), 7.10-7.06 (m, 3H), 6.56-6.47 (m, 4H), 4.70-4.68 (m, 1H), 4.36-4.35 (m, 2H), 3.56-3.52 (m, 1H), 3.27-3.21 (m, 1H), 2.23-2.19 (m, 1H), 1.97 (m, 3H).

[0527] HPLC (Agilent-1200-A2): Rt: 9.68 min, 98% purity.

Synthesis of Compound 12

[0528] ##STR00222##

Step 1: Synthesis of (R)-1-(2-phenoxyphenyl)-3-(4-(1-phenylpyrrolidin-2-yl)thiazol-2-yl)urea

[0529] ##STR00223##

[0530] To a solution of (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (100 mg, 0.4 mmol, 1 eq) in DCM (4 mL) were added Triphosgene (60 mg, 0.2 mmol, 0.5 eq), DMAP (159 mg, 1.3 mmol, 3.2 eq) at 0? C. The solution was stirred at 0? C. for 2 h. 2-phenoxyaniline (76 mg, 0.41 mmol, 1 eq) was added to the solution. After stirring at room temperature for 16 h. The solution was extracted with DCM (5 mL?3), washed with water (5 mL?3), brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated to give a crude, the crude was purification by prep.TLC (DCM/MeOH=20:1, v/v) to give the desired product (50 mg, 0.10 mmol, 26%) as a white solid.

[0531] LCMS (Agilent-1290): Rt: 4.44 min, m/z [M+1]+=457.3/458.2

[0532] HNMR (400 MHz, DMSO-d6): ? ppm: 11.00 (s, 1H), 8.92 (s, 1H), 8.25-8.23 (m, 1H), 7.42-7.40 (m, 2H), 7.38-7.00 (m, 7H), 6.91-6.88 (m, 1H), 6.61 (s, 1H), 6.56-6.52 (m, 1H), 6.48-6.46 (m, 2H), 4.67-4.65 (m, 1H), 3.55-3.51 (m, 1H), 3.31-3.20 (m, 1H), 2.18-2.11 (m, 1H), 2.04-1.91 (m, 3H).

[0533] HPLC (Agilent-1200-A2): Rt: 16.02 min, 98% purity.

Synthesis of Compound 13

[0534] ##STR00224##

Step 1: Synthesis of (R)-phenyl(4-((4-(1-phenylpyrrolidin-2-yl)thiazol-2-yl)amino)phenyl)methanone

[0535] ##STR00225##

[0536] To a solution of (4-bromophenyl)(phenyl)methanone (106 mg, 0.4 mmol, 1 eq) in dioxane (6 mL) were added (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (100 mg, 0.4 mmol, 1 eq), Pd2(dba).sub.3 (42 mg, 0.04 mmol, 0.1 eq), xantphos (47.2 mg, 0.08 mmol, 0.2 eq) and Cs.sub.2CO.sub.3 (398 mg, 1.22 mmol, 3 eq). The solution was stirred at 100? C. for 16 h. The reaction was concentrated to give a crude, the crude was purified by prep.TLC (DCM/MeOH=10/1, v/v) to give the desired product (72 mg, 0.16 mmol, 41%) as a yellow solid.

[0537] LCMS (Agilet-1290): Rt: 4.43 min, m/z [M+1]+=426.1/427.2

[0538] HNMR (400 MHz, DMSO-d6): ? ppm: 10.67 (s, 1H), 7.78-7.73 (m, 4H), 7.71-7.51 (m, 5H), 7.12-7.08 (m, 2H), 6.57-6.52 (m, 4H), 4.77-4.75 (m, 1H), 3.60-3.55 (m, 1H), 3.29-3.23 (m, 1H), 2.27-2.20 (m, 1H), 2.15-1.98 (m, 3H).

[0539] HPLC (Agilent-1200-A2): Rt: 15.73 min, 96% purity.

Synthesis of Compound 14

[0540] ##STR00226##

Step 1: Synthesis of methyl (R)-2-(pyridin-4-ylmethoxy)propanoate

[0541] ##STR00227##

[0542] To a solution of methyl (R)-2-hydroxypropanoate (1 g, 9.6 mmol, 1.5 eq) in DMF (20 mL) was added NaH (0.56 g, 14 mmol, 2.2 eq) at 0? C. After stirring at 0? C. for 0.5 h, 4-(bromomethyl)pyridine (1.6 g, 6.3 mmol, 1 eq) was added to the solution. The solution was stirred at room temperature for 2 h. The solution was quenched with NH4Cl solution (20 ml), extracted with EtOAc (20 mL?3), washed with water (30 mL?3), brine (30 mL), dried over Na.sub.2SO.sub.4 and concentrated to give a crude, the residue was purified by silica gel column (PE/EtOAc=2/1, v/v) to give the desired product (300 mg, 9.6 mmol, 24%) as a yellow oil.

[0543] LCMS (Waters-QDa-02): Rt 1.35 min; [M+1].sup.+=196.1

Step 2: Synthesis of (R)-2-(pyridin-4-ylmethoxy)propanoic acid

[0544] ##STR00228##

[0545] To a solution of methyl (R)-2-(pyridin-4-ylmethoxy)propanoate (300 mg, 1.53 mmol, 1 eq) in THE (3 mL) and H.sub.2 (1 mL) was added LiOH (111 mg, 4.61 mmol, 3 eq). After stirring at room temperature for 2 h, the reaction mixture was adjusted PH to 2 by HCl aqueous solution (1 M) and concentrated to give the crude (270 mg) as a yellow solid.

[0546] LCMS (Waters-QDa-02): Rt 0.94 min; [M+1].sup.+=182.08

Step 3: Synthesis of (R)N-(4-(2-isopropoxypropan-2-yl)thiazol-2-yl)-2-(pyridin-4-ylmethoxy)propanamide

[0547] ##STR00229##

[0548] To a solution of (R)-2-(pyridin-4-ylmethoxy)propanoic acid (280 mg, 1.4 mmol, 1.5 eq) in DMA (3 mL) were added 4-(2-isopropoxypropan-2-yl)thiazol-2-amine (100 mg, 0.93 mmol, 1 eq), EDCI (144 mg, 0.75 mmol, 1.5 eq) and DMAP (122 mg, 1 mmol, 2 eq). After stirring at 100? C. for 3 h in microwave. The solution was extracted with EtOAc (3 mL?3), washed with water (5 mL?3), brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated to give a crude, the crude was purification by prep.TLC (DCM/MeOH=10:1, v/v) to give the desired product (60 mg, 0.93 mmol, 33%) as a white solid.

[0549] LCMS (Agilent-1290): Rt: 2.26 min, m/z [M+1]+=364.1

[0550] HNMR (400 MHz, DMSO-d6): ? ppm: 12.29 (s, 1H), 8.53-8.52 (m, 2H), 7.37-7.35 (m, 2H), 7.05 (s, 1H), 4.62-4.49 (m, 2H), 4.30-4.25 (m, 1H), 3.63-3.57 (m, 1H), 1.46 (s, 6H), 1.40-1.38 (m, 3H), 0.93-0.91 (m, 6H).

[0551] HPLC (Agilent-1200-A2): Rt: 9.48 min, 100% purity.

Synthesis of Compound 15

[0552] ##STR00230##

Step 1: Synthesis of methyl (S)-2-(pyridin-4-ylmethoxy)propanoate

[0553] ##STR00231##

[0554] To a solution of methyl (S)-2-hydroxypropanoate (1 g, 9.6 mmol, 1 eq) in DMF (20 mL) was added NaH (0.56 g, 14 mmol, 2.2 eq) at 0? C. After stirring at 0? C. for 0.5 h, 4-(bromomethyl)pyridine (1.6 g, 6.3 mmol, 1 eq) was added to the solution. The solution was stirred at room temperature for 2 h. The solution was quenched with NH4Cl solution (20 ml), extracted with EtOAc (20 mL?3), washed with water (30 mL?3), brine (30 mL), dried over Na.sub.2SO.sub.4 and concentrated to give a crude, the residue was purified by silica gel column (PE/EtOAc=2/1, v/v) to give the desired product (160 mg, 9.6 mmol, 8%) as a yellow oil.

[0555] LCMS (Waters-QDa-02): Rt 1.36 min; [M+1]+=196.08

Step 2: Synthesis of (S)-2-(pyridin-4-ylmethoxy)propanoic acid

[0556] ##STR00232##

[0557] To a solution of methyl (S)-2-(pyridin-4-ylmethoxy)propanoate (160 mg, 0.82 mmol, 1 eq) in THF (3 mL) and H.sub.2O (1 mL) was added LiOH (58 mg, 2.46 mmol, 3 eq). After stirring at room temperature for 2 h, the reaction mixture was adjusted PH to 2 by HCl aqueous solution (1 M) and concentrated to give the crude (140 mg) as a yellow solid.

[0558] LCMS (Waters-QDa-02): Rt 0.91 min; [M+1].sup.30=182.08

Step 3: Synthesis of (S)N-(4-(2-isopropoxypropan-2-yl)thiazol-2-yl)-2-(pyridin-4-ylmethoxy)propanamide

[0559] ##STR00233##

[0560] To a solution of (S)-2-(pyridin-4-ylmethoxy)propanoic acid (67 mg, 0.37 mmol, 1.5 eq) in DMA (2 mL) were added 4-(2-isopropoxypropan-2-yl)thiazol-2-amine (50 mg, 0.25 mmol, 1 eq), EDCI (71 mg, 0.37 mmol, 1.5 eq) and DMAP (61 mg, 0.5 mmol, 2 eq). After stirring at 100? C. for 1 h in microwave. The solution was extracted with EtOAc (3 mL?3), washed with water (5 mL?3), brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated to give a crude, the crude was purification by prep.TLC (DCM/MeOH=10:1, v/v) to give the desired product (8.5 mg, 0.25 mmol, 8%) as a white solid.

[0561] LCMS (Agilent-1290): Rt: 2.25 min, m/z [M+1]+=364.1

[0562] HNMR (400 MHz, DMSO-d6): ? ppm: 12.28 (s, 1H), 8.53-8.51 (m, 2H), 7.37-7.35 (m, 2H), 7.05 (s, 1H), 4.62-4.49 (m, 2H), 4.30-4.25 (m, 1H), 3.63-3.57 (m, 1H), 1.46 (s, 6H), 1.40-1.38 (m, 3H), 0.93-0.91 (m, 6H).

[0563] HPLC (Agilent-1200-A2): Rt: 9.44 min, 100% purity.

Synthesis of Compound 16

[0564] ##STR00234##

Step 1: Synthesis of 1-(4-(2-isopropoxypropan-2-yl)thiazol-2-yl)-3-(2-(pyridin-4-yl)ethyl)urea

[0565] ##STR00235##

[0566] To a solution of 4-(2-isopropoxypropan-2-yl)thiazol-2-amine (50 mg, 0.24 mmol, 1 eq) in DCM (4 mL) were added Triphosgene (37 mg, 0.12 mmol, 0.5 eq), DMAP (97 mg, 0.79 mmol, 3.2 eq) at 0? C. The solution was stirred at 0? C. for 2 h. 2-(pyridin-4-yl)ethan-1-amine (31 mg, 0.24 mmol, 1 eq) was added to the solution. After stirring at room temperature for 16 h. The solution was extracted with DCM (5 mL?3), washed with water (5 mL?3), brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated to give a crude, the crude was purification by prep.TLC (DCM/MeOH=20:1, v/v) to give the desired product (20 mg, 0.057 mmol, 22%) as a white solid.

[0567] LCMS (Agilent-1290): Rt: 1.93 min, m/z [M+1]+=349.2

[0568] HNMR (400 MHz, DMSO-d6): ? ppm: 10.54 (s, 1H), 8.48-8.45 (m, 2H), 7.26-7.25 (m, 2H), 6.82 (s, 1H), 6.41 (s, 1H), 3.62-3.56 (m, 1H), 3.43-3.38 (m, 2H), 2.80-2.76 (m, 2H), 1.41 (s, 6H), 0.90-0.89 (m, 6H).

[0569] HPLC (Agilent-1200-A2): Rt: 8.49 min, 98% purity.

Synthesis of Compound 17

[0570] ##STR00236##

Step 1: Synthesis of 1-(4-(2-isopropoxypropan-2-yl)thiazol-2-yl)-3-(pyridin-4-ylmethyl)urea

[0571] ##STR00237##

[0572] To a solution of 4-(2-isopropoxypropan-2-yl)thiazol-2-amine (200 mg, 0.99 mmol, 1 eq) in DCM (6 mL) were added Triphosgene (148 mg, 0.49 mmol, 0.5 eq), DMAP (390 mg, 3.19 mmol, 3.2 eq) at 0? C. The solution was stirred at 0? C. for 2 h. pyridin-4-ylmethanamine (108 mg, 0.99 mmol, 1 eq) was added to the solution. After stirring at room temperature for 16 h. The solution was extracted with DCM (5 mL?3), washed with water (5 mL?3), brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated to give a crude, the crude was purification by prep.TLC (DCM/MeOH=20:1, v/v) to give the desired product (185 mg, 0.99 mmol, 55%) as a white solid.

[0573] LCMS (Agilent-1290): Rt: 1.97 min, m/z [M+1]+=335.2/336.2

[0574] HNMR (400 MHz, DMSO-d6): ? ppm: 10.83 (s, 1H), 8.50-8.49 (m, 2H), 7.27-7.26 (m, 2H), 7.00 (s, 1H), 6.83 (s, 1H), 4.37-4.35 (m, 2H), 3.63-3.57 (m, 1H), 1.43 (s, 6H), 0.92-0.90 (m, 6H).

[0575] HPLC (Agilent-1200-A2): Rt: 8.41 min, 100% purity.

Synthesis of Compound 18

[0576] ##STR00238##

Step 1: Synthesis of 1-(4-(2-isopropoxypropan-2-yl)thiazol-2-yl)-3-(2-phenoxyphenyl)urea

[0577] ##STR00239##

[0578] To a solution of 2-phenoxyaniline (46 mg, 0.24 mmol, 1 eq) in DCM (4 mL) were added Triphosgene (37 mg, 0.12 mmol, 0.5 eq), DMAP (97 mg, 0.79 mmol, 3.2 eq) at 0? C. The solution was stirred at 0? C. for 2 h. 4-(2-isopropoxypropan-2-yl)thiazol-2-amine (50 mg, 0.24 mmol, 1 eq) was added to the solution. After stirring at room temperature for 16 h. The solution was extracted with DCM (5 mL?3), washed with water (5 mL?3), brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated to give a crude, the crude was purification by prep.TLC (DCM/MeOH=20:1, v/v) to give the desired product (20 mg, 0.048 mmol, 19%) as a white solid.

[0579] LCMS (Agilent-1290): Rt: 4.18 min, m/z [M+1]+=412.2

[0580] HNMR (400 MHz, DMSO-d6): ? ppm: 11.14 (s, 1H), 8.80 (s, 1H), 8.26-8.23 (m, 1H), 7.42-7.37 (m, 2H), 7.18-7.12 (m, 2H), 7.05-7.00 (m, 3H), 6.99-6.90 (m, 2H), 3.63-3.57 (m, 1H), 1.42 (s, 6H), 0.90-0.89 (m, 6H).

[0581] HPLC (Agilent-1200-A2): Rt: 9.70 min, 100% purity.

Synthesis of Compound 19

[0582] ##STR00240##

Step 1: 3-(4-(2-isopropoxypropan-2-yl)thiazol-2-yl)-1-methyl-1-(pyridin-4-ylmethyl)urea

[0583] ##STR00241##

[0584] To a solution of 4-(2-isopropoxypropan-2-yl)thiazol-2-amine (50 mg, 0.24 mmol, 1 eq) in DCM (4 mL) were added Triphosgene (37 mg, 0.12 mmol, 0.5 eq), DMAP (97 mg, 0.79 mmol, 3.2 eq) at 0? C. The solution was stirred at 0? C. for 2 h. N-methyl-1-(pyridin-4-yl)methanamine (30 mg, 0.24 mmol, 1 eq) was added to the solution. After stirring at room temperature for 16 h. The solution was extracted with DCM (5 mL?3), washed with water (5 mL?3), brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated to give a crude, the crude was purification by prep.TLC (DCM/MeOH=20:1, v/v) to give the desired product (40 mg, 0.11 mmol, 45%) as a white solid.

[0585] LCMS (Agilent-1290): Rt: 2.05 min, m/z [M+1]+=349.2/350.2

[0586] HNMR (400 MHz, DMSO-d6): ? ppm: 10.91 (s, 1H), 8.52-8.51 (s, 2H), 7.22-7.20 (s, 2H), 6.86 (s, 1H), 4.62 (s, 2H), 3.62-3.56 (m, 1H), 3.29 (s, 3H), 1.45 (s, 6H), 0.92-0.90 (m, 6H).

[0587] HPLC (Agilent-1200-A2): Rt: 8.42 min, 99% purity.

Synthesis of Compound 20

[0588] ##STR00242##

Step 1: Synthesis of tert-butyl (2-(pyridin-4-yl)ethyl)carbamate

[0589] ##STR00243##

[0590] To a solution of 2-(pyridin-4-yl)ethan-1-amine (400 mg, 3.27 mmol, 1 eq) in DCM (5 mL) were added Boc.sub.2O (1.07 g, 4.91 mmol, 1.5 eq) and TEA (663 mg, 6.55 mmol, 2 eq). After stirring at room temperature for 16 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column (DCM/MeOH=50/1, v/v) to give a mixture of desired product (700 mg, 3.27 mmol, 96%) as a white oil.

[0591] LCMS (Waters-QDa-02): Rt 2.90 min; [M+1].sup.+=223.2

Step 2: Synthesis of N-methyl-2-(pyridin-4-yl)ethan-1-amine

[0592] ##STR00244##

[0593] To a solution of tert-butyl (2-(pyridin-4-yl)ethyl)carbamate (100 mg, 0.45 mmol, 1 eq) in THE (3 mL) was added LiAlH4 (51 mg, 1.35 mmol, 3 eq). After stirring at 100? C. for 3 h, the reaction mixture was quenched with water (1 mL) and added diatomite to filtered with (DCM/MeOH=10:1) ammonia. The mixture was concentrated to give the crude (70 mg, crude) as a white solid.

[0594] LCMS (Waters-QDa-02): Rt 0.34 min; [M+1].sup.+=136.9

Step 3: Synthesis of tert-butyl methyl(2-(pyridin-4-yl)ethyl)carbamate

[0595] ##STR00245##

[0596] To a mixture of N-methyl-2-(pyridin-4-yl)ethan-1-amine (280 mg, 2.05 mmol, 1 eq) in DCM (5 mL) were added Boc2 O (493 mg, 2.26 mmol, 1.1 eq), TEA (416 mg, 4.1 mmol, 2.0 eq) and DMAP (25 mg, 0.2 mmol, 0.1 eq). After stirring at room temperature for 16 h, the reaction mixture was concentrated under reduced pressure to give a crude, the crude was purification by prep.TLC (DCM/MeOH=20:1, v/v) to give the desired product (88 mg, 2.05 mmol, 16%) as a white solid.

[0597] LCMS (Waters-QDa-02): Rt 0.55 min; [M+1].sup.+=236.7

Step 4: Synthesis of N-methyl-2-(pyridin-4-yl)ethan-1-amine

[0598] ##STR00246##

[0599] To a solution of tert-butyl methyl(2-(pyridin-4-yl)ethyl)carbamate (88 g, 0.37 mmol, 1 eq) in dioxane (1 mL) was added HCl/dioxane (2 mL). The reaction concentrated to give the desired product (80 mg crude).

[0600] LCMS (Waters-QDa-02): Rt 0.34 min; [M+1]+=136.9

Step 5: Synthesis of 3-(4-(2-isopropoxypropan-2-yl)thiazol-2-yl)-1-methyl-1-(2-(pyridin-4-yl)ethyl)urea

[0601] ##STR00247##

[0602] To a solution of N-methyl-2-(pyridin-4-yl)ethan-1-amine (80 mg crude, 0.58 mmol, 1.5 eq) in DCM (5 mL) were added Triphosgene (68 mg, 0.22 mmol, 0.5 eq) and DMAP (270 mg, 1.47 mmol, 3.2 eq). The reaction mixture was stirred at 0? C. for 2 h. 4-(2-isopropoxypropan-2-yl)thiazol-2-amine (80 mg, 0.58 mmol, 1 eq) was added to the solution. The reaction mixture was stirred at room temperature for 16 h. The solution was concentrated to give a crude, the crude was purification by prep.TLC (DCM/MeOH=10:1, v/v) to give the desired product (60 mg, 0.58 mmol, 36%) as a white solid.

[0603] LCMS (Agilent-1290): Rt: 1.95 min, m/z [M+1]+=363.2

[0604] HNMR (400 MHz, DMSO-d6): ? ppm: 10.69 (s, 1H), 8.45-8.44 (s, 2H), 7.30-7.28 (m, 2H), 6.83 (s, 1H), 3.62-3.56 (m, 3H), 2.94 (s, 3H), 2.84-2.80 (m, 2H), 1.45 (s, 6H), 0.91-0.90 (m, 6H).

[0605] HPLC (Agilent-1200-A2): Rt: 8.54 min, 99% purity.

Synthesis of Compound 21

[0606] ##STR00248##

Step 1: Synthesis of 2-(pyridin-4-yl)ethyl (4-(2-isopropoxypropan-2-yl)thiazol-2-yl)carbamate

[0607] ##STR00249##

[0608] To a solution of 4-(2-isopropoxypropan-2-yl)thiazol-2-amine (100 mg, 0.49 mmol, 1 eq) in DCM (5 mL) were added Triphosgene (74 mg, 0.24 mmol, 0.5 eq), DMAP (195 mg, 1.59 mmol, 3.2 eq) at 0? C. The solution was stirred at 0? C. for 2 h. 2-(pyridin-4-yl)ethan-1-ol (61 mg, 0.49 mmol, 1 eq) was added to the solution. After stirring at room temperature for 16 h. The solution was extracted with DCM (3 mL?3), washed with water (5 mL?3), brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated to give a crude, the crude was purification by prep.TLC (DCM/MeOH=20:1, v/v) to give the desired product (100 mg, 0.49 mmol, 57%) as a white solid.

[0609] LCMS (Agilent-1290): Rt: 2.15 min, m/z [M+1]+=350.1

[0610] HNMR (400 MHz, DMSO-d6): ? ppm: 11.77 (s, 1H), 8.48-8.46 (m, 2H), 7.34-7.32 (m, 2H), 6.98 (s, 1H), 4.39-4.35 (m, 2H), 3.61-3.53 (m, 1H), 2.7-2.94 (m, 2H), 1.43 (s, 6H), 0.90-0.89 (m, 6H).

[0611] HPLC (Agilent-1200-A2): Rt: 8.65 min, 96% purity.

Synthesis of Compound 22

[0612] ##STR00250##

Step 1: Synthesis of (4-((4-(2-isopropoxypropan-2-yl)thiazol-2-yl)amino)phenyl)(phenyl)methanone

[0613] ##STR00251##

[0614] To a solution of 4-(2-isopropoxypropan-2-yl)thiazol-2-amine (50 mg, 0.25 mmol, 1 eq) in dioxane (5 mL) were added (4-bromophenyl)(phenyl)methanone (65 mg, 0.25 mmol, 1 eq), Pd2(dba).sub.3 (26 mg, 0.025 mmol, 0.1 eq), xantphos (29 mg, 0.05 mmol, 0.2 eq) and Cs.sub.2CO.sub.3 (244 mg, 0.75 mmol, 3 eq). The solution was stirred at 100? C. for 16 h. The reaction was concentrated to give a crude, the crude was purified by prep.TLC (DCM/MeOH=10/1, v/v) to give the desired product (15 mg, 0.03 mmol, 15%) as a yellow solid.

[0615] LCMS (Agilent-1290): Rt: 4.13 min, m/z [M+1]+=381.1

[0616] HNMR (400 MHz, DMSO-d6): ? ppm: 10.66 (s, 1H), 7.80-7.52 (m, 9H), 6.85 (s, 1H), 3.72-3.63 (m, 1H), 1.49 (s, 6H), 0.95-0.94 (m, 6H).

[0617] HPLC (Agilent-1200-A2): Rt: 8.64 min, 100% purity.

Synthesis of Compound 23

[0618] ##STR00252##

Step 1: Synthesis of (R)-1-(4-benzoylphenyl)-3-(4-(1-phenylpyrrolidin-2-yl)thiazol-2-yl)urea

[0619] ##STR00253##

[0620] To a solution of (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (100 mg, 0.4 mmol, 1 eq) in DCM (3 mL) were added Triphosgene (60 mg, 0.2 mmol, 0.5 eq), DMAP (159 mg, 1.3 mmol, 3.2 eq) at 0? C. The solution was stirred at 0? C. for 2 h. (4-aminophenyl)(phenyl)methanone (80 mg, 0.4 mmol, 1 eq) was added to the solution. After stirring at room temperature for 16 h. The solution was extracted with DCM (5 mL?3), washed with water (5 mL?3), brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated to give a crude, the crude was purification by prep.TLC (DCM/MeOH=20:1, v/v) to give the desired product (26 mg, 0.055 mmol, 13%) as a white solid.

[0621] LCMS (Agilent-1290): Rt: 4.20 min, m/z [M+1]+=469.2/470.2

[0622] HNMR (400 MHz, DMSO-d6): ? ppm: 10.64 (s, 1H), 9.34 (s, 1H), 7.76-7.63 (m, 8H), 7.57-7.53 (m, 2H), 7.12-7.08 (m, 2H), 6.66 (s, 1H), 6.57-6.54 (m, 1H), 6.51-6.49 (m, 2H), 4.74-4.72 (m, 1H), 3.59-3.55 (m, 1H), 3.27-3.23 (m, 1H), 2.26-2.22 (m, 1H), 2.09-1.97 (m, 3H).

[0623] HPLC (Agilent-1200-A2): Rt: 14.93 min, 95% purity.

Synthesis of Compound 24

[0624] ##STR00254##

Step 1: Synthesis of methyl 1-(2-(pyridin-4-yl)ethyl)-1H-pyrazole-5-carboxylate

[0625] ##STR00255##

[0626] To a solution of 2-(pyridin-4-yl)ethan-1-ol (500 mg, 4.06 mmol, 1 eq) and in dry THE (10 mL) were added methyl 1H-pyrazole-5-carboxylate (500 mg, 4.06 mmol, 1 eq), PPh3 (1.59 g, 6.09 mmol, 1.5 eq) and DIAD (820 mg, 6.09 mmol, 1.5 eq). After stirring at room temperature for 5 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column (DCM/MeOH=100/1, v/v) to give a mixture of desired product (930 mg, 4.06 mmol, 99% yield) as a yellow oil.

[0627] LCMS (Waters-QDa-02): Rt 1.90 min; [M+1].sup.+=231.9

Step 2: Synthesis of 1-(2-(pyridin-4-yl)ethyl)-1H-pyrazole-5-carboxylic acid

[0628] ##STR00256##

[0629] To a solution of methyl 1-(2-(pyridin-4-yl)ethyl)-1H-pyrazole-5-carboxylate (930 mg, 4 mmol, 1 eq) in MeOH (9 mL) and H.sub.2O (3 ml) was added LiOH (193 mg, 2 mmol, 2 eq). After stirring at room temperature for 2 h, the reaction mixture was adjusted PH to 1-2, by HCl aqueous solution (3 M) and concentrated to give the desired product (868 mg, 4 mmol, 100% yield) as a yellow oil.

[0630] LCMS (Waters-QDa-02): Rt 1.90 min; [M+1].sup.+=217.9

Step 3: Synthesis of N-(4-(2-isopropoxypropan-2-yl)thiazol-2-yl)-1-(2-(pyridin-4-yl)ethyl)-1H-pyrazole-5-carboxamide

[0631] ##STR00257##

[0632] To a mixture of 1-(2-(pyridin-4-yl)ethyl)-1H-pyrazole-5-carboxylic acid (216 mg, 0.99 mmol, 2 eq) in DMA (3 mL) were added 4-(2-isopropoxypropan-2-yl)thiazol-2-amine (100 mg, 0.49 mmol, 1 eq), EDCI (143 mg, 0.74 mmol, 1.5 eq) and DMAP (152 mg, 1.24 mmol, 2.5 eq). After stirring at 100? C. for 3 h in microwave, the reaction mixture was extracted with EtOAc (5 mL?3), washed with water (5 mL?3), brine (5 ml), dried over NaSO3 and concentrated to give a crude, the crude was purification with prep.TLC (DCM/MeOH=10:1, v/v) to give the desired product (29 mg, 0.49 mmol, 14%) as a yellow solid.

[0633] LCMS (Agilent-1290): Rt: 2.29 min, m/z [M+1]+=400.2

[0634] HNMR (400 MHz, DMSO-d6): ? ppm: 12.65 (s, 1H), 8.41-8.39 (m, 2H), 7.56 (s, 1H), 7.35-7.34 (m, 1H), 7.16-7.11 (m, 3H), 4.85-4.81 (m, 2H), 3.65-3.59 (m, 1H), 3.13-3.10 (m, 2H), 1.50 (s, 6H), 0.93-0.92 (m, 6H).

[0635] HPLC (Agilent-1200-A2): Rt: 6.41 min, 94% purity.

Synthesis of Compound 25

[0636] ##STR00258##

Step 1: Synthesis of 7-bromo-1-(pyridin-4-ylmethyl)-1H-pyrrolo[2,3-c]pyridine

[0637] ##STR00259##

[0638] To a solution of 7-bromo-1H-pyrrolo[2,3-c]pyridine (100 mg, 0.5 mmol, 1 eq) in DMF (5 mL) were added 4-(bromomethyl)pyridine (129 mg, 0.5 mmol, 1 eq) and Cs.sub.2CO.sub.3 (498 mg, 1.5 mmol, 3.0 eq). After stirring at room temperature for 16 h, the reaction was extracted with EtOAc (5 mL?3), washed with water (5 mL?3), brine (5 ml), dried over NaSO.sub.4 and concentrated to give a crude, the crude was purified by prep.TLC (PE/EtOAc=1/1, v/v) to give the desired product (110 mg, 0.5 mmol, 76%) as a white oil.

[0639] LCMS (Waters-QDa-02): Rt 1.80 min; [M+1].sup.+=288.1/290.2

Step 2: Synthesis of 4-(2-isopropoxypropan-2-yl)-N-(1-(pyridin-4-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)thiazol-2-amine

[0640] ##STR00260##

[0641] To a solution of 7-bromo-1-(pyridin-4-ylmethyl)-1H-pyrrolo[2,3-c]pyridine (110 mg, 0.38 mmol, 1 eq) in dioxane (5 mL) were added 4-(2-isopropoxypropan-2-yl)thiazol-2-amine (76 mg, 0.38 mmol, 1 eq), Pd2(dba).sub.3 (39 mg, 0.03 mmol, 0.1 eq), xantphos (44 mg, 0.06 mmol, 0.2 eq) and Cs.sub.2CO.sub.3 (374 mg, 1.14 mmol, 3.0 eq). After stirring at 100? C. for 16 h, the reaction mixture was concentrated in vacuo. The residue was purified by prep.TLC (DCM/MeOH=10/1, v/v) to give the desired product (107 mg, 0.38 mmol, 69%) as a white solid.

[0642] LCMS (SHIMADZU-2020-P2): Rt: 3.15 min, m/z [M+1]+=408.2

[0643] HNMR (400 MHz, DMSO-d6): ? ppm: 13.95 (s, 1H), 8.46 (s, 2H), 7.67 (s, 1H), 7.47 (s, 1H), 7.07 (s, 2H), 6.84 (s, 1.5H), 6.52 (s, 1H), 5.98 (s, 2H), 3.65 (s, 1H), 1.49 (s, 6H), 0.96 (s, 6H).

[0644] HPLC (Agilent-1200-A2): Rt: 8.19 min, 95% purity.

Synthesis of Compound 26

[0645] ##STR00261##

Step 1: N-(4-(pyridin-2-yl)thiazol-2-yl)-1-(pyridin-4-ylmethyl)-1H-pyrrole-2-carboxamide

[0646] ##STR00262##

[0647] To a solution of 4-(pyridin-2-yl)thiazol-2-amine (200 mg, 1.13 mmol, 1 eq) in DMA (3 mL) were added 1-(pyridin-4-ylmethyl)-1H-pyrrole-2-carboxylic acid (295 mg, 1.24 mmol, 1.1 eq), EDCI (324 mg, 1.69 mmol, 1.5 eq) and DMAP (414 mg, 3.39 mmol, 3.0 eq). After stirring at 100? C. for 1 h in microwave, the reaction was extracted with EtOAc (5 mL?3), washed with water (5 mL?3), brine (5 ml), dried over NaSO4 and concentrated to give a crude, the crude was purified by prep.TLC (DCM/MeOH=10/1, v/v) to give the desired product (20 mg, 1.13 mmol, 4.9%) as a white solid.

[0648] LCMS (Agilent-1290): Rt: 2.05 min, m/z [M+1].sup.+=362.2/363.2

[0649] HNMR (400 MHz, DMSO-d6): ? ppm: 12.35 (s, 1H), 8.60-8.58 (m, 1H), 8.49-8.47 (m, 2H), 8.13 (s, 1.5H), 8.00-7.98 (m, 1H), 7.89-7.85 (m, 1H), 7.77 (s, 1H), 7.57-7.55 (m, 1H), 7.35-7.30 (m, 2H), 6.98-6.97 (m, 2H), 6.30-6.29 (m, 1H), 5.70 (s, 2H).

[0650] HPLC (Agilent-1200-A2): Rt: 7.78 min, 98% purity.

Synthesis of Compound 27

[0651] ##STR00263##

Synthesis of methyl 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrrole-2-carboxylate

[0652] ##STR00264##

[0653] To a solution of 4-(chloromethyl)-3,5-dimethylisoxazole (2 g, 0.014 mol, 1 eq) in CH.sub.3CN (30 mL) were added methyl 1H-pyrrole-2-carboxylate (1.9 g, 0.015 mol, 1.1 eq) and Cs.sub.2CO.sub.3 (13.5 g, 0.042 mol, 3 eq) at RT. After stirring at 90? C. for 16 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column (PE/EtOAc=2/1, v/v) to give a mixture of desired product (2 g, 0.014 mol, 62%) as a white solid.

[0654] LCMS (Waters-QDa-02): Rt 1.89 min; [M+1].sup.+=235.0

Step 2: Synthesis of 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrrole-2-carboxylic acid

[0655] ##STR00265##

[0656] To a solution of methyl 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrrole-2-carboxylate (1 g, 0.0043 mol, 1 eq) in MeOH (12 mL) and H.sub.2 (4 mL) was added LiOH (305 mg, 0.0129 mmol, 3 eq). After stirring at room temperature for 4 h, the reaction mixture was acid adjustment, and extracted with EtOAc (5 mL?3), washed with water (5 mL?3), brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo give the desired product (400 mg, 0.0043 mol, 44%) as a yellow solid.

[0657] LCMS (Water-QDa-02): Rt 1.34 min; [M+1].sup.+=221.1

Step 3: Synthesis of 1-((3,5-dimethylisoxazol-4-yl)methyl)-N-(4-(2-isopropoxypropan-2-yl)thiazol-2-yl)-1H-pyrrole-2-carboxamide

[0658] ##STR00266##

[0659] To a mixture of 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrrole-2-carboxylic acid (165 mg, 0.75 mmol, 1.5 eq) in DMA (3 mL) were added 4-(2-isopropoxypropan-2-yl)thiazol-2-amine (100 mg, 0.5 mmol, 1 eq) and EDCI (144 mg, 0.75 mmol, 1.5 eq) and DMAP (153 mg, 1.25 mmol, 2.5 eq). After stirring at 100? C. for 3 h in microwave, the reaction mixture was extracted with EtOAc (5 mL?3), washed with water (5 mL?3), brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by prep.TLC (DCM/MeOH=10/1, v/v) to give the desired product (50 mg, 0.75 mmol, 25%) as a white oil.

[0660] LCMS (Agilent-1290): Rt: 3.62 min, m/z [M+1].sup.+=403.1.

[0661] HNMR (400 MHz, DMSO-d6): ? ppm: 12.18 (s, 1H), 7.39-7.38 (m, 1H), 7.20-7.19 (m, 1H), 7.00 (s, 1H), 6.17-6.15 (d, J=8 Hz, 1H), 5.41 (s, 2H), 3.65-3.56 (m, 1H), 2.26 (s, 3H), 1.99 (s, 3H), 1.48 (s, 6H), 0.92-0.91 (d, J=4 Hz, 6H).

[0662] HPLC (Agilent-1200-A2): Rt: 13.71 min, 99% purity.

Synthesis of Compound 28

[0663] ##STR00267##

Step 1

[0664] ##STR00268##

[0665] A 20 mL vial with stir bar was charged with cyclopropanol (86.4 ?L, 4 eq., 1.36 mmol) in tetrahydrofuran (3 mL, 0.11 M). Sodium hydride 60% w/w (55.9 mg, 4.1 eq., 1.4 mmol) was added to the reaction mixture at 0? C. and stirred at room temperature for 30 minutes. After 30 minutes, tert-butyl N-[4-(bromomethyl)-1,3-thiazol-2-yl]carbamate (0.1 g, 1 eq., 341 ?mol) was added to the reaction mixture at 0? C., and stirred at room temperature overnight. The reaction mixture was diluted with saturated aqueous NH.sub.4Cl (5 mL), extracted with EtOAc (5 mL?3), and washed with brine. The organic layers were dried over MgSO.sub.4, filtered, and concentrated in vacuo. The crude material was purified via normal-phase silica gel chromatography (0-100% EtOAc in hexanes) to give the desired product (63 mg, 68% yield). LCMS (+ESI): calc. [M+H]+=271; found 271.

Step 2

[0666] ##STR00269##

[0667] An 8 mL vial with stir bar was charged with tert-butyl N-[4-(cyclopropoxymethyl)-1,3-thiazol-2-yl]carbamate (63 mg, 1 eq., 233 ?mol) and DCM (2 mL, 0.12 M). Trifluoroacetic acid (0.5 mL, 28 eq., 6.53 mmol) was added and the reaction mixture stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo to give the desired product, assuming quantitative yield (66 mg, 100% yield). LCMS (+ESI): calc. [M+H]+=171; found 171.

Step 3

[0668] ##STR00270##

[0669] A 4 ml vial with stir bar was charged with 1-[(pyridin-4-yl)methyl]-1H-pyrrole-2-carboxylic acid (39 mg, 1 eq., 193 ?mol), 4-(cyclopropoxymethyl)-1,3-thiazol-2-amine; trifluoroacetic acid (66 mg, 1.2 eq., 231 ?mol), 4-(dimethylamino)pyridin-1-ium (95 mg, 4 eq., 771 ?mol), ({[3-(dimethylamino)propyl]imino}methylidene)(ethyl)amine hydrochloride (55.5 mg, 1.5 eq., 289 ?mol), and dimethylacetamide (750 ?L, 0.26 M). The reaction mixture was stirred at 80? C. for 3 hours. The crude reaction mixture was purified directly via C.sub.18 reverse-phase silica gel chromatography (0-100% ACN in water) to give the desired product (12.5 mg, 18% yield). LCMS (+ESI): calc. [M+H]+=355; found 355.

Synthesis of Compound 29

[0670] ##STR00271##

Step 1: 2-(pyridin-4-yl)ethyl (4-(2-isopropoxypropan-2-yl)thiazol-2-yl)carbamate

[0671] ##STR00272##

[0672] To a solution of 4-(2-isopropoxypropan-2-yl)thiazol-2-amine (100 mg, 0.49 mmol, 1 eq) in DCM (5 mL) were added Triphosgene (74 mg, 0.24 mmol, 0.5 eq), DMAP (195 mg, 1.59 mmol, 3.2 eq) at 0? C. The solution was stirred at 0? C. for 2 h. 2-(pyridin-4-yl)ethan-1-ol (61 mg, 0.49 mmol, 1 eq) was added to the solution. After stirring at room temperature for 16 h. The solution was extracted with DCM (3 mL?3), washed with water (5 mL?3), brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated to give a crude, the crude was purification by prep.TLC (DCM/MeOH=20:1, v/v) to give the desired product (100 mg, 0.49 mmol, 57%) as a white solid.

LCMS (Agilent-1290): Rt: 2.15 min, m/z [M+1]+=350.1

HNMR (400 MHz, DMSO-d6): ? ppm: 11.77 (s, 1H), 8.48-8.46 (m, 2H), 7.34-7.32 (m, 2H), 6.98 (s, 1H), 4.39-4.35 (m, 2H), 3.61-3.53 (m, 1H), 2.7-2.94 (m, 2H), 1.43 (s, 6H), 0.90-0.89 (m, 6H).

[0673] HPLC (Agilent-1200-A2): Rt: 8.65 min, 96% purity.

Synthesis of Compounds 48 and 49

Intermediate 1-2

[0674] ##STR00273##

Step 1: methyl 4-fluoro-1-(pyridin-4-ylmethyl)-1H-pyrrole-2-carboxylate

[0675] ##STR00274##

[0676] To a solution of methyl 4-fluoro-1H-pyrrole-2-carboxylate (2 g, 14 mmol, 1 eq) in THE (20 mL) was slowly added NaH (60%, 1.7 g, 42 mmol, 3 eq) at 0? C. under N.sub.2. The mixture was stirred at r. t. for 1 h. 4-(bromomethyl)pyridine hydrobromide (7.1 g, 28 mmol, 2 eq) was added and reaction mixture was stirred at RT overnight. The reaction mixture was adjusted to pH=5 with HCl and concentrated under reduced pressure. The residue was purified by silica gel column (DCM/MeOH=20/1, v/v) to give the product (1.6 g, 50%) as a brown solid.

[0677] LCMS (Waters-QDa-02): Rt 0.93 min; [M+1].sup.+=235.0

Step 2: 4-fluoro-1-(pyridin-4-ylmethyl)-1H-pyrrole-2-carboxylic acid

[0678] ##STR00275##

[0679] To a solution of methyl 4-fluoro-1-(pyridin-4-ylmethyl)-1H-pyrrole-2-carboxylate (900 mg, 3.84 mmol, 1 eq) in MeOH (4.5 mL) and H.sub.2 (2 mL) was added NaOH (306 mg, 7.68 mmol, 2 eq). After stirring at 35? C. for 4 h, the reaction mixture was acid adjustment, and concentrated in vacuo give the desired product (1400 mg, contain NaCl) as a yellow solid.

[0680] LCMS (Water-QDa-02): Rt 0.81 min; [M+1].sup.+=221

Intermediate 2-2

[0681] ##STR00276##

Step 1: 3-Bromo-1,2,4-thiadiazol-5-amine

[0682] ##STR00277##

[0683] To a solution of 3-bromo-5-chloro-1,2,4-thiadiazole (5 g, 25.1 mmol, 1 eq) in ethanol (15 mL) was added 28% (w/w) ammonia aqueous solution (3.4 mL, 50.1 mmol, 2 eq). The mixture was stirred at 70? C. for 3 h. The reaction mixture was cooled to room temperature, and sodium hydrogen carbonate aqueous solution was added to the mixture. The precipitate was filtered, and the resulting solid was washed with water and dried to afford compound 2-1 (3.8 g, yield:84.4%) as a white solid.

[0684] LCMS (Water-QDa-02): Rt 0.89 min; [M+1].sup.+=181

Step 2: tert-butyl (3-bromo-1,2,4-thiadiazol-5-yl)carbamate

[0685] ##STR00278##

[0686] To a solution of compound 2-1 (3.8 g 13.5 mmol, 1 eq) in THE (38 mL) were added N,N-dimethyl-4-aminopyridine (82.5 mg, 0.675 mmol, 0.05 eq), di-tert-butyl dicarbonate (3.7 mL, 16.2 mmol, 1.2 eq), and the mixture was stirred at 50? C. for 1 hour. The reaction mixture was evaporated, and to the residue was added dichloromethane-methanol. The insoluble matter in the solution was filtered, the filtrate was evaporated, and the residue was purified by silica-gel column chromatography (PE:EA=10:1) to give compound 2-2 (4.7 g yield:79.6%) as a white solid.

[0687] LCMS (Water-QDa-02): Rt 1.25; [M?1].sup.+=279

Compound 49

[0688] ##STR00279##

Step 1: tert-butyl (E)-(3-styryl-1,2,4-thiadiazol-5-yl)carbamate

[0689] ##STR00280##

[0690] To a solution of tert-butyl (3-bromo-1,2,4-thiadiazol-5-yl)carbamate (200 mg, 0.714 mmol, 1 eq) in H.sub.2O (0.4 mL) and 1,4-dioxane (2 mL) were added (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (492 mg, 2.142 mmol, 3 eq), K.sub.2CO.sub.3 (296 mg, 2.142 mmol, 3 eq), and Pd(dppf)Cl.sub.2 (51 mg, 0.071 mmol, 0.1 eq). The mixture was stirred at 100? C. by microwave under a N.sub.2 atmosphere for 3 h. The reaction mixture was extracted with EtOAc (5 mL?3), washed with water (5 mL?3), brine (5 mL), dried over Na.sub.2SO.sub.4, concentrated in vacuo and purified by revered phase column to give the desired product (145 mg, 0.478 mmol, 67%) as a white solid.

[0691] LCMS (Agilent-1290): Rt 2.578 min; [M+1].sup.+=304.

Step 2: (E)-3-styryl-1,2,4-thiadiazol-5-amine

[0692] ##STR00281##

[0693] To a solution of tert-butyl (E)-(3-styryl-1,2,4-thiadiazol-5-yl)carbamate (145 mg, 0.478 mmol, 1 eq) in DCM (1.8 mL) was added TFA (1.8 mL) at 0? C. The mixture was stirred at room temperature for 3 h. The reaction mixture was basified by Na.sub.2CO.sub.3 solution, and extracted with EtOAc (5 mL?3), washed with water (5 mL?3), brine (5 mL), dried over Na.sub.2SO.sub.4, concentrated in vacuo and purified by Prep.TLC (DCM/MeOH=20/1, v/v) to give the desired product (52 mg, 0.256 mmol, 54%) as a white solid.

[0694] LCMS (Agilent-1290): Rt 1.514 min; [M+1].sup.+=204.

Step 3: (E)-4-fluoro-1-(pyridin-4-ylmethyl)-N-(3-styryl-1,2,4-thiadiazol-5-yl)-1H-pyrrole-2-carboxamide

[0695] ##STR00282##

[0696] To a solution of (E)-3-styryl-1,2,4-thiadiazol-5-amine (52 mg, 0.256 mmol, 1 eq) in DMA (1 mL) were added 4-fluoro-1-(pyridin-4-ylmethyl)-1H-pyrrole-2-carboxylic acid (113 mg, 0.512 mmol, 2 eq), EDCI (81 mg, 0.512 mmol, 2 eq) and DMAP (63 mg, 0.512 mmol, 2 eq). The mixture was stirred at 100? C. by microwave for 3 h. The reaction mixture was extracted with EtOAc (5 mL?3), washed with water (5 mL?3), brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by prep.TLC (DCM/MeOH=20/1, v/v) to give the desired product (10 mg, 0.025 mmol, 9.6%) as a white solid.

[0697] LCMS (Agilent-1290): Rt: 1.750 min, m/z [M+1].sup.+=406.

[0698] HNMR (400 MHz, DMSO-d6): ? 8.49 (d, J=5.0 Hz, 2H), 7.69-7.58 (m, 3H), 7.41 (t, J=7.4 Hz, 2H), 7.35 (d, J=7.2 Hz, 1H), 7.30 (s, 1H), 7.20 (d, J=11.3 Hz, 2H), 7.03 (d, J=4.9 Hz, 2H), 5.71 (s, 2H).

[0699] HPLC (Agilent-1200-A2): Rt: 10.649 min, 96.1% purity.

Synthesis of Compound 48

[0700] ##STR00283##

Step 1: tert-butyl (3-(4-methylpiperazin-1-yl)-1,2,4-thiadiazol-5-yl)carbamate

[0701] ##STR00284##

[0702] A solution of tert-butyl (3-bromo-1,2,4-thiadiazol-5-yl)carbamate (500 mg, 1.785 mmol, 1 eq) in 1-methylpiperazine (5 mL) was heated at 120? C. for 16 h. The reaction mixture was extracted with EtOAc (5 mL?3), washed with water (5 mL?3), brine (5 mL), dried over Na.sub.2SO.sub.4, concentrated in vacuo and purified by silica gel column (DCM/MeOH=20/1, v/v) to give the desired product (230 mg, 0.769 mmol, 43%) as a white solid.

[0703] LCMS (Agilent-1290): Rt 0.831 min; [M+1].sup.+=300.

Step 2: 3-(4-methylpiperazin-1-yl)-1,2,4-thiadiazol-5-amine

[0704] ##STR00285##

[0705] To a solution of tert-butyl (3-(4-methylpiperazin-1-yl)-1,2,4-thiadiazol-5-yl)carbamate (230 mg, 0.769 mmol, 1 eq) in DCM (2 mL) was added TFA (2 mL) at 0? C. The mixture was stirred at room temperature for 3 h, the reaction mixture was basified by Na.sub.2CO.sub.3 solution and extracted with EtOAc (5 mL?3), washed with water (5 mL?3), brine (5 mL), dried over Na.sub.2SO.sub.4, and concentrated in vacuo to give the desired product (90 mg, 0.452 mmol, 59%) as a white solid.

[0706] LCMS (Agilent-1290): Rt 1.500 min; [M+1].sup.+=200.

Step 3: 4-fluoro-N-(3-(4-methylpiperazin-1-yl)-1,2,4-thiadiazol-5-yl)-1-(pyridin-4-ylmethyl)-1H-pyrrole-2-carboxamide

[0707] ##STR00286##

[0708] To a solution of 3-(4-methylpiperazin-1-yl)-1,2,4-thiadiazol-5-amine (90 mg, 0.452 mmol, 1 eq) in NMP (1 mL) were added 4-fluoro-1-(pyridin-4-ylmethyl)-1H-pyrrole-2-carboxylic acid (198 mg, 0.903 mmol, 2 eq), HATU (343 mg, 0.903 mmol, 2 eq) and DIEA (175 mg, 1.354 mmol, 3 eq). The mixture was stirred at 130? C. by microwave for 2 h. The reaction mixture was extracted with EtOAc (5 mL?3), washed with water (5 mL?3), brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by prep.TLC (DCM/MeOH=10/1, v/v) to give the desired product (5 mg, 0.012 mmol, 2.8%) as a yellow solid.

[0709] LCMS (Agilent-1290): Rt: 0.922 min, m/z [M+1].sup.+=402.

[0710] HNMR (400 MHz, DMSO-d6): ? 8.60-8.38 (m, 2H), 7.43-7.32 (m, 2H), 7.00 (d, J=4.9 Hz, 2H), 5.61 (s, 2H), 3.51 (d, J=5.1 Hz, 4H), 2.37 (t, J=5.0 Hz, 4H), 2.20 (s, 3H).

[0711] HPLC (Agilent-1200-A3): Rt: 8.290 min, 96.8% purity.

Synthesis of Compound 37

[0712] ##STR00287##

[0713] A mixture of 1-[(pyridin-4-yl)methyl]-1H-pyrrole-2-carboxylic acid (50 mg, 247 ?mol), 3-tert-butyl-1H-1,2,4-triazol-5-amine (30 mg, 214 ?mol) N-(3-tert-butyl-1H-1,2,4-triazol-5-yl)-1-[(pyridin-4-yl)methyl]-1H-pyrrole-2-carboxamide (55 mg, 170 ?mol), and EDCI (57.6 mg, 1.5 eq., 371 ?mol) in dimethylacetamide (578 ?L, 6.21 mmol) was heated at 80? C. for 24 hour. The reaction mixture was diluted with methanol and the product precipitated as a yellow solid, which was collected by filtration. LCMS [M+H]+ expected=362.4. Found=362.0

Synthesis of Compound 50

[0714] ##STR00288##

[0715] A mixture of 1-[(pyridin-4-yl)methyl]-1H-pyrrole-2-carboxylic acid (50 mg, 247 ?mol), 3-tert-butyl-1,2,4-thiadiazol-5-amine (38.9 mg, 247 ?mol) N-(3-tert-butyl-1H- and EDCI (57.6 mg, 1.5 eq., 371 ?mol) and 4-(dimethylamino)pyridin-1-ium (60.9 mg, 2 eq., 495 ?mol) in dimethylacetamide (578 ?L, 6.21 mmol) was heated at 80? C. for 24 hour. The reaction mixture was subjected directly to chromatography C.sub.18, ISCO, 5-95 ACN/water. LCMS [M+H]+ expected=342.4. Found=342.0

Example 2. Identifying Molecules that Inhibit PrP Synthesis

[0716] Flp-In 293 T-Rex? cells are transfected with pcDNATM5/FRT/TO plasmid inserted with cDNA encoding Prion protein signal sequence plus 10 amino acids (PrionSS) fused to Gaussia Luciferase (GLuc) (SEQ ID NO: 1). Transfected cells are selected for resistance to the selectable markers Hygromycin and Blasticidin to create a stable cell line that contains the PrionSS-GLuc cDNA insert whose expression is regulated under the T-Rex? system. The day before assay, cells are trypsinized and plated in 384-well tissue culture plates. The next day, compound dilutions in DMSO/media containing doxycycline are added to the wells and incubated at 37? C., 5% CO2. 24 hours later, coelenterazine substrate is added to each well and luciferase signal is quantified using Tecan Infinite M1000 Pro for potency determination.

[0717] Treatment with compound reduces the amount of PrionSS-GLuc protein expressed as measured by reduced luminescence, which indicates that the compound inhibits the secretion of, and thus the biosynthesis of, Prion protein.

[0718] The sequence of the PrionSS-Gluc insert is SE ID NO: 1):

TABLE-US-00005 MANLGCWMLVLFVATWSDLGLCKKRPKPGGWNKPTENNEDFNIVAVASN FATTDLDADRGKLPGKKLPLEVLKEMEANARKAGCTRGCLICLSHIKCT PKMKKFIPGRCHTYEGDKESAQGGIGEAIVDIPEIPGFKDLEPMEQFIA QVDLCVDCTTGCLKGLANVQCSDLLKKWLPQRCATFASKIQGQVDKIKG AGGD

Example 3. HiBit Assay for Quantifying Potency of Protein Secretion Inhibitors

[0719] The assay utilized the T-REx?-293 Cell Line, which constitutively expressed the TetR protein, and a plasmid-based transfection, where the signal peptide (SP) for Prion protein (PRP)+10 amino acids form the mature domain (MANLGCWMLVLFVATWSDLGLCKKRPKPGG SEQ ID NO: 2) in-frame with HaloTag-Hibit fusion protein under the control by TetO. Cells were maintained at 37? C. at 5% CO.sub.2 for 24 h after transfection with the plasmid, then treated with compounds. At the same time, doxycycline was added, which enabled expression of the SP-HaloTag-HiBit fusion protein that was secreted from the cells. If the chemical molecules tested were active against the SP of Prion translational translocation of the protein was inhibited and expression of the protein was reduced.

[0720] The readout of this assay was the Nano-Glo? HiBiT Extracellular Detection System, a luminescence-based assay where the secreted SP-HaloTag-HiBit fusion protein was quantified by adding a nonlytic detection reagent containing the substrate furimazine and Large BiT (LgBit), the large subunit used for high-affinity binding to HiBit. The HiBit-LgBit-furimazine complex generated a bright, luminescent enzyme. The amount of luminescence generated was proportional to the amount of HiBiT-tagged protein accessible in the medium.

[0721] This assay resulted in a dose response curve for each chemical entity, performed as 3-fold dilutions from 30 ?M to 1M and includes DMSO (no compound=baseline inhibition) and uninduced (no doxycycline) controls, from which an IC50 was be calculated. The assay, as described here, was designed to test compounds in triplicate against Prion protein.

[0722] This assay was modified to test for the inhibition of the secretion of Programmed Cell Death Receptor 1 (PDCD1) and Prion (PRNP). For those experiments, the secretion of SP-HaloTag-HiBit fusion proteins that incorporated the signal peptide+10 amino acids from the mature domain of either PDCD1 or PRNP was measured as described above. The sequence of the SP+10 mature amino acids of PDCD1 was [[MQIPQAPWPVVWAVLQLGWRPGWPLDSPDRPWN (SEQ ID NO:3)]]. The sequence of the SP+10 mature amino acids of PRNP was [[MANLGCWMLVFVATWSDLGLCKKRPKPGGWN (SEQ ID NO: 4)]].

[0723] The results of the HiBit assays are summarized in the tables below.

TABLE-US-00006 HiBit Assay IC.sub.50 for PDCD1 Construct # (?M) 1 ? 2 ? 3 ? 4 ? 5 ? 6 ? 7 ? 8 +++ 9 ? 10 ? 11 ? 12 ? 13 ? 14 ? 15 ? 16 ? 17 ? 18 ? 19 ? 20 ? 21 ? 22 ? 23 ? 24 + 25 +++ 26 ? 27 ? 28 ? 29 ? 30 ? 31 ? 32 ? 33 ? 35 ? 36 ? 37 ++++ 38 + 39 ? 43 ++++ 44 + 45 ? 46 ? 47 ? 48 + 49 ++++ 50 ++++ ++++ stands for <5 ?M; +++ stands for 5-10 ?M; ++ stands for 10-30 ?M; + stands for >30 ?M, and ? stands for no data.

TABLE-US-00007 HiBit Assay IC.sub.50 for PRP Construct # (?M) 1 + 2 + 3 + 4 ++ 5 +++ 6 + 7 ++ 8 ++++ 9 ? 10 ++ 11 + 12 + 13 + 14 + 15 + 16 ? 17 + 18 + 19 + 20 + 21 + 22 + 23 + 24 + 25 ++ 26 ? 27 ? 28 ? 29 ? 30 ? 31 ? 32 ? 33 ? 35 ? 36 ? 37 +++ 38 + 39 ++ 43 +++ 44 + 45 + 46 + 47 + 48 + 49 ++++ 50 ++++ ++++ stands for <5 ?M; +++ stands for 5-10 ?M; ++ stands for 10-30 ?M; + stands for >30 ?M, and ? stands for no data.

Numbered Embodiments

[0724] 1. A compound, or pharmaceutically acceptable salt thereof, having the structure of Formula 1:

##STR00289## [0725] wherein [0726] R.sub.1 is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.7 cycloalkyl, optionally substituted C.sub.2-C.sub.9 heterocycle, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.2-C.sub.9 heteroaryl, C.sub.2-C.sub.9 heteroaryl C.sub.1-C.sub.6 alkyl, or R.sub.a-R.sub.b-R.sub.c, [0727] wherein R.sub.a is optionally substituted C.sub.6-C.sub.10 arylene or optionally substituted C.sub.2-C.sub.9 heteroarylene; [0728] R.sub.b is O or optionally substituted C.sub.1-C.sub.6 alkylene, and [0729] R.sub.c is optionally substituted C.sub.6-C.sub.10 aryl; [0730] Z is absent, optionally substituted C.sub.3-C.sub.10 cycloalkylene, optionally substituted C.sub.2-C.sub.9 heterocyclylene, C.sub.6-C.sub.10 arylene, or optionally substituted C.sub.2-C.sub.9 heteroarylene; [0731] Y is absent, O, or NR.sub.3; [0732] X is absent or optionally substituted C.sub.1-C.sub.6 alkylene; [0733] W is absent, S, O or NR.sub.3; [0734] n is 0 or 1; [0735] A is S, O, NH, or CH; [0736] B is C or N; [0737] R.sub.2 is optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.3-C.sub.7 cycloalkyl, optionally substituted C.sub.2-C.sub.9 heterocycle, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.2-C.sub.9 heteroaryl; optionally substituted C.sub.2-C.sub.9 heteroaryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.7 cycloalkyl C.sub.1-C.sub.6 aryl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, cyano, or has the structure X.sub.1OY.sub.1; [0738] wherein X.sub.1 is optionally substituted C.sub.1-C.sub.6 alkylene, and [0739] Y.sub.1 is optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.8 cycloalkyl, or optionally [0740] substituted C.sub.6-C.sub.10 aryl; and [0741] and [0742] each R.sub.3 is, independently, H or C.sub.1-C.sub.6 alkyl.

[0743] 2. The compound, or pharmaceutically acceptable salt thereof, of embodiment 1: [0744] wherein R.sub.1 is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.7 cycloalkyl, optionally substituted C.sub.2-C.sub.9 heterocycle, optionally substituted C.sub.6-C.sub.10 aryl, or optionally substituted C.sub.2-C.sub.9 heteroaryl; [0745] Z is absent, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, C.sub.6-C.sub.10 aryl, or optionally substituted C.sub.2-C.sub.9 heteroaryl; [0746] Y is absent, O, or NR.sub.3; [0747] X is absent or optionally substituted C.sub.1-C.sub.6 alkylene; [0748] W is absent, S, O or NR.sub.3 [0749] n is 0 or 1; [0750] A is S, O, or CH; [0751] B is C or N; [0752] R.sub.2 is optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.7 cycloalkyl, optionally substituted C.sub.2-C.sub.9 heterocycle, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.2-C.sub.9 heteroaryl; optionally substituted C.sub.2-C.sub.9 heteroaryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.7 cycloalkyl C.sub.1-C.sub.6 aryl, optionally substituted C.sub.6-C.sub.10; and [0753] each R.sub.3 is, independently, H or C.sub.1-C.sub.6 alkyl.

[0754] 3. The compound, or pharmaceutically acceptable salt thereof, of embodiment 1 or 2, wherein n is 1.

[0755] 4. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 3, wherein the compound has the structure of Formula II:

##STR00290##

[0756] 5. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 3, wherein the compound has the structure of Formula III:

##STR00291##

[0757] 6. The compound, or pharmaceutically acceptable salt thereof, of embodiment 1 or 3, wherein the compound has the structure of Formula IV:

##STR00292##

[0758] 7. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 4 to 6, wherein Z is optionally substituted C.sub.6-C.sub.10 aryl, or optionally substituted C.sub.2-C.sub.9 heteroaryl.

[0759] 8. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 7, wherein Y is O or NR.sub.3.

[0760] 9. The compound, or pharmaceutically acceptable salt thereof, of embodiment 8, wherein Y is O.

[0761] 10. The compound, or pharmaceutically acceptable salt thereof, of embodiment 8, wherein Y is NR.sub.3.

[0762] 11. The compound, or pharmaceutically acceptable salt thereof, of embodiment 8, wherein Y is NH.

[0763] 12. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 11, X is optionally substituted C.sub.1-C.sub.6 alkylene.

[0764] 13. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 12, wherein W is S, O or NR.sub.3.

[0765] 14. The compound, or pharmaceutically acceptable salt thereof, of embodiment 13, wherein W is S.

[0766] 15. The compound, or pharmaceutically acceptable salt thereof, of embodiment 13, wherein W is O.

[0767] 16. The compound, or pharmaceutically acceptable salt thereof, of embodiment 13, wherein W is NR.sub.3.

[0768] 17. The compound, or pharmaceutically acceptable salt thereof, of embodiment 16, wherein W is NH.

[0769] 18. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 3, wherein A is S and B is C.

[0770] 19. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 3 or 18, wherein the compound has the structure:

##STR00293## [0771] wherein Y is O or NR.sub.3.

[0772] 20. The compound, or pharmaceutically acceptable salt thereof, of embodiment 19, wherein X is optionally substituted C.sub.1-C.sub.6 alkylene.

[0773] 21. The compound, or pharmaceutically acceptable salt thereof, of embodiments 19 or 20, wherein Y is 0.

[0774] 22. The compound, or pharmaceutically acceptable salt thereof, of embodiment 19 or 20, wherein Y is NR.sub.3.

[0775] 23. The compound, or pharmaceutically acceptable salt thereof, of embodiment 22, wherein Y is NH.

[0776] 24. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 3 or 18, wherein the compound has the structure of Formula VI:

##STR00294## [0777] wherein W is NR.sub.3.

[0778] 25. The compound, or pharmaceutically acceptable salt thereof, of embodiment 24, wherein X is optionally substituted C.sub.1-C.sub.6 alkylene.

[0779] 26. The compound, or pharmaceutically acceptable salt thereof, of embodiment 24 or 25, wherein W is NH.

[0780] 27. The compound, or pharmaceutically acceptable salt thereof, of embodiment 1 or 2, wherein n is 0.

[0781] 28. The compound, or pharmaceutically acceptable salt thereof, of embodiment 27, wherein A is S and B is C.

[0782] 29. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 6, 8 to 18, 27, or 28, wherein Z is optionally substituted phenylene, optionally substituted pyridinylene, optionally substituted pyrimidinylene, optionally substituted pyridazinylene, optionally substituted pyrazinylene, optionally substituted triazinylene, optionally substituted tetrazinylene, optionally substituted thiophenylene, optionally substituted pyrrolylene, optionally substituted furanylene, optionally substituted pyrazolylene, optionally substituted thiazolylene, optionally substituted oxadiazolylene, optionally substituted thiadiazolylene, optionally substituted isoxazolylene, optionally substituted isothiazolylene, optionally substituted thiazolylene, optionally substituted oxazolylene, optionally substituted imidazolylene, optionally substituted cyclohexylene, optionally substituted cyclopentylene, optionally substituted cyclobutylene, optionally substituted cyclopropylene, optionally substituted cycloheptylene, optionally substituted cyclooctylene, optionally substituted indolylene, or optionally substituted azaindolylene.

[0783] 30. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 18, or 27 to 29, wherein Z has the structure of Formula VIIi:

##STR00295## [0784] wherein A, B, C and D are, each, independently, N, CH, or CR.sub.4; and [0785] each R.sub.4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol.

[0786] 31. The compound, or pharmaceutically acceptable salt thereof, of embodiment 30, wherein Z has the structure of Formula VIIIi:

##STR00296## [0787] wherein B, C, and D are each, independently, CH or CR.sub.4.

[0788] 32. The compound, or pharmaceutically acceptable salt thereof, of embodiment 30, wherein Z has the structure of Formula IXi:

##STR00297## [0789] wherein A, C, and D are each, independently, CH or CR.sub.4.

[0790] 33. The compound, or pharmaceutically acceptable salt thereof, of embodiment 30, wherein Z has the structure of Formula Xi:

##STR00298## [0791] wherein A, B, and D are each, independently, CH or CR.sub.4.

[0792] 34. The compound, or pharmaceutically acceptable salt thereof, of embodiment 30, wherein Z has the structure of Formula Xli:

##STR00299## [0793] wherein A, B, and C are each, independently, CH or CR.sub.4.

[0794] 35. The compound, or pharmaceutically acceptable salt thereof, of embodiment 30, wherein Z has the structure of Formula XIIi:

##STR00300## [0795] wherein A and B are each, independently, CH or CR.sub.4.

[0796] 36. The compound, or pharmaceutically acceptable salt thereof, of embodiment 30, wherein Z has the structure of Formula XIIIi:

##STR00301## [0797] wherein A and D are each, independently, CH or CR.sub.4.

[0798] 37. The compound, or pharmaceutically acceptable salt thereof, of embodiment 30, wherein Z has the structure of Formula XIVi:

##STR00302## [0799] wherein C and D are each, independently, CH or CR.sub.4.

[0800] 38. The compound, or pharmaceutically acceptable salt thereof, of embodiment 30, wherein Z has the structure of Formula XVi:

##STR00303## [0801] wherein B and D are each, independently, CH or CR.sub.4.

[0802] 39. The compound, or pharmaceutically acceptable salt thereof, of embodiment 30, wherein Z has the structure of Formula XVIi:

##STR00304## [0803] wherein B and C are each, independently, CH or CR.sub.4.

[0804] 40. The compound, or pharmaceutically acceptable salt thereof, of embodiment 30, wherein Z has the structure of Formula XVIIi:

##STR00305## [0805] wherein A and C are each, independently, CH or CR.sub.4.

[0806] 41. The compound, or pharmaceutically acceptable salt thereof, of embodiment 30, wherein Z has the structure of Formula XVIIIi:

##STR00306## [0807] wherein A is CH or CR.sub.4.

[0808] 42. The compound, or pharmaceutically acceptable salt thereof, of embodiment 30, wherein Z has the structure of Formula XIXi:

##STR00307## [0809] wherein D Is CH or CR.sub.4

[0810] 43. The compound, or pharmaceutically acceptable salt thereof, of embodiment 30, wherein Z has the structure of Formula XXi:

##STR00308## [0811] wherein B is CH or CR.sub.4.

[0812] 44. The compound, or pharmaceutically acceptable salt thereof, of embodiment 30, wherein Z has the structure of Formula XXIi:

##STR00309## [0813] wherein C is CH or CR.sub.4.

[0814] 45. The compound, or pharmaceutically acceptable salt thereof, of embodiment 30, wherein Z has the structure of Formula XXIIi:

##STR00310## [0815] wherein A, B, C, and D are each, independently, CH or CR.sub.4

[0816] 46. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 6, 8 to 18, or 27 to 29, wherein Z has the structure of Formula XXIlli:

##STR00311## [0817] wherein o is 0, 1, 2, 3, or 4; and

[0818] each R.sub.4 is, independently, optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol.

[0819] 47. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 6, 8 to 18, or 27 to 29, wherein Z has the structure of Formula XXIi:

##STR00312## [0820] wherein o is 0, 1, 2, or 3; and each R.sub.4 is, independently, optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl

[0821] 48. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 18, or 27 to 29, wherein Z has the structure of Formula XXVi:

##STR00313## [0822] wherein [0823] F and G are each, independently, N, CH, or CR.sub.4; [0824] each R.sub.4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol; and E is NH, O, or S. [0825] 49. The compound, or pharmaceutically acceptable salt thereof, of embodiment 48, wherein Z has the structure of Formula XXVIi:

##STR00314## [0826] wherein F and G are each, independently, CH or CR.sub.4.

[0827] 50. The compound, or pharmaceutically acceptable salt thereof, of embodiment 48, wherein Z has the structure of Formula XXVIIi:

##STR00315## [0828] wherein F and G are each, independently, CH or CR.sub.4.

[0829] 51. The compound, or pharmaceutically acceptable salt thereof, of embodiment 48, wherein Z has the structure of Formula XXVIIIi:

##STR00316## [0830] wherein F and G are each, independently, CH or CR.sub.4.

[0831] 52. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 18, or 27 to 29, wherein Z has the structure of Formula XXIXi:

##STR00317## [0832] wherein [0833] F and G are each, independently, N, CH, or CR.sub.4; [0834] each R.sub.4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol; and [0835] E is NH, O, or S.

[0836] 53. The compound, or pharmaceutically acceptable salt thereof, of embodiment 52, wherein Z has the structure of Formula XXXi:

##STR00318## [0837] wherein F and G are each, independently, CH or CR.sub.4.

[0838] 54. The compound, or pharmaceutically acceptable salt thereof, of embodiment 52, wherein Z has the structure of Formula XXXIi:

##STR00319## [0839] wherein F and G are each, independently, CH or CR.sub.4.

[0840] 55. The compound, or pharmaceutically acceptable salt thereof, of embodiment 52, wherein Z has the structure of Formula XXXIIi:

##STR00320## [0841] wherein F and G are each, independently, CH or CR.sub.4.

[0842] 56. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 18, or 27 to 29, wherein Z has the structure of Formula XXXIIIi:

##STR00321## [0843] wherein [0844] F and G are each, independently, N, CH, or CR.sub.4; [0845] each R.sub.4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol; and [0846] E is NH, O, or S.

[0847] 57. The compound, or pharmaceutically acceptable salt thereof, of embodiment 56, wherein Z has the structure of Formula XXXIVi:

##STR00322## [0848] wherein F and G are each, independently, CH or CR.sub.4.

[0849] 58. The compound, or pharmaceutically acceptable salt thereof, of embodiment 56, wherein Z has the structure of Formula XXXVi:

##STR00323## [0850] wherein F and G are each, independently, CH or CR.sub.4.

[0851] 59. The compound, or pharmaceutically acceptable salt thereof, of embodiment 56, wherein Z has the structure of Formula XXXVIi:

##STR00324## [0852] wherein F and G are each, independently, CH or CR.sub.4.

[0853] 60. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 18, or 27 to 29, wherein Z has the structure of Formula XXXVIIi:

##STR00325## [0854] wherein [0855] F, G, and H are each, independently, N, CH, or CR.sub.4; [0856] each R.sub.4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol; and [0857] E is N or CH.

[0858] 61. The compound, or pharmaceutically acceptable salt thereof, of embodiment 60, wherein Z has the structure of Formula XXXVIIIi:

##STR00326##

[0859] 62. The compound, or pharmaceutically acceptable salt thereof, of embodiment 60, wherein Z has the structure of Formula XXXIXi:

##STR00327##

[0860] 63. The compound, or pharmaceutically acceptable salt thereof, of embodiment 60, wherein Z has the structure of Formula XXXXi:

##STR00328##

[0861] 64. The compound, or pharmaceutically acceptable salt thereof, of embodiment 60, wherein Z has the structure of Formula XXXXIi:

##STR00329##

[0862] 65. The compound, or pharmaceutically acceptable salt thereof, of embodiment 60, wherein Z has the structure of Formula XXXXIVi:

##STR00330##

[0863] 66. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 18, or 27 to 29, wherein Z has the structure of Formula XXXXIIi:

##STR00331## [0864] wherein A, B, C, and D are each, independently, CH, CR.sub.4, or N; and [0865] each R.sub.4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol.

[0866] 67. The compound, or pharmaceutically acceptable salt thereof, of embodiment 66, wherein Z has the structure of Formula XXXXIIIi:

##STR00332##

[0867] 68. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 18, or 27 to 29, wherein Z has the structure of Formula XXXXVi:

##STR00333## [0868] wherein A, B, C, and D are each, independently, CH, CR.sub.4, or N; and [0869] each R.sub.4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol

[0870] 69. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1, 2, or 27 to 29, wherein the compound has the structure of Formula VII:

##STR00334## [0871] wherein A, B, C and D are, each, independently, N, CH, or CR.sub.4; and [0872] each R.sub.4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol.

[0873] 70. The compound, or pharmaceutically acceptable salt thereof, of embodiment 69, wherein the compound has the structure of Formula VIII:

##STR00335## [0874] wherein B, C, and D are each, independently, CH or CR.sub.4.

[0875] 71. The compound, or pharmaceutically acceptable salt thereof, of embodiment 69, wherein the compound has the structure of formula IX:

##STR00336## [0876] wherein A, C, and D are each, independently, CH or CR.sub.4.

[0877] 72. The compound, or pharmaceutically acceptable salt thereof, of embodiment 69, wherein the compound has the structure of formula X:

##STR00337## [0878] wherein A, B, and D are each, independently, CH or CR.sub.4.

[0879] 73. The compound, or pharmaceutically acceptable salt thereof, of embodiment 69, wherein the compound has the structure of Formula XI:

##STR00338## [0880] wherein A, B, and C are each, independently, CH or CR.sub.4.

[0881] 74. The compound, or pharmaceutically acceptable salt thereof, of embodiment 69, wherein the compound has the structure of Formula XII:

##STR00339## [0882] wherein A and B are each, independently, CH or CR.sub.4.

[0883] 75. The compound, or pharmaceutically acceptable salt thereof, of embodiment 69, wherein the compound has the structure of Formula XIII:

##STR00340## [0884] wherein A and D are each, independently, CH or CR.sub.4.

[0885] 76. The compound, or pharmaceutically acceptable salt thereof, of embodiment 69, wherein the compound has the structure of Formula XIII:

##STR00341## [0886] wherein C and D are each, independently, CH or CR.sub.4.

[0887] 77. The compound, or pharmaceutically acceptable salt thereof, of embodiment 69, wherein the compound has the structure of Formula XV:

##STR00342## [0888] wherein B and D are each, independently, CH or CR.sub.4.

[0889] 78. The compound, or pharmaceutically acceptable salt thereof, of embodiment 69, wherein the compound has the structure of Formula XVI:

##STR00343## [0890] wherein B and C are each, independently, CH or CR.sub.4.

[0891] 79. The compound, or pharmaceutically acceptable salt thereof, of embodiment 69, wherein the compound has the structure of Formula XVII:

##STR00344## [0892] wherein A and C are each, independently, CH or CR.sub.4.

[0893] 80. The compound, or pharmaceutically acceptable salt thereof, of embodiment 69, wherein the compound has the structure of Formula XVIII:

##STR00345## [0894] wherein A is CH or CR.sub.4.

[0895] 81. The compound, or pharmaceutically acceptable salt thereof, of embodiment 69, wherein the compound has the structure of Formula XIX:

##STR00346## [0896] wherein D Is CH or CR.sub.4

[0897] 82. The compound, or pharmaceutically acceptable salt thereof, of embodiment 69, wherein the compound has the structure of Formula XX:

##STR00347## [0898] wherein B is CH or CR.sub.4.

[0899] 83. The compound, or pharmaceutically acceptable salt thereof, of embodiment 69, wherein the compound has the structure of Formula XXI:

##STR00348## [0900] wherein C is CH or CR.sub.4.

[0901] 84. The compound, or pharmaceutically acceptable salt thereof, of embodiment 69, wherein the compound has the structure of Formula XXII:

##STR00349## [0902] wherein A, B, C, and D are each, independently, CH or CR.sub.4.

[0903] 85. The compound, or pharmaceutically acceptable salt thereof, of one of embodiments 1, 2, 27 26 to 29, wherein the compound has the structure of Formula XXIII

##STR00350## [0904] wherein o is 0, 1, 2, 3, or 4; and [0905] each R.sub.4 is, independently, optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol.

[0906] 86. The compound, or pharmaceutically acceptable salt thereof, of one of embodiments 1, 2, or 27 to 29, wherein the compound has the structure of Formula XXIV:

##STR00351## [0907] wherein o is 0, 1, 2, or 3; and [0908] each R.sub.4 is, independently, optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol.

[0909] 87. The compound, or pharmaceutically acceptable salt thereof, of one of embodiments 1, 2, or 27 to 29, wherein the compound has the structure of Formula XXV:

##STR00352## [0910] wherein; [0911] each R.sub.4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol; [0912] E is NH, O, or S; and [0913] F and G are each, independently, N, CH, or CR.sub.4.

[0914] 88. The compound, or pharmaceutically acceptable salt thereof, of embodiment 87, wherein the compound has the structure of Formula XXVI:

##STR00353## [0915] wherein F and G are each, independently, CH or CR.sub.4.

[0916] 89. The compound, or pharmaceutically acceptable salt thereof, of embodiment 87, wherein the compound has the structure of Formula XXVII:

##STR00354## [0917] wherein F and G are each, independently, CH or CR.sub.4.

[0918] 90. The compound, or pharmaceutically acceptable salt thereof, of embodiment 87, wherein the compound has the structure of Formula XXVIII:

##STR00355## [0919] wherein F and G are each, independently, CH or CR.sub.4.

[0920] 91. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1, 2, or 27 to 29, wherein the compound has the structure of Formula XXIX:

##STR00356## [0921] wherein [0922] each R.sub.4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol; [0923] E is NH, O, or S; and [0924] F and G are each, independently, N, CH, or CR.sub.4.

[0925] 92. The compound, or pharmaceutically acceptable salt thereof, of embodiment 91, wherein the compound has the structure of Formula XXX:

##STR00357## [0926] wherein F and G are each, independently, CH or CR.sub.4.

[0927] 93. The compound, or pharmaceutically acceptable salt thereof, of embodiment 91, wherein the compound has the structure of Formula XXXI:

##STR00358## [0928] wherein F and G are each, independently, CH or CR.sub.4.

[0929] 94. The compound, or pharmaceutically acceptable salt thereof, of embodiment 91, wherein the compound has the structure of Formula XXXII:

##STR00359## [0930] wherein F and G are each, independently, CH or CR.sub.4.

[0931] 95. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1, 2, or 27 to 29, wherein the compound has the structure of Formula XXXIII:

##STR00360## [0932] wherein [0933] F and G are each, independently, N, CH, or CR.sub.4; [0934] each R.sub.4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol; and [0935] E is NH, O, or S.

[0936] 96. The compound, or pharmaceutically acceptable salt thereof, of embodiment 95, wherein the compound has the structure of Formula XXXIV:

##STR00361## [0937] wherein F and G are each, independently, CH or CR.sub.4.

[0938] 97. The compound, or pharmaceutically acceptable salt thereof, of embodiment 95, wherein the compound has the structure of Formula XXXV:

##STR00362## [0939] wherein F and G are each, independently, CH or CR.sub.4.

[0940] 98. The compound, or pharmaceutically acceptable salt thereof, of embodiment 95, wherein the compound has the structure of Formula XXXVI:

##STR00363## [0941] wherein F and G are each, independently, CH or CR.sub.4.

[0942] 99. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1, 2, or 27 to 29, wherein the compound has the structure of Formula XXXVII:

##STR00364## [0943] wherein [0944] each R.sub.4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol; [0945] E is N or CH [0946] F, G, and H are each, independently, N, CH, or CR.sub.4.

[0947] 100. The compound, or pharmaceutically acceptable salt thereof, of embodiment 99, wherein the compound has the structure of Formula XXXVIII:

##STR00365##

[0948] 101. The compound, or pharmaceutically acceptable salt thereof, of embodiment 99, wherein the compound has the structure of Formula XXXIX:

##STR00366##

[0949] 102. The compound, or pharmaceutically acceptable salt thereof, of embodiment 99, wherein the compound has the structure of Formula XXXX:

##STR00367##

[0950] 103. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1, 2, or 97 to 99, wherein the compound has the structure of Formula XXXXII:

##STR00368## [0951] wherein A, B, C, and D are each, independently, CH, CR.sub.4, or N; and [0952] each R.sub.4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino azido, cyano, nitro, or thiol.

[0953] 104. The compound, or pharmaceutically acceptable salt thereof, of embodiment 103, wherein the compound has the structure of Formula XXXXIII:

##STR00369##

[0954] 105. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 18 or 27 to 104, wherein X is C.sub.1-C.sub.6 alkylene.

[0955] 106. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 18 or 27 to 105, wherein Y is O or NR.sub.3.

[0956] 107. The compound, or pharmaceutically acceptable salt thereof, of embodiment 106, wherein Y is O.

[0957] 108. The compound, or pharmaceutically acceptable salt thereof, of embodiment 106, wherein Y is NR.sub.3.

[0958] 109. The compound, or pharmaceutically acceptable salt thereof, of embodiment 106, wherein Y is NH.

[0959] 110. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 18 or 27 to 109, wherein W is S, O, or NR.sub.3

[0960] 111. The compound, or pharmaceutically acceptable salt thereof, of embodiment 110, wherein W is S.

[0961] 112. The compound, or pharmaceutically acceptable salt thereof, of embodiment 110, wherein W is O.

[0962] 113. The compound, or pharmaceutically acceptable salt thereof, of embodiment 110, wherein W is NR.sub.3.

[0963] 114. The compound, or pharmaceutically acceptable salt thereof, of embodiment 113, wherein W is NH.

[0964] 115. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 114, wherein R.sub.2 is an optionally substituted C.sub.1-C.sub.6 alkyl group.

[0965] 116. The compound, or pharmaceutically acceptable salt thereof, of embodiment 115, wherein R.sub.2 is

##STR00370##

[0966] 117. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 114, wherein R.sub.2 is optionally substituted C.sub.2-C.sub.9 heterocyclyl, such as an optionally substituted pyrrolidine.

[0967] 118. The compound, or pharmaceutically acceptable salt thereof, of embodiment 115, wherein R.sub.2 is optionally substituted with a halogen, e.g., a fluorine.

[0968] 119. The compound, or pharmaceutically acceptable salt thereof, of embodiment 117, wherein R.sub.2 is

##STR00371##

[0969] 120. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 114, wherein R.sub.2 is an optionally substituted C.sub.2-C.sub.9 heteroaryl, such as an optionally substituted pyridine or optionally substituted oxazole.

[0970] 121. The compound, or pharmaceutically acceptable salt thereof, of embodiment 120, wherein R.sub.2 is

##STR00372##

[0971] 122. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 114, wherein R.sub.2 has the structure X.sub.1OY.sub.1.

[0972] 123. The compound, or pharmaceutically acceptable salt thereof, of embodiment 122, wherein X.sub.1 is optionally substituted with one or two methyl groups.

[0973] 124. The compound, or pharmaceutically acceptable salt thereof, of embodiment 122 or 123, wherein Y.sub.1 is optionally substituted phenyl or optionally substituted cyclopropyl.

[0974] 125. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 122 to 123, [0975] wherein R.sub.2 is, or

##STR00373##

[0976] 126. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 114, wherein R.sub.2 is an optionally substituted C.sub.6-C.sub.10 aryl.

[0977] 127. The compound, or pharmaceutically acceptable salt thereof, of embodiment 126, wherein R.sub.2 is

phenyl,

##STR00374##

[0978] 128. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 114, wherein R.sup.2 is an optionally substituted C.sub.2-C.sub.6 alkenyl.

[0979] 129. The compound, or pharmaceutically acceptable salt thereof, of embodiment 128, wherein R.sup.2 is

##STR00375##

[0980] 130. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 129, wherein R.sub.1 is an optionally substituted C.sub.2-C.sub.9 heteroaryl.

[0981] 131. The compound, or pharmaceutically acceptable salt thereof, of embodiment 130, wherein R.sub.1 is

##STR00376##

[0982] 132. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 129, wherein R.sub.1 is R.sub.a-R.sub.b-R.sub.c.

[0983] 133. The compound, or pharmaceutically acceptable salt thereof, of embodiment 132, wherein R.sub.a is an optionally substituted C.sub.6-C.sub.10 arylene.

[0984] 134. The compound, or pharmaceutically acceptable salt thereof, of embodiment 132 wherein R.sub.c is an optionally substituted C.sub.2-C.sub.9 heteroarylene.

[0985] 135. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 132 to 134, wherein R.sub.b is O.

[0986] 136. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 132, 133, or 135, wherein R.sub.1 is

##STR00377##

[0987] 137. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 132 to 134, wherein R.sub.b is an optionally substituted C.sub.1-C.sub.6 alkylene.

[0988] 138. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 132, 133, or 137, wherein R.sub.b is

##STR00378##

[0989] 139. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 129, wherein R.sub.1 is an optionally substituted optionally substituted C.sub.2-C.sub.9 heteroaryl C.sub.1-C.sub.6 alkyl.

[0990] 140 The compound, or pharmaceutically acceptable salt thereof, of embodiment 139, wherein R.sub.1 is

##STR00379##

[0991] 141. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 129, wherein R.sub.1 is an optionally substituted C.sub.6-C.sub.10 aryl.

[0992] 142. The compound, or pharmaceutically acceptable salt thereof, of embodiment 141, wherein R.sub.1 is

##STR00380##

[0993] 143. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 142, wherein X is

##STR00381##

[0994] 144. The compound, or pharmaceutically acceptable salt thereof, of embodiment 143, wherein X is

##STR00382##

[0995] 145. A compound having the structure of any one of compounds 1 to 50 in Table 1, or a pharmaceutically acceptable salt thereof.

[0996] 146. A compound having the structure

##STR00383##

[0997] 147. A pharmaceutical composition comprising a compound of any one of embodiments 1 to 146, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0998] 148. A method of treating a Sec61-associated disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 146 or a pharmaceutical composition of embodiment 147.

[0999] 149. The method of embodiment 148, wherein the disease or disorder is selected from amyloidosis, light chain amyloidosis, autoantibody diseases, chronic kidney disease, fibrosis, neurodegeneration, autoimmune disease, genetically-defined kidney disease, viral disease, influenza, dengue virus, zika virus, hepatitis B virus, hepatitis C virus, SARS-CoV-2, human immunodeficiency virus, malaria, cancer, glioma, myeloma, multiple types of cancer with solid tumors, autoimmune diseases, rheumatoid arthritis, ankylosing spondylitis, celiac disease, multiple sclerosis, atopic dermatitis, Crohn's disease, psoriasis, allergic asthma, autoimmune antibody diseases, myasthenia gravis, neuromyelitis optica, warm antibody hemolytic anemia, prion disease, immune thrombocytopenic purpura, chronic inflammatory demyelinating polyradiculoneuropathy, fibrotic diseases, idiopathic pulmonary fibrosis, endometriosis, nonalcoholic steatohepatitis, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, hypercholesterolemia, Creutzfeldt-Jakob disease, Gerstmann-Strsussler-Scheinker syndrome, high cholesterol, metabolic syndrome, and fatal familial insomnia.

[1000] 150. The method of embodiment 149, wherein the disease is a viral disease.

[1001] 151. The method of embodiment 149, wherein the disease is cancer.

[1002] 152. The method of embodiment 149, wherein the disease is prion disease.

[1003] 153. The method of embodiment 149, wherein the disorder is light chain amyloidosis.

[1004] 154. The method of embodiment 149, wherein the disease is autoimmune antibody disease.

[1005] 155. The method of embodiment 149, wherein the disease is genetically-defined kidney disease.

[1006] 156. The method of embodiment 149, wherein the disease is malaria.

[1007] 157. A method of inhibiting the translocation of a target protein through Sec61, the method comprising contacting a cell with an effective amount of a compound of any one of embodiments 1 to 146, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 147.

[1008] 158. The method of embodiment 157, wherein inhibition of translocation is selective for a target protein over a non-target protein.

[1009] 159. A compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 146 or a pharmaceutical composition of embodiment 147 for use in a treating a Sec61-associated disease or disorder in a subject in need thereof.

[1010] 160. The compound, or pharmaceutically acceptable salt thereof, or pharmaceutically composition for use according to embodiment 159, wherein the disease or disorder is selected from amyloidosis, light chain amyloidosis, autoantibody diseases, chronic kidney disease, fibrosis, neurodegeneration, autoimmune disease, genetically-defined kidney disease, viral disease, influenza, dengue virus, zika virus, hepatitis B virus, hepatitis C virus, SARS-CoV-2, human immunodeficiency virus, malaria, cancer, glioma, myeloma, multiple types of cancer with solid tumors, autoimmune diseases, rheumatoid arthritis, ankylosing spondylitis, celiac disease, multiple sclerosis, atopic dermatitis, Crohn's disease, psoriasis, allergic asthma, autoimmune antibody diseases, myasthenia gravis, neuromyelitis optica, warm antibody hemolytic anemia, prion disease, immune thrombocytopenic purpura, chronic inflammatory demyelinating polyradiculoneuropathy, fibrotic diseases, idiopathic pulmonary fibrosis, endometriosis, nonalcoholic steatohepatitis, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, hypercholesterolemia, Creutzfeldt-Jakob disease, Gerstmann-Strsussler-Scheinker syndrome, high cholesterol, metabolic syndrome, and fatal familial insomnia.

[1011] 161. The compound, or pharmaceutically acceptable salt thereof, or pharmaceutically composition for use according to embodiment 160, wherein the disease is a viral disease.

[1012] 162. The compound, or pharmaceutically acceptable salt thereof, or pharmaceutically composition for use according to embodiment 160, wherein the disease is cancer.

[1013] 163. The compound, or pharmaceutically acceptable salt thereof, or pharmaceutically composition for use according to embodiment 160, wherein the disease is prion disease.

[1014] 164. The compound, or pharmaceutically acceptable salt thereof, or pharmaceutically composition for use according to embodiment 160, wherein the disorder is light chain amyloidosis.

[1015] 165. The compound, or pharmaceutically acceptable salt thereof, or pharmaceutically composition for use according to embodiment 160, wherein the disease is autoimmune antibody disease.

[1016] 166. The compound, or pharmaceutically acceptable salt thereof, or pharmaceutically composition for use according to embodiment 160, wherein the disease is genetically-defined kidney disease.

[1017] 167. The compound, or pharmaceutically acceptable salt thereof, or pharmaceutically composition for use according to embodiment 160, wherein the disease is malaria.

[1018] 168. A compound of any one of embodiments 1 to 146, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 147, for use in inhibiting the translocation of a target protein through Sec61.

[1019] 169. The compound, or pharmaceutically acceptable salt thereof, or pharmaceutically composition for use according to embodiment 166, wherein inhibition of translocation is selective for a target protein over a non-target protein.

Other Embodiments

[1020] Various modifications and variations of the described invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the invention.

[1021] All references, patents, patent application publications, and patent applications recited herein ae hereby incorporated by reference in their entirety.

[1022] Other embodiments are in the claims.