Protein Secretion Inhibitors

Abstract

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

Description

[Technical field]

[0001] The present invention relates generally to small molecules that inhibit protein secretion by inhibiting the Sec61 protein secretion complex. The present invention further relates to a method of treating a subject having a disorder associated with the Sec61 protein secretion complex. The present invention further relates to a method of inhibiting Sec61-mediated translocation of a target protein. [Background technology]

[0002] Numerous proteins are secreted from cells, including proteins associated with diseases. Sec61 is a membrane protein complex involved in the secretion of proteins, some of which are associated with diseases, from cells. Sec61 is a component of the translocon, a complex of proteins that translocates proteins from the cytosol to the endoplasmic reticulum. Molecules that can selectively inhibit the secretion of specific disease-related proteins via Sec61, thereby preventing their secretion from cells, are useful as therapeutic agents. Known inhibitors of protein secretion do not selectively inhibit the translocation of specific disease-related proteins via Sec61. Thus, selective inhibitors of Sec61 are needed. Summary of the Invention

[0003] In certain embodiments, the disclosure provides a compound having the structure of Formula I, or a pharma- ceutically acceptable salt thereof:

[0004] [ka]

[0005] During the ceremony, R 1 is H, optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 3 ~C 7 Cycloalkyl, optionally substituted C 2 ~C 9Heterocycle, optionally substituted C 6 ~C 10 Aryl, optionally substituted C 2 ~C 9 Heteroaryl, C 2 ~C 9 Heteroaryl C 1 ~C 6 Alkyl, or R a -R b -R c and R a is optionally substituted C 6 ~C 10 Arylene or optionally substituted C 2 ~C 9 Heteroarylene, R b is -O- or optionally substituted C 1 ~C 6 is alkylene, R c is optionally substituted C 6 ~C 10 is aryl, Z is absent or optionally substituted C 3 ~C 10 Cycloalkylene, optionally substituted C 2 ~C 9 Heterocyclylene, C 6 ~C 10 Arylene or optionally substituted C 2 ~C 9 Heteroarylene, Y is absent, O, or NR 3 and X is an optionally absent or substituted C 1 ~C 6 is alkylene, W is absent, S, O, or NR 3 and n is 0 or 1, A is S, O, NH, or CH; B is C or N; R 2is optionally substituted C 1~6 Alkyl, optionally substituted C 2 ~C 6 Alkenyl, optionally substituted C 3~7 Cycloalkyl, optionally substituted C 2~9 Heterocycle, optionally substituted C 6 ~C 10 Aryl, optionally substituted C 2~9 Heteroaryl, optionally substituted C 2 ~C 9 Heteroaryl C 1 ~C 6 Alkyl, optionally substituted C 3 ~C 7 Cycloalkyl C 1 ~C 6 Aryl, optionally substituted C 1 ~C 6 Heteroalkyl or cyano, or X 1 -OY 1 The structure is X 1 is optionally substituted C 1 ~C 6 is alkylene, Y 1 is optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 3 ~C 8 Cycloalkyl or optionally substituted C 6 ~C 10 aryl, and Each R 3 are independently H or C 1 ~C 6 It is an alkyl.

[0006] In one embodiment, R 1 is H, optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 3 ~C 7 Cycloalkyl, optionally substituted C 2 ~C 9Heterocycle, optionally substituted C 6 ~C 10 Aryl or optionally substituted C 2 ~C 9 is heteroaryl, Z is absent or optionally substituted C 3 ~C 10 Cycloalkyl, optionally substituted C 2 ~C 9 Heterocyclyl, C 6 ~C 10 Aryl or optionally substituted C 2 ~C 9 is heteroaryl, Y is absent, O, or NR 3 and X is absent or optionally substituted C 1 ~C 6 is alkylene, W is absent, S, O, or NR 3 and n is 0 or 1, A is S, O, or CH; B is C or N; Each R 3 are independently H or C 1 ~C 6 It is an alkyl.

[0007] In one embodiment, n is 1. In certain embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, has the structure of formula II:

[0008] [ka]

[0009] In certain embodiments of the compound of formula II or a pharma- ceutically acceptable salt thereof, Z is an optionally substituted C 6 ~C 10 Aryl or optionally substituted C 2 ~C9 In certain embodiments of the compound of formula II or a pharma- ceutically acceptable salt thereof, Y is O or NR 3 In certain embodiments of the compound of formula II or a pharma- ceutically acceptable salt thereof, Y is O. In certain embodiments of the compound of formula II or a pharma- ceutically acceptable salt thereof, Y is NR 3 In certain embodiments of the compound of formula II or a pharma- ceutically acceptable salt thereof, Y is NH. In certain embodiments of the compound of formula II or a pharma- ceutically acceptable salt thereof, X is an optionally substituted C 1 ~C 6 In certain embodiments of the compound of formula II or a pharma- ceutically acceptable salt thereof, W is S, O, or NR 3 In certain embodiments of the compound of formula II or a pharma- ceutically acceptable salt thereof, W is S. In certain embodiments of the compound of formula II or a pharma- ceutically acceptable salt thereof, W is O. In certain embodiments of the compound of formula II or a pharma- ceutically acceptable salt thereof, W is NR 3 In certain embodiments of the compound of formula II or a pharma- ceutically acceptable salt thereof, W is NH.

[0010] In certain embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, has the structure of formula III:

[0011] [ka]

[0012] In certain embodiments of the compound of formula III or a pharma- ceutically acceptable salt thereof, Z is an optionally substituted C 6 ~C 10 Aryl or optionally substituted C 2 ~C 9 In certain embodiments of the compound of formula III or a pharma- ceutically acceptable salt thereof, Y is O or NR3 In certain embodiments of the compound of formula III or a pharma- ceutically acceptable salt thereof, Y is O. In certain embodiments of the compound of formula III or a pharma- ceutically acceptable salt thereof, Y is NR 3 In certain embodiments of the compound of formula III or a pharma- ceutically acceptable salt thereof, Y is NH. In certain embodiments of the compound of formula III or a pharma- ceutically acceptable salt thereof, X is an optionally substituted C 1 ~C 6 In certain embodiments of the compound of formula III or a pharma- ceutically acceptable salt thereof, W is S, O, or NR 3 In certain embodiments of the compound of formula III or a pharma- ceutically acceptable salt thereof, W is S. In certain embodiments of the compound of formula III or a pharma- ceutically acceptable salt thereof, W is O. In certain embodiments of the compound of formula III or a pharma- ceutically acceptable salt thereof, W is NR 3 In certain embodiments of the compound of formula III or a pharma- ceutically acceptable salt thereof, W is NH.

[0013] In certain embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, has the structure of formula IV:

[0014] [ka]

[0015] In certain embodiments of the compound of formula IV or a pharma- ceutically acceptable salt thereof, Z is an optionally substituted C 6 ~C 10 Aryl or optionally substituted C 2 ~C 9 In certain embodiments of the compound of formula IV or a pharma- ceutically acceptable salt thereof, Y is O or NR 3In certain embodiments of the compound of formula IV or a pharma- ceutically acceptable salt thereof, Y is O. In certain embodiments of the compound of formula IV or a pharma- ceutically acceptable salt thereof, Y is NR 3 In certain embodiments of the compound of formula IV or a pharma- ceutically acceptable salt thereof, Y is NH. In certain embodiments of the compound of formula IV or a pharma- ceutically acceptable salt thereof, X is an optionally substituted C 1 ~C 6 In certain embodiments of the compound of formula IV or a pharma- ceutically acceptable salt thereof, W is S, O, or NR 3 In certain embodiments of the compound of formula IV or a pharma- ceutically acceptable salt thereof, W is S. In certain embodiments of the compound of formula IV or a pharma- ceutically acceptable salt thereof, W is O. In certain embodiments of the compound of formula IV or a pharma- ceutically acceptable salt thereof, W is NR 3 In certain embodiments of the compound of formula IV or a pharma- ceutically acceptable salt thereof, W is NH.

[0016] In certain embodiments of the compounds of formula I or pharma- ceutically acceptable salts thereof, A is S and B is C. In one embodiment, the compound of formula I, or a pharma- ceutically acceptable salt thereof, has the structure of formula V:

[0017] [ka]

[0018] In the formula, Y is O or NR 3 It is. In certain embodiments of the compound of formula V or a pharma- ceutically acceptable salt thereof, X is an optionally substituted C 1 ~C 6 In certain embodiments of the compound of formula V or a pharma- ceutically acceptable salt thereof, Y is O. In certain embodiments of the compound of formula V or a pharma- ceutically acceptable salt thereof, Y is NR3 In certain embodiments of the compound of formula V or a pharma- ceutically acceptable salt thereof, Y is NH.

[0019] In one embodiment, the compound of formula I, or a pharma- ceutically acceptable salt thereof, has the structure of formula VI:

[0020] [ka]

[0021] In the formula, W is NR 3 It is. In certain embodiments of the compound of formula VI or a pharma- ceutically acceptable salt thereof, X is an optionally substituted C 1 ~C 6 In certain embodiments of the compound of formula VI or a pharma- ceutically acceptable salt thereof, W is NH.

[0022] In certain embodiments of the compounds of formula I or pharma- ceutically acceptable salts thereof, n is 0. In certain embodiments of a compound of any one of Formulae I-IV or a pharma- ceutically acceptable salt thereof, Z is optionally substituted phenylene, optionally substituted pyridinylene, optionally substituted pyrimidinylene, optionally substituted pyridazinylene, pyrazinylene, 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. In some embodiments, Z is substituted with at least one halogen, for example, at least one fluorine.

[0023] In some embodiments, Z has the structure of formula VIIi:

[0024] [ka]

[0025] In the formula, A, B, C, and D are each independently N, CH, or CR. 4 and Each R 4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol.

[0026] In some embodiments, Z has the structure of formula VIIIi:

[0027] [ka]

[0028] In the formula, B, C, and D are each independently CH or CR 4 It is. In some embodiments, Z has the structure of formula IXi:

[0029] [ka]

[0030] In the formula, A, C, and D are each independently CH or CR 4 It is. In some embodiments, Z has the structure of formula Xi:

[0031] [ka]

[0032] In the formula, A, B, and D are each independently CH or CR 4 It is. In some embodiments, Z has the structure of formula XIi:

[0033] [ka]

[0034] In the formula, A, B, and C each independently represent CH or CR. 4 It is. In certain embodiments, Z has the structure of formula XIIi:

[0035] [ka]

[0036] In the formula, A and B are each independently CH or CR 4 It is. In some embodiments, Z has the structure of formula XIIIi:

[0037] [ka]

[0038] In the formula, A and D are each independently CH or CR 4 It is. In some embodiments, Z has the structure of formula XIVi:

[0039] [ka]

[0040] In the formula, C and D are each independently CH or CR 4 It is. In some embodiments, Z has the structure of formula XVi:

[0041] [ka]

[0042] In the formula, B and D are each independently CH or CR 4 It is. In some embodiments, Z has the structure of formula XVIi:

[0043] [ka]

[0044] In the formula, B and C are each independently CH or CR 4 It is. In some embodiments, Z has the structure of formula XVIIi:

[0045] [ka]

[0046] In the formula, A and C are each independently CH or CR 4 It is. In certain embodiments, Z has the structure of any one of formulas XVIIIi:

[0047] [ka]

[0048] In the formula, A is CH or CR 4 It is. In certain embodiments, Z has the structure of formula XIXi:

[0049] [ka]

[0050] In the formula, D is CH or CR 4 It is. In some embodiments, Z has the structure of formula XXi:

[0051] [ka]

[0052] In the formula, B is CH or CR 4 It is. In some embodiments, Z has the structure of formula XXIi:

[0053] [ka]

[0054] In the formula, C is CH or CR 4 It is. In some embodiments, Z has the structure of formula XXIIi:

[0055] [ka]

[0056] In the formula, A, B, C, and D are each independently CH or CR 4 It is. In some embodiments, Z has the structure of formula XXIIIi:

[0057] [ka]

[0058] wherein o is 0, 1, 2, 3, or 4; and Each R 4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol.

[0059] In some embodiments, Z has the structure of formula XXIVi:

[0060] [ka]

[0061] wherein o is 0, 1, 2, or 3; and Each R 4is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol.

[0062] In some embodiments, Z has the structure of formula XXVi:

[0063] [ka]

[0064] During the ceremony, F and G are each independently N, CH, or CR. 4 and Each R 4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol; and E is NH, O, or S.

[0065] In some embodiments, Z has the structure of formula XXVIi:

[0066] [ka]

[0067] In the formula, F and G are each independently CH or CR 4 It is. In some embodiments, Z has the structure of formula XXVIIi:

[0068] [ka]

[0069] In the formula, F and G are each independently CH or CR 4 It is. In some embodiments, Z has the structure of formula XXVIIIi:

[0070] [ka]

[0071] In the formula, F and G are each independently CH or CR 4 It is. In some embodiments, Z has the structure of formula XXIXi:

[0072] [ka]

[0073] During the ceremony, F and G are each independently N, CH, or CR. 4 and Each R 4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol; and E is NH, O, or S.

[0074] In some embodiments, Z has the structure of formula XXXi:

[0075] [ka]

[0076] In the formula, F and G are each independently CH or CR 4 It is. In some embodiments, Z has the structure of formula XXXIi:

[0077] [ka]

[0078] In the formula, F and G are each independently CH or CR 4 It is. In some embodiments, Z has the structure of formula XXXIIi:

[0079] [ka]

[0080] In the formula, F and G are each independently CH or CR 4 It is. In some embodiments, Z has the structure of formula XXXIIIi:

[0081] [ka]

[0082] During the ceremony, E is NH, O, or S; F and G are each independently N, CH, or CR. 4 and Each R 4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol.

[0083] In some embodiments, Z has the structure of formula XXXIVi:

[0084] [ka]

[0085] In the formula, F and G are each independently CH or CR 4 It is. In some embodiments, Z has the structure of formula XXXVi:

[0086] [ka]

[0087] In the formula, F and G are each independently CH or CR 4 It is. In some embodiments, Z has the structure of formula XXXVIi:

[0088] [ka]

[0089] In the formula, F and G are each independently CH or CR 4 It is. In some embodiments, Z has the structure of formula XXXVIIi:

[0090] [ka]

[0091] where E is N or CH; F, G, and H are each independently N, CH, or CR. 4 and Each R 4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol.

[0092] In certain embodiments, Z has the structure of formula XXXVIIIi:

[0093] [ka]

[0094] In certain embodiments, Z has the structure of formula XXXIXi:

[0095] [ka]

[0096] In some embodiments, Z has the structure of formula XXXXi:

[0097] [ka]

[0098] In certain embodiments, Z has the structure of formula XXXXIi:

[0099] [ka]

[0100] In certain embodiments, Z has the structure of formula XXXXIVi:

[0101] [ka]

[0102] In some embodiments, Z has the structure of formula XXXXIIi:

[0103] [ka]

[0104] In the formula, A, B, C, and D each independently represent CH, CR 4 , or N. In certain embodiments, Z has the structure of formula XXXXIIIi:

[0105] [ka]

[0106] In some embodiments, Z has the structure of formula XXXXVi:

[0107] [ka]

[0108] In the formula, A, B, C, and D each independently represent CH, CR 4 , or N, and Each R 4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol.

[0109] In one embodiment, the compound of formula I, or a pharma- ceutically acceptable salt thereof, has the structure of formula VII:

[0110] [ka]

[0111] wherein A, B, C, and D are independently N, CH, or CR. 4 and Each R 4is optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol.

[0112] In certain embodiments, the compound of formula VII or a pharma- ceutically acceptable salt thereof has the structure of formula VIII:

[0113] [ka]

[0114] In the formula, B, C, and D are each independently CH or CR 4 It is. In certain embodiments, the compound of formula VII or a pharma- ceutically acceptable salt thereof has the structure of formula IX:

[0115] [ka]

[0116] In the formula, A, C, and D are each independently CH or CR 4 It is. In one embodiment, the compound of formula VII or a pharma- ceutically acceptable salt thereof has the structure of formula X:

[0117] [ka]

[0118] In the formula, A, B, and D are each independently CH or CR 4 It is. In one embodiment, the compound of formula VII or a pharma- ceutically acceptable salt thereof has the structure of formula XI:

[0119] [ka]

[0120] In the formula, A, B, and C each independently represent CH or CR. 4 It is. In certain embodiments, the compound of formula VII or a pharma- ceutically acceptable salt thereof has the structure of formula XII:

[0121] [ka]

[0122] In the formula, A and B are each independently CH or CR 4 It is. In certain embodiments, the compound of formula VII or a pharma- ceutically acceptable salt thereof has the structure of formula XIII:

[0123] [ka]

[0124] In the formula, A and D are each independently CH or CR 4 It is. In one embodiment, the compound of formula VII or a pharma- ceutically acceptable salt thereof has the structure of formula XIV:

[0125] [ka]

[0126] In the formula, C and D are each independently CH or CR 4 It is. In one embodiment, the compound of formula VII or a pharma- ceutically acceptable salt thereof has the structure of formula XV:

[0127] [ka]

[0128] In the formula, B and D are each independently CH or CR 4 It is. In one embodiment, the compound of formula VII or a pharma- ceutically acceptable salt thereof has the structure of formula XVI:

[0129] [ka]

[0130] In the formula, B and C are each independently CH or CR 4 It is. In certain embodiments, the compound of formula VII or a pharma- ceutically acceptable salt thereof has the structure of formula XVII:

[0131] [ka]

[0132] In the formula, A and C are each independently CH or CR 4 It is. In certain embodiments, the compound of formula VII or a pharma- ceutically acceptable salt thereof has the structure of formula XVIII:

[0133] [ka]

[0134] In the formula, A is CH or CR 4 It is. In one embodiment, the compound of formula VII or a pharma- ceutically acceptable salt thereof has the structure of formula XIX:

[0135] [ka]

[0136] In the formula, D is CH or CR 4 It is. In one embodiment, the compound of formula VII or a pharma- ceutically acceptable salt thereof has the structure of formula XX:

[0137] [ka]

[0138] In the formula, B is CH or CR 4 It is. In certain embodiments, the compound of formula VII or a pharma- ceutically acceptable salt thereof has the structure of formula XXI:

[0139] [ka]

[0140] In the formula, C is CH or CR 4 It is. In certain embodiments, the compound of formula VIII or a pharma- ceutically acceptable salt thereof has the structure of formula XXII:

[0141] [ka]

[0142] In the formula, A, B, C, and D are each independently CH or CR 4 It is. In one embodiment, the compound of formula I or a pharma- ceutically acceptable salt thereof has the structure of formula XXIII:

[0143] [ka]

[0144] wherein o is 0, 1, 2, 3, or 4; and Each R 4is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol.

[0145] In one embodiment, the compound of formula I, or a pharma- ceutically acceptable salt thereof, has the structure of formula XXIV:

[0146] [ka]

[0147] wherein o is 0, 1, 2, or 3; and Each R 4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol.

[0148] In one embodiment, the compound of formula I, or a pharma- ceutically acceptable salt thereof, has the structure of formula XXV:

[0149] [ka]

[0150] where E is NH, O, or S; F and G are each independently N, CH, or CR. 4 and Each R 4is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol.

[0151] In certain embodiments, the compound of formula XXV or a pharma- ceutically acceptable salt thereof has the structure of formula XXVI:

[0152] [ka]

[0153] In the formula, F and G are each independently CH or CR 4 It is. In certain embodiments, the compound of formula XXV or a pharma- ceutically acceptable salt thereof has the structure of formula XXVII:

[0154] [ka]

[0155] In the formula, F and G are each independently CH or CR 4 It is. In certain embodiments, the compound of formula XXV or a pharma- ceutically acceptable salt thereof has the structure of formula XXVIII:

[0156] [ka]

[0157] In the formula, F and G are each independently CH or CR 4 It is. In one embodiment, the compound of formula I, or a pharma- ceutically acceptable salt thereof, has the structure of formula XXIX:

[0158] [ka]

[0159] where E is NH, O, or S; F and G are each independently N, CH, or CR. 4 and Each R 4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol.

[0160] In one embodiment, the compound of formula XXIX or a pharma- ceutically acceptable salt thereof has the structure of formula XXX:

[0161] [ka]

[0162] In the formula, F and G are each independently CH or CR 4 It is. In one embodiment, the compound of formula XXIX or a pharma- ceutically acceptable salt thereof has the structure of formula XXXI:

[0163] [ka]

[0164] In the formula, F and G are each independently CH or CR 4 It is. In certain embodiments, the compound of formula XXIX or a pharma- ceutically acceptable salt thereof has the structure of formula XXXII:

[0165] [ka]

[0166] In the formula, F and G are each independently CH or CR 4 It is. In one embodiment, the compound of formula I or a pharma- ceutically acceptable salt thereof has the structure of formula XXXIII:

[0167] [ka]

[0168] where E is NH, O, or S; F and G are each independently N, CH, or CR. 4 and Each R 4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol.

[0169] In certain embodiments, the compound of formula XXXIII or a pharma- ceutically acceptable salt thereof has the structure of formula XXXIV:

[0170] [ka]

[0171] In the formula, F and G are each independently CH or CR 4 It is. In certain embodiments, the compound of formula XXXIII or a pharma- ceutically acceptable salt thereof has the structure of formula XXXV:

[0172] [ka]

[0173] In the formula, F and G are each independently CH or CR 4 It is. In certain embodiments, the compound of formula XXXIII or a pharma- ceutically acceptable salt thereof has the structure of formula XXXVI:

[0174] [ka]

[0175] In the formula, F and G are each independently CH or CR 4 It is. In one embodiment, the compound of formula I, or a pharma- ceutically acceptable salt thereof, has the structure of formula XXXVII:

[0176] [ka]

[0177] where E is N or CH; F, G, and H are each independently N, CH, or CR. 4 and Each R 4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol.

[0178] In certain embodiments, the compound of formula XXXVII or a pharma- ceutically acceptable salt thereof has the structure of formula XXXVIII:

[0179] [ka]

[0180] In certain embodiments, the compound of formula XXXVI or a pharma- ceutically acceptable salt thereof has the structure of formula XXXIX:

[0181] [ka]

[0182] In certain embodiments, the compound of formula XXXVII or a pharma- ceutically acceptable salt thereof has the structure of formula XXXX:

[0183] [ka]

[0184] In certain embodiments, the compound of formula XXXVII or a pharma- ceutically acceptable salt thereof has the structure of formula XXXXIii:

[0185] [ka]

[0186] In one embodiment, the compound of formula I, or a pharma- ceutically acceptable salt thereof, has the structure of formula XXXXII:

[0187] [ka]

[0188] In the formula, A, B, C, and D each independently represent CH, CR 4 , or N, and Each R 4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol.

[0189] In certain embodiments, the compound of formula XXXXII or a pharma- ceutically acceptable salt thereof has the structure of formula XXXXIII:

[0190] [ka]

[0191] In certain embodiments of the compound of any one of formulas VII-XXXXIII, or a pharma- ceutically acceptable salt thereof, X is C 1 ~C 6 In certain embodiments of the compound of any one of formulas VII-XXXXIII, or a pharma- ceutically acceptable salt thereof, Y is O or NR 3 In certain embodiments of the compound of any one of formulas VII-XXXXIII, or a pharma- ceutically acceptable salt thereof, Y is O. In certain embodiments of the compound of any one of formulas VII-XXXXIII, Y is NR 3 In certain embodiments of the compound of any one of formulas VII-XXXXIII, Y is NH. In certain embodiments of the compound of any one of formulas VII-XXXXIII, or a pharma- ceutically acceptable salt thereof, W is S, O, or NR 3 In certain embodiments of the compound of any one of formulas VII-XXXXIII, or a pharma- ceutically acceptable salt thereof, W is S. In certain embodiments of the compound of any one of formulas VII-XXXXIII, or a pharma- ceutically acceptable salt thereof, W is O. In certain embodiments of the compound of any one of formulas VII-XXXXIII, or a pharma- ceutically acceptable salt thereof, W is NR 3 In certain embodiments of the compound of any one of formulas VII-XXXXIII, or a pharma- ceutically acceptable salt thereof, W is S, O, or NH.

[0192] In certain embodiments of a compound of any one of Formulas I-XXXXIII or a pharma- ceutically acceptable salt thereof, R 2is optionally substituted C 1 ~C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, neopentyl, or hexyl. 2 teeth

[0193] [ka]

[0194] It is. In certain embodiments of a compound of any one of Formulas I-XXXXIII or a pharma- ceutically acceptable salt thereof, R 2 is optionally substituted C 2 ~C 9 In one embodiment, R 2 is an optionally substituted pyrrolidinyl group. In one embodiment, R 2 is substituted with one or more fluorines, e.g., one fluorine substituent, two fluorine substituents, or three fluorine substituents. 2 teeth,

[0195] [ka]

[0196] It is. In certain embodiments of a compound of any one of Formulas I-XXXXIII or a pharma- ceutically acceptable salt thereof, R 2 is optionally substituted C 2 ~C 9 In one embodiment, R is an optionally substituted pyridine or an optionally substituted oxazole. 2 is an optionally substituted pyridinyl group. In one embodiment, R 2 teeth,

[0197] [ka]

[0198] It is. In certain embodiments of a compound of any one of Formulas I-XXXXIII or a pharma- ceutically acceptable salt thereof, R 2 is optionally substituted C 1 ~C 6 Heteroalkyl, for example, optionally substituted methoxy, ethoxy, propoxy, or butoxy.

[0199] In certain embodiments of the compound of any one of formulas I-XXXXIII, R 2 X 1 -OY 1 In one embodiment, X 1 is substituted with at least one methyl group, e.g., one methyl group, two methyl groups, or three methyl groups. In one embodiment, Y 1 is an optionally substituted phenyl group. 1 is an optionally substituted cyclopropyl group. 2 teeth,

[0200] [ka]

[0201] It is. In certain embodiments of a compound of any one of Formulas I-XXXXIII or a pharma- ceutically acceptable salt thereof, R 2 is optionally substituted C 6 ~C 10 In one embodiment, R 2 is phenyl,

[0202] [ka]

[0203] It is. In certain embodiments of the compound of any one of formulas I-XXXXIII, R 2 is optionally substituted C 2 ~C 6 In one embodiment, R 2 teeth,

[0204] [ka]

[0205] It is. In certain embodiments of a compound of any one of Formulas I-XXXXIII or a pharma- ceutically acceptable salt thereof, R 1 is optionally substituted C 2 ~C 9 Heteroaryl, for example, optionally substituted pyridinyl or optionally substituted oxazolyl. 1 teeth,

[0206] [ka]

[0207] It is. In certain embodiments of a compound of any one of Formulas I-XXXXIII or a pharma- ceutically acceptable salt thereof, R 1 is R a -R b -R c In one embodiment, R a is optionally substituted C 6 ~C 10 In one embodiment, R a is optionally substituted C 2 ~C 9 In one embodiment, R b is -O-. In one embodiment, R 1 teeth,

[0208] [ka]

[0209] In one embodiment, R b is optionally substituted C 1 ~C 6 In one embodiment, R 1 teeth,

[0210] [ka]

[0211] It is. In certain embodiments of a compound of any one of Formulas I-XXXXIII or a pharma- ceutically acceptable salt thereof, R 1 is optionally substituted C 2 ~C 9 Heteroaryl C 1 ~C 6 In one embodiment, R 1 teeth,

[0212] [ka]

[0213] It is. In certain embodiments of a compound of any one of Formulas I-XXXXIII or a pharma- ceutically acceptable salt thereof, R 1 is optionally substituted C 6 ~C 10 aryl, e.g., optionally substituted phenyl. In one embodiment, R 1 teeth,

[0214] [ka]

[0215] It is. In certain embodiments of the compound of any one of formulas I-XXXXIII, or a pharma- ceutically acceptable salt thereof, X is

[0216] [ka]

[0217] In one embodiment, X is

[0218] [ka]

[0219] It is. In some embodiments, the compound of any one of Formulas I-XXXXIII has the structure 144:

[0220] In one embodiment, the compound has the structure:

[0221] [ka]

[0222] or a pharma- ceutically acceptable salt thereof. In certain embodiments, a compound of any one of Formulas I-XXXXIII has the structure of any one of compounds 1-50 in Table 1.

[0223] In another aspect, the disclosure provides a pharmaceutical composition comprising any of the above compounds, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. In another aspect, the disclosure provides a method of treating a Sec61-associated disorder in a subject in need of treatment, the method comprising administering to or contacting a cell with an effective amount of any of the above compounds or a pharma- ceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising any of the above compounds or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient.

[0224] Diseases or disorders associated with Sec61 include amyloidosis, light chain amyloidosis, autoantibody diseases, chronic kidney disease, fibrosis, neurodegeneration, autoimmune diseases, genetically defined kidney disease, viral diseases, influenza, dengue virus, Zika virus, hepatitis B virus, hepatitis C virus, SARS-CoV-2, human immunodeficiency virus, malaria, cancer, glioma, myeloma, multiple cancers with solid tumors, autoimmune diseases, rheumatoid arthritis, ankylosing spondylitis, celiac disease, multiple sclerosis, atopic dermatitis, Crohn's disease, psoriasis, and allergic asthma. These conditions include, but are not limited to, 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-Sträussler-Scheinker syndrome, hypercholesterolemia, metabolic syndrome, and fatal familial insomnia.

[0225] In certain embodiments, the disclosure provides a method of treating a viral disease, cancer, a prion disease, a light chain amyloidosis, an autoimmune antibody disease, a genetically defined kidney disease, or malaria, comprising administering to or contacting a cell with an effective amount of any of the compounds described above or a pharma- ceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising any of the compounds described above or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In another aspect, the disclosure provides a method of inhibiting Sec-61-mediated translocation of a target protein, comprising contacting a cell with an effective amount of any of the compounds described above or a pharma- ceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising any of the compounds described above or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In certain embodiments, the inhibition of translocation is selective for the target protein over non-target proteins.

[0226] chemical terms It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0227] The term "acyl," as used herein, refers to a hydrogen or alkyl group (as defined herein) attached to the parent molecular group through a carbonyl group (as defined herein), such as formyl (i.e., a carboxaldehyde group), acetyl, trifluoroacetyl, propionyl, and butanoyl. Exemplary unsubstituted acyl groups contain 1 to 6, 1 to 11, or 1 to 21 carbons.

[0228] The term "alkyl" as used herein refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms). Alkylene is a divalent alkyl group.

[0229] The term "alkenyl," as used herein, alone or in combination with other groups, refers to a straight-chain or branched-chain hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).

[0230] The term "alkynyl," as used herein, alone or in combination with other groups, refers to a straight- or branched-chain hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).

[0231] As used herein, the term “amino” refers to —N(R N1 ) 2 where each R N1 are independently H, OH, and NO 2 , N(R N2 ) 2 , S.O. 2 OR N2 , S.O. 2 R N2, SOR N2 , an N-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), and these R N1 Each of the groups may be substituted, or two R N1 are bonded to form an alkylene or heteroalkylene, and each R N2 is independently H, alkyl, or aryl. For the present invention, an amino group is an unsubstituted amino (i.e., -NH 2 ) or substituted amino (i.e., -N(R N1 ) 2 ).

[0232] The term "aryl" as used herein refers to a monocyclic or polycyclic carbocyclic aromatic radical of 6 to 12 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl, and 1H-indenyl.

[0233] As used herein, the term "arylalkyl" refers to an alkyl group substituted with an aryl group. Exemplary unsubstituted arylalkyl groups are those having 7 to 30 carbons (e.g., 7 to 16 or 7 to 20 carbons, e.g., C 6~10 Aryl C 1~6 Alkyl, C 6~10 Aryl C 1~10 Alkyl, or C 6~10 Aryl C 1~20 alkyl), for example, benzyl and phenethyl. In certain embodiments, alkyl and aryl can each be further substituted with 1, 2, 3, or 4 substituents (defined herein) for each group.

[0234] As used herein, the term "azido" refers to a -N 3 Represents a group. The term "cyano" as used herein refers to a -CN group. As used herein, the term "carbocyclyl" refers to a non-aromatic C 3~12 It refers to monocyclic, bicyclic, or tricyclic structures in which the rings are formed by carbon atoms. Carbocyclyl structures include cycloalkyl groups and unsaturated carbocyclyl radicals.

[0235] The term "cycloalkyl" as used herein refers to a saturated non-aromatic monovalent carbomonocyclic or carbopolycyclic radical of three to ten, preferably three to six, carbon atoms. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl.

[0236] The term "halogen" as used herein means a radical of fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo). The term "heteroalkyl" as used herein refers to an alkyl group (as defined herein) in which one or more of the constituent carbon atoms is replaced by nitrogen, oxygen, or sulfur. In certain embodiments, the heteroalkyl group may be further substituted with one, two, three, or four substituents as set forth herein for alkyl groups. An example of a heteroalkyl group is alkoxy (e.g., methoxy and ethoxy), and the term "alkoxy" as used herein refers to alkyl-O-. Heteroalkylene is a divalent heteroalkyl group.

[0237] The term "heteroalkenyl" as used herein refers to an alkenyl group (as defined herein) in which one or more of the constituent carbon atoms is replaced by nitrogen, oxygen, or sulfur. In certain embodiments, a heteroalkenyl group can be further substituted with one, two, three, or four substituents as set forth herein for an alkenyl group. An example of a heteroalkenyl group is alkenoxy, and the term "alkenoxy" as used herein refers to alkenyl-O-. A heteroalkenylene is a divalent heteroalkenyl group.

[0238] The term "heteroalkynyl" as used herein refers to an alkynyl group (as defined herein) in which one or more of the constituent carbon atoms is replaced by nitrogen, oxygen, or sulfur. In certain embodiments, a heteroalkynyl group may be further substituted with one, two, three, or four substituents as set forth herein for alkynyl groups. An example of a heteroalkynyl group is alkynoxy, where the term "alkynoxy" as used herein refers to alkynyl-O-. Heteroalkynylene is a divalent heteroalkynyl group.

[0239] The term "heteroaryl" as used herein refers to an aromatic monocyclic or polycyclic radical of 5 to 12 atoms having at least one aromatic ring containing 1, 2, or 3 ring heteroatoms selected from N, O, and S with the remaining ring atoms being C. One or two ring carbon atoms of the heteroaryl group may be substituted with a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazoyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, oxaxolyl, and thiazolyl.

[0240] As used herein, the term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group. Exemplary unsubstituted heteroarylalkyl groups include those having 7 to 30 carbons (e.g., 7 to 16 or 7 to 20 carbons, e.g., C 2 ~C 9 Heteroaryl C 1~6 Alkyl, C 2 ~C 9 Heteroaryl C 1~10 Alkyl, or C 1~20 C 2 ~C 9 In certain embodiments, alkyl and heteroaryl may each be further substituted with 1, 2, 3, or 4 substituents, as indicated herein for each group.

[0241] The term "heterocyclyl" as used herein means a monocyclic or polycyclic radical having 3 to 12 atoms, with at least one ring containing 1, 2, 3, or 4 ring heteroatoms selected from N, O, or S, and where the ring is not aromatic. Examples of heterocyclyl include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl.

[0242] As used herein, the term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group. Exemplary unsubstituted heterocyclylalkyl groups include those having 7 to 30 carbons (e.g., 7 to 16 or 7 to 20 carbons, e.g., C 2 ~C 9 Heterocyclyl C 1~6 Alkyl, C 2 ~C 9 Heterocyclyl C 1 ~C 10 Alkyl, or C 2 ~C 9 Heterocyclyl C 1 ~C 20 In certain embodiments, alkyl and heterocyclyl may each be further substituted with 1, 2, 3, or 4 substituents, as indicated herein for each group.

[0243] The term "hydroxyl" as used herein refers to an --OH group. The term "N-protecting group" as used herein refers to a group intended to protect an amino group against undesired reactions during a synthetic process. Commonly used N-protecting groups are described in "Protective Groups in Organic Synthesis", 3 rdEdition (John Wiley & Sons, New York, 1999). N-protecting groups include acyl, aryloyl, or carbamyl groups, such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, as well as chiral auxiliaries, such as protected or unprotected D,L, or D,L-amino groups. p-toluenesulfonyl; carbamate-forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl; , 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl Examples of aryl groups include aryl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl, arylalkyl groups such as benzyl, triphenylmethyl, and benzyloxymethyl, and silyl groups such as trimethylsilyl.Preferred N-protecting groups are allyloxycarbonyl (alloc), formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[0244] As used herein, the term "nitro" refers to -NO 2 Represents a group. The term "thiol" as used herein refers to a --SH group. Each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups may be substituted or unsubstituted. If substituted, typically 1 to 4 substituents may be present, unless otherwise specified. Substituents include, for example, alkyl (e.g., unsubstituted and substituted, where the substituents include any of the groups described herein, e.g., aryl, halo, hydroxy), aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halogen (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclyl, amino (e.g., NH 2 or mono- or dialkylamino), azido, cyano, nitro, or thiol. Another exemplary substituent is oxo. For example, a carbonyl group is a carbon (e.g., an alkyl carbon, an alkenyl carbon, an alkynyl carbon, a heteroalkyl carbon, a heteroalkenyl carbon, a heteroalkynyl carbon, a carbocyclyl carbon, etc.) substituted with an oxo. Meanwhile, sulfur can be substituted with one or two oxo groups (e.g., -SO- or -SO in a substituted heteroalkyl, heteroalkenyl, heteroalkynyl, or heterocyclyl group). 2-). The aryl, carbocyclyl (e.g., cycloalkyl), heteroaryl, and heterocyclyl groups may also be substituted with alkyl (unsubstituted and substituted, for example, arylalkyl (e.g., substituted and unsubstituted benzyl)).

[0245] The compounds of the present invention may have one or more asymmetric carbon atoms and may exist in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, or mixtures of diastereoisomeric racemates. Optically active forms can be obtained, for example, by resolution of racemates, asymmetric synthesis, or asymmetric chromatography (chromatography using chiral adsorbents or eluents). That is, some of the disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain asymmetrically substituted carbon atoms that act as chiral centers. "Enantiomer" means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms and have an arrangement of substituents around one or more chiral carbon atoms. Enantiomers of a compound can be prepared by separating the enantiomer from a racemate using one or more well-known techniques and methods, such as, for example, chiral chromatography and separation methods based thereon. Suitable techniques and / or methods for separating the enantiomers of the compounds described herein from a racemic mixture can be readily determined by one of ordinary skill in the art. "Racemate" or "racemic mixture" refers to a compound containing two enantiomers, and such mixtures do not exhibit optical activity, i.e., do not rotate the plane of polarized light. "Geometric isomer" refers to isomers that differ in the orientation of substituent atoms in relation to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic ring system. Atoms (other than H) on each side of a carbon-carbon double bond can be in the E configuration (substituents are on opposite sides of the carbon-carbon double bond) or the Z configuration (substituents are oriented on the same side). "R", "S", "S" and "S" are examples of isomers that are not related to each other. * ", "R *", "E", "Z", "cis", and "trans" indicate configurations relative to the core molecule. Some of the disclosed compounds may exist in the form of atropisomers. Atropisomers are stereoisomers resulting from hindered rotation around a single bond, where the steric strain barrier to rotation is high enough to allow isolation of the conformers. The compounds of the invention can be prepared as individual isomers by isomer-specific synthesis or separated from an isomeric mixture. Common separation techniques include forming a salt of the free base of each isomer of the isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming a salt of the acid form of each isomer of the isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of the isomeric pair using an optically pure acid, amine, or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or separating isomeric mixtures of either the starting materials or the final products using a variety of well-known chromatographic methods. When the stereochemistry of a disclosed compound is indicated by name or structure, the indicated stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight relative to the other stereoisomers. When a single enantiomer is indicated by name or structure, the indicated enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure by weight. When a single diastereomer is indicated by name or structure, the indicated diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Percent optical purity is the ratio of the weights of the enantiomers or the weight of the enantiomer plus the weight of its optical isomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer or the weight of all diastereomers.When the stereochemistry of a disclosed compound is indicated by name or structure, the indicated stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% molar fraction pure relative to the other stereoisomer. When a single enantiomer is indicated by name or structure, the indicated enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% molar fraction pure. When a single diastereomer is indicated by name or structure, the indicated diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% molar fraction pure. Percent purity by mole fraction is the ratio of moles of enantiomers or moles of enantiomer plus moles of its optical isomer. Similarly, percent purity by mole fraction is the ratio of the moles of diastereomers or the moles of diastereomers plus the moles of its isomer. When a disclosed compound is shown by name or structure without indicating stereochemistry and the compound has at least one chiral center, the name or structure should be understood to encompass either an enantiomer of the compound without the corresponding optical isomer, a racemic mixture of the compound, or a mixture enriched in one enantiomer over its corresponding optical isomer. When a disclosed compound is shown by name or structure without indicating stereochemistry and the compound has two or more chiral centers, the name or structure should be understood to encompass a diastereomer without the other diastereomer, some diastereomers without other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs where one diastereomer is enriched over the other diastereomer(s), or mixtures of diastereomers where one or more diastereomers are enriched over the other diastereomers. The present invention encompasses all of these forms.

[0246] definition In this application, unless otherwise clear from the context, (i) the term "a" may be understood to mean "at least one," (ii) the terms "comprising" and "including" may be understood to include the recited components or steps, whether a component or step is presented alone or in combination with one or more other components or steps, (iii) the term "about" may be understood to allow for standard deviation, as would be apparent to one of ordinary skill in the art, and (iv) when a range is provided, the range is inclusive.

[0247] The term "about" as used herein refers to a value in the range of ±10% of the value following the term "about." When a value or parameter is described herein with "about," the variation of the value or parameter itself is included (and indicated). For example, the description "about X" describes "X."

[0248] The term "administration" as used herein refers to administering a composition (e.g., a compound or a formulation comprising Compound 1) to a subject or system. Administration to an animal subject (e.g., a human) can be by any suitable route. For example, in certain embodiments, administration can be bronchial (including by bronchial instillation), buccal, enteral, intradermal, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, intravaginal, and intravitreal.

[0249] The "effective amount" of a compound (e.g., Compound 1) may vary depending on factors such as the disease state, age, sex, and weight of an individual, and the ability of the compound to induce a desired response. A therapeutically effective amount also means an amount in which any toxic or harmful effects of a compound are outweighed by therapeutically beneficial effects. An effective amount also means an amount sufficient to provide a useful effect, e.g., a clinical useful effect.

[0250] In practicing the methods of this invention, an "effective amount" of any one of the compounds of this invention, or any combination of the compounds of this invention, or a pharma- ceutically acceptable salt thereof, is administered, either alone or in combination, by any of the common and accepted methods known in the art.

[0251] The term "pharmaceutical composition" as used herein refers to a composition comprising a compound described herein formulated with a pharmaceutically acceptable excipient, which is manufactured or sold as part of a regimen for the treatment of a mammalian disease, with the approval of a government regulatory agency. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., tablet, capsule, caplet, gelcap, or syrup), for topical administration (e.g., as a cream, gel, lotion, or ointment), for intravenous administration (e.g., as a sterile solution free of particulate embolic material, in a solvent system suitable for intravenous use), or in any other pharmaceutically acceptable formulation.

[0252] The term "pharmaceutical acceptable excipient" as used herein refers to any component other than the compounds described herein (e.g., a medium that can suspend or dissolve an active compound) that has the properties of being substantially non-toxic and non-inflammatory in patients.Excipients include, for example, anti-adhesive agents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (coloring agents), emollients, emulsifiers, bulking agents (diluents), film-forming or coating agents, flavoring agents, flavoring agents, glidants (glidants), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, and water for hydration. Excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0253] The term "pharmaceutically acceptable salt" as used herein means any pharmaceutically acceptable salt of a compound of formula (I). For example, pharmaceutically acceptable salts of any of the compounds described herein include salts that are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, or allergic response, and that are commensurate with a reasonable benefit-risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the compounds described herein, or can be prepared separately by reacting the free base group with a suitable organic acid.

[0254] The compounds of the present invention may have ionizable groups so that they can be prepared as pharmaceutically acceptable salts.These salts may be, for example, acid addition salts, including inorganic or organic acids, or salts may be prepared from inorganic or organic bases when the compounds of the present invention are in acidic form.In many cases, compounds are prepared or used as pharmaceutically acceptable salts, and these pharmaceutically acceptable salts are prepared as addition products of pharmaceutically acceptable acids or bases.Suitable pharmaceutically acceptable acids and bases, as well as methods for preparing suitable salts, are well known in the art.Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic and organic acids and bases.

[0255] Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, and 2-hydroxy-ethanesulfonate. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary, and amine cations, such as, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

[0256] As used herein, the term "Sec61-associated disorder" is a disorder caused by a polypeptide that is translocated via Sec61. The term "selective" as used herein refers to preferential inhibition of a target process (e.g., translocation of a particular protein through a protein secretion complex such as Sec-61) rather than a non-target process. A compound of the present disclosure that is selective may inhibit a target process at a concentration 10-fold or more than a non-target process (e.g., a compound that is selective may inhibit a target process at a concentration 10-fold or more, 20-fold or more, 50-fold or more, 100-fold or more, 1000-fold or more, 10000-fold or more, 100000-fold or more, 1000000-fold or more). A compound that is selective may be described as having "pharmacologically relevant selectivity" if it is sufficiently selective to inhibit a target process (e.g., translocation of a disease-related protein through Sec61) in a subject while being tolerated by the subject over the course of administration to the subject.

[0257] The term "subject" as used herein refers to any organism to which the composition according to the present invention can be administered, for example, for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Exemplary subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may be a human or animal that is seeking or in need of treatment, is in need of treatment, is undergoing treatment, will be undergoing treatment in the future, or is being seen by a trained professional for a particular disease or illness.

[0258] The terms "treatment", "treated" or "treating" as used herein refer to both therapeutic treatment and prophylactic or preventative measures, where the subject aims to prevent or slow (alleviate) an undesirable physiological condition, disorder or disease, or to obtain beneficial or desired clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, reduction in the extent of the disease, disorder or disease, stabilization (i.e., not worsening) of the disease, disorder or disease state, delay in onset or slowing of progression of the disease, disorder or disease, improvement or remission (whether partial or complete) of the disease, disorder or disease state (whether detectable or not), improvement in at least one measurable physical parameter (not necessarily recognized by the patient), or improvement or amelioration of the disease, disorder or disease. Treatment includes eliciting a clinically significant response without an excessive level of side effects. Treatment also includes prolonging survival compared to the expected survival if not receiving treatment.

[0259] As used herein, the term "translocation" refers to the process by which proteins move between cellular compartments. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Methods and materials for use in this disclosure are described herein, but other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0260] The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description, and from the claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0261] The present invention features compounds useful for selectively inhibiting protein secretion, for example, by selectively inhibiting the Sec61 protein secretion complex. Exemplary compounds described herein include compounds having a structure according to Formula I:

[0262] [ka]

[0263] or a pharma- ceutically acceptable salt thereof. 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 diseases and / or disorders associated with Sec61, and the use of these compounds in the selective inhibition of Sec61, are described herein.

[0264] Sec61 inhibitors Exemplary Sec61 inhibitors disclosed herein include compounds of Formula I:

[0265] [ka]

[0266] During the ceremony, R 1 is H, optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 3 ~C 7 Cycloalkyl, optionally substituted C 2 ~C 9 Heterocycle, optionally substituted C 6 ~C 10 Aryl, optionally substituted C 2 ~C 9 Heteroaryl, C 2 ~C 9 Heteroaryl C 1 ~C 6 Alkyl, or R a -Rb -R c and R a is C 6 ~C 10 is an arylene, R b is -O- or optionally substituted C 1 ~C 6 is alkylene, R c is C 6 ~C 10 is aryl, Z is absent or optionally substituted C 3 ~C 10 Cycloalkylene, optionally substituted C 2 ~C 9 Heterocyclylene, C 6 ~C 10 Arylene or optionally substituted C 2 ~C 9 Heteroarylene, Y is absent, O, or NR 3 and X is an optionally absent or substituted C 1 ~C 6 is alkylene, W is absent, S, O, or NR 3 and n is 0 or 1, A is S, O, or CH; B is C or N; R 2 is optionally substituted C 1~6 Alkyl, optionally substituted C 2 ~C 6 Alkenyl, optionally substituted C 3~7 Cycloalkyl, optionally substituted C 2~9 Heterocycle, optionally substituted C 6 ~C 10 Aryl, optionally substituted C 2~9 Heteroaryl, optionally substituted C 2 ~C 9 Heteroaryl C 1~C 6 Alkyl, optionally substituted C 3 ~C 7 Cycloalkyl C 1 ~C 6 Aryl, optionally substituted C 1 ~C 6 heteroalkyl, or cyano; and Each R 3 are independently H or C 1 ~C 6 It is an alkyl.

[0267] Exemplary Sec61 inhibitors described herein include compounds of Formula II, below:

[0268] [ka]

[0269] Exemplary Sec61 inhibitors described herein include compounds of Formula III, below:

[0270] [ka]

[0271] Exemplary Sec61 inhibitors described herein include compounds of Formula IV:

[0272] [ka]

[0273] Exemplary Sec61 inhibitors described herein include compounds of Formula V:

[0274] [ka]

[0275] In the formula, Y is O or NR 3 It is. Exemplary Sec61 inhibitors described herein include compounds of Formula VI:

[0276] [ka]

[0277] In the formula, W is NR 3 It is. Exemplary Sec61 inhibitors described herein include compounds of Formula VII:

[0278] [ka]

[0279] In the formula, A, B, C, and D are each independently N, CH, or CR. 4 and Each R 4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol.

[0280] Exemplary Sec61 inhibitors described herein include compounds of Formula VIII:

[0281] [ka]

[0282] In the formula, B, C, and D are each independently CH or CR 4 It is. Exemplary Sec61 inhibitors described herein include compounds of Formula IX:

[0283] [ka]

[0284] In the formula, A, C, and D are each independently CH or CR 4 It is. Exemplary Sec61 inhibitors described herein include compounds of formula X:

[0285] [ka]

[0286] In the formula, A, B, and D are each independently CH or CR 4 It is. Exemplary Sec61 inhibitors described herein include compounds of formula XI:

[0287] [ka]

[0288] In the formula, A, B, and C each independently represent CH or CR. 4 It is. Exemplary Sec61 inhibitors described herein include compounds of formula XII:

[0289] [ka]

[0290] In the formula, A and B are each independently CH or CR 4 It is. Exemplary Sec61 inhibitors described herein include compounds of formula XIII:

[0291] [ka]

[0292] In the formula, A and D are each independently CH or CR4 It is. Exemplary Sec61 inhibitors described herein include compounds of formula XIV:

[0293] [ka]

[0294] In the formula, C and D are each independently CH or CR 4 It is. Exemplary Sec61 inhibitors described herein include compounds of Formula XV:

[0295] [ka]

[0296] In the formula, B and D are each independently CH or CR 4 It is. Exemplary Sec61 inhibitors described herein include compounds of Formula XVI:

[0297] [ka]

[0298] In the formula, B and C are each independently CH or CR 4 It is. Exemplary Sec61 inhibitors described herein include compounds of Formula XVII:

[0299] [ka]

[0300] In the formula, A and C are each independently CH or CR 4 It is. Exemplary Sec61 inhibitors described herein include compounds of Formula XVIII:

[0301] [ka]

[0302] In the formula, A is CH or CR 4 It is. Exemplary Sec61 inhibitors described herein include compounds of formula XIX:

[0303] [ka]

[0304] In the formula, D is CH or CR 4 It is. Exemplary Sec61 inhibitors described herein include compounds of formula XX:

[0305] [ka]

[0306] In the formula, B is CH or CR 4 It is. Exemplary Sec61 inhibitors described herein include compounds of formula XXI:

[0307] [ka]

[0308] In the formula, C is CH or CR 4 It is. Exemplary Sec61 inhibitors described herein include compounds of Formula XXII:

[0309] [ka]

[0310] In the formula, A, B, C, and D are each independently CH or CR4 It is. Exemplary Sec61 inhibitors described herein include compounds of Formula XXIII:

[0311] [ka]

[0312] wherein o is 0, 1, 2, 3, or 4; and Each R 4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol.

[0313] Exemplary Sec61 inhibitors described herein include compounds of Formula XXIV:

[0314] [ka]

[0315] wherein o is 0, 1, 2, or 3; and Each R 4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol.

[0316] Exemplary Sec61 inhibitors described herein include compounds of Formula XXV:

[0317] [ka]

[0318] where E is NH, O, or S; F and G are each independently N, CH, or CR. 4 and Each R 4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol.

[0319] Exemplary Sec61 inhibitors described herein include compounds of Formula XXVI:

[0320] [ka]

[0321] In the formula, F and G are each independently CH or CR 4 It is. Exemplary Sec61 inhibitors described herein include compounds of Formula XXVII:

[0322] [ka]

[0323] In the formula, F and G are each independently CH or CR 4 It is. Exemplary Sec61 inhibitors described herein include compounds of Formula XXVIII:

[0324] [ka]

[0325] In the formula, F and G are each independently CH or CR 4 It is. Exemplary Sec61 inhibitors described herein include compounds of formula XXIX:

[0326] [ka]

[0327] where E is NH, O, or S; F and G are each independently N, CH, or CR. 4 and Each R 4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol.

[0328] Exemplary Sec61 inhibitors described herein include compounds of formula XXX:

[0329] [ka]

[0330] In the formula, F and G are each independently CH or CR 4 It is. Exemplary Sec61 inhibitors described herein include compounds of formula XXXI:

[0331] [ka]

[0332] In the formula, F and G are each independently CH or CR 4 It is. Exemplary Sec61 inhibitors described herein include compounds of formula XXXII:

[0333] [ka]

[0334] In the formula, F and G are each independently CH or CR 4 It is. Exemplary Sec61 inhibitors described herein include compounds of formula XXXIII:

[0335] [ka]

[0336] During the ceremony, E is NH, O, or S; F and G are each independently N, CH, or CR. 4 and Each R 4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol.

[0337] Exemplary Sec61 inhibitors described herein include compounds of formula XXXIV:

[0338] [ka]

[0339] In the formula, F and G are each independently CH or CR 4 It is. Exemplary Sec61 inhibitors described herein include compounds of formula XXXV:

[0340] [ka]

[0341] In the formula, F and G are each independently CH or CR 4 It is. Exemplary Sec61 inhibitors described herein include compounds of formula XXXVI:

[0342] [ka]

[0343] In the formula, F and G are each independently CH or CR 4 It is. Exemplary Sec61 inhibitors described herein include compounds of formula XXXVII:

[0344] [ka]

[0345] where E is N or CH; F, G, and H are each independently N, CH, or CR. 4 and Each R 4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol.

[0346] Exemplary Sec61 inhibitors described herein include compounds of Formula XXXVIII:

[0347] [ka]

[0348] Exemplary Sec61 inhibitors described herein include compounds of formula XXXIX:

[0349] [ka]

[0350] Exemplary Sec61 inhibitors described herein include compounds of formula XXXX:

[0351] [ka]

[0352] Exemplary Sec61 inhibitors described herein include compounds of formula XXXXI:

[0353] [ka]

[0354] Exemplary Sec61 inhibitors described herein include compounds of formula XXXXII:

[0355] [ka]

[0356] In the formula, A, B, C, and D each independently represent CH, CR 4 , or N, and Each R 4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol.

[0357] Exemplary Sec61 inhibitors described herein include compounds of formula XXXXIII:

[0358] [ka]

[0359] The Sec61 inhibitors described herein include any one of the compounds in Table 1. Table 1: Compounds of the invention

[0360] [Table 1-1]

[0361] [Table 1-2]

[0362] [Table 1-3]

[0363] [Table 1-4]

[0364] [Table 1-5]

[0365] Pharmaceutical Compositions 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. Thus, in one aspect, the invention provides a pharmaceutical composition comprising a compound of the invention mixed with a suitable diluent, carrier, or excipient.

[0366] The compounds of the present invention can be used in the form of free base, in the form of salts, in the form of solvates, and as prodrugs. All forms are within the scope of the present invention. According to the method of the present invention, the described compounds or their salts, solvates, or prodrugs can be administered to patients in various forms depending on the selected route of administration, as will be understood by those skilled in the art. The compounds of the present invention can be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration, and the pharmaceutical composition is formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, pulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration can be by continuous infusion over a selected period of time.

[0367] The compounds of the present invention can be administered orally, for example, with an inert diluent or an assimilable edible carrier, or enclosed in hard or soft shell gelatin capsules, or compressed into tablets, or incorporated directly into the food of the diet.For oral therapeutic administration, the compounds of the present invention can be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers.

[0368] The compounds of the invention may be administered parenterally. Solutions of the compounds of the invention may be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions may be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof with or without alcohol, and in oils. These preparations may contain a preservative to prevent the growth of microorganisms under ordinary conditions of storage and use. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003, 2006). th ed.) and The United States Pharmacopeia: The National Formulary, published in 1999 (USP24NF19).

[0369] 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 it can be easily administered via syringe.

[0370] Compositions for nasal administration can conveniently be formulated as aerosols, drops, gels, and powders. Aerosol formulations typically contain a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent, and are usually provided in single or multiple doses in a sterile form in a sealed container, which can take the form of a cartridge or refill for use in a nebulizer device. Alternatively, the sealed container may be an integrated dispenser, such as a single-dose nasal inhaler, or an aerosol dispenser with a metering valve so that it can be discarded after use. If the dosage form includes an aerosol dispenser, it will contain a propellant, which can be a compressed gas, such as compressed air, or an organic propellant, such as a fluorochlorohydrocarbon. Aerosol dosage forms can also take the form of a pump-atomizer.

[0371] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, gelatin, and glycerin. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

[0372] The compounds of the invention can be administered to animals, including humans, alone or in combination with a pharma- ceutically acceptable carrier, as described herein, the proportion of the carrier being determined according to the solubility and chemical nature of the compound, the chosen route of administration, and standard pharmaceutical practice.

[0373] dose The dosage of the compound of the present invention and / or the composition containing the compound of the present invention may vary depending on many factors, such as the pharmacodynamic properties of the compound, the mode of administration, the age, health condition and weight of the subject to be treated, the nature and extent of symptoms, the frequency of treatment, and the type of concurrent treatment (if any), and the clearance rate of the compound in the animal to be treated.Those skilled in the art can determine the appropriate dosage based on the above factors.The compound of the present invention may be initially administered at a suitable dosage, which may be adjusted as necessary depending on clinical response.

[0374] Protein secretion A myriad of proteins are secreted from cells. In humans, secreted proteins are transported from the cytosol to the outside of the cell via the protein secretion pathway. The protein secretion pathway includes the endoplasmic reticulum, the Golgi apparatus, secretory or transport vesicles, and the cell membrane. To be secreted from a cell, a protein must pass through biological membranes that divide the cell into compartments. The passage of proteins from the cytosol to the membrane of the endoplasmic reticulum is facilitated by the translocon, a protein complex that contains at least Sec61.

[0375] A polypeptide secreted from a cell may contain a signal peptide. A signal peptide is a sequence of amino acids located at the N-terminus of a secreted polypeptide. A signal peptide promotes targeting of a polypeptide to a translocon, for example, to Sec61. In some cases, after translocation through a translocon, for example through Sec61, the signal peptide is cleaved from the polypeptide, generating a free signal peptide and a mature polypeptide.

[0376] Inhibition of Sec61 Sec61 is a membrane protein complex that translocates nascent proteins from the cytosol to the endoplasmic reticulum in humans. Sec61 is a heterotrimeric complex containing three subunits, SecY, SecE, and SecG. Newly synthesized polypeptides enter the membrane of the endoplasmic reticulum via Sec61 from ribosomes that associate with Sec61. Sec61 contains a channel through which the polypeptide passes and a luminal plug that blocks passage through the channel when closed. The polypeptide interacts with another part of Sec61 when the luminal plug is displaced and the channel opens.

[0377] The present inventors have discovered small molecules that selectively inhibit the translocation of certain 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, the conserved portion of the Sec61 inhibitor binds to Sec61. In some embodiments, the variable portion of the Sec61 inhibitor contacts the signal peptide of a nascent polypeptide that is in the process of translocating through Sec61. In some embodiments, the contact between the variable portion of the Sec61 inhibitor and the signal peptide of the nascent polypeptide blocks 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.

[0378] In some embodiments, the signal peptide is orthogonal and independent of the mature protein sequence, hi some embodiments, targeting the signal portion of the polypeptide allows for inhibition of a target without a druggable handle.

[0379] In some embodiments, body components, such as the immune system, recognize cells by proteins expressed on the cell surface. In some embodiments, cell identity is determined by proteins expressed on the cell surface. In some embodiments, selective targeting of Sec61-mediated translocation of proteins expressed on the cell surface allows selective editing of proteins expressed on the cell surface. In some embodiments, selective targeting of Sec61-mediated translocation of proteins expressed on the cell surface allows non-destructive changes to cell identity. In some embodiments, selective targeting of Sec61-mediated translocation of proteins expressed on the cell surface allows removal of surface proteins without damaging the cell.

[0380] In certain embodiments, selective targeting of Sec61-mediated translocation of proteins allows for targeting of tissue types inaccessible to other modalities, e.g., brain (mABS) and non-liver (siRNA).

[0381] In one embodiment, selective targeting of Sec61-mediated translocation of newly made proteins and cells that actively synthesize proteins allows for targeting of dynamically regulated targets and synthesis-sensitive cells.

[0382] In one embodiment, by selectively targeting Sec61-mediated translocation of irreversible virulence proteins, one can target irreversible virulence protein aggregation and irreversible virulence protein cascades.

[0383] In one embodiment, selective targeting of viral protein translocation through Sec61 blocks viral protein secretion and inhibits viral replication. Treatment method The compounds described herein may be used to treat diseases and / or disorders associated with secreted proteins translocated through Sec61. In certain embodiments, the compounds described herein selectively inhibit the translocation of disease-related proteins through Sec61. Diseases and / or disorders associated with Sec61 that can be treated by the compounds described herein include amyloidosis, light chain amyloidosis, autoantibody diseases, chronic kidney disease, fibrosis, neurodegeneration, autoimmune diseases, genetically defined kidney diseases, viral diseases, influenza, dengue virus, Zika virus, hepatitis B virus, hepatitis C virus, SARS-CoV-2, human immunodeficiency virus, malaria, cancer, glioma, myeloma, various cancers with solid tumors, autoimmune diseases, rheumatoid arthritis, ankylosing spondylitis, celiac disease, multiple sclerosis, and atopic dermatitis. , Crohn's disease, psoriasis, allergic asthma, autoimmune antibody diseases, myasthenia gravis, neuromyelitis optica, warm antibody hemolytic anemia, prion diseases, 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-Sträussler-Scheinker syndrome, high cholesterol, metabolic syndrome, and fatal familial insomnia.

[0384] Light-chain amyloidosis Amyloidosis is a group of diseases characterized by harmful and undesirable accumulation of misfolded amyloid proteins in various tissues. Non-limiting examples of tissues that may suffer from accumulation of misfolded amyloid proteins include kidney, heart, brain, liver, thyroid, adrenal gland, musculoskeletal system, eye, and oral cavity. Light chain amyloidosis is a form of amyloidosis characterized by accumulation of amyloid proteins formed from antibody light chains (AL) produced in bone marrow by plasma cells. Secretion of light chains in plasma cells is promoted by Sec61. In light chain amyloidosis, amyloid proteins are deposited in tissues throughout the body, including but not limited to the kidney, heart, digestive system, liver, and nervous system. Without wishing to be bound by theory, inhibiting light chain translocation by Sec61 may reduce the level of amyloid derived from light chains present in tissues, including but not limited to the kidney, heart, digestive system, liver, and nervous system.

[0385] Prion diseases Prion diseases are fatal neurodegenerative disorders caused by elevated levels of misfolded prion protein (PrP). Individuals with prion diseases may experience brain dysfunction, leading to memory, personality, and behavioral changes, dementia, and ataxia. PrP is translocated from the cytosol to the endoplasmic reticulum by Sec61. Without wishing to be bound by theory, inhibiting Sec61-mediated translocation of PrP may reduce circulating PrP levels, for example, in the brain.

[0386] autoimmune antibody disease Autoimmune antibody diseases are characterized by the failure of the immune system to distinguish between host and foreign antigens. In some instances, autoimmune antibody diseases are composed of immunoglobulin G (IgG) that has pathogenic effects on the body. The neonatal fragment crystallizable receptor (FcRn) is a protective IgG receptor and positively correlates with the levels of circulating IgG. FcRn translocates into the endoplasmic reticulum via Sec61. Without wishing to be bound by theory, inhibition of FcRn translocation may reduce IgG levels.

[0387] Genetically defined kidney disease Genetically defined kidney disease includes a group of kidney diseases that have genetic origin. Non-limiting examples of genetically defined kidney disease include end-stage kidney disease (ESKD) and focal segmental glomerulosclerosis (FSGS). APOL1 is a protein associated with genetically defined kidney disease. APOL1 translocates into the endoplasmic reticulum via Sec61. Without wishing to be bound by theory, inhibiting the translocation of APOL1 by Sec61 can reduce the level of APOL1 in the kidney, thus preserving podocytes and slowing the progression of kidney disease.

[0388] malaria Malaria is a disease caused by the parasite Plasmodium falciparum. P. falciparum utilizes Sec61 to transport proteins important for its survival and replication into host erythrocytes. Without wishing to be bound by theory, inhibition of Sec61-mediated translocation of P. falciparum proteins can inhibit the replication of P. falciparum.

[0389] Viral diseases All viruses utilize the cellular machinery of their host cells for replication. Non-limiting examples of viruses whose ability to replicate in host cells may be Sec61-dependent include influenza virus, 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 transport of viral proteins to biological membranes (e.g., transport to the endoplasmic reticulum). Without wishing to be bound by theory, inhibiting the translocation of viral proteins via Sec61 may prevent viral replication in host cells.

[0390] cancer Cancer is a group of diseases characterized by harmful, abnormal, uncontrolled and unwanted proliferation of cells. Cancer occurs in multiple tissues and organs, including lung, breast, bladder, colon, rectum, uterus, testes, kidney, blood, lymphatic system, liver, bile duct, skin, pancreas, prostate, thyroid, brain, spinal cord, and stomach. Cancer cells differ from healthy cells in their protein expression profile. For example, cancer cells may express proteins involved in tumor metastasis (e.g., CD74) at higher levels than healthy cells.

[0391] Without wishing to be bound by theory, proteins that translocate through Sec61 in cancer cells may be different from proteins that translocate through Sec61 in healthy cells. Furthermore, proteins that translocate through Sec61 in both cancer cells and healthy cells may translocate through Sec61 at a higher rate in cancer cells than in healthy cells. Furthermore, cancer cells may depend on proteins that translocate through Sec61 for survival (e.g., increased proliferation or evasion from immune recognition). Cancer cell proliferation may be inhibited by inhibiting the translocation of proteins that translocate through Sec61 in cancer cells but not in healthy cells and / or by inhibiting the translocation of proteins that translocate through Sec61 at a higher level in cancer cells than in healthy cells and / or by inhibiting the translocation of proteins that cancer cells depend on for increased proliferation or evasion from immune recognition.

[0392] Equivalence and Scope Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is not intended that the scope of the present invention be limited to the foregoing description.

[0393] The following examples are illustrative only and are not intended to limit the invention in any way. EXAMPLES

[0394] Example 1: Synthesis of Compounds Compounds of the invention can be synthesized according to one or more of the exemplary syntheses set forth below.

[0395] Materials and Methods NMR Instrumentation: NMR spectra were recorded at 400 MHz using a QOne AS400 400 MHz spectrometer.

[0396] LC-MS (Aglient-P2): LC: Agilent Technologies 1290 series, binary pump, diode array detector, Agilent EclipsePlus RRHD C18, 1.8 μm, 3.0 × 50 mm, mobile phase: A: 0.05% (v / v) formic acid in water, B: 0.05% (v / v) formic acid in MeCN, flow rate: 0.8 mL / min, 25 °C, detector: 214 nm, 254 nm.

[0397] Timetable:

[0398] [Table 2]

[0399] LC-MS (SHIMADZU-2020-P2): LC: Shimadzu LC-20AD series, binary pump, diode array detector, Waters Sunfire, 3.5 μm, 4.6 x 50 mm column, mobile phase: A: 0.05% (v / v) formic acid in water, B: 0.05% (v / v) formic acid in MeCN, flow rate: 1 mL / min, 25 o C, Detectors: 214 nm, 254 nm. Gradient stop time, 5 min. Timetable:

[0400] [Table 3]

[0401] 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 o C, Vcap: 4500V 2. Sample preparation: Samples were dissolved in methanol at 1-10 μg / mL and then filtered through a 0.22 μm filtration membrane. Injection volume: 1-10 μL HPLC (Agilent-1200-A2) LC: Agilent Technologies 1200 series, binary pump, diode array detector, column temperature: 35°C, detection wavelength: 214 nm, 254 nm, mobile phase A: 0.1% (v / v) TFA in water, 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 minutes Timetable:

[0402] [Table 4]

[0403] Synthesis of intermediate 1 Step 1: Synthesis of methyl (2R)-4,4-difluoro-1-[phenyl]pyrrolidine-2-carboxylate

[0404] [ka]

[0405] In a 100 mL round bottom flask equipped with a stir bar was added methyl (2R)-4,4-difluoropyrrolidine-2-carboxylate (2.00 g, 4.4 mmol, 1.00 equiv), phenylboronic acid (1.59 g, 13.0 mmol, 3 equiv), Cu(OAc) 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) were charged under nitrogen atmosphere. The reaction flask was then evacuated and filled with oxygen, which was repeated twice. The vial was capped and placed in a 25° C. bath. The reaction mixture was stirred under oxygen atmosphere at 25° C. for 48 h using an oxygen balloon. The reaction mixture was poured into DCM (150 mL) and NH 3 H 2 Quench by addition of O (20 mL) and 2 The organic layer was washed with 2×30 mL of NaClO (1×50 mL) and brine (3×50 mL). 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography to give the desired product. LCMS (+ESI): calculated [M+H]+=242, found 242. Step 2: Synthesis of 2-(2-chloroacetyl)-4,4-difluoro-1-[phenyl]pyrrolidine

[0406] [ka]

[0407] A 20 mL vial equipped with a 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 THF (1.0 mL, 0.2 M). The reaction mixture was cooled to 0° C. and tert-butyl magnesium 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 3 (2x50 mL). The combined aqueous layers were extracted with EtOAc (1x50 mL) and the combined organic layers were washed with Na 2 SO 4 The mixture was dried at 4° C., filtered and concentrated in vacuo, and the crude material obtained was used in the next step without further purification.

[0408] LCMS(+ESI): Calculated [M+H]+=260, Found 260 Step 3: Synthesis of (R)-4-(1-phenyl-4,4-difluoropyrrolidin-2-yl)thiazol-2-amine (Intermediate I)

[0409] [ka]

[0410] A 20 mL vial equipped with a 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 diluted with saturated NaHCO 3 (2x100ml) and the combined aqueous layers were extracted with EtOAc (1x100ml). 2 SO 4The mixture was dried at 40° C., filtered and concentrated in vacuo The crude material was purified by silica gel chromatography to give the desired product.

[0411] LCMS(+ESI): Calculated [M+H]+=282, Found 282 Intermediate 1 can be used to prepare compounds of the invention. For example, the following procedure illustrates the synthesis of compounds of the invention, including amides, using Intermediate 1 and a carboxylic acid.

[0412] Synthesis of amides using intermediate 1 and carboxylic acids Intermediate 1 was added to a solution of carboxylic acid and EDCI in DMF, followed by the addition of DIPEA. After 24 h, the mixture was diluted with EtOAc and washed with water (4x), then the organic fraction was concentrated in vacuo and purified using silica gel chromatography.

[0413] Synthesis of 2-(pyridin-4-yl)ethyl (R)-(4-(1-phenylpyrrolidin-2-yl)thiazol-2-yl)carbamate (Compound 1)

[0414] [ka]

[0415] 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 dropwise a solution of DMAP (99 mg, 0.84 mmol) in DCM (1 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, and then (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (51 mg, 0.24 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. After the stirring was complete, 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) and concentrated with NaCl. 2 SO 4The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1, v / v) to give the title compound (15 mg, 16% yield) as a pink solid.

[0416] LCMS (Agilent-S12): Retention time = 2.65 minutes, m / z[M+H]+395.2 1H NMR(400MHz,DMSO-d6)δ11.71(s,1H),8.49-8.47(m,2H),7.34-7.32(m,2H) ,7.09(t,J=8.4Hz,2H),6.66(s,1H),6.55(t,J=7.2Hz,1H),6.47(d,J=8.0Hz ,2H),4.69(d,J=7.6Hz,1H),4.40(t,J=6.4Hz,2H),3.56(t,J=8.0Hz,1H),3. 26-3.16(m,1H),2.97(t,J=6.4Hz,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)

[0417] [ka]

[0418] A vial equipped with a 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, the vial is capped, and the vial is 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 washed with Na 2 SO 4 Dry at 40° C., filter and concentrate in vacuo. The resulting crude material was purified by silica gel chromatography and preparative HPLC or RP column to give the desired product.

[0419] Synthesis of 3-((4-pyridyl)methoxy)pyridinyl(R)-(4-(4,4-difluoro-1-phenylpyrrolidin-2-yl)thiazol-2-yl)amine (Compound 36)

[0420] [ka]

[0421] A vial equipped with a 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 is capped and placed in a 100° C. bath. The reaction mixture is stirred at 100° 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 washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo. The crude material obtained was purified by silica gel chromatography and preparative HPLC or RP column to give the desired product.

[0422] Synthesis of compound 2

[0423] [ka]

[0424] Step 1: Synthesis of ethyl 3-(pyridin-4-yloxy)propanoate

[0425] [ka]

[0426] A solution of pyridin-4-ol (500 mg, 5.26 mmol, 1 equiv.) in DMF (8 mL) was o At C, NaH (316 g, 7.89 mmol, 1.5 equiv.) was added. The solution was cooled to 0 oC for 0.5 h, and then ethyl 3-bromopropanoate (1.42 g, 7.89 mmol, 1.5 equiv) was added to the solution. The solution was stirred at room temperature for 4 h. Then the solution was extracted with EtOAc (10 mLx3), washed with water (10 mLx3), brine (10 mL), and diluted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give the crude product, which was purified 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.

[0427] LCMS (Waters-QDa-02): Retention time 1.01 min, [M+1] + =196.09 Step 2: Synthesis of 3-(pyridin-4-yloxy)propanoic acid

[0428] [ka]

[0429] Dissolve ethyl 3-(pyridin-4-yloxy)propanoate (650 mg, 3.33 mmol, 1 equiv) in THF (9 mL) and H 2 To a solution of 2H2O (3 mL) was added LiOH (240 mg, 9.99 mmol, 3 equiv.). After stirring at room temperature for 2 h, the reaction mixture was adjusted to pH 2 with aqueous HCl (1 M) and concentrated to give the crude product (550 mg) as a yellow solid.

[0430] LCMS (Waters-QDa-02): Retention time 0.27 min, [M+1] + =168.05 Step 3: Synthesis of (R)-N-(4-(1-phenylpyrrolidin-2-yl)thiazol-2-yl)-3-(pyridin-4-yloxy)propanamide

[0431] [ka]

[0432] To a solution of 3-(pyridin-4-yloxy)propanoic acid (380 mg, 2.27 mmol, 2 equiv.) in DMA (3 mL) was added (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (100 mg, 1.13 mmol, 1 equiv.), EDCI (117 mg, 0.61 mmol, 1.5 equiv.), and DMAP (100 mg, 0.81 mmol, 2 equiv.). o C for 1 h in a microwave. Then the solution was extracted with EtOAc (3 mLx3), washed with water (5 mLx3), brine (5 mL), dried over Na2SO4, and concentrated to give the crude product. The crude product was purified by preparative TLC (DCM / MeOH=10:1, v / v) to give the desired product (6 mg, 0.015 mmol, 1%) as a white solid.

[0433] LCMS (Agilent-1290): Retention time 2.61 minutes, m / z[M+1]+=395.1 / 396.2 HNMR(400MHz,DMSO-d6):δppm: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=8Hz,1H),6.41(s,1H),4.74-4.72(m,1H),4.28(s,2H),3.5 8-3.54(m,2H),2.98-2.94(m,2H),2.26-2.19(m,1H),2.01-1.93(m,3H) HPLC (Agilent-1200-A2): Retention time 10.47 minutes, 96% purity Synthesis of compound 3

[0434] [ka]

[0435] Step 1: Synthesis of 3-((tert-butoxycarbonyl)amino)propanoic acid

[0436] [ka]

[0437] To a solution of 3-aminopropanoic acid (1 g, 11.23 mmol, 1 equiv.) in MeOH (15 mL), 2 O (2.7 g, 12.35 mmol, 1.1 equiv.) and TEA (2.3 g, 22.46 mmol, 2.0 equiv.) were added. After stirring at room temperature for 16 h, the reaction product was adjusted to pH 2 with aqueous HCl (1 M), extracted with DCM (30 mL x 3), washed with water (20 mL x 3), brine (20 mL), and diluted with Na 2 SO 4 After drying at rt and concentration, the desired product (2.11 g, 11.23 mmol, 99%) was obtained as a white solid.

[0438] HNMR: (400MHz, DMSO-d 6 )δppm: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

[0439] [ka]

[0440] To a solution of 3-((tert-butoxycarbonyl)amino)propanoic acid (300 mg, 1.58 mmol, 2 equiv.) in DMF (6 mL), o At C, (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (200 mg, 0.79 mmol, 1 equiv.), DIEA (369 mg, 1.58 mmol, 2 equiv.), and HATU (621 mg, 1.63 mmol, 2 equiv.) were added. The mixture was stirred at room temperature for 16 h. The solution was then extracted with EtOAc (6 mLx3), washed with water (6 mLx3), brine (6 mL), and diluted with NaCl. 2 SO 4The mixture was dried at 40° C. and concentrated to give the crude product, which 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.

[0441] LCMS (Waters-QDa-02): Retention time 1.89 minutes, [M+1] + =417.19 / 418.34 Step 3: (R)-3-amino-N-(4-(1-phenylpyrrolidin-2-yl)thiazol-2-yl)propanamide

[0442] [ka]

[0443] 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 equiv) in dioxane (3 mL) was added HCl / dioxane (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.

[0444] LCMS (Waters-QDa-02): Retention time 0.67 min, [M+1] + =317.19 / 418.20 Step 4: Synthesis of (R)-N-(4-(1-phenylpyrrolidin-2-yl)thiazol-2-yl)-3-(pyridin-4-ylamino)propanamide

[0445] [ka]

[0446] To a solution of (R)-3-amino-N-(4-(1-phenylpyrrolidin-2-yl)thiazol-2-yl)propanamide (300 mg, 0.94 mmol, 1 equiv.) in DMF (5 mL) was added 4-fluoropyridine (125 mg, 0.94 mmol, 1 equiv.) and Cs2CO3 (924 mg, 2.85 mmol, 3 equiv.). The solution was diluted to 100 o The mixture was stirred at C for 16 h. The reaction product was extracted with ethyl acetate (6 mLx3), washed with water (6 mLx3), brine (6 mL), dried over Na2SO4, and concentrated to give the crude product. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1, v / v) to give the desired product (80 mg, 0.94 mmol, 21%) as a yellow solid.

[0447] LCMS (SHIMADZU-2020-P2): Retention time 3.45 minutes, m / z[M+1]+=394.2 / 385.1 HNMR(400MHz,DMSO-d6):δppm:11.99(s,1H),8.01-8.00(d,J=4Hz,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) HPLC (Agilent-1200-A2): Retention time 10.40 minutes, 98% purity Synthesis of compound 4

[0448] [ka]

[0449] Step 1: Synthesis of (R)-N-(4-((R)-1-phenylpyrrolidin-2-yl)thiazol-2-yl)-2-(pyridin-4-ylmethoxy)propanamide

[0450] [ka]

[0451] To a solution of (S)-2-(pyridin-4-ylmethoxy)propanoic acid (210 mg, 1.16 mmol, 2 equiv.) in DMA (3 mL) was added (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (142 mg, 0.58 mmol, 1 equiv.), EDCI (111 mg, 0.57 mmol, 1.5 equiv.), and DMAP (141 mg, 1.16 mmol, 2 equiv.). o The solution was stirred at 4°C for 5 h in a microwave. Then the solution was extracted with EtOAc (3 mLx3), washed with water (5 mLx3), brine (5 mL), and added with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give the crude product, which was purified by preparative TLC (DCM / MeOH=10:1, v / v) to give the desired product (18 mg, 0.04 mmol, 7%) as a white solid.

[0452] LCMS (Agilent-1290): Retention time 2.74 minutes, m / z[M+1]+=409.2 / 410.2 HNMR(400MHz,DMSO-d6):δppm: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) HPLC (Agilent-1200-A2): Retention time 10.77 minutes, 98% purity Synthesis of compound 5

[0453] [ka]

[0454] Step 1: Synthesis of (S)-N-(4-((R)-1-phenylpyrrolidin-2-yl)thiazol-2-yl)-2-(pyridin-4-ylmethoxy)propanamide

[0455] [ka]

[0456] To a solution of (S)-2-(pyridin-4-ylmethoxy)propanoic acid (50 mg, 0.3 mmol, 1.5 equiv.) in DMA (2 mL) was added (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (50 mg, 0.25 mmol, 1 equiv.), EDCI (58 mg, 0.3 mmol, 1.5 equiv.), and DMAP (49 mg, 0.4 mmol, 2 equiv.). o After stirring in a microwave at 4° C. for 2 h, the solution was extracted with EtOAc (3 mLx3), washed with water (5 mLx3), brine (5 mL), and added with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give the crude product, which was purified by preparative TLC (DCM / MeOH=10:1, v / v) to give the desired product (20 mg, 0.04 mmol, 4%) as a white solid.

[0457] LCMS (Agilent-1290): Retention time 2.77 minutes, m / z[M+1]+=409.2 / 410.2 HNMR(400MHz,DMSO-d6):δppm: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=8Hz,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) HPLC (Agilent-1200-A2): Retention time 10.71 minutes, 98% purity Synthesis of compound 6

[0458] [ka]

[0459] Step 1: Synthesis of (R)-1-methyl-3-(4-(1-phenylpyrrolidin-2-yl)thiazol-2-yl)-1-(2-(pyridin-4-yl)ethyl)urea

[0460] [ka]

[0461] To a solution of (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (100 mg, 0.4 mmol, 1 equiv) in DCM (4 mL), o At C, triphosgene (60 mg, 0.2 mmol, 0.5 equiv.) and DMAP (159 mg, 1.3 mmol, 3.2 equiv.) were added. The solution was diluted with 0 o C for 2 h. To this solution was added N-methyl-2-(pyridin-4-yl)ethan-1-amine (111 mg, 0.81 mmol, 2 equiv.). The solution was stirred at room temperature for 16 h. The solution was then extracted with DCM (5 mLx3), washed with water (5 mLx3), brine (5 mL), and diluted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give the crude product, which was purified by preparative TLC (DCM / MeOH=20:1, v / v) to give the desired product (56 mg, 0.13 mmol, 33%) as a white solid.

[0462] LCMS (Agilent): Retention time 2.53 minutes, m / z[M+1] + =408.4 / 409.3 HNMR(400MHz,DMSO-d6):δppm: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),6.4 9-6.46(m,3H),4.68-4.66(d,J=8Hz,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) HPLC (Agilent-1200-A2): Retention time 9.51 minutes, 97% purity Synthesis of compound 7

[0463] [ka]

[0464] Step 1: Synthesis of 3-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid

[0465] [ka]

[0466] To a solution of 3-amino-2-methylpropanoic acid (500 mg, 4.85 mmol, 1 equiv) in MeOH (25 mL) was added Boc 2 O (1.16 g, 5.33 mmol, 1.1 equiv.) and TEA (982 mg, 9.7 mmol, 2.0 equiv.) were added. After stirring at room temperature for 16 h, the reaction product was adjusted to pH 2 with aqueous HCl (1 M), extracted with DCM (30 mL x 3), washed with water (20 mL x 3), brine (20 mL), and diluted with Na 2 SO 4 The mixture was dried at rt and concentrated to give the desired product (900 mg, 4.85 mmol, 91%) as a white solid.

[0467] HNMR(400MHz,DMSO-d6):δppm: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=8Hz,3H) Step 2: Synthesis of tert-butyl (2-methyl-3-oxo-3-((4-((R)-1-phenylpyrrolidin-2-yl)thiazol-2-yl)amino)propyl)carbamate

[0468] [ka]

[0469] To a solution of 3-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (414 mg, 2.03 mmol, 2.5 equiv.) in DMF (6 mL), o At C, (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (200 mg, 0.82 mmol, 1 equiv.), DIEA (369 mg, 2.04 mmol, 2.5 equiv.), and HATU (369 mg, 2.86 mmol, 3.5 equiv.) were added. The mixture was stirred at room temperature for 16 h. The solution was then extracted with EtOAc (6 mLx3), washed with water (6 mLx3), brine (6 mL), and diluted with NaCl. 2 SO 4 The mixture was dried at 40° C. and concentrated to give the crude product, which 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.

[0470] LCMS (Waters-QDa-02): Retention time 1.98 minutes, [M+1] + =431.1 / 432.2 Step 3: Synthesis of 3-amino-2-methyl-N-(4-((R)-1-phenylpyrrolidin-2-yl)thiazol-2-yl)propanamide

[0471] [ka]

[0472] 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 equiv) in dioxane (2 mL) was added HCl / dioxane (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.

[0473] LCMS (Waters-QDa-02): Retention time 0.93 minutes, [M+1] + =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

[0474] [ka]

[0475] A solution of 3-amino-2-methyl-N-(4-((R)-1-phenylpyrrolidin-2-yl)thiazol-2-yl)propanamide (50 mg, 0.15 mmol, 1 equiv.) in DMF (5 mL) was treated with 4-fluoropyridine (21 mg, 0.15 mmol, 1 equiv.) and Cs 2 CO 3 (155 mg, 0.45 mmol, 3 equiv.) was added. The solution was diluted with 100 o C for 16 h. The reaction product was extracted with ethyl acetate (6 mLx3), washed with water (6 mLx3), brine (6 mL), dried over Na2SO4, and concentrated to give the crude product. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1, v / v) to give the desired product (7 mg, 0.15 mmol, 11%) as a yellow solid.

[0476] LCMS (Agilent-1290): Retention time 2.65 minutes, m / z[M+1]+=408.2 / 409.3 HNMR(400MHz,DMSO-d6):δppm: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=8Hz,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) HPLC (Agilent-1200-A2): Retention time 13.86 minutes, 100% purity Synthesis of compound 8

[0477] [ka]

[0478] Step 1: Synthesis of 2-chloro-3-(pyridin-4-ylmethoxy)pyridine

[0479] [ka]

[0480] To a mixture of 2-chloropyridin-3-ol (500 mg, 3.8 mmol, 1 equiv.) in DMF (15 mL), o At C, NaH (310 mg, 7.7 mmol, 2 equiv.) was added. o After stirring at RT for 0.5 h, 4-(chloromethyl)pyridine (947 mg, 5.8 mmol, 1.5 equiv) was added to the solution. The solution was stirred at room temperature for 16 h. The solution was diluted with NH 4 The mixture was quenched with Cl solution (20 mL), extracted with EtOAc (20 mLx3), washed with water (30 mLx3), brine (30 mL), and added with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give the crude product. 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.

[0481] LCMS (Waters-QDa-02): Retention time 1.34 minutes, [M+1] + =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

[0482] [ka]

[0483] To a solution of (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (96 mg, 0.4 mmol, 1 equiv.) in dioxane (5 mL), 2-chloro-3-(pyridin-4-ylmethoxy)pyridine (86 mg, 0.4 mmol, 1 equiv.), Pd2(dba)3 (40 mg, 0.03 mmol, 0.1 equiv.), Xantphos (45 mg, 0.07 mmol, 0.2 equiv.), and Cs2CO3 (385 mg, 1.18 mmol, 3 equiv.) were added. The solution was stirred at 100° C. for 16 h. The reaction product was concentrated to give the crude product. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1, v / v) to give the desired product (60 mg, 0.13 mmol, 35%) as a yellow solid.

[0484] LCMS (Agilent-1290): Retention time 3.24 minutes, m / z[M+1]+=430.2 / 432.2 HNMR(400MHz,DMSO-d6):δppm: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) HPLC (Agilent-1200-A2): Retention time 11.01 minutes, 98% purity Synthesis of compound 9

[0485] [ka]

[0486] Step 1: Synthesis of (R)-1-(4-(1-phenylpyrrolidin-2-yl)thiazol-2-yl)-3-(2-(pyridin-4-yl)ethyl)urea

[0487] [ka]

[0488] To a solution of (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (100 mg, 0.4 mmol, 1 equiv) in DCM (4 mL), o At C, triphosgene (61 mg, 0.4 mmol, 0.5 equiv.) and DMAP (160 mg, 1.3 mmol, 3.2 equiv.) were added. The solution was diluted with 0 o C for 2 h. 2-(Pyridin-4-yl)ethan-1-amine (47 mg, 0.4 mmol, 1 eq.) was added to the solution. Stirred at room temperature for 16 h. Then the solution was extracted with DCM (5 mLx3), washed with water (5 mLx3), brine (5 mL), and added with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give the crude product, which was purified by preparative TLC (DCM / MeOH=20:1, v / v) to give the desired product (10 mg, 0.02 mmol, 6%) as a white solid.

[0489] LCMS (Agilent-1290): Retention time 2.42 minutes, m / z[M+1]+=394.1 / 395.2 HNMR(400MHz,DMSO-d6):δppm: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) HPLC (Agilent-1200-A2): Retention time 9.91 minutes, 95% purity Synthesis of compound 10

[0490] [ka]

[0491] Step 1: Synthesis of (R)-1-methyl-3-(4-(1-phenylpyrrolidin-2-yl)thiazol-2-yl)-1-(pyridin-4-ylmethyl)urea

[0492] [ka]

[0493] To a solution of (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (100 mg, 0.4 mmol, 1 equiv) in DCM (4 mL), o At C, triphosgene (61 mg, 0.2 mmol, 0.5 equiv.) and DMAP (160 mg, 1.3 mmol, 3.2 equiv.) were added. The solution was diluted with 0 o C for 2 h. N-Methyl-1-(pyridin-4-yl)methanamine (50 mg, 0.4 mmol, 1 eq.) was added to the solution. The solution was stirred at room temperature for 16 h. The solution was then extracted with DCM (5 mLx3), washed with water (5 mLx3), brine (5 mL), and diluted with Na 2 SO 4The mixture was dried at 40° C. and concentrated to give the crude product, which was purified by preparative TLC (DCM / MeOH=20:1, v / v) to give the desired product (40 mg, 0.1 mmol, 25%) as a white solid.

[0494] LCMS (Agilent-1290): Retention time 2.53 minutes, m / z[M+1]+=394.1 / 395.2 HNMR(400MHz,DMSO-d6):δppm: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=8Hz,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) HPLC (Agilent-1200-A2): Retention time 9.82 minutes, 99% purity Synthesis of compound 11

[0495] [ka]

[0496] Step 1: Synthesis of (R)-1-(4-(1-phenylpyrrolidin-2-yl)thiazol-2-yl)-3-(pyridin-4-ylmethyl)urea

[0497] [ka]

[0498] To a solution of (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (100 mg, 0.4 mmol, 1 equiv) in DCM (4 mL), o At C, triphosgene (61 mg, 0.2 mmol, 0.5 equiv.) and DMAP (160 mg, 1.3 mmol, 3.2 equiv.) were added. The solution was diluted with 0 oC for 2 h. Pyridin-4-ylmethanamine (44 mg, 0.4 mmol, 1 eq) was added to the solution. The solution was stirred at room temperature for 16 h. The solution was then extracted with DCM (5 mLx3), washed with water (5 mLx3), brine (5 mL), and diluted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give the crude product, which was purified by preparative TLC (DCM / MeOH=20:1, v / v) to give the desired product (25 mg, 0.06 mmol, 16%) as a white solid.

[0499] LCMS (Agilent-1290): Retention time 2.45 minutes, m / z[M+1]+=380.1 / 381.2 HNMR(400MHz,DMSO-d6):δppm: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) HPLC (Agilent-1200-A2): Retention time 9.68 minutes, 98% purity Synthesis of compound 12

[0500] [ka]

[0501] Step 1: Synthesis of (R)-1-(2-phenoxyphenyl)-3-(4-(1-phenylpyrrolidin-2-yl)thiazol-2-yl)urea

[0502] [ka]

[0503] To a solution of (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (100 mg, 0.4 mmol, 1 equiv) in DCM (4 mL), oAt C, triphosgene (60 mg, 0.2 mmol, 0.5 equiv.) and DMAP (159 mg, 1.3 mmol, 3.2 equiv.) were added. The solution was diluted with 0 o C for 2 h. 2-Phenoxyaniline (76 mg, 0.41 mmol, 1 equiv.) was added to the solution. The solution was stirred at room temperature for 16 h. Then the solution was extracted with DCM (5 mLx3), washed with water (5 mLx3), brine (5 mL), and added with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give the crude product, which was purified by preparative TLC (DCM / MeOH=20:1, v / v) to give the desired product (50 mg, 0.10 mmol, 26%) as a white solid.

[0504] LCMS (Agilent-1290): Retention time 4.44 minutes, m / z[M+1]+=457.3 / 458.2 HNMR(400MHz,DMSO-d6):δppm: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) HPLC (Agilent-1200-A2): Retention time 16.02 minutes, 98% purity Synthesis of compound 13

[0505] [ka]

[0506] Step 1: Synthesis of (R)-phenyl(4-((4-(1-phenylpyrrolidin-2-yl)thiazol-2-yl)amino)phenyl)methanone

[0507] [ka]

[0508] A solution of (4-bromophenyl)(phenyl)methanone (106 mg, 0.4 mmol, 1 equiv.) in dioxane (6 mL) was diluted with (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (100 mg, 0.4 mmol, 1 equiv.), Pd 2 (dba) 3 (42 mg, 0.04 mmol, 0.1 equiv.), Xantphos (47.2 mg, 0.08 mmol, 0.2 equiv.), and Cs 2 CO 3 (398 mg, 1.22 mmol, 3 equiv.) was added. The solution was diluted with 100 o C for 16 h. The reaction mixture was concentrated to give the crude product, which was purified by preparative TLC (DCM / MeOH=10 / 1, v / v) to give the desired product (72 mg, 0.16 mmol, 41%) as a yellow solid.

[0509] LCMS (Agilet-1290): Retention time 4.43 minutes, m / z[M+1]+=426.1 / 427.2 HNMR(400MHz,DMSO-d6):δppm: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) HPLC (Agilent-1200-A2): Retention time 15.73 minutes, 96% purity Synthesis of compound 14

[0510] [ka]

[0511] Step 1: Synthesis of methyl (R)-2-(pyridin-4-ylmethoxy)propanoate

[0512] [ka]

[0513] To a solution of methyl (R)-2-hydroxypropanoate (1 g, 9.6 mmol, 1.5 equiv.) in DMF (20 mL), o At C, NaH (0.56 g, 14 mmol, 2.2 equiv.) was added. o After stirring at RT for 0.5 h, 4-(bromomethyl)pyridine (1.6 g, 6.3 mmol, 1 equiv.) 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 mLx3), washed with water (30 mLx3), brine (30 mL), and concentrated with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give the crude product. 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.

[0514] LCMS (Waters-QDa-02): Retention time 1.35 minutes, [M+1] + =196.1 Step 2: Synthesis of (R)-2-(pyridin-4-ylmethoxy)propanoic acid

[0515] [ka]

[0516] Methyl (R)-2-(pyridin-4-ylmethoxy)propanoate (300 mg, 1.53 mmol, 1 equiv.) in THF (3 mL) and H 2 To a solution of 2H2O (1 mL) was added LiOH (111 mg, 4.61 mmol, 3 equiv.). After stirring at room temperature for 2 h, the reaction mixture was adjusted to pH 2 with aqueous HCl (1 M) and concentrated to give the crude product (270 mg) as a yellow solid.

[0517] LCMS (Waters-QDa-02): Retention time 0.94 min, [M+1] + =182.08 Step 3: Synthesis of (R)-N-(4-(2-isopropoxypropan-2-yl)thiazol-2-yl)-2-(pyridin-4-ylmethoxy)propanamide

[0518] [ka]

[0519] To a solution of (R)-2-(pyridin-4-ylmethoxy)propanoic acid (280 mg, 1.4 mmol, 1.5 equiv.) in DMA (3 mL) was added 4-(2-isopropoxypropan-2-yl)thiazol-2-amine (100 mg, 0.93 mmol, 1 equiv.), EDCI (144 mg, 0.75 mmol, 1.5 equiv.), and DMAP (122 mg, 1 mmol, 2 equiv.). o The mixture was stirred in a microwave at 4° C. for 3 h. The solution was then extracted with EtOAc (3 mL×3), washed with water (5 mL×3), brine (5 mL), dried over Na2SO4, and concentrated to give the crude product. The crude product was purified by preparative TLC (DCM / MeOH=10:1, v / v) to give the desired product (60 mg, 0.93 mmol, 33%) as a white solid.

[0520] LCMS (Agilent-1290): Retention time 2.26 minutes, m / z[M+1]+=364.1 HNMR(400MHz,DMSO-d6):δppm: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) HPLC (Agilent-1200-A2): Retention time 9.48 minutes, 100% purity Synthesis of compound 15

[0521] [ka]

[0522] Step 1: Synthesis of methyl (S)-2-(pyridin-4-ylmethoxy)propanoate

[0523] [ka]

[0524] To a solution of methyl (S)-2-hydroxypropanoate (1 g, 9.6 mmol, 1 equiv.) in DMF (20 mL), o At C, NaH (0.56 g, 14 mmol, 2.2 equiv.) was added. o After stirring at RT for 0.5 h, 4-(bromomethyl)pyridine (1.6 g, 6.3 mmol, 1 equiv.) 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 mLx3), washed with water (30 mLx3), brine (30 mL), and concentrated with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give the crude product. 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.

[0525] LCMS (Waters-QDa-02): Retention time 1.36 minutes, [M+1] + =196.08 Step 2: Synthesis of (S)-2-(pyridin-4-ylmethoxy)propanoic acid

[0526] [ka]

[0527] Methyl (S)-2-(pyridin-4-ylmethoxy)propanoate (160 mg, 0.82 mmol, 1 equiv.) in THF (3 mL) and H 2To a solution of 2H2O (1 mL) was added LiOH (58 mg, 2.46 mmol, 3 equiv.). After stirring at room temperature for 2 h, the reaction mixture was adjusted to pH 2 with aqueous HCl (1 M) and concentrated to give the crude product (140 mg) as a yellow solid.

[0528] LCMS (Waters-QDa-02): Retention time 0.91 min, [M+1] + =182.08 Step 3: Synthesis of (S)-N-(4-(2-isopropoxypropan-2-yl)thiazol-2-yl)-2-(pyridin-4-ylmethoxy)propanamide

[0529] [ka]

[0530] To a solution of (S)-2-(pyridin-4-ylmethoxy)propanoic acid (67 mg, 0.37 mmol, 1.5 equiv.) in DMA (2 mL) was added 4-(2-isopropoxypropan-2-yl)thiazol-2-amine (50 mg, 0.25 mmol, 1 equiv.), EDCI (71 mg, 0.37 mmol, 1.5 equiv.), and DMAP (61 mg, 0.5 mmol, 2 equiv.). o After stirring at C for 1 h in a microwave, the solution was extracted with EtOAc (3 mLx3), washed with water (5 mLx3), brine (5 mL), dried over Na2SO4, and concentrated to give the crude product, which was purified by preparative TLC (DCM / MeOH=10:1, v / v) to give the desired product (8.5 mg, 0.25 mmol, 8%) as a white solid.

[0531] LCMS (Agilent-1290): Retention time 2.25 minutes, m / z[M+1]+=364.1 HNMR(400MHz,DMSO-d6):δppm: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) HPLC (Agilent-1200-A2): Retention time 9.44 minutes, 100% purity Synthesis of compound 16

[0532] [ka]

[0533] Step 1: Synthesis of 1-(4-(2-isopropoxypropan-2-yl)thiazol-2-yl)-3-(2-(pyridin-4-yl)ethyl)urea

[0534] [ka]

[0535] To a solution of 4-(2-isopropoxypropan-2-yl)thiazol-2-amine (50 mg, 0.24 mmol, 1 equiv) in DCM (4 mL), o At C, triphosgene (37 mg, 0.12 mmol, 0.5 equiv.) and DMAP (97 mg, 0.79 mmol, 3.2 equiv.) were added. The solution was diluted with 0 o C for 2 h. 2-(Pyridin-4-yl)ethan-1-amine (31 mg, 0.24 mmol, 1 eq.) was added to the solution. Stirred at room temperature for 16 h. Then the solution was extracted with DCM (5 mLx3), washed with water (5 mLx3), brine (5 mL), and added with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give the crude product, which was purified by preparative TLC (DCM / MeOH=20:1, v / v) to give the desired product (20 mg, 0.057 mmol, 22%) as a white solid.

[0536] LCMS (Agilent-1290): Retention time 1.93 minutes, m / z[M+1]+=349.2 HNMR(400MHz,DMSO-d6):δppm: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) HPLC (Agilent-1200-A2): Retention time 8.49 minutes, 98% purity Synthesis of compound 17

[0537] [ka]

[0538] Step 1: Synthesis of 1-(4-(2-isopropoxypropan-2-yl)thiazol-2-yl)-3-(pyridin-4-ylmethyl)urea

[0539] [ka]

[0540] To a solution of 4-(2-isopropoxypropan-2-yl)thiazol-2-amine (200 mg, 0.99 mmol, 1 equiv.) in DCM (6 mL), o At C, triphosgene (148 mg, 0.49 mmol, 0.5 equiv.) and DMAP (390 mg, 3.19 mmol, 3.2 equiv.) were added. The solution was diluted with 0 o C for 2 h. Pyridin-4-ylmethanamine (108 mg, 0.99 mmol, 1 equiv.) was added to the solution. The solution was stirred at room temperature for 16 h. The solution was then extracted with DCM (5 mLx3), washed with water (5 mLx3), brine (5 mL), and diluted with Na 2 SO 4The mixture was dried at 40° C. and concentrated to give the crude product, which was purified by preparative TLC (DCM / MeOH=20:1, v / v) to give the desired product (185 mg, 0.99 mmol, 55%) as a white solid.

[0541] LCMS (Agilent-1290): Retention time 1.97 minutes, m / z[M+1]+=335.2 / 336.2 HNMR(400MHz,DMSO-d6):δppm: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) HPLC (Agilent-1200-A2): Retention time 8.41 minutes, 100% purity Synthesis of compound 18

[0542] [ka]

[0543] Step 1: Synthesis of 1-(4-(2-isopropoxypropan-2-yl)thiazol-2-yl)-3-(2-phenoxyphenyl)urea

[0544] [ka]

[0545] To a solution of 2-phenoxyaniline (46 mg, 0.24 mmol, 1 equiv) in DCM (4 mL), o At C, triphosgene (37 mg, 0.12 mmol, 0.5 equiv.) and DMAP (97 mg, 0.79 mmol, 3.2 equiv.) were added. The solution was diluted with 0 oC for 2 h. 4-(2-isopropoxypropan-2-yl)thiazol-2-amine (50 mg, 0.24 mmol, 1 eq.) was added to the solution. The solution was stirred at room temperature for 16 h. Then the solution was extracted with DCM (5 mLx3), washed with water (5 mLx3), brine (5 mL), and diluted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give the crude product, which was purified by preparative TLC (DCM / MeOH=20:1, v / v) to give the desired product (20 mg, 0.048 mmol, 19%) as a white solid.

[0546] LCMS (Agilent-1290): Retention time 4.18 minutes, m / z[M+1]+=412.2 HNMR(400MHz,DMSO-d6):δppm: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) HPLC (Agilent-1200-A2): Retention time 9.70 minutes, 100% purity Synthesis of compound 19

[0547] [ka]

[0548] Step 1: 3-(4-(2-isopropoxypropan-2-yl)thiazol-2-yl)-1-methyl-1-(pyridin-4-ylmethyl)urea

[0549] [ka]

[0550] To a solution of 4-(2-isopropoxypropan-2-yl)thiazol-2-amine (50 mg, 0.24 mmol, 1 equiv) in DCM (4 mL), oAt C, triphosgene (37 mg, 0.12 mmol, 0.5 equiv.) and DMAP (97 mg, 0.79 mmol, 3.2 equiv.) were added. The solution was diluted with 0 o C for 2 h. N-Methyl-1-(pyridin-4-yl)methanamine (30 mg, 0.24 mmol, 1 eq.) was added to the solution. The solution was stirred at room temperature for 16 h. The solution was then extracted with DCM (5 mLx3), washed with water (5 mLx3), brine (5 mL), and diluted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give the crude product, which was purified by preparative TLC (DCM / MeOH=20:1, v / v) to give the desired product (40 mg, 0.11 mmol, 45%) as a white solid.

[0551] LCMS (Agilent-1290): Retention time 2.05 minutes, m / z[M+1]+=349.2 / 350.2 HNMR(400MHz,DMSO-d6):δppm: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) HPLC (Agilent-1200-A2): Retention time 8.42 minutes, 99% purity Synthesis of compound 20

[0552] [ka]

[0553] Step 1: Synthesis of tert-butyl (2-(pyridin-4-yl)ethyl)carbamate

[0554] [ka]

[0555] To a solution of 2-(pyridin-4-yl)ethan-1-amine (400 mg, 3.27 mmol, 1 equiv) in DCM (5 mL) was added Boc2 O (1.07 g, 4.91 mmol, 1.5 equiv.) and TEA (663 mg, 6.55 mmol, 2 equiv.) were added. 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 the mixture of desired products (700 mg, 3.27 mmol, 96%) as a white oil.

[0556] LCMS (Waters-QDa-02): Retention time 2.90 minutes, [M+1] + =223.2 Step 2: Synthesis of N-methyl-2-(pyridin-4-yl)ethan-1-amine

[0557] [ka]

[0558] A solution of tert-butyl (2-(pyridin-4-yl)ethyl)carbamate (100 mg, 0.45 mmol, 1 equiv.) in THF (3 mL) was added to LiAlH 4 (51 mg, 1.35 mmol, 3 eq.) was added. o After stirring at C for 3 h, the reaction mixture was quenched with water (1 mL), diatomaceous earth was added (DCM / MeOH=10:1) and filtered with ammonia. The mixture was concentrated to give the crude product (70 mg crude) as a white solid.

[0559] LCMS (Waters-QDa-02): Retention time 0.34 min, [M+1] + =136.9 Step 3: Synthesis of tert-butyl methyl (2-(pyridin-4-yl)ethyl)carbamate

[0560] [ka]

[0561] To a mixture of N-methyl-2-(pyridin-4-yl)ethan-1-amine (280 mg, 2.05 mmol, 1 equiv.) in DCM (5 mL) was added Boc2O (493 mg, 2.26 mmol, 1.1 equiv.), TEA (416 mg, 4.1 mmol, 2.0 equiv.), and DMAP (25 mg, 0.2 mmol, 0.1 equiv.). After stirring at room temperature for 16 h, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative TLC (DCM / MeOH=20:1, v / v) to give the desired product (88 mg, 2.05 mmol, 16%) as a white solid.

[0562] LCMS (Waters-QDa-02): Retention time 0.55 min, [M+1] + =236.7 Step 4: Synthesis of N-methyl-2-(pyridin-4-yl)ethan-1-amine

[0563] [ka]

[0564] 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 mixture was concentrated to give the desired product (80 mg crude).

[0565] LCMS (Waters-QDa-02): Retention time 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

[0566] [ka]

[0567] To a solution of N-methyl-2-(pyridin-4-yl)ethan-1-amine (80 mg crude, 0.58 mmol, 1.5 equiv.) in DCM (5 mL) was added triphosgene (68 mg, 0.22 mmol, 0.5 equiv.) and DMAP (270 mg, 1.47 mmol, 3.2 equiv.). The reaction mixture was cooled to 0°C. o C for 2 h. 4-(2-isopropoxypropan-2-yl)thiazol-2-amine (80 mg, 0.58 mmol, 1 equiv.) was added to the solution. The reaction mixture was stirred at room temperature for 16 h. The solution was concentrated to give the crude product. The crude product was purified by preparative TLC (DCM / MeOH=10:1, v / v) to give the desired product (60 mg, 0.58 mmol, 36%) as a white solid.

[0568] LCMS (Agilent-1290): Retention time 1.95 minutes, m / z[M+1]+=363.2 HNMR(400MHz,DMSO-d6):δppm: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) HPLC (Agilent-1200-A2): Retention time 8.54 minutes, 99% purity Synthesis of compound 21

[0569] [ka]

[0570] Step 1: Synthesis of 2-(pyridin-4-yl)ethyl (4-(2-isopropoxypropan-2-yl)thiazol-2-yl)carbamate

[0571] [ka]

[0572] To a solution of 4-(2-isopropoxypropan-2-yl)thiazol-2-amine (100 mg, 0.49 mmol, 1 equiv.) in DCM (5 mL), o At C, triphosgene (74 mg, 0.24 mmol, 0.5 equiv.) and DMAP (195 mg, 1.59 mmol, 3.2 equiv.) were added. The solution was diluted with 0 o C for 2 h. 2-(pyridin-4-yl)ethan-1-ol (61 mg, 0.49 mmol, 1 equiv.) was added to the solution. The solution was stirred at room temperature for 16 h. The solution was then extracted with DCM (3 mLx3), washed with water (5 mLx3), brine (5 mL), and diluted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give the crude product, which was purified by preparative TLC (DCM / MeOH=20:1, v / v) to give the desired product (100 mg, 0.49 mmol, 57%) as a white solid.

[0573] LCMS (Agilent-1290): Retention time 2.15 minutes, m / z[M+1]+=350.1 HNMR(400MHz,DMSO-d6):δppm: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) HPLC (Agilent-1200-A2): Retention time 8.65 minutes, 96% purity Synthesis of compound 22

[0574] [ka]

[0575] Step 1: Synthesis of (4-((4-(2-isopropoxypropan-2-yl)thiazol-2-yl)amino)phenyl)(phenyl)methanone

[0576] [ka]

[0577] A solution of 4-(2-isopropoxypropan-2-yl)thiazol-2-amine (50 mg, 0.25 mmol, 1 equiv.) in dioxane (5 mL) was added to a solution of (4-bromophenyl)(phenyl)methanone (65 mg, 0.25 mmol, 1 equiv.), Pd 2 (dba) 3 (26 mg, 0.025 mmol, 0.1 equiv.), Xantphos (29 mg, 0.05 mmol, 0.2 equiv.), and Cs 2 CO 3 (244 mg, 0.75 mmol, 3 equiv.) was added. The solution was diluted to 100 o C for 16 h. The reaction mixture was concentrated to give the crude product, which was purified by preparative TLC (DCM / MeOH=10 / 1, v / v) to give the desired product (15 mg, 0.03 mmol, 15%) as a yellow solid.

[0578] LCMS (Agilent-1290): Retention time 4.13 minutes, m / z[M+1]+=381.1 HNMR(400MHz,DMSO-d6):δppm: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) HPLC (Agilent-1200-A2): Retention time 8.64 minutes, 100% purity Synthesis of compound 23

[0579] [ka]

[0580] Step 1: Synthesis of (R)-1-(4-benzoylphenyl)-3-(4-(1-phenylpyrrolidin-2-yl)thiazol-2-yl)urea

[0581] [ka]

[0582] To a solution of (R)-4-(1-phenylpyrrolidin-2-yl)thiazol-2-amine (100 mg, 0.4 mmol, 1 equiv) in DCM (3 mL), o At C, triphosgene (60 mg, 0.2 mmol, 0.5 equiv.) and DMAP (159 mg, 1.3 mmol, 3.2 equiv.) were added. The solution was diluted with 0 o C for 2 h. (4-aminophenyl)(phenyl)methanone (80 mg, 0.4 mmol, 1 equiv.) was added to the solution. The solution was stirred at room temperature for 16 h. Then the solution was extracted with DCM (5 mLx3), washed with water (5 mLx3), brine (5 mL), and diluted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give the crude product, which was purified by preparative TLC (DCM / MeOH=20:1, v / v) to give the desired product (26 mg, 0.055 mmol, 13%) as a white solid.

[0583] LCMS (Agilent-1290): Retention time 4.20 minutes, m / z[M+1]+=469.2 / 470.2 HNMR(400MHz,DMSO-d6):δppm: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) HPLC (Agilent-1200-A2): Retention time 14.93 minutes, 95% purity Synthesis of compound 24

[0584] [ka]

[0585] Step 1: Synthesis of methyl 1-(2-(pyridin-4-yl)ethyl)-1H-pyrazole-5-carboxylate

[0586] [ka]

[0587] A solution of 2-(pyridin-4-yl)ethan-1-ol (500 mg, 4.06 mmol, 1 equiv.) in dry THF (10 mL) was added to methyl 1H-pyrazole-5-carboxylate (500 mg, 4.06 mmol, 1 equiv.), PPh 3 (1.59 g, 6.09 mmol, 1.5 equiv.), and DIAD (820 mg, 6.09 mmol, 1.5 equiv.) were added. 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 the desired product mixture (930 mg, 4.06 mmol, 99% yield) as a yellow oil.

[0588] LCMS (Waters-QDa-02): Retention time 1.90 minutes, [M+1] + =231.9 Step 2: Synthesis of 1-(2-(pyridin-4-yl)ethyl)-1H-pyrazole-5-carboxylic acid

[0589] [ka]

[0590] Methyl 1-(2-(pyridin-4-yl)ethyl)-1H-pyrazole-5-carboxylate (930 mg, 4 mmol, 1 equiv.) in MeOH (9 mL) and H 2 To a solution of 2H2O (3 mL) was added LiOH (193 mg, 2 mmol, 2 equiv.) After stirring at room temperature for 2 h, the reaction mixture was adjusted to pH 1-2 with aqueous HCl (3 M) and concentrated to give the desired product (868 mg, 4 mmol, 100% yield) as a yellow oil.

[0591] LCMS (Waters-QDa-02): Retention time 1.90 minutes, [M+1] + =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

[0592] [ka]

[0593] To a mixture of 1-(2-(pyridin-4-yl)ethyl)-1H-pyrazole-5-carboxylic acid (216 mg, 0.99 mmol, 2 equiv.) in DMA (3 mL) was added 4-(2-isopropoxypropan-2-yl)thiazol-2-amine (100 mg, 0.49 mmol, 1 equiv.), EDCI (143 mg, 0.74 mmol, 1.5 equiv.), and DMAP (152 mg, 1.24 mmol, 2.5 equiv.). o After stirring in a microwave at C for 3 h, the reaction mixture was extracted with EtOAc (5 mLx3), washed with water (5 mLx3), brine (5 mL), dried over NaSO3, and concentrated to give the crude product, which was purified by preparative TLC (DCM / MeOH=10:1, v / v) to give the desired product (29 mg, 0.49 mmol, 14%) as a yellow solid.

[0594] LCMS (Agilent-1290): Retention time 2.29 minutes, m / z[M+1]+=400.2 HNMR(400MHz,DMSO-d6):δppm: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) HPLC (Agilent-1200-A2): Retention time 6.41 minutes, 94% purity Synthesis of compound 25

[0595] [ka]

[0596] Step 1: Synthesis of 7-bromo-1-(pyridin-4-ylmethyl)-1H-pyrrolo[2,3-c]pyridine

[0597] [ka]

[0598] A solution of 7-bromo-1H-pyrrolo[2,3-c]pyridine (100 mg, 0.5 mmol, 1 equiv.) in DMF (5 mL) was diluted with 4-(bromomethyl)pyridine (129 mg, 0.5 mmol, 1 equiv.) and Cs 2 CO 3 (498 mg, 1.5 mmol, 3.0 equiv.) was added. After stirring at room temperature for 16 h, the reaction product was extracted with EtOAc (5 mL x 3), washed with water (5 mL x 3), brine (5 ml), and added with NaSO 4 The mixture was dried at 40° C. and concentrated to give the crude product, which was purified by preparative TLC (PE / EtOAc=1 / 1, v / v) to give the desired product (110 mg, 0.5 mmol, 76%) as a white oil.

[0599] LCMS (Waters-QDa-02): Retention time 1.80 minutes, [M+1] + =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

[0600] [ka]

[0601] A solution of 7-bromo-1-(pyridin-4-ylmethyl)-1H-pyrrolo[2,3-c]pyridine (110 mg, 0.38 mmol, 1 equiv.) in dioxane (5 mL) was added to 4-(2-isopropoxypropan-2-yl)thiazol-2-amine (76 mg, 0.38 mmol, 1 equiv.), Pd2 (dba) 3 (39 mg, 0.03 mmol, 0.1 equiv.), Xantphos (44 mg, 0.06 mmol, 0.2 equiv.), and Cs 2 CO 3 (374 mg, 1.14 mmol, 3.0 equiv.) was added. o After stirring at C for 16 h, the reaction mixture was concentrated in vacuo, and the residue was purified by preparative TLC (DCM / MeOH=10 / 1, v / v) to give the desired product (107 mg, 0.38 mmol, 69%) as a white solid.

[0602] LCMS (SHIMADZU-2020-P2): Retention time 3.15 minutes, m / z[M+1]+=408.2 HNMR(400MHz,DMSO-d6):δppm:13.95(s,1H),8.46(s,2H),7.67(s,1H),7.47(s,1H),7.0 7(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) HPLC (Agilent-1200-A2): Retention time 8.19 minutes, 95% purity Synthesis of compound 26

[0603] [ka]

[0604] Step 1: N-(4-(pyridin-2-yl)thiazol-2-yl)-1-(pyridin-4-ylmethyl)-1H-pyrrole-2-carboxamide

[0605] [ka]

[0606] To a solution of 4-(pyridin-2-yl)thiazol-2-amine (200 mg, 1.13 mmol, 1 equiv.) in DMA (3 mL) was added 1-(pyridin-4-ylmethyl)-1H-pyrrole-2-carboxylic acid (295 mg, 1.24 mmol, 1.1 equiv.), EDCI (324 mg, 1.69 mmol, 1.5 equiv.), and DMAP (414 mg, 3.39 mmol, 3.0 equiv.). o After stirring at C for 1 h in a microwave, the reaction product was extracted with EtOAc (5 mLx3), washed with water (5 mLx3), brine (5 mL), dried over NaSO4, and concentrated to give the crude product, which was purified by preparative TLC (DCM / MeOH=10 / 1, v / v) to give the desired product (20 mg, 1.13 mmol, 4.9%) as a white solid.

[0607] LCMS (Agilent-1290): Retention time 2.05 minutes, m / z[M+1]+=362.2 / 363.2 HNMR(400MHz,DMSO-d6):δppm: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) HPLC (Agilent-1200-A2): Retention time 7.78 minutes, 98% purity Synthesis of compound 27

[0608] [ka]

[0609] Step 1: Synthesis of methyl 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrrole-2-carboxylate

[0610] [ka]

[0611] CH of 4-(chloromethyl)-3,5-dimethylisoxazole (2 g, 0.014 mol, 1 equiv.) 3 In a solution of CN (30 mL), methyl 1H-pyrrole-2-carboxylate (1.9 g, 0.015 mol, 1.1 equiv.) and Cs 2 CO 3 (13.5g, 0.042mol, 3eq) was added at room temperature. o After stirring at 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 the desired products (2 g, 0.014 mol, 62%) as a white solid.

[0612] LCMS (Waters-QDa-02): Retention time 1.89 minutes, [M;1] + =235.0 Step 2: Synthesis of 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrrole-2-carboxylic acid

[0613] [ka]

[0614] Methyl 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrrole-2-carboxylate (1 g, 0.0043 mol, 1 equiv.) in MeOH (12 mL) and H 2 To the solution in 20O (4 mL) was added LiOH (305 mg, 0.0129 mmol, 3 equiv.). After stirring at room temperature for 4 h, the reaction mixture was acidified, extracted with EtOAc (5 mLx3), washed with water (5 mLx3), brine (5 mL), and added with Na 2 SO 4 It was dried at rt and concentrated in vacuo to give the desired product (400 mg, 0.0043 mol, 44%) as a yellow solid.

[0615] LCMS (Waters-QDa-02): Retention time 1.34 minutes, [M+1] + =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

[0616] [ka]

[0617] To a mixture of 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrrole-2-carboxylic acid (165 mg, 0.75 mmol, 1.5 equiv.) in DMA (3 mL) was added 4-(2-isopropoxypropan-2-yl)thiazol-2-amine (100 mg, 0.5 mmol, 1 equiv.) and EDCI (144 mg, 0.75 mmol, 1.5 equiv.) and DMAP (153 mg, 1.25 mmol, 2.5 equiv.). o After stirring at 4° C. for 3 h in a microwave, the reaction mixture was extracted with EtOAc (5 mLx3), washed with water (5 mLx3), brine (5 mL), and added with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate and concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH=10 / 1, v / v) to give the desired product (50 mg, 0.75 mmol, 25%) as a white oil.

[0618] LCMS (Agilent-1290): Retention time 3.62 minutes, m / z[M+1] + =403.1 HNMR(400MHz,DMSO-d6):δppm: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=8Hz,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=4Hz,6H) HPLC (Agilent-1200-A2): Retention time 13.71 minutes, 99% purity Synthesis of compound 28

[0619] [ka]

[0620] Step 1:

[0621] [ka]

[0622] A 20 mL vial equipped with a stir bar was charged with cyclopropanol (86.4 μL, 4 equiv, 1.36 mmol) in tetrahydrofuran (3 mL, 0.11 M). Sodium hydride 60% w / w (55.9 mg, 4.1 equiv, 1.4 mmol) was added to the reaction mixture at 0° C. and stirred at room temperature for 30 min. After 30 min, tert-butyl N-[4-(bromomethyl)-1,3-thiazol-2-yl]carbamate (0.1 g, 1 equiv, 341 μmol) was added to the reaction mixture at 0° C. and stirred overnight at room temperature. The reaction mixture was diluted with saturated NH 4 It was diluted with aqueous Cl (5 mL), extracted with EtOAc (5 mLx3), and washed with brine. The organic layer was washed with MgSO 4 The crude material was purified by normal phase silica gel chromatography (0-100% EtOAc in hexanes) to give the desired product (63 mg, 68% yield). LCMS (+ESI): calculated [M+H]+=271, found 271. Step 2:

[0623] [ka]

[0624] An 8 mL vial equipped with a stir bar was charged with tert-butyl N-[4-(cyclopropoxymethyl)-1,3-thiazol-2-yl]carbamate (63 mg, 1 eq, 233 μmol) and DCM (2 mL, 0.12 M). Trifluoroacetic acid (0.5 mL, 28 eq, 6.53 mmol) was added and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo to give the desired product with an estimated quantitative yield (66 mg, 100% yield). LCMS (+ESI): Calculated [M+H]+=171, Found 171 Step 3:

[0625] [ka]

[0626] A 4 ml vial equipped with a stir bar was charged with 1-[(pyridin-4-yl)methyl]-1H-pyrrole-2-carboxylic acid (39 mg, 1 equiv., 193 μmol), 4-(cyclopropoxymethyl)-1,3-thiazol-2-amine, trifluoroacetic acid (66 mg, 1.2 equiv., 231 μmol), 4-(dimethylamino)pyridin-1-ium (95 mg, 4 equiv., 771 μmol), ({[3-(dimethylamino)propyl]imino}methylidene)(ethyl)amine hydrochloride (55.5 mg, 1.5 equiv., 289 μmol), and dimethylacetamide (750 μL, 0.26 M). The reaction mixture was stirred at 80° C. for 3 h. The crude reaction mixture was directly purified by C18 reverse phase silica gel chromatography (0-100% ACN in water) to give the desired product (12.5 mg, 18% yield). LCMS(+ESI): Calculated [M+H]+=355, Found 355 Synthesis of compound 29

[0627] [ka]

[0628] Step 1: 2-(pyridin-4-yl)ethyl (4-(2-isopropoxypropan-2-yl)thiazol-2-yl)carbamate

[0629] [ka]

[0630] To a solution of 4-(2-isopropoxypropan-2-yl)thiazol-2-amine (100 mg, 0.49 mmol, 1 equiv.) in DCM (5 mL), o At C, triphosgene (74 mg, 0.24 mmol, 0.5 equiv.) and DMAP (195 mg, 1.59 mmol, 3.2 equiv.) were added. The solution was diluted with 0 o C for 2 h. 2-(pyridin-4-yl)ethan-1-ol (61 mg, 0.49 mmol, 1 equiv.) was added to the solution. The solution was stirred at room temperature for 16 h. The solution was then extracted with DCM (3 mLx3), washed with water (5 mLx3), brine (5 mL), and diluted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give the crude product, which was purified by preparative TLC (DCM / MeOH=20:1, v / v) to give the desired product (100 mg, 0.49 mmol, 57%) as a white solid.

[0631] LCMS (Agilent-1290): Retention time 2.15 minutes, m / z[M+1]+=350.1 HNMR(400MHz,DMSO-d6):δppm: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) HPLC (Agilent-1200-A2): Retention time 8.65 minutes, 96% purity Synthesis of compounds 48 and 49 Intermediate 1-2

[0632] [ka]

[0633] Step 1: Methyl 4-fluoro-1-(pyridin-4-ylmethyl)-1H-pyrrole-2-carboxylate

[0634] [ka]

[0635] To a solution of methyl 4-fluoro-1H-pyrrole-2-carboxylate (2 g, 14 mmol, 1 equiv.) in THF (20 mL), add 0.05 mL of NaH (60%, 1.7 g, 42 mmol, 3 equiv.). o C and N 2 The mixture was stirred at room temperature for 1 h. 4-(Bromomethyl)pyridine hydrobromide (7.1 g, 28 mmol, 2 equiv.) was added and the reaction mixture was stirred at room temperature 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.

[0636] LCMS (Waters-QDa-02): Retention time 0.93 minutes, [M+1] + =235.0 Step 2: 4-Fluoro-1-(pyridin-4-ylmethyl)-1H-pyrrole-2-carboxylic acid

[0637] [ka]

[0638] Methyl 4-fluoro-1-(pyridin-4-ylmethyl)-1H-pyrrole-2-carboxylate (900 mg, 3.84 mmol, 1 equiv.) in MeOH (4.5 mL) and H 2 To a solution of 2O (2 mL) was added NaOH (306 mg, 7.68 mmol, 2 equiv.). o After stirring at C for 4 h, the reaction mixture was acidified and concentrated in vacuo to give the desired product (1400 mg, contained NaCl) as a yellow solid.

[0639] LCMS (water-QDa-02): Retention time 0.81 min, [M+1] + =221 Intermediate 2-2

[0640] [ka]

[0641] Step 1: 3-Bromo-1,2,4-thiadiazol-5-amine

[0642] [ka]

[0643] To a solution of 3-bromo-5-chloro-1,2,4-thiadiazole (5 g, 25.1 mmol, 1 equiv.) in ethanol (15 mL) was added 28% (w / w) aqueous ammonia (3.4 mL, 50.1 mmol, 2 equiv.). The mixture was stirred for 70 o The mixture was stirred at C for 3 hours. The reaction mixture was cooled to room temperature, and aqueous sodium bicarbonate solution was added to the mixture. The precipitate was filtered, and the obtained solid was washed with water and dried to obtain compound 2-1 (3.8 g, yield 84.4%) as a white solid.

[0644] LCMS (water-QDa-02): Retention time 0.89 min, [M+1] + =181 Step 2: tert-Butyl (3-bromo-1,2,4-thiadiazol-5-yl)carbamate

[0645] [ka]

[0646] To a solution of compound 2-1 (3.8 g, 13.5 mmol, 1 equiv.) in THF (38 mL), N,N-dimethyl-4-aminopyridine (82.5 mg, 0.675 mmol, 0.05 equiv.) and di-tert-butyl dicarbonate (3.7 mL, 16.2 mmol, 1.2 equiv.) were added, and the mixture was stirred for 50 min.o The mixture was stirred at C for 1 hour. The reaction mixture was concentrated, and dichloromethane-methanol was added to the residue. The insoluble material in the solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (PE:EA=10:1) to obtain compound 2-2 (4.7 g, yield 79.6%) as a white solid.

[0647] LCMS (water-QDa-02): Retention time 1.25 minutes, [M-1] + =279 compound 49

[0648] [ka]

[0649] Step 1: tert-Butyl (E)-(3-styryl-1,2,4-thiadiazol-5-yl)carbamate

[0650] [ka]

[0651] tert-Butyl (3-bromo-1,2,4-thiadiazol-5-yl)carbamate (200 mg, 0.714 mmol, 1 equiv.) 2 In a solution of (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (492 mg, 2.142 mmol, 3 equiv.), K 2 CO 3 (296 mg, 2.142 mmol, 3 equiv.), and Pd(dppf)Cl 2 (51 mg, 0.071 mmol, 0.1 equiv) was added. The mixture was heated at 100 o N in C 2 The reaction mixture was stirred under atmospheric pressure for 3 hours. The reaction mixture was extracted with EtOAc (5 mLx3), washed with water (5 mLx3), brine (5 mL), and then washed with Na 2 SO 4It was dried at 40° C., concentrated in vacuo and purified by reverse phase column to give the desired product (145 mg, 0.478 mmol, 67%) as a white solid.

[0652] LCMS (Agilent-1290): Retention time 2.578 minutes, [M+1] + =304 Step 2: (E)-3-Styryl-1,2,4-thiadiazol-5-amine

[0653] [ka]

[0654] To a solution of tert-butyl (E)-(3-styryl-1,2,4-thiadiazol-5-yl)carbamate (145 mg, 0.478 mmol, 1 equiv.) in DCM (1.8 mL), o C, TFA (1.8 mL) was added. The mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with Na 2 CO 3 The solution was made basic with ethyl acetate (5 mLx3), extracted with EtOAc (5 mLx3), washed with water (5 mLx3), brine (5 mL), and added with Na 2 SO 4 The mixture was dried over rt, concentrated in vacuo, and purified by preparative TLC (DCM / MeOH=20 / 1, v / v) to give the desired product (52 mg, 0.256 mmol, 54%) as a white solid.

[0655] LCMS (Agilent-1290): Retention time 1.514 minutes, [M+1] + =204 Step 3: (E)-4-Fluoro-1-(pyridin-4-ylmethyl)-N-(3-styryl-1,2,4-thiadiazol-5-yl)-1H-pyrrole-2-carboxamide

[0656] [ka]

[0657] To a solution of (E)-3-styryl-1,2,4-thiadiazol-5-amine (52 mg, 0.256 mmol, 1 equiv.) in DMA (1 mL) was added 4-fluoro-1-(pyridin-4-ylmethyl)-1H-pyrrole-2-carboxylic acid (113 mg, 0.512 mmol, 2 equiv.), EDCI (81 mg, 0.512 mmol, 2 equiv.), and DMAP (63 mg, 0.512 mmol, 2 equiv.). The mixture was heated at 100° C. for 2 h in a microwave oven. o The reaction mixture was stirred at RT for 3 h. The reaction mixture was extracted with EtOAc (5 mLx3), washed with water (5 mLx3), brine (5 mL), and added with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate and concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH=20 / 1, v / v) to give the desired product (10 mg, 0.025 mmol, 9.6%) as a white solid.

[0658] LCMS (Agilent-1290): Retention time 1.750 minutes, m / z[M+1] + =406 HNMR(400MHz,DMSO-d6):δ8.49(d,J=5.0Hz,2H),7.69-7.58(m,3H),7.41(t,J=7.4Hz,2H),7 .35(d,J=7.2Hz,1H),7.30(s,1H),7.20(d,J=11.3Hz,2H),7.03(d,J=4.9Hz,2H),5.71(s,2H) HPLC (Agilent-1200-A2): Retention time 10.649 minutes, 96.1% purity Synthesis of compound 48

[0659] [ka]

[0660] Step 1: tert-Butyl (3-(4-methylpiperazin-1-yl)-1,2,4-thiadiazol-5-yl)carbamate

[0661] [ka]

[0662] A solution of tert-butyl (3-bromo-1,2,4-thiadiazol-5-yl)carbamate (500 mg, 1.785 mmol, 1 equiv.) in 1-methylpiperazine (5 mL) was dissolved in 120 mL of o The reaction mixture was heated at 4°C for 16 h. The reaction mixture was extracted with EtOAc (5 mLx3), washed with water (5 mLx3), brine (5 mL), and added with Na 2 SO 4 The mixture was dried at rt, 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.

[0663] LCMS (Agilent-1290): Retention time 0.831 min, [M+1] + =300 Step 2: 3-(4-methylpiperazin-1-yl)-1,2,4-thiadiazol-5-amine

[0664] [ka]

[0665] To a solution of tert-butyl (3-(4-methylpiperazin-1-yl)-1,2,4-thiadiazol-5-yl)carbamate (230 mg, 0.769 mmol, 1 equiv.) in DCM (2 mL), o C, TFA (2 mL) was added. The mixture was stirred at room temperature for 3 h, and the reaction mixture was diluted with Na 2 CO 3 The solution was made basic with ethyl acetate (5 mLx3), extracted with EtOAc (5 mLx3), washed with water (5 mLx3), brine (5 mL), and added with Na 2 SO 4 It was dried at rt and concentrated in vacuo to give the desired product (90 mg, 0.452 mmol, 59%) as a white solid.

[0666] LCMS (Agilent-1290): Retention time 1.500 minutes, [M+1] + =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

[0667] [ka]

[0668] To a solution of 3-(4-methylpiperazin-1-yl)-1,2,4-thiadiazol-5-amine (90 mg, 0.452 mmol, 1 equiv.) in NMP (1 mL) was added 4-fluoro-1-(pyridin-4-ylmethyl)-1H-pyrrole-2-carboxylic acid (198 mg, 0.903 mmol, 2 equiv.), HATU (343 mg, 0.903 mmol, 2 equiv.), and DIEA (175 mg, 1.354 mmol, 3 equiv.). The mixture was heated for 130 min in a microwave oven. o The reaction mixture was stirred at RT for 2 h. The reaction mixture was extracted with EtOAc (5 mLx3), washed with water (5 mLx3), brine (5 mL), and added with Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH=10 / 1, v / v) to give the desired product (5 mg, 0.012 mmol, 2.8%) as a yellow solid.

[0669] LCMS (Agilent-1290): Retention time 0.922 min, m / z[M+1] + =402 HNMR(400MHz,DMSO-d6):δ8.60-8.38(m,2H),7.43-7.32(m,2H),7.00(d,J=4.9 Hz,2H),5.61(s,2H),3.51(d,J=5.1Hz,4H),2.37(t,J=5.0Hz,4H),2.20(s,3H) HPLC (Agilent-1200-A3): Retention time 8.290 minutes, 96.8% purity Synthesis of compound 37

[0670] [ka]

[0671] A mixture of 1-[(pyridin-4-yl)methyl]-1H-pyrrole-2-carboxylic acid (50 mg, 247 μmol), 3-tert-butyl-1H-1,2,4-triazol-5-amine (30 mg, 214 μmol), N-(3-tert-butyl-1H-1,2,4-triazol-5-yl)-1-[(pyridin-4-yl)methyl]-1H-pyrrole-2-carboxamide (55 mg, 170 μmol), and EDCI (57.6 mg, 1.5 equiv, 371 μmol) in dimethylacetamide (578 μL, 6.21 mmol) was heated at 80° C. for 24 hours. The reaction mixture was diluted with methanol and the product precipitated as a yellow solid, which was collected by filtration. LCMS [M+H]+ estimated = 362.4, found = 362.0 Synthesis of compound 50

[0672] [ka]

[0673] A mixture of 1-[(pyridin-4-yl)methyl]-1H-pyrrole-2-carboxylic acid (50 mg, 247 μmol), 3-tert-butyl-1,2,4-thiadiazol-5-amine (38.9 mg, 247 μmol), N-(3-tert-butyl-1H- and EDCI (57.6 mg, 1.5 equiv, 371 μmol) and 4-(dimethylamino)pyridin-1-ium (60.9 mg, 2 equiv, 495 μmol) in dimethylacetamide (578 μL, 6.21 mmol) was heated at 80° C. for 24 h. The reaction mixture was subjected directly to chromatography C18, ISCO, 5-95 ACN / water. LCMS [M+H]+ estimated = 342.4, found = 342.0 Example 2: Identification of molecules that inhibit the synthesis of PrP Flp-ln293T-Rex™ cells are transformed with pcDNATM5 / FRT / TO plasmid, which contains a cDNA (SEQ ID NO:1) encoding 10 amino acids (PrionSS) fused to Gaussia luciferase (GLuc) in addition to the prion protein signal sequence. The transformed cells are selected for resistance to the selectable markers hygromycin and blasticidin to prepare stable cell lines containing the PrionSS-GLuc cDNA insert, whose expression is regulated under the T-Rex™ system. The day before the assay, the cells are trypsinized and seeded into 384-well tissue culture plates. The next day, compound dilutions in DMSO / medium containing doxycycline are added to the wells and incubated at 37° C., 5% CO2, and after 24 hours, coelenterazine substrate is added to each well and luciferase signal is quantified using a Tecan Infinite M1000 Pro for potency measurement.

[0674] If the amount of expressed PrionSS-GLuc protein is reduced by treatment with a compound and a decrease in luminescence is measured, this indicates that the compound inhibits the secretion of prion protein and therefore inhibits the biosynthesis of prion protein.

[0675] The sequence of the PrionSS-Gluc insert is as follows (SEQ ID NO:1): MANLGCWMLVLFVATWSDLGLCKKRPKPGGWNKPTENNEDFNIVAVASNFATTDLDADRGKLPGKKLPLEVLKEMEANARKAGCTRGCLICLSHIKCTPKMKKFIPGRCHTYEGDKESAQGGIGEAIVDIPEIPGFKDLEPMEQFIAQVDLCVDCTTGCLKGLANVQCSDLLKKWLPQRCATFASKIQGQVDKIKGAGGD Example 3: HiBit assay to quantify the potency of protein secretion inhibitors The assay utilized the T-REx™-293 cell line (which constitutively expresses the TetR protein) and plasmid-based transfection. In the transfection, the prion protein (PRP) + 10 amino acid signal peptide (SP) forms the mature domain (MANLGCWMLVLFVATWSDLGLCKKRPKPGG SEQ ID NO: 2) in frame with the HaloTag-Hibit fusion protein under the control of TetO. After transfection with the plasmid, the cells were maintained at 37°C and 5% CO2 for 24 hours and then treated with the compounds. At the same time, doxycycline was added to allow the expression of the SP-HaloTag-HiBit fusion protein secreted from the cells. If the tested chemical molecule was active against the SP of prion, the cotranslational translocation of the protein was inhibited and the expression of the protein was reduced.

[0676] The assay was measured by the Nano-Glo® HiBiT extracellular detection system. This is a luminescence-based assay in which secreted SP-HaloTag-HiBit fusion protein is quantified by adding a non-soluble detection reagent containing the substrate furimazine and large BiT (LgBit), a large subunit used for high affinity binding to HiBit. The HiBit-LgBit-furimazine complex produced a bright luminescent enzyme. The amount of luminescence produced was proportional to the amount of HiBiT-labeled protein accessible in the medium.

[0677] The assay generated dose-response curves for each chemical performed as 3-fold dilutions from 30 μM to 1 nM. The assay included DMSO (no compound = baseline inhibition) and uninduced (no doxycycline) controls, and IC values ​​were calculated from the dose-response curves. 50 The assay described herein was designed to test compounds in triplicate against the prion protein.

[0678] This assay was modified to test inhibition of secretion of programmed cell death receptor 1 (PDCD1) and prion (PRNP). For these experiments, secretion of SP-HaloTag-HiBit fusion proteins incorporating the signal peptide +10 amino acids from either the mature domain of 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).

[0679] The results of the HiBit assay are summarized in the table below.

[0680] [Table 5]

[0681] ++++ represents <5 μM, +++ represents 5–10 μM, ++ represents 10–30 μM, + represents >30 μM, and - represents no data.

[0682] [Table 6]

[0683] ++++ represents <5 μM, +++ represents 5–10 μM, ++ represents 10–30 μM, + represents >30 μM, and - represents no data. Numbered embodiments 1. A compound having the structure of Formula I below, or a pharma- ceutically acceptable salt thereof.

[0684] [ka]

[0685] (In the formula, R 1is H, optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 3 ~C 7 Cycloalkyl, optionally substituted C 2 ~C 9 Heterocycle, optionally substituted C 6 ~C 10 Aryl, optionally substituted C 2 ~C 9 Heteroaryl, C 2 ~C 9 Heteroaryl C 1 ~C 6 Alkyl, or R a -R b -R c and R a is optionally substituted C 6 ~C 10 Arylene or optionally substituted C 2 ~C 9 is heteroarylene, R b is -O- or optionally substituted C 1 ~C 6 is alkylene, R c is optionally substituted C 6 ~C 10 is aryl, Z is absent or optionally substituted C 3 ~C 10 Cycloalkylene, optionally substituted C 2 ~C 9 Heterocyclylene, C 6 ~C 10 Arylene or optionally substituted C 2 ~C 9 is heteroarylene, Y is absent, O, or NR 3 and X is an optionally absent or substituted C 1 ~C 6 is alkylene, W is absent, S, O, or NR 3 and n is 0 or 1, A is S, O, NH, or CH; B is C or N; R 2 is optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 2 ~C 6 Alkenyl, optionally substituted C 3 ~C 7 Cycloalkyl, optionally substituted C 2 ~C 9 Heterocycle, optionally substituted C 6 ~C 10 Aryl, optionally substituted C 2 ~C 9 Heteroaryl, optionally substituted C 2 ~C 9 Heteroaryl C 1 ~C 6 Alkyl, optionally substituted C 3 ~C 7 Cycloalkyl C 1 ~C 6 Aryl, optionally substituted C 1 ~C 6 Heteroalkyl or cyano, or X 1 -OY 1 The structure is X 1 is optionally substituted C 1 ~C 6 is alkylene, Y 1 is optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 3 ~C 8 Cycloalkyl or optionally substituted C 6 ~C 10 is aryl, and Each R 3 are independently H or C 1 ~C6 It is an alkyl group. 2. A compound of embodiment 1 or a pharma- ceutically acceptable salt thereof, R 1 is H, optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 3 ~C 7 Cycloalkyl, optionally substituted C 2 ~C 9 Heterocycle, optionally substituted C 6 ~C 10 Aryl or optionally substituted C 2 ~C 9 is heteroaryl, Z is absent or optionally substituted C 3 ~C 10 Cycloalkyl, optionally substituted C 2 ~C 9 Heterocyclyl, C 6 ~C 10 Aryl or optionally substituted C 2 ~C 9 is heteroaryl, Y is absent, O, or NR 3 and X is an optionally absent or substituted C 1 ~C 6 is alkylene, W is absent, S, O, or NR 3 and n is 0 or 1, A is S, O, or CH; B is C or N; R 2 is optionally substituted C 1~6 Alkyl, optionally substituted C 3~7 Cycloalkyl, optionally substituted C 2~9 Heterocycle, optionally substituted C 6 ~C 10 Aryl, optionally substituted C 2~9 Heteroaryl, optionally substituted C 2 ~C9 Heteroaryl C 1 ~C 6 Alkyl, optionally substituted C 3 ~C 7 Cycloalkyl C 1 ~C 6 Aryl or optionally substituted C 6 ~C 10 and Each R 3 are independently H or C 1 ~C 6 The compound of embodiment 1, or a pharma- ceutically acceptable salt thereof, wherein R is alkyl.

[0686] 3. The compound of embodiment 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein n is 1. 4. The compound of any one of embodiments 1-3, wherein said compound has the structure of formula II:

[0687] [ka]

[0688] 5. The compound of any one of embodiments 1-3, wherein said compound has the structure of formula III:

[0689] [ka]

[0690] 6. The compound of embodiment 1 or 3, wherein said compound has the structure of formula IV: or a pharma- ceutically acceptable salt thereof.

[0691] [ka]

[0692] 7. Z is an optionally substituted C 6 ~C 10 Aryl or optionally substituted C2 ~C 9 The compound of any one of embodiments 4-6, or a pharma- ceutically acceptable salt thereof, wherein: R is heteroaryl.

[0693] 8. Y is O or NR 3 or a pharma- ceutically acceptable salt thereof. 9. The compound of embodiment 8, wherein Y is O, or a pharma- ceutically acceptable salt thereof.

[0694] 10. Y is NR 3 or a pharma- ceutically acceptable salt thereof. 11. The compound of embodiment 8, or a pharma- ceutically acceptable salt thereof, wherein Y is NH. 12.X is optionally substituted C 1 ~C 6 12. The compound of any one of embodiments 1-11, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkylene.

[0695] 13.W is S, O, or NR 3 13. The compound of any one of embodiments 1-12, wherein: 14. The compound of embodiment 13, or a pharma- ceutically acceptable salt thereof, wherein W is S.

[0696] 15. The compound of embodiment 13, or a pharma- ceutically acceptable salt thereof, wherein W is O. 16. W is NR 3 or a pharma- ceutically acceptable salt thereof. 17. The compound of embodiment 16, or a pharma- ceutically acceptable salt thereof, wherein W is NH.

[0697] 18. The compound of any one of embodiments 1-3, wherein A is S and B is C, or a pharma- ceutically acceptable salt thereof. 19. The compound of any one of embodiments 1-3 or 18, wherein the compound has the structure: or a pharma- ceutically acceptable salt thereof.

[0698] [ka]

[0699] (wherein Y is O or NR 3 It is.) 20.X is optionally substituted C 1 ~C 6 The compound of embodiment 19, or a pharma- ceutically acceptable salt thereof, wherein R is an alkylene.

[0700] 21. The compound of embodiment 19 or 20, or a pharma- ceutically acceptable salt thereof, wherein Y is O. 22. Y is NR 3 21. The compound of embodiment 19 or 20, wherein:

[0701] 23. The compound of embodiment 22, or a pharma- ceutically acceptable salt thereof, wherein Y is NH. 24. The compound of any one of embodiments 1-3 or 18, wherein the compound has the structure of formula VI: or a pharma- ceutically acceptable salt thereof.

[0702] [ka]

[0703] (Wherein, W is NR 3 It is.) 25.X is optionally substituted C 1 ~C 6 25. The compound of embodiment 24, or a pharma- ceutically acceptable salt thereof, wherein R is alkylene.

[0704] 26. The compound of embodiment 24 or 25, or a pharma- ceutically acceptable salt thereof, wherein W is NH. 27. The compound of embodiment 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein n is 0.

[0705] 28. The compound of embodiment 27, wherein A is S and B is C, or a pharma- ceutically acceptable salt thereof. 29. 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, substituted 29. The compound of any one of embodiments 1-6, 8-18, 27, or 28, or a pharma- ceutically acceptable salt thereof, wherein R is an optionally substituted isothiazolylene, an optionally substituted thiazolylene, an optionally substituted oxazolylene, an optionally substituted imidazolylene, an optionally substituted cyclohexylene, an optionally substituted cyclopentylene, an optionally substituted cyclobutylene, an optionally substituted cyclopropylene, an optionally substituted cycloheptylene, an optionally substituted cyclooctylene, an optionally substituted indolylene, or an optionally substituted azaindolylene.

[0706] 30. The compound of any one of embodiments 1-18 or 27-29, wherein Z has the structure of formula VIIi: or a pharma- ceutically acceptable salt thereof.

[0707] [ka]

[0708] (In the formula, A, B, C, and D are each independently N, CH, or CR. 4 and Each R 4are independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol. 31. The compound of embodiment 30, wherein Z has the structure of formula VIIIi: or a pharma- ceutically acceptable salt thereof.

[0709] [ka]

[0710] (In the formula, B, C, and D each independently represent CH or CR 4 It is.) 32. The compound of embodiment 30, wherein Z has the structure of formula IXi: or a pharma- ceutically acceptable salt thereof.

[0711] [ka]

[0712] (In the formula, A, C, and D each independently represent CH or CR 4 It is.) 33. The compound of embodiment 30, wherein Z has the structure of formula Xi: or a pharma- ceutically acceptable salt thereof.

[0713] [ka]

[0714] (In the formula, A, B, and D each independently represent CH or CR 4 It is.) 34. The compound of embodiment 30, wherein Z has the structure of formula XIi: or a pharma- ceutically acceptable salt thereof.

[0715] [ka]

[0716] (In the formula, A, B, and C each independently represent CH or CR 4 It is.) 35. The compound of embodiment 30, wherein Z has the structure of formula XIIi: or a pharma- ceutically acceptable salt thereof.

[0717] [ka]

[0718] (In the formula, A and B each independently represent CH or CR 4 It is.) 36. The compound of embodiment 30, wherein Z has the structure of formula XIIIi: or a pharma- ceutically acceptable salt thereof.

[0719] [ka]

[0720] (In the formula, A and D each independently represent CH or CR 4 It is.) 37. Z is the compound of embodiment 30 having the structure of formula XIVi: or a pharma- ceutically acceptable salt thereof.

[0721] [ka]

[0722] (In the formula, C and D each independently represent CH or CR 4 It is.) 38. The compound of embodiment 30, wherein Z has the structure of formula XVi: or a pharma- ceutically acceptable salt thereof.

[0723] [ka]

[0724] (In the formula, B and D each independently represent CH or CR 4 It is.) 39. The compound of embodiment 30, wherein Z has the structure of formula XVIi: or a pharma- ceutically acceptable salt thereof.

[0725] [ka]

[0726] (In the formula, B and C each independently represent CH or CR 4 It is.) 40. The compound of embodiment 30, wherein Z has the structure of formula XVIIi: or a pharma- ceutically acceptable salt thereof.

[0727] [ka]

[0728] (In the formula, A and C each independently represent CH or CR 4 It is.) 41. The compound of embodiment 30, wherein Z has the structure of formula XVIIIi: or a pharma- ceutically acceptable salt thereof.

[0729] [ka]

[0730] (Wherein, A is CH or CR 4 It is.) 42. The compound of embodiment 30, wherein Z has the structure of formula XIXi: or a pharma- ceutically acceptable salt thereof.

[0731] [ka]

[0732] (Wherein, D is CH or CR 4 It is.) 43. The compound of embodiment 30, wherein Z has the structure of formula XXi: or a pharma- ceutically acceptable salt thereof.

[0733] [ka]

[0734] (Wherein, B is CH or CR 4 It is.) 44. The compound of embodiment 30, wherein Z has the structure of formula XXIi: or a pharma- ceutically acceptable salt thereof.

[0735] [ka]

[0736] (Wherein, C is CH or CR 4 It is.) 45. The compound of embodiment 30, wherein Z has the structure of formula XXIIi: or a pharma- ceutically acceptable salt thereof.

[0737] [ka]

[0738] (In the formula, A, B, C, and D each independently represent CH or CR 4 It is.) 46. ​​The compound of any one of embodiments 1-6, 8-18, or 27-29, wherein Z has the structure of formula XXIIIi: or a pharma- ceutically acceptable salt thereof.

[0739] [ka]

[0740] (wherein o is 0, 1, 2, 3, or 4; and Each R 4are independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol. 47. The compound of any one of embodiments 1-6, 8-18, or 27-29, wherein Z has the structure of formula XXIVi: or a pharma- ceutically acceptable salt thereof.

[0741] [ka]

[0742] (wherein o is 0, 1, 2, or 3; and Each R 4 are independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, or optionally substituted heteroaryl. 48. The compound of any one of embodiments 1-18 or 27-29, wherein Z has the structure of formula XXVi: or a pharma- ceutically acceptable salt thereof.

[0743] [ka]

[0744] (In the formula, F and G are each independently N, CH, or CR. 4 and Each R 4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol; and E is NH, O, or S. 49. The compound of embodiment 48, wherein Z has the structure of formula XXVIi: or a pharma- ceutically acceptable salt thereof.

[0745] [ka]

[0746] (In the formula, F and G each independently represent CH or CR 4 It is.) 50. The compound of embodiment 48, wherein Z has the structure of formula XXVIIi: or a pharma- ceutically acceptable salt thereof.

[0747] [ka]

[0748] (In the formula, F and G each independently represent CH or CR 4 It is.) 51. The compound of embodiment 48, wherein Z has the structure of formula XXVIIIi: or a pharma- ceutically acceptable salt thereof.

[0749] [ka]

[0750] (In the formula, F and G each independently represent CH or CR 4 It is.) 52. The compound of any one of embodiments 1-18 or 27-29, wherein Z has the structure of formula XXIXi: or a pharma- ceutically acceptable salt thereof.

[0751] [ka]

[0752] (In the formula, F and G are each independently N, CH, or CR. 4 and Each R4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol; and E is NH, O, or S. 53. The compound of embodiment 52, wherein Z has the structure of formula XXXi: or a pharma- ceutically acceptable salt thereof.

[0753] [ka]

[0754] (In the formula, F and G each independently represent CH or CR 4 It is.) 54. The compound of embodiment 52, wherein Z has the structure of formula XXXIi: or a pharma- ceutically acceptable salt thereof.

[0755] [ka]

[0756] (In the formula, F and G each independently represent CH or CR 4 It is.) 55. The compound of embodiment 52, wherein Z has the structure of formula XXXIIi: or a pharma- ceutically acceptable salt thereof.

[0757] [ka]

[0758] (In the formula, F and G each independently represent CH or CR 4 It is.) 56. The compound of any one of embodiments 1-18 or 27-29, wherein Z has the structure of formula XXXIIIi: or a pharma- ceutically acceptable salt thereof.

[0759] [ka]

[0760] (In the formula, F and G are each independently N, CH, or CR. 4 and Each R 4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol; and E is NH, O, or S. 57. The compound of embodiment 56, wherein Z has the structure of formula XXXIVi: or a pharma- ceutically acceptable salt thereof.

[0761] [ka]

[0762] (In the formula, F and G each independently represent CH or CR 4 It is.) 58. The compound of embodiment 56, wherein Z has the structure of formula XXXVi: or a pharma- ceutically acceptable salt thereof.

[0763] [ka]

[0764] (In the formula, F and G each independently represent CH or CR 4 It is.) 59. The compound of embodiment 56, wherein Z has the structure of formula XXXVIi: or a pharma- ceutically acceptable salt thereof.

[0765] [ka]

[0766] (In the formula, F and G each independently represent CH or CR 4 It is.) 60. The compound of any one of embodiments 1-18 or 27-29, wherein Z has the structure of formula XXXVIIi: or a pharma- ceutically acceptable salt thereof.

[0767] [ka]

[0768] (In the formula, F, G, and H are each independently N, CH, or CR. 4 and Each R 4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol; and E is N or CH. 61. The compound of embodiment 60, wherein Z has the structure of formula XXXVIIIi: or a pharma- ceutically acceptable salt thereof.

[0769] [ka]

[0770] 62. The compound of embodiment 60, wherein Z has the structure of formula XXXIXi: or a pharma- ceutically acceptable salt thereof.

[0771] [ka]

[0772] 63. The compound of embodiment 60, wherein Z has the structure of formula XXXXi: or a pharma- ceutically acceptable salt thereof.

[0773] [ka]

[0774] 64. The compound of embodiment 60, wherein Z has the structure of formula XXXXIi: or a pharma- ceutically acceptable salt thereof.

[0775] [ka]

[0776] 65. Z is the compound of embodiment 60 having the structure of formula XXXXIVi: or a pharma- ceutically acceptable salt thereof.

[0777] [ka]

[0778] 66. The compound of any one of embodiments 1-18 or 27-29, wherein Z has the structure of formula XXXXIIi below, or a pharma- ceutically acceptable salt thereof.

[0779] [ka]

[0780] (In the formula, A, B, C, and D each independently represent CH, CR 4 , or N, and Each R 4 are independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol. 67. The compound of embodiment 66, wherein Z has the structure of formula XXXXIIIi: or a pharma- ceutically acceptable salt thereof.

[0781] [ka]

[0782] 68. The compound of any one of embodiments 1-18 or 27-29, wherein Z has the structure of formula XXXXVi below, or a pharma- ceutically acceptable salt thereof.

[0783] [ka]

[0784] (In the formula, A, B, C, and D each independently represent CH, CR 4 , or N, and Each R 4 are independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol. 69. The compound of any one of embodiments 1, 2, or 27-29, wherein the compound has the structure of formula VII:

[0785] [ka]

[0786] (In the formula, A, B, C, and D are each independently N, CH, or CR. 4 and Each R 4are independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol. 70. The compound of embodiment 69, wherein the compound has the structure of formula VIII:

[0787] [ka]

[0788] (In the formula, B, C, and D each independently represent CH or CR 4 It is.) 71. The compound of embodiment 69, wherein the compound has the structure of formula IX:

[0789] [ka]

[0790] (In the formula, A, C, and D each independently represent CH or CR 4 It is.) 72. The compound of embodiment 69, wherein the compound has the structure of formula X:

[0791] [ka]

[0792] (In the formula, A, B, and D each independently represent CH or CR 4 It is.) 73. The compound of embodiment 69, wherein the compound has the structure of formula XI: or a pharma- ceutically acceptable salt thereof.

[0793] [ka]

[0794] (In the formula, A, B, and C each independently represent CH or CR 4 It is.) 74. The compound of embodiment 69, wherein the compound has the structure of formula XII: or a pharma- ceutically acceptable salt thereof.

[0795] [ka]

[0796] (In the formula, A and B each independently represent CH or CR 4 It is.) 75. The compound of embodiment 69, wherein the compound has the structure of formula XIII: or a pharma- ceutically acceptable salt thereof.

[0797] [ka]

[0798] (In the formula, A and D each independently represent CH or CR 4 It is.) 76. The compound of embodiment 69, wherein the compound has the structure of formula XIV: or a pharma- ceutically acceptable salt thereof.

[0799] [ka]

[0800] (In the formula, C and D each independently represent CH or CR 4 It is.) 77. The compound of embodiment 69, wherein the compound has the structure of formula XV: or a pharma- ceutically acceptable salt thereof.

[0801] [ka]

[0802] (In the formula, B and D each independently represent CH or CR 4 It is.) 78. The compound of embodiment 69, wherein the compound has the structure of formula XVI: or a pharma- ceutically acceptable salt thereof.

[0803] [ka]

[0804] (In the formula, B and C each independently represent CH or CR 4 It is.) 79. The compound of embodiment 69, wherein the compound has the structure of formula XVII:

[0805] [ka]

[0806] (In the formula, A and C each independently represent CH or CR 4 It is.) 80. The compound of embodiment 69, wherein the compound has the structure of formula XVIII:

[0807] [ka]

[0808] (Wherein, A is CH or CR 4 It is.) 81. The compound of embodiment 69, wherein the compound has the structure of formula XIX:

[0809] [ka]

[0810] (Wherein, D is CH or CR 4 It is.) 82. The compound of embodiment 69, wherein the compound has the structure of formula XX:

[0811] [ka]

[0812] (Wherein, B is CH or CR 4 It is.) 83. The compound of embodiment 69, wherein the compound has the structure of formula XXI: or a pharma- ceutically acceptable salt thereof.

[0813] [ka]

[0814] (Wherein, C is CH or CR 4 It is.) 84. The compound of embodiment 69, wherein the compound has the structure of formula XXII: or a pharma- ceutically acceptable salt thereof.

[0815] [ka]

[0816] (In the formula, A, B, C, and D each independently represent CH or CR 4 It is.) 85. The compound of any one of embodiments 1, 2, 27, 26-29, wherein the compound has the structure of formula XXIII:

[0817] [ka]

[0818] (wherein o is 0, 1, 2, 3, or 4; and Each R 4 are independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol. 86. The compound of any one of embodiments 1, 2, or 27-29, wherein the compound has the structure of formula XXIV:

[0819] [ka]

[0820] (wherein o is 0, 1, 2, or 3; and Each R 4 are independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol. 87. The compound of any one of embodiments 1, 2, or 27-29, wherein the compound has the structure of formula XXV:

[0821] [ka]

[0822] (In the formula, Each R 4 are independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol; E is NH, O, or S, and F and G are each independently N, CH, or CR. 4 It is.) 88. The compound of embodiment 87, wherein the compound has the structure of formula XXVI: or a pharma- ceutically acceptable salt thereof.

[0823] [ka]

[0824] (In the formula, F and G each independently represent CH or CR 4 It is.) 89. The compound of embodiment 87, wherein the compound has the structure of formula XXVII: or a pharma- ceutically acceptable salt thereof.

[0825] [ka]

[0826] (In the formula, F and G each independently represent CH or CR 4 It is.) 90. The compound of embodiment 87, wherein the compound has the structure of formula XXVIII: or a pharma- ceutically acceptable salt thereof.

[0827] [ka]

[0828] (In the formula, F and G each independently represent CH or CR 4 It is.) 91. The compound of any one of embodiments 1, 2, or 27-29, wherein the compound has the structure of formula XXIX:

[0829] [ka]

[0830] (In the formula, Each R 4 are independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol; E is NH, O, or S, and F and G are each independently N, CH, or CR. 4 It is.) 92. The compound of embodiment 91, wherein the compound has the structure of formula XXX: or a pharma- ceutically acceptable salt thereof.

[0831] [ka]

[0832] (In the formula, F and G each independently represent CH or CR 4 It is.) 93. The compound of embodiment 91, wherein the compound has the structure of formula XXXI: or a pharma- ceutically acceptable salt thereof.

[0833] [ka]

[0834] (In the formula, F and G each independently represent CH or CR 4 It is.) 94. The compound of embodiment 91, wherein the compound has the structure of formula XXXII: or a pharma- ceutically acceptable salt thereof.

[0835] [ka]

[0836] (In the formula, F and G each independently represent CH or CR 4 It is.) 95. The compound of any one of embodiments 1, 2, or 27-29, wherein the compound has the structure of formula XXXIII:

[0837] [ka]

[0838] (In the formula, F and G are each independently N, CH, or CR. 4 and Each R 4 is independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol; and E is NH, O, or S. 96. The compound of embodiment 95, wherein the compound has the structure of formula XXXIV: or a pharma- ceutically acceptable salt thereof.

[0839] [ka]

[0840] (In the formula, F and G each independently represent CH or CR 4 It is.) 97. The compound of embodiment 95, wherein the compound has the structure of formula XXXV: or a pharma- ceutically acceptable salt thereof.

[0841] [ka]

[0842] (In the formula, F and G each independently represent CH or CR 4 It is.) 98. The compound of embodiment 95, wherein the compound has the structure of formula XXXVI: or a pharma- ceutically acceptable salt thereof.

[0843] [ka]

[0844] (In the formula, F and G each independently represent CH or CR 4 It is.) 99. The compound of any one of embodiments 1, 2, or 27-29, wherein the compound has the structure of formula XXXVII:

[0845] [ka]

[0846] (In the formula, Each R 4 are independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol; E is N or CH; F, G, and H are each independently N, CH, or CR. 4 It is.) 100. The compound of embodiment 99, wherein the compound has the structure of formula XXXVIII: or a pharma- ceutically acceptable salt thereof.

[0847] [ka]

[0848] 101. The compound of embodiment 99, wherein the compound has the structure of formula XXXIX:

[0849] [ka]

[0850] 102. The compound of embodiment 99, wherein the compound has the structure of formula XXXX:

[0851] [ka]

[0852] 103. The compound of any one of embodiments 1, 2, or 97-99, wherein the compound has the structure of formula XXXXII:

[0853] [ka]

[0854] (In the formula, A, B, C, and D each independently represent CH, CR 4 , or N, and Each R 4 are independently optionally substituted aryl, optionally substituted carbocyclyl, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol. 104. The compound of embodiment 103, wherein the compound has the structure of formula XXXXIII: or a pharma- ceutically acceptable salt thereof.

[0855] [ka]

[0856] 105.X is C 1 ~C 6 The compound of any one of embodiments 18 or 27-104, or a pharma- ceutically acceptable salt thereof, wherein R is alkylene. 106.Y is O or NR 3 or a pharma- ceutically acceptable salt thereof.

[0857] 107. The compound of embodiment 106, wherein Y is O, or a pharma- ceutically acceptable salt thereof. 108.Y is NR 3 or a pharma- ceutically acceptable salt thereof.

[0858] 109. The compound of embodiment 106, or a pharma- ceutically acceptable salt thereof, wherein Y is NH. 110.W is S, O, or NR 3 or a pharma- ceutically acceptable salt thereof.

[0859] 111. The compound of embodiment 110, wherein W is S, or a pharma- ceutically acceptable salt thereof. 112. The compound of embodiment 110, wherein W is O, or a pharma- ceutically acceptable salt thereof. 113.W is NR 3 or a pharma- ceutically acceptable salt thereof.

[0860] 114. The compound of embodiment 113, or a pharma- ceutically acceptable salt thereof, wherein W is NH. 115.R 2 is optionally substituted C 1 ~C 6 The compound of any one of embodiments 1-114, or a pharma- ceutically acceptable salt thereof, wherein is an alkyl group.

[0861] 116.R 2 teeth,

[0862] [ka]

[0863] or a pharma- ceutically acceptable salt thereof. 117.R 2 is optionally substituted C 2 ~C 9 The compound of any one of embodiments 1-114, or a pharma- ceutically acceptable salt thereof, wherein the heterocyclyl (eg, optionally substituted pyrrolidine) is substituted or unsubstituted pyrrolidine.

[0864] 118.R 2 The compound of embodiment 115, or a pharma- ceutically acceptable salt thereof, wherein is optionally substituted with halogen (eg, fluorine). 119.R 2 teeth,

[0865] [ka]

[0866] or a pharma- ceutically acceptable salt thereof. 120.R 2 is optionally substituted C 2 ~C 9 The compound of any one of embodiments 1-114, or a pharma- ceutically acceptable salt thereof, wherein: R is an optionally substituted pyridine or an optionally substituted oxazole;

[0867] 121.R 2 teeth,

[0868] [ka]

[0869] or a pharma- ceutically acceptable salt thereof. 122.R 2 X 1 -OY 1 115. The compound of any one of embodiments 1-114, having the structure:

[0870] 123.X 1 is optionally substituted with one or two methyl groups, or a pharma- ceutically acceptable salt thereof. 124.Y 1 124. The compound of embodiment 122 or 123, wherein is optionally substituted phenyl or optionally substituted cyclopropyl, or a pharma- ceutically acceptable salt thereof.

[0871] 125.R 2 teeth,

[0872] [ka]

[0873] or a pharma- ceutically acceptable salt thereof. 126.R 2 is optionally substituted C 6 ~C 10 The compound of any one of embodiments 1-114, or a pharma- ceutically acceptable salt thereof, wherein: R is aryl.

[0874] 127.R 2 teeth,

[0875] [ka]

[0876] or a pharma- ceutically acceptable salt thereof. 128.R 2 is optionally substituted C 2 ~C 6 The compound of any one of embodiments 1-114, or a pharma- ceutically acceptable salt thereof, wherein: R is aryl;

[0877] 129.R 2 teeth,

[0878] [ka]

[0879] or a pharma- ceutically acceptable salt thereof. 130.R 1 is optionally substituted C 2 ~C 9 The compound of any one of embodiments 1-129, or a pharma- ceutically acceptable salt thereof, wherein: R is heteroaryl.

[0880] 131.R 1 teeth,

[0881] [ka]

[0882] or a pharma- ceutically acceptable salt thereof. 132.R 1 is R a -R b -R c or a pharma- ceutically acceptable salt thereof.

[0883] 133.R a is optionally substituted C 6 ~C 10 The compound of embodiment 132, or a pharma- ceutically acceptable salt thereof, wherein: 134.R c is optionally substituted C 2 ~C 9 The compound of embodiment 132, or a pharma- ceutically acceptable salt thereof, wherein:

[0884] 135.R b The compound of any one of embodiments 132-134, or a pharma- ceutically acceptable salt thereof, wherein is -O-. 136.R 1 teeth,

[0885] [ka]

[0886] 136. The compound of any one of embodiments 132, 133, or 135, wherein: 137.R b is optionally substituted C 1 ~C 6 The compound of any one of embodiments 132-134, or a pharma- ceutically acceptable salt thereof, wherein R is an alkylene.

[0887] 138.R b teeth,

[0888] [ka]

[0889] 138. The compound of any one of embodiments 132, 133, or 137, wherein: 139.R 1 is optionally substituted C 2 ~C 9 Heteroaryl C 1 ~C 6 The compound of any one of embodiments 1-129, or a pharma- ceutically acceptable salt thereof, wherein R is alkyl.

[0890] 140.R 1 teeth,

[0891] [ka]

[0892] or a pharma- ceutically acceptable salt thereof. 141.R 1 is optionally substituted C 6 ~C 10 The compound of any one of embodiments 1-129, or a pharma- ceutically acceptable salt thereof, wherein: R is aryl.

[0893] 142.R 1 teeth,

[0894] [ka]

[0895] or a pharma- ceutically acceptable salt thereof. 143.X is

[0896] [ka]

[0897] or a pharma- ceutically acceptable salt thereof. 144.X is

[0898] [ka]

[0899] or a pharma- ceutically acceptable salt thereof. 145. A compound having the structure of any one of compounds 1 to 50 in Table 1, or a pharma- ceutically acceptable salt thereof.

[0900] 146. The following structure:

[0901] [ka]

[0902] A compound having the formula: 147. A pharmaceutical composition comprising a compound according to any one of embodiments 1-146 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient.

[0903] 148. A method for treating a disease or disorder associated with Sec61 in a subject in need of such treatment, comprising administering to the subject an effective amount of a compound of any one of embodiments 1 to 146 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 147.

[0904] 149. The disease or disorder is amyloidosis, light chain amyloidosis, autoantibody disease, 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, various cancers with solid tumors, autoimmune disease, rheumatoid arthritis, ankylosing spondylitis, celiac disease, multiple sclerosis, atopic dermatitis, Crohn's disease, psoriasis, allergic asthma, autoimmune diseases ... autoimmune diseases, rheumatoid arthritis, ankylosing spondylitis, celiac disease, multiple sclerosis, autoimmune diseases, rheumatoid arthritis, ankylosing spon 149. The method of embodiment 148, wherein the disease is selected from autoimmune antibody diseases, myasthenia gravis, neuromyelitis optica, warm antibody hemolytic anemia, prion diseases, 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-Sträussler-Scheinker syndrome, high cholesterol, metabolic syndrome, and fatal familial insomnia.

[0905] 150. The method of embodiment 149, wherein the disease is a viral disease. 151. The method of embodiment 149, wherein the disease is cancer. 152. The method of embodiment 149, wherein the disease is a prion disease.

[0906] 153. The method of embodiment 149, wherein the disorder is light chain amyloidosis. 154. The method of embodiment 149, wherein the disease is an autoimmune antibody disease. 155. The method of embodiment 149, wherein the disease is a genetically defined kidney disease.

[0907] 156. The method of embodiment 149, wherein the disease is malaria. 157. A method for inhibiting Sec61-mediated translocation of a target protein, comprising contacting a cell with an effective amount of a compound of any one of embodiments 1 to 146 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 147.

[0908] 158. The method of embodiment 157, wherein the inhibition of translocation is selective for the target protein over non-target proteins. 159. A compound of any one of embodiments 1-146 or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition of embodiment 147 for use in treating a disease or disorder associated with Sec61 in a subject in need of such treatment.

[0909] 160. The disease or disorder is selected from the group consisting of amyloidosis, light chain amyloidosis, autoantibody disease, 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, various cancers with solid tumors, autoimmune disease, rheumatoid arthritis, ankylosing spondylitis, celiac disease, multiple sclerosis, atopic dermatitis, Crohn's disease, psoriasis, allergic asthma, autoimmune antibody disease, myasthenia gravis, optic nerve disorder ... 159. The compound or a pharmacologic acceptable salt thereof or pharmaceutical composition for use according to embodiment 159, selected from chronic inflammatory demyelinating polyradiculoneuropathy, 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-Sträussler-Scheinker syndrome, high cholesterol, metabolic syndrome, and fatal familial insomnia.

[0910] 161. The compound or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition for use according to embodiment 160, wherein said disease is a viral disease. 162. The compound or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition for use according to embodiment 160, wherein the disease is cancer.

[0911] 163. The compound or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition for use according to embodiment 160, wherein the disease is a prion disease. 164. The compound or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition for use according to embodiment 160, wherein said disorder is light chain amyloidosis.

[0912] 165. The compound or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition for use according to embodiment 160, wherein the disease is an autoimmune antibody disease. 166. The compound or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition for use according to embodiment 160, wherein the disease is a genetically defined renal disease.

[0913] 167. The compound or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition for use according to embodiment 160, wherein the disease is malaria. 168. A compound of any one of embodiments 1 to 146 or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition of embodiment 147 for use in inhibiting translocation of a target protein via Sec61.

[0914] 169. The compound or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition for use according to embodiment 166, wherein the inhibition of translocation is selective for the target protein over non-target proteins.

[0915] Other embodiments Various modifications and variations of the described invention will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the invention. Although the invention has been described in terms of 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.

[0916] All references, patents, published patent applications, and patent applications mentioned herein are hereby incorporated by reference in their entirety. Other embodiments are within the claims.

Claims

1. A compound having the structure of formula I below or a pharmaceutically acceptable salt thereof. 【Chemical 1】 (In the formula, R １ is H, optionally substituted C １ ~C ６ alkyl, optionally substituted C ３ ~C ７ cycloalkyl, optionally substituted C ２ ~C ９ heterocycle, optionally substituted C ６ ~C １０ aryl, optionally substituted C ２ ~C ９ heteroaryl, C ２ ~C ９ heteroaryl C １ ~C ６ alkyl, or R ａ -R ｂ -R ｃ and R ａ is an optionally substituted C ６ -C １０ -arylene or an optionally substituted C ２ -C ９ -heteroarylene, R ｂ is -O- or optionally substituted C １ ~C ６ alkylene, R ｃ is optionally substituted C ６ -C １０ aryl, and Z is C which may be absent or substituted ３ ~C １０ cycloalkylene, C which may be substituted ２ ~C ９ heterocyclylene, C ６ ~C １０ arylene, or C which may be substituted ２ ~C ９ heteroarylene, and Y is absent, O, or NR ３ and X is C which may be absent or substituted １ ~C ６ is alkylene, W is absent, S, O, or NR ３ and n is 0 or 1, A is S, O, NH, or CH ２ and B is CH or N, R ２ is optionally substituted C １～６ alkyl, optionally substituted C ２ -C ６ alkenyl, optionally substituted C ３～７ cycloalkyl, optionally substituted C ２～９ heterocycle, optionally substituted C ６ -C １０ aryl, optionally substituted C ２～９ heteroaryl, optionally substituted C ２ -C ９ heteroaryl C １ -C ６ alkyl, optionally substituted C ３ -C ７ cycloalkyl C １ -C ６ aryl, optionally substituted C １ -C ６ is heteroalkyl, or cyano, or has the structure of X １ -O-Y １ and has the structure of X １ is an optionally substituted C １ -C ６ alkylene, Y １ is optionally substituted C １ -C ６ alkyl, optionally substituted C ３ -C ８ cycloalkyl, or optionally substituted C ６ -C １０ aryl, and Each R ３ is independently H or C １ to C ６ alkyl.)

2. The compound according to claim 1, wherein the compound has the structure of formula II below or a pharmaceutically acceptable salt thereof. 【Chemical 2】

3. The compound according to claim 1, wherein the compound has the structure of formula IV below or a pharmaceutically acceptable salt thereof. [Chemical 3]

4. Z is optionally substituted C ６ -C １０ aryl or optionally substituted C ２ -C ９ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is heteroaryl.

5. Y is O or NR ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is O or NR

6. W is S, O, or NR ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein W is S, O, or NR

7. The compound according to claim 1, wherein the compound has the structure of formula V below or a pharmaceutically acceptable salt thereof. 【Chemical 4】 (wherein Y is O or NR ３ ).

8. The compound according to claim 1, wherein the compound has the structure of formula VI below or a pharmaceutically acceptable salt thereof. 【Chemical Formula 5】 (In the formula, W is NR ３ is.)

9. The compound according to claim 1, wherein n is 0 or a pharmaceutically acceptable salt thereof.

10. Z has the structure of formula VIIi below, the compound according to claim 1 or a pharmaceutically acceptable salt thereof. 【Chemical Formula 6】 (wherein A, B, C, and D are each independently N, CH, or CR ４ and Each R ４ is, independently, optionally substituted aryl, optionally substituted carbocyclic, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol.)

11. Z has the structure of formula VIIIi below, [Chemical Formula 7] or Z has the structure of formula XXIIi below, the compound according to claim 10 or a pharmaceutically acceptable salt thereof. 【Chemical 8】 (wherein A, B, C, and D are each independently CH or CR ４ ).

12. Z has the structure of formula XXXVIIi below, the compound according to claim 1 or a pharmaceutically acceptable salt thereof. 【Chemical Formula 9】 (In the formula, E is N or CH, F, G, and H are each independently N, CH, or CR ４ and Each R ４ is, independently, optionally substituted aryl, optionally substituted carbocyclic, halogen, hydroxyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoazide, cyano, nitro, or thiol.)

13. Z has the structures of formula XXXVIIIi, formula XXXIXi, formula XXXXi, formula XXXXIi below, the compound according to claim 12 or a pharmaceutically acceptable salt thereof. 【Chemical 10】

14. Z has the structure of formula XXXXIIIi below, the compound according to claim 1 or a pharmaceutically acceptable salt thereof. 【Chemical 11】

15. X is C １ to C ６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X is alkylene.

16. R ２ is optionally substituted C １ -C ６ alkyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C2-C9 heteroaryl, phenyl, or X1-O-Y1, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

17. R １ is optionally substituted C ２ -C ９ heteroaryl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

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

19. A pharmaceutical composition comprising the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

20. The pharmaceutical composition according to claim 19, for treating a Sec61-related disease or disorder in a subject in need of treatment.

21. The disease or disorder is selected from amyloidosis, light chain amyloidosis, autoimmune disease, 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, various cancers with solid tumors, autoimmune disease, rheumatoid arthritis, ankylosing spondylitis, celiac disease, multiple sclerosis, atopic dermatitis, Crohn's disease, psoriasis, allergic asthma, autoimmune antibody disease, myasthenia gravis, neuromyelitis optica, warm antibody hemolytic anemia, prion disease, immune thrombocytopenic purpura, chronic inflammatory demyelinating polyneuropathy, fibrotic disease, idiopathic pulmonary fibrosis, endometriosis, non-alcoholic steatohepatitis, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, hypercholesterolemia, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, hypercholesterol, metabolic syndrome, and fatal familial insomnia, the pharmaceutical composition according to claim 20.

22. The disease is a viral disease, cancer, prion disease, light chain amyloidosis, autoimmune antibody disease, genetically defined kidney disease, or malaria, the pharmaceutical composition according to claim 21.

23. The pharmaceutical composition according to claim 19 for inhibiting the translocation of a target protein via Sec61.

24. The pharmaceutical composition according to claim 23, wherein the inhibition of translocation is selective for the target protein over non-target proteins.

Images