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MODULATORS OF THE INTEGRATED STRESS RESPONSE PATHWAY

20230125481 · 2023-04-27

    Inventors

    Cpc classification

    International classification

    Abstract

    The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, wherein R.sup.1, R.sup.2, R.sup.2a, R.sup.3, R.sup.a1, R.sup.a2, R.sup.a4, R.sup.a5, X.sup.1, X.sup.1a, A.sup.1 and A.sup.2 have the meaning as indicated in the description and claims. The invention further relates to pharmaceutical compositions comprising said compounds, their use as medicament and in a method for treating and preventing of one or more diseases or disorders associated with integrated stress response.

    ##STR00001##

    Claims

    1-28. (canceled)

    29. A compound of formula (I) ##STR00068## or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein X.sup.1 is C(R.sup.a6) or N; X.sup.1a is a covalent single bond, CH(R.sup.a3), O, N(R.sup.a7), or CH(R.sup.a3)CH.sub.2; R.sup.a1, R.sup.a2, and R.sup.a3 are independently selected from the group consisting of H, halogen, OH, O—C.sub.1-4 alkyl, C.sub.1-4 alkyl, and A.sup.2a, and R.sup.a4, R.sup.a5, and R.sup.a6 are independently selected from the group consisting of H, halogen, C.sub.1-4 alkyl, and A.sup.2a, provided that only one of R.sup.a1, R.sup.a2, R.sup.a3, R.sup.a4, R.sup.a5, and R.sup.a6 is A.sup.2a; optionally R.sup.a1 and R.sup.a2 form a covalent single bond; optionally R.sup.a2 and R.sup.a4 form a methylene group; optionally R.sup.a4 and R.sup.a6 form an ethylene group; optionally R.sup.a4 and R.sup.a5 are joined to form an oxo group; R.sup.a7 is H, C(O)OC.sub.1-4 alkyl, or C.sub.1-4 alkyl, wherein C(O)OC.sub.1-4 alkyl and C.sub.1-4alkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, OH, and O—C.sub.1-3 alkyl, wherein the substituents are the same or different; A.sup.1 is C.sub.5 cycloalkylene, C.sub.5 cycloalkenylene, a nitrogen ring atom containing 5-membered heterocyclene, or a 7- to 12-membered heterobicyclene, which includes a nitrogen ring atom containing 5-membered heterocycle, wherein said heterocycle is attached to the nitrogen ring atom shown in formula (I) and wherein A.sup.1 is optionally substituted with one or more R.sup.4, which are the same or different; each R.sup.4 is independently oxo (═O) where the ring is at least partially saturated, thiooxo (═S) where the ring is at least partially saturated, halogen, CN, OR.sup.5, or C.sub.1-6 alkyl, wherein C.sub.1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; R.sup.5 is H or C.sub.1-6 alkyl, wherein C.sub.1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; A.sup.2 is R.sup.6a or A.sup.2a; R.sup.6a is OR.sup.6a1, SR.sup.6a1, N(R.sup.6a1R.sup.6a2), C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OR.sup.6a3, and A.sup.2a, wherein the substituents are the same or different; R.sup.6a1 and R.sup.6a2 are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and A.sup.2a, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OR.sup.6a3, and A.sup.2a, wherein the substituents are the same or different; R.sup.6a3 is H or C.sub.1-4 alkyl, wherein C.sub.1-4 alkyl is optionally substituted with one or more halogen, which are the same or different; A.sup.2a is phenyl or 3- to 7-membered heterocyclyl, wherein A.sup.2a is optionally substituted with one or more R.sup.6, which are the same or different; each R.sup.6 is independently R.sup.6b, OH, OR.sup.6b, halogen, or CN, wherein R.sup.6b is cyclopropyl, C.sub.1-6alkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl, and wherein R.sup.6b is optionally substituted with one or more halogen, which are the same or different; or two R.sup.6 are joined to form together with the atoms to which they are attached a ring A.sup.2b; A.sup.2b is phenyl or 3- to 7-membered heterocyclyl, wherein A.sup.2b is optionally substituted with one or more R.sup.7, which are the same or different; each R.sup.7 is independently C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different; R.sup.1 is H or C.sub.1-4 alkyl, wherein C.sub.1-4 alkyl is optionally substituted with one or more halogen, which are the same or different; R.sup.2 is H, F, or C.sub.1-4 alkyl, wherein C.sub.1-4 alkyl is optionally substituted with one or more halogen, which are the same or different; and R.sup.3 is A.sup.3, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more R.sup.8, which are the same or different; or R.sup.2 and R.sup.3 are joined to form together with the oxygen atom and carbon atom to which they are attached a ring A.sup.3a, wherein A.sup.3a is a 7- to 12-membered heterobicyclyl, wherein 7- to 12-membered heterobicyclyl is optionally substituted with one or more R.sup.10, which are the same or different; R.sup.2 is H or F; each R.sup.8 is independently halogen, CN, C(O)OR.sup.9, OR.sup.9, C(O)R.sup.9, C(O)N(R.sup.9R.sup.9a), S(O).sub.2N(R.sup.9R.sup.9a), S(O)N(R.sup.9R.sup.9a), S(O).sub.2R.sup.9, S(O)R.sup.9, N(R.sup.9)S(O).sub.2N(R.sup.9aR.sup.9b), SR.sup.9, N(R.sup.9R.sup.9a), NO.sub.2, OC(O)R.sup.9, N(R.sup.9)C(O)R.sup.9a, N(R.sup.9)SO.sub.2R.sup.9a, N(R.sup.9)S(O)R.sup.9a, N(R.sup.9)C(O)N(R.sup.9aR.sup.9b), N(R.sup.9)C(O)OR.sup.9a, OC(O)N(R.sup.9R.sup.9a), or A.sup.3; R.sup.9, R.sup.9a, and R.sup.9b are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different, or one OH, or one OC.sub.1-4 alkyl, or one A.sup.3; each A.sup.3 is independently phenyl, naphthyl, 3- to 7-membered heterocyclyl, or 7- to 12-membered heterobicyclyl, wherein A.sup.3 is optionally substituted with one or more R.sup.10, which are the same or different; each R.sup.10 is independently halogen, CN, C(O)OR.sup.1, OR.sup.11, C(O)R.sup.11, C(O)N(R.sup.11R.sup.11a), S(O).sub.2N(R.sup.11R.sup.11a), S(O)N(R.sup.11R.sup.11a), S(O).sub.2R.sup.11, S(O)R.sup.11, N(R.sup.11)S(O).sub.2N(R.sup.11aR.sup.11b), SR.sup.11, N(R.sup.11R.sup.11a), NO.sub.2, OC(O)R.sup.11, N(R.sup.11)C(O)R.sup.11a, N(R.sup.11)S(O).sub.2R.sup.11a, N(R.sup.11)S(O)R.sup.11a, N(R.sup.11)C(O)OR.sup.11a, N(R.sup.11)C(O)N(R.sup.11aR.sup.11b), OC(O)N(R.sup.11R.sup.11a), oxo (═O) where the ring is at least partially saturated, C.sub.1-6alkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more R.sup.12, which are the same or different; R.sup.11, R.sup.11a, and R.sup.11b are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different; each R.sup.12 is independently halogen, CN, C(O)OR.sup.13, OR.sup.13, C(O)R.sup.13, C(O)N(R.sup.3R.sup.13a), S(O).sub.2N(R.sup.3R.sup.13a), S(O)N(R.sup.13R.sup.13a), S(O).sub.2R.sup.13, S(O)R.sup.13, N(R.sup.13)S(O).sub.2N(R.sup.13aR.sup.13b), SR.sup.13, N(R.sup.13R.sup.13a), NO.sub.2, OC(O)R.sup.13, N(R.sup.13)C(O)R.sup.13a, N(R.sup.13)SO.sub.2R.sup.13a, N(R.sup.13)S(O)R.sup.13a, N(R.sup.13)C(O)N(R.sup.13aR.sup.13b), N(R.sup.13)C(O)OR.sup.13a, or OC(O)N(R.sup.13R.sup.13a); and R.sup.13, R.sup.13a, and R.sup.13b are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different, provided that the following compounds or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof are excluded: ##STR00069## ##STR00070## ##STR00071## ##STR00072## ##STR00073## ##STR00074##

    30. The compound of claim 29 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein X.sup.1 is CH.

    31. The compound of claim 29 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein X.sup.1a is a covalent single bond, CH(R.sup.a3), or CH(R.sup.a3)CH.sub.2.

    32. The compound of claim 29 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R.sup.a1, R.sup.a2, R.sup.a3, R.sup.a4, R.sup.a5, and R.sup.a6 are H; or R.sup.a1 is OH and R.sup.a2, R.sup.a3, R.sup.a4, R.sup.a5, and R.sup.a6 are H; or R.sup.a1, R.sup.a3, R.sup.a5, and R.sup.a6 are H and R.sup.a2 and R.sup.a4 form a methylene group; or R.sup.a1 and R.sup.a2 form a covalent single bond and R.sup.a3, R.sup.a4, R.sup.a5, and R.sup.a6 are H.

    33. The compound of claim 29 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R.sup.a1, R.sup.a2, R.sup.a3, R.sup.a4, R.sup.a5, and R.sup.a6 are H.

    34. The compound of claim 29 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A.sup.1 is a nitrogen ring atom containing 5-membered heterocyclene and wherein A.sup.1 is optionally substituted with one or more R.sup.4, which are the same or different.

    35. The compound of claim 29 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A.sup.1 is a nitrogen ring atom containing 5-membered heterocyclene selected from the group of bivalent heterocycles consisting of oxadiazole, imidazole, imidazolidine, pyrazole, and triazole, and wherein A.sup.1 is optionally substituted with one or more R.sup.4, which are the same or different.

    36. The compound of claim 29 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A.sup.1 is unsubstituted or substituted with one or two R.sup.4, which are the same or different.

    37. The compound of claim 29 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R.sup.4 is oxo where the ring is at least partly saturated, or methyl.

    38. The compound of claim 29 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A.sup.1 is ##STR00075##

    39. The compound of claim 29 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A.sup.2 is R.sup.6.

    40. The compound of claim 39 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R.sup.6a is OR.sup.6a1 and R.sup.6a1 is A.sup.2a or C.sub.1-6 alkyl, optionally substituted with one or more halogen and/or one A.sup.2a and/or one OR.sup.6a3; or R.sup.6a is C.sub.1-6 alkyl, optionally substituted with one or more halogen and/or one A.sup.2a and/or one OR.sup.6a3.

    41. The compound of claim 39 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R.sup.6a is OR.sup.6a1 and R.sup.6a1 is C.sub.1-6 alkyl, optionally substituted with one or more F and/or one OR.sup.6a3; or R.sup.6a is C.sub.1-6 alkyl, optionally substituted with one or more halogen and/or one OR.sup.6a3.

    42. The compound of claim 29 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A.sup.2 is A.sup.2a.

    43. The compound of claim 42 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A.sup.2a is phenyl, or 5- to 6-membered aromatic heterocyclyl, and wherein A.sup.2a is optionally substituted with one or more R.sup.6, which are the same or different.

    44. The compound of claim 29 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A.sup.2a is substituted with one or two R.sup.6, which are the same or different.

    45. The compound of claim 29 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each R.sup.6 is independently F, Cl, CF.sub.3, OCH.sub.3, OCF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, or cyclopropyl.

    46. The compound of claim 29 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R.sup.2 is H.

    47. The compound of claim 29 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R.sup.3 is A.sup.3.

    48. The compound of claim 29 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A.sup.3 is phenyl, pyridyl, pyrazinyl, or pyrimidazyl and wherein A.sup.3 is optionally substituted with one or more R.sup.10, which are the same or different.

    49. The compound of claim 29 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A.sup.3 is substituted with one or two R.sup.10, which are the same or different.

    50. The compound of claim 29 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R.sup.2 and R.sup.3 are joined together with the oxygen and carbon atom to which they are attached to form a dihydrobenzopyran ring, wherein the ring is optionally substituted with one or more R.sup.10, which are the same or different.

    51. The compound of claim 29 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R.sup.10 is independently F, Cl, CF.sub.3, CH═O, CH.sub.2OH, or CH.sub.3.

    52. The compound of claim 29 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the compound is 2-(4-chloro-3-fluorophenoxy)-N-{1-[5-(5-chloropyridin-2-yl)-1,3,4-oxadiazol-2-yl]piperidin-4-yl}acetamide; 2-[(6-chloro-5-fluoropyridin-3-yl)oxy]-N-{1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-4-yl}acetamide; 2-(4-chloro-3-fluorophenoxy)-N-[(3R*,4R*)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxypiperidin-4-yl]acetamide; 2-(4-chloro-3-fluoro-phenoxy)-N-[1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-4-piperidyl]acetamide; 2-(4-Chloro-3-fluorophenoxy)-N-{1-[5-(4,4,4-trifluorobutyl)-1,3,4-oxadiazol-2-yl]piperidin-4-yl}acetamide; 2-(4-Chloro-3-fluorophenoxy)-N-[(1R,5S,6R)-3-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.0]hexan-6-yl]acetamide; 2-(4-Chloro-3-fluorophenoxy)-N-{4-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperazin-1-yl}acetamide; 2-(4-Chloro-3-fluorophenoxy)-N-{1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]azepan-4-yl}acetamide; 2-(4-Chloro-3-fluorophenoxy)-N-[(3R,4R)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxypiperidin-4-yl]acetamide; 2-(4-Chloro-3-fluorophenoxy)-N-[(35,45)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxypiperidin-4-yl]acetamide; 2-(4-Chloro-3-fluorophenoxy)-N-[(45)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]azepan-4-yl]acetamide; 2-(4-chloro-3-fluorophenoxy)-N-[(4R)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]azepan-4-yl]acetamide; 2-(4-chloro-3-fluorophenoxy)-N-(1-{5-[3-(trifluoromethoxy)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-4-yl)acetamide; or 2-(4-chloro-3-fluorophenoxy)-N-(1-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-4-yl)acetamide.

    53. A pharmaceutical composition comprising at least one compound of formula (I) ##STR00076## or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein X.sup.1 is C(R.sup.a6) or N; X.sup.1a is a covalent single bond, CH(R.sup.a3), O, N(R.sup.a7), or CH(R.sup.a3)CH.sub.2; R.sup.a1, R.sup.a2, and R.sup.a3 are independently selected from the group consisting of H, halogen, OH, O—C.sub.1-4 alkyl, C.sub.1-4 alkyl, and A.sup.2a, and R.sup.a4, R.sup.aS, and R.sup.a6 are independently selected from the group consisting of H, halogen, C.sub.1-4 alkyl, and A.sup.2a, provided that only one of R.sup.a1, R.sup.a2, R.sup.a3, R.sup.a4, R.sup.a5, and R.sup.a6 is A.sup.2a; optionally R.sup.a1 and R.sup.a2 form a covalent single bond; optionally R.sup.a2 and R.sup.a4 form a methylene group; optionally R.sup.a4 and R.sup.a6 form an ethylene group; optionally R.sup.a4 and R.sup.a5 are joined to form an oxo group; R.sup.a7 is H, C(O)OC.sub.1-4 alkyl, or C.sub.1-4 alkyl, wherein C(O)OC.sub.1-4 alkyl and C.sub.1-4alkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, OH, and O—C.sub.1-3 alkyl, wherein the substituents are the same or different; A.sup.1 is C.sub.5 cycloalkylene, C.sub.5 cycloalkenylene, a nitrogen ring atom containing 5-membered heterocyclene, or a 7- to 12-membered heterobicyclene, which includes a nitrogen ring atom containing 5-membered heterocycle, wherein said heterocycle is attached to the nitrogen ring atom shown in formula (I) and wherein A.sup.1 is optionally substituted with one or more R.sup.4, which are the same or different; each R.sup.4 is independently oxo (═O) where the ring is at least partially saturated, thiooxo (═S) where the ring is at least partially saturated, halogen, CN, OR.sup.5, or C.sub.1-6 alkyl, wherein C.sub.1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; R.sup.5 is H or C.sub.1-6 alkyl, wherein C.sub.1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; A.sup.2 is R.sup.6a or A.sup.2a; R.sup.6a is OR.sup.6a, SR.sup.6a, N(R.sup.6a1R.sup.6a2), C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OR.sup.6a3, and A.sup.2a, wherein the substituents are the same or different; R.sup.6a1 and R.sup.6a2 are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and A.sup.2a, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OR.sup.6a3, and A.sup.2a, wherein the substituents are the same or different; R.sup.6a3 is H or C.sub.1-4 alkyl, wherein C.sub.1-4 alkyl is optionally substituted with one or more halogen, which are the same or different; A.sup.2a is phenyl or 3- to 7-membered heterocyclyl, wherein A.sup.2a is optionally substituted with one or more R.sup.6, which are the same or different; each R.sup.6 is independently R.sup.6b, OH, OR.sup.6b, halogen, or CN, wherein R.sup.6b is cyclopropyl, C.sub.1-6alkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl, and wherein R.sup.6b is optionally substituted with one or more halogen, which are the same or different; or two R.sup.6 are joined to form together with the atoms to which they are attached a ring A.sup.2b; A.sup.2b is phenyl or 3- to 7-membered heterocyclyl, wherein A.sup.2b is optionally substituted with one or more R.sup.7, which are the same or different; each R.sup.7 is independently C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different; R.sup.1 is H or C.sub.1-4 alkyl, wherein C.sub.1-4 alkyl is optionally substituted with one or more halogen, which are the same or different; R.sup.2 is H, F, or C.sub.1-4 alkyl, wherein C.sub.1-4 alkyl is optionally substituted with one or more halogen, which are the same or different; and R.sup.3 is A.sup.3, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more R.sup.8, which are the same or different; or R.sup.2 and R.sup.3 are joined to form together with the oxygen atom and carbon atom to which they are attached a ring A.sup.3a, wherein A.sup.3a is a 7- to 12-membered heterobicyclyl, wherein 7- to 12-membered heterobicyclyl is optionally substituted with one or more R.sup.10, which are the same or different; R.sup.2 is H or F; each R.sup.8 is independently halogen, CN, C(O)OR.sup.9, OR.sup.9, C(O)R.sup.9, C(O)N(R.sup.9R.sup.9a), S(O).sub.2N(R.sup.9R.sup.9a), S(O)N(R.sup.9R.sup.9a), S(O).sub.2R.sup.9, S(O)R.sup.9, N(R.sup.9)S(O).sub.2N(R.sup.9aR.sup.9b), SR.sup.9, N(R.sup.9R.sup.9a), NO.sub.2, OC(O)R.sup.9, N(R.sup.9)C(O)R.sup.9a, N(R.sup.9)SO.sub.2R.sup.9a, N(R.sup.9)S(O)R.sup.9a, N(R.sup.9)C(O)N(R.sup.9aR.sup.9b), N(R.sup.9)C(O)OR.sup.9a, OC(O)N(R.sup.9R.sup.9a), or A.sup.3; R.sup.9, R.sup.9a, and R.sup.9b are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different, or one OH, or one OC.sub.1-4 alkyl, or one A.sup.3; each A.sup.3 is independently phenyl, naphthyl, 3- to 7-membered heterocyclyl, or 7- to 12-membered heterobicyclyl, wherein A.sup.3 is optionally substituted with one or more R.sup.10, which are the same or different; each R.sup.10 is independently halogen, CN, C(O)OR.sup.1, OR.sup.11, C(O)R.sup.11, C(O)N(R.sup.11R.sup.11a), S(O).sub.2N(R.sup.11R.sup.11a), S(O)N(R.sup.11R.sup.11a), S(O).sub.2R.sup.11, S(O)R.sup.11, N(R.sup.11)S(O).sub.2N(R.sup.11aR.sup.11b), SR.sup.11, N(R.sup.11R.sup.11a), NO.sub.2, OC(O)R.sup.11, N(R.sup.11)C(O)R.sup.11a, N(R.sup.11)S(O).sub.2R.sup.11a, N(R.sup.11)S(O)R.sup.11a, N(R.sup.11)C(O)OR.sup.11a, N(R.sup.11)C(O)N(R.sup.11aR.sup.11b), OC(O)N(R.sup.11R.sup.11a), oxo (═O) where the ring is at least partially saturated, C.sub.1-6alkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more R.sup.12, which are the same or different; R.sup.11, R.sup.11a, and R.sup.11b are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different; each R.sup.12 is independently halogen, CN, C(O)OR.sup.13, OR.sup.13, C(O)R.sup.13, C(O)N(R.sup.13R.sup.13a), S(O).sub.2N(R.sup.3R.sup.13a), S(O)N(R.sup.13R.sup.13a), S(O).sub.2R.sup.13, S(O)R.sup.13, N(R.sup.13)S(O).sub.2N(R.sup.13aR.sup.13b), SR.sup.13, N(R.sup.13R.sup.13a), NO.sub.2, OC(O)R.sup.13, N(R.sup.13)C(O)R.sup.13a, N(R.sup.13)SO.sub.2R.sup.13a, N(R.sup.13)S(O)R.sup.13a, N(R.sup.13)C(O)N(R.sup.13aR.sup.13b), N(R.sup.13)C(O)OR.sup.13a, or OC(O)N(R.sup.13R.sup.13a); and R.sup.13, R.sup.13a, and R.sup.13b are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different; together with a pharmaceutically acceptable carrier, optionally in combination with one or more other bioactive compounds or pharmaceutical compositions.

    54. A method for treating, controlling, delaying, or preventing in a mammalian patient in need of the treatment of one or more diseases or disorders associated with integrated stress response, wherein the method comprises administering to said patient a therapeutically effective amount of a compound of formula (I) ##STR00077## or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein X.sup.1 is C(R.sup.a6) or N; X.sup.1a is a covalent single bond, CH(R.sup.a3), O, N(R.sup.a7), or CH(R.sup.a3)CH.sub.2; R.sup.a1, R.sup.a2, and R.sup.a3 are independently selected from the group consisting of H, halogen, OH, O—C.sub.1-4 alkyl, C.sub.1-4 alkyl, and A.sup.2a, and R.sup.a4, R.sup.a5, and R.sup.a6 are independently selected from the group consisting of H, halogen, C.sub.1-4 alkyl, and A.sup.2a, provided that only one of R.sup.a1, R.sup.a2, R.sup.a3, R.sup.a4, R.sup.a5, and R.sup.a6 is A.sup.2a; optionally R.sup.a1 and R.sup.a2 form a covalent single bond; optionally R.sup.a2 and R.sup.a4 form a methylene group; optionally R.sup.a4 and R.sup.a6 form an ethylene group; optionally R.sup.a4 and R.sup.a5 are joined to form an oxo group; R.sup.a7 is H, C(O)OC.sub.1-4 alkyl, or C.sub.1-4 alkyl, wherein C(O)OC.sub.1-4 alkyl and C.sub.1-4alkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, OH, and O—C.sub.1-3 alkyl, wherein the substituents are the same or different; A.sup.1 is C.sub.5 cycloalkylene, C.sub.5 cycloalkenylene, a nitrogen ring atom containing 5-membered heterocyclene, or a 7- to 12-membered heterobicyclene, which includes a nitrogen ring atom containing 5-membered heterocycle, wherein said heterocycle is attached to the nitrogen ring atom shown in formula (I) and wherein A.sup.1 is optionally substituted with one or more R.sup.4, which are the same or different; each R.sup.4 is independently oxo (═O) where the ring is at least partially saturated, thiooxo (═S) where the ring is at least partially saturated, halogen, CN, OR.sup.5, or C.sub.1-6 alkyl, wherein C.sub.1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; R.sup.5 is H or C.sub.1-6 alkyl, wherein C.sub.1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; A.sup.2 is R.sup.6a or A.sup.2a; R.sup.6a is OR.sup.6a, SR.sup.6a, N(R.sup.6a1R.sup.6a2), C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OR.sup.6a3, and A.sup.2a, wherein the substituents are the same or different; R.sup.6a1 and R.sup.6a2 are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and A.sup.2a, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OR.sup.6a3, and A.sup.2a, wherein the substituents are the same or different; R.sup.6a3 is H or C.sub.1-4 alkyl, wherein C.sub.1-4 alkyl is optionally substituted with one or more halogen, which are the same or different; A.sup.2a is phenyl or 3- to 7-membered heterocyclyl, wherein A.sup.2a is optionally substituted with one or more R.sup.6, which are the same or different; each R.sup.6 is independently R.sup.6b, OH, OR.sup.6b, halogen, or CN, wherein R.sup.6b is cyclopropyl, C.sub.1-6alkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl, and wherein R.sup.6b is optionally substituted with one or more halogen, which are the same or different; or two R.sup.6 are joined to form together with the atoms to which they are attached a ring A.sup.2b; A.sup.2b is phenyl or 3- to 7-membered heterocyclyl, wherein A.sup.2b is optionally substituted with one or more R.sup.7, which are the same or different; each R.sup.7 is independently C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different; R.sup.1 is H or C.sub.1-4 alkyl, wherein C.sub.1-4 alkyl is optionally substituted with one or more halogen, which are the same or different; R.sup.2 is H, F, or C.sub.1-4 alkyl, wherein C.sub.1-4 alkyl is optionally substituted with one or more halogen, which are the same or different; and R.sup.3 is A.sup.3, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more R.sup.8, which are the same or different; or R.sup.2 and R.sup.3 are joined to form together with the oxygen atom and carbon atom to which they are attached a ring A.sup.3a, wherein A.sup.3a is a 7- to 12-membered heterobicyclyl, wherein 7- to 12-membered heterobicyclyl is optionally substituted with one or more R.sup.10, which are the same or different; R.sup.2 is H or F; each R.sup.8 is independently halogen, CN, C(O)OR.sup.9, OR.sup.9, C(O)R.sup.9, C(O)N(R.sup.9R.sup.9a), S(O).sub.2N(R.sup.9R.sup.9a), S(O)N(R.sup.9R.sup.9a), S(O).sub.2R.sup.9, S(O)R.sup.9, N(R.sup.9)S(O).sub.2N(R.sup.9aR.sup.9b), SR.sup.9, N(R.sup.9R.sup.9a), NO.sub.2, OC(O)R.sup.9, N(R.sup.9)C(O)R.sup.9a, N(R.sup.9)SO.sub.2R.sup.9a, N(R.sup.9)S(O)R.sup.9a, N(R.sup.9)C(O)N(R.sup.9aR.sup.9b), N(R.sup.9)C(O)OR.sup.9a, OC(O)N(R.sup.9R.sup.9a), or A.sup.3; R.sup.9, R.sup.9a, and R.sup.9b are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different, or one OH, or one OC.sub.1-4 alkyl, or one A.sup.3; each A.sup.3 is independently phenyl, naphthyl, 3- to 7-membered heterocyclyl, or 7- to 12-membered heterobicyclyl, wherein A.sup.3 is optionally substituted with one or more R.sup.10, which are the same or different; each R.sup.10 is independently halogen, CN, C(O)OR.sup.11, OR.sup.11, C(O)R.sup.11, C(O)N(R.sup.11R.sup.11a), S(O).sub.2N(R.sup.1R.sup.11a), S(O)N(R.sup.11R.sup.11a), S(O).sub.2R.sup.11, S(O)R.sup.11, N(R.sup.11)S(O).sub.2N(R.sup.11aR.sup.11b), SR.sup.11, N(R.sup.11R.sup.11a), NO.sub.2, OC(O)R.sup.11, N(R.sup.11)C(O)R.sup.11a, N(R.sup.11)S(O).sub.2R.sup.11a, N(R.sup.11)S(O)R.sup.11a, N(R.sup.11)C(O)OR.sup.11a, N(R.sup.11)C(O)N(R.sup.11aR.sup.11b), OC(O)N(R.sup.11R.sup.11a), oxo (═O) where the ring is at least partially saturated, C.sub.1-6alkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more R.sup.12, which are the same or different; R.sup.11, R.sup.11a, and R.sup.11b are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different; each R.sup.12 is independently halogen, CN, C(O)OR.sup.13, OR.sup.13a, C(O)R.sup.13, C(O)N(R.sup.3R.sup.13a), S(O).sub.2N(R.sup.3R.sup.13a), S(O)N(R.sup.13R.sup.13a), S(O).sub.2R.sup.13, S(O)R.sup.13, N(R.sup.13)S(O).sub.2N(R.sup.13aR.sup.13b), SR.sup.13, N(R.sup.13R.sup.13a), NO.sub.2, OC(O)R.sup.13, N(R.sup.13)C(O)R.sup.13a, N(R.sup.13)SO.sub.2R.sup.13a, N(R.sup.13)S(O)R.sup.13a, N(R.sup.13)C(O)N(R.sup.13aR.sup.13b), N(R.sup.13)C(O)OR.sup.13a, or OC(O)N(R.sup.13R.sup.13a); and R.sup.13, R.sup.13a, and R.sup.13b are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different.

    55. A method for treating, controlling, delaying, or preventing in a mammalian patient in need of the treatment of one or more diseases or disorders selected from the group consisting of leukodystrophies, intellectual disability syndrome, neurodegenerative diseases and disorders, neoplastic diseases, infectious diseases, inflammatory diseases, musculoskeletal diseases, metabolic diseases, ocular diseases as well as diseases selected from the group consisting of organ fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lung, chronic and acute diseases of the kidney, myocardial infarction, cardiovascular disease, arrhythmias, atherosclerosis, spinal cord injury, ischemic stroke, and neuropathic pain, wherein the method comprises administering to said patient a therapeutically effective amount of a compound of formula (I) ##STR00078## or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein X.sup.1 is C(R.sup.a6) or N; X.sup.1a is a covalent single bond, CH(R.sup.a3), O, N(R.sup.a7), or CH(R.sup.a3)CH.sub.2; R.sup.a1, R.sup.a2, and R.sup.a3 are independently selected from the group consisting of H, halogen, OH, O—C.sub.1-4 alkyl, C.sub.1-4 alkyl, and A.sup.2a, and R.sup.a4, R.sup.a5, and R.sup.a6 are independently selected from the group consisting of H, halogen, C.sub.1-4 alkyl, and A.sup.2a, provided that only one of R.sup.a1, R.sup.a2, R.sup.a3, R.sup.a4, R.sup.a5, and R.sup.a6 is A.sup.2a; optionally R.sup.a1 and R.sup.a2 form a covalent single bond; optionally R.sup.a2 and R.sup.a4 form a methylene group; optionally R.sup.a4 and R.sup.a6 form an ethylene group; optionally R.sup.a4 and R.sup.a5 are joined to form an oxo group; R.sup.a7 is H, C(O)OC.sub.1-4 alkyl, or C.sub.1-4 alkyl, wherein C(O)OC.sub.1-4 alkyl and C.sub.1-4alkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, OH, and O—C.sub.1-3 alkyl, wherein the substituents are the same or different; A.sup.1 is C.sub.5 cycloalkylene, C.sub.5 cycloalkenylene, a nitrogen ring atom containing 5-membered heterocyclene, or a 7- to 12-membered heterobicyclene, which includes a nitrogen ring atom containing 5-membered heterocycle, wherein said heterocycle is attached to the nitrogen ring atom shown in formula (I) and wherein A.sup.1 is optionally substituted with one or more R.sup.4, which are the same or different; each R.sup.4 is independently oxo (═O) where the ring is at least partially saturated, thiooxo (═S) where the ring is at least partially saturated, halogen, CN, OR.sup.5, or C.sub.1-6 alkyl, wherein C.sub.1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; R.sup.5 is H or C.sub.1-6 alkyl, wherein C.sub.1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; A.sup.2 is R.sup.6a or A.sup.2a; R.sup.6a is OR.sup.6a, SR.sup.6a, N(R.sup.6a1R.sup.6a2), C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OR.sup.6a3, and A.sup.2a, wherein the substituents are the same or different; R.sup.6a1 and R.sup.6a2 are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and A.sup.2a, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OR.sup.6a3, and A.sup.2a, wherein the substituents are the same or different; R.sup.6a3 is H or C.sub.1-4 alkyl, wherein C.sub.1-4 alkyl is optionally substituted with one or more halogen, which are the same or different; A.sup.2a is phenyl or 3- to 7-membered heterocyclyl, wherein A.sup.2a is optionally substituted with one or more R.sup.6, which are the same or different; each R.sup.6 is independently R.sup.6b, OH, OR.sup.6b, halogen, or CN, wherein R.sup.6b is cyclopropyl, C.sub.1-6alkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl, and wherein R.sup.6b is optionally substituted with one or more halogen, which are the same or different; or two R.sup.6 are joined to form together with the atoms to which they are attached a ring A.sup.2b; A.sup.2b is phenyl or 3- to 7-membered heterocyclyl, wherein A.sup.2b is optionally substituted with one or more R.sup.7, which are the same or different; each R.sup.7 is independently C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different; R.sup.1 is H or C.sub.1-4 alkyl, wherein C.sub.1-4 alkyl is optionally substituted with one or more halogen, which are the same or different; R.sup.2 is H, F, or C.sub.1-4 alkyl, wherein C.sub.1-4 alkyl is optionally substituted with one or more halogen, which are the same or different; and R.sup.3 is A.sup.3, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more R.sup.8, which are the same or different; or R.sup.2 and R.sup.3 are joined to form together with the oxygen atom and carbon atom to which they are attached a ring A.sup.3a, wherein A.sup.3a is a 7- to 12-membered heterobicyclyl, wherein 7- to 12-membered heterobicyclyl is optionally substituted with one or more R.sup.10, which are the same or different; R.sup.2 is H or F; each R.sup.8 is independently halogen, CN, C(O)OR.sup.9, OR.sup.9, C(O)R.sup.9, C(O)N(R.sup.9R.sup.9a), S(O).sub.2N(R.sup.9R.sup.9a), S(O)N(R.sup.9R.sup.9a), S(O).sub.2R.sup.9, S(O)R.sup.9, N(R.sup.9)S(O).sub.2N(R.sup.9aR.sup.9b), SR.sup.9, N(R.sup.9R.sup.9a), NO.sub.2, OC(O)R.sup.9, N(R.sup.9)C(O)R.sup.9a, N(R.sup.9)SO.sub.2R.sup.9a, N(R.sup.9)S(O)R.sup.9a, N(R.sup.9)C(O)N(R.sup.9aR.sup.9b), N(R.sup.9)C(O)OR.sup.9a, OC(O)N(R.sup.9R.sup.9a), or A.sup.3; R.sup.9, R.sup.9a, and R.sup.9b are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different, or one OH, or one OC.sub.1-4 alkyl, or one A.sup.3; each A.sup.3 is independently phenyl, naphthyl, 3- to 7-membered heterocyclyl, or 7- to 12-membered heterobicyclyl, wherein A.sup.3 is optionally substituted with one or more R.sup.10, which are the same or different; each R.sup.10 is independently halogen, CN, C(O)OR.sup.11, OR.sup.11, C(O)R.sup.11, C(O)N(R.sup.11R.sup.11a), S(O).sub.2N(R.sup.11R.sup.11a), S(O)N(R.sup.11R.sup.11a), S(O).sub.2R.sup.1, S(O)R.sup.11, N(R.sup.11)S(O).sub.2N(R.sup.11aR.sup.11b), SR.sup.11, N(R.sup.11R.sup.11a), NO.sub.2, OC(O)R.sup.11, N(R.sup.11)C(O)R.sup.11, N(R.sup.11)S(O).sub.2R.sup.11a, N(R.sup.11)S(O)R.sup.11a, N(R.sup.11)C(O)OR.sup.11a, N(R.sup.11)C(O)N(R.sup.11aR.sup.11b), OC(O)N(R.sup.11R.sup.11a), oxo (═O) where the ring is at least partially saturated, C.sub.1-6alkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more R.sup.12, which are the same or different; R.sup.11, R.sup.11a, and R.sup.11b are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different; each R.sup.12 is independently halogen, CN, C(O)OR.sup.13, OR.sup.13, C(O)R.sup.13, C(O)N(R.sup.3R.sup.13a), S(O).sub.2N(R.sup.3R.sup.13a), S(O)N(R.sup.3R.sup.13a), S(O).sub.2R.sup.13, S(O)R.sup.13, N(R.sup.13)S(O).sub.2N(R.sup.13aR.sup.13b), SR.sup.13, N(R.sup.13R.sup.13a), NO.sub.2, OC(O)R.sup.13, N(R.sup.13)C(O)R.sup.13a, N(R.sup.13)SO.sub.2R.sup.13a, N(R.sup.13)S(O)R.sup.13a, N(R.sup.13)C(O)N(R.sup.13aR.sup.13b), N(R.sup.13)C(O)OR.sup.13a, or OC(O)N(R.sup.13R.sup.13a); and R.sup.13, R.sup.13a, and R.sup.13b are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl, wherein C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different.

    Description

    EXAMPLES

    I Chemical Synthesis

    Experimental Procedures:

    [0153] The following Abbreviations and Acronyms are used: [0154] ACN Acetonitrile [0155] AgSO.sub.3CF.sub.3 silver-trifluoromethanesulfonate [0156] aq aqueous [0157] BOP reagent benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate [0158] Brine saturated solution of NaCl in water [0159] CDI carbonyldiimidazole [0160] CV column volume [0161] δ chemical shifts in parts per million [0162] DCM dichloromethane [0163] DMSO dimethylsulfoxide [0164] DMSO-d.sub.6 deuterated dimethylsulfoxide [0165] DIPEA diisopropylethylamine [0166] DMF dimethyl formamide [0167] ESI+ positive ionisation mode [0168] ESI− negative ionisation mode [0169] Et.sub.3N triethylamine [0170] EtOAc ethyl acetate [0171] Et.sub.2O diethyl ether [0172] h hour(s) [0173] H.sub.2 hydrogen atmosphere [0174] HATU 1-[Bis(dimethylamino)methylidene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium-3-oxide hexa fluorophosphates [0175] HCl hydrochloric acid [0176] HPLC high-performance liquid chromatography [0177] J NMR coupling constant [0178] K.sub.2CO.sub.3 potassium carbonate [0179] KF potassium fluoride [0180] MgSO.sub.4 magnesium sulphate [0181] mL millilitre (s) [0182] min minutes [0183] N.sub.2 nitrogen atmosphere [0184] Na.sub.2SO.sub.4 sodium sulphate [0185] NaHCO.sub.3 sodium bicarbonate [0186] NaOH sodium hydroxide [0187] NMR Nuclear Magnetic Resonance [0188] Pd/C palladium on carbon [0189] r.t. room temperature [0190] RT retention time [0191] satd saturated [0192] TBAHS tetrabutylammonium hydrogensulfate [0193] T3P propylphosphonic anhydride [0194] TBME tert-butyl-methylether [0195] TFA Trifluoroacetic acid [0196] THE tetrahydrofuran [0197] TMS-CF.sub.3 (trifluoromethyl)trimethylsilane [0198] TsCl tosyl chloride [0199] Selectfluor 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane; ditetrafluoroborate

    NMR Conditions

    [0200] Unless otherwise stated, .sup.1H NMR spectra were recorded at 500 MHz or 400 MHz on either a Bruker Avance III HD 500 MHz or Bruker Avance III HD 400 MHz spectrometer, respectively. Chemical shifts, S, are quoted in parts per million (ppm) and are referenced to the residual solvent peak. The following abbreviations are used to denote the multiplicities and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), hep (heptet), m (multiplet), pent (pentet), td (triplet of doublets), qd (quartet of doublets), app. (apparent) and br. (broad). Coupling constants, J, are quoted to the nearest 0.1 Hz.

    Analytical LCMS Conditions are as Follows:

    System 1 (S1): Acidic IPC Method

    [0201] Analytical S1 HPLC-MS were performed on Shimadzu LCMS-2010EV systems using a reverse phase Kinetex Core shell C18 columns (2.1 mm×50 mm, 5 μm; temperature: 40° C.) and a gradient of 5-100% B (A=0.1% formic acid in H.sub.2O; B=0.1% formic acid in ACN) over 1.2 min then 100% B for 0.1 min, with an injection volume of 3 μL at flow rate of 1.2 mL/min. UV spectra were recorded at 215 nm using a SPD-M20A photo diode array detector. Mass spectra were obtained over the range m/z 150 to 850 at a sampling rate of 2 scans per sec using a LCMS2010EV. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

    System 2 (S2): Acidic IPC Method (MSQ2 and MSQ4):

    [0202] Analytical S2 were performed on a Waters Acquity uPLC system column: Waters UPLC® CSHTM C18 2.1×100 mm, 1.7 μm; eluent A: water+0.1 vol % formic acid, eluent B: acetonitrile+0.1 vol % formic acid; gradient: 0-1.1 min 5-100% B, 1.1-1.35 min 100% B, 1.35-1.4 min 100-5% B, 1.4-1.5 min 5% B; flow 0.9 mL/min; injection volume 2 μL; temperature: 40° C.; UV scan: 215 nm; PDA Spectrum range: 200-400 nm step: 1 nm; MSD signal settings-scan pos: 150-850. Data were integrated and reported using Waters MassLynx and OpenLynx software.

    System 3 (S3): Basic IPC Method:

    [0203] Column: Waters UPLC® BEHTM C18 2.1×30 mm, 1.7 μm; eluent A: 2 mM ammonium bicarbonate, buffered to pH10, eluent B: acetonitrile; gradient: 0-0.75 min 5-100% B, 0.75-0.85 min 100% B, 0.85-0.9 min 100-5% B, 0.9-1.0 min 5% B; flow 1 mL/min; injection volume 2 μL; temperature: 40° C.; UV scan: 215 nm; PDA Spectrum range: 200-400 nm step: 1 nm; MSD signal settings-scan pos: 100-1000. Data were integrated and reported using Waters MassLynx and OpenLynx software.

    System 4 (S4): Acidic Final Method (MSQ1 and MSQ2):

    [0204] Analytical S4 were performed on a Waters Acquity uPLC system with Waters PDA and ELS detectors using a Phenomenex Kinetex-XB C18 column (2.1 mm×100 mm, 1.7 μM; temperature: 40° C.) and a gradient of 5-100% B (A=0.1% formic acid in H.sub.2O; B=0.1% formic acid in ACN) over 5.3 min then 100% B for 0.5 min, with an injection solution of 3 μL at flow rate of 0.6 mL/min. UV spectra were recorded at 215 nm using a Waters Acquity photo diode array detector. Mass spectra were obtained over the range m/z 150 to 850 at a sampling rate of 5 scans per sec using a Waters SQD. Data were integrated and reported using Waters MassLynx and OpenLynx software.

    System 5 (S5): Acidic Final Method (Shimadzu)

    [0205] 5% Solvent B for 1 min and then Linear gradient 5-100% solvent B in 5.5 min+2.5 min 100% solvent B at flow rate 1.0 mL/min. Column ATLANTIS dC18 (50×3.0 mm). Solvent A=0.1% Formic acid in H.sub.2O, Solvent B=0.1% Formic acid in ACN. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

    System 6 (S6): Basic Final Method

    [0206] Analytical METCR1603 HPLC-MS were performed on a Agilent G1312A system with Waters 2996 PDA detector and Waters 2420 ELS detector using a Phenomenex Gemini-NX C18 column (2.0×100 mm, 3 μm column; temperature: 40° C.) and a gradient of 5-100% (A=2 mM ammonium bicarbonate, buffered to pH 10; B=ACN) over 5.5 min then 100% B for 0.4 min, with an injection volume of 3 μL and at flow rate of 0.6 mL/min. UV spectra were recorded at 215 nm using a Waters Acquity photo diode array detector. Mass spectra were obtained over the range m/z 150 to 850 at a sampling rate of 5 scans per sec using a Waters ZQ mass detector. Data were integrated and reported using Waters MassLynx and OpenLynx software.

    Purification Methods are as Follows:

    Method 1: Acidic Early Method

    [0207] Purifications by preparative LC (acidic pH, early elution method) were performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm×100 mm, 10 μM; temperature: r.t.) and a gradient of 10-95% B (A=0.1% formic acid in H.sub.2O; B=0.1% formic acid in ACN) over 14.44 min then 95% B for 2.11 min, with an injection volume of 1500 μL at flow rate of 40 mL/min. UV spectra were recorded at 215 nm using a Gilson detector.

    Method 2: Acidic Standard Method

    [0208] Purifications by preparative LC (acidic pH, standard elution method) were performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm×10 mm, 10 μM; temperature: r.t.) and a gradient of 30-95% B (A=0.1% formic acid in water; B=0.1% formic acid in ACN) over 11.00 min then 95% B for 2.10 min, with an injection volume of 1500 μL at flow rate of 40 mL/min. UV spectra were recorded at 215 nm using a Gilson detector.

    Method 3: Basic Early Method

    [0209] Instrument: pump: Gilson 331 & 332; auto injector: Gilson GX281; UV detector: Gilson 159; collector: Gilson GX281 or pump: Gilson 333 & 334; auto injector: Gilson GX281; UV detector: Gilson 155; collector: Gilson GX281; Column: Waters Xbridge C18 30×100 mm, 10 μm; eluent A: water+0.2 vol % ammonium hydroxide, eluent B: acetonitrile+0.2 vol % ammonium hydroxide; gradient: 0-0.8 min 10% B, 0.8-14. 5 min 10-95% B, 14.5-16.7 min 95% B; flow 40 mL/min; injection volume 1500 μL; temperature: 25° C.; UV scan: 215 nm.

    Method 4: Basic Standard Method

    [0210] Instrument: pump: Gilson 331 & 332; auto injector: Gilson GX281; UV detector: Gilson 159; collector: Gilson GX281 or pump: Gilson 333 & 334; auto injector: Gilson GX281; UV detector: Gilson 155; collector: Gilson GX281; Column: Waters Xbridge C18 30×100 mm, 10 μm; eluent A: water+0.2 vol % ammonium hydroxide, eluent B: acetonitrile+0.2 vol % ammonium hydroxide; gradient: 0-1.1 min 30% B, 1.1-10.05 min 30-95% B, 10.05-11.5 min 95% B; flow 40 mL/min; injection volume 1500 μL; temperature: 25° C.; UV scan: 215 nm.

    Method 5: Reverse Phase Chromatography Using Acidic pH, Standard Elution Method

    [0211] Purifications by FCC on reverse phase silica (acidic pH, standard elution method) were performed on Biotage Isolera systems using the appropriate SNAP C18 cartridge and a gradient of 10% B (A=0.1% formic acid in H.sub.2O; B=0.1% formic acid in ACN) over 1.7 CV then 10-100% B over 19.5 CV and 100% B for 2 CV.

    Chiral Separation Methods:

    Method C1

    [0212] Purification method=15% IPA: 85% heptane; Chiralcel OD-H, 20×250 mm, 5 μm at 18 mL/min. Sample diluent: MeOH, ACN.

    Method C2

    [0213] Purification method=Ethanol with Cellulose-4, 21.2×250 mm, 5 μm column at 9 mL/min. Sample diluent: EtOH, MeOH.

    General Synthesis:

    [0214] All the compounds have been synthesised with a purity>95% unless otherwise specified.

    [0215] 2-(4-Chlorophenyl)-5-methanesulfonyl-1,3,4-oxadiazole was prepared according to literature reference Ger. Offen. (1992), DE 4033412 A1.

    ##STR00012##

    Intermediate 1: 5-(5-chloropyridin-2-yl)-2,3-dihydro-1,3,4-oxadiazol-2-one

    [0216] ##STR00013##

    [0217] To a mixture of CDI (284 mg, 1.75 mmol) and 5-chloropyridine-2-carbohydrazide (250 mg, 1.46 mmol) in anhydrous THF (2.5 mL) was added Et.sub.3N (0.43 mL, 3.06 mmol) and the resultant mixture was stirred at r.t. for 5 min. A further portion of CDI (284 mg, 1.75 mmol) was added and the reaction mixture was stirred at r.t. for 1.5 h. A further portion of CDI (284 mg, 1.75 mmol) was added and the reaction mixture was stirred at r.t. for 16 h. The reaction mixture was diluted with EtOAc (50 mL), and washed with 1 M aq HCl solution (25 mL) and brine (25 mL). The organic extracts were dried over Na.sub.2SO.sub.4, concentrated in vacuo, and triturated with Et.sub.2O to afford the title compound (90% purity, 226 mg, 1.03 mmol, 71% yield) as a white solid; .sup.1H NMR (400 MHz, DMSO-d6) δ 8.78 (dd, J=2.4, 0.6 Hz, 1H), 8.13 (dd, J=8.5, 2.5 Hz, 1H), 7.94 (dd, J=8.5, 0.6 Hz, 1H); M/Z: 198, 200 [M+H].sup.+, ESI+, RT=0.87 min (S1).

    ##STR00014##

    Step 2.a: tert-butyl N-{1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-4-yl}carbamate

    [0218] ##STR00015##

    [0219] To a solution of 2-(4-chlorophenyl)-5-methanesulfonyl-1,3,4-oxadiazole (58% purity, 291 mg, 0.652 mmol) in anhydrous DMF (2 mL) was added K.sub.2CO.sub.3 (185 mg, 1.34 mmol) and tert-butyl N-(4-piperidyl)carbamate (99 μL, 0.799 mmol) and the reaction mixture was stirred at r.t. for 21 h. H.sub.2O (15 mL) was added and the resultant solution was extracted with EtOAc (2×10 mL). The combined organic extracts were washed with H.sub.2O (2×5 mL), brine (5 mL), dried over MgSO.sub.4 and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting 0-30% EtOAc in heptane, to afford the title compound (85% purity, 190 mg, 0.426 mmol, 65% yield) as a white powder; .sup.1H NMR (400 MHz, chloroform-d) δ 7.87-7.81 (m, 2H), 7.44-7.40 (m, 2H), 4.08 (d, J=8.8 Hz, 2H), 3.27-3.14 (m, 3H), 2.12-2.05 (m, 2H), 1.75-1.57 (m, 2H), 1.45 (s, 9H); M/Z. 379, 381 [M+H].sup.+, ESI+, RT=1.20 min (S1).

    Intermediate 2 (Step 2.b): 1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-4-amine; trifluoroacetic acid

    [0220] ##STR00016##

    [0221] To a solution of tert-butyl N-{1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-4-yl}carbamate (85% purity, 147 mg, 0.329 mmol) in DCM (2 mL) was added TFA (0.27 mL, 3.62 mmol) and the resultant mixture was stirred at r.t. for 1 h. The reaction mixture was concentrated in vacuo to afford 210 mg of the title compound in quantitative yield as an orange gum; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.97-7.87 (m, 5H), 7.65-7.60 (m, 2H), 4.09-3.98 (m, 2H), 3.39-3.24 (m, 1H), 3.24-3.14 (m, 2H), 2.05-1.95 (m, 2H), 1.58-165 (m, 2H); M/Z: 279, 281 [M+H].sup.+, ESI+, RT=0.83 min (S1).

    ##STR00017##

    Intermediate 3 (Step 3.a) 2-(4-chloro-3-fluorophenoxy)acetyl chloride

    [0222] ##STR00018##

    [0223] To a solution of 2-(4-chloro-3-fluorophenoxy)acetic acid (5.16 g, 22.7 mmol) in DCM (45 mL) at 0° C. was added oxalyl dichloride (10 mL, 0.115 mol) followed by DMF (81 μL, 1.11 mmol). The ice bath was removed and the reaction was stirred at r.t. for 17 h. The solvent was removed under reduced pressure to afford the title compound (90% purity, 5.30 g, 21.4 mmol, 94% yield) as a orange oil; .sup.1H NMR (400 MHz, Chloroform-d) δ 7.31 (t, J=8.6 Hz, 1H), 6.75 (dt, J=10.2, 2.9 Hz, 1H), 6.66 (ddd, J=8.9, 2.9, 1.2 Hz, 1H), 4.96 (s, 2H).

    ##STR00019##

    Step 4.a: tert-butyl 4-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-1-carboxylate

    [0224] ##STR00020##

    [0225] To a solution of 2-(4-chloro-3-fluorophenoxy)acetyl chloride (500 mg, 2.24 mmol, Intermediate 3) in DCM (15 mL) was added tert-butyl 4-aminopiperidine-1-carboxylate (458 mg, 2.24 mmol) and DIPEA (0.78 mL, 4.48 mmol) and the resultant mixture was stirred at r.t. for 2 h. H.sub.2O (25 mL) was added and the resultant solution was extracted with DCM (2×50 mL). The combined organic extracts were dried over MgSO.sub.4 and concentrated in vacuo to afford the title compound (83% purity, 1.05 g, 2.24 mmol, 100% yield) as a brown oil; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.04 (d, J=8.0 Hz, 1H), 7.49 (t, J=8.9 Hz, 1H), 7.06 (dd, J=11.4, 2.8 Hz, 1H), 6.84 (ddd, J=9.0, 2.8, 1.1 Hz, 1H), 4.50 (s, 2H), 3.93-3.74 (m, 3H), 2.85 (d, J=35.4 Hz, 2H), 1.74-1.62 (m, 2H), 1.39 (s, 9H), 1.36-1.26 (m, 2H); M/Z: 287, 289 [M-Boc+H].sup.+, ESI+, RT=1.22 min (S1).

    Intermediate 4 (Step 4.b): 2-(4-chloro-3-fluorophenoxy)-N-(piperidin-4-yl)acetamide

    [0226] ##STR00021##

    [0227] Tert-butyl 4-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-1-carboxylate (867 mg, 2.24 mmol) was dissolved in 4 M HCl in 1,4-dioxane (10 mL) and the resultant mixture was stirred at r.t. for 17 h. The reaction mixture was concentrated in vacuo, and the resultant residue was dissolved in satd aq NaHCO.sub.3 solution (25 mL) and extracted with DCM (2×50 mL). The combined organic extracts were dried over MgSO.sub.4 and concentrated in vacuo to afford the title compound (531 mg, 1.85 mmol, 83% yield) as an off-white solid; .sup.1H NMR (500 MHz, chloroform-d) δ 7.32 (t, J=8.6 Hz, 1H), 6.76 (dd, J=10.3, 2.8 Hz, 1H), 6.68 (ddd, J=8.9, 2.8, 1.2 Hz, 1H), 6.34 (d, J=7.4 Hz, 1H), 4.44 (s, 2H), 3.97 (ddp, J=11.6, 8.4, 4.2 Hz, 1H), 3.10 (d, J=12.6 Hz, 2H), 2.72 (t, J=9.7 Hz, 2H), 1.98-1.91 (m, 4H), 1.40 (td, J=15.2, 7.8 Hz, 1H); M/Z: 287, 289 [M+H].sup.+, ESI+, RT=0.82 min (S1).

    ##STR00022##

    Step 5.a: tert-butyl (1R,5S,6S)-6-[2-(4-chloro-3-fluorophenoxy)acetamido]-3-azabicyclo[3.1.0]hexane-3-carboxylate

    [0228] ##STR00023##

    [0229] To a solution of tert-butyl (1R,5S,6S)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (699 mg, 3.53 mmol) in DCM (25 mL) was added DIPEA (0.92 mL, 5.29 mmol), followed by 2-(4-chloro-3-fluorophenoxy)acetyl chloride (787 mg, 3.53 mmol, Intermediate 3) and the resultant mixture was stirred at r.t. for 24 h. The reaction mixture was diluted with H.sub.2O (20 mL) and extracted with DCM (2×50 mL). The combined organic extracts were dried over MgSO.sub.4 and concentrated in vacuo to afford 1.43 g of the title compound in quantitative yield as a brown viscous oil; .sup.1H NMR (500 MHz, chloroform-d) δ 7.32 (t, J=8.6 Hz, 1H), 6.73 (dd, J=10.3, 2.8 Hz, 1H), 6.65 (ddd, J=8.9, 2.8, 1.2 Hz, 1H), 6.53 (s, 1H), 4.43 (s, 2H), 3.72 (t, J=10.3 Hz, 2H), 3.40 (t, J=11.7 Hz, 2H), 2.51 (d, J=2.3 Hz, 1H), 1.77-1.69 (m, 2H), 1.43 (s, 9H); M/Z: 285, 287 [M-Boc+H].sup.+, ESI+, RT=1.18 min (S1).

    Intermediate 5 (Step 5.b): N-[(1R,5S,6S)-3-azabicyclo[3.1.0]hexan-6-yl]-2-(4-chloro-3-fluorophenoxy)acetamide

    [0230] ##STR00024##

    [0231] To a solution tert-butyl (1R,5S,6S)-6-[2-(4-chloro-3-fluorophenoxy)acetamido]-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.36 g, 3.53 mmol) in DCM (15 mL) and 1,4-dioxane (40 mL) at 0° C., was added 4 M HCl in 1,4-dioxane (25 mL) and the resultant mixture was stirred at r.t. for 20 h. The reaction mixture was concentrated in vacuo, dissolved in satd aq NaHCO.sub.3 solution and extracted with EtOAc (4×50 mL). The combined organic extracts were dried over MgSO.sub.4 and concentrated in vacuo to afford the title compound (88% purity, 713 mg, 2.20 mmol, 62% yield) as a pale yellow oil; .sup.1H NMR (400 MHz, chloroform-d) δ 7.32 (t, J=8.6 Hz, 1H), 6.73 (dd, J=10.3, 2.8 Hz, 1H), 6.65 (ddd, J=8.9, 2.8, 1.3 Hz, 1H), 6.44 (s, 1H), 4.42 (s, 2H), 3.20 (d, J=11.6 Hz, 2H), 2.96 (d, J=11.5 Hz, 2H), 2.56 (d, J=2.6 Hz, 1H), 1.71-1.56 (m, 2H); M/Z: 285, 287 [M+H].sup.+, ESI+, RT=0.86 min (S1).

    ##STR00025##

    Step 6.a: tert-butyl 4-[2-(4-chloro-3-fluorophenoxy)acetamido]piperazine-1-carboxylate

    [0232] ##STR00026##

    [0233] To a solution of tert-butyl 4-aminopiperazine-1-carboxylate (100 mg, 0.497 mmol) in DCM (10 mL) was added Et.sub.3N (0.14 mL, 0.994 mmol) and 2-(4-chloro-3-fluorophenoxy)acetyl chloride (122 mg, 0.547 mmol, Intermediate 3) and the resultant mixture was stirred at r.t. for 1 h. The reaction mixture was diluted with H.sub.2O (20 mL) and extracted with DCM (2×25 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting 0-100% EtOAc in heptane, to afford the title compound (90% purity, 153 mg, 0.355 mmol, 71% yield) as a white solid; .sup.1H NMR (500 MHz, chloroform-d) δ 7.33 (t, J=8.6 Hz, 1H), 7.20 (s, 1H), 6.75 (dd, J=10.2, 2.9 Hz, 1H), 6.70-6.64 (m, 1H), 4.49 (s, 2H), 3.63-3.53 (m, 4H), 2.81 (t, J=4.7 Hz, 4H), 1.45 (s, 9H); M/Z: 288, 290 [M-Boc+H].sup.+, ESI+, RT=1.17 min (S1).

    Intermediate 6 (Step 6.b): 2-(4-chloro-3-fluorophenoxy)-N-(piperazin-1-yl)acetamide dihydrochloride

    [0234] ##STR00027##

    [0235] To a solution of tert-butyl 4-[2-(4-chloro-3-fluorophenoxy)acetamido]piperazine-1-carboxylate (90% purity, 153 mg, 0.355 mmol) in DCM (15 mL) was added 4 M HCl in 1,4-dioxane (1.0 mL, 4.00 mmol) and the resultant mixture was stirred at r.t. overnight. The reaction mixture was concentrated in vacuo to afford the title compound (90% purity, 142 mg, 0.354 mmol, 100% yield) as a white solid; M/Z: 288 [M+H].sup.+, ESI+, RT=0.86 min (S1).

    ##STR00028##

    Step 7.a: tert-butyl 4-[2-(4-chloro-3-fluorophenoxy)acetamido]azepane-1-carboxylate

    [0236] ##STR00029##

    [0237] To a solution of tert-butyl 4-aminoazepane-1-carboxylate (150 mg, 0.700 mmol) in DCM (2 mL) at 0° C. was added Et.sub.3N (0.20 mL, 1.43 mmol) and 2-(4-chloro-3-fluorophenoxy)acetyl chloride (156 mg, 0.699 mmol, Intermediate 3) in DCM (2 mL) and the resultant mixture stirred at r.t. for 6 h. The reaction mixture was diluted with DCM (30 mL), washed with satd aq NaHCO.sub.3 solution (2×20 mL) and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting 0-100% EtOAc in heptane, to afford the title compound (84% purity, 242 mg, 0.507 mmol, 72% yield) as a yellow oil; .sup.1H NMR (500 MHz, chloroform-d) δ 7.32 (t, J=8.6 Hz, 1H), 6.78-6.73 (m, 1H), 6.68 (ddd, J=8.9, 2.8, 1.2 Hz, 1H), 6.46-6.36 (m, 1H), 4.43 (s, 2H), 4.09-3.94 (m, 1H), 3.82-3.55 (m, 1H), 3.55-3.46 (m, 1H), 3.41-3.21 (m, 1H), 3.18-3.05 (m, 1H), 2.11-1.96 (m, 2H), 1.75-1.62 (m, 2H), 1.62-1.49 (m, 2H), 1.46 (s, 9H); M/Z: 423, 425 [M+Na].sup.+, ESI+, RT=1.25 min (S1).

    Intermediate 7 (Step 7.b): N-(azepan-4-yl)-2-(4-chloro-3-fluorophenoxy)acetamide

    [0238] ##STR00030##

    [0239] To a solution of tert-butyl 4-[2-(4-chloro-3-fluorophenoxy)acetamido]azepane-1-carboxylate (84% purity, 242 mg, 0.507 mmol) in DCM (5 mL) was added TFA (0.20 mL, 2.69 mmol) and the resultant mixture was stirred at r.t. for 24 h. The reaction mixture was diluted with satd aq NaHCO.sub.3 solution (20 mL) and extracted with DCM (2×25 mL). The combined organic extracts were concentrated in vacuo to afford the title compound (92% purity, 132 mg, 0.404 mmol, 80% yield) as a yellow oil; .sup.1H NMR (500 MHz, chloroform-d) δ 7.31 (t, J=8.6 Hz, 1H), 7.13 (d, J=8.5 Hz, 1H), 6.76 (dd, J=10.4, 2.8 Hz, 1H), 6.68 (ddd, J=8.9, 2.8, 1.2 Hz, 1H), 4.45 (s, 2H), 4.28-4.34 (m, 1H), 3.01-2.93 (m, 2H), 2.87-2.80 (m, 1H), 2.79-2.71 (m, 1H), 1.94 (dq, J=15.1, 4.7 Hz, 2H), 1.83-1.69 (m, 2H), 1.68-1.60 (m, 2H); M/Z: 301, 303 [M+H].sup.+, ESI+, RT=0.81 min (S1).

    ##STR00031##

    Step 8.a: tert-butyl N-[1-(hydrazinecarbonyl)piperidin-4-yl]carbamate

    [0240] ##STR00032##

    [0241] To a solution of tert-butyl N-(4-piperidyl)carbamate (5.00 g, 25.0 mmol) in anhydrous THE (50 mL) was added CDI (8.10 g, 49.9 mmol) and DIPEA (8.7 mL, 49.9 mmol) and the resultant mixture was stirred at r.t. for 2 h. Hydrazine (1.86 mL, 60.0 mmol) was then added and stirred at 45° C. for 24 h. The reaction mixture was cooled to r.t., concentrated in vacuo, and triturated using H.sub.2O to afford the title compound (94% purity, 5.28 g, 19.2 mmol, 77% yield) as a white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.59 (s, 1H), 6.81 (d, J=7.6 Hz, 1H), 3.88-3.77 (m, 4H), 3.45-3.34 (m, 1H), 2.75-2.65 (m, 2H), 1.69-1.60 (m, 2H), 1.38 (s, 9H), 1.19 (qd, J=12.2, 4.0 Hz, 2H); M/Z: 203 [M+H].sup.+, ESI+, RT=0.73 min (S1).

    Step 8.b: tert-butyl N-{1-[N′-(5,5,5-trifluoropentanoyl)hydrazinecarbonyl]piperidin-4-yl}carbamate

    [0242] ##STR00033##

    [0243] To a solution of 5,5,5-trifluoropentanoic acid (121 mg, 0.774 mmol) in DMF (1.5 mL) was added DIPEA (0.54 mL, 3.10 mmol), and T3P (50%, 0.51 mL, 0.852 mmol) and the resultant mixture was stirred at r.t. for 15 μmin. A solution of tert-butyl N-[1-(hydrazinecarbonyl)piperidin-4-yl]carbamate (200 mg, 0.774 mmol) in DMF (1.5 mL) was added and the resultant mixture was stirred at r.t. for 45 min. The reaction mixture was diluted with H.sub.2O (20 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO.sub.4, and concentrated in vacuo to afford the title compound (108 mg, 0.272 mmol, 35% yield) as a white solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.40 (d, J=1.7 Hz, 1H), 8.38 (d, J=1.6 Hz, 1H), 6.87 (d, J=7.6 Hz, 1H), 3.86 (d, J=13.4 Hz, 2H), 3.40 (s, 1H), 2.83-2.72 (m, 2H), 2.39-2.23 (m, 2H), 2.19 (t, J=7.2 Hz, 2H), 1.70 (ddd, J=23.3, 15.6, 8.6 Hz, 4H), 1.38 (s, 9H), 1.23 (td, J=13.0, 11.3, 6.4 Hz, 2H); M/Z: 419 [M+Na].sup.+, ESI+, RT=0.99 min (S1).

    Step 8.c: tert-butyl N-{1-[5-(4,4,4-trifluorobutyl)-1,3,4-oxadiazol-2-yl]piperidin-4-yl}carbamate

    [0244] ##STR00034##

    [0245] To a solution of tert-butyl N-{1-[N-(5,5,5-trifluoropentanoyl)hydrazinecarbonyl]piperidin-4-yl}carbamate (104 mg, 0.262 mmol) in anhydrous ACN (4 mL) was added TsCl (125 mg, 0.656 mmol), 3A molecular sieves and K.sub.2CO.sub.3 (181 mg, 1.31 mmol). The resultant mixture was stirred at 80° C. for 2.5 h, filtered, and the solid washed with ACN (20 mL). The filtrate was washed with satd aq NaHCO.sub.3 solution (2×20 mL) and brine (20 mL), dried over MgSO.sub.4 and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting 0-100% EtOAc in heptane to afford the title compound (44 mg, 0.115 mmol, 44% yield) as an off-white solid; .sup.1H NMR (400 MHz, chloroform-d) δ 4.47 (s, 1H), 3.99-3.85 (m, 2H), 3.65 (s, 1H), 3.17-3.03 (m, 2H), 2.79 (t, J=7.3 Hz, 2H), 2.29-2.14 (m, 2H), 2.01 (p, J=7.2 Hz, 4H), 1.44 (s, 11H); M/Z: 379 [M+H].sup.+, ESI+, RT=1.17 min (S1).

    Intermediate 8 (Step 8.d): 1-[5-(4,4,4-trifluorobutyl)-1,3,4-oxadiazol-2-yl]piperidin-4-amine hydrochloride

    [0246] ##STR00035##

    [0247] To a solution of tert-butyl N-{1-[5-(4,4,4-trifluorobutyl)-1,3,4-oxadiazol-2-yl]piperidin-4-yl}carbamate (40 mg, 0.106 mmol) in anhydrous DCM (1.36 mL) was added 4 M HCl in 1,4-dioxane (1.36 mL) and the resultant mixture was stirred at r.t. for 2 h. The reaction mixture was concentrated in vacuo to afford 24 mg of the title compound in quantitative yield as an off white solid; M/Z: 279 [M+H].sup.+, ESI+, RT=0.79 min (S1).

    ##STR00036##

    Step 9.a: tert-butyl N-[(3R*,4R*)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxypiperidin-4-yl]carbamate

    [0248] ##STR00037##

    [0249] To a solution of 2-(4-chlorophenyl)-5-methanesulfonyl-1,3,4-oxadiazole (250 mg, 0.792 mmol) in anhydrous DMF (5 mL) was added tert-butyl N-[(3R*,4R*)-3-hydroxy-4-piperidyl]carbamate (206 mg, 0.952 mmol) and K.sub.2CO.sub.3 (222 mg, 1.61 mmol). The resultant mixture was stirred at r.t. for 17 h, diluted with DCM (20 mL) and washed with H.sub.2O (20 mL) 20 and brine (20 mL). The organic extracts were isolated and concentrated in vacuo. The residue was purified by preparative HPLC (Method 1) to afford the title compound (90% purity, 105 mg, 0.239 mmol, 30% yield) as a white powder; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.90-7.86 (m, 2H), 7.62-7.58 (m, 2H), 6.80 (d, J=6.6 Hz, 1H), 5.13 (d, J=4.7 Hz, 1H), 3.89 (dd, J=12.9, 3.1 Hz, 1H), 3.79 (dt, J=12.9, 3.9 Hz, 1H), 3.48-3.36 (m, 2H), 3.23 (ddd, J=13.5, 10.7, 3.1 Hz, 1H), 3.04 (dd, J=12.9, 8.6 Hz, 1H), 1.98-1.85 (m, 1H), 1.50-1.41 (m, 1H), 1.39 (s, 9H); M/Z: 395, 397 [M+H].sup.+, ESI+, RT=1.15 min (S1).

    Intermediate 9 (Step 9.b): (3R*,4R*)-4-amino-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-ol

    [0250] ##STR00038##

    [0251] To a solution of tert-butyl N-[(3R*,4R*)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxypiperidin-4-yl]carbamate (90% purity, 105 mg, 0.239 mmol) in DCM (1.70 mL) was added TFA (85 μL, 1.14 mmol) and the resultant mixture was stirred at r.t for 6 h. The reaction mixture was concentrated in vacuo and purified using an SCX-2 cartridge, first flushing with MeOH and then eluting with 7 M NH.sub.3 in MeOH, to afford 81 mg of the title compound in quantitative yield as a brown oil; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.92-7.88 (m, 2H), 7.69 (s, 2H), 7.65-7.62 (m, 2H), 5.90 (d, J=5.0 Hz, 1H), 4.09-4.02 (m, 1H), 3.99 (d, J=13.4 Hz, 1H), 3.55 (tt, J=9.9, 4.9 Hz, 1H), 3.19 (td, J=13.1, 2.7 Hz, 1H), 3.09-3.00 (m, 1H), 2.96 (dd, J=12.6, 10.5 Hz, 1H), 2.06-1.98 (m, 1H), 1.62 (qd, J=12.6, 4.7 Hz, 1H); M/Z: 295, 297 [M+H].sup.+, ESI+, RT=0.55 min (S2).

    ##STR00039##

    Step 10.a: 2-(4-chloro-3-fluorophenoxy)-N-[1-(hydrazinecarbonyl)piperidin-4-yl]acetamide

    [0252] ##STR00040##

    [0253] To a solution of 2-(4-chloro-3-fluorophenoxy)-N-(piperidin-4-yl)acetamide (9.11 g, 31.1 mmol, Intermediate 4) in anhydrous THE (100 mL) was added DIPEA (11 mL, 62.2 mmol) and CDI (100%, 10.09 g, 62.2 mmol) and the resultant mixture was stirred at r.t. for 2 h. Hydrazine hydrate (1:1, 4.5 mL, 93.4 mmol) was then added and the resultant mixture was stirred at 45° C. for 18 h. The reaction mixture was concentrated in vacuo and the resultant residue was triturated using H.sub.2O to afford the title compound (9.41 g, 27.3 mmol, 88% yield) as a beige powder; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.03 (d, J=8.0 Hz, 1H), 7.65 (s, 1H), 7.50 (t, J=8.9 Hz, 1H), 7.07 (dd, J=11.4, 2.8 Hz, 1H), 6.85 (ddd, J=9.0, 2.8, 1.1 Hz, 1H), 4.51 (s, 2H), 3.94-3.71 (m, 5H), 2.85-2.68 (m, 2H), 1.73-1.57 (m, 2H), 1.44-1.22 (m, 2H); M/Z: 345, 347 [M+H].sup.+, ESI+, RT=0.61 min (S2).

    Step 10.b: N-[1-(5-amino-1,3,4-oxadiazol-2-yl)piperidin-4-yl]-2-(4-chloro-3-fluorophenoxy)acetamide

    [0254] ##STR00041##

    [0255] To a solution of 2-(4-chloro-3-fluorophenoxy)-N-[1-(hydrazinecarbonyl)piperidin-4-yl]acetamide (2.00 g, 5.74 mmol) in 1,4-dioxane (20 mL) was added NaHCO.sub.3 (724 mg, 8.61 mmol) in H.sub.2O (5 mL) followed by BrCN (608 mg, 5.74 mmol) and the resultant mixture was stirred at r.t. for 20 h. The reaction mixture was diluted with H.sub.2O (30 mL) and extracted with EtOAc (2×70 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford the title compound (1.69 g, 4.48 mmol, 78% yield) as a beige powder; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.08 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.9 Hz, 1H), 7.07 (dd, J=11.4, 2.8 Hz, 1H), 6.86 (ddd, J=9.0, 2.9, 1.2 Hz, 1H), 6.42 (s, 2H), 4.52 (s, 2H), 3.94-3.79 (m, 1H), 3.67-3.56 (m, 2H), 3.04-2.92 (m, 2H), 1.82-1.68 (m, 2H), 1.63-1.46 (m, 2H); M/Z: 370, 372 [M+H].sup.+, ESI+, RT=0.68 min (S2).

    Intermediate 10 (Step 10.c): N-[1-(5-bromo-1,3,4-oxadiazol-2-yl)piperidin-4-yl]-2-(4-chloro-3-fluorophenoxy)acetamide

    [0256] ##STR00042##

    [0257] To a solution of N-[1-(5-amino-1,3,4-oxadiazol-2-yl)piperidin-4-yl]-2-(4-chloro-3-fluorophenoxy)acetamide (1.69 g, 4.48 mmol) in anhydrous ACN (30 mL) was added CuBr (2.02 g, 8.96 mmol) and the resultant mixture was stirred at r.t. for 5 min. Tert-butyl nitrite (90%, 1.20 mL, 8.96 mmol) was added and the resultant mixture was stirred at r.t. for 8 h. The reaction mixture was concentrated in vacuo, diluted with H.sub.2O (30 mL) and Rochelle's salt (30 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4, concentrated in vacuo and purified by chromatography on silica gel, eluting 0-100% EtOAc in heptane to afford the title compound (712 mg, 1.56 mmol, 35% yield) as a yellow solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.09 (d, J=7.9 Hz, 1H), 7.57-7.43 (m, 1H), 7.08 (dd, J=11.4, 2.8 Hz, 1H), 6.91-6.79 (m, 1H), 4.53 (s, 2H), 3.96-3.84 (m, 1H), 3.81-3.71 (m, 2H), 3.24-3.10 (m, 2H), 1.88-1.75 (m, 2H), 1.65-1.44 (m, 2H); M/Z: 433, 435 [M+H].sup.+, ESI+, RT=0.87 min (S2).

    ##STR00043##

    Step 11.a: tert-butyl 2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetate

    [0258] ##STR00044##

    [0259] To a solution of 6-chloro-5-fluoropyridin-3-ol (4.90 g, 33.2 mmol) in DMF (50 mL) was added tert-butyl 2-bromoacetate (4.5 mL, 34.9 mmol) and K.sub.2CO.sub.3 (13.8 g, 0.0996 mol) and the resultant mixture was stirred at 65° C. for 2 h. The reaction mixture was cooled to r.t., suspended in EtOAc (100 mL), and washed with water (2×50 mL) and brine (50 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford the title compound (9.00 g, 32.7 mmol, 98% yield) as a brown oil; .sup.1H NMR (500 MHz, chloroform-d) δ 7.91 (d, J=2.6 Hz, 1H), 7.07 (dd, J=9.1, 2.6 Hz, 1H), 4.55 (s, 2H), 1.53-1.39 (m, 9H); M/Z: 262, 264 [M+H].sup.+, ESI+, RT=1.00 min (S2).

    Step 11.b: 2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetic acid

    [0260] ##STR00045##

    [0261] 4 M HCl in 1,4-dioxane (25 mL, 98.0 mmol) was added to tert-butyl 2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetate (9.00 g, 32.7 mmol) and the resultant mixture was stirred at r.t. for 2 h. A further portion of 4 M HCl in 1,4-dioxane (25 mL, 98.0 mmol) was added and the reaction mixture was stirred at 50° C. for 5 h. The reaction mixture was concentrated in vacuo and then triturated using Et.sub.2O and heptane. The resultant precipitate was filtered under vacuum to afford the title compound (6.48 g, 31.2 mmol, 96% yield) as an off white solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 13.22 (s, 1H), 8.07 (d, J=2.6 Hz, 1H), 7.76 (dd, J=10.4, 2.6 Hz, 1H), 4.85 (s, 2H); M/Z: 206, 208 [M+H].sup.+, ESI+, RT=0.60 min (S2).

    ##STR00046##

    Example 1: 2-(4-chloro-3-fluorophenoxy)-N-{1-[5-(5-chloropyridin-2-yl)-1,3,4-oxadiazol-2-yl]piperidin-4-yl}acetamide

    [0262] ##STR00047##

    [0263] To a solution of 5-(5-chloropyridin-2-yl)-2,3-dihydro-1,3,4-oxadiazol-2-one (90% purity, 70 mg, 0.319 mmol, Intermediate 1) in anhydrous DMF (1.5 mL) was added DIPEA (0.14 mL, 0.797 mmol) and BOP reagent (169 mg, 0.383 mmol) and stirred under N.sub.2 at r.t. for 30 min. 2-(4-Chloro-3-fluorophenoxy)-N-(piperidin-4-yl)acetamide (91 mg, 0.319 mmol, Intermediate 4) was added and the reaction mixture was stirred at r.t. for 1 h. H.sub.2O (25 mL) was added and the resultant solution was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO.sub.4, and concentrated in vacuo. The resultant residue was purified by preparative HPLC (Method 3) and triturated using Et.sub.2O to afford the title compound (59 mg, 0.123 mmol, 39% yield) as an off-white solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.76 (d, J=2.4 Hz, 1H), 8.12 (dd, J=8.5, 2.4 Hz, 2H), 8.06 (d, J=8.5 Hz, 1H), 7.50 (t, J=8.9 Hz, 1H), 7.08 (dd, J=11.4, 2.8 Hz, 1H), 6.89-6.83 (m, 1H), 4.54 (s, 2H), 4.00-3.89 (m, 3H), 3.31-3.22 (m, 2H), 1.89-1.81 (m, 2H), 1.58 (qd, J=12.5, 4.2 Hz, 2H); M/Z: 466, 468, 470 [M+H].sup.+, ESI+, RT=3.18 min (S4).

    ##STR00048##

    Example 2: 2-[(6-chloro-5-fluoropyridin-3-yl)oxy]-N-{1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-4-yl}acetamide

    [0264] ##STR00049##

    [0265] To a solution of 2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetic acid (88 mg, 0.428 mmol, Intermediate 11), T3P (50%, 0.28 mL, 0.471 mmol) and DIPEA (0.22 mL, 1.28 mmol) in DMF (1 mL) was added 1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-4-amine; trifluoroacetic acid (80% purity, 210 mg, 0.428 mmol, Intermediate 2) in DMF (1 mL) and the resultant mixture was stirred at r.t. for 30 min. H.sub.2O was added and the resultant precipitate was filtered under vacuum. The residue was purified by chromatography on silica gel eluting 0-100% EtOAc in heptane, then 0-50% MeOH in EtOAc, then triturated using Et.sub.2O and EtOH to afford the title compound (19 mg, 0.0399 mmol, 9.3% yield) as a white solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.17 (d, J=7.9 Hz, 1H), 8.08 (d, J=2.5 Hz, 1H), 7.91 (d, J=8.6 Hz, 2H), 7.71 (dd, J=10.3, 2.6 Hz, 1H), 7.62 (d, J=8.6 Hz, 2H), 4.66 (s, 2H), 3.99-3.89 (m, 3H), 3.24 (t, J=11.3 Hz, 2H), 1.90-1.81 (m, 2H), 1.58 (qd, J=12.5, 4.2 Hz, 2H); M/Z: 466, 468, 470 [M+H].sup.+, ESI+, RT=3.27 min (S4).

    ##STR00050##

    Example 3: 2-(4-chloro-3-fluorophenoxy)-N-[(3R*,4R*)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxypiperidin-4-yl]acetamide

    [0266] ##STR00051##

    [0267] To a solution of 2-(4-chloro-3-fluorophenoxy)acetic acid (56 mg, 0.274 mmol) in anhydrous DMF (2 mL) was added DIPEA (144 μL, 0.824 mmol) and HATU (107 mg, 0.281 mmol) and stirred at r.t. for 10 min. (3R*,4R*)-4-amino-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-ol (80 mg, 0.271 mmol, Intermediate 9) was added and the reaction was stirred at r.t. for 19 h. The reaction mixture was retreated with HATU (50 mg) and DIPEA (70 μL) and the resultant mixture was stirred at r.t. for 5 h. The reaction mixture was concentrated in vacuo, redissolved in H.sub.2O (20 mL) and extracted with DCM (2×50 mL). The combined organic extracts were isolated, concentrated in vacuo, and purified by preparative HPLC (Method 1) to afford the title compound (53 mg, 0.111 mmol, 41% yield) as a white powder; .sup.1H NMR (500 MHz, chloroform-d) δ 7.87-7.81 (m, 2H), 7.46-7.41 (m, 2H), 7.34 (t, J=8.6 Hz, 1H), 6.77 (dd, J=10.2, 2.9 Hz, 1H), 6.68 (ddd, J=8.9, 2.8, 1.2 Hz, 1H), 6.56 (d, J=6.9 Hz, 1H), 4.57-4.48 (m, 2H), 4.29 (ddd, J=13.2, 4.9, 1.8 Hz, 1H), 4.21-4.13 (m, 1H), 4.03-3.94 (m, 1H), 3.70-3.64 (m, 1H), 3.64-3.62 (m, 1H), 3.18 (td, J=13.1, 2.8 Hz, 1H), 3.03 (dd, J=13.1, 10.0 Hz, 1H), 2.16-2.10 (m, 1H), 1.76 (qd, J=12.6, 4.7 Hz, 1H), mixture of trans diastereomers; M/Z: 481, 483, 485 [M+H].sup.+, ESI+, RT=3.26 min (S4).

    ##STR00052##

    Example 4: 2-(4-chloro-3-fluoro-phenoxy)-N-[1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-4-piperidyl]acetamide

    [0268] ##STR00053##

    [0269] To a solution of 1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-4-amine; trifluoroacetic acid (79% purity, 190 mg, 0.382 mmol, Intermediate 2) in DCM (4 mL) at 0° C. was added Et.sub.3N (533 μL, 3.82 mmol) followed by 2-(4-chloro-3-fluorophenoxy)acetyl chloride (86 mg, 0.386 mmol, Intermediate 3) and the resultant mixture was stirred at r.t. for 1 h. The reaction mixture was quenched using satd aq NaHCO.sub.3 solution and the organic layer was separated and concentrated in vacuo. The resultant residue was purified by preparative HPLC (Method 2) to afford the title compound (18 mg, 0.0371 mmol, 9.7% yield) as a white powder; .sup.1H NMR (500 MHz, chloroform-d) δ 7.87-7.82 (m, 2H), 7.46-7.40 (m, 2H), 7.33 (t, J=8.6 Hz, 1H), 6.75 (dd, J=10.2, 2.8 Hz, 1H), 6.70-6.65 (m, 1H), 6.40 (d, J=8.0 Hz, 1H), 4.46 (s, 2H), 4.18-4.07 (m, 3H), 3.29-3.20 (m, 2H), 2.14-2.05 (m, 2H), 1.67-1.55 (m, 2H); M/Z: 465, 467, 469 [M+H].sup.+, ESI+, RT=3.65 min (S4).

    [0270] Example compound 5 in Table 1 was synthesised according to the general route 15 as exemplified by Example 4, using the corresponding intermediate and purification method.

    TABLE-US-00001 TABLE 1 Intermediates LCMS Ex Structure Name and methods data 1H NMR E5 [00054]embedded image 2-(4-Chloro-3- fluoro- phenoxy)-N- {1-[5-(4,4,4- trifluorobutyl)- 1,3,4- oxadiazol-2- yl]piperidin-4- yl}acetamide 1-[5-(4,4,4- Trifluorobutyl)- 1,3,4-oxadiazol- 2-yl]piperidin- 4-amine hydrochloride) (Intermediate 8 - Method 4) M/Z: 465, 467 [M + H].sup.+, ESI+, RT = 3.27 min (S4). .sup.1H NMR (500 MHz, chloroform-d) δ 7.32 (t, J = 8.6 Hz, 1H), 6.75 (dd, J = 10.3, 2.9 Hz, 1H), 6.67 (ddd, J = 8.9, 2.8, 1.2 Hz, 1H), 6.38 (d, J = 8.0 Hz, 1H), 4.45 (s, 2H), 4.09 (ddp, J = 11.7, 8.2, 4.1 Hz, 1H), 4.03-3.92 (m, 2H), 3.20-3.10 (m, 2H), 2.79 (t, J = 7.4 Hz, 2H), 2.29-2.16 (m, 2H), 2.09-1.97 (m, 4H), 1.56 (qd, J = 12.0, 4.3 Hz, 2H).

    ##STR00055##

    Example 6: 2-(4-chloro-3-fluorophenoxy)-N-{1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]azepan-4-yl}acetamide

    [0271] ##STR00056##

    [0272] To a solution of 2-(4-chlorophenyl)-5-methanesulfonyl-1,3,4-oxadiazole (82% purity, 88 mg, 0.279 μmmol) in DMF (1.7 μmL) was added N-(azepan-4-yl)-2-(4-chloro-3-fluorophenoxy)acetamide (92% purity, 110 mg, 0.336 mmol, Intermediate 7) and K.sub.2CO.sub.3 (79 mg, 0.572 mmol) and the resultant mixture was stirred at r.t. under N.sub.2 for 17 h. The reaction mixture was diluted with EtOAc (30 mL) and washed with brine (2×20 mL). The combined organic extracts were dried over MgSO.sub.4, concentrated in vacuo and purified by preparative HPLC (Method 1) to afford the title compound (21 mg, 0.0421 mmol, 15% yield) as a white powder; 1H NMR (400 MHz, chloroform-d) δ 7.85-7.79 (m, 2H), 7.45-7.39 (m, 2H), 7.31-7.27 (m, 1H), 6.71 (dd, J=10.3, 2.9 Hz, 1H), 6.66-6.60 (m, 1H), 6.45-6.38 (m, 1H), 4.42 (s, 2H), 4.19-4.09 (m, 1H), 3.92 (ddd, J=14.7, 5.9, 4.1 Hz, 1H), 3.80-3.70 (m, 1H), 3.68-3.61 (m, 1H), 3.53-3.42 (m, 1H), 2.23-2.14 (m, 1H), 2.07-1.97 (m, 2H), 1.94-1.80 (m, 2H), 1.69-1.60 (m, 1H); M/Z: 479, 481, 483 [M+H].sup.+, ESI+, RT=3.79 min (S6).

    [0273] Example compounds in Table 2 were synthesised according to the general route 16 as exemplified by Example 6, using the corresponding intermediates and purification methods.

    TABLE-US-00002 TABLE 2 Intermediates LCMS Ex Structure Name and methods data 1H NMR E7 [00057]embedded image 2-(4-Chloro-3- fluoro- phenoxy)-N- [(1R,5S,6R)-3- [5-(4- chlorophenyl)- 1,3,4- oxadiazol-2- yl]-3- N-[(1R,5S,6S)- 3- Azabicyclo [3.1.0] hexan-6-yl]-2- (4-chloro-3- fluorophenoxy) acetamide (Intermediate 5 - Method 4) M/Z: 463, 465, 467 [M + H].sup.+, ESI+, RT = 3.52 min (S4). .sup.1H NMR (500 MHz, Chloroform-d) δ 7.90- 7.79 (m, 2H), 7.47-7.39 (m, 2H), 7.33 (t, J = 8.6 Hz, 1H), 6.74 (dd, J = 10.2, 2.9 Hz, 1H), 6.66 (ddd, J = 8.9, 2.8, 1.2 Hz, 1H), 6.61 (s, 1H), 4.45 (s, 2H), 3.98 (d, J = 10.2 Hz, 2H), 3.77-3.66 (m, azabicyclo 2H), 2.64 (d, J = 2.3 Hz, [3.1.0]hexan- 1H), 1.99-1.94 (m, 2H). 6-yl] acetamide E8 [00058]embedded image 2-(4-Chloro-3- fluoro- phenoxy)- N-{4-[5-(4- chlorophenyl)- 1,3,4- oxadiazol-2- yl]piperazin-1- 2-(4-Chloro-3- fluorophenoxy)- N-(piperazin-1- yl)acetamide dihydrochloride (Intermediate 6 - Method 2) M/Z: 466, 468, 470 [M + H].sup.+, ESI+, RT = 3.40 min (S4). Contains mixture of cis and trans amide conformers. .sup.1H NMR (500 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.98 (s, 1H), 7.97-7.86 (m, 2H), 7.67-7.58 (m, 2H), 7.56- 7.41 (m, 1H), 7.14- yl}acetamide 6.98 (m, 1H), 6.93-6.74 (m, 1H), 4.99 (s, 1H), 4.52 (s, 1H), 4.05-3.83 (m, 1H), 3.65-3.56 (m, 2H), 3.20-3.10 (m, 1H), 2.95-2.87 (m, 2H), 2.74- 2.63 (m, 1H).

    ##STR00059##

    Example 9: 2-(4-chloro-3-fluorophenoxy)-N-(1-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-4-yl)acetamide

    [0274] ##STR00060##

    [0275] To a solution of 2-(trifluoromethoxy)ethan-1-ol (28 mg, 0.219 mmol) in anhydrous THF (1 mL) at 0° C. was added NaH (5.3 mg, 0.219 mmol) and the resultant mixture was stirred at 0° C. for 10 μmin. N-[1-(5-bromo-1,3,4-oxadiazol-2-yl)piperidin-4-yl]-2-(4-chloro-3-fluorophenoxy)acetamide (50 mg, 0.110 mmol, Intermediate 10) in anhydrous THF (1 mL) was added and the resultant mixture was stirred at r.t. for 1 h. H.sub.2O (0.5 mL) was added, then concentrated in vacuo and purified by preparative HPLC (Method 4) to afford the title compound (22 mg, 0.0456 mmol, 42% yield) as a white powder; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.08 (d, J=7.9 Hz, 1H), 7.58-7.42 (m, 1H), 7.14-7.01 (m, 1H), 6.94-6.79 (m, 1H), 4.61-4.55 (m, 2H), 4.53 (s, 2H), 4.48-4.41 (m, 2H), 3.98-3.81 (m, 1H), 3.74-3.63 (m, 2H), 3.14-3.00 (m, 2H), 1.84-1.71 (m, 2H), 1.62-1.46 (m, 2H); M/Z: 483, 485 [M+H].sup.+, ESI+, RT=3.32 min (S4).

    ##STR00061##

    Example 10: 2-(4-chloro-3-fluorophenoxy)-N-(1-{5-[3-(trifluoromethoxy)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-4-yl)acetamide

    [0276] ##STR00062##

    [0277] To a solution of N-[1-(5-bromo-1,3,4-oxadiazol-2-yl)piperidin-4-yl]-2-(4-chloro-3-fluorophenoxy)acetamide (50 mg, 0.115 mmol, Intermediate 10) in anhydrous THF (2 mL) was added 3-(trifluoromethoxy)azetidine (24 mg, 0.173 mmol) and K.sub.2CO.sub.3 (24 mg, 0.173 mmol) and the resultant mixture was stirred at r.t. under N.sub.2 for 2 h. The reaction mixture was heated at 80° C. for 20 h. The reaction mixture was diluted with H.sub.2O (20 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4, concentrated in vacuo, and purified by preparative HPLC (Method 4) to afford the title compound (10 mg, 0.0211 mmol, 18% yield) as a white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.08 (d, J=7.9 Hz, 1H), 7.50 (t, J=8.9 Hz, 1H), 7.07 (dd, J=11.4, 2.8 Hz, 1H), 6.86 (dd, J=9.0, 1.8 Hz, 1H), 5.30 (ddd, J=10.9, 6.7, 4.3 Hz, 1H), 4.53 (s, 2H), 4.38 (dd, J=9.5, 6.8 Hz, 2H), 4.11 (dd, J=9.6, 4.1 Hz, 2H), 3.92-3.80 (m, 1H), 3.71-3.60 (m, 2H), 3.03 (t, J=11.2 Hz, 2H), 1.83-1.72 (m, 2H), 1.52 (qd, J=12.3, 4.1 Hz, 2H); M/Z: 494, 496 [M+H].sup.+, ESI+, RT=3.25 min (S4).

    ##STR00063##

    Example 11 and 12: Chiral separation of 2-(4-chloro-3-fluorophenoxy)-N-[(3R*,4R*)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxypiperidin-4-yl]acetamide

    [0278] 2-(4-chloro-3-fluorophenoxy)-N-[(3R*,4R*)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxypiperidin-4-yl]acetamide (48 mg, 0.0997 mmol) was subjected to chiral purification using Method C1, affording enantiomers 2-(4-chloro-3-fluorophenoxy)-N-[(3R,4R)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxypiperidin-4-yl]acetamide (100% chiral purity, 18.5 mg, 0.0369 mmol, 37% yield) and 2-(4-chloro-3-fluorophenoxy)-N-[(3S,4S)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxypiperidin-4-yl]acetamide (98% chiral purity, 17.5 mg, 0.0345 mmol), 35% yield) as white powders. The stereochemistry of each enantiomer was arbitrarily assigned.

    [0279] Example compounds in Table 3 were chirally purified according to the general route 19 as exemplified by Example 11 and 12, using the corresponding intermediates and methods.

    TABLE-US-00003 TABLE 3 Intermediate LCMS Ex Structure Name and Method data 1H NMR E11 [00064]embedded image 2-(4-Chloro- 3-fluoro- phenoxy)- N-[(3R,4R)- 1-[5-(4- chlorophenyl)- 1,3,4- oxadiazol-2- 2-(4-chloro-3- fluorophenoxy)- N-[(3R*,4R*)-1- [5-(4- chlorophenyl)- 1,3,4-oxadiazol- 2-yl]-3- hydroxy- M/Z: 481, 483, 485 [M + H].sup.+, ESI+, RT = 3.27 min (S4). 1H NMR (400 MHz, chloroform-d) δ 7.87- 7.82 (m, 2H), 7.47-7.41 (m, 2H), 7.34 (t, J = 8.6 Hz, 1H), 6.77 (dd, J = 10.1, 2.9 Hz, 1H), 6.71- 6.65 (m, 1H), 6.59-6.52 (m, 1H), 4.58-4.48 (m, yl]-3- piperidin-4- 2H), 4.34-4.24 (m, 1H), hydroxy- yl]acetamide 4.20-4.13 (m, 1H), 4.04- piperidin-4- (Example 3 - 3.93 (m, 1H), 3.71- yl]acetamide Method C1) 3.63 (m, 1H), 3.62 (d, J = 4.5 Hz, 1H), 3.23-3.14 (m, 1H), 3.03 (dd, J = 13.1, 10.1 Hz, 1H), 2.17- 2.09 (m, 1H), 1.83- 1.69 (m, 1H). E12 [00065]embedded image 2-(4-Chloro-3- fluoro- phenoxy)- N-[(3S,4S)- 1-[5-(4- chlorophenyl)- 1,3,4- oxadiazol-2- 2-(4-chloro-3- fluorophenoxy)- N-[(3R*,4R*)-1- [5-(4- chlorophenyl)- 1,3,4-oxadiazol- 2-yl]-3- hydroxy- M/Z: 481, 483, 485 [M + H]+, ESI+, RT = 3.27 min (S4). .sup.1H NMR (400 MHz, chloroform-d) δ 7.87- 7.82 (m, 2H), 7.47-7.41 (m, 2H), 7.34 (t, J = 8.6 Hz, 1H), 6.77 (dd, J = 10.2, 2.9 Hz, 1H), 6.68 (ddd, J = 8.9, 2.9, 1.2 Hz, 1H), 6.59-6.54 (m, 1H), yl]-3- piperidin-4- 4.59-4.47 (m, 2H), 4.34- hydroxy- yl]acetamide 4.25 (m, 1H), 4.20- piperidin-4- (Example 3 - 4.12 (m, 1H), 4.04-3.93 yl]acetamide Method C1) (m, 1H), 3.73-3.61 (m, 2H), 3.18 (td, J = 13.4, 2.8 Hz, 1H), 3.03 (dd, J = 13.0, 9.9 Hz, 1H), 2.13 (dd, J = 13.2, 4.3 Hz, 1H), 1.76 (qd, J = 12.5, 4.8 Hz, 1H). E13 [00066]embedded image 2-(4-Chloro-3- fluoro- phenoxy)- N-[(4S)-1-[5- (4- chlorophenyl)- 1,3,4- 2-(4-Chloro-3- fluorophenoxy)- N-{1-[5-(4- chlorophenyl)- 1,3,4-oxadiazol- 2-yl]azepan-4- yl}acetamide M/Z: 479, 481, 483 [M + H].sup.+, ESI+, RT = 3.77 min (S6). .sup.1H NMR (500 MHz, chloroform-d) δ 7.84- 7.80 (m, 2H), 7.44-7.40 (m, 2H), 7.29 (t, J = 8.6 Hz, 1H), 6.71 (dd, J = 10.3, 2.9 Hz, 1H), 6.63 (ddd, J = 8.9, 2.9, 1.2 Hz, oxadiazol-2- (Example 6 - 1H), 6.42 (d, J = 8.0 Hz, yl]azepan-4- Method C2) 1H), 4.42 (s, 2H), 4.18- yl]acetamide 4.09 (m, 1H), 3.92 (ddd, J = 14.8, 5.8, 3.8 Hz, 1H), 3.79-3.71 (m, 1H), 3.65 (dt, J = 13.6, 4.9 Hz, 1H), 3.53-3.43 (m, 1H), 2.23-2.15 (m, IH), 2.07-1.98 (m, 2H), 1.94- 1.80 (m, 2H), 1.63 (q, J = 10.4 Hz, 1H). E14 [00067]embedded image 2-(4-chloro-3- fluoro- phenoxy)- N-[(4R)-1- [5-(4- chlorophenyl)- 1,3,4- 2-(4-chloro-3- fluorophenoxy)- N-{1-[5-(4- chlorophenyl)- 1,3,4-oxadiazol- 2-yl]azepan-4- yl}acetamide M/Z: 479, 481, 483 [M + H]+, ESI+, RT = 3.77 min (S6). .sup.1H NMR (400 MHz, chloroform-d) δ 7.86- 7.77 (m, 2H), 7.45-7.38 (m, 2H), 7.32-7.26 (m, 1H), 6.71 (dd, J = 10.3, 2.9 Hz, 1H), 6.66-6.60 (m, 1H), 6.41 (d, J = 8.1 oxadiazol-2- (Example 6 - Hz, 1H), 4.42 (s, 2H), yl]azepan-4- Method C2) 4.20-4.09 (m, 1H), 3.97- yl]acetamide 3.87 (m, 1H), 3.81- 3.71 (m, 1H), 3.69-3.60 (m, 1H), 3.53-3.43 (m, 1H), 2.25-2.14 (m, 1H), 2.08-1.96 (m, 2H), 1.95- 1.81 (m, 2H), 1.69- 1.57 (m, 1H).

    II Biological Assay

    HEK-ATF4 High Content Imaging Assay

    [0280] Example compounds were tested in the HEK-ATF4 High Content Imaging assay to assess their pharmacological potency to prevent Tunicamycin induced ISR. Wild-type HEK293 cells were plated in 384-well imaging assay plates at a density of 12,000 cells per well in growth medium (containing DMEM/F12, 10% FBS, 2 mM L-Glutamine, 100 U/mL Penicillin—100 μg/mL Streptomycin) and incubated at 37° C., 5% CO.sub.2. 24-hrs later, the medium was changed to 50 μl assay medium per well (DMEM/F12, 0.3% FBS, 2 mM L-Glutamine, 100 U/mL Penicillin—100 μg/mL Streptomycin). Example compounds were serially diluted in dimethyl sulfoxide (DMSO), spotted into intermediate plates and prediluted with assay medium containing 3.3 μM Tunicamycin to give an 11-fold excess of final assay concentration. In addition to the example compound testing area, the plates also contained multiples of control wells for assay normalization purposes, wells containing Tunicamycin but no example compounds (High control), as well as wells containing neither example compound nor Tunicamycin (Low control). The assay was started by transferring 5 μl from the intermediate plate into the assay plates, followed by incubation for 6 hrs at 37° C., 5% CO.sub.2. Subsequently, cells were fixed (4% PFA in PBS, 20 min at room temperature) and submitted to indirect ATF4 immunofluorescence staining (primary antibody rabbit anti ATF4, clone D4B8, Cell Signaling Technologies; secondary antibody Alexa Fluor 488 goat anti-rabbit IgG (H+L), Thermofisher Scientific). Nuclei were stained using Hoechst dye (Thermofisher Scientific), and plates were imaged on an Opera Phenix High Content imaging platform equipped with 405 nm and 488 nm excitation. Finally, images were analyzed using script based algorithms. The main readout HEK-ATF4 monitored the ATF4 signal ratio between nucleus and cytoplasm. Tunicamycin induced an increase in the overall ATF4 ratio signal, which was prevented by ISR modulating example compounds. In addition, HEK-CellCount readout was derived from counting the number of stained nuclei corresponding to healthy cells. This readout served as an internal toxicity control. The example compounds herein did not produce significant reduction in CellCount.

    [0281] Activity of the tested example compounds is provided in Table 4 as follows:

    +++=IC50 1-500 nM; ++=IC50>500-2000 nM; +=IC50>2000-15000 nM

    [0282]

    TABLE-US-00004 TABLE 4 Example number Activity 1 +++ 2 +++ 3 +++ 4 +++ 5 ++ 6 ++ 7 ++ 8 +++ 9 +++ 10 +++ 11 ++ 12 +++ 13 ++ 14 +

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