JPWO2021151865A5

JPWO2021151865A5 -

Info

Publication number: JPWO2021151865A5
Application number: JP2022545799A
Authority: JP
Publication date: 2024-02-02

Claims

Formula (I)

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, in which:
X ¹ is C(R ^a6 ) or N;
X ^1a is a covalent single bond; CH(R ^a3 ), O, N(R ^a7 ), or CH(R ^a3 )CH ₂ ;
R ^a1 , R ^a2 , R ^a3 are independently selected from the group consisting of H; halogen; OH; O-C _1-4 alkyl; C _1-4 alkyl; and A ^2a ;
and R ^a4 , R ^a5 , R ^a6 are independently selected from the group consisting of H; halogen; C _1-4 alkyl; and A ^2a , with the proviso that R ^a1 , R ^a2 , R ^a3 , R ^a4 , R ^a5 , Only one of R ^a6 is A ^2a ;
Optionally R ^a1 and R ^a2 form a covalent single bond;
Optionally R ^a2 and R ^a4 form a methylene group;
Optionally R ^a4 and R ^a6 form an ethylene group;
Optionally, R ^a4 and R ^a5 are joined to form an oxo group;
R ^a7 is H, C(O)OC _1-4 alkyl, or C _1-4 alkyl, where C(O)OC _1-4 alkyl and C _1-4 alkyl are halogen, OH, and O optionally substituted with one or more substituents selected from the group consisting of -C _1-3 alkyl, wherein the substituents are the same or different, preferably R ^a7 is H;
A ¹ is C ₅ cycloalkylene, C ₅ cycloalkenylene, 5-membered heterocyclene containing a nitrogen ring atom, or 7- to 12-membered heterobicyclene containing a 5-membered heterocycle containing a nitrogen ring atom, where the heterocycle is , attached to the nitrogen ring atom as shown in formula (I), and wherein A ¹ is optionally substituted with one or more R ⁴ , the same or different;
Each R ⁴ is independently oxo (=O) [when the ring is at least partially saturated], thioxo (=S) [when the ring is at least partially saturated], halogen, CN, OR ⁵ , or C _1-6 alkyl, where C _1-6 alkyl is optionally substituted with one or more halogens, which are the same or different;
R ⁵ is H or C _1-6 alkyl, where C _1-6 alkyl is optionally substituted with one or more halogens, which are the same or different;
A ² is R ^6a or A ^2a ;
R ^6a is OR ^6a1 , SR ^6a1 , N(R ^6a1 R ^6a2 ); C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl, where C _1-6 alkyl, C _2-6 Alkenyl and C _2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen; CN; OR ^6a3 ; and A ^2a , where the substituents are the same or Different;
R ^6a1 , R ^6a2 are independently selected from the group consisting of H; C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; and A ^2a , where C _1-6 alkyl; C _{2 -6} alkenyl; and C _2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen; CN; OR ^6a3 ; and A ^2a , where the substituents are the same or different;
R ^6a3 is H; or C _1-4 alkyl, where C _1-4 alkyl is optionally substituted with one or more halogens, which are the same or different;
A ^2a is phenyl; or 3-7 membered heterocyclyl, where A ^2a is optionally substituted with one or more R ⁶ , which are the same or different;
Each R ⁶ is independently R ^6b , OH, OR ^6b , halogen, or CN, where R ^6b is cyclopropyl, C _1-6 alkyl, C _2-6 alkenyl, or C _2-6 alkynyl and where R ^6b is optionally substituted with one or more halogens, the same or different; or two R ⁶ are conjugated and together with the atoms to which they are attached ring A form ^2b ;
A ^2b is phenyl; or 3-7 membered heterocyclyl, where A ^2b is optionally substituted with one or more R ⁷ , which are the same or different;
Each R ⁷ is independently C _1-6 alkyl, C _2-6 alkenyl, or C _2-6 alkynyl, where C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are , optionally substituted with one or more halogens, the same or different;
R ¹ is H or C _1-4 alkyl, preferably H, where C _1-4 alkyl is optionally substituted with one or more halogens, the same or different;
R ² is H; F; or C _1-4 alkyl, where C _1-4 alkyl is optionally substituted with one or more halogens, the same or different; and R ³ ^is , C _1-6 alkyl, C _2-6 alkenyl, or C _2-6 alkynyl, where C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are the same or different one or R ² and ^{R 3} ^are joined to form a ring A ^3a together with the oxygen and carbon atoms to which they are attached, where A ^3a is , 7-12 membered heterobicyclyl, where the 7-12 membered heterobicyclyl is optionally substituted with one or more R ¹⁰ that are the same or different;
R ^2a is H or F, preferably H;
Each R ⁸ is independently halogen; CN, C(O)OR ⁹ , OR ⁹ , C(O)R ⁹ , C(O)N(R ⁹ R ^9a ), S(O) ₂ N(R ⁹ R ^9a ), S(O)N(R ⁹ R ^9a ), S(O) ₂ R ⁹ , S(O)R ⁹ , N(R ⁹ )S(O) ₂ N(R ^9a R ^9b ), SR ⁹ , N( ^R9R9a ), _NO2 , OC ⁽ O) ^R9 , N( ^R9 ) ^C (O) ^R9a , N( ^R9 ) _SO2R9
^a , N(R ⁹ )S(O)R ^9a , N(R ⁹ )C(O)N(R ^9a R ^9b ), N(R ⁹ )C(O)OR ^9a , OC(O)N(R ⁹ R ^9a ), or A ³ ;
R ⁹ , R ^9a , R ^9b are independently selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, where C _1-6 alkyl, C _{2-6 -6} alkenyl, and C _2-6 alkynyl are optionally substituted with one or more halogens, the same or different, or one OH, or one OC _1-4 alkyl, or one A ³ ;
Each A ³ is independently phenyl, naphthyl, 3- to 7-membered heterocyclyl, or 7- to 12-membered heterobicyclyl, where A ³ is optionally substituted with one or more R ¹⁰ that are the same or different. ;
Each R ¹⁰ is independently halogen, CN, C(O)OR ¹¹ , OR ¹¹ , C(O)R ¹¹ , C(O)N(R ¹¹ R ^11a ), S(O) ₂ N(R ¹¹ R ^11a ), S(O)N(R ¹¹ R ^11a ), S(O) ₂ R ¹¹ , S(O)R ¹¹ , N(R ¹¹ )S(O) ₂ N(R ^11a R ^11b ), SR ¹¹ , N(R ¹¹ R ^11a ), NO ₂ , OC(O)R ¹¹ , N(R ¹¹ )C(O)R ^11a , N(R ¹¹ )S(O) ₂ R ^11a , N(R ¹¹ ) S(O)R ^11a , N(R ¹¹ )C(O)OR ^11a , N(R ¹¹ )C(O)N(R ^11a R ^11b ), OC(O)N(R ¹¹ R ^11a ), Oxo( =O) [when the ring is at least partially saturated], C _1-6 alkyl, C _2-6 alkenyl, or C _2-6 alkynyl, where C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl optionally substituted with one or more R ¹² which are the same or different;
R ¹¹ , R ^11a , R ^11b are independently selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, where C _1-6 alkyl, C _{2-6 -6} alkenyl, and C _2-6 alkynyl optionally substituted with one or more halogens, which are the same or different;
Each R ¹² is independently halogen, CN, C(O)OR ¹³ , OR ¹³ , C(O)R ¹³ , C(O)N(R ¹³ R ^13a ), S(O) ₂ N(R ¹³ R ^13a ), S(O)N(R ¹³ R ^13a ), S(O) ₂ R ¹³ , S(O)R ¹³ , N(R ¹³ )S(O) ₂ N(R ^13a R ^13b ), SR ¹³ , N(R ¹³ R ^13a ), NO ₂ , OC(O)R ¹³ , N(R ¹³ )C(O)R ^13a , N(R ¹³ )SO ₂ R ^13a , N(R ¹³ )S(O ) R ^13a , N(R ¹³ )C(O)N(R ^13a R ^13b ), N(R ¹³ )C(O)OR ^13a , or OC(O)N(R ¹³ R ^13a );
R ¹³ , R ^13a , R ^13b are independently selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, where C _1-6 alkyl, C _{2-6 -6} alkenyl and C _2-6 alkynyl are optionally substituted with one or more halogens, the same or different,
However, the following compounds:

or the above-mentioned compounds or their pharmaceutically acceptable salts, solvates, hydrates, excluding pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof. , tautomers or stereoisomers.

The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein X ¹ is CH.

X ^1a is a covalent single bond; CH(R ^a3 ) or CH(R ^a3 )CH ₂ , preferably CH(R ^a3 ) or CH(R ^a3 )CH ₂ , more preferably CH(R ^a3 ), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

R ^a1 , R ^a2 , R ^a3 , R ^a4 , R ^a5 , R ^a6 are H; or R ^a1 is OH and R ^a2 , R ^a3 , R ^a4 , R ^a5 , R ^a6 are H; or R ^a1 , R ^a3 , R ^a5 , R ^a6 are H, and R ^a2 and R ^a4 form a methylene group; or R ^a1 and R ^a2 form a covalent single bond, and R ^a3 , R ^a4 , R ^a5 , R ^a6 are H, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof according to any one of claims 1 to 3 body.

The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein R ^a1 , R ^a2 , R ^a3 , R ^a4 , R ^a5 , and R ^a6 are H; Hydrates, tautomers or stereoisomers.

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

A ¹ is a nitrogen ring atom-containing 5-membered heterocyclene selected from the group of divalent heterocycles consisting of oxadiazole, imidazole, imidazolidine, pyrazole and triazole, preferably oxadiazole, and where A a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate thereof, wherein 1 is optionally substituted with one or more ^R ⁴ which are the same or different; Hydrates, tautomers or stereoisomers.

A compound according to any one of claims 1 to 7, wherein A ¹ is unsubstituted or substituted with one or two of the same or different R ⁴ , preferably A ¹ is unsubstituted, or Pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof.

A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate thereof, wherein R ⁴ is oxo [if the ring is at least partially saturated] or methyl; Hydrates, tautomers or stereoisomers.

^A1 is

The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein A ² is R ^6a .

R ^6a is OR ^6a1 and R ^6a1 is preferably A ^2a or C 1-6 optionally substituted with one or more halogens and/or one A ^2a and/or one _OR ^6a3 or R ^6a is C _1-6 alkyl optionally substituted with one or more halogens and/or one A ^2a and/or one OR ^6a3 . A compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

R ^6a is OR ^6a1 and R ^6a1 is preferably C _1-6 alkyl optionally substituted with one or more F and/or one OR ^6a3 ; or R ^6a is one or a pharmaceutically acceptable salt, solvate, aqueous compound according to claim 11 or 12, which is C _1-6 alkyl optionally substituted with or more halogen and/or one OR ^6a3 . hydrate, tautomer or stereoisomer.

The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein A ² is A ^2a .

A ^2a is phenyl or a 5- to 6-membered aromatic heterocyclyl, preferably pyridyl, pyrazinyl, pyridazinyl, pyrazolyl or 1,2,4-oxadiazolyl, and where A ^2a is the same or different one 15. A compound according to claim 14, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, optionally substituted with R ⁶ or more.

A ^2a is optionally substituted with one or two R ⁶ which are the same or different.
10, 14 and 15, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

According to any one of claims 1-10, 14-16, each R ⁶ is independently F, Cl, CF ₃ , OCH ₃ , OCF ₃ , CH ₃ , CH ₂ CH ₃ , or cyclopropyl. A described compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein R ² is H;

The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein R ³ is A ³ .

Any one of claims 1 to 19, wherein A ³ is phenyl, pyridyl, pyrazinyl or pyrimidazyl, and wherein A ³ is optionally substituted with one or more R ¹⁰ , which are the same or different. or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate, hydrate thereof, wherein A ³ is substituted with one or two R ¹⁰ that are the same or different. substance, tautomer or stereoisomer.

R ² and R ³ are joined together with the oxygen atom and carbon atom to which they are attached to form a dihydrobenzopyran ring, where the ring contains one or more R ¹⁰ , the same or different. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate thereof, optionally substituted with , preferably said ring is substituted with one or two R ¹⁰ , hydrates, tautomers or stereoisomers.

A compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is independently F, Cl, CF ₃ , CH═O, CH ₂ OH or CH ₃ , solvates, hydrates, tautomers or stereoisomers.

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]piperidine- 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]piperidine-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-[(3S,4S)-1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-3- hydroxypiperidin-4-yl]acetamide;
2-(4-chloro-3-fluorophenoxy)-N-[(4S)-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-oxadiazole -2-yl}piperidin-4-yl)acetamide, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, according to any one of claims 1 to 23. body or stereoisomer.

At least one compound as defined in any one of claims 1 to 24, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, is a pharmaceutical composition, optionally in combination with one or more other bioactive compounds or pharmaceutical compositions.

A compound as defined in any one of claims 1 to 24 or a pharmaceutically acceptable compound thereof in the manufacture of a medicament for the treatment or prevention of one or more diseases or disorders associated with the integrated stress response. Use of salts, solvates, hydrates, tautomers or stereoisomers.

One or more diseases selected from the group consisting of leukodystrophy, intellectual disability syndrome, neurodegenerative diseases and disorders, neoplastic diseases, infectious diseases, inflammatory diseases, musculoskeletal diseases, metabolic diseases, and ophthalmic diseases. or disorders, as well as organ fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lungs, chronic and acute diseases of the kidneys, myocardial infarction, cardiovascular diseases, arrhythmia, atherosclerosis, spinal cord injury, ischemic stroke. A compound as defined in any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease selected from the group consisting of , and neuropathic pain. , use of solvates, hydrates, tautomers or stereoisomers.

Use of a compound as defined in any one of claims 1 to 24, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, in the manufacture of a medicament.