US 12,715,865 B2Granted

Modulators of the integrated stress response pathway

AssigneeEvotec International GmbH

InventorsChristopher John Brown, James Lindsay Carr, Mohamad Sabbah, Jeffrey Michael Schkeryantz, Daryl Simon Walter

Life of this patent

Estimating the term…

Abstract

The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, wherein R1, R2, R2a, R3, Ra1, Ra2, Ra4, Ra5, X1, X1a, A1 and A2 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.

Claims26

Dependent claims

A compound of formula (I)

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein
X1 is C(Ra6) or N;
X1a is a covalent single bond, CH(Ra3), O, N(Ra7), or CH(Ra3)CH2;
Ra1, Ra2, and Ra3 are independently selected from the group consisting of H, halogen, OH, O—C1-4 alkyl, C1-4 alkyl, and A2a,
and Ra4, Ra5, and Ra6 are independently selected from the group consisting of H, halogen, C1-4 alkyl, and A2a, provided that only one of Rai, Ra2, Ra3, Ra4, Ra5, and Ra6 is A2a;
optionally Ra1 and Ra2 form a covalent single bond;
optionally Ra2 and Ra4 form a methylene group;
optionally Ra4 and Ra6 form an ethylene group;
optionally Ra4 and Ra5 are joined to form an oxo group;
Ra7 is H, C(O)OC1-4 alkyl, or C1-4 alkyl, wherein C(O)OC1-4 alkyl and C1-4 alkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, OH, and O—C1-3 alkyl, wherein the substituents are the same or different;
A1 is C5 cycloalkylene, C5 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 A1 is optionally substituted with one or more R4, which are the same or different;
each R4 is independently oxo (═O) where the ring is at least partially saturated, thiooxo (═S) where the ring is at least partially saturated, halogen, CN, OR5, or C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
R5 is H or C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
A2 is R6a or A2a;
R6a is OR6a1, SR6a1, N(R6a1R6a2), C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OR6a3, and A2a, wherein the substituents are the same or different;
R6a1 and R6a2 are independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and A2a, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OR6a3, and A2a, wherein the substituents are the same or different;
R6a3 is H or C1-4 alkyl, wherein C1-4 alkyl is optionally substituted with one or more halogen, which are the same or different;
A2a is phenyl or 3 to 7 membered heterocyclyl, wherein A2a is optionally substituted with one or more R6, which are the same or different;
each R6 is independently R6b, OH, OR6b, halogen, or CN, wherein R6b is cyclopropyl, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, and wherein R6b is optionally substituted with one or more halogen, which are the same or different;
or
two R6 are joined to form together with the atoms to which they are attached a ring A2b;
A2b is phenyl or 3 to 7 membered heterocyclyl, wherein A2b is optionally substituted with one or more R7, which are the same or different;
each R7 is independently C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
R1 is H or C1-4 alkyl, wherein C1-4 alkyl is optionally substituted with one or more halogen, which are the same or different;
R2 is H, F, or C1-4 alkyl, wherein C1-4 alkyl is optionally substituted with one or more halogen, which are the same or different;
and
R3 is A3, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more R8, which are the same or different;
or
R2 and R3 are joined to form together with the oxygen atom and carbon atom to which they are attached a ring A3a, wherein A3a is a 7 to 12 membered heterobicyclyl, wherein 7 to 12 membered heterobicyclyl is optionally substituted with one or more R10, which are the same or different;
R2a is H or F;
each R8 is independently halogen, CN, C(O)OR9, OR9, C(O)R9, C(O)N(R9R9a), S(O)2N(R9R9a), S(O)N(R9R9a), S(O)2R9, S(O)R9, N(R9)S(O)2N(R9aR9b), SR9, N(R9R9a), NO2, OC(O)R9, N(R9)C(O)R9a, N(R9)SO2R9a, N(R9)S(O)R9a, N(R9)C(O)N(R9aR9b), N(R9)C(O)OR9a, OC(O)N(R9R9a), or A3;
R9, R9a, and R9b are independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different, or one OH, or one OC1-4 alkyl, or one A3;
each A3 is independently phenyl, naphthyl, 3 to 7 membered heterocyclyl, or 7 to 12 membered heterobicyclyl, wherein A3 is optionally substituted with one or more R10, which are the same or different;
each R10 is independently halogen, CN, C(O)OR11, OR11, C(O)R11, C(O)N(R11R11a), S(O)2N(R11R11a), S(O)N(R11R11a), S(O)2R11, S(O)R11, N(R11)S(O)2N(R11aR11b), SR11, N(R11R11a), NO2, OC(O)R11, N(R11)C(O)R11a, N(R11)S(O)2R11a, N(R11)S(O)R11a, N(R11)C(O)OR11a, N(R11)C(O)N(R11aR11b), OC(O)N(R11R11a), oxo (═O) where the ring is at least partially saturated, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more R12, which are the same or different;
R11, R11a, and R11b are independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
each R12 is independently halogen, CN, C(O)OR13, OR13, C(O)R13, C(O)N(R13R13a), S(O)2N(R13R13a), S(O)N(R13R13a), S(O)2R13, S(O)R13, N(R13)S(O)2N(R13aR13b), SR13, N(R13R13a), NO2, OC(O)R13, N(R13)C(O)R13a, N(R13)SO2R13a, N(R13)S(O)R13a N(R13)C(O)N(R13aR13b), N(R13)C(O)OR13a, or OC(O)N(R13R13a);
R13, R13a, and R13b are independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 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:

34 more elements

A pharmaceutical composition comprising at least one compound of formula (I)

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein
X1 is C(Ra6) or N;
X1a is a covalent single bond, CH(Ra3), O, N(Ra7), or CH(Ra3)CH2;
Ra1, Ra2, and Ra3 are independently selected from the group consisting of H, halogen, OH, O—C1-4 alkyl, C1-4 alkyl, and A2a,
and Ra4, Ra5, and Ra6 are independently selected from the group consisting of H, halogen, C1-4 alkyl, and A2a, provided that only one of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6 is A2a;
optionally Ra1 and Ra2 form a covalent single bond;
optionally Ra2 and Ra4 form a methylene group;
optionally Ra4 and Ra6 form an ethylene group;
optionally Ra4 and Ra5 are joined to form an oxo group;
Ra7 is H, C(O)OC1-4 alkyl, or C1-4 alkyl, wherein C(O)OC1-4 alkyl and C1-4 alkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, OH, and O—C1-3 alkyl, wherein the substituents are the same or different;
A1 is C5 cycloalkylene, C5 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 A1 is optionally substituted with one or more R4, which are the same or different;
each R4 is independently oxo (═O) where the ring is at least partially saturated, thiooxo (═S) where the ring is at least partially saturated, halogen, CN, OR5, or C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
R5 is H or C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
A2 is R6a or A2a;
R6a is OR6a1, SR6a1, N(R6a1R6a2), C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OR6a3, and A2a, wherein the substituents are the same or different;
R6a1 and R6a2 are independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and A2a, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OR6a3, and A2a, wherein the substituents are the same or different;
R6a3 is H or C1-4 alkyl, wherein C1-4 alkyl is optionally substituted with one or more halogen, which are the same or different;
A2a is phenyl or 3 to 7 membered heterocyclyl, wherein A2a is optionally substituted with one or more R6, which are the same or different;
each R6 is independently R6b, OH, OR6b, halogen, or CN, wherein R6b is cyclopropyl, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, and wherein R6b is optionally substituted with one or more halogen, which are the same or different;
or
two R6 are joined to form together with the atoms to which they are attached a ring A2b;
A2b is phenyl or 3 to 7 membered heterocyclyl, wherein A2b is optionally substituted with one or more R7, which are the same or different;
each R7 is independently C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
R1 is H or C1-4 alkyl, wherein C1-4 alkyl is optionally substituted with one or more halogen, which are the same or different;
R2 is H, F, or C1-4 alkyl, wherein C1-4 alkyl is optionally substituted with one or more halogen, which are the same or different;
and
R3 is A3, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more R′, which are the same or different;
or
R2 and R3 are joined to form together with the oxygen atom and carbon atom to which they are attached a ring A3a, wherein A3a is a 7 to 12 membered heterobicyclyl, wherein 7 to 12 membered heterobicyclyl is optionally substituted with one or more R10, which are the same or different;
R2a is H or F;
each R8 is independently halogen, CN, C(O)OR9, OR9, C(O)R9, C(O)N(R9R9a), S(O)2N(R9R9a), S(O)N(R9R9a), S(O)2R9, S(O)R9, N(R9)S(O)2N(R9aR9b), SR9, N(R9R9a), NO2, OC(O)R9, N(R9)C(O)R9a, N(R9)SO2R9a, N(R9)S(O)R9a, N(R9)C(O)N(R9aR9b), N(R9)C(O)OR9a, OC(O)N(R9R9a), or A3;
R9, R9a, and R9b are independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different, or one OH, or one OC1-4 alkyl, or one A3;
each A3 is independently phenyl, naphthyl, 3 to 7 membered heterocyclyl, or 7 to 12 membered heterobicyclyl, wherein A3 is optionally substituted with one or more R10, which are the same or different;
each R10 is independently halogen, CN, C(O)OR11, OR11, C(O)R11, C(O)N(R11R11a), S(O)2N(R11R11a), S(O)N(R11R11a), S(O)2R11, S(O)R11, N(R11)S(O)2N(R11aR11b), SR11, N(R11R11a), NO2, OC(O)R11, N(R11)C(O)R11a, N(R11)S(O)2R11a, N(R11)S(O)R11a N(R11)C(O)OR11a, N(R11)C(O)N(R11aR11b), OC(O)N(R11R11a), oxo (═O) where the ring is at least partially saturated, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more R12, which are the same or different;
R11, R11a, and R11b are independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
each R12 is independently halogen, CN, C(O)OR13, OR13, C(O)R13, C(O)N(R13R13a), S(O)2N(R13R13a), S(O)N(R13R13a), S(O)2R13, S(O)R13, N(R13)S(O)2N(R13aR13b), SR13, N(R13R13a), NO2, OC(O)R13, N(R13)C(O)R13a, N(R13)SO2R13a, N(R13)S(O)R13a N(R13)C(O)N(R13aR13b), N(R13)C(O)OR13a, or OC(O)N(R13R13a);
R13, R13a, and R13b are independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 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.

35 more elements

A method for treating, controlling, or delaying in a mammalian patient in need of treatment of one or more diseases or disorders, wherein the method comprises administering to said patient a therapeutically effective amount of a compound of formula (I)

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein
X1 is C(Ra6) or N;
X1a is a covalent single bond, CH(Ra3), O, N(Ra7), or CH(Ra3)CH2;
Ra1, Ra2, and Ra3 are independently selected from the group consisting of H, halogen, OH, O—C1-4 alkyl, C1-4 alkyl, and A2a,
and Ra4, Ra5, and Ra6 are independently selected from the group consisting of H, halogen, C1-4 alkyl, and A2a, provided that only one of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6 is A2a;
optionally Ra1 and Ra2 form a covalent single bond;
optionally Ra2 and Ra4 form a methylene group;
optionally Ra4 and Ra6 form an ethylene group;
optionally Ra4 and Ra5 are joined to form an oxo group;
Ra7 is H, C(O)OC1-4 alkyl, or C1-4 alkyl, wherein C(O)OC1-4 alkyl and C1-4 alkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, OH, and O—C1-3 alkyl, wherein the substituents are the same or different;
A1 is C5 cycloalkylene, C5 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 A1 is optionally substituted with one or more R4, which are the same or different;
each R4 is independently oxo (═O) where the ring is at least partially saturated, thiooxo (═S) where the ring is at least partially saturated, halogen, CN, OR5, or C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
R5 is H or C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
A2 is R6a or A2a;
R6a is OR6a1, SR6a1, N(R6a1R6a2), C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OR6a3, and A2a, wherein the substituents are the same or different;
R6a1 and R6a2 are independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and A2a, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OR6a3, and A2a, wherein the substituents are the same or different;
R6a3 is H or C1-4 alkyl, wherein C1-4 alkyl is optionally substituted with one or more halogen, which are the same or different;
A2a is phenyl or 3 to 7 membered heterocyclyl, wherein A2a is optionally substituted with one or more R6, which are the same or different;
each R6 is independently R6b, OH, OR6b, halogen, or CN, wherein R6b is cyclopropyl, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, and wherein R6b is optionally substituted with one or more halogen, which are the same or different;
or
two R6 are joined to form together with the atoms to which they are attached a ring A2b;
A2b is phenyl or 3 to 7 membered heterocyclyl, wherein A2b is optionally substituted with one or more R7, which are the same or different;
each R7 is independently C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
R1 is H or C1-4 alkyl, wherein C1-4 alkyl is optionally substituted with one or more halogen, which are the same or different;
R2 is H, F, or C1-4 alkyl, wherein C1-4 alkyl is optionally substituted with one or more halogen, which are the same or different;
and
R3 is A3, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more R8, which are the same or different;
or
R2 and R3 are joined to form together with the oxygen atom and carbon atom to which they are attached a ring A3a, wherein A3a is a 7 to 12 membered heterobicyclyl, wherein 7 to 12 membered heterobicyclyl is optionally substituted with one or more R10, which are the same or different;
R2a is H or F;
each R8 is independently halogen, CN, C(O)OR9, OR9, C(O)R9, C(O)N(R9R9a), S(O)2N(R9R9a), S(O)N(R9R9a), S(O)2R9, S(O)R9, N(R9)S(O)2N(R9aR9b), SR9, N(R9R9a), NO2, OC(O)R9, N(R9)C(O)R9a, N(R9)SO2R9a, N(R9)S(O)R9a, N(R9)C(O)N(R9aR9b), N(R9)C(O)OR9a, OC(O)N(R9R9a), or A3;
R9, R9a, and R9b are independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different, or one OH, or one OC1-4 alkyl, or one A3;
each A3 is independently phenyl, naphthyl, 3 to 7 membered heterocyclyl, or 7 to 12 membered heterobicyclyl, wherein A3 is optionally substituted with one or more R10, which are the same or different;
each R10 is independently halogen, CN, C(O)OR11, OR11, C(O)R11, C(O)N(R11R11a), S(O)2N(R11R11a), S(O)N(R11R11a), S(O)2R11, S(O)R11, N(R11)S(O)2N(R11aR11b), SR11, N(R11R11a), NO2, OC(O)R11, N(R11)C(O)R11a, N(R11)S(O)2R11a, N(R11)S(O)R11a N(R11)C(O)OR11a, N(R11)C(O)N(R11aR11b), OC(O)N(R11R11a), oxo (═O) where the ring is at least partially saturated, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more R12, which are the same or different;
R11, R11a, and R11b are independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
each R12 is independently halogen, CN, C(O)OR13, OR13, C(O)R13, C(O)N(R13R13a), S(O)2N(R13R13a), S(O)N(R13R13a), S(O)2R13, S(O)R13, N(R13)S(O)2N(R13aR13b), SR13, N(R13R13a), NO2, OC(O)R13, N(R13)C(O)R13a, N(R13)SO2R13a, N(R13)S(O)R13a N(R13)C(O)N(R13aR13b), N(R13)C(O)OR13a, or OC(O)N(R13R13a);
R13, R13a, and R13b are independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different, wherein the one or more diseases or disorders are selected from:
(i) leukodystrophies,
(ii) intellectual disability syndrome,
(iii) neurodegenerative diseases and disorders selected from Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington's disease, multiple sclerosis, Parkinson's disease, prion diseases, and tauopathies,
(iv) neoplastic diseases selected from brain cancer, breast cancer, cervix cancer, colon cancer, liver cancer, lung cancer, esophageal cancer, prostate cancer, and skin cancer,
(v) infectious diseases selected from infections caused by human immunodeficiency virus type 1, influenza A virus, hepatitis C virus, Epstein-Barr virus, herpes simplex virus 1, severe acute respiratory syndrome coronavirus, and severe acute respiratory syndrome coronavirus 2,
(vi) traumatic brain injury,
(vii) neuropathic pain,
(viii) metabolic diseases selected from non-alcoholic steatohepatitis and non-alcoholic fatty liver disease,
(ix) ocular diseases selected from neovascular glaucoma, and neovascular age-related macular degeneration (AMD),
(x) organ fibrosis selected from liver fibrosis, lung fibrosis, and kidney fibrosis,
(xi) myocardial infarction,
(xii) arrhythmias, atherosclerosis,
(xiii) spinal cord injury, and
(xiv) ischemic stroke.

48 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/759,490Filed 26 Jan 2021
Priority: EP 2015403128 Jan 2020
Published: US 2023/0125481 A127 Apr 2023
Granted: 25 Aug 2026
Term ends: Not estimatedThe source records don’t support an estimate.

Classification27 codes

A61K 31/454
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
C07D 413/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61K 31/4545
Containing further heterocyclic ring systems: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
A61K 31/55
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having seven-membered rings, e.g. azelastine, pentylenetetrazole

Family

US 2023/0125481 A1Pre-grant publication · published 27 Apr 2023
US 12,715,865 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of formula (I)

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein
X1 is C(Ra6) or N;
X1a is a covalent single bond, CH(Ra3), O, N(Ra7), or CH(Ra3)CH2;
Ra1, Ra2, and Ra3 are independently selected from the group consisting of H, halogen, OH, O—C1-4 alkyl, C1-4 alkyl, and A2a,
and Ra4, Ra5, and Ra6 are independently selected from the group consisting of H, halogen, C1-4 alkyl, and A2a, provided that only one of Rai, Ra2, Ra3, Ra4, Ra5, and Ra6 is A2a;
optionally Ra1 and Ra2 form a covalent single bond;
optionally Ra2 and Ra4 form a methylene group;
optionally Ra4 and Ra6 form an ethylene group;
optionally Ra4 and Ra5 are joined to form an oxo group;
Ra7 is H, C(O)OC1-4 alkyl, or C1-4 alkyl, wherein C(O)OC1-4 alkyl and C1-4 alkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, OH, and O—C1-3 alkyl, wherein the substituents are the same or different;
A1 is C5 cycloalkylene, C5 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 A1 is optionally substituted with one or more R4, which are the same or different;
each R4 is independently oxo (═O) where the ring is at least partially saturated, thiooxo (═S) where the ring is at least partially saturated, halogen, CN, OR5, or C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
R5 is H or C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
A2 is R6a or A2a;
R6a is OR6a1, SR6a1, N(R6a1R6a2), C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OR6a3, and A2a, wherein the substituents are the same or different;
R6a1 and R6a2 are independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and A2a, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OR6a3, and A2a, wherein the substituents are the same or different;
R6a3 is H or C1-4 alkyl, wherein C1-4 alkyl is optionally substituted with one or more halogen, which are the same or different;
A2a is phenyl or 3 to 7 membered heterocyclyl, wherein A2a is optionally substituted with one or more R6, which are the same or different;
each R6 is independently R6b, OH, OR6b, halogen, or CN, wherein R6b is cyclopropyl, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, and wherein R6b is optionally substituted with one or more halogen, which are the same or different;
or
two R6 are joined to form together with the atoms to which they are attached a ring A2b;
A2b is phenyl or 3 to 7 membered heterocyclyl, wherein A2b is optionally substituted with one or more R7, which are the same or different;
each R7 is independently C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
R1 is H or C1-4 alkyl, wherein C1-4 alkyl is optionally substituted with one or more halogen, which are the same or different;
R2 is H, F, or C1-4 alkyl, wherein C1-4 alkyl is optionally substituted with one or more halogen, which are the same or different;
and
R3 is A3, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more R8, which are the same or different;
or
R2 and R3 are joined to form together with the oxygen atom and carbon atom to which they are attached a ring A3a, wherein A3a is a 7 to 12 membered heterobicyclyl, wherein 7 to 12 membered heterobicyclyl is optionally substituted with one or more R10, which are the same or different;
R2a is H or F;
each R8 is independently halogen, CN, C(O)OR9, OR9, C(O)R9, C(O)N(R9R9a), S(O)2N(R9R9a), S(O)N(R9R9a), S(O)2R9, S(O)R9, N(R9)S(O)2N(R9aR9b), SR9, N(R9R9a), NO2, OC(O)R9, N(R9)C(O)R9a, N(R9)SO2R9a, N(R9)S(O)R9a, N(R9)C(O)N(R9aR9b), N(R9)C(O)OR9a, OC(O)N(R9R9a), or A3;
R9, R9a, and R9b are independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different, or one OH, or one OC1-4 alkyl, or one A3;
each A3 is independently phenyl, naphthyl, 3 to 7 membered heterocyclyl, or 7 to 12 membered heterobicyclyl, wherein A3 is optionally substituted with one or more R10, which are the same or different;
each R10 is independently halogen, CN, C(O)OR11, OR11, C(O)R11, C(O)N(R11R11a), S(O)2N(R11R11a), S(O)N(R11R11a), S(O)2R11, S(O)R11, N(R11)S(O)2N(R11aR11b), SR11, N(R11R11a), NO2, OC(O)R11, N(R11)C(O)R11a, N(R11)S(O)2R11a, N(R11)S(O)R11a, N(R11)C(O)OR11a, N(R11)C(O)N(R11aR11b), OC(O)N(R11R11a), oxo (═O) where the ring is at least partially saturated, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more R12, which are the same or different;
R11, R11a, and R11b are independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
each R12 is independently halogen, CN, C(O)OR13, OR13, C(O)R13, C(O)N(R13R13a), S(O)2N(R13R13a), S(O)N(R13R13a), S(O)2R13, S(O)R13, N(R13)S(O)2N(R13aR13b), SR13, N(R13R13a), NO2, OC(O)R13, N(R13)C(O)R13a, N(R13)SO2R13a, N(R13)S(O)R13a N(R13)C(O)N(R13aR13b), N(R13)C(O)OR13a, or OC(O)N(R13R13a);
R13, R13a, and R13b are independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 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:

34 more elements

Facts

Application

17/759,490Filed 26 Jan 2021

Priority

EP 2015403128 Jan 2020

Published

US 2023/0125481 A127 Apr 2023

Granted

25 Aug 2026

Term ends

Not estimatedThe source records don’t support an estimate.

Classification27 codes

A61K 31/454
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
C07D 413/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61K 31/4545
Containing further heterocyclic ring systems: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
A61K 31/55
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having seven-membered rings, e.g. azelastine, pentylenetetrazole