US2023047589A1PendingUtilityA1
Inhibitors of integrated stress response pathway
Est. expiryDec 13, 2037(~11.4 yrs left)· nominal 20-yr term from priority
Inventors:Sebastian BernalesLuz Marina Delgado OyarzoGonzalo Esteban Núñez VasquezGonzalo Andrés Ureta DíazBrahmam PujalaDayanand PanpatilBhawana BhattSarvajit Chakravarty
C07D 401/12C07D 491/048C07D 211/58A61P 21/00C07D 265/36C07C 235/36A61K 31/428A61P 35/00C07D 413/12C12N 5/0018A61P 25/28C07C 231/12C07D 263/24C07D 215/18C07D 307/85C07D 277/68A61P 29/00C07D 405/12A61K 31/4525A61K 31/445C07C 231/14C12N 2500/32A61K 31/343
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Claims
Abstract
The present disclosure relates generally to therapeutic agents that may be useful as inhibitors of Integrated Stress Response (ISR) pathway.
Claims
exact text as granted — not AI-modified1 - 9 . (canceled)
10 . A compound of formula (XX-I-2):
or a pharmaceutically acceptable salt thereof;
wherein:
R Y5 is hydrogen or C 1 -C 6 alkyl;
R N is hydrogen or C 1 -C 6 alkyl;
A 13 is selected from the group consisting of:
C 6 -C 10 aryl optionally substituted with one or more R 95 substituents; and
5-10 membered heteroaryl optionally substituted with one or more R 95 substituents;
R 95 is selected, independently at each occurrence, from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OH, —O(C 1 -C 6 alkyl), —O(C 1 -C 6 haloalkyl), —SH, —S(C 1 -C 6 alkyl), —S(C 1 -C 6 haloalkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —NH(C 1 -C 6 haloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 haloalkyl) 2 , —NR 95-a R 95-b , —CN, —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)O(C 1 -C 6 haloalkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)NH(C 1 -C 6 haloalkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —C(O)N(C 1 -C 6 haloalkyl), —C(O)NR 95-a R 95-b , —S(O) 2 OH, —S(O) 2 O(C 1 -C 6 alkyl), —S(O) 2 O(C 1 -C 6 haloalkyl), —S(O) 2 NH 2 , —S(O) 2 NH(C 1 -C 6 alkyl), —S(O) 2 NH(C 1 -C 6 haloalkyl), —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 N(C 1 -C 6 haloalkyl) 2 , —S(O) 2 NR 95-a R 95-b , —OC(O)H, —OC(O)(C 1 -C 6 alkyl), —OC(O)(C 1 -C 6 haloalkyl), —N(H)C(O)H, —N(H)C(O)(C 1 -C 6 alkyl), —N(H)C(O)(C 1 -C 6 haloalkyl), —N(C 1 -C 6 alkyl)C(O)H, —N(C 1 -C 6 alkyl)C(O)(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)C(O)(C 1 -C 6 haloalkyl), —N(C 1 -C 6 haloalkyl)C(O)H, —N(C 1 -C 6 haloalkyl)C(O)(C 1 -C 6 alkyl), —N(C 1 -C 6 haloalkyl)C(O)(C 1 -C 6 haloalkyl), —OS(O) 2 (C 1 -C 6 alkyl), —OS(O) 2 (C 1 -C 6 haloalkyl), —N(H)S(O) 2 (C 1 -C 6 alkyl), —N(H)S(O) 2 (C 1 -C 6 haloalkyl), —N(C 1 -C 6 alkyl)S(O) 2 (C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)S(O) 2 (C 1 -C 6 haloalkyl), —N(C 1 -C 6 haloalkyl)S(O) 2 (C 1 -C 6 alkyl), and —N(C 1 -C 6 haloalkyl)S(O) 2 (C 1 -C 6 haloalkyl);
wherein R 95-a and R 95-b are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;
R 88 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —C(O)(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 haloalkyl), —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)O(C 1 -C 6 haloalkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)NH(C 1 -C 6 haloalkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —C(O)N(C 1 -C 6 haloalkyl) 2 , —C(O)NR 88-a R 88-b , —S(O) 2 OH, —S(O) 2 O(C 1 -C 6 alkyl), —S(O) 2 O(C 1 -C 6 haloalkyl), —S(O) 2 NH 2 , —S(O) 2 NH(C 1 -C 6 alkyl), —S(O) 2 NH(C 1 -C 6 haloalkyl), —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 N(C 1 -C 6 haloalkyl), and —S(O) 2 NR 88-a R 88-b ;
wherein R 88-a and R 88-b are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;
R 89 is selected, independently at each occurrence, from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OH, —O(C 1 -C 6 alkyl), —O(C 1 -C 6 haloalkyl), —SH, —S(C 1 -C 6 alkyl), —S(C 1 -C 6 haloalkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —NH(C 1 -C 6 haloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 haloalkyl) 2 , —NR 89-a R 89-b , —CN, —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)O(C 1 -C 6 haloalkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)NH(C 1 -C 6 haloalkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —C(O)N(C 1 -C 6 haloalkyl) 2 , —C(O)NR 89-a R 89-b , —S(O) 2 OH, —S(O) 2 O(C 1 -C 6 alkyl), —S(O) 2 O(C 1 -C 6 haloalkyl), —S(O) 2 NH 2 , —S(O) 2 NH(C 1 -C 6 alkyl), —S(O) 2 NH(C 1 -C 6 haloalkyl), —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 N(C 1 -C 6 haloalkyl) 2 , —S(O) 2 NR 89-a R 89-b , —OC(O)H, —OC(O)(C 1 -C 6 alkyl), —OC(O)(C 1 -C 6 haloalkyl), —N(H)C(O)H, —N(H)C(O)(C 1 -C 6 alkyl), —N(H)C(O)(C 1 -C 6 haloalkyl), —N(C 1 -C 6 alkyl)C(O)H, —N(C 1 -C 6 alkyl)C(O)(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)C(O)(C 1 -C 6 haloalkyl), —N(C 1 -C 6 haloalkyl)C(O)H, —N(C 1 -C 6 haloalkyl)C(O)(C 1 -C 6 alkyl), —N(C 1 -C 6 haloalkyl)C(O)(C 1 -C 6 haloalkyl), —OS(O) 2 (C 1 -C 6 alkyl), —OS(O) 2 (C 1 -C 6 haloalkyl), —N(H)S(O) 2 (C 1 -C 6 alkyl), —N(H)S(O) 2 (C 1 -C 6 haloalkyl), —N(C 1 -C 6 alkyl)S(O) 2 (C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)S(O) 2 (C 1 -C 6 haloalkyl), —N(C 1 -C 6 haloalkyl)S(O) 2 (C 1 -C 6 alkyl), and —N(C 1 -C 6 haloalkyl)S(O) 2 (C 1 -C 6 haloalkyl),
wherein R 89-a and R 89-b are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle.
11 - 15 . (canceled)
16 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
17 . A pharmaceutical composition comprising a compound of claim 10 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
18 . A method of treating a disease or disorder mediated by an integrated stress response (ISR) pathway in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of claim 10 , or a pharmaceutically acceptable salt thereof.
19 . A method of producing a protein, comprising contacting a eukaryotic cell comprising a nucleic acid encoding the protein with the compound of claim 10 , or a salt thereof.
20 . A method of culturing a eukaryotic cell comprising a nucleic acid encoding a protein, comprising contacting the eukaryotic cell with an in vitro culture medium comprising the compound of claim 10 , or a salt thereof.
21 . A method of producing a protein, comprising contacting a cell-free protein synthesis (CFPS) system comprising eukaryotic initiation factor 2 (eIF2) and a nucleic acid encoding a protein with the compound of claim 10 , or a salt thereof.
22 . An in vitro cell culture medium, comprising the compound of claim 10 , or a salt thereof and nutrients for cellular growth.
23 . A cell-free protein synthesis (CFPS) system comprising eukaryotic initiation factor 2 (eIF2) and a nucleic acid encoding a protein with the compound of claim 10 , or a salt thereof.
24 . The method of claim 18 , wherein the disease or disorder mediated by an integrated stress response (ISR) pathway is a neurodegenerative disease, an inflammatory disease, an autoimmune disease, a metabolic syndrome, a cancer, a vascular disease, a musculoskeletal disease, an ocular disease, or a genetic disorder.
25 . The method of claim 24 , wherein the disease or disorder mediated by an integrated stress response (ISR) pathway is a neurodegenerative disease.
26 . The method of claim 25 , wherein the neurodegenerative disease is vanishing white matter disease.
27 . The method of claim 25 , wherein the neurodegenerative disease is amyotrophic lateral sclerosis (ALS).
28 . The method of claim 25 , wherein the neurodegenerative disease is frontotemporal dementia (FTD).
29 . The method of claim 24 , wherein the disease or disorder mediated by an integrated stress response (ISR) pathway is an inflammatory disease.
30 . The method of claim 24 , wherein the disease or disorder mediated by an integrated stress response (ISR) pathway is an autoimmune disease.
31 . The method of claim 24 , wherein the disease or disorder mediated by an integrated stress response (ISR) pathway is a metabolic syndrome.
32 . The method of claim 24 , wherein the disease or disorder mediated by an integrated stress response (ISR) pathway is a cancer.
33 . The method of claim 32 , wherein the cancer is prostate cancer.
34 . The method of claim 24 , wherein the disease or disorder mediated by an integrated stress response (ISR) pathway is a musculoskeletal disease.
35 . The method of claim 34 , wherein the musculoskeletal disease is muscular atrophy.
36 . The method of claim 24 , wherein the disease or disorder mediated by an integrated stress response (ISR) pathway is a genetic disorder.
37 . The method of claim 36 , wherein the genetic disorder is Down syndrome.
38 . The method of claim 24 , wherein the disease or disorder mediated by an integrated stress response (ISR) pathway is a vascular disease.
39 . The method of claim 24 , wherein the disease or disorder mediated by an integrated stress response (ISR) pathway is an ocular disease.
40 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R Y5 is hydrogen.
41 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R N is hydrogen.
42 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein A 13 is C 6 -C 10 aryl optionally substituted with one or more R 95 substituents.
43 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein A 13 is selected from the group consisting of
wherein the * represents the attachment point to the remainder of the molecule.
44 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein A 13 is selected from the group consisting of
wherein the * represents the attachment point to the remainder of the molecule.
45 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein A 13 is
wherein the * represents the attachment point to the remainder of the molecule.
46 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein A 13 is
wherein the * represents the attachment point to the remainder of the molecule.
47 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 88 is hydrogen.
48 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 89 is selected, independently at each occurrence, from the group consisting of hydrogen and halogen.
49 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein the moiety
wherein # represents the attachment point to the remainder of the molecule, is
wherein # represents the attachment point to the remainder of the molecule.
50 . A compound of formula (1-3):
or a pharmaceutically acceptable salt thereof;
wherein:
X 2 is CH or N;
R Y1 is hydrogen or C 1 -C 6 alkyl;
Y 2 is selected from the group consisting of a bond, NR Y2 , and O; provided that when X 2 is N, then Y 2 is a bond;
R Y2 is hydrogen or C 1 -C 6 alkyl;
r and s, independently of each other, are 0, 1, or 2;
A 1 is selected from the group consisting of:
a substituent of formula (A 1 -a)
wherein
* represents the attachment point to the remainder of the molecule;
Z 1 is selected from the group consisting of CR Z1-1 R Z1-2 , NR Z1-2 O, S, and —CR Z1-1 ═CR Z1-1 —;
wherein R Z1-1 is H or R″; and R Z1-2 is H or R 14 ;
Z 2 is selected from the group consisting of CR Z2-1 R Z2-2 , NR Z2-2 ; O, S, and —CR Z2-1 ═CR Z2-1 —;
wherein R Z2-1 is H or R 14 ; and R Z2-2 is H or R 14 ;
Z 3 , independently at each occurrence, is C or N, provided that at least one Z 3 is C;
R 13 is hydrogen or R 14 , or R 13 and R Z1-2 are taken together to form a double bond between the carbon atom bearing R 13 and Z 1 , or R 13 and R Z2-2 are taken together to form a double bond between the carbon atom bearing R 13 and Z 2 ; and
x1 is 1, 2, 3, or 4, and at least one R 14 is halogen;
R 14 is selected, independently at each occurrence, from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OH, —O(C 1 -C 6 alkyl), —O(C 1 -C 6 haloalkyl), —SH, —S(C 1 -C 6 alkyl), —S(C 1 -C 6 haloalkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —NH(C 1 -C 6 haloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 haloalkyl) 2 , —NR 14-a R 14-b , —CN, —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)O(C 1 -C 6 haloalkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)NH(C 1 -C 6 haloalkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —C(O)N(C 1 -C 6 haloalkyl) 2 , —C(O)NR 14-a R 14-b , —S(O) 2 OH, —S(O) 2 O(C 1 -C 6 alkyl), —S(O) 2 O(C 1 -C 6 haloalkyl), —S(O) 2 NH 2 , —S(O) 2 NH(C 1 -C 6 alkyl), —S(O) 2 NH(C 1 -C 6 haloalkyl), —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 N(C 1 -C 6 haloalkyl) 2 , —S(O) 2 NR 14-a R 14-b , —OC(O)H, —OC(O)(C 1 -C 6 alkyl), —OC(O)(C 1 -C 6 haloalkyl), —N(H)C(O)H, —N(H)C(O)(C 1 -C 6 alkyl), —N(H)C(O)(C 1 -C 6 haloalkyl), —N(C 1 -C 6 alkyl)C(O)H, —N(C 1 -C 6 alkyl)C(O)(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)C(O)(C 1 -C 6 haloalkyl), —N(C 1 -C 6 haloalkyl)C(O)H, —N(C 1 -C 6 haloalkyl)C(O)(C 1 -C 6 alkyl), —N(C 1 -C 6 haloalkyl)C(O)(C 1 -C 6 haloalkyl), —OS(O) 2 (C 1 -C 6 alkyl), —OS(O) 2 (C 1 -C 6 haloalkyl), —N(H)S(O) 2 (C 1 -C 6 alkyl), —N(H)S(O) 2 (C 1 -C 6 haloalkyl), —N(C 1 -C 6 alkyl)S(O) 2 (C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)S(O) 2 (C 1 -C 6 haloalkyl), —N(C 1 -C 6 haloalkyl)S(O) 2 (C 1 -C 6 alkyl), and —N(C 1 -C 6 haloalkyl)S(O) 2 (C 1 -C 6 haloalkyl);
wherein R 14-a and R 14-b are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;
A 2 is C 6 -C 10 aryl substituted by at least one halogen substituent and optionally further substituted with one or more R 16 substituents, or 5-10 membered heteroaryl substituted by at least one halogen substituent and optionally further substituted with one or more R 16 substituents;
R 16 is selected, independently at each occurrence, from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OH, —O(C 1 -C 6 alkyl), —O(C 1 -C 6 haloalkyl), —SH, —S(C 1 -C 6 alkyl), —S(C 1 -C 6 haloalkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —NH(C 1 -C 6 haloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 haloalkyl) 2 , —NR 16-a R 16-b , —CN, —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)O(C 1 -C 6 haloalkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)NH(C 1 -C 6 haloalkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —C(O)N(C 1 -C 6 haloalkyl) 2 , —C(O)NR 16-a R 16-b , —S(O) 2 OH, —S(O) 2 O(C 1 -C 6 alkyl), —S(O) 2 O(C 1 -C 6 haloalkyl), —S(O) 2 NH 2 , —S(O) 2 NH(C 1 -C 6 alkyl), —S(O) 2 NH(C 1 -C 6 haloalkyl), —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 N(C 1 -C 6 haloalkyl) 2 , —S(O) 2 NR 16-a R 16-b , —OC(O)H, —OC(O)(C 1 -C 6 alkyl), —OC(O)(C 1 -C 6 haloalkyl), —N(H)C(O)H, —N(H)C(O)(C 1 -C 6 alkyl), —N(H)C(O)(C 1 -C 6 haloalkyl), —N(C 1 -C 6 alkyl)C(O)H, —N(C 1 -C 6 alkyl)C(O)(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)C(O)(C 1 -C 6 haloalkyl), —N(C 1 -C 6 haloalkyl)C(O)H, —N(C 1 -C 6 haloalkyl)C(O)(C 1 -C 6 alkyl), —N(C 1 -C 6 haloalkyl)C(O)(C 1 -C 6 haloalkyl), —OS(O) 2 (C 1 -C 6 alkyl), —OS(O) 2 (C 1 -C 6 haloalkyl), —N(H)S(O) 2 (C 1 -C 6 alkyl), —N(H)S(O) 2 (C 1 -C 6 haloalkyl), —N(C 1 -C 6 alkyl)S(O) 2 (C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)S(O) 2 (C 1 -C 6 haloalkyl), —N(C 1 -C 6 haloalkyl)S(O) 2 (C 1 -C 6 alkyl), and —N(C 1 -C 6 haloalkyl)S(O) 2 (C 1 -C 6 haloalkyl);
wherein R 16-a and R 16-b are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;
R 1a and R 1b are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and halogen;
R 2a and R 2b are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and halogen;
when present, R 3a and R 3b are independently at each occurrence selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and halogen;
when present, R 4a and R 4b are independently at each occurrence selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and halogen;
or alternatively, R 1a and R 2a are taken together to form a C 1 -C 6 alkylene moiety;
or alternatively, R 1a and an R 3a moiety, when present, are taken together to form a C 1 -C 6 alkylene moiety, and R 1b and the R 3b in the geminal position to the R 3a taken together with R 1a , are both hydrogen;
or alternatively, an R 3a moiety, when present, and an R 4a moiety, when present, are taken together to form a C 1 -C 6 alkylene moiety, and the R 3b in the geminal position to the R 3a taken together with the R 4a moiety and the R 4b in the geminal position to the R 4a taken together with the R 3a moiety, are both hydrogen;
R 9a and R 9b are taken together to form an oxo (═O) substituent or an imido (═NH) substituent, or alternatively, R 9a and R 9b are both hydrogen;
R 10a is selected from the group consisting of hydrogen, —OR 10a-a , and —NR 10a-b R 10a-c ;
R 10b is hydrogen;
R 12a and R 12b are taken together to form an oxo (═O) substituent, or alternatively, R 12a and R 12b are both hydrogen;
R 10a-a is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;
or R 10a-a and R Y2 may be taken together to form a carbonyl (C═O) moiety; and
R 10a-b and R 10a-c , independently of each other, are selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl.
51 . A compound of formula (2-3):
or a pharmaceutically acceptable salt thereof;
wherein:
X 1 and X 2 , independently of each other, are CH or N; provided that at least one of X 1 and X 2 is CH;
Y 1 is selected from the group consisting of a bond, NR Y1 , and O; provided that when X 1 is N, then Y 1 is a bond;
R Y1 is hydrogen or C 1 -C 6 alkyl;
Y 2 is selected from the group consisting of a bond, NR Y2 , and O; provided that when X 2 is N, then Y 2 is a bond;
R Y2 is hydrogen or C 1 -C 6 alkyl;
q1 is 1;
r and s, independently of each other, are 0, 1, or 2;
A 1 is C 6 -C 10 aryl substituted by at least one halogen substituent and optionally further substituted with one or more R 14 substituents, or 5-10 membered heteroaryl substituted by at least one halogen substituent and optionally further substituted with one or more R 14 substituents;
R 14 is selected, independently at each occurrence, from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OH, —O(C 1 -C 6 alkyl), —O(C 1 -C 6 haloalkyl), —SH, —S(C 1 -C 6 alkyl), —S(C 1 -C 6 haloalkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —NH(C 1 -C 6 haloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 haloalkyl) 2 , —NR 14-a R 14-b , —CN, —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)O(C 1 -C 6 haloalkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)NH(C 1 -C 6 haloalkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —C(O)N(C 1 -C 6 haloalkyl) 2 , —C(O)NR 14-a R 14-b , —S(O) 2 OH, —S(O) 2 O(C 1 -C 6 alkyl), —S(O) 2 O(C 1 -C 6 haloalkyl), —S(O) 2 NH 2 , —S(O) 2 NH(C 1 -C 6 alkyl), —S(O) 2 NH(C 1 -C 6 haloalkyl), —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 N(C 1 -C 6 haloalkyl) 2 , —S(O) 2 NR 14-a R 14-b , —OC(O)H, —OC(O)(C 1 -C 6 alkyl), —OC(O)(C 1 -C 6 haloalkyl), —N(H)C(O)H, —N(H)C(O)(C 1 -C 6 alkyl), —N(H)C(O)(C 1 -C 6 haloalkyl), —N(C 1 -C 6 alkyl)C(O)H, —N(C 1 -C 6 alkyl)C(O)(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)C(O)(C 1 -C 6 haloalkyl), —N(C 1 -C 6 haloalkyl)C(O)H, —N(C 1 -C 6 haloalkyl)C(O)(C 1 -C 6 alkyl), —N(C 1 -C 6 haloalkyl)C(O)(C 1 -C 6 haloalkyl), —OS(O) 2 (C 1 -C 6 alkyl), —OS(O) 2 (C 1 -C 6 haloalkyl), —N(H)S(O) 2 (C 1 -C 6 alkyl), —N(H)S(O) 2 (C 1 -C 6 haloalkyl), —N(C 1 -C 6 alkyl)S(O) 2 (C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)S(O) 2 (C 1 -C 6 haloalkyl), —N(C 1 -C 6 haloalkyl)S(O) 2 (C 1 -C 6 alkyl), and —N(C 1 -C 6 haloalkyl)S(O) 2 (C 1 -C 6 haloalkyl);
wherein R 14-a and R 14-b are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;
A 2 is C 6 -C 10 aryl substituted by at least one halogen substituent and optionally further substituted with one or more R 16 substituents, or 5-10 membered heteroaryl substituted by at least one halogen substituent and optionally further substituted with one or more R 16 substituents;
R 16 is selected, independently at each occurrence, from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OH, —O(C 1 -C 6 alkyl), —O(C 1 -C 6 haloalkyl), —SH, —S(C 1 -C 6 alkyl), —S(C 1 -C 6 haloalkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —NH(C 1 -C 6 haloalkyl), —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 haloalkyl) 2 , —NR 16-b , —CN, —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)O(C 1 -C 6 haloalkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)NH(C 1 -C 6 haloalkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —C(O)N(C 1 -C 6 haloalkyl) 2 , —C(O)NR 16-a R 16-b , —S(O) 2 OH, —S(O) 2 O(C 1 -C 6 alkyl), —S(O) 2 O(C 1 -C 6 haloalkyl), —S(O) 2 NH 2 , —S(O) 2 NH(C 1 -C 6 alkyl), —S(O) 2 NH(C 1 -C 6 haloalkyl), —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 N(C 1 -C 6 haloalkyl) 2 , —S(O) 2 NR 16-a R 16-b , —OC(O)H, —OC(O)(C 1 -C 6 alkyl), —OC(O)(C 1 -C 6 haloalkyl), —N(H)C(O)H, —N(H)C(O)(C 1 -C 6 alkyl), —N(H)C(O)(C 1 -C 6 haloalkyl), —N(C 1 -C 6 alkyl)C(O)H, —N(C 1 -C 6 alkyl)C(O)(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)C(O)(C 1 -C 6 haloalkyl), —N(C 1 -C 6 haloalkyl)C(O)H, —N(C 1 -C 6 haloalkyl)C(O)(C 1 -C 6 alkyl), —N(C 1 -C 6 haloalkyl)C(O)(C 1 -C 6 haloalkyl), —OS(O) 2 (C 1 -C 6 alkyl), —OS(O) 2 (C 1 -C 6 haloalkyl), —N(H)S(O) 2 (C 1 -C 6 alkyl), —N(H)S(O) 2 (C 1 -C 6 haloalkyl), —N(C 1 -C 6 alkyl)S(O) 2 (C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)S(O) 2 (C 1 -C 6 haloalkyl), —N(C 1 -C 6 haloalkyl)S(O) 2 (C 1 -C 6 alkyl), and —N(C 1 -C 6 haloalkyl)S(O) 2 (C 1 -C 6 haloalkyl);
wherein R 16-a and R 16-b are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;
R 1a and R 1b are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and halogen;
R 2a and R 2b are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and halogen;
when present, R 3a and R 3b are independently at each occurrence selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and halogen;
when present, R 4a and R 4b are independently at each occurrence selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and halogen;
or alternatively, R 1a and R 2a are taken together to form a C 1 -C 6 alkylene moiety;
or alternatively, R 1a and an R 3a moiety, when present, are taken together to form a C 1 -C 6 alkylene moiety, and R 1b and the R 3b in the geminal position to the R 3a taken together with R 1a , are both hydrogen;
or alternatively, an R 3a moiety, when present, and an R 4a moiety, when present, are taken together to form a C 1 -C 6 alkylene moiety, and the R 3b in the geminal position to the R 3a taken together with the R 4a moiety and the R 4b in the geminal position to the R 4a taken together with the R 3a moiety, are both hydrogen;
R 5a and R 5b are taken together to form an oxo (═O) substituent or an imido (═NH) substituent, or alternatively;
R 6a is hydrogen;
R 6b is hydrogen;
R 9a and R 9b are taken together to form an oxo (═O) substituent or an imido (═NH) substituent, or alternatively, R 9a and R 9b are both hydrogen;
R 10a is selected from the group consisting of hydrogen, —OR 10a-a , and —NR 10a-b R 10a-c ;
R 10b is hydrogen;
R 12a and R 12b are taken together to form an oxo (═O) substituent, or alternatively, R 12a and R 12b are both hydrogen;
R 10a-a is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;
or R 10a-a and R Y2 may be taken together to form a carbonyl (C═O) moiety;
R 10a-b and R 10a-c , independently of each other, are selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; and
provided that when X 2 is N, then:
A 1 is C 6 -C 10 aryl substituted by at least two halogen substituents and optionally further substituted with one or more 10 4 substituents, or 5-10 membered heteroaryl substituted by at least two halogen substituents and optionally further substituted with one or more R 14 substituents; and
A 2 is C 6 -C 10 aryl substituted by at least two halogen substituents and optionally further substituted with one or more 10 6 substituents, or 5-10 membered heteroaryl substituted by at least two halogen substituents and optionally further substituted with one or more R 16 substituents.Join the waitlist — get patent alerts
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