US2023248752A1PendingUtilityA1
Prodrugs of alox-15 inhibitors and methods of using the same
Est. expiryJan 15, 2039(~12.5 yrs left)· nominal 20-yr term from priority
A61K 31/675A61K 31/415C07D 231/10C07D 231/14
79
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Claims
Abstract
Described herein are compounds and pharmaceutical compositions containing such compounds which are prodrugs of ALOX-15 inhibitors. Also described herein are methods for using such compounds in the treatment of disease.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound having the structure of Formula (I) or Formula (II):
wherein:
R 1 is —P(O)(OH) 2 , —C(O)N(R 9 )C 2-6 alkyl-OC(O)R 7 ,
Ring A is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 2-9 heteroaryl;
Ring B is selected from C 2-9 heterocycloalkyl and C 2-9 heteroaryl;
R 2 , R 3 , R 4 , and R 5 are each independently selected from H, halogen, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, —OR 10 , —SR 10 , —N(R 10 ) 2 , —C(O)OR 10 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —N(R 11 )C(O)N(R 10 ) 2 , —N(R 11 )C(O)OR 10 , —N(R 11 )C(O)R 12 , —N(R 11 )S(O) 2 R 12 , —C(O)R 12 , —S(O)R 12 , —S(O) 2 R 12 , —S(O) 2 N(R 10 ) 2 , and —OC(O)R 12 , wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 13 ;
R 6 is selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;
R 7 is selected from C 1-6 alkyl or —C 1-6 alkyl-N(R 14 ) 2 ;
each R 8 is independently selected from halogen, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, —OR 10 , —SR 10 , —N(R 10 ) 2 , —C(O)OR 10 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —N(R 11 )C(O)N(R 10 ) 2 , —N(R 11 )C(O)OR 10 , —N(R 11 )C(O)R 12 , —N(R 11 )S(O) 2 R 12 , —C(O)R 12 , —S(O)R 12 , —S(O) 2 R 12 , —S(O) 2 N(R 10 ) 2 , and —OC(O)R 12 , wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 13 ;
R 9 is selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;
each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl;
each R 11 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;
each R 12 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 13 ;
each R 13 is independently selected from halogen, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, —OR 15 , —SR 15 , —N(R 16 )(R 17 ), —C(O)OR 16 , —C(O)N(R 16 )(R 17 ), —C(O)C(O)N(R 16 )(R 17 ), —OC(O)N(R 16 )(R 17 ), —N(R 18 )C(O)N(R 16 )(R 17 ), —N(R 18 )C(O)OR 19 , —N(R 18 )C(O)R 19 , —N(R 18 )S(O) 2 R 19 , —C(O)R 19 , —S(O) 2 R 19 , —S(O) 2 N(R 16 )(R 17 ), and —OC(O)R 19 , wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, —CH 2 —C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, —CH 2 —C 2-9 heterocycloalkyl, C 6-10 aryl, —CH 2 —C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —OR 15 , —SR 15 , —N(R 15 ) 2 , —C(O)OR 15 , —C(O)N(R 15 ) 2 , —C(O)C(O)N(R 15 ) 2 , —OC(O)N(R 15 ) 2 , —N(R 16 )C(O)N(R 15 ) 2 , —N(R 16 )C(O)OR 15 , —N(R 16 )C(O)R 17 , —N(R 16 )S(O) 2 R 17 , —C(O)R 17 , —S(O) 2 R 17 , —S(O) 2 N(R 15 ) 2 , and —OC(O)R 17 ;
each R 14 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;
each R 15 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl;
each R 16 is independently selected from H and C 1-6 alkyl;
each R 17 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl;
each R 18 is independently selected from H and C 1-6 alkyl;
each R 19 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl; and
n is 0, 1, 2, 3, or 4;
or a pharmaceutically acceptable salt or solvate thereof.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I):
3 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (II):
4 . The compound of any one of claims 1 - 3 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is
5 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ib):
6 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IIb):
7 . The compound of any one of claims 4 - 6 , or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C 2-9 heteroaryl.
8 . The compound of any one of claims 4 - 7 , or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C 2-9 heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
9 . The compound of any one of claims 4 - 8 , or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C 2-9 heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
10 . The compound of any one of claims 4 - 9 , or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is pyridinyl.
11 . The compound of any one of claims 4 - 6 , or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is phenyl.
12 . The compound of any one of claims 1 - 11 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is C 1-6 alkyl.
13 . The compound of any one of claims 1 - 3 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is
14 . The compound of claim 13 , or a pharmaceutically acceptable salt or solvate thereof, wherein Ring B is C 2-9 heteroaryl.
15 . The compound of claim 14 , or a pharmaceutically acceptable salt or solvate thereof, wherein Ring B is C 2-9 heteroaryl selected from pyrazolyl, pyrrolyl, and imidazolyl.
16 . The compound of claim 13 , or a pharmaceutically acceptable salt or solvate thereof, wherein Ring B is C 2-9 heterocycloalkyl.
17 . The compound of claim 16 , or a pharmaceutically acceptable salt or solvate thereof, wherein Ring B is C 2-9 heterocycloalkyl selected from pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl.
18 . The compound of any one of claims 1 - 17 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 8 is independently selected from halogen and unsubstituted C 1-6 alkyl.
19 . The compound of any one of claims 1 - 18 , or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2.
20 . The compound of any one of claims 1 - 17 , or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
21 . The compound of any one of claims 1 - 3 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is —C(O)N(R 9 )C 2-6 alkyl-OC(O)R 7 .
22 . The compound of any one of claims 1 - 21 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 is C 1-6 alkyl.
23 . The compound of any one of claims 1 - 21 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 is —C 1-6 alkyl-N(R 14 ) 2 .
24 . The compound of any one of claims 1 - 3 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is —P(O)(OH) 2 .
25 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ia):
26 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IIa):
27 . The compound of any one of claims 1 - 26 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 , R 3 , R 4 , and R 5 are each independently selected from H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 13 .
28 . The compound of any one of claims 1 - 27 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 , R 3 , R 4 , and R 5 are each independently selected from H, halogen, and C 1-6 alkyl optionally substituted with one, two, or three R 13 .
29 . The compound of any one of claims 1 - 28 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 , R 3 , R 4 , and R 5 are each independently selected from H and halogen.
30 . The compound of any one of claims 1 - 29 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 , R 3 , R 4 , and R 5 are each independently halogen.
31 . The compound of any one of claims 1 - 30 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is H.
32 . The compound of any one of claims 1 - 30 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is C 1-6 alkyl.
33 . A compound having the structure:
or a pharmaceutically acceptable salt or solvate thereof.
34 . A compound selected from:
or a pharmaceutically acceptable salt or solvate thereof.
35 . A compound selected from:
or a pharmaceutically acceptable salt or solvate thereof.
36 . A compound selected from:
or a pharmaceutically acceptable salt or solvate thereof.
37 . A compound selected from:
or a pharmaceutically acceptable salt or solvate thereof.
38 . A compound selected from:
or a pharmaceutically acceptable salt or solvate thereof.
39 . A pharmaceutical composition comprising a compound of any one of claims 1 - 38 , or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient.
40 . A method of treating an eosinophilic airway disease in a mammal in need thereof, comprising administering to the mammal a compound of any one of claims 1 - 38 , or a pharmaceutically acceptable salt or solvate thereof.
41 . The method of claim 40 , wherein the eosinophilic airway disease is selected from asthma, chronic rhinosinusitis, nasal polyposis, and allergic rhinitis.
42 . A method of treating an eosinophilic gastrointestinal disease in a mammal in need thereof, comprising administering to the mammal a compound of any one of claims 1 - 38 , or a pharmaceutically acceptable salt or solvate thereof.
43 . The method of claim 42 , wherein the eosinophilic gastrointestinal disease is selected from eosinophilic esophagitis and eosinophilic gastroenteritis.Cited by (0)
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