Ether linked triazoles as nrf2 activators

Patent metadata

Field	Value
Publication number	US-2025084077-A1
Application number	US-202418808878-A
Country	US
Kind code	A1
Filing date	Aug 19, 2024
Priority date	Dec 15, 2016
Publication date	Mar 13, 2025
Grant date	—

Abstract

The present invention relates to ether-linked triazole compounds, methods of making them, pharmaceutical compositions containing them and their use as NRF2 activators. In particular, the invention relates to compounds of Formula(I), and pharmaceutically acceptable salts thereof:

First claim

1 . A compound of Formula (I):

wherein:
B is —O(CH 2 )-triazolyl, —O(CH 2 ) m , —O(CH 2 ) m -oxazolyl, —O(CH 2 ) m -oxadiazolyl and —O(CH 2 ) m -isoxazolyl, wherein each of the —O(CH 2 )-triazolyl, —O(CH 2 ) m , —O(CH 2 ) m , —O(CH 2 ) m -oxazolyl, —O(CH 2 ) m -oxadiazolyl or —O(CH 2 ) m -isoxazolyl is unsubstituted or substituted by 1 or 2 substituents independently selected from —C 1-6 alkyl, —(CH 2 ) m —O—C 1-3 alkyl, —(CH 2 ) n —C 3-7 cycloalkyl, —(CH 2 ) m —C 4-7 heterocycloalkyl, —(CH 2 ) n -phenyl, —(CH 2 ) n -phenyl-(CH 2 ) n -aryl, —(CH 2 ) n -phenyl-(CH 2 ) n -heteroaryl, —(CH 2 ) n —C 3-7 cycloalkyl, —(CH 2 ) n —C 3-7 heterocycloalkyl, —(CH 2 ) n —C 3-7 heterocycloalkyl-(CH 2 ) n —C 3-7 heterocycloalkyl, —(CH 2 ) n —C 3-7 heterocycloalkyl-C(O)R′, —(CH 2 ) n —C 3-7 heterocycloalkyl-C(O) C 3-7 heterocycloalkyl, —(CH 2 ) n —C 3-7 heterocycloalkyl-C(O)—C 3-7 cycloalkyl, —(CH 2 ) n —C 3-7 heterocycloalkyl-C(O)aryl, —(CH 2 ) n -phenyl-(CH 2 ) n —C 4-7 heterocycloalkyl, —(CH 2 ) 2 —O—(CH 2 ) 2 —OR 4 , CN, C 1-6 alkylNR 4 R 5 , C 1-6 alkylNC(O)R 7 , C 1-6 alkylNC(O)OR 4 and halo and wherein each of the moieties —(CH 2 ) n -phenyl, —(CH 2 ) n -phenyl-(CH 2 ) n -aryl, —(CH 2 ) n -phenyl-(CH 2 ) n -heteroaryl, —(CH 2 ) n —C 3-7 cycloalkyl, —(CH 2 ) n —C 3-7 heterocycloalkyl, —(CH 2 ) n —C 3-7 heterocycloalkyl-(CH 2 ) n —C 3-7 heterocycloalkyl, —(CH 2 ) n —C 3-7 heterocycloalkyl-C(O)R′, —(CH 2 ) n —C 3-7 heterocycloalkyl-C(O) C 3-7 heterocycloalkyl, —(CH 2 ) n —C 3-7 heterocycloalkyl-C(O)—C 3-7 cycloalkyl, —(CH 2 ) n —C 3-7 heterocycloalkyl-C(O)aryl, —(CH 2 ) n -phenyl-(CH 2 ) n —C 4-7 heterocycloalkyl, —(CH 2 ) 2 —O—(CH 2 ) 2 —OR 4 are unsubstituted or further substituted by 1, 2 or 3 substituents independently selected from —C 1-4 alkyl, —SO 2 R 4 , halo, —(CH 2 ) n , —(CH 2 ) n C(O)OR 4 , —(CH 2 ) m OH, —C(O)R 7 ;
D is —C(O)OH, —C(O)CR′, —C(O)NHSO 2 CH 3 , —SO 2 NHC(O)CH 3 , 5-(trifluoromethyl)-4H-1,2,4-triazol-2-yl, or tetrazolyl;
R 1 is independently hydrogen, —OH, —C 1-3 alkyl, —C 1-3 alkylOR′, F, —C 3-6 spirocycloalkyl, oxetane, or the two R 1 groups together with the carbon to which they are attached form a cyclopropyl group;
R′ is hydrogen, —C 1-4 alkyl or —NH 2 ;
R 2 is hydrogen, —C 1-4 alkyl, —CF 3 , or halo;
R 3 is —(CH 2 ) m ;
R 4 is hydrogen or —C 1-3 alkyl;
or, when R 2 is —C 1-4 alkyl, R 3 is —(CH 2 ) m —, and m is 2 or 3, R 2 and R 3 together form a cycloalkyl ring fused to the phenyl ring to which they are attached;
A is tetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl, piperidinyl, tetrahydrobenzazepinyl, phenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, tetrahydropyrrolopyrazinyl, imidazopyridinyl, pyridyl, benzimidazolyl, tetrahydrobenzodiazepinyl, piperidopyrimidinyl, dioxidotetrahydrothiophenyl, tetrahydroimidazodiazepinyl, pyrrolidinyl, oxazepane or morpholinyl;
wherein each of tetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl, piperidinyl, tetrahydrobenzazepinyl, phenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, tetrahydropyrrolopyrazinyl, imidazopyridinyl, pyridyl, benzimidazolyl, tetrahydrobenzodiazepinyl, piperidopyrimidinyl, dioxidotetrahydrothiophenyl, tetrahydroimidazodiazepinyl, pyrrolidinyl, oxazepane or morpholinyl is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C 1-3 alkyl, —C 3-6 spirocycloalkyl, halo, CN, —O—C 1-3 alkyl, —CH 2 —O—CH 3 , and OH;
and wherein the piperidinyl is further unsubstituted or substituted by a substituent independently selected from pyrazolyl, —CH 2 pyrazolyl, and oxadiazolyl each of which is unsubstituted or substituted by —C 1-3 alkyl, or, when A is piperidinyl, it is unsubstituted or substituted by —SO 2 R, wherein R is C 1-3 alkyl, phenyl or C 3-7 cycloalkyl;
and wherein the oxazepane is further unsubstituted or substituted by 1 or 2 substituents independently selected from —C 1-3 alkyl and —C 3-7 cycloalkyl;
and wherein the morpholinyl is further unsubstituted or substituted by phenyl which phenyl is unsubstituted or independently substituted by a substituent selected from C 1-3 alkyl and —O—C 1-3 alkyl;
and wherein the pyrrolidinyl is further optionally substituted by a triazolyl group which is optionally substituted by —C 1-3 alkyl;
and wherein the imidazolyl, triazolyl, pyrazolyl, and tetrazolyl groups each are further unsubstituted or substituted by 1, 2 or 3 substituents independently selected from —CH 2 —C 4-7 cycloalkyl, —CH 2 —C 5-7 heterocycloalkyl, —CH 2 -azabicycloheptanyl, —CH 2 -oxepane, and —CH 2 — azabicyclohexanyl, and wherein each of —CH 2 —C 4-7 cycloalkyl, —CH 2 —C 5-7 heterocycloalkyl, —CH 2 — azabicycloheptanyl, —CH 2 -oxepane, or —CH 2 -azabicyclohexanyl, including the —CH 2 —, are further unsubstituted or substituted by 1 or 2 substituents independently selected from —C 1-3 alkyl and F; or, A is,

R 5 is hydrogen or C 1-5 alkyl;
R 6 is hydrogen or —C 1-4 alkyl;
R 7 is hydrogen, aryl, heteroaryl, C 5-10 heterocycloalkyl, —C 1-4 alkyl or —C 3-7 cycloalkyl;
X is independently CH or N;
Y is independently CH or N;
Z is O, CH 2 , NR 5 , S, S(O), SO 2 ;
wherein, when A is,

 A is unsubstituted of substituted by one, two or three substituents independently selected from halo, —CF 3 , —C 1-4 alkyl, —CN, —OMe, —C(O)NH 2 , —OCF 3 , and —C 1-4 alkylNR 6 R 8 ;
R 8 is hydrogen, —C 1-5 alkyl, —C 3-7 cycloalkyl, —C 4-8 heterocycloalkyl, —C 1-5 alkoxy, —C 1-3 alkyl-O—C 1 -3alkyl, —C 1-3 alkyl-NH—C 1-3 alkyl, —C 1-3 alkyl-SO 2 C 1-3 alkyl, —C 1-3 alkyl-C 4 -8heterocycloalkyl, —C 1-3 alkyl-C(O)NR 5 R 6 , or heteroaryl, wherein each of —C 1-5 alkyl, —C 3-7 cycloalkyl, —C 4-7 heterocycloalkyl, —C 1-5 alkoxy, —C 1-3 alkyl-O—C 1-3 alkyl, —C 1-3 alkyl-NH—C 1-3 alkyl, —C 1-3 alkyl-C(O)NR 5 R 6 , or heteroaryl is unsubstituted or substituted by one or two substituents independently selected from —OH,
—CO 2 H, —C(O)NR 5 R 6 , —C(O)OR 5 , —N—C(O)—C 1-3 alkyl, F, —CN, —CH—F 2 , —CF 3 , —(CH 2 ) n —O—(CH 2 ) m —CH 3 , and —C 3-7 cycloalkyl, a 5-6-membered heteroaryl ring containing 1, 2 or 3 heteroatoms selected from O, N and S;
R 9 is -phenyl, —C 3-7 cycloalkyl, —C 3-7 heterocycloalkyl containing 1 or 2 heteroatoms selected from O, N and S, -5-10-membered aryl ring or a -5-10-membered heteroaryl ring, containing 1, 2 or 3 heteroatoms selected from O, N and S, wherein each of -phenyl, —C 3-7 cycloalkyl, —C 3-7 heterocycloalkyl containing 1 or 2 heteroatoms selected from O, N and S, -5-10-membered aryl ring or a -5-10-membered heteroaryl ring, containing 1, 2 or 3 heteroatoms selected from O, N and S is unsubstituted or independently substituted by one or two substituents selected from halo, —C(O)OH, —CF 3 , —C 1-4 alkyl, —CN, —OMe, —C(O)NH 2 , —OCF 3 , and —C 1-4 alkylNR 6 R 8 ;
R 10 is independently selected from hydrogen, halo, —C(O)OH, —CF 3 , —C 1-4 alkyl, —CN, —OMe, —C(O)NH 2 , —OCF 3 , and —C 1-4 alkylNR 6 R 8 ;
m is 1, 2, 3 or 4; and
n is 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.

2 . A compound of claim 1 wherein:
B is —O(CH 2 )-triazolyl wherein the —O(CH 2 ) 2 triazolyl is unsubstituted or substituted by 1 or 2 substituents independently selected from —C 1-6 alkyl, —(CH 2 ) n -phenyl, —(CH 2 ) n —C 3-7 heterocycloalkyl, —(CH 2 ) n -phenyl-(CH 2 ) n -aryl and —(CH 2 ) n -phenyl-(CH 2 ) n -heteroaryl, and wherein each of —C 1-6 alkyl, —(CH 2 ) n -phe

Assignees

• Astex Therapeutics Ltd

Inventors

• Cooper Anthony William James
• Goodwin Nicole Cathleen
• Griffiths-Jones Charlotte Mary
• Heightman Thomas Daniel
• Kerns Jeffrey K
• Willems Hendrika Maria Gerarda
• Yan Hongxing

Classifications

• C07D513/04

  Ortho-condensed systems · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D419/14 Primary

  containing three or more hetero rings · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D249/04

  1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles · CPC title