US2023047178A1PendingUtilityA1
Heteroaryl compounds and uses thereof
Est. expiryMay 9, 2038(~11.8 yrs left)· nominal 20-yr term from priority
C09K 19/3441C07D 401/10C07D 471/04A61P 25/28C07D 417/14C07D 487/04C09K 19/34C07D 498/04C07D 413/10A61K 2123/00C09K 19/3483C07D 495/04C07D 277/66G01N 33/6896C07D 417/10A61K 51/0431G01N 2800/2821A61K 51/0455A61K 49/0021C09K 19/3497A61K 51/04A61K 49/00
67
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
Described herein are compounds of formula (I), and pharmaceutically acceptable salts, solvates, hydrates, isotopically labeled derivatives and radiolabeled derivative thereof, and pharmaceutical compositions thereof. Also provided are methods and kits involving the inventive compounds or compositions for detecting and imaging Tau aggregates in the brain for detection of Alzheimer's disease (AD) in a subject.
Claims
exact text as granted — not AI-modified1 .- 15 . (canceled)
16 . A heteroaryl compound having a structure of formula (I), or a pharmaceutically acceptable salt, a solvate, a hydrate, an isotopically labeled derivative or a radiolabeled derivative thereof,
wherein, W is N—R or C—R 1 ;
R is absent or C 1-6 alkyl, and the C 1-6 alkyl of which is optionally substituted by the substituent selected from the group consisting of OH, halogen, C 3-6 heterocycloalkyloxy, toluenesulfonyloxy and phenyl which is further optionally substituted by C 1-3 alkoxy, OH or C 1-3 alkyl; the heteroatom contained in the C 3-6 heterocycloalkyloxy is selected from the group consisting of N, O and S;
R 1 is H, halogen, OH, NH 2 , C 1-6 alkoxycarbonyl, C 1-6 alkyl, C 1-6 alkylamino or C 1-6 alkoxy, and OH, NH 2 , C 1-6 alkoxycarbonyl, C 1-6 alkyl, C 1-6 alkylamino or C 1-6 alkoxy of which is optionally substituted by the substituent selected from the group consisting of halogen, OH, C 3-6 heterocycloalkyloxy and toluenesulfonyloxy;
T is C—R 3 or N;
R 3 is H, OH, C 1-6 alkoxy or halogen;
Z is N or C;
U is N—R 4 , S, O or C—R 5 ;
R 4 is absent, H, C 1-6 alkyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl or benzoyl, and the C 1-6 alkyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl and benzoyl of which is optionally substituted by the substituents selected from the group consisting of halogen, OH, C 1-3 alkoxy, C 3-6 heterocycloalkyloxy and toluenesulfonyloxy;
R 5 is H or C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted by halogen and/or OH;
V is CH, N or NH;
Q is CH or N;
X is CH or N;
Y is CR 6 or N;
R 6 is selected from the group consisting of H, NH 2 and a C 1-6 alkoxy, and NH 2 and the C 1-6 alkoxy is optionally substituted by C 1-3 alkyl and/or halogen;
J is CH or N;
K is CH or N;
provided that X and Y are not N simultaneously, and J and Y are not N simultaneously;
R′ is halogen, OH, C 1-6 alkyl or C 1-6 alkoxy;
R″ is halogen, OH, NH 2 , C 1-6 alkoxy, C 1-6 alkylamino or C 3-6 heterocycloalkyl, and OH, NH 2 , C 1-6 alkoxy, C 1-6 alkylamino and C 3-6 heterocycloalkyl of which is optionally substituted by the substituent selected from the group consisting of oxo, OH, halogen, C 3-6 cycloalkyl, C 1-4 alkoxy carbonyl, C 3-6 heterocycloalkyloxy, toluenesulfonyloxy and phenyl which is further optionally substituted by OH and/or C 1-3 alkoxy;
R′″ is H, OH or halogen;
m is 0, 1, 2;
n is 0, 1, 2; provided that U and V are both containing N atom, R 1 and R 3 are not CF 3 or Cl;
the structural unit
is selected from the group consisting of
wherein, in Formula I-(c), U is O or S; Z is CH or N;
R a is selected from the group consisting of H, OH, halogen, C 1-3 alkyl, C 1-3 alkoxy, NH 2 , C 1-3 alkylamino and C 1-6 alkoxycarbonyl, and OH, C 1-3 alkyl, C 1-3 alkoxy, NH 2 , C 1-3 alkylamino or C 1-6 alkoxycarbonyl of which is optionally substituted by OH, halogen, C 2-6 heterocycloalkyloxy or toluenesulfonyloxy;
R b is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkoxycarbonyl, C 1-3 alkylcarbonyl, benzyl and benzoyl, and the C 1-6 alkyl, C 1-6 alkoxycarbonyl, C 1-3 alkylcarbonyl or benzoyl of which is optionally substituted by halogen, OH, C 1-3 alkoxy, C 2-6 heterocycloalkyloxy or toluenesulfonyloxy.
17 . The heteroaryl compound having a structure of formula (I), or a pharmaceutically acceptable salt, a solvate, a hydrate, an isotopically labeled derivative or a radiolabeled derivative thereof according to claim 16 , wherein the moiety of
is selected from the group consisting of
wherein R′ is H or F.
18 . The heteroaryl compound having a structure of formula (I), or a pharmaceutically acceptable salt, a solvate, a hydrate, an isotopically labeled derivative or a radiolabeled derivative thereof according to claim 16 , which is of the structure of formula (II),
wherein, X is CH or N; Y is CH or N, provided that X and Y are not N simultaneously;
the structural unit
is selected from the group consisting of
wherein, in Formula I-(c), U is O or S; Z is CH or N;
R a is selected from the group consisting of H, OH, halogen, C 1-3 alkyl, C 1-3 alkoxy, NH 2 , C 1-3 alkylamino and C 1-6 alkoxycarbonyl, and OH, C 1-3 alkyl, C 1-3 alkoxy, NH 2 , C 1-3 alkylamino or C 1-6 alkoxycarbonyl of which is optionally substituted by OH, halogen, C 3-6 heterocycloalkyloxy or toluenesulfonyloxy;
R b is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkoxycarbonyl, C 1-3 alkylcarbonyl, benzyl and benzoyl, and the C 1-6 alkyl, C 1-6 alkoxycarbonyl, C 1-3 alkylcarbonyl or benzoyl of which is optionally substituted by halogen, OH, C 1-3 alkoxy, C 3-6 heterocycloalkyloxy or toluenesulfonyloxy.
19 . The heteroaryl compound having a structure of formula (I), or a pharmaceutically acceptable salt, a solvate, a hydrate, an isotopically labeled derivative or a radiolabeled derivative thereof according to claim 16 , wherein,
R is C 1-3 alkyl which is optionally substituted by the substituent selected from the group consisting of F, OH, p-toluenesulfonyloxy, C 3-5 heterocycloalkyloxy and phenyl which is optionally substituted by OH or methoxy; and/or, R 1 is H, F, OH, NH 2 , C 1-3 alkoxycarbonyl, C 1-3 alkyl, C 1-3 alkylamino or C 1-3 alkoxy; and OH, NH 2 , C 1-3 alkoxycarbonyl, C 1-3 alkyl, C 1-3 alkylamino or C 1-3 alkoxy of which is optionally substituted by the substituent selected from the group consisting of F, OH, p-toluenesulfonyloxy and C 3-5 heterocycloalkyloxy; and/or, R 3 is C 1-3 alkoxy, F or Cl; and/or, R 4 is C 1-3 alkyl, C 1-4 alkoxycarbonyl, C 1-3 alkylcarbonyl or benzoyl, and C 1-3 alkyl, C 1-4 alkoxycarbonyl, C 1-3 alkylcarbonyl or benzoyl of which is optionally substituted by the substituents selected from the group consisting of F, OH, methoxy, C 3-5 heterocycloalkyloxy and p-toluenesulfonyloxy; and/or, R 5 is C 1-3 alkyl; and/or, R 6 is selected from the group consisting of H, NH 2 and a C 1-3 alkoxy, and NH 2 and the C 1-3 alkoxy is optionally substituted by C 1-3 alkyl and/or F; and/or, R′ is F, C 1-3 alkyl or C 1-3 alkoxy; and/or, R″ is F, C 1-3 alkoxy, C 1-3 alkylamino or C 3-5 heterocycloalkyl, and OH, NH 2 , C 1-3 alkoxy, C 1-3 alkylamino or C 3-5 heterocycloalkyl of which is optionally substituted by the substituent selected from the group consisting of oxo, OH, F, Cl, C 3-5 cycloalkyl, C 1-3 alkoxy carbonyl, C 3-5 heterocycloalkyloxy, p-toluenesulfonyloxy and phenyl which is further optionally substituted by OH, methoxy or ethoxy; and/or, R′″ is F or Cl.
20 . The heteroaryl compound having a structure of formula (I), or a pharmaceutically acceptable salt, a solvate, a hydrate, an isotopically labeled derivative or a radiolabeled derivative thereof according to claim 18 , wherein,
in formula I-(c), Z is CH, U is S or O; and/or, R a is selected from the group consisting of H, OH, F, Cl, methyl, ethyl, methoxy, ethoxy, n-propoxy, NH 2 , N-methylamino, N-ethylamino, N-n-propylamino, N,N-dimethylamino, methylethylamino, methoxycarbonyl and tert-butoxy carbonyl, and OH, methyl, ethyl, methoxy, ethoxy, n-propoxy, NH 2 , N-methylamino, N-ethylamino, N-n-propylamino, N,N-dimethylamino, methylethylamino, methoxycarbonyl and tert-butoxy carbonyl of which is optionally substituted by OH, F, Cl, C 3-5 heterocycloalkyloxy or toluenesulfonyloxy; and/or, R b is H, C 1-3 alkyl, C 1-4 alkoxycarbonyl, C 1-3 alkylcarbonyl, benzyl or benzoyl, and the C 1-3 alkyl, C 1-4 alkoxycarbonyl, C 1-3 alkylcarbonyl or benzoyl of which is optionally substituted by F, Cl, OH, C 1-3 alkoxy, C 3-5 heterocycloalkyloxy or toluenesulfonyloxy.
21 . The heteroaryl compound having a structure of formula (I), or a pharmaceutically acceptable salt, a solvate, a hydrate, an isotopically labeled derivative or a radiolabeled derivative thereof according to claim 18 , wherein,
R a is H, F, OH, NH 2 , methoxy, ethoxy,
R b is H, methyl,
22 . The heteroaryl compound having a structure of formula (I), or a pharmaceutically acceptable salt, a solvate, a hydrate, an isotopically labeled derivative or a radiolabeled derivative thereof according to claim 16 , wherein,
R is
and/or, R 1 is F, OH, NH 2 ,
and/or, R 3 is F, OH, methoxy;
and/or, R 4 is H, methyl,
and/or, R 5 is H, methyl or ethyl;
and/or, R′ is F, OH, methyl or methoxy;
and/or, R″ is F, Cl, OH, NH 2 , methyl,
methoxy, ethoxy,
and/or, R′″ is H or F.
23 . A heteroaryl compound having a structure of formula (I), or a pharmaceutically acceptable salt, a solvate, a hydrate, an isotopically labeled derivative or a radiolabeled derivative thereof, which is selected from the group consisting of
24 . A process for preparing the heteroaryl compound having a structure of formula (I), or a pharmaceutically acceptable salt, a solvate, a hydrate, an isotopically labeled derivative or a radiolabeled derivative thereof according to claim 16 ,
when the structural unit
is
comprising the steps of
(i) reacting compound 1 with compound 2 to give compound 3 at −78° C. in an organic solvent and in the presence of a base;
(ii) reacting the compound 3 obtained from step (i) with compound 4 in an organic solvent and in the presence of a base and a Pd catalyst at 80° C.;
when the structural unit
is
and R b is
comprising reacting compound 5 with compound 11 at 60° C. in an organic solvent and in the presence of a base;
wherein RC is H, C 1-5 alkyl, C 1 -5 alkoxycarbonyl, C 1-2 alkylcarbonyl and phenyl, and the C 1-5 alkyl, C 1 -5 alkoxycarbonyl, C 1-2 alkylcarbonyl and phenyl of which is optionally substituted by halogen, OH, C 1-3 alkoxy, C 3-6 heterocycloalkyloxy or toluenesulfonyloxy;
when the structural unit
is
and R b is
comprising reacting compound 5 with compound 13 at 50° C. in an organic solvent and in the presence of a base;
wherein R d is H or C 1-3 alkyl;
when the structural unit
is
where U is O and Z is N, comprising reacting compound 15 with compound 16 at 120° C. in polyphosphoric acid (PPA);
when the structural unit
is
where U is S and Z is C, comprising reacting compound 18 with compound 19 at 90° C. in an organic solvent and in the presence of a base and a Pd catalyst;
when the structural unit
is
wherein R b is H, comprising the steps of
i) reacting compound 26 with compound 27 to form compound 28 in an organic solvent and in the presence of a Pd catalyst, CuI and an organic base at room temperature;
ii) reacting the compound 28 obtained from step i) with DBU to form compound 29 in a mixed solvent of MeOH and H 2 O at 80° C.;
iii) reacting the compound 29 obtained from step ii) with compound 30 to form compound 31 in an organic solvent and in the presence of a Pd catalyst and a base at 80° C.;
when the structural unit
is
comprising the steps of
i) reacting compound 32 with compound 33 to form compound 34 in an alcoholic solvent and in the presence of a base at 80° C.;
ii) reacting the compound 34 obtained from step i) with compound 30 in an organic solvent and in the presence of a base and a Pd catalyst at 80° C.;
25 . The process according to claim 24 , wherein,
when the structural unit
is
comprising the steps of
(i) reacting compound 1 with compound 2 to give compound 3 at −78° C. in THF and in the presence of s-butyllithium;
(ii) reacting the compound 3 obtained from step (i) with compound 4 in DMF and in the presence of Na 2 CO 3 and Pd(PPh 3 ) 4 at 80° C.;
when the structural unit
is
and R b is
comprising reacting compound 5 with compound 11 at 60° C. in DMF and in the presence of Cs 2 CO 3 ; wherein R c is a C 1-3 alkyl or a halogenated C 1-3 alkyl;
when the structural unit
is
and R b
comprising reacting compound 5 with compound 13 at 50° C. in DMF and in the presence of K 2 CO 3 ;
when the structural unit is where U is 0 and Z is N, comprising reacting compound 15 with compound 16 at 120° C. in polyphosphoric acid (PPA);
when the structural unit
is
where U is S and Z is C, comprising reacting compound 18 with compound 19 at 90° C. in CH 3 CN and in the presence of K 2 CO 3 and Pd(PPh 3 ) 4 ;
when the structural unit
is
wherein R b is H, comprising the steps of i) reacting compound 26 with compound 27 to form compound 28 in DMF and in the presence of Pd(PPh 3 ) 2 Cl 2, CuI and triethanolamine at room temperature;
ii) reacting the compound 28 obtained from step i) with DBU to form compound 29 in a mixed solvent of MeOH and H 2 O at 80° C.;
iii) reacting the compound 29 obtained from step ii) with compound 30 to form compound 31 in DMF and in the presence of Pd(PPh 3 ) 4 and Na 2 CO 3 at 80° C.; when the structural unit
is
comprising the steps of i) reacting compound 32 with compound 33 to form compound 34 in EtOH and in the presence of NaHCO 3 at 80° C.;
ii) reacting the compound 34 obtained from step i) with compound 30 in DMF and in the presence of K 2 CO 3 and Pd(PPh 3 ) 4 at 80° C. .
26 . A pharmaceutical composition comprising heteroaryl compound having a structure of formula (I), or pharmaceutically acceptable salt, solvate, hydrate, isotopically labeled derivative or radiolabeled derivative thereof according to claim 16 , and optionally a pharmaceutically acceptable excipient.
27 . A method of Tau imaging, comprising the steps of (a) administering to a subject an effective amount of the heteroaryl compound having a structure of formula (I), or a pharmaceutically acceptable salt, a solvate, a hydrate, an isotopically labeled derivative or a radiolabeled derivative thereof according to claim 16 ; and
(b) imaging the brain of the subject.
28 . A method of Tau imaging, comprising the steps of (a) administering to a subject an effective amount of the pharmaceutical composition according to claim 26 ; and
(b) imaging the brain of the subject.Join the waitlist — get patent alerts
Track US2023047178A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.