US2016137607A1PendingUtilityA1
Autophagy Inhibitors
Est. expiryMay 9, 2031(~4.8 yrs left)· nominal 20-yr term from priority
C07D 221/16C07D 219/10C07D 401/12C07D 219/12C07D 471/04C07D 219/08
48
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Claims
Abstract
The present invention relates to compounds of formulas III and V that are useful as pharmaceutical agents, particularly as autophagy inhibitors.
Claims
exact text as granted — not AI-modified1 . A compound of formula III
or a pharmaceutically acceptable salt thereof, wherein:
Q is CH or N;
R N is —H
R 1 is —H, —F, —Cl, —Br, or —CF 3 ;
R 2 is —CH(R 2-1 ) n1 —(C 2 ) n2 —W n3 —X;
n 1 is 0 or 1;
R 2-1 is —H, C 1 -C 3 alkyl, or C 3 cycloalkyl;
n 2 is 1 or 3;
n 3 is 0 or 1, with the provisos that (1) when n 1 or n 2 are other than 0, n 3 must be 0, (2) when n 3 is 1, n 1 and n 2 are both 0, (3) when n 1 is 1, X 1-2 and X 1-3 must be taken together with the attached nitrogen atom to form a monocyclic structure;
W is a cyclic structure of three through seven atoms consisting of carbon, nitrogen, and sulfur, with the proviso that there not be more than one nitrogen or sulfur atom in the ring optionally containing 1 through 3 double bonds;
X is —NX 1-2 X 1-3 , where X 1-2 is H, linear or branched C 1 -C 4 alkyl, cyclopropyl, cyclobutyl —SO 2 —X 1-4 where X 1-4 is selected from —H and C 1 -C 3 alkyl, and —CO—X 1-4 where X 1-4 is as defined above; and X 1-3 is linear or branched C 1 -C 4 substituted alkyl with one
or
R 3 is —H, —F, —Cl, —Br, —CF 3 , —OR 3-1 where R 3-1 is —H, C 1 -C 6 alkyl or —CO—R 3-2 where R 3-2 is C 1 -C 3 alkyl or phenyl, —N(R 3-1 ) 2 where the R 3-1 are the same or different and are as defined above, —SR 3-1 where R 3-1 is as defined above, —S(O)—R 3-1 where R 3-1 is as defined above, or —SO 2 —R 3-1 where R 3-1 is as defined above;
R 4 is —H, —F, —Cl, —Br, —CF 3 , —OR 4-1 where R 4-1 is —H, C 1 -C 6 alkyl or —CO—R 4-2 where R 4-2 is C 1 -C 3 alkyl or phenyl, —N(R 4-1 ) 2 where the R 4-1 are the same or different and are as defined above, —SR 4-1 where R 4-1 is as defined above, —S(O)—R 4-1 where R 4-1 is as defined above, or —SO 2 —R 4-1 where R 4-1 is as defined above;
R 5 is —H, —F, —Cl, —Br, —CF 3 , —OR 5-1 where R 5-1 is —H, C 1 -C 6 alkyl or —CO—R 5-2 where R 5-2 is C 1 -C 3 alkyl or phenyl, —N(R 5-1 ) 2 where the R 5-1 are the same or different and are as defined above, —SR 5-1 where R 5-1 is as defined above, —S(O)—R 5-1 where R 5-1 is as defined above, or —SO 2 —R 5-1 where R 5-1 is as defined above;
with the proviso that one of R 1 , R 3 , R 4 and R 5 must be other than —H.
2 - 10 . (canceled)
11 . The compound of claim 1 , wherein
Q is CH or N; R N is —H; R 1 is —H, —F, —Cl, —Br, or —CF 3 ; R 2 is —CH(R 2-1 )—(CH 2 ) n2 —W n3 —X; wherein:
R 2-1 is —H, C 1 -C 3 alkyl, or C 3 cycloalkyl;
n 2 is 1 or 3;
n 3 is 0
X is
where X 1-2 is selected from the group consisting of H, linear or branched C 1 -C 4 alkyl, cyclopropyl, cyclobutyl , and —SO 2 —X 1-4 where X 1-4 is selected from —H and C 1 -C 3 alkyl; and X 1-3 is a linear or branched C 1 -C 4 alkyl substituted with one cyclopropyl;
R 3 is —H, —F, —Cl, —Br, —CF 3 , —OR 4-1 where R 4-1 is —H or C 1 -C 6 alkyl, —N(R 4-1 ) 2 where the R 4-1 are the same or different and are as defined above, or —SR 4-1 where R 4-1 is as defined above;
R 4 is —H, —F, —Cl, —Br, —CF 3 , —OR 4-1 where R 4-1 is —H or C 1 -C 6 alkyl, —N(R 4-1 ) 2 where the R 4-1 are the same or different and are as defined above, or —SR 4-1 where R 4-1 is as defined above;
R 5 is —H, —F, —Cl, —Br, —CF 3 , —OR 4-1 where R 4-1 is —H or C 1 -C 6 alkyl, —N(R 4-1 ) 2 where the R 4-1 are the same or different and are as defined above, or —SR 4-1 where R 4-1 is as defined above;
with the proviso that one of R 1 , R 3 , R 4 , and R 5 must be other than —H.
12 . The compound of claim 11 , wherein R 2 is selected from the group consisting of:
13 . The compound of claim 11 , wherein R 2 is selected from the group consisting of:
14 . A compound of formula III
or a pharmaceutically acceptable salt thereof, wherein:
Q is CH or N;
R N is —H;
R 1 is —H, —F, —Cl, —Br, or —CF 3 ;
R 2 is —CH(R 2-1 ) n1 —(CH 2-1 ) n2 —W n3 —W wherein:
n 1 is 0 or 1;
R 2-1 is —H, C 1 -C 3 alkyl, or C 3 cycloalkyl;
n 2 is 1 or 3;
n 3 is 0 or 1, with the provisos that (1) when n 1 or n 2 are other than 0, n 3 must be 0, (2) when n 3 is 1, n 1 and n 2 are both 0, (3) when n 1 is 1, X 1-2 and X 1-3 must be taken together with the attached nitrogen atom to form a monocyclic structure;
W is a cyclic structure of three through seven atoms consisting of carbon, nitrogen, and sulfur, with the proviso that there not be more than one nitrogen or sulfur atom in the ring optionally containing 1 through 3 double bonds;
X is —NX 1-2 X 1-3 , where the X 1-2 and X 1-3 are taken together with the attached nitrogen atom to form a monocyclic structure that is piperazin-1-yl optionally substituted in the 4-position with C1-C3 alkyl, —CO—(C 1 -C 3 alkyl), —SO 2 —H, or —SO 2 —(C 1 -C 3 ) alkyl; piperidin-1-yl or piperidin-4-yl both optionally substituted with one —F, —Cl, C 1 -C 3 alkyl, —CO—(C 1 -C 3 alkyl), —SO 2 —H, or —SO 2 —(C1-C3)alkyl; or pyrrolidin-1-yl, pyrrolinin-2-yl, or pyrrolidin-3-yl all optionally substituted with one —F, Cl, Cl-C 3 alkyl, —CO—(C 1 -C 3 alkyl), —SO 2 —H, or —SO2—(C 1 -C 3 )alkyl;
R 3 is —H, —F, —Cl, —Br, —CF 3 , —OR 3-1 where R 3-1 is —H, C 1 -C 6 alkyl, or —CO—R 3-2 where R 3-2 is C 1 -C 3 alkyl or phenyl, —N(R 3-1 ) 2 where the R 3-1 are the same or different and are as defined above, —SR 34 where R 3-1 is as defined above, —S(O)—R 3 . 1 where R 3-1 is as defined above, or —SO 2 - R 3-1 where R 3-1 is as defined above;
R 4 is —H, —F, —Cl, —Br, —CF 3 , —OR 4-1 where R 4-1 is —H, C 1 -C 6 alkyl or —CO—R 4-2 where R 4-2 is C 1 -C 3 alkyl or phenyl, —N(R 2-1 ) 2 where the R 3-1 are the same or different and are as defined above, —SR 3-1 where R 3-1 is as defined above, —S(O)—R 3-1 where 4 1 is as defined above, or —SO 2 —R 3-1 where R 4-1 is as defined above;
R 5 is —H, —F, —Cl, —Br, —CF 3 , —OR 5-1 where R 5-1 is —H, C 1 -C 6 alkyl or —CO—R 5-2 where R 5-2 is C 2 -C 3 alkyl or phenyl, —N(R 5-4 ) 2 where the R 5-1 are the same or different and are as defined above, —SR 5-1 where R 5-1 is as defined above, —S(O)—R 5-1 where R 5-1 is as defined above, or —SO 2 —R 5-1 where R 5-1 isas defined above;
with the proviso that one of R 1 , R 3 , R 4 and R 5 must be other than H.
15 . The compound of claim 14 , wherein
Q is CH or N; R N is —H; R 1 is —H, —F, —Cl, —Br, or —CF 3 ; R 2 is —CH(R 2-1 )—(CH 2 ) n2 —W n3 —X; wherein:
R 2-1 is —H, C 1 -C 3 alkyl, or C 3 cycloalkyl;
n 2 is 1 or 3;
n 3 is 0;
X is —NX 1-2 X 1-3 , where the X 1-2 and X 1-3 are taken together with the attached nitrogen atom to form a monocyclic structure that is piperazin-1-yl optionally substituted in the 4-position with C1-C3 alkyl, —CO—(C 1 -C 3 alkyl), —SO 2 —H, or —SO 2 —(C 1 -C 3 ) alkyl;
R 3 is —H, —F, —Cl, —Br, —CF 3 , —OR 4-1 where R 4-1 is —H or C 1 -C 6 alkyl, —N(R 4-1 ) 2 where the R 4-1 are the same or different and are as defined above, or —SR 4-1 where R 4-1 is as defined above; R 4 is —H, —F, —Cl, —Br, —CF 3 , —OR 4-1 where R 4-1 is —H or C 1 -C 6 alkyl, —N(R 4-1 ) 2 where the R 4-1 are the same or different and are as defined above, or —SR 4-1 where R 4-1 is as defined above; R 5 is —H, —F, —Cl, —Br, —CF 3 , —OR 4-1 where R 4-1 is —H or C 1 -C 6 alkyl, —N(R 4-1 ) 2 where the R 4-1 are the same or different and are as defined above, or —SR 4-1 where R 4-1 is as defined above;
with the proviso that one of R 1 , R 3 , R 4 , and R 5 must be other than —H.
16 . The compound of claim 15 , wherein R 2 is selected from the group consisting of:
17 . The compound of claim 15 , wherein the optionally substituted monocyclic structure is selected from the group consisting of pyrrolidin-1-yl, N-(1-methylpyrrolidin-3-yl), N-(4-methylpiperazin-1-yl), and N-(1-ethylpiperadin-4-yl).
18 . A compound of formula III
or a pharmaceutically acceptable salt thereof, wherein:
Q is CH or N;
R N is —H;
R 1 is —H, —F, —Cl, —Br, or —CF 3 ;
R 2 is selected from the group consisting of:
R 3 is —H, —F, —Cl, —Br, —CF 3 , —OR 3-1 where R 3-1 is —H, C 1 -C 6 alkyl, or —CO—R 3-2 where R 3-2 is C 1 -C 3 alkyl or phenyl, —N(R 3-1 ) 2 where the R 3-1 are the same or different and are as defined above, —SR 3-1 where R 3-1 is as defined above, —S(O)—R 3-1 where R 3-1 is as defined above, or —SO 2 —R 3-1 where R 3-1 is as defined above;
R 4 is —H, —F, —Cl, —Br, —CF 3 , —OR 4-1 where R 4-1 is —H, C 1 -C 6 alkyl or —CO—R 4-2 where R 4-2 is C 1 -C 3 alkyl or phenyl, —N(R 4-1 ) 2 where the R 4-1 are the same or different and are as defined above, —SR 4-1 where R 4-1 is as defined above, —S(O)—R 4-1 where R 4-1 is as defined above, or —SO 2 —R 4-1 where R 4-1 is as defined above;
R 5 is —H, —F, —Cl, —Br, —CF 3 , OR 5-1 where R 5-1 is —H, C 1 -C 6 alkyl or —CO—R 5-2 where —CO—R 5-2 is C 1 -C 3 alkyl or phenyl, —N(R 5-1 ) 2 where the R 5-1 are the same or different and are as defined above, —SR 5-1 where R 5-1 is as defined above, —S(O)—R 5-1 where R 5-1 is as defined above, or —SO 2 —R 5-1 where R 5-1 is as defined above;
with the proviso that one of R 1 , R 3 , R 4 and R 5 must be other than —H.
19 . The compound of claim 18 , wherein:
Q is CH or N; R N is —H; R 1 is —H, —F, —Cl, —Br, or —CF 3 ; R 2 is selected from the group consisting of:
R 3 is —H, —F, —Cl, —Br, —CF 3 , —OR 4-1 where R 4-1 is —H or C 1 -C 6 alkyl, —N(R 4-1 ) 2 where the R 4-1 are the same or different and are as defined above, or —SR 4-1 where R 4-1 is as defined above;
R 4 is —H, —F, —Br, —CF 3 , —OR 4-1 where R 4-1 is —H or C 1 -C 6 alkyl, —N(4 1 ) 2 where the R 4-1 are the same or different and are as defined above, or —SR 4-1 where R 4-1 is as defined above;
R 5 is —H, —F, —Cl, —Br, —CF 3 , —OR 4-1 where R 4-1 is —H or C 1 -C 6 alkyl, —N(R 4-1 ) 2 where the
R 4-1 are the same or different and are as defined above, or —SR 4-1 where R 4-1 is as defined above;
with the proviso that one of R 1 , R 3 , R 4 , and R 5 must be other than —H.
20 . A compound selected from the group consisting of:
Example
Structure
Name
4
6-Chloro-2-methoxy-N-(4- (pyrrolidin-1-yl)butyl)acridin-9- amine
7
6-Chloro-2-methoxy-N-(4-(4- methylpiperazin-1- yl)butyl)acridin-9-amine
10
N 1 -(6-Chloro-2-methoxyacridin- 9-yl)-N 4 -(cyclopropylmethyl)-N 4 - methylbutane-1,4-diamine
12
N 1 -(6-Chloro-2-methoxyacridin- 9-yl)-N 4 -cyclopropyl-N 4 - ethylbutane-1,4-diamine
13
N 1 -(6-Chloro-2- methoxyacridin-9-yl)-N 4 - (cyclopropylmethyl)-N 4 - ethylbutane-1,4-diamine
17
6-Chloro-2-fluoro-N-(2-(4- methylpiperazin-1- yl)ethyl)acridin-9-amine
19
3-Chloro-N-(2-(4- methylpiperazin-1- yl)ethyl)acridin-9-amine
20
6-Fluoro-2-methoxy-N-(2-(4- methylpiperazin-1- yl)ethyl)acridin-9-amine
21
6-Chloro-2-methoxy-N-(2-(4- methylpiperazin-1- yl)ethyl)acridin-9-amine
23
7-Chloro-2-methoxy-N-(2-(4- methylpiperazin-1- yl)ethyl)benzo[b][1,5] naphthyridin-10-amine
29
6-Chloro-2-fluoro-N-(1-(4- methylpiperazin-1-yl)propan- 2-yl)acridin-9-amine
30
N 1 -(acridin-9-yl)-N 4 - (cyclopropylmethyl)-N 4 - methylbutane-1,4-diamine
31
N 1 -(cyclopropylmethyl)-N 4 -(2- fluoroacridin-9-yl)-N 1 - methylbutane-1,4-diamine
32
N 1 -(2-chloroacridin-9-yl)-N 4 - (cyclopropylmethyl)-N 4 - methylbutane-1,4-diamine
33
N 1 -(cyclopropylmethyl)-N 4 -(2- methoxyacridin-9-yl)-N 1 - methylbutane-1,4-diamine
34
N 1 -(6-bromo-2- methoxyacridin-9-yl)-N 4 - (cyclopropylmethyl)-N 4 - methylbutane-1,4-diamine
35
N 1 -(cyclopropyl-methyl)-N 4 - (6-fluoro-2-methoxyacridin-9- yl)-N 1 -methylbutane-1,4- diamine
36
N 1 -(6-chloro-2-fluoroacridin- 9-yl)-N 4 -(cyclopropylmethyl)- N 4 -methylbutane-1,4-diamine
37
N 1 -(cyclopropylmethyl)-N 4 - (2,6-dichloroacridin-9-yl)-N 1 - methylbutane-1,4-diamine
38
N 1 -(3-chloroacridin-9-yl)-N 4 - (cyclopropylmethyl)-N 4 - methylbutane-1,4-diamine
39
7-chloro-10-(4-((cyclopropyl- methyl)(methyl)amino)butyl amino)benzo[b][1,5] naphthyridin-2-ol
40
N 1 -(7- chlorobenzo[b][1,5]naphthyridin- 10-yl)-N 4 - (cyclopropylmethyl)-N 4 - methylbutane-1,4-diamine
41
N 1 -(cyclopropylmethyl)-N 4 - (2,7-dichlorobenzo[b][1,5] naphthyridin-10-yl)-N 1 - methylbutane-1,4-diamine
42
N 1 -(7-chloro-2-methoxy benzo[b][1,5]naphthyridin-10- yl)-N 4 -(cyclopropylmethyl)-N 4 - methylbutane-1,4-diamine
45
N 1 -(6-chloro-2- methoxyacridin-9-yl)-N 3 - (cyclopropylmethyl)-N 3 - methylpropane-1,3-diamine
46
N 1 -(6-chloro-2- methoxyacridin-9-yl)-N 2 - (cyclopropylmethyl)-N 2 - methylethane-1,2-diamine
47
N 4 -(6-chloro-2- methoxyacridin-9-yl)-N 1 - (cyclopropylmethyl)-N 1 - methylpentane-1,4-diamine
48
N 4 -(6-chloro-2- methoxyacridin-9-yl)-N 1 - (cyclopropylmethyl)-N 1 - methylhexane-1,4-diamine
49
N 4 -(6-chloro-2- methoxyacridin-9-yl)-N 1 - (cyclopropylmethyl)-5- methoxy-N 1 -methylpentane- 1,4-diamine
53
N-(4-(6-chloro-2- methoxyacridin-9- ylamino)butyl)-N- (cyclopropylmethyl) methanesulfonamide
54
N 1 -(6-chloro-2- methoxyacridin-9-yl)-N 4 - (cyclopropylmethyl)butane- 1,4-diamine
56
N 1 -(6-chloro-2- methoxyacridin-9-yl)-N 4 - cyclopropyl-N 4 -methylbutane- 1,4-diamine
57
6-chloro-2-fluoro-N-(1- morpholinopropan-2- yl)acridin-9-amine
58
7-Chloro-2-methoxy-N-(1-(4- methylpiperazin-1-yl)propan- 2-yl)benzo[b][1,5]naphthyridin- 10-amine
59
7-Chloro-2-methoxy-N-(1- morpholinpropan-2- yl)benzo[b][1,5]naphthyridin- 10-amine
64
6-chloro-2-methoxy-N-(4- morpholinobutyl)acridin-9- amine
21 . The compound of claim 1 , 14 , 18 , or 20 , further comprising a pharmaceutically acceptable carrier, excipient, or diluent.
22 . A method of treating a condition or disease, comprising administering to a subject in need of such treatment a compound according to claim 1 , 14 , 18 , or 20 .
23 . The method of claim 22 , where in the condition or disease is cancer, a neurodegenerative disorder, an autoimmune disorder, a cardiovascular disorder, a metabolic disorder, hamartoma syndrome, a genetic muscle disorder, or a myopathy.
24 . The method of claim 23 , wherein the condition or disease is cancer.Cited by (0)
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