US2021371417A1PendingUtilityA1
Azaindole compounds as histone methyltransferase inhibitors
Assignee: GLOBAL BLOOD THERAPEUTICS INCPriority: Jun 9, 2017Filed: Aug 6, 2021Published: Dec 2, 2021
Est. expiryJun 9, 2037(~10.9 yrs left)· nominal 20-yr term from priority
C07D 519/00A61P 7/00C07D 487/04C07D 471/04
63
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Claims
Abstract
The present disclosure provides certain angular tricyclic compounds that are histone methyltransferases G9a and/or GLP inhibitors and are therefore useful for the treatment of diseases treatable by inhibition of G9a and/or GLP such as cancers and hemoglobinopathies (e.g., beta-thalassemia and sickle cell disease). Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
Claims
exact text as granted — not AI-modifiedWhat is claimed:
1 . A compound of Formula (I):
wherein:
X is N or CR 1 ;
Y is N or CR 2 ;
P, Q, T, and U are independently CH, C (when R 4 or R 5 is attached), or N; provided that at least one and not more than two of P, Q, T and U are N;
Z is O, S, or NR 6 , wherein R 6 is hydrogen, alkyl, or cycloalkyl;
R 1 is hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cycloalkyl;
R 2 is hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cycloalkyl;
R 3 is —W-alkylene-R 7 , wherein:
W is bond, NH, O, or S;
alkylene is optionally substituted with R 8 , wherein R 8 is halo, haloalkyl, haloalkoxy, hydroxy, or alkoxy, and one CH 2 in the alkylene is optionally replaced with NH or O; and
R 7 is —NR a R b , wherein R a and R b are independently hydrogen, alkyl, or haloalkyl; or R a and R b together with the nitrogen to which they are attached form heterocycloamino, bridged heterocycloamino, or spiroheterocycloamino, wherein the heterocycloamino, the bridged heterocycloamino and the spiroheterocycloamino are optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkyl, hydroxy, alkoxy, and haloalkoxy; or
R 7 is heterocyclyl that is attached to the alkylene at a ring carbon atom and is optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkyl, hydroxy, alkoxy and haloalkoxy;
R 4 and R 5 are independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, halo, hydroxy, haloalkoxy, alkoxy, cyano, NH 2 , NR c R d , alkoxyalkylamino, hydroxyalkylamino, aminoalkylamino, hydroxyalkyl, alkoxyalkyl, alkylthio, alkoxyalkyloxy, phenyl, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, heterocyclylamino, 5-8 membered bridged heterocycloamino or spiroheterocycloamino, wherein the phenyl, the cycloalkyl, the heteroaryl, and the heterocyclyl either alone or as part of another group are optionally substituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxy, NH 2 , alkylamino, dialkylamino, carboxy, carboxyalkyl, and alkoxycarbonyl, and wherein the alkyl of R 4 and R 5 is optionally substituted with cycloalkyl, and the alkenyl and the alkynyl of R 4 and R 5 are independently optionally substituted with hydroxy or cycloalkyl;
R c is hydrogen, alkyl, cycloalkyl, or heterocyclyl;
R d is alkyl, cycloalkyl, or heterocyclyl; or
R c and R d together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloamino; and
v and w are independently 0 or 1;
or a pharmaceutically acceptable salt thereof.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is NR 6 .
3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 6 is H.
4 . The compound of claim 1 , 2 , or 3 , or a pharmaceutically acceptable salt thereof, wherein X is CR 1 ; and Y is CR 2 .
5 . The compound of any one of claims 1 - 4 , or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.
6 . The compound of any one of claims 1 - 4 , or a pharmaceutically acceptable salt thereof, wherein R 2 is alkoxy.
7 . The compound of claim 1 , 2 , or 3 , or a pharmaceutically acceptable salt thereof, wherein X is CR 1 ; and Y is N.
8 . The compound of any one of claims 1 - 7 , or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen.
9 . The compound of any one of claims 1 - 7 , or a pharmaceutically acceptable salt thereof, wherein R 1 is alkoxy.
10 . The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 1 is methoxy.
11 . The compound of any one of claims 1 - 7 , or a pharmaceutically acceptable salt thereof, wherein R 1 is alkyl.
12 . The compound of any one of claims 1 - 11 , or a pharmaceutically acceptable salt thereof, wherein P is N; and Q, T, and U are each CH.
13 . The compound of any one of claims 1 - 11 , or a pharmaceutically acceptable salt thereof, wherein P, Q and U are each CH; and T is N.
14 . The compound of any one of claims 1 - 11 , or a pharmaceutically acceptable salt thereof, wherein P and T are each N; and Q and U are each CH.
15 . The compound of any one of claims 1 - 11 , or a pharmaceutically acceptable salt thereof, wherein P is C (wherein R 4 is attached); Q is N; and T and U are each CH.
16 . The compound of any one of claims 1 - 11 , or a pharmaceutically acceptable salt thereof, wherein P, T and U are each CH; and Q is N.
17 . The compound of any one of claims 1 - 11 , or a pharmaceutically acceptable salt thereof, wherein P, Q and T are each CH; and U is N.
18 . The compound of any one of claims 1 - 11 , or a pharmaceutically acceptable salt thereof, wherein P and U are each CH; T is C (wherein R 5 is attached) and Q is N.
19 . The compound of any one of claims 1 - 11 , or a pharmaceutically acceptable salt thereof, wherein P is C (wherein R 4 is attached); Q is N; T is C (wherein R 5 is attached); and U is CH.
20 . The compound of any one of claims 1 - 11 , or a pharmaceutically acceptable salt thereof, wherein P and T are each CH; Q and U is N.
21 . The compound of any one of claims 1 - 11 , or a pharmaceutically acceptable salt thereof, wherein P and Q are each CH; T is C (wherein R 5 is attached); and U is N.
22 . The compound of any one of claims 1 - 11 , or a pharmaceutically acceptable salt thereof, wherein P is C (wherein R 4 is attached); Q is N; T is CH; and U is C (wherein R 5 is attached).
23 . The compound of any one of claims 1 - 11 , or a pharmaceutically acceptable salt thereof, wherein P is C (wherein R 4 is attached); Q is N; T is CH; and U is N.
24 . The compound of any one of claims 1 - 11 , or a pharmaceutically acceptable salt thereof, wherein P is C (wherein R 4 is attached); Q is N; T is CR 5 (wherein R 5 is attached); and U is N.
25 . The compound of any one of claims 1 - 11 , or a pharmaceutically acceptable salt thereof, wherein Q is N; and P, T, and U are independently CH or C (when R 4 or R 5 is attached).
26 . The compound of claim 25 , or a pharmaceutically acceptable salt thereof, wherein P is CR 4 .
27 . The compound of claim 25 or 26 , or a pharmaceutically acceptable salt thereof, wherein T is CH.
28 . The compound of claim 25 or 26 , or a pharmaceutically acceptable salt thereof, wherein T is CR 5 .
29 . The compound of any one of claims 25 - 27 , or a pharmaceutically acceptable salt thereof, wherein U is CH.
30 . The compound of any one of claims 25 - 27 , or a pharmaceutically acceptable salt thereof, wherein U is CR 5 .
31 . The compound of any one of claims 1 - 30 , or a pharmaceutically acceptable salt thereof, wherein W is O.
32 . The compound of any one of claims 1 - 31 , or a pharmaceutically acceptable salt thereof, wherein the alkylene in —W-alkylene-R 7 is unsubstituted.
33 . The compound of any one of claims 1 - 30 , or a pharmaceutically acceptable salt thereof, wherein —W-alkylene- in R 3 is —(CH 2 ) 2 —*, —(CH 2 ) 3 —*, —(CH 2 ) 4 —*, —CH 2 CH(CH 3 )CH 2 —*, *—CH 2 CH(CH 3 )CH 2 —, —O—(CH 2 )—*, —O—(CH 2 ) 2 —*, —O—(CH 2 ) 2 —O—(CH 2 ) 2 —*, —O—(CH 2 ) 3 —*, —OCH 2 CH(F)CH 2 —*, —OCH 2 CH(OH)CH 2 —*, —OCH 2 CH(OCH 3 )CH 2 —*, or —OCH 2 CH(OCF 3 )CH 2 —*, wherein the * indicates the point of attachment to R 7 .
34 . The compound of any one of claims 1 - 30 , or a pharmaceutically acceptable salt thereof, wherein —W-alkylene- is —(CH 2 ) 2 —*, —(CH 2 ) 3 —*, —(CH 2 ) 4 —*, —CH 2 CH(CH 3 )CH 2 —*, —O—(CH 2 ) 2 —*, —O—(CH 2 ) 2 —O—(CH 2 ) 2 —*, or —O—(CH 2 ) 3 —*, wherein the * indicates the point of attachment to R 7 .
35 . The compound of claim 34 , or a pharmaceutically acceptable salt thereof, wherein —W-alkylene- is —O—(CH 2 ) 3 —*, wherein the * indicates the point of attachment to R 7 .
36 . The compound of any one of claims 1 - 35 , or a pharmaceutically acceptable salt thereof, wherein R 7 is —NR a R b , wherein R a and R b are independently hydrogen, alkyl, or haloalkyl.
37 . The compound of claim 36 , or a pharmaceutically acceptable salt thereof, wherein R a and R b are independently methyl, ethyl, n-propyl or isopropyl.
38 . The compound of claim 36 , or a pharmaceutically acceptable salt thereof, wherein —NR a R b is NH 2 , methylamino, ethylamino, dimethylamino, diethylamino, diisopropylamino or (ethyl)(methyl)amino.
39 . The compound of claim 38 , or a pharmaceutically acceptable salt thereof, wherein —NR a R b is dimethylamino.
40 . The compound of any one of claims 1 - 35 , or a pharmaceutically acceptable salt thereof, wherein R 7 is —NR a R b , wherein —NR a R b together with the nitrogen to which they are attached form a heterocycloamino, wherein the heterocycloamino is optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkyl, hydroxy, alkoxy and haloalkoxy.
41 . The compound of claim 40 , wherein the heterocycloamino is a 4-membered heterocycloamino or a 5-membered heterocycloamino optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkyl, hydroxy, alkoxy and haloalkoxy.
42 . The compound of claim 40 , or a pharmaceutically acceptable salt thereof, wherein the heterocycloamino is azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl or 3-azabicyclo[3.1.1]heptan-3-yl, each heterocycloamino optionally substituted with one or two substituents independently selected from methyl, hydroxy, methoxy, and fluoro.
43 . The compound of any one of claims 40 - 42 , or a pharmaceutically acceptable salt thereof, wherein R 7 is —NR a R b , wherein R a and R b together with the nitrogen to which they are attached form pyrrolidin-1-yl, 3(S)-fluoropyrrolidin-1-yl, 3 (R)-fluoropyrrolidin-1-yl, 2-methylpyrrolidin-1-yl, 3,5-dimethylpyrrolidin-1-yl, or 3,3-dimethylpyrrolidin-1-yl.
44 . The compound of claim 43 , or a pharmaceutically acceptable salt thereof, wherein R 7 is —NR a R b , wherein R a and R b together with the nitrogen to which they are attached form pyrrolidin-1-yl.
45 . The compound of any one of claims 1 - 35 , or a pharmaceutically acceptable salt thereof, wherein R 7 is heterocyclyl that is attached to the alkylene at a ring carbon atom and is optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkyl, hydroxy, alkoxy and haloalkoxy.
46 . The compound of claim 45 , or a pharmaceutically acceptable salt thereof, wherein R 7 is piperidin-3-yl.
47 . The compound of claim 45 , or a pharmaceutically acceptable salt thereof, wherein R 7 is piperidin-3-yl optionally substituted with alkyl.
48 . The compound of any one of claims 1 - 30 , or a pharmaceutically acceptable salt thereof, wherein R 3 is —O—(CH 2 ) 3 -pyrrolidin-1-yl, —O—(CH 2 ) 3 -piperidin-1-yl, —O—(CH 2 )-piperidin-3-yl, or —O—(CH 2 ) 3 -morpholin-4-yl, wherein pyrrolidin-1-yl, piperidin-1-yl, piperidin-3-yl and morpholin-4-yl are each optionally substituted with one or two substituents independently selected from methyl, hydroxy, methoxy, and fluoro.
49 . The compound of any one of claim 1 - 11 , 18 , 19 , 21 , 22 or 24 - 48 , or a pharmaceutically acceptable salt thereof, wherein w is 0.
50 . The compound of any one of claims 1 - 48 , or a pharmaceutically acceptable salt thereof, wherein w is 1.
51 . The compound of claim 50 , or a pharmaceutically acceptable salt thereof, wherein R 5 is NH 2 , halo, alkyl, hydroxy, alkoxy, cycloalkyl, or hydroxyalkyl.
52 . The compound of claim 51 , or a pharmaceutically acceptable salt thereof, wherein R 5 is NH 2 , fluoro, chloro, methyl, ethyl, hydroxy, methoxy, cyclopropyl, cyclopentyl, or hydroxymethyl.
53 . The compound of claim 51 , or a pharmaceutically acceptable salt thereof, wherein R 5 is alkyl.
54 . The compound of claim 51 , or a pharmaceutically acceptable salt thereof, wherein R 5 is cycloalkyl.
55 . The compound of claim 51 , or a pharmaceutically acceptable salt thereof, wherein R 5 is halo.
56 . The compound of claim 51 , or a pharmaceutically acceptable salt thereof, wherein R 5 is hydroxy or hydroxyalkyl.
57 . The compound of claim 51 , or a pharmaceutically acceptable salt thereof, wherein R 5 is NH 2 .
58 . The compound of claim 51 , or a pharmaceutically acceptable salt thereof, wherein R 5 is alkoxy.
59 . The compound of any one of claim 1 - 11 , 15 , 19 or 22 - 58 , or a pharmaceutically acceptable salt thereof, wherein v is 0.
60 . The compound of any one of claims 1 - 58 , or a pharmaceutically acceptable salt thereof, wherein v is 1.
61 . The compound of claim 60 , or a pharmaceutically acceptable salt thereof, wherein R 4 is hydroxy.
62 . The compound of claim 60 , or a pharmaceutically acceptable salt thereof, wherein R 4 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, halo, haloalkoxy, alkoxy, cyano, NH 2 , NR c R d , alkoxyalkylamino, hydroxyalkylamino, aminoalkylamino, hydroxyalkyl, alkoxyalkyl, alkylthio, alkoxyalkyloxy, phenyl, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, 5-8 membered bridged heterocycloamino or spiroheterocycloamino, wherein the phenyl, the heteroaryl, and the heterocyclyl either alone or as part of another group are optionally substituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, NH 2 , alkylamino, dialkylamino, carboxy, carboxyalkyl, and alkoxycarbonyl, and wherein the alkyl of R 4 is optionally substituted with cycloalkyl, and the alkenyl and the alkynyl of R 4 are optionally substituted with hydroxy or cycloalkyl; R c is hydrogen, alkyl, cycloalkyl, or heterocyclyl; and R d is alkyl, cycloalkyl, or heterocyclyl; or R c and R d together with the nitrogen to which they are attached form a 4- to 6-membered heterocycloamino.
63 . The compound of claim 62 , or a pharmaceutically acceptable salt thereof, wherein R 4 is alkyl or cycloalkyl.
64 . The compound of claim 63 , or a pharmaceutically acceptable salt thereof, wherein R 4 is cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, or cyclopentyl, wherein the cyclopropyl, the cyclobutyl, and the cyclopentyl are optionally substituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, NH 2 , alkylamino, dialkylamino, carboxy, carboxyalkyl, and alkoxycarbonyl.
65 . The compound of claim 62 , or a pharmaceutically acceptable salt thereof, wherein R 4 is NH 2 , NR c R d , alkoxyalkylamino, hydroxyalkylamino or aminoalkylamino.
66 . The compound of claim 62 , or a pharmaceutically acceptable salt thereof, wherein R 4 is heteroaryl, heterocyclyl, 5-8 membered bridged heterocycloamino or spiroheterocycloamino, wherein the heteroaryl and the heterocyclyl either alone or as part of another group are optionally substituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, NH 2 , alkylamino, dialkylamino, carboxy, carboxyalkyl, and alkoxycarbonyl.
67 . The compound of claim 62 or 66 , or a pharmaceutically acceptable salt thereof, wherein R 4 is heterocyclyl.
68 . The compound of claim 62 , 66 or 67 , or a pharmaceutically acceptable salt thereof, wherein the heterocyclyl is a heterocycloamino optionally substituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, NH 2 , alkylamino, dialkylamino, carboxy, carboxyalkyl, and alkoxycarbonyl, and wherein the alkyl, alkenyl and alkynyl are optionally substituted with hydroxy and an unsubstituted cycloalkyl.
69 . The compound of claim 68 , or a pharmaceutically acceptable salt thereof, wherein the heterocycloamino is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.
70 . The compound of claim 62 or 65 , or a pharmaceutically acceptable salt thereof, wherein R 4 is NR c R d .
71 . The compound of claim 70 , or a pharmaceutically acceptable salt thereof, wherein R c and R d together with the nitrogen to which they are attached form a 4- to 6-membered heterocycloamino.
72 . The compound of claim 62 , or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl, ethyl, n-propyl, isopropyl, tert-butyl, ethynyl, fluoro, chloro, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclopent-1-en-1-yl, 2-cyclopropylethynyl, 2-cyclopropylethenyl, 2-cyclopropylethyl, pyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl, 2-isopropylpyrrolidin-1-yl, 2,2-dimethylpyrrolidin-1-yl, 2-isopropylpyrrolidin-1-yl, 2-(carboxymethyl)pyrrolidin-1-yl, 2-carboxypyrrolidin-1-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 4-hydroxypiperidin-1-yl, morpholin-4-yl, oxetan-3-yl, oxetan-2-yl, oxan-2-yl, oxan-3-yl oxan-4-yl, tetrahydropyran-4-yl, 1,2,3,6-tetrahydropyridin-4-yl, 3,6-dihydro-2H-pyran-4-yl, tetrahydrofuran-3-yl, azetidine-1-yl, 3-hydroxyazetidin-1-yl, pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, oxan-4-yloxy, pyrrolidin-3-yloxy, 2-ethoxyeth-1-yl, 3-methoxyprop-1-yl, methylamino, ethylamino, n-propylamino, n-butylamino, isopropylamino, isobutylamino, tertbutylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, (cyclopropylmethyl)amino, (cyclobutylmethyl)amino, (cyclopentylmethyl)amino, (cyclohexylmethyl)amino, dimethylamino, diethylamino, dimethylamino, di-(n-propyl)amino, di-(isopropyl)amino, di-(n-butyl)amino, di-(isobutyl)amino, di-(tertbutyl)amino, (methyl)(ethyl)amino, 2-ethoxyethylamino, 3-methoxyprop-2-ylamino, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, imidazole-1-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, oxazol-5-yl, oxazol-2-yl, oxazol-4-yl, 1,2,4-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-1-yl, hydroxymethyl, 4-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 2-difluoromethoxypyridin-4-yl, 6-difluoromethoxypyridin-3-yl, 4-methylaminopyridin-2-yl, 2-methylaminopyridin-4-yl, 6-methylamino-pyridin-2-yl, 4-difluoromethylphenyl, 2-hydroxyprop-2-yl, 4-(2-hydroxypropyl)phenyl, 4-(2-hydroxypropan-2-yl)phenyl, 2-(carboxymethyl)phenyl, 2-carboxyphenyl, 2-methoxyethoxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy and tert-butoxy, hydroxy, methylsulfenyl, 3-hydroxy-3-methylbut-1-yn-1-yl, 3-hydroxy-3-methylbut-1-en-1-yl, 3-hydroxy-3-methylbutyl, 2-hydroxypropan-2-yl, 1-azaspiro[3,4]octan-1-yl, 4-azaspiro[2,4]heptan-4-yl, 5-azaspiro[3,4]octan-5-yl, 1-azaspiro[3,3]heptan-1-yl, 2-oxa-5-azaspiro[3,4]octan-5-yl, 6-oxa-1-azaspiro[3,3]heptan-1-yl, 6-oxa-1-azaspiro[3,4]octan-1-yl, 7-oxa-1-azaspiro[4,4]nonan-1-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, or 7,7-dioxido-7-thia-1-azaspiro[4.4]nonan-1-yl.
73 . The compound of claim 72 , or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, or tert-butyl.
74 . The compound of claim 73 , or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl, ethyl, n-propyl, or isopropyl.
75 . The compound of claim 72 , or a pharmaceutically acceptable salt thereof, wherein R 4 is cyclopropyl, 1-methylcyclopropyl, cyclobutyl, or cyclopentyl.
76 . The compound of claim 75 , or a pharmaceutically acceptable salt thereof, wherein R 4 is cyclopropyl.
77 . The compound of claim 72 , or a pharmaceutically acceptable salt thereof, wherein R 4 is pyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl, 2-isopropylpyrrolidin-1-yl, 2,2-dimethylpyrrolidin-1-yl, 2-isopropylpyrrolidin-1-yl, 2-(carboxymethyl)pyrrolidin-1-yl, 2-carboxypyrrolidin-1-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 4-hydroxypiperidin-1-yl, morpholin-4-yl, oxetan-3-yl, oxetan-2-yl, oxan-2-yl, oxan-3-yl oxan-4-yl, tetrahydropyran-4-yl, 1,2,3,6-tetrahydropyridin-4-yl, 3,6-dihydro-2H-pyran-4-yl, tetrahydrofuran-3-yl, azetidine-1-yl, 3-hydroxyazetidin-1-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, imidazole-1-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, oxazol-5-yl, oxazol-2-yl, oxazol-4-yl, 1,2,4-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-1-yl, hydroxymethyl, 4-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 2-difluoromethoxypyridin-4-yl, 6-difluoromethoxypyridin-3-yl, 4-methylaminopyridin-2-yl, 2-methylaminopyridin-4-yl, or 6-methylamino-pyridin-2-yl.
78 . The compound of claim 77 , or a pharmaceutically acceptable salt thereof, wherein R 4 is pyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl, 2-isopropylpyrrolidin-1-yl, 2,2-dimethylpyrrolidin-1-yl, 2-isopropylpyrrolidin-1-yl, 2-(carboxymethyl)pyrrolidin-1-yl, or 2-carboxypyrrolidin-1-yl.
79 . The compound of claim 72 , or a pharmaceutically acceptable salt thereof, wherein R 4 is 1-azaspiro[3,4]octan-1-yl, 4-azaspiro[2,4]heptan-4-yl, 5-azaspiro[3,4]octan-5-yl, 1-azaspiro[3,3]heptan-1-yl, 2-oxa-5-azaspiro[3,4]octan-5-yl, 6-oxa-1-azaspiro[3,3]heptan-1-yl, 6-oxa-1-azaspiro[3,4]octan-1-yl, 7-oxa-1-azaspiro[4,4]nonan-1-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, or 7,7-dioxido-7-thia-1-azaspiro[4.4]nonan-1-yl.
80 . The compound of claim 72 , or a pharmaceutically acceptable salt thereof, wherein R 4 is methylamino, ethylamino, n-propylamino, n-butylamino, isopropylamino, isobutylamino, tertbutylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, (cyclopropylmethyl)amino, (cyclobutylmethyl)amino, (cyclopentylmethyl)amino, (cyclohexylmethyl)amino, dimethylamino, diethylamino, dimethylamino, di-(n-propyl)amino, di-(isopropyl)amino, di-(n-butyl)amino, di-(isobutyl)amino, di-(tertbutyl)amino, or (methyl)(ethyl)amino.
81 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CR 1 ; Y is CR 2 , P is CH or CR 4 ; Q is N; T is CH or CR 5 ; U is CH or N; R 1 and R 2 are independently hydrogen or methoxy; R 3 is —O—(CH 2 ) 2 —R 7 , —O—(CH 2 ) 3 —R 7 or —O—(CH 2 ) 4 —R 7 ; R 7 is —NR a R b , wherein R a and R b are independently methyl, ethyl, n-propyl or isopropyl, or —NR a R b together with the nitrogen to which they are attached form a 4-membered heterocycloamino or a 5-membered heterocycloamino wherein each heterocycloamino is optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkyl, hydroxy, alkoxy and haloalkoxy; R 4 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, heterocyclyl, NH 2 , or NR c R d , wherein the cyclopropyl, the cyclobutyl, and the cyclopentyl are optionally substituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, NH 2 , alkylamino, dialkylamino, carboxy, carboxyalkyl, and alkoxycarbonyl; R 5 is NH 2 ; R c is hydrogen, alkyl, cycloalkyl, or heterocyclyl; and R d is alkyl, cycloalkyl or heterocyclyl; or R c and R d together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloamino.
82 . The compound of claim 81 , or a pharmaceutically acceptable salt thereof, wherein R 1 is methoxy; and R 2 is hydrogen.
83 . The compound of claim 81 or 82 , or a pharmaceutically acceptable salt thereof, wherein R 3 is —O—(CH 2 ) 3 —R 7 .
84 . The compound of any one of claims 81 - 83 , or a pharmaceutically acceptable salt thereof, wherein R 7 is —NR a R b , wherein R a and R b are independently methyl, ethyl, n-propyl or isopropyl.
85 . The compound of claim 84 , or a pharmaceutically acceptable salt thereof, wherein R a and R b are each methyl.
86 . The compound of any one of claims 81 - 85 , or a pharmaceutically acceptable salt thereof, wherein R 7 is —NR a R b , wherein —NR a R b together with the nitrogen to which they are attached form a 4-membered heterocycloamino or a 5-membered heterocycloamino wherein each heterocycloamino is optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkyl, hydroxy, alkoxy and haloalkoxy.
87 . The compound of claim 86 , or a pharmaceutically acceptable salt thereof, wherein NR a R b together with the nitrogen to which they are attached form pyrrolidin-1-yl.
88 . The compound of any one of claims 81 - 87 , or a pharmaceutically acceptable salt thereof, wherein P is CH.
89 . The compound of any one of claims 81 - 87 , or a pharmaceutically acceptable salt thereof, wherein P is CR 4 .
90 . The compound of claim 89 , or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl, ethyl, n-propyl, isopropyl, or cyclopropyl.
91 . The compound of claim 89 , or a pharmaceutically acceptable salt thereof, wherein R 4 is cyclopropyl, cyclobutyl, or cyclopentyl, wherein cyclopropyl, cyclobutyl, and cyclopentyl are optionally substituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, NH 2 , alkylamino, dialkylamino, carboxy, carboxyalkyl, and alkoxycarbonyl.
92 . The compound of claim 89 , or a pharmaceutically acceptable salt thereof, wherein R 4 is NH 2 , NR c R d , or 4- to 6-membered heterocyclyl.
93 . The compound of any one of claims 81 - 92 , or a pharmaceutically acceptable salt thereof, wherein T is CH.
94 . The compound of any one of claims 81 - 93 , or a pharmaceutically acceptable salt thereof, wherein U is CH.
95 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is selected from the group consisting of: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101 and 102 as shown in Table 1, or a parent compound of a salt as shown in Table 1, or a pharmaceutically acceptable salt of the parent compound.
96 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is selected from the group consisting of: la, 2a, 3a, 4a, 5a, 6a, 7a, 8a, 9a, 10a, 11a, 12a, 13a, 14a, 15a, 16a, 17a, 18a, 19a, 20a, 21a, 22a, 23a, 24a, 25a, 26a, 27a, 28a, 29a, 30a, 31a, 32a, 33a, 34a, 35a, 36a, 37a, 38a, 39a, 40a, 41a, 42a, 43a, 44a, 45a, 46a, 47a, 48a, 49a, 50a, 51a, 52a, 53a, 54a, 55a, 56a, 57a, 58a, 59a, 60a, 61a, 62a, 63a, 64a, 65a, 66a and 67a as shown in Table 2.
97 . A pharmaceutical composition comprising a compound of any one of claims 1 - 96 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.
98 . A method of inhibiting the activity of G9a comprising contacting a cell that contains G9a with an effective amount of a compound of any one of claims 1 - 96 , or a pharmaceutically acceptable salt thereof, and thereby inhibiting the activity of the G9a.
99 . A method of inhibiting the activity of GLP comprising contacting a cell that contains GLP with an effective amount of a compound of any one of claims 1 - 96 , or a pharmaceutically acceptable salt thereof, and thereby inhibiting the activity of GLP.
100 . A method of increasing fetal hemoglobin (HbF) protein levels comprising contacting a cell characterized as having impaired production of β-globin with an effective amount of a compound of any one of claims 1 - 96 , or a pharmaceutically acceptable salt thereof, and thereby increasing fetal hemoglobin (HbF) protein levels.
101 . A method of inhibiting the polymerization of hemoglobin S molecules comprising contacting a cell characterized as having a hemoglobin S mutation with an effective amount of a compound of any one of claims 1 - 96 , or a pharmaceutically acceptable salt thereof, and thereby inhibiting the polymerization of hemoglobin S molecules.
102 . A method of inhibiting G9a activity in a subject comprising administering to the subject suffering from a disease that is treatable by fetal hemoglobin an effective amount of a compound of any one of claims 1 - 96 , or a pharmaceutically acceptable salt thereof.
103 . A method of inhibiting GLP activity in a subject comprising administering to the subject suffering from a disease that is treatable by fetal hemoglobin an effective amount of a compound of any one of claims 1 - 96 , or a pharmaceutically acceptable salt thereof.
104 . A method for treating a disease comprising administrating to a subject suffering from a disease treatable by fetal hemoglobin an effective amount of a compound of any one of claims 1 - 96 , or a pharmaceutically acceptable salt thereof.
105 . A method for treating a disease characterized by impaired production of β-globin comprising administrating to a subject suffering from the disease characterized by impaired production of β-globin an effective amount of a compound of any one of claims 1 - 96 , or a pharmaceutically acceptable salt thereof.
106 . The method of claim 105 , wherein the disease is beta-thalassemia.
107 . A method for treating a disease characterized by increased concentration of polymerized hemoglobin S molecules comprising administrating to a subject suffering from the disease characterized by increased concentration of polymerized hemoglobin S molecules an effective amount of a compound of any one of claims 1 - 96 , or a pharmaceutically acceptable salt thereof.
108 . The method of claim 107 , wherein the disease is sickle cell disease.
109 . A method of ameliorating or treating a hemoglobinopathy, comprising administering an effective amount of a compound of any one of claims 1 - 96 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 97 to a subject in need thereof.
110 . The method of claim 109 , wherein the hemoglobinopathy is sickle cell disease.
111 . The method of claim 109 , wherein the hemoglobinopathy is beta-thalassemia.
112 . Use of an effective amount of a compound of any one of claims 1 - 96 , or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for inhibiting the activity of G9a in a cell that contains G9a.
113 . Use of an effective amount of a compound of any one of claims 1 - 96 , or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for inhibiting the activity of GLP in a cell that contains GLP.
114 . Use of an effective amount of a compound of any one of claims 1 - 96 , or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for increasing fetal hemoglobin (HbF) protein levels in a cell characterized as having impaired production of β-globin.
115 . Use of an effective amount of a compound of any one of claims 1 - 96 , or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for inhibiting the polymerization of hemoglobin S molecules in a cell characterized as having a hemoglobin S mutation.
116 . Use of an effective amount of a compound of any one of claims 1 - 96 , or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease treatable by fetal hemoglobin.
117 . Use of an effective amount of a compound of any one of claims 1 - 96 , or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease treatable by fetal hemoglobin.
118 . Use of an effective amount of a compound of any one of claims 1 - 96 , or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease characterized by impaired production of β-globin.
119 . The use of claim 118 , wherein the disease is beta-thalassemia.
120 . Use of an effective amount of a compound of any one of claims 1 - 96 , or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease characterized by increased concentration of polymerized hemoglobin S molecules.
121 . The use of claim 120 , wherein the disease is sickle cell disease.
122 . Use of an effective amount of a compound of any one of claims 1 - 96 , or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for ameliorating or treating a hemoglobinopathy.
123 . The use of claim 122 , wherein the hemoglobinopathy is sickle cell disease.
124 . The use of claim 122 , wherein the hemoglobinopathy is beta-thalassemia.Join the waitlist — get patent alerts
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