Compounds which inhibit RNA polymerase
This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that inhibit RNA polymerase I (Pol I). Said chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) Pol I activity contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions containing the same as well as methods of using and making the same.
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H or C 1-3 alkyl;
R 2 is selected from the group consisting of:
(a) —NR 6 R 7 , wherein R 6 and R 7 are independently selected from the group consisting of: H and C 1-6 alkyl which is optionally substituted with from 1-6 R a ;
(b) —OR 8 , wherein R 8 is H or C 1-6 alkyl which is optionally substituted with from 1-6 R a ; and
(c) heterocyclyl of 4-12 ring atoms, wherein from 1-3 ring atoms are ring heteroatoms each independently selected from the group consisting of N, NH, N(R d ), O, and S(O) 0-2 , wherein the heterocyclyl is optionally substituted with from 1-6 R b ,
L 1 is a bond or C 1-6 alkylene which is optionally substituted with from 1-6 R c , provided that when L 1 is a bond, then R 2 is heterocyclyl that is attached to L 1 via a ring carbon atom;
R 3a , R 3b , R 3c , R 4a , R 4b , R 5a , R 5b , R 5c , and R 5d are each independently selected from the group consisting of: H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and OH;
each occurrence of R a and R c is independently selected from the group consisting of: —OH; -halo; —NR′R″; C 1-4 alkoxy; C 1-4 haloalkoxy; —C(═O)O(C 1-4 alkyl); —C(═O)(C 1-4 alkyl); —C(═O)OH; —CONR′R″; —S(O) 1-2 NR′R″; —S(O) 1-2 (C 1-4 alkyl); and cyano;
each occurrence of R b is independently selected from the group consisting of: C 1-6 alkyl; C 1-6 haloalkyl; oxo; —OH; -halo; —NR′R″; C 1-4 alkoxy; C 1-4 haloalkoxy; —C(—O)O(C 1-4 alkyl); —C(═O)(C 1-4 alkyl); —C(═O)OH; —CONR′R″; —S(O) 1-2 NR′R″; —S(O) 1-2 (C 1-4 alkyl); and cyano;
each occurrence of R d is independently C 1-6 alkyl; —C(O)(C 1-4 alkyl); or —C(O)O(C 1-4 alkyl); and
each occurrence of R′ and R″ is independently H or C 1-3 alkyl.
2 . The compound of claim 1 , wherein L 1 is C 1-6 alkylene optionally substituted with from 1-6 R c .
3 . The compound of claim 1 , wherein L 1 is unsubstituted C 1-4 alkylene.
4 . The compound of claim 3 , wherein L 1 is selected from the group consisting of
wherein aa is the point of attachment to R 2 .
5 . The compound of claim 1 , wherein R 2 is NR 6 R 7 .
6 . The compound of claim 1 , wherein R 2 is selected from the group consisting of: NH(C 1-3 alkyl) and N(C 1-3 alkyl) 2 .
7 . The compound of claim 6 , wherein R 2 is NMe 2 .
8 . The compound of claim 1 , wherein R 2 is heterocyclyl of 4-12 ring atoms, wherein from 1-3 ring atoms are ring heteroatoms each independently selected from the group consisting of N, NH, N(R d ), O, and S(O) 0-2 , wherein the heterocyclyl is optionally substituted with from 1-6 R b .
9 . The compound of claim 1 , wherein R 2 is heterocyclyl of 4-8 ring atoms, wherein from 1-2 ring atoms are ring heteroatoms each independently selected from the group consisting of N, NH, N(R d ), O, and S(O) 0-2 , wherein the heterocyclyl is optionally substituted with from 1-6 R b , wherein at least 1 ring atom is N, NH, or N(R d ).
10 . The compound of claim 1 , wherein R 2 is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, or 8-oxa-3-azabicyclo[3.2.1]octanyl, each of which is optionally substituted with from 1-2 R b .
11 . The compound of claim 1 , wherein R 2 is pyrrolidinyl which is optionally substituted with from 1-2 R b , wherein the ring nitrogen is optionally substituted with R d .
12 . The compound of claim 8 , wherein each R b is independently selected from the group consisting of: halo; —OH; oxo; C 1-3 alkyl; and C 1-3 alkoxy.
13 . The compound of claim 1 , wherein R 1 is H.
14 . The compound of claim 1 , wherein R 3a , R 3b , R 3c , R 4a , R 4b , R 5a , R 5b , R 5c , and R 5d are each H.
15 . The compound of claim 1 , wherein the compound is selected from the group consisting of the compounds in the table below, or a pharmaceutically acceptable salt thereof:
Com-
pound
No.
Structure
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
16 . A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.
17 . A method for activating upstream p53 pathways in a mammalian cell, wherein the method comprises contacting a cell or population of cells with a compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof.
18 . A method for modulating RNA Pol I activity in a mammalian cell, wherein the method comprises contacting a cell or population of cells with a compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof.
19 . A method for treating cancer in a subject, wherein the method comprises administering to the subject a compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof.
20 . A method for treating an autoimmune disease or disorder in a subject, wherein the method comprises administering to the subject a compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof.
21 . A method for treating a condition associated with inflammation or pain in a subject, wherein the method comprises administering to the subject a compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof.