CD73 inhibitors
Described herein are CD73 inhibitors and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for the treatment of cancer, infections, and neurodegenerative diseases.
1 . A compound of Formula (I),
or a pharmaceutically acceptable salt thereof, wherein
X is —O—, —CH 2 —, —S—, —S(O) 2 —, or —NR′;
R 1 is -L 1 R 10 ;
L′ is a bond or an optionally substituted branched or straight C 1-6 alkylene chain, wherein up to two carbon atoms of L 1 are optionally and independently replaced by —NR′—, —S—, —O—, —OC(O)—, —C(O)O—, —C(O)—, —C(O)C(O)—, —C(O)NR′—, —NR′C(O)—, —NR′C(O)O—, —S(O) 2 NR′—, -NR'S(O) 2 —, —C(O)NR′NR′—, —NR′C(O)NR′—, —OC(O)NR′—, —NR′NR′—, -NR'S(O) 2 NR′—, —S(O)—, or —S(O) 2 —;
R 10 is selected from R′, halo, —CN, and —CF 3 ;
each R′ is independently selected from —H, and an optionally substituted group selected from a C 1-6 alkyl, a C 2-6 alkenyl, a C 2-6 alkynyl, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two occurrences of R′ are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R 2 is -L 2 -R 20 ;
L 2 is a bond or an optionally substituted branched or straight C 1-6 alkylene chain, wherein up to two carbon atoms of L 2 are optionally and independently replaced by —NR″; —S—, —O—, —OC(O)—, —C(O)O—, —C(O)—, —C(O)C(O)—, —C(O)NR″—, —NR″C(O)—, —NR″C(O)O—, —S(O) 2 NR″—, —NR″S(O) 2 —, —C(O)NR″NR″—, —NR″C(O)NR″—, —OC(O)NR″—, —NR″NR″—, —NR″S(O) 2 NR″—, —S(O)—, or —S(O) 2 —;
R 20 is independently selected from R″, halo, —CN, and —CF 3 ,
each R″ is independently selected from —H, and an optionally substituted group selected from a C 1-6 alkyl, a C 2-6 alkenyl, a C 2-6 alkynyl, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two occurrences of R″ are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each of R 3 and R 4 is independently selected from —H, C 1-3 alkyl, and a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R A is
n is 1, 2, or 3;
each R 5 is independently -L 3 -R 30 ;
each L 3 is independently a bond or an optionally substituted branched or straight C 1-6 alkylene chain, wherein up to two carbon atoms of L 3 are optionally and independently replaced by —NR′″—, —S—, —O—, —OC(O)—, —C(O)O—, —C(O)—, —C(O)C(O)—, —C(O)NR′″—, —NR′″C(O)—, —NR′″C(O)O—, —S(O) 2 NR′″—, —NR″'S(O) 2 —, —C(O)NR′″NR′″—, —NR′″C(O)NR′″—, —OC(O)NR′″—, —NR′″NR″>-, —NR″'S(O) 2 NR′″—, —S(O)—, or —S(O) 2 —;
each R 30 is independently selected from R′″, halo, —CN, and —CF 3 ;
each R′″ is independently selected from —H, and an optionally substituted group selected from a C 1-6 alkyl, a C 2-6 alkenyl, a C 2-6 alkynyl, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two occurrences of R″ are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and
R 6 is —H, —CN, halo, or C 1-6 alkyl;
provided that if R 1 is —H, then R 2 is other than —H.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is —O—.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
L 1 is an optionally substituted branched or straight C 1-4 alkylene chain, wherein up to one carbon atom of L 1 is optionally and independently replaced by —NR′—, —S—, —O—, —OC(O)—, —C(O)O—, —C(O)—, —C(O)C(O)—, —C(O)NR′—, or —NR′C(O)—;
R 10 is R′; and
each R′ is independently selected from —H, and an optionally substituted group selected from a C 1-3 alkyl or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
4 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
L′ is an optionally substituted branched or straight C 1-4 alkylene chain, wherein one carbon atom of L′ is optionally and independently replaced by —O—, —OC(O)—, —C(O)O—, or ˜ C(O)—; and
R 10 is independently selected from —H, —CH 3 , —CH 2 CH 3 , and an optionally substituted group selected from
5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
L 1 is an optionally substituted branched or straight C 1-3 alkylene chain, wherein one carbon atom of L 1 is optionally and independently replaced by —O—, —OC(O)—, —C(O)O—, or —C(O)—; and
R 10 is —H or
6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —H, —CH 3 , —CH 2 —OH, —CH 2 —CH 3 , —CH 2 —O—CH 3 , —CH 2 C(O) OH, —CH 2 —O—CH 2 —C(O) OH, —CH 2 —O—CH 2 —C(O) CH 3 , —C(O) OH,
7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
L 2 is an optionally substituted branched or straight Cua alkylene chain, wherein one carbon atom of L 2 is optionally replaced by —NR″ “, —O—, —OC(O)—, —C(O)O—, —C(O)—, —C(O)NR”-, or —NR″C(O)—;
R 20 is R″; and
each R″ is independently selected from —H, an optionally substituted C 1-3 alkyl, and an optionally substituted S-membered heteroaryl.
8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
L 2 is an optionally substituted branched or straight C 1-4 alkylene chain, wherein one carbon atom of L 2 is optionally replaced by —O—, —OC(O)—, —C(O)O—, or —C(O)—; and
R 20 is —H or an optionally substituted C 1-3 alkyl.
9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is —H, —CH 3 , —CH 2 —OH, —CH 2 —O—CH 3 , —CH 2 C(O) OH, —C(O) OH,
10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each of R 3 and R 4 is independently H or C 1-3 alkyl.
11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each of R 3 and R 4 is —H.
12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2;
each L 3 is independently a bond or an optionally substituted branched or straight C 1-6 alkylene chain, wherein up to two carbon atoms of L 3 are optionally and independently replaced by —NR′″—, —S—, —O—, —OC(O)—, —C(O)O—, —C(O)—, —C(O)NR′″—, —NR′″C(O)—, —S(O)—, or —S(O) 2 —;
each R 30 is R′″ or halo; and
each R′″ is independently selected from —H, and an optionally substituted group selected from a C 1-6 alkyl, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
13 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 2 and at least one occurrence of R 5 is halo.
14 . The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein one occurrence of R 5 is halo, and a second occurrence of R 5 is -L 3 -R 30 ; wherein L 3 is independently a bond or an optionally substituted branched or straight C 1-4 alkylene chain, wherein one carbon atom of L 3 is optionally and independently replaced by —NR′″—, —S—, or —O—;
R 30 is R′″; and
each R′″ is independently selected from —H, and an optionally substituted group selected from a C 1-3 alkyl, and a 4-6-membered saturated, partially unsaturated, or fully unsaturated carbocycle.
15 . The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein one occurrence of R 5 is —Cl, —Br, or —F, and the second occurrence of R 5 is -L 3 -R 30 ; wherein L 3 is independently a bond or an optionally substituted branched or straight C 1-3 alkylene chain, wherein one carbon atom of L 3 is optionally and independently replaced by —NR″′—; R 30 is R′″; and each R′″ is independently selected from —H, and an optionally substituted group selected from a C 1-3 alkyl, or a 4-6-membered saturated, partially unsaturated, or fully unsaturated carbocycle.
16 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A is
wherein Z is halo, and R 5 is -L 3 -R 30 ; wherein L′ is independently a bond or an optionally substituted branched or straight C 1-4 alkylene chain, wherein one carbon atom of L 3 is optionally and independently replaced by —NR″, —S—, or —O—; R 30 is R′″; and each R′″ is independently selected from —H, and an optionally substituted group selected from a C 1-3 alkyl, a 4-6-membered saturated, partially unsaturated, or fully unsaturated carbocycle, or a 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic carbocycle.
17 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A is
and R 5a is —H, —CH 3 ,
wherein ring B is
18 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A is
19 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A is
wherein Z is halo, and R 5 is -L 3 -R 30 ; wherein L 3 is independently a bond or an optionally substituted branched or straight C 1-4 alkylene chain, wherein one carbon atom of L 3 is optionally and independently replaced by —NR′″—, —S—, or —O—; R 30 is R′″; and each R′″ is independently selected from —H, and an optionally substituted group selected from a C 1-3 alkyl, a 4-6-membered saturated, partially unsaturated, or fully unsaturated carbocycle, or a 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic carbocycle.
20 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A is
and R 5a is —H, —CH 3 ,
wherein ring B is
21 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A is
22 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is a compound of Formula (Ia-1) or (Ia-2):
23 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is a compound of Formula (Ia-3) or (Ia-4):
24 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is a compound of Formula (Ia-7):
wherein R 5a is —H, —CH 3 ,
wherein ring B is
25 . The compound of claim 24 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (Ia-7) is a compound of Formula (Ia-8) or (Ia-9):
26 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (D) is a compound of Formula (Ib-1) or (Ib-2):
27 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is a compound of Formula (Ib-3) or (Ib-4):
28 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is a compound of Formula (Ib-7):
wherein R 5a is —H, —CH 3 ,
wherein ring B is
29 . The compound of claim 28 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (Ib-7) is a compound of Formula (Ib-8) or (Ib-9):
30 . A compound selected from the group consisting of:
or a
pharmaceutically acceptable salt thereof.
31 . A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle, carrier, or adjuvant.