US2020115404A1PendingUtilityA1
Cd73 inhibitors and uses thereof
Est. expiryMar 31, 2037(~10.7 yrs left)· nominal 20-yr term from priority
C07F 9/65616C07D 495/04C07D 487/14C07D 473/34C07D 473/16C07D 487/04C07D 473/30C07F 9/6561C07D 473/00C07H 19/23C07H 19/167C07H 19/12A61P 35/00
56
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
Compounds that modulate CD73 activity, pharmaceutical compositions containing these compounds, and methods of using these compounds for treating diseases associated with CD73 activity are described herein.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula (III):
or a pharmaceutically acceptable salt thereof, wherein:
W 1 is selected from N, NR 8 , CR 6 , and S;
W 2 and W 3 are each independently selected from N and CR 6 ;
W 4 and W 5 are each independently selected from N and C;
W 6 is selected from N, CR 6 , and S;
wherein at least one of W 1 , W 2 , W 3 , W 4 , W 5 , and W 6 is N, and provided that:
when W 1 , W 2 , W 3 , W 5 , and W 6 are N, W 4 is not N; and
when either W 1 or W 6 is S, the other is CR 6 ;
R 15 is selected from —NR 1 R 2 , —OR 1 , —SR 1 and —CN; and C 3-12 membered carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more R 7 ;
R 1 is selected from hydrogen; and C 1-6 alkyl and C 3-12 carbocycle, each of which is optionally substituted with one or more R 7 ;
R 2 is selected from C 1-6 alkyl, C 3-12 carbocycle, 3- to 12-membered heterocycle and benzyl, each of which is optionally substituted with one or more R 7 ; or
R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a 3- to 12-membered heterocycle, optionally substituted with one or more R 7 ;
R 3 is selected from hydrogen, halogen, cyano, —N(R 8 ) 2 and —OR 8 ; and C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 carbocycle, 3- to 12-membered heterocycle and benzyl, each of which is optionally substituted with one or more R 7 ;
A is selected from —O—, —S—, —S(═O)— and —S(═O) 2 —;
X and Y are independently selected from —O— and —NR 8 —;
R 4 and R 5 are independently selected from:
hydrogen; and
C 1-6 alkyl, phenyl, and 3- to 12-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO 2 , —CN, —OR 8 , —SR 8 , —N(R 8 ) 2 , —NR 9 R 10 , —S(═O)R 8 , —S(═O) 2 R 8 , —S(═O) 2 N(R 8 ) 2 , —S(═O) 2 NR 9 R 10 , —NR 8 S(═O) 2 R 8 , —NR 8 S(═O) 2 N(R 8 ) 2 , —NR 8 S(═O) 2 NR 9 R 10 , —S—S—R 8 , —S—C(O)R 8 , —C(O)R 8 , —C(O)OR 8 , —OC(O)R 8 , —OC(O)OR 8 , —OC(O)N(R 8 ) 2 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 8 , —NR 8 C(O)OR 8 , —NR 8 C(O)N(R 8 ) 2 , —NR 8 C(O)NR 9 R 10 , —C(O)N(R 8 ) 2 , —C(O)NR 9 R 10 , —P(O)(OR 8 ) 2 , —P(O)(R 8 ) 2 , —OP(O)(OR 8 ) 2 , ═O, ═S, ═N(R 8 ), C 3-12 carbocycle, and 3- to 12-membered heterocycle; or
R 4 and R 5 are taken together with the atoms to which they are attached to form a 3- to 12-membered heterocycle, optionally substituted with one or more R 7 ;
R 6 is selected from hydrogen, halogen and cyano; and C 1-6 alkyl, optionally substituted with one or more R 7 ;
R 7 is independently selected at each occurrence from:
halogen, —NO 2 , —CN, —OR 8 , —SR 8 , —N(R 8 ) 2 , —NR 9 R 10 , —S(═O)R 8 , —S(═O) 2 R 8 , —S(═O) 2 N(R 8 ) 2 , —S(═O) 2 NR 9 R 10 , —NR 8 S(═O) 2 R 8 , —NR 8 S(═O) 2 N(R 8 ) 2 , —NR 8 S(═O) 2 NR 9 R 10 , —C(O)R 8 , —C(O)OR 8 , —OC(O)R 8 , —OC(O)OR 8 , —OC(O)N(R 8 ) 2 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 8 , —NR 8 C(O)OR 8 , —NR 8 C(O)N(R 8 ) 2 , —NR 8 C(O)NR 9 R 10 , —C(O)N(R 8 ) 2 , —C(O)NR 9 R 10 , —P(O)(OR 8 ) 2 , —P(O)(R 8 ) 2 , ═O, ═S, and ═N(R 8 );
C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO 2 , —CN, —OR 8 , —SR 8 , —N(R 8 ) 2 , —NR 9 R 10 , —S(═O)R 8 , —S(═O) 2 R 8 , —S(═O) 2 N(R 8 ) 2 , —S(═O) 2 NR 9 R 10 , —NR 8 S(═O) 2 R 8 , —NR 8 S(═O) 2 N(R 8 ) 2 , —NR 8 S(═O) 2 NR 9 R 10 , —C(O)R 8 , —C(O)OR 8 , —OC(O)R 8 , —OC(O)OR 8 , —OC(O)N(R 8 ) 2 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 8 , —NR 8 C(O)OR 8 , —NR 8 C(O)N(R 8 ) 2 , —NR 8 C(O)NR 9 R 10 , —C(O)N(R 8 ) 2 , —C(O)NR 9 R 10 , —P(O)(OR 8 ) 2 , —P(O)(R 8 ) 2 , ═O, ═S, ═N(R 8 ), C 3-12 carbocycle, and 3- to 12-membered heterocycle; and
C 3-12 carbocycle and 3- to 12-membered heterocycle,
wherein each C 3-12 carbocycle and 3- to 12-membered heterocycle in R 7 is independently optionally substituted with one or more substituents selected from halogen, —NO 2 , —CN, —OR 8 , —SR 8 , —N(R 8 ) 2 , —NR 9 R 10 , —S(═O)R 8 , —S(═O) 2 R 8 , —S(═O) 2 N(R 8 ) 2 , —S(═O) 2 NR 9 R 10 , —NR 8 S(═O) 2 R 8 , —NR 8 S(═O) 2 N(R 8 ) 2 , —NR 8 S(═O) 2 NR 9 R 10 , —C(O)R 8 , —C(O)OR 8 , —OC(O)R 8 , —OC(O)OR 8 , —OC(O)N(R 8 ) 2 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 8 , —NR 8 C(O)OR 8 , —NR 8 C(O)N(R 8 ) 2 , —NR 8 C(O)NR 9 R 10 , —C(O)N(R 8 ) 2 , —C(O)NR 9 R 10 , —P(O)(OR 8 ) 2 , —P(O)(R 8 ) 2 , ═O, ═S, ═N(R 8 ), C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
R 8 is independently selected at each occurrence from hydrogen; and C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, —CN, —NO 2 , —NH 2 , —NHCH 3 , —NHCH 2 CH 3 , ═O, —OH, —OCH 3 , —OCH 2 CH 3 , C 3-12 carbocycle, or 3- to 6-membered heterocycle;
R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 7 ;
R 13 is selected from hydrogen and C 1-6 alkyl; and
R 14 is selected from hydrogen and R 7 .
2 . The compound of claim 1 , wherein W 5 is N.
3 . The compound of claim 1 , wherein W 5 is C.
4 . The compound of claim 3 , wherein one of W 1 or W 6 is S.
5 . The compound of claim 3 , wherein W 4 is N.
6 . The compound of any one of claims 1 to 5 , wherein R 13 is hydrogen.
7 . The compound of any one of claims 1 to 6 , wherein R 14 is selected from hydrogen and phenyl.
8 . The compound of any one of claims 1 to 7 , wherein R 15 is —NR 1 R 2 .
9 . The compound of any one of claims 1 to 8 , wherein A is —O—.
10 . The compound of any one of claims 1 to 8 , wherein A is selected from —S—, —S(═O)— and —S(═O) 2 —.
11 . A compound of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
W 1 , W 2 and W 3 are each independently selected from N and CR 6 , wherein at least one of W 1 , W 2 and W 3 is N;
R 1 is selected from hydrogen; and C 1-6 alkyl and C 3-12 carbocycle, each of which is optionally substituted with one or more R 7 ;
R 2 is selected from C 1-6 alkyl, C 3-12 carbocycle, 3- to 12-membered heterocycle and benzyl, each of which is optionally substituted with one or more R 7 ; or
R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a 3- to 12-membered heterocycle, optionally substituted with one or more R 7 ;
R 3 is selected from hydrogen, halogen and cyano; and C 1-6 alkyl, C 3-12 carbocycle, 3- to 12-membered heterocycle and benzyl, each of which is optionally substituted with one or more R 7 ;
A is selected from —S—, —S(═O)— and —S(═O) 2 —;
X and Y are independently selected from —O— and —NR 8 —;
R 4 and R 5 are independently selected from:
hydrogen; and
C 1-6 alkyl and phenyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO 2 , —CN, —OR 8 , —SR 8 , —N(R 8 ) 2 , —NR 9 R 10 , —S(═O)R 8 , —S(═O) 2 R 8 , —S(═O) 2 N(R 8 ) 2 , —S(═O) 2 NR 9 R 10 , —NR 8 S(═O) 2 R 8 , —NR 8 S(═O) 2 N(R 8 ) 2 , —NR 8 S(═O) 2 NR 9 R 10 , —S—S—R 8 , —S—C(O)R 8 , —C(O)R 8 , —C(O)OR 8 , —OC(O)R 8 , —OC(O)OR 8 , —OC(O)N(R 8 ) 2 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 8 , —NR 8 C(O)OR 8 , —NR 8 C(O)N(R 8 ) 2 , —NR 8 C(O)NR 9 R 10 , —C(O)N(R 8 ) 2 , —C(O)NR 9 R 10 , —P(O)(OR 8 ) 2 , —P(O)(R 8 ) 2 , —OP(O)(OR 8 ) 2 , ═O, ═S, ═N(R 8 ), C 3-12 carbocycle, and 3- to 12-membered heterocycle;
R 6 is selected from hydrogen, halogen and cyano; and C 1-6 alkyl, optionally substituted with one or more R 7 ;
R 7 is independently selected at each occurrence from:
halogen, —NO 2 , —CN, —OR 8 , —SR 8 , —N(R 8 ) 2 , —NR 9 R 10 , —S(═O)R 8 , —S(═O) 2 R 8 , —S(═O) 2 N(R 8 ) 2 , —S(═O) 2 NR 9 R 10 , —NR 8 S(═O) 2 R 8 , —NR 8 S(═O) 2 N(R 8 ) 2 , —NR 8 S(═O) 2 NR 9 R 10 , —C(O)R 8 , —C(O)OR 8 , —OC(O)R 8 , —OC(O)OR 8 , —OC(O)N(R 8 ) 2 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 8 , —NR 8 C(O)OR 8 , —NR 8 C(O)N(R 8 ) 2 , —NR 8 C(O)NR 9 R 10 , —C(O)N(R 8 ) 2 , —C(O)NR 9 R 10 , —P(O)(OR 8 ) 2 , —P(O)(R 8 ) 2 , ═O, ═S, and ═N(R 8 );
C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO 2 , —CN, —OR 8 , —SR 8 , —N(R 8 ) 2 , —NR 9 R 10 , —S(═O)R 8 , —S(═O) 2 R 8 , —S(═O) 2 N(R 8 ) 2 , —S(═O) 2 NR 9 R 10 , —NR 8 S(═O) 2 R 8 , —NR 8 S(═O) 2 N(R 8 ) 2 , —NR 8 S(═O) 2 NR 9 R 10 , —C(O)R 8 , —C(O)OR 8 , —OC(O)R 8 , —OC(O)OR 8 , —OC(O)N(R 8 ) 2 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 8 , —NR 8 C(O)OR 8 , —NR 8 C(O)N(R 8 ) 2 , —NR 8 C(O)NR 9 R 10 , —C(O)N(R 8 ) 2 , —C(O)NR 9 R 10 , —P(O)(OR 8 ) 2 , —P(O)(R 8 ) 2 , ═O, ═S, ═N(R 8 ), C 3-12 carbocycle, and 3- to 12-membered heterocycle; and
C 3-12 carbocycle and 3- to 12-membered heterocycle,
wherein each C 3-12 carbocycle and 3- to 12-membered heterocycle in R 7 is independently optionally substituted with one or more substituents selected from halogen, —NO 2 , —CN, —OR 8 , —SR 8 , —N(R 8 ) 2 , —NR 9 R 10 , —S(═O)R 8 , —S(═O) 2 R 8 , —S(═O) 2 N(R 8 ) 2 , —S(═O) 2 NR 9 R 10 , —NR 8 S(═O) 2 R 8 , —NR 8 S(═O) 2 N(R 8 ) 2 , —NR 8 S(═O) 2 NR 9 R 10 , —C(O)R 8 , —C(O)OR 8 , —OC(O)R 8 , —OC(O)OR 8 , —OC(O)N(R 8 ) 2 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 8 , —NR 8 C(O)OR 8 , —NR 8 C(O)N(R 8 ) 2 , —NR 8 C(O)NR 9 R 10 , —C(O)N(R 8 ) 2 , —C(O)NR 9 R 10 , —P(O)(OR 8 ) 2 , —P(O)(R 8 ) 2 , ═O, ═S, ═N(R 8 ), C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
R 8 is independently selected at each occurrence from hydrogen; and C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, —CN, —NO 2 , —NH 2 , —NHCH 3 , —NHCH 2 CH 3 , ═O, —OH, —OCH 3 , —OCH 2 CH 3 , C 3-12 carbocycle, or 3- to 6-membered heterocycle; and
R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 7 .
12 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
W 1 , W 2 and W 3 are each independently selected from N and CR 6 , wherein at least one of W 1 , W 2 and W 3 is N;
R 1 is selected from hydrogen; and C 1-6 alkyl and C 3-12 carbocycle, each of which is optionally substituted with one or more R 7 ;
R 2 is selected from C 1-6 alkyl, C 3-12 carbocycle, 3- to 12-membered heterocycle and benzyl, each of which is optionally substituted with one or more R 7 ; or
R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a 3- to 12-membered heterocycle, optionally substituted with one or more R 7 ;
R 3 is selected from halogen and cyano; and C 1-6 alkyl, C 3-12 carbocycle, 3- to 12-membered heterocycle and benzyl, each of which is optionally substituted with one or more R 7 ;
X and Y are independently selected from —O— and —NR 8 —;
R 4 and R 5 are independently selected from:
hydrogen; and
C 1-6 alkyl and phenyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO 2 , —CN, —OR, —SR, —N(R 8 ) 2 , —NR 9 R 10 , —S(═O)R 8 , —S(═O) 2 R 8 , —S(═O) 2 N(R 8 ) 2 , —S(═O) 2 NR 9 R 10 , —NR 8 S(═O) 2 R 8 , —NR 8 S(═O) 2 N(R 8 ) 2 , —NR 8 S(═O) 2 NR 9 R 10 , —S—S—R 8 , —S—C(O)R 8 , —C(O)R 8 , —C(O)OR 8 , —OC(O)R 8 , —OC(O)OR 8 , —OC(O)N(R 8 ) 2 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 8 , —NR 8 C(O)OR 8 , —NR 8 C(O)N(R 8 ) 2 , —NR 8 C(O)NR 9 R 10 , —C(O)N(R 8 ) 2 , —C(O)NR 9 R 10 , —P(O)(OR 8 ) 2 , —P(O)(R 8 ) 2 , —OP(O)(OR 8 ) 2 , ═O, ═S, ═N(R 8 ), C 3-12 carbocycle, and 3- to 12-membered heterocycle;
R 6 is selected from hydrogen, halogen and cyano; and C 1-6 alkyl, optionally substituted with one or more R 7 ;
R 7 is independently selected at each occurrence from:
halogen, —NO 2 , —CN, —OR 8 , —SR 8 , —N(R 8 ) 2 , —NR 9 R 10 , —S(═O)R 8 , —S(═O) 2 R 8 , —S(═O) 2 N(R 8 ) 2 , —S(═O) 2 NR 9 R 10 , —NR 8 S(═O) 2 R 8 , —NR 8 S(═O) 2 N(R 8 ) 2 , —NR 8 S(═O) 2 NR 9 R 10 , —C(O)R 8 , —C(O)OR 8 , —OC(O)R 8 , —OC(O)OR 8 , —OC(O)N(R 8 ) 2 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 8 , —NR 8 C(O)OR 8 , —NR 8 C(O)N(R 8 ) 2 , —NR 8 C(O)NR 9 R 10 , —C(O)N(R 8 ) 2 , —C(O)NR 9 R 10 , —P(O)(OR 8 ) 2 , —P(O)(R 8 ) 2 , ═O, ═S, and ═N(R 8 );
C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO 2 , —CN, —OR 8 , —SR 8 , —N(R 8 ) 2 , —NR 9 R 10 , —S(═O)R 8 , —S(═O) 2 R 8 , —S(═O) 2 N(R 8 ) 2 , —S(═O) 2 NR 9 R 10 , —NR 8 S(═O) 2 R 8 , —NR 8 S(═O) 2 N(R 8 ) 2 , —NR 8 S(═O) 2 NR 9 R 10 , —C(O)R 8 , —C(O)OR 8 , —OC(O)R 8 , —OC(O)OR 8 , —OC(O)N(R 8 ) 2 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 8 , —NR 8 C(O)OR 8 , —NR 8 C(O)N(R 8 ) 2 , —NR 8 C(O)NR 9 R 10 , —C(O)N(R 8 ) 2 , —C(O)NR 9 R 10 , —P(O)(OR 8 ) 2 , —P(O)(R 8 ) 2 , ═O, ═S, ═N(R 8 ), C 3-12 carbocycle, and 3- to 12-membered heterocycle; and
C 3-12 carbocycle and 3- to 12-membered heterocycle,
wherein each C 3-12 carbocycle and 3- to 12-membered heterocycle in R 7 is independently optionally substituted with one or more substituents selected from halogen, —NO 2 , —CN, —OR 8 , —SR 8 , —N(R 8 ) 2 , —NR 9 R 10 , —S(═O)R 8 , —S(═O) 2 R 8 , —S(═O) 2 N(R 8 ) 2 , —S(═O) 2 NR 9 R 10 , —NR 8 S(═O) 2 R 8 , —NR 8 S(═O) 2 N(R 8 ) 2 , —NR 8 S(═O) 2 NR 9 R 10 , —C(O)R 8 , —C(O)OR 8 , —OC(O)R 8 , —OC(O)OR 8 , —OC(O)N(R 8 ) 2 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 8 , —NR 8 C(O)OR 8 , —NR 8 C(O)N(R 8 ) 2 , —NR 8 C(O)NR 9 R 10 , —C(O)N(R 8 ) 2 , —C(O)NR 9 R 10 , —P(O)(OR 8 ) 2 , —P(O)(R 8 ) 2 , ═O, ═S, ═N(R 8 ), C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
R 8 is independently selected at each occurrence from hydrogen; and C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, —CN, —NO 2 , —NH 2 , —NHCH 3 , —NHCH 2 CH 3 , ═O, —OH, —OCH 3 , —OCH 2 CH 3 , C 3-12 carbocycle, or 3- to 6-membered heterocycle; and
R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 7 .
13 . The compound of any one of the preceding claims, wherein R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a 3- to 12-membered heterocycle, optionally substituted with one or more R 7 .
14 . The compound of claim 13 , wherein R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a 3- to 12-membered heterocycle, optionally substituted with one or more substituents independently selected from halogen, —CN, C 1-4 alkyl, C 1-3 haloalkyl, —OH and —NH 2 .
15 . The compound of any one of the preceding claims, wherein R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form optionally substituted 3- to 7-membered monocyclic heterocycloalkyl or optionally substituted 5- to 12-membered fused bicyclic heterocycloalkyl.
16 . The compound of any one of claims 1 to 12 , wherein R 2 is selected from C 1-6 alkyl, C 3-12 carbocycle, 3- to 12-membered heterocycle and benzyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —CN, C 1-4 alkyl, C 1-3 haloalkyl, —OH and —NH 2 .
17 . The compound of any one of claims 1 to 12 , wherein R 2 is benzyl, optionally substituted with one or more R 7 .
18 . The compound of claim 17 , wherein R 2 is benzyl, optionally substituted with one or more substituents independently selected from halogen, —CN, C 1-4 alkyl, C 1-3 haloalkyl, —OH and —NH 2 .
19 . The compound of any one of claims 1 to 10 , represented by Formula (III-A) or (III-B):
or a pharmaceutically acceptable salt thereof, wherein:
R 11 is selected from C 1-6 alkyl and C 3-12 carbocycle, each of which is optionally substituted with one or more R 7 ;
R 12 is independently selected at each occurrence from R 7 ; and
n is an integer from 0 to 3.
20 . The compound of claim 11 , represented by Formula (II-A) or (II-B):
or a pharmaceutically acceptable salt thereof, wherein:
R 11 is selected from C 1-6 alkyl and C 3-12 carbocycle, each of which is optionally substituted with one or more R 7 ;
R 12 is independently selected at each occurrence from R 7 ; and
n is an integer from 0 to 3.
21 . The compound of claim 12 , represented by Formula (I-A) or (I-B):
or a pharmaceutically acceptable salt thereof, wherein:
R 11 is selected from C 1-6 alkyl and C 3-12 carbocycle, each of which is optionally substituted with one or more R 7 ;
R 12 is independently selected at each occurrence from R 7 ; and
n is an integer from 0 to 3.
22 . The compound of any one of claims 19 to 21 , wherein R 11 is C 1-4 alkyl.
23 . The compound of claim 22 , wherein R 11 is selected from methyl, ethyl, iso-propyl and tert-butyl.
24 . The compound of any one of claims 19 to 21 , wherein R 11 is selected from C 1-4 alkyl and C 3-12 cycloalkyl, each of which is optionally substituted with one or more R 7 .
25 . The compound of any one of claims 19 to 24 , wherein R 12 is independently selected at each occurrence from halogen, —CN, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkyl and C 1-4 haloalkyl.
26 . The compound of any one of claims 19 to 25 , wherein R 12 is independently selected at each occurrence from halogen, —CN, C 1-4 alkyl and C 1-4 haloalkyl.
27 . The compound of any one of claims 19 to 26 , wherein R 12 is independently selected at each occurrence from F, —CN, —CH 3 and —CF 3 .
28 . The compound of any one of claims 19 to 27 , wherein n is an integer from 1 to 3.
29 . The compound of any one of claims 1 to 10 , represented by Formula (III-C):
or a pharmaceutically acceptable salt thereof, wherein:
Z is selected from C 3-12 cycloalkyl and 3- to 12-membered heterocycloalkyl, each of which is optionally substituted with one or more R 7 .
30 . The compound of claim 11 , represented by Formula (II-C):
or a pharmaceutically acceptable salt thereof, wherein:
Z is selected from C 3-12 cycloalkyl and 3- to 12-membered heterocycloalkyl, each of which is optionally substituted with one or more R 7 .
31 . The compound of claim 12 , represented by Formula (I-C):
or a pharmaceutically acceptable salt thereof, wherein:
Z is selected from C 3-12 cycloalkyl and 3- to 12-membered heterocycloalkyl, each of which is optionally substituted with one or more R 7 .
32 . The compound of any one of claims 29 to 31 , wherein Z is selected from C 3-12 monocyclic cycloalkyl or C 5-12 fused bicyclic cycloalkyl, each of which is optionally substituted with one or more R 7 .
33 . The compound of claim 32 , wherein Z is C 5-12 fused bicyclic cycloalkyl, optionally substituted with one or more R 7 .
34 . The compound of any one of claims 29 to 33 , wherein Z is substituted with one or more substituents independently selected from halogen, —CN, C 1-4 alkyl and C 1-3 haloalkyl.
35 . The compound of any one of claims 1 to 12 or 16 to 34 , wherein R 1 is selected from hydrogen and —CH 3 .
36 . The compound of any one of the preceding claims, wherein W 3 is N.
37 . The compound of any one of the preceding claims, wherein W 2 is N or CH.
38 . The compound of claim 37 , wherein W 2 is N.
39 . The compound of any one of the preceding claims, wherein W 1 is N or CH.
40 . The compound of claim 39 , wherein W 1 is N.
41 . The compound of any one of claims 1 to 35 , wherein W 1 is N or CH, W 2 is N and W 3 is N.
42 . The compound of any one of claims 1 to 11 , 19 , 20 , 29 or 30 , wherein R 3 is selected from halogen and cyano; and C 1-6 alkyl, C 3-12 carbocycle, 3- to 12-membered heterocycle and benzyl, each of which is optionally substituted with one or more R 7 .
43 . The compound of any one of claims 1 to 11 , 19 , 20 , 29 or 30 , wherein R 3 is selected from hydrogen, halogen, —CN, C 1-3 alkyl and C 1-3 haloalkyl.
44 . The compound of any one of the preceding claims, wherein R 3 is selected from halogen, —CN, C 1-3 alkyl and C 1-3 haloalkyl.
45 . The compound of claim 44 , wherein R 3 is selected from —Cl and —CN.
46 . The compound of any one of claims 1 to 45 , wherein at least one of R 4 and R 5 is C 1-6 alkyl, optionally substituted at each occurrence with one or more substituents selected from halogen, —OR 8 , —S—S—R 8 , —S—C(O)R 8 , —OC(O)R 8 , —OC(O)OR 8 and —P(O)(OR 8 ) 2 .
47 . The compound of any one of claims 1 to 45 , wherein R 4 and R 5 are independently selected from C 1-6 alkyl, optionally substituted at each occurrence with one or more substituents selected from halogen, —OR, —S—S—R 8 , —S—C(O)R 8 , —OC(O)R 8 , —OC(O)OR 8 and —P(O)(OR 8 ) 2 .
48 . The compound of any one of claims 1 to 45 , wherein R 4 and R 5 are independently selected from hydrogen and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted at each occurrence with one or more substituents selected from halogen, —OR 8 , —S—S—R 8 , —S—C(O)R 8 , —OC(O)R 8 , —OC(O)OR 8 and —P(O)(OR 8 ) 2 .
49 . The compound of any one of claims 1 to 45 , wherein R 4 and R 5 are independently selected from —CH 2 OC(O)R 8 and —CH 2 OC(O)OR 8 .
50 . The compound of claim 47 , wherein R 4 and R 5 are independently selected from —CH 2 OC(O)C(CH 3 ) 3 , —CH 2 OC(O)OCH(CH 3 ) 2 , —CH 2 OC(O)CH 3 , —CH 2 CH 2 —S—S—(CH 2 ) 2 OH and —CH 2 CH 2 —S—C(O)CH 3 .
51 . The compound of any one of claims 1 to 45 , wherein:
R 4 is phenyl, optionally substituted with —OR 8 ;
R 5 is C 1-6 alkyl substituted with one or more substituents selected from —OC(O)R 8 , —C(O)OR 8 , and —OC(O)OR 8 ; and
R 8 is C 1-6 alkyl.
52 . The compound of any one of claims 1 to 51 , wherein X and Y are each —O—.
53 . The compound of any one of claims 1 to 51 , wherein one of X and Y is —O— and the other one of X and Y is —NR 8 —.
54 . The compound of any one of the preceding claims, wherein:
W 1 is selected from N and CR 6 ; W 2 is selected from N and CH; W 3 is N; R 1 is selected from hydrogen and C 1-4 alkyl; R 3 is selected from halogen and cyano; and R 6 is selected from hydrogen, halogen, cyano and C 1-4 alkyl.
55 . The compound of any one of the preceding claims, wherein:
W 1 is selected from N and CR 6 ; W 2 is selected from N and CH; W 3 is N; R 1 is selected from hydrogen and C 1-4 alkyl; R 3 is selected from halogen and cyano; and R 6 is selected from halogen, cyano and C 1-4 alkyl.
56 . The compound of any one of the preceding claims, wherein —X—R 4 and —Y—R 5 are each —OH.
57 . The compound of any one of claims 1 to 10 , wherein R 3 is selected from optionally substituted C 2 -alkynyl and —OR 8 .
58 . The compound of claim 57 , wherein R 3 is selected from
59 . The compound of any one of claims 1 to 10 , wherein:
W 1 is selected from N and CR 6 ;
W 2 is selected from N and CH;
W 3 is N;
W 4 is C;
W 5 is N;
W 6 is CH;
R 1 is selected from hydrogen and C 1-4 alkyl;
R 3 is selected from halogen and cyano; and
R 6 is selected from hydrogen, halogen, cyano and C 1-4 alkyl.
60 . The compound of any one of claims 1 to 10 , wherein:
W 1 is CH;
W 2 is N;
W 3 is N;
W 4 is C;
W 5 is N;
W 6 is CH;
R 1 is selected from hydrogen;
R 2 is C 3-12 carbocycle; and
R 3 is selected from optionally substituted C 2 -alkynyl and —OR 8 .
61 . A substantially pure stereoisomer of the compound of any one of the preceding claims.
62 . The stereoisomer of claim 61 , wherein the stereoisomer is provided in at least 90% diastereomeric excess.
63 . A compound selected from Table 1.
64 . A pharmaceutical composition comprising a compound or salt of any one of the preceding claims and a pharmaceutically acceptable carrier or diluent.
65 . A method of inhibiting CD73-catalyzed hydrolysis of adenosine monophosphate, comprising contacting CD73 with an effective amount of the compound of any one of claims 1 to 63 .
66 . The method of claim 65 , wherein the contacting comprising contacting a cell that expresses CD73.
67 . The method of claim 65 or 66 , wherein the contacting takes place in vivo.Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.