Isothiazolopyrimidinones, pyrazolopyrimidinones, and pyrrolopyrimidinones as ubiquitin-specific protease 7 inhibitors
The disclosure relates to inhibitors of USP7 inhibitors useful in the treatment of cancers, neurodegenerative diseases, immunological disorders, inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, and bacterial infections and diseases, having the Formula: where R 1 , R 2 , R 3 , R 4 , R 5 , R 5′ , X 1 , X 2 , X 3 , n, and m are described herein.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, and tautomer thereof,
wherein:
X 1 is C, S, or S(O);
X 2 is S or NR 6 ;
X 3 is N or CR 7 , wherein, one of X 2 or X 3 is N;
R 1 is H, OH, SH, NH 2 , or F;
R 2 is (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, heterocycloalkyl, —NR 10 R 11 , or —OR 10 , wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 8 ;
R 3 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl
R 4 is H, (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 12 ;
R 5 and R 5′ are independently H, D, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, or CN;
R 6 is H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, or (C 1 -C 6 ) haloalkyl;
R 7 is H, D, (C 1 -C 6 ) alkyl, halogen, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 14 ;
each R 8 is independently D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —(C 1 -C 3 )-alkylene-O—(C 1 -C 6 ) alkyl, —(C 0 -C 4 )-alkylene-aryl, —(C 0 -C 4 )-alkylene-heteroaryl, (C 3 -C 10 ) cycloalkyl, heterocycloalkyl, —(C 0 -C 4 )-alkylene-O-aryl, —(C 0 -C 4 )-alkylene-O-heteroaryl, —O—(C 3 -C 8 )cycloalkyl, —S-heteroaryl, —CN, —C(O)R 19 , —CO(O)R 19 , —C(O)NR 19 R 20 , —S(O) q R 19 , —S(O) q NR 19 R 20 , —NR 19 S(O) q R 20 , —(C 0 -C 3 )-alkylene-NR 19 R 20 , —NR 19 C(O)R 20 , —NR 19 C(O)C(O)R 20 , —NR 19 C(O)NR 19 R 20 , —P(O)((C 1 -C 6 ) alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , or —OR 19 , wherein the alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 9 ; or
two R 8 together when on adjacent atoms form a (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 9 ; or two R 8 together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent atoms form an aryl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more R 9 ;
each R 9 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, (C 6 -C 14 ) aryl, heteroaryl, —NH 2 , —OH, CN, —C(O)R 21 , —C(O)NR 21 R 22 , —NR 21 C(O)R 22 , —NR 21 R 22 , —S(O) q R 21 , —S(O) q NR 21 R 22 , —NR 21 S(O) q R 22 , oxo, —P(O)((C 1 -C 6 ) alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , —O-aryl, CN, or —O-heteroaryl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 24 ;
R 10 and R 11 are independently H, (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 16 ; or
R 10 and R 11 together with the nitrogen to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 16 ;
each R 12 is independently D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —OH, —NH 2 , —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, (C 6 -C 14 ) aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C 3 -C 8 )cycloalkyl, —C(O)O(C 1 -C 6 ) alkyl, —C(O)NR 25 R 26 , —S(O) q NR 25 R 26 , —NR 25 R 26 , —NR 25 C(O)NR 25 R 26 , —NR 25 C(O)OR 26 , —NR 25 S(O) q R 26 , —NR 25 C(O)R 26 , halogen, —P(O)((C 1 -C 6 ) alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , or —SF 5 , wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 13 ; or
two R 12 together when on adjacent atoms form a (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 13 ; or two R 12 together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R 13 ; or two R 12 together when on adjacent atoms form an aryl ring optionally substituted with one or more R 13 ; or two R 12 together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more R 13 ;
each R 13 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, (C 6 -C 14 ) aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C 3 -C 8 )cycloalkyl, —OH, or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 27 ;
each R 14 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , —OH, (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 15 ;
each R 15 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, OH, or CN;
each R 16 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, (C 1 -C 6 ) hydroxyalkyl, —OH, CN, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 17 ;
each R 17 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, —OH, or CN;
each R 18 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —OH, —NH 2 , or CN;
each R 19 and R 20 is independently H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 23 ;
each R 21 and R 22 is independently H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 23 ;
each R 23 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —OH, or CN;
each R 24 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —NR 25 C(O)R 26 , —NR 25 S(O) q R 26 , —C(O)R 25 , —C(O)NR 25 R 26 , —NR 25 R 26 , —S(O) q R 25 , —S(O) q NR 25 R 26 , —P(O)((C 1 -C 6 ) alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , —OH, or CN;
each R 25 and R 26 is independently at each occurrence H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl;
each R 27 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, —OH, or CN;
m is 0 or 1;
n is 1; and
q is independently at each occurrence 0, 1, or 2.
2. The compound of claim 1 , wherein X 1 is C.
3. The compound of claim 1 , wherein X 2 is S and X 3 is N.
4. The compound of claim 1 , wherein X 2 is NR 6 and X 3 is CR 7 .
5. The compound of claim 1 , wherein R 1 is OH.
6. The compound of claim 1 , wherein R 4 is H (C 6 -C 14 ) aryl, or heteroaryl.
7. The compound of claim 1 , wherein R 5 is H.
8. The compound of claim 1 , wherein R 5′ is H.
9. The compound of claim 1 , wherein is R 6 is H.
10. The compound of claim 1 , wherein R 7 is H.
11. The compound of claim 1 , having Formula (Ia), Formula (Id) or Formula (Ig):
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or thereof,
wherein:
X 1 is C, S, or S(O);
R 1 is H, OH, SH, NH 2 , or F;
R 2 is (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, heterocycloalkyl, or NR 10 R 11 , wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 8 ;
R 3 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl
R 4 is (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 12 ;
R 5 and R 5′ are independently H, D, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, or CN;
each R 8 is independently D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —(C 1 -C 3 )-alkylene-O—(C 1 -C 6 ) alkyl, —(C 0 -C 4 )-alkylene-aryl, —(C 0 -C 4 )-alkylene-heteroaryl, (C 3 -C 10 ) cycloalkyl, heterocycloalkyl, —(C 0 -C 4 )-alkylene-O-aryl, —(C 0 -C 4 )-alkylene-O-heteroaryl, —O—(C 3 -C 8 )cycloalkyl, —S-heteroaryl, —CN, —C(O)R 19 , —CO(O)R 19 , —C(O)NR 19 R 20 , —S(O) q R 19 , —S(O) q NR 19 R 20 , —NR 19 S(O) q R 20 , —(C 0 -C 3 )-alkylene-NR 19 R 20 , —NR 19 C(O)R 20 , —NR 19 C(O)C(O)R 20 , —NR 19 C(O)NR 19 R 20 , —P(O)((C 1 -C 6 ) alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , or —OR 19 , wherein the alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 9 ; or
two R 8 together when on adjacent atoms form a (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 9 ; or two R 8 together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent atoms form an aryl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more R 9 ;
each R 9 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, (C 6 -C 14 ) aryl, heteroaryl, —NH 2 , OH, CN, —C(O)R 21 , —C(O)NR 21 R 22 , —NR 21 C(O)R 22 , —NR 21 R 22 , —S(O) q R 21 , —S(O) q NR 21 R 22 , —NR 21 S(O) q R 22 , oxo, —P(O)((C 1 -C 6 ) alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , —O-aryl, CN, or —O-heteroaryl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 24 ;
R 10 and R 11 are independently H, (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 16 ; or
R 10 and R 11 together with the nitrogen to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 16 ;
each R 12 is independently D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —OH, —NH 2 , —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, (C 6 -C 14 ) aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C 3 -C 8 )cycloalkyl, —C(O)O(C 1 -C 6 ) alkyl, —C(O)NR 25 R 26 , —S(O) q NR 25 R 26 , —NR 25 R 26 , —NR 25 C(O)NR 25 R 26 , —NR 25 C(O)OR 26 , —NR 25 S(O) q R 26 , —NR 25 C(O)R 26 , halogen, —P(O)((C 1 -C 6 ) alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , or —SF 5 , wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 13 ; or
two R 12 together when on adjacent atoms form a (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 13 ; or two R 12 together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R 13 ; or two R 12 together when on adjacent atoms form an aryl ring optionally substituted with one or more R 13 ; or two R 12 together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more R 13 ;
each R 13 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, (C 6 -C 14 ) aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C 3 -C 8 )cycloalkyl, —OH, or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 27 ;
each R 16 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, (C 1 -C 6 ) hydroxyalkyl, —OH, CN, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 17 ;
each R 17 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, —OH, or CN;
each R 18 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —OH, —NH 2 , or CN;
each R 19 and R 20 is independently H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 23 ;
each R 21 and R 22 is independently H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 23 ;
each R 23 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —OH, or CN;
each R 24 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —NR 25 C(O)R 26 , —NR 25 S(O) q R 26 , —C(O)R 25 , —C(O)NR 25 R 26 , —NR 25 R 26 , —S(O) q R 25 , —S(O) q NR 25 R 26 , —P(O)((C 1 -C 6 ) alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , —OH, or CN;
each R 25 and R 26 is independently at each occurrence H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl;
each R 27 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, —OH, or CN;
m is 0 or 1;
n is 1; and
q is independently at each occurrence 0, 1, or 2.
12. The compound of claim 1 , having Formula (Ib), Formula (Ie), or Formula (Ih):
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof,
wherein:
X 1 is C, S, or S(O);
R 1 is H, OH, SH, NH 2 , or F;
R 2 is (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, heterocycloalkyl, or NR 10 R 11 , wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 8 ;
R 3 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl
R 4 is (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 12 ;
R 5 and R 5′ are independently H, D, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, or CN;
R 6 is H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, or (C 1 -C 6 ) haloalkyl;
each R 8 is independently D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —(C 1 -C 3 )-alkylene-O—(C 1 -C 6 ) alkyl, —(C 0 -C 4 )-alkylene-aryl, —(C 0 -C 4 )-alkylene-heteroaryl, (C 3 -C 10 ) cycloalkyl, heterocycloalkyl, —(C 0 -C 4 )-alkylene-O-aryl, —(C 0 -C 4 )-alkylene-O-heteroaryl, —O—(C 3 -C 8 )cycloalkyl, —S-heteroaryl, —CN, —C(O)R 19 , —CO(O)R 19 , —C(O)NR 19 R 20 , —S(O) q R 19 , —S(O) q NR 19 R 20 , —NR 19 S(O) q R 20 , —(C 0 -C 3 )-alkylene-NR 19 R 20 , —NR 19 C(O)R 20 , —NR 19 C(O)C(O)R 20 , —NR 19 C(O)NR 19 R 20 , —P(O)((C 1 -C 6 ) alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , or —OR 19 , wherein the alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 9 ; or
two R 8 together when on adjacent atoms form a (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 9 ; or two R 8 together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent atoms form an aryl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more R 9 ;
each R 9 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, (C 6 -C 14 ) aryl, heteroaryl, —NH 2 , OH, CN, —C(O)R 21 , —C(O)NR 21 R 22 , —NR 21 C(O)R 22 , —NR 21 R 22 , —S(O) q R 21 , —S(O) q NR 21 R 22 , —NR 21 S(O) q R 22 , oxo, —P(O)((C 1 -C 6 ) alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , —O-aryl, CN, or —O-heteroaryl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 24 ;
R 10 and R 11 are independently H, (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 16 ; or
R 10 and R 11 together with the nitrogen to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 16 ;
each R 12 is independently D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —OH, —NH 2 , —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, (C 6 -C 14 ) aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C 3 -C 8 )cycloalkyl, —C(O)O(C 1 -C 6 ) alkyl, —C(O)NR 25 R 26 , —S(O) q NR 25 R 26 , —NR 25 R 26 , —NR 25 C(O)NR 25 R 26 , —NR 25 C(O)OR 26 , —NR 25 S(O) q R 26 , —NR 25 C(O)R 26 , halogen, —P(O)((C 1 -C 6 ) alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , or —SF 5 , wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 13 ; or
two R 12 together when on adjacent atoms form a (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 13 ; or two R 12 together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R 13 ; or two R 12 together when on adjacent atoms form an aryl ring optionally substituted with one or more R 13 ; or two R 12 together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more R 13 ;
each R 13 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, (C 6 -C 14 ) aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C 3 -C 8 )cycloalkyl, —OH, or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 27 ;
each R 16 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, (C 1 -C 6 ) hydroxyalkyl, —OH, CN, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 17 ;
each R 17 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, —OH, or CN;
each R 18 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —OH, —NH 2 , or CN;
each R 19 and R 20 is independently H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 23 ;
each R 21 and R 22 is independently H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 23 ;
each R 23 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —OH, or CN;
each R 24 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —NR 25 C(O)R 26 , —NR 25 S(O) q R 26 , —C(O)R 25 , —C(O)NR 25 R 26 , —NR 25 R 26 , —S(O) q R 25 , —S(O) q NR 25 R 26 , —P(O)((C 1 -C 6 ) alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , —OH, or CN;
each R 25 and R 26 is independently at each occurrence H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl;
each R 27 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, —OH, or CN;
m is 0 or 1;
n is 1; and
q is independently at each occurrence 0, 1, or 2.
13. The compound of claim 1 , having Formula (Ic), Formula (If), or Formula (Ii):
or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, and tautomer thereof,
wherein:
X 1 is C, S, or S(O);
R 1 is H, OH, SH, NH 2 , or F;
R 2 is (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, heterocycloalkyl, or NR 10 R 11 , wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 8 ;
R 3 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl
R 4 is (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 12 ;
R 5 and R 5′ are independently H, D, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, or CN;
R 6 is H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, or (C 1 -C 6 ) haloalkyl;
R 7 is H, D, (C 1 -C 6 ) alkyl, halogen, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 14 ;
each R 8 is independently D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —(C 1 -C 3 )-alkylene-O—(C 1 -C 6 ) alkyl, —(C 0 -C 4 )-alkylene-aryl, —(C 0 -C 4 )-alkylene-heteroaryl, (C 3 -C 10 ) cycloalkyl, heterocycloalkyl, —(C 0 -C 4 )-alkylene-O-aryl, —(C 0 -C 4 )-alkylene-O-heteroaryl, —O—(C 3 -C 8 )cycloalkyl, —S-heteroaryl, —CN, —C(O)R 19 , —CO(O)R 19 , —C(O)NR 19 R 20 , —S(O) q R 19 , —S(O) q NR 19 R 20 , —NR 19 S(O) q R 20 , —(C 0 -C 3 )-alkylene-NR 19 R 20 , —NR 19 C(O)R 20 , —NR 19 C(O)C(O)R 20 , —NR 19 C(O)NR 19 R 20 , —P(O)((C 1 -C 6 ) alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , or —OR 19 , wherein the alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 9 ; or
two R 8 together when on adjacent atoms form a (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 9 ; or two R 8 together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent atoms form an aryl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more R 9 ;
each R 9 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, (C 6 -C 14 ) aryl, heteroaryl, —NH 2 , OH, CN, —C(O)R 21 , —C(O)NR 21 R 22 , —NR 21 C(O)R 22 , —NR 21 R 22 , —S(O) q R 21 , —S(O) q NR 21 R 22 , —NR 21 S(O) q R 22 , oxo, —P(O)((C 1 -C 6 ) alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , —O-aryl, CN, or —O-heteroaryl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 24 ;
R 10 and R 11 are independently H, (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 16 ; or
R 10 and R 11 together with the nitrogen to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 16 ;
each R 12 is independently D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —OH, —NH 2 , —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, (C 6 -C 14 ) aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C 3 -C 8 )cycloalkyl, —C(O)O(C 1 -C 6 ) alkyl, —C(O)NR 25 R 26 , —S(O) q NR 25 R 26 , —NR 25 R 26 , —NR 25 C(O)NR 25 R 26 , —NR 25 C(O)OR 26 , —NR 25 S(O) q R 26 , —NR 25 C(O)R 26 , halogen, —P(O)((C 1 -C 6 ) alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , or —SF 5 , wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 13 ; or
two R 12 together when on adjacent atoms form a (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 13 ; or two R 12 together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R 13 ; or two R 12 together when on adjacent atoms form an aryl ring optionally substituted with one or more R 13 ; or two R 12 together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more R 13 ;
each R 13 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, (C 6 -C 14 ) aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C 3 -C 8 )cycloalkyl, —OH, or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 27 ;
each R 14 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , —OH, (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 15 ;
each R 15 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, OH, or CN;
each R 16 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, (C 1 -C 6 ) hydroxyalkyl, —OH, CN, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 17 ;
each R 17 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, —OH, or CN;
each R 18 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —OH, —NH 2 , or CN;
each R 19 and R 20 is independently H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 23 ;
each R 21 and R 22 is independently H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 23 ;
each R 23 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —OH, or CN;
each R 24 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —NR 25 C(O)R 26 , —NR 25 S(O) q R 26 , —C(O)R 25 , —C(O)NR 25 R 26 , —NR 25 R 26 , —S(O) q R 25 , —S(O) q NR 25 R 26 , —P(O)((C 1 -C 6 ) alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , —OH, or CN;
each R 25 and R 26 is independently at each occurrence H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl;
each R 27 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, —OH, or CN;
m is 0 or 1;
n is 1; and
q is independently at each occurrence 0, 1, or 2.
14. The compound of claim 1 selected from:
6-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one;
6-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-3-(4-methoxyphenyl)-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one;
3-(4-fluorophenyl)-6-{[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one;
6-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-3-[3-(hydroxymethyl)phenyl]-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one;
6-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-3-(4-fluorophenyl)-1H,6H,7H-pyrazolo[4,3-d]pyrimidin-7-one;
6-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-3-(4-methoxyphenyl)-1H,6H,7H-pyrazolo[4,3-d]pyrimidin-7-one;
6-{[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-3-phenyl-1H, 6H,7H-pyrazolo[4,3-d]pyrimidin-7-one;
6-{[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one;
3-(4-fluoro-3-methoxyphenyl)-6-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one;
3-(4-fluorophenyl)-6-({4-hydroxy-1-[5-(4-methylpiperazin-1-yl)pyridine-2-carbonyl]piperidin-4-yl}methyl)-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one;
6-{[4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl]methyl}-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one;
6-({4-hydroxy-1-[(3S)-3-phenylbutanoyl]piperidin-4-yl}methyl)-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one;
6-({4-hydroxy-1-[(3R)-3-phenylbutanoyl]piperidin-4-yl}methyl)-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one;
6-({4-hydroxy-1-[3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one;
6-({4-hydroxy-1-[(3S)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one;
6-({4-hydroxy-1-[(3R)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one;
6-{[1-(4,4-difluoro-3-phenylbutanoyl)-4-hydroxypiperidin-4-yl]methyl}-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one;
6-({1-[(3R)-4,4-difluoro-3-phenylbutanoyl]-4-hydroxypiperidin-4-yl}methyl)-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one;
6-({1-[(3S)-4,4-difluoro-3-phenylbutanoyl]-4-hydroxypiperidin-4-yl}methyl)-3-phenyl-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one;
3-(4-fluorophenyl)-6-{[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-1H, 6H,7H-pyrazolo[4,3-d]pyrimidin-7-one;
6-{[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-3-(4-methoxyphenyl)-1H,6H,7H-pyrazolo[4,3-d]pyrimidin-7-one;
4-({3-[4-fluoro-3-(piperazin-1-yl)phenyl]-7-oxo-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-6-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide;
6-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-3-[4-(hydroxymethyl)phenyl]-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one;
6-{[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-3-[4-(hydroxymethyl)phenyl]-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one;
3-(4-fluorophenyl)-6-{[4-hydroxy-1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]methyl}-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one;
4-hydroxy-N,N-dimethyl-4-{[7-oxo-3-(4-{[2-(piperidin-1-yl)ethyl]amino}phenyl)-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-6-yl]methyl}piperidine-1-carboxamide;
1-[2-(3-{6-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-7-oxo-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-3-yl}phenoxy)ethyl]imidazolidin-2-one;
3-({4-hydroxy-1-[(3R)-3-phenylbutanoyl]piperidin-4-yl}methyl)-3H,4H,5H-pyrrolo[3,2-d]pyrimidin-4-one;
6-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-3-phenyl-1H,6H,7H-pyrazolo[4,3-d]pyrimidin-7-one;
6-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-3-(4-fluorophenyl)-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one; or
6-{[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-3-(4-methoxyphenyl)-6H,7H-[1,2]thiazolo[4,5-d]pyrimidin-7-one.
15. A pharmaceutical composition comprising, a compound of claim 1 , and a pharmaceutically acceptable carrier.