Pyrrolotriazinones and imidazotriazinones as ubiquitin-specific protease 7 inhibitors
The invention 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′ , R 6 , X 1 , X 2 , m, and n are described herein.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt or tautomer thereof,
wherein:
X 1 is C, S, or S(O);
X 2 is CR 7 or N;
R 1 is H, D, —OH, —SH, —NH 2 , —NH(C 1 -C 4 ) alkyl, —N((C 1 -C 4 ) alkyl) 2 , or F;
R 2 is (C 1 —C) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, heterocycloalkyl, —NR 25 R 26 , or —OR 25 , wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 8 ;
each R 3 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 21 ; or
two R 3 together when on adjacent carbons form a (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 21 ; or two R 3 together form a (C 3 -C 8 ) spirocycloalkyl optionally substituted with one or more R 21 ; or two R 3 together form a spiroheterocycloalkyl optionally substituted with one or more R 21 ; or two R 3 together when on adjacent carbons form an aryl ring optionally substituted with one or more R 21 ; or two R 3 together when on adjacent carbons form an heteroaryl ring optionally substituted with one or more R 21 ;
R 4 is H, (C 1 -C 6 ) alkyl, CD 3 , (C 6 -C 14 ) aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 22 ;
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, —CH 2 OH, —CH 2 NH 2 , or halogen;
R 6 is H, D, or (C 1 -C 6 ) alkyl;
R 7 is H, D, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, halogen, —NR 17 C(O)R 18 , CN, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , —NR 17 C(O)NR 18 R 19 , or —C(O)NR 17 R 18 , wherein the alkyl, alkenyl, and alkynyl are optionally substituted with one or more R 21 ;
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, —(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, halogen, —CN, —C(O)R 12 , —CO(O)R 12 , —C(O)NR 12 R 13 , —S(O) q R 12 , —S(O) q NR 12 R 13 , —NR 12 S(O) q R 13 , —(C 0 -C 3 )-alkylene-NR 12 R 13 , —NR 12 C(O)R 13 , —NR 12 C(O)C(O)R 13 , —NR 12 C(O)NR 12 R 13 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , or —OR 12 , wherein alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 9 ;
each R 9 is independently at each occurrence D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, (C 6 -C 14 ) aryl, heteroaryl, halogen, —OH, —CN, —C(O)R 14 , —C(O)NR 14 R 15 , —NR 14 C(O)R 15 , —NR 14 R 15 , —S(O) q R 14 , —S(O) q NR 14 R 15 , —NR 14 S(O) q R 15 , oxo, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , —O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 10 ; or
two R 9 together with the atoms to which they are attached form a (C 6 -C 14 ) aryl ring optionally substituted with one or more R 10 ; or two R 9 together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one or more R 10 ; or two R 9 together with the atoms to which they are attached form a (C 5 -C 8 ) cycloalkyl ring optionally substituted with one or more R 10 ; or two R 9 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 10 ;
each R 10 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 23 C(O)R 24 , —NR 23 S(O) q R 24 , —C(O)R 23 , —C(O)NR 23 R 24 , —NR 23 R 24 , —S(O) q R 23 , —S(O) q NR 23 R 24 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , —OH, or CN; or
two R 10 together with the atoms to which they are attached form a (C 6 -C 14 ) aryl ring optionally substituted with one or more R 11 ; or two R 10 together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one or more R 11 ; or two R 10 together with the atoms to which they are attached form a (C 5 -C 8 ) cycloalkyl ring optionally substituted with one or more R 11 ; or two R 10 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 11 ;
each R 11 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 12 and R 13 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 16 ;
each R 14 and R 15 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 16 ; or
R 14 and R 15 together with the nitrogen to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 16 , when R 9 is —C(O)NR 14 R 15 ;
each R 16 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;
R 17 is independently H or (C 1 -C 6 ) alkyl;
R 18 is independently (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 20 ;
R 19 is independently H or (C 1 -C 6 ) alkyl;
each R 20 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, CN, (C 6 -C 14 ) aryl, —O(C 6 -C 14 ) aryl, or heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more R 21 ; or
two R 20 together with the atoms to which they are attached form a (C 6 -C 14 ) aryl ring optionally substituted with one or more R 21 ; or two R 20 together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one or more R 21 ; or two R 20 together with the atoms to which they are attached form a (C 5 -C 8 ) cycloalkyl ring optionally substituted with one or more R 21 ; or two R 20 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 21 ;
each R 21 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 22 is independently at each occurrence D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, (C 6 -C 14 ) aryl, heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C 3 -C 8 )cycloalkyl, —S(O) q (C 1 -C 6 ) alkyl, —C(O)O(C 1 -C 6 ) alkyl, —C(O)NR 23 R 24 , —S(O) q NR 23 R 24 , —NR 23 R 24 , —NR 23 C(O)NR 23 R 24 , —NR 23 C(O)OR 24 , —NR 23 S(O) q R 23 , —NR 23 C(O)R 24 , halogen, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 or —OH, wherein alkyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, —OH, CN, —NH 2 , —NH(C 1 -C 4 ) alkyl, —N((C 1 -C 4 ) alkyl) 2 , (C 6 -C 14 ) aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl are optionally substituted one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl —OH, CN, —NH 2 , —NH(C 1 -C 4 ) alkyl, or —N((C 1 -C 4 ) alkyl) 2 ;
each R 23 and R 24 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 25 and R 26 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, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, —OH, CN, —NH 2 , —NH(C 1 -C 4 ) alkyl, or —N((C 1 -C 4 ) alkyl) 2 ;
m is 0, 1, 2, 3, or 4;
n is 0, 1, 2, or 3; 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 N.
4. The compound of claim 1 , wherein X 2 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 or (C 1 -C 6 ) alkyl.
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 R 6 is H.
10. The compound of claim 1 , wherein R 7 is H, halogen, —NR 17 C(O)R 18 , or —NR 17 C(O)NR 18 R 19 .
11. The compound of claim 1 , having Formula (Ia), Formula (Ib), Formula (Ic), or Formula (Id):
or a pharmaceutically acceptable salt or tautomer thereof,
wherein:
X 1 is C, S, or S(O);
R 2 is (C 1 -C 8 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, heterocycloalkyl, —NR 25 R 26 , or —OR 25 , wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 8 ;
each R 3 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 21 ; or
two R 3 together when on adjacent carbons form a (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 21 ; or two R 3 together form a (C 3 -C 8 ) spirocycloalkyl optionally substituted with one or more R 21 ; or two R 3 together form a spiroheterocycloalkyl optionally substituted with one or more R 21 ; or two R 3 together when on adjacent carbons form an aryl ring optionally substituted with one or more R 21 ; or two R 3 together when on adjacent carbons form an heteroaryl ring optionally substituted with one or more R 21 ;
R 4 is H, (C 1 -C 6 ) alkyl, CD 3 , (C 6 -C 14 ) aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 22 ;
R 6 is H, D, or (C 1 -C 6 ) alkyl;
R 7 is H, D, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, halogen, —NR 17 C(O)R 18 , CN, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , —NR 17 C(O)NR 18 R 19 , or —C(O)NR 17 R 18 , wherein the alkyl, alkenyl, and alkynyl are optionally substituted with one or more R 21 ;
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, —(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, halogen, —CN, —C(O)R 12 , —CO(O)R 12 , —C(O)NR 12 R 13 , —S(O) q R 12 , —S(O) q NR 12 R 13 , —NR 12 S(O) q R 13 , —(C 0 -C 3 )-alkylene-NR 12 R 13 , —NR 12 C(O)R 13 , —NR 12 C(O)C(O)R 13 , —NR 12 C(O)NR 12 R 13 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , or —OR 12 wherein alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 9 ;
each R 9 is independently at each occurrence D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, (C 6 -C 14 ) aryl, heteroaryl, halogen, —OH, —CN, —C(O)R 14 , —C(O)NR 14 R 15 , —NR 14 C(O)R 15 , —NR 14 R 15 , —S(O) q R 14 , —S(O) q NR 14 R 15 , —NR 14 S(O) q R 15 , oxo, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , —O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 10 ; or
two R 9 together with the atoms to which they are attached form a (C 6 -C 14 ) aryl ring optionally substituted with one or more R 10 ; or two R 9 together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one or more R 10 ; or two R 9 together with the atoms to which they are attached form a (C 5 -C 8 ) cycloalkyl ring optionally substituted with one or more R 10 ; or two R 9 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 10 ;
each R 10 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 23 C(O)R 24 , —NR 23 S(O) q R 24 , —C(O)R 23 , —C(O)NR 23 R 24 , —NR 23 R 24 , —S(O) q R 23 , —S(O) q NR 23 R 24 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , —OH, or CN; or
two R 10 together with the atoms to which they are attached form a (C 6 -C 14 ) aryl ring optionally substituted with one or more R 11 ; or two R 10 together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one or more R 11 ; or two R 10 together with the atoms to which they are attached form a (C 5 -C 8 ) cycloalkyl ring optionally substituted with one or more R 11 ; or two R 10 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 11 ;
each R 11 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 12 and R 13 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 16 ;
each R 14 and R 15 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 16 ; or
R 14 and R 15 together with the nitrogen to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 16 , when R 9 is —C(O)NR 14 R 15 ;
each R 16 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;
R 17 is independently H or (C 1 -C 6 ) alkyl;
R 18 is independently (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 20 ;
R 19 is independently H or (C 1 -C 6 ) alkyl;
each R 20 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, CN, (C 6 -C 14 ) aryl, —O(C 6 -C 14 ) aryl, or heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more R 21 ; or
two R 20 together with the atoms to which they are attached form a (C 6 -C 14 ) aryl ring optionally substituted with one or more R 21 ; or two R 20 together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one or more R 21 ; or two R 20 together with the atoms to which they are attached form a (C 5 -C 8 ) cycloalkyl ring optionally substituted with one or more R 21 ; or two R 20 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 21 ;
each R 21 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 22 is independently at each occurrence D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, (C 6 -C 14 ) aryl, heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C 3 -C 8 )cycloalkyl, —S(O) q (C 1 -C 6 ) alkyl, —C(O)O(C 1 -C 6 ) alkyl, —C(O)NR 23 R 24 , —S(O) q NR 23 R 24 , —NR 23 R 24 , —NR 23 C(O)NR 23 R 24 , —NR 23 C(O)OR 24 , —NR 23 S(O) q R 23 , —NR 23 C(O)R 24 , halogen, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 or —OH, wherein alkyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, —OH, CN, —NH 2 , —NH(C 1 -C 4 ) alkyl, —N((C 1 -C 4 ) alkyl) 2 , (C 6 -C 14 ) aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl are optionally substituted one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl —OH, CN, —NH 2 , —NH(C 1 -C 4 ) alkyl, or —N((C 1 -C 4 ) alkyl) 2 ;
each R 23 and R 24 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 25 and R 26 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, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, —OH, CN, —NH 2 , —NH(C 1 -C 4 ) alkyl, or —N((C 1 -C 4 ) alkyl) 2 ;
m is 0, 1, 2, 3, or 4; and
q is independently at each occurrence 0, 1, or 2.
12. The compound of claim 1 , having Formula (Ie) or Formula (If):
or a pharmaceutically acceptable salt or tautomer thereof,
wherein:
X 1 is C, S, or S(O);
Ar is (C 6 -C 14 ) aryl or heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more R 8 ;
each R 3 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 21 ; or
two R 3 together when on adjacent carbons form a (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 21 ; or two R 3 together form a (C 3 -C 8 ) spirocycloalkyl optionally substituted with one or more R 21 ; or two R 3 together form a spiroheterocycloalkyl optionally substituted with one or more R 21 ; or two R 3 together when on adjacent carbons form an aryl ring optionally substituted with one or more R 21 ; or two R 3 together when on adjacent carbons form an heteroaryl ring optionally substituted with one or more R 21 ;
R 4 is H, (C 1 -C 6 ) alkyl, CD 3 , (C 6 -C 14 ) aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 22 ;
R 6 is H, D, or (C 1 -C 6 ) alkyl;
R 7 is H, D, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, halogen, —NR 17 C(O)R 18 , CN, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , —NR 17 C(O)NR 18 R 19 , or —C(O)NR 17 R 18 , wherein the alkyl, alkenyl, and alkynyl are optionally substituted with one or more R 21 ;
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, —(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, halogen, —CN, —C(O)R 12 , —CO(O)R 12 , —C(O)NR 12 R 13 , —S(O) q R 12 , —S(O) q NR 12 R 13 , —NR 12 S(O) q R 13 , —(C 0 -C 3 )-alkylene-NR 12 R 13 , —NR 12 C(O)R 13 , —NR 12 C(O)C(O)R 13 , —NR 12 C(O)NR 12 R 13 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , or —OR 12 , wherein alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 9 ;
each R 9 is independently at each occurrence D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, (C 6 -C 14 ) aryl, heteroaryl, halogen, —OH, —CN, —C(O)R 14 , —C(O)NR 14 R 15 , —NR 14 C(O)R 15 , —NR 14 R 15 , —S(O) q R 14 , —S(O) q NR 14 R 15 , —NR 14 S(O) q R 15 , oxo, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , —O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 10 ; or
two R 9 together with the atoms to which they are attached form a (C 6 -C 14 ) aryl ring optionally substituted with one or more R 10 ; or two R 9 together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one or more R 10 ; or two R 9 together with the atoms to which they are attached form a (C 5 -C 8 ) cycloalkyl ring optionally substituted with one or more R 10 ; or two R 9 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 10 ;
each R 10 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 23 C(O)R 24 , —NR 23 S(O) q R 24 , —C(O)R 23 , —C(O)NR 23 R 24 , —NR 23 R 24 , —S(O) q R 23 , —S(O) q NR 23 R 24 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , —OH, or CN; or
two R 10 together with the atoms to which they are attached form a (C 6 -C 14 ) aryl ring optionally substituted with one or more R 11 ; or two R 10 together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one or more R 11 ; or two R 10 together with the atoms to which they are attached form a (C 5 -C 8 ) cycloalkyl ring optionally substituted with one or more R 11 ; or two R 10 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 11 ;
each R 11 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 12 and R 13 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 16 ;
each R 14 and R 15 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 16 ; or
R 14 and R 15 together with the nitrogen to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 16 , when R 9 is —C(O)NR 14 R 15 ;
each R 16 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;
R 17 is independently H or (C 1 -C 6 ) alkyl;
R 18 is independently (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 20 ;
R 19 is independently H or (C 1 -C 6 ) alkyl;
each R 20 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, CN, (C 6 -C 14 ) aryl, —O(C 6 -C 14 ) aryl, or heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more R 21 ; or
two R 20 together with the atoms to which they are attached form a (C 6 -C 14 ) aryl ring optionally substituted with one or more R 21 ; or two R 20 together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one or more R 21 ; or two R 20 together with the atoms to which they are attached form a (C 5 -C 8 ) cycloalkyl ring optionally substituted with one or more R 21 ; or two R 20 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 21 ;
each R 21 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 22 is independently at each occurrence D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, (C 6 -C 14 ) aryl, heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C 3 -C 8 )cycloalkyl, —S(O) q (C 1 -C 6 ) alkyl, —C(O)O(C 1 -C 6 ) alkyl, —C(O)NR 23 R 24 , —S(O) q NR 23 R 24 , —NR 23 R 24 , —NR 23 C(O)NR 23 R 24 , —NR 23 C(O)OR 24 , —NR 23 S(O) q R 23 , —NR 23 C(O)R 24 , halogen, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 or —OH, wherein alkyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, —OH, CN, —NH 2 , —NH(C 1 -C 4 ) alkyl, —N((C 1 -C 4 ) alkyl) 2 , (C 6 -C 14 ) aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl are optionally substituted one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl —OH, CN, —NH 2 , —NH(C 1 -C 4 ) alkyl, or —N((C 1 -C 4 ) alkyl) 2 ;
each R 23 and R 24 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 m is independently at each occurrence 0, 1, 2, 3, or 4; and
q is independently at each occurrence 0, 1, or 2.
13. The compound of claim 1 , having Formula (Ig) or Formula (Ih):
or a pharmaceutically acceptable salt or tautomer thereof,
wherein:
X 1 is C, S, or S(O);
Cy is (C 5 -C 8 ) cycloalkyl or heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 8 ;
each R 3 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 21 ; or
two R 3 together when on adjacent carbons form a (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 21 ; or two R 3 together form a (C 3 -C 8 ) spirocycloalkyl optionally substituted with one or more R 21 ; or two R 3 together form a spiroheterocycloalkyl optionally substituted with one or more R 21 ; or two R 3 together when on adjacent carbons form an aryl ring optionally substituted with one or more R 21 ; or two R 3 together when on adjacent carbons form an heteroaryl ring optionally substituted with one or more R 21 ;
R 4 is H, (C 1 -C 6 ) alkyl, CD 3 , (C 6 -C 14 ) aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 22 ;
R 6 is H, D, or (C 1 -C 6 ) alkyl;
R 7 is H, D, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, halogen, —NR 17 C(O)R 18 , CN, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , —NR 17 C(O)NR 18 R 19 , or —C(O)NR 17 R 18 , wherein the alkyl, alkenyl, and alkynyl are optionally substituted with one or more R 21 ;
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, —(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, halogen, —CN, —C(O)R 12 , —CO(O)R 12 , —C(O)NR 12 R 13 , —S(O) q R 12 , —S(O) q NR 12 R 13 , —NR 12 S(O) q R 13 , —(C 0 -C 3 )-alkylene-NR 12 R 13 , —NR 12 C(O)R 13 , —NR 12 C(O)C(O)R 13 , —NR 12 C(O)NR 12 R 13 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , or —OR 12 , wherein alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 9 ;
each R 9 is independently at each occurrence D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, (C 6 -C 14 ) aryl, heteroaryl, halogen, —OH, —CN, —C(O)R 14 , —C(O)NR 14 R 15 , —NR 14 C(O)R 15 , —NR 14 R 15 , —S(O) q R 14 , —S(O) q NR 14 R 15 , —NR 14 S(O) q R 15 , oxo, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , —O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 10 ; or
two R 9 together with the atoms to which they are attached form a (C 6 -C 14 ) aryl ring optionally substituted with one or more R 10 ; or two R 9 together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one or more R 10 ; or two R 9 together with the atoms to which they are attached form a (C 5 -C 8 ) cycloalkyl ring optionally substituted with one or more R 10 ; or two R 9 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 10 ;
each R 10 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 23 C(O)R 24 , —NR 23 S(O) q R 24 , —C(O)R 23 , —C(O)NR 23 R 24 , —NR 23 R 24 , —S(O) q R 23 , —S(O) q NR 23 R 24 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , —OH, or CN; or
two R 10 together with the atoms to which they are attached form a (C 6 -C 14 ) aryl ring optionally substituted with one or more R 11 ; or two R 10 together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one or more R 11 ; or two R 10 together with the atoms to which they are attached form a (C 5 -C 8 ) cycloalkyl ring optionally substituted with one or more R 11 ; or two R 10 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 11 ;
each R 11 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 12 and R 13 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 16 ;
each R 14 and R 15 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 16 ; or
R 14 and R 15 together with the nitrogen to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 16 , when R 9 is —C(O)NR 14 R 15 ;
each R 16 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;
R 17 is independently H or (C 1 -C 6 ) alkyl;
R 18 is independently (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 20 ;
R 19 is independently H or (C 1 -C 6 ) alkyl;
each R 20 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, CN, (C 6 -C 14 ) aryl, —O(C 6 -C 14 ) aryl, or heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more R 21 ; or
two R 20 together with the atoms to which they are attached form a (C 6 -C 14 ) aryl ring optionally substituted with one or more R 21 ; or two R 20 together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one or more R 21 ; or two R 20 together with the atoms to which they are attached form a (C 5 -C 8 ) cycloalkyl ring optionally substituted with one or more R 21 ; or two R 20 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 21 ;
each R 21 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 22 is independently at each occurrence D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, (C 6 -C 14 ) aryl, heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C 3 -C 8 )cycloalkyl, —S(O) q (C 1 -C 6 ) alkyl, —C(O)O(C 1 -C 6 ) alkyl, —C(O)NR 23 R 24 , —S(O) q NR 23 R 24 , —NR 23 R 24 , —NR 23 C(O)NR 23 R 24 , —NR 23 C(O)OR 24 , —NR 23 S(O) q R 23 , —NR 23 C(O)R 24 , halogen, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 or —OH, wherein alkyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, —OH, CN, —NH 2 , —NH(C 1 -C 4 ) alkyl, —N((C 1 -C 4 ) alkyl) 2 , (C 6 -C 14 ) aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl are optionally substituted one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl —OH, CN, —NH 2 , —NH(C 1 -C 4 ) alkyl, or —N((C 1 -C 4 ) alkyl) 2 ;
each R 23 and R 24 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 m is independently at each occurrence 0, 1, 2, 3, or 4; and
q is independently at each occurrence 0, 1, or 2.
14. The compound of claim 1 , having Formula (Ii)
or a pharmaceutically acceptable salt or tautomer thereof,
wherein:
X 1 is C, S, or S(O);
R 2 is (C 1 -C 8 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, heterocycloalkyl, —NR 25 R 26 , or —OR 25 , wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 8 ;
each R 3 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 21 ; or
two R 3 together when on adjacent carbons form a (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 21 ; or two R 3 together form a (C 3 -C 8 ) spirocycloalkyl optionally substituted with one or more R 21 ; or two R 3 together form a spiroheterocycloalkyl optionally substituted with one or more R 21 ; or two R 3 together when on adjacent carbons form an aryl ring optionally substituted with one or more R 21 ; or two R 3 together when on adjacent carbons form an heteroaryl ring optionally substituted with one or more R 21 ;
R 4 is H, (C 1 -C 6 ) alkyl, CD 3 , (C 6 -C 14 ) aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 22 ;
R 6 is H, D, or (C 1 -C 6 ) alkyl;
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, —(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, halogen, —CN, —C(O)R 12 , —CO(O)R 12 , —C(O)NR 12 R 13 , —S(O) q R 12 , —S(O) q NR 12 R 13 , —NR 12 S(O) q R 13 , —(C 0 -C 3 )-alkylene-NR 12 R 13 , —NR 12 C(O)R 13 , —NR 12 C(O)C(O)R 13 , —NR 12 C(O)NR 12 R 13 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , or —OR 12 , wherein alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 9 ;
each R 9 is independently at each occurrence D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, (C 6 -C 14 ) aryl, heteroaryl, halogen, —OH, —CN, —C(O)R 14 , —C(O)NR 14 R 15 , —NR 14 C(O)R 15 , —NR 14 R 15 , —S(O) q R 14 , —S(O) q NR 14 R 15 , —NR 14 S(O) q R 15 , oxo, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , —O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 10 ; or
two R 9 together with the atoms to which they are attached form a (C 6 -C 14 ) aryl ring optionally substituted with one or more R 10 ; or two R 9 together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one or more R 10 ; or two R 9 together with the atoms to which they are attached form a (C 5 -C 8 ) cycloalkyl ring optionally substituted with one or more R 10 ; or two R 9 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 10 ;
each R 10 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 23 C(O)R 24 , —NR 23 S(O) q R 24 , —C(O)R 23 , —C(O)NR 23 R 24 , —NR 23 R 24 , —S(O) q R 23 , —S(O) q NR 23 R 24 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , —OH, or CN; or
two R 10 together with the atoms to which they are attached form a (C 6 -C 14 ) aryl ring optionally substituted with one or more R 11 ; or two R 10 together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one or more R 11 ; or two R 10 together with the atoms to which they are attached form a (C 5 -C 8 ) cycloalkyl ring optionally substituted with one or more R 11 ; or two R 10 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 11 ;
each R 11 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 12 and R 13 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 16 ;
each R 14 and R 15 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 16 ; or
R 14 and R 15 together with the nitrogen to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 16 , when R 9 is —C(O)NR 14 R 15 ;
each R 16 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;
R 17 is independently H or (C 1 -C 6 ) alkyl;
R 18 is independently (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 20 ;
R 19 is independently H or (C 1 -C 6 ) alkyl;
each R 20 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, CN, (C 6 -C 14 ) aryl, —O(C 6 -C 14 ) aryl, or heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more R 21 ; or
two R 20 together with the atoms to which they are attached form a (C 6 -C 14 ) aryl ring optionally substituted with one or more R 21 ; or two R 20 together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one or more R 21 ; or two R 20 together with the atoms to which they are attached form a (C 5 -C 8 ) cycloalkyl ring optionally substituted with one or more R 21 ; or two R 20 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 21 ;
each R 21 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 22 is independently at each occurrence D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, (C 6 -C 14 ) aryl, heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C 3 -C 8 )cycloalkyl, —S(O) q (C 1 -C 6 ) alkyl, —C(O)O(C 1 -C 6 ) alkyl, —C(O)NR 23 R 24 , —S(O) q NR 23 R 24 , —NR 23 R 24 , —NR 23 C(O)NR 23 R 24 , —NR 23 C(O)OR 24 , —NR 23 S(O) q R 23 , —NR 23 C(O)R 24 , halogen, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 or —OH, wherein alkyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, —OH, CN, —NH 2 , —NH(C 1 -C 4 ) alkyl, —N((C 1 -C 4 ) alkyl) 2 , (C 6 -C 14 ) aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl are optionally substituted one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl —OH, CN, —NH 2 , —NH(C 1 -C 4 ) alkyl, or —N((C 1 -C 4 ) alkyl) 2 ;
each R 23 and R 24 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 25 and R 26 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, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, —OH, CN, —NH 2 , —NH(C 1 -C 4 ) alkyl, or —N((C 1 -C 4 ) alkyl) 2 ;
each m is independently at each occurrence 0, 1, 2, 3, or 4; and
q is independently at each occurrence 0, 1, or 2.
15. The compound of claim 1 selected from:
3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-([1,1′-biphenyl]-2-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(2-(thiophen-3-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(3′-fluoro-[1,1′-biphenyl]-2-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(3-(benzo[d][1,3]dioxol-5-yl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(2′-methyl-[1,1′-biphenyl]-3-carbonyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(4′-methyl-[1,1′-biphenyl]-3-carbonyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(4′-methoxy-[1,1′-biphenyl]-3-carbonyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(4′-fluoro-3′-methyl-[1,1′-biphenyl]-3-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(3′-methoxy-[1,1′-biphenyl]-3-carbonyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-([1,1′-biphenyl]-3-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(4′-chloro-[1,1′-biphenyl]-3-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(3′-chloro-[1,1′-biphenyl]-3-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(4′-isopropyl-[1,1′-biphenyl]-3-carbonyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(4′-(trifluoromethyl)-[1,1′-biphenyl]-3-carbonyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3′-(4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3 (4H)-yl)methyl)piperidine-1-carbonyl)-[1,1′-biphenyl]-4-carboxamide;
3-((1-(3′,4′-dimethyl-[1,1′-biphenyl]-3-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3′-(4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3 (4H)-yl)methyl)piperidine-1-carbonyl)-[1,1′-biphenyl]-2-carbonitrile;
3′-(4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3 (4H)-yl)methyl)piperidine-1-carbonyl)-[1,1′-biphenyl]-4-carbonitrile;
3-((4-hydroxy-1-(3-(5-methylthiophen-2-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(3-(quinolin-6-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(3-(imidazo[1,2-a]pyridin-6-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(3-(benzo[d]thiazol-5-yl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(3-(5-methyl-1H-indazol-4-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(3-(1-methyl-1H-indol-2-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
N-cyclopentyl-3′-(4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3 (4H)-yl)methyl)piperidine-1-carbonyl)-[1,1′-biphenyl]-3-carboxamide;
3-((4-hydroxy-1-(3-(thiophen-2-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(3-(thiophen-3-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(2′-fluoro-[1,1′-biphenyl]-3-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(3′-fluoro-[1,1′-biphenyl]-3-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
2-(4-(4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3 (4H)-yl)methyl)piperidine-1-carbonyl)phenyl)-2-methylpropanenitrile;
3-((4-hydroxy-1-(2-phenyloxazole-5-carbonyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(1-(benzo[d]oxazol-2-yl)piperidine-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(3-(1H-pyrazol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(3′-methoxy-[1,1′-biphenyl]-4-carbonyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-([1,1′-biphenyl]-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(3′-ethoxy-[1,1′-biphenyl]-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
4′-(4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3 (4H)-yl)methyl)piperidine-1-carbonyl)-N,N-dimethyl-[1,1′-biphenyl]-4-carboxamide;
3-((4-hydroxy-1-(4′-(pyrrolidine-1-carbonyl)-[1,1′-biphenyl]-4-carbonyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(2′,5′-dimethoxy-[1,1′-biphenyl]-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
N-ethyl-4′-(4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3 (4H)-yl)methyl)piperidine-1-carbonyl)-[1,1′-biphenyl]-4-carboxamide;
3-((4-hydroxy-1-(4-(quinolin-3-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(4-(quinolin-6-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(3′,5′-dimethoxy-[1,1′-biphenyl]-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(4-(2-methylquinolin-6-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(4-(benzo[d]oxazol-5-yl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
6-chloro-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(3-chloro-[1,1′-biphenyl]-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(3-chloro-4′-(pyrrolidine-1-carbonyl)-[1,1′-biphenyl]-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(4′-(piperidine-1-carbonyl)-[1,1′-biphenyl]-4-carbonyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(2-benzyl-3,3-dimethylbutanoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
2-benzyl-3-(4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)piperidin-1-yl)-3-oxopropanenitrile;
3-((4-hydroxy-1-(4-(2-phenylpropan-2-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
(R)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrrolo[2, 1-f][1,2,4]triazin-4(3H)-one;
3-((1-(3-(1H-pyrrol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(2-(1,2,3,4-tetrahydronaphthalen-2-yl)acetyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(4-(thiazol-4-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(2-benzylbutanoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(4-(phenylsulfonyl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2, 1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(4-(phenylthio)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(2-methyl-3-phenylpropanoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(4-((1H-benzo[d]imidazol-1-yl)methyl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(4-((1H-pyrazol-1-yl)methyl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(4-((5-methyl-1H-tetrazol-1-yl)methyl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(4-((5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(4-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(4-(thiophen-2-ylmethyl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(4-benzoylbenzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(4-(ethyl(phenyl)amino)benzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
4-(4-(4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3 (4H)-yl)methyl)piperidine-1-carbonyl)piperazin-1-yl)benzonitrile;
3-((4-hydroxy-1-(4-(4-(methyl sulfonyl)phenyl)piperazine-1-carbonyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(2-chloro-4-(piperidin-1-ylmethyl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-7-methylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(2-methyl-3-phenylpropanoyl)piperidin-4-yl)methyl)-7-methylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3′-chloro-4′-(4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3 (4H)-yl)methyl)piperidine-1-carbonyl)-N,N-dimethyl-[1,1′-biphenyl]-4-carboxamide;
3-((1-(3-chloro-4′-(piperidine-1-carbonyl)-[1,1′-biphenyl]-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(4-phenoxybenzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
(R)—N-(3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)acetamide;
(R)-1-(3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-methylurea;
3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-methylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
3-((4-hydroxy-1-(2-methyl-3-phenylpropanoyl)piperidin-4-yl)methyl)-6-methylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one;
1-(3-chlorophenyl)-3-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)urea;
1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-(m-tolyl)urea;
1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-(4-fluorobenzyl)urea;
1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-(4-fluorophenyl)urea;
1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-(p-tolyl)urea;
1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-(2,3-dihydro-1H-inden-5-yl)urea;
1-(4-chlorobenzyl)-3-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)urea;
1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-(4-methylbenzyl)urea;
1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-(3,5-difluorophenyl)urea;
1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-(2-fluorobenzyl)urea;
(R)-1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo [2,1-f][1,2,4]triazin-6-yl)-3-(1-phenylethyl)urea;
1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-(3-fluorophenyl)urea;
1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-(3-fluoro-2-methylphenyl)urea;
1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-(2,3-dimethylphenyl)urea;
1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-(2,4-dimethylphenyl)urea;
1-(4-cyanophenyl)-3-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)urea;
1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-(3-methoxyphenyl)urea;
N-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-4-(trifluoromethyl)benzamide;
N-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-2-(2, 6-dichlorophenyl)acetamide;
N-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-2-(4-(trifluoromethoxy)phenoxy)acetamide;
N-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-2-(3,4-dichlorophenoxy)acetamide;
N-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-2-(2,3-dichlorophenoxy)acetamide;
N-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3,4-dimethylbenzamide;
3-chloro-N-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-4-methylbenzamide;
N-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-2, 5-dimethylbenzamide;
N-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-2-(trifluoromethoxy)benzamide;
2,4-dichloro-N-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)benzamide;
N-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-2-phenylthiazole-4-carboxamide;
3-(4-chlorophenyl)-N-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)butanamide;
N-(4′-(4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3 (4H)-yl)methyl)piperidine-1-carbonyl)-[1,1′-biphenyl]-2-yl)methacrylamide;
3-((1-benzoyl-4-hydroxypiperidin-4-yl)methyl)-7-phenylimidazo[5,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-fluorophenyl)imidazo[5, 1-J][1,2,4]triazin-4(3H)-one;
3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-p-tolylimidazo [1,5-f][1,2,4]triazin-4 (3H)-one;
3-([4-Hydroxy-1-[3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl]methyl)-7-(4-methylphenyl)-3H,4H-imidazo[4,3-f][1,2,4]triazin-4-one;
(S)-3-((1-(3-(1H-pyrazol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(p-tolyl) imidazo[5,1-f][1,2,4]triazin-4(3H)-one;
(R)-3-((1-(3-(1H-pyrazol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(p-tolyl) imidazo[5,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(2-cyclopropyloxazole-5-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-fluorophenyl) imidazo[5,1-f][1,2,4]triazin-4(3H)-one;
3-((1-(4-(1H-pyrazol-1-yl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-fluorophenyl) imidazo[5,1-f][1,2,4]triazin-4(3H)-one;
7-(4-fluorophenyl)-3-((4-hydroxy-1-(4-methylbenzoyl)piperidin-4-yl)methyl)imidazo[5, 1-f][1,2,4]triazin-4(3H)-one; or
3-((1-(3-fluoro-4-methylbenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-fluorophenyl) imidazo[5,1-f][1,2,4]triazin-4(3H)-one,
or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition comprising, a compound of claim 1 and a pharmaceutically acceptable carrier.