IP Library › Granted Patent US 10,519,128

Granted Patent B2

US 10,519,128 · App. 16/179,111 · Granted Dec 31, 2019

Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors

Inventors: Stephanos Ioannidis (Natick, MA); Adam Charles Talbot (Guilford, CT); Bruce Follows (Littleton, MA); Alexandre Joseph Buckmelter (Acton, MA); Minghua Wang (Acton, MA); Ann-Marie Campbell (Monroe, CT); David R. Lancia, Jr. (Boston, MA)

Assignee: FORMA Therapeutics, Inc.

C07D401/06 C07D239/88 C07D471/04 C07D487/04

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Quick Facts

Patent No.: US 10,519,128
App. No.: 16/179,111
Granted: Dec 31, 2019
Kind: B2

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Abstract

The present 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 4′ , X 1 , Y 1 , Y 2 , Y 3 , Y 4 , n, and m are described herein.

Claims (132)

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X 1 is C;

Y 1 is N or CH;

Y 2 is N or CR 5 ;

Y 3 is N or CR 6 ;

Y 4 is N or CR 7 ;

R 1 is —OH;

R 2 is (C 1 -C 6 ) alkyl, (C 6 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 5 -C 6 ) cycloalkyl, 5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, or NR 10 R 11 , wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R 8 ;

each R 3 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 3 -C 8 ) cycloalkyl, or 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R 20 ; or

two R 3 together when on adjacent carbons form a (C 3 -C 8 ) cycloalkyl optionally substituted with one to three R 20 ; or

two R 3 together when attached to the same carbon atom form a (C 3 -C 8 ) spirocycloalkyl optionally substituted with one to three R 20 ; or

two R 3 together when attached to the same carbon atom form a 3- to 7-membered spiroheterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, optionally substituted with one to three R 20 ; or

two R 3 together when on adjacent carbons form a (C 6 -C 14 ) aryl ring optionally substituted with one to three R 20 ; or two R 3 together when on adjacent carbons form a 5- or 6-membered heteroaryl ring comprising 1 to 3 heteroatoms selected from O, N, and S optionally substituted with one to three R 20 ;

R 4 and R 4′ are independently H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, or CN;

R 5 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, halogen, NO 2 , or CN, wherein the alkyl is optionally substituted with one to three R 12 ;

R 6 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, NO 2 , —NH 2 , —NHC(O)(C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 5 -C 8 ) cycloalkyl, or 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R 13 ;

R 7 is H, (C 1 -C 6 ) alkyl, (C 6 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 5 -C 6 ) cycloalkyl, 5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —O—(C 6 ) aryl, —O-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, —N((C 1 -C 6 ) alkyl)-(C 6 -C 14 ) aryl, —NH—(C 6 -C 14 ) aryl, —N((C 1 -C 6 ) alkyl)-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, or —NH-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R 14 ;

each R 8 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 1 -C 3 )-alkylene-O—(C 1 -C 6 ) alkyl, —(C 0 -C 4 )-alkylene-(C 6 ) aryl-(C 0 -C 4 )-alkylene-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 3 -C 10 ) cycloalkyl, 5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —(C 0 -C 4 )-alkylene-O—(C 6 ) aryl, —(C 0 -C 4 )-alkylene-O-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, —O—(C 5 -C 6 ) cycloalkyl, —S-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, —C(O)R 21 , —CO(O)R 21 , —C(O)NR 21 R 22 , —(C 0 -C 3 )-alkylene-NR 21 R 22 , —NR 21 C(O)R 22 , —NR 21 C(O)C(O)R 22 , —NR 21 C(O)NR 21 R 22 , or —OR 21 , wherein the alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R 9 ;

or two R 8 together when on adjacent atoms form a (C 5 -C 6 ) cycloalkyl optionally substituted with one to three R 9 ;

or two R 8 together when on adjacent atoms form a 5- to 6-membered heterocycloalkyl ring comprising 1 to 3 heteroatoms selected from O, N, and S, optionally substituted with one to three R 9 ; or two R 8 together when on adjacent atoms form a (C 6 ) aryl ring optionally substituted with one to three R 9 ;

or two R 8 together when on adjacent atoms form a 5- or 6-membered heteroaryl ring comprising 1 to 3 heteroatoms selected from O, N, and S optionally substituted with one to three 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 5 -C 6 ) cycloalkyl, 5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —(C 0 -C 3 )-alkylene-(C 6 ) aryl, —(C 0 -C 3 )-alkylene-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, —NH 2 , —OH, —C(O)R 23 , —C(O)NR 23 R 24 , —NR 23 C(O)R 24 , —NR 23 R 24 , -oxo, —O—(C 6 ) aryl, CN, or —O-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R 19 ;

R 10 and R 11 are independently H, or (C 1 -C 6 ) alkyl optionally substituted with one to three R 17 ;

or R 10 and R 11 together with the nitrogen to which they are attached form a 3- to 7-membered heterocycloalkyl ring comprising 1 to 3 heteroatoms selected from O, N, and S, optionally substituted with one to three R 17 ;

each R 12 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, —NH 2 , (C 1 -C 6 ) alkylamino, or di(C 1 -C 6 ) alkylamino;

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, CN, —OH, —NH 2 , —C(O)(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, (C 6 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 5 -C 6 ) cycloalkyl, 5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —O—(C 6 ) aryl, —O-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, —O-5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —O—(C 5 -C 6 ) cycloalkyl, —C(O)O(C 1 -C 6 ) alkyl, —C(O)NR 26 R 27 , —NR 26 R 27 , —NR 26 C(O)NR 26 R 27 , —NR 26 C(O)OR 27 , —NR 26 C(O)R 27 , halogen, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R 15 ;

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, —OH, —NH 2 , —C(O)(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, (C 6 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 5 -C 6 ) cycloalkyl, 5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —O—(C 6 ) aryl, —O-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, —O-5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —O—(C 5 -C 6 ) cycloalkyl, —C(O)O(C 1 -C 6 ) alkyl, —C(O)NR 26 R 27 , —NR 26 R 27 , —NR 26 C(O)NR 26 R 27 , —NR 26 C(O)OR 27 , —NR 26 C(O)R 27 , halogen, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R 16 ;

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, —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(O)(C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, (C 6 -C 14 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 5 -C 6 ) cycloalkyl, 5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —O—(C 6 ) aryl, —O-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, —O-5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —O—(C 5 -C 6 ) cycloalkyl, —OH, or CN, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R 28 ;

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 1 -C 6 ) hydroxyalkyl, —OH, CN, —C(O)(C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, wherein the alkyl is optionally substituted with one to three R 18 ;

each R 18 is independently (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, —OH, or CN;

each R 19 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 26 C(O)R 27 , —C(O)R 26 , —C(O)NR 26 R 27 , —NR 26 R 27 , —OH, or CN;

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, —NH 2 , or CN;

each R 21 and R 22 is independently H, (C 1 -C 6 ) alkyl, (C 6 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 5 -C 6 ) cycloalkyl, or 5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one to three R 25 ;

each R 23 and R 24 is independently H, (C 1 -C 6 ) alkyl, (C 6 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 5 -C 6 ) cycloalkyl, or 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one to three R 25 ;

each R 25 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 26 and R 27 is independently at each occurrence H, or (C 1 -C 6 ) alkyl;

each R 28 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, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, —OH, or CN;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2 or 3; and

provided that the compound is further characterized by any one or more of the following:

i. at least one of Y 1 , Y 2 , Y 3 , or Y 4 is N;

ii. at least one of R 6 or R 7 is an optionally substituted (C 6 -C 14 ) aryl;

iii. R 5 is (C 1 -C 6 ) alkyl or (C 1 -C 6 ) haloalkyl, wherein the alkyl of R 5 is substituted with an R 12 that is (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —C(O)(C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, or di(C 1 -C 6 ) alkylamino;

iv. R 6 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, —NHC(O)(C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 5 -C 8 ) cycloalkyl, or 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein

the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl of R 6 is substituted with an R 13 that is (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —OH, —NH 2 , (C 1 -C 6 ) alkylamino, or di(C 1 -C 6 ) alkylamino; or

the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl of R 6 is substituted with an R 13 that is (C 1 -C 6 ) alkyl, or that is 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the heterocycloalkyl is substituted with one to three R 15 ; or

V. R 7 is (C 1 -C 6 ) alkyl, (C 6 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 5 -C 6 ) cycloalkyl, 5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —O—(C 6 ) aryl, —O-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, —N((C 1 -C 6 ) alkyl)-(C 6 -C 14 ) aryl, —NH—(C 6 -C 14 ) aryl, —N((C 1 -C 6 ) alkyl)-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, or —NH-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl of R 7 is substituted with an R 14 that is (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, (C 1 -C 6 ) alkylamino, or di(C 1 -C 6 ) alkylamino.

2. The compound of claim 1 , wherein either:

a. at least one of Y 1 , Y 2 , Y 3 , or Y 4 , is N; or at least one of R 6 or R 7 is independently (C 6 -C 14 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 5 -C 8 ) cycloalkyl, or 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S; or

b. at least one of Y 1 , Y 2 , Y 3 , or Y 4 , is N; and at least one of R 6 or R 7 is independently (C 6 -C 14 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 5 -C 8 ) cycloalkyl, or 5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S.

3. The compound of claim 1 , wherein

each R 19 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 26 R 27 , —OH, or CN;

each R 21 and R 22 is independently H or (C 1 -C 6 ) alkyl;

each R 23 and R 24 is independently H or (C 1 -C 6 ) alkyl; and

each R 28 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, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, —OH, or CN.

4. The compound of claim 3 , wherein R 4 and R 4′ are H.

5. The compound of claim 4 , wherein m is 0.

6. The compound of claim 4 , wherein n is 1.

7. The compound of claim 5 , wherein n is 1.

8. The compound of claim 2 , wherein

each R 19 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 26 R 27 , —OH, or CN;

each R 21 and R 22 is independently H or (C 1 -C 6 ) alkyl;

each R 23 and R 24 is independently H or (C 1 -C 6 ) alkyl; and

9. The compound of claim 2 , wherein R 4 and R 4′ are H.

10. The compound of claim 9 , wherein m is 0.

11. The compound of claim 10 , wherein n is 1.

12. The compound of claim 11 , wherein n is 1.

13. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X 1 is C;

Y 1 is N or CH;

Y 2 is N or CR 5 ;

Y 3 is N or CR 6 ;

Y 4 is N or CR 7 ;

R 1 is —OH;

R 2 is (C 1 -C 6 ) alkyl, (C 6 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 5 -C 6 ) cycloalkyl, 5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, or —NR 10 R 11 , wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R 8 ;

R 4 and R 4′ are independently H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, or CN;

R 5 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, halogen, NO 2 , or CN, wherein the alkyl is optionally substituted with one to three R 12 ;

R 6 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, NO 2 , —NH 2 , —NHC(O)(C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 5 -C 5 ) cycloalkyl, or 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R 13 ;

each R 8 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 1 -C 3 )-alkylene-O—(C 1 -C 6 ) alkyl, —(C 0 -C 4 )-alkylene-(C 6 ) aryl-(C 0 -C 4 )-alkylene-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from 0, N, and S, (C 3 -C 10 ) cycloalkyl, 5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —(C 0 -C 4 )-alkylene-O—(C 6 ) aryl, —(C 0 -C 4 )-alkylene-O-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, —O—(C 5 -C 6 ) cycloalkyl, —S-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, —C(O)R 21 , —CO(O)R 21 , —C(O)NR 21 R 22 , —(C 0 -C 3 )-alkylene-NR 21 R 22 , —NR 21 C(O)R 22 , —NR 21 C(O)C(O)R 22 , —NR 21 C(O)NR 21 R 22 , or —OR 21 , wherein the alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R 9 ;

or two R 8 together when on adjacent atoms form a (C 5 -C 6 ) cycloalkyl optionally substituted with one to three R 9 ;

or two R 8 together when on adjacent atoms form a 5- or 6-membered heteroaryl ring comprising 1 to 3 heteroatoms selected from O, N, and S optionally substituted with one to three 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 5 -C 6 ) cycloalkyl, 5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —(C 0 -C 3 )-alkylene-(C 6 ) aryl, —(C 0 -C 3 )-alkylene-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, —NH 2 , —OH, —C(O)R 23 , —C(O)NR 23 R 24 , —NR 23 C(O)R 24 , —NR 23 R 24 , OXO, —O—(C 6 ) aryl, CN, or −O-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R 19 ;

R 10 and R 11 are independently H, or (C 1 -C 6 ) alkyl optionally substituted with one to three R 17 ;

each R 18 is independently (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, —OH, or CN;

each R 25 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 26 and R 27 is independently at each occurrence H, or (C 1 -C 6 ) alkyl;

m is 0;

n is 1; and

provided that the compound is further characterized by any one or more of the following:

i. at least one of Y 1 , Y 2 , Y 3 , or Y 4 is N;

ii. at least one of R 6 or R 7 is an optionally substituted (C 6 -C 14 ) aryl;

the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl of R 6 is substituted with an R 13 that is (C 1 -C 6 ) alkyl or that is 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein in the heterocycloalkyl is substituted with one to three R 15 ; or

v. R 7 is (C 1 -C 6 ) alkyl, (C 6 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 5 -C 6 ) cycloalkyl, 5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —O—(C 6 ) aryl, —O-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, —N((C 1 -C 6 ) alkyl)-(C 6 -C 14 ) aryl, —NH—(C 6 -C 14 ) aryl, —N((C 1 -C 6 ) alkyl)-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, or —NH-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl of R 7 is substituted with an R 14 that is (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, (C 1 -C 6 ) alkylamino, or di(C 1 -C 6 ) alkylamino.

14. The compound of claim 13 , wherein

each R 19 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 26 R 27 , —OH, or CN;

each R 21 and R 22 is independently H or (C 1 -C 6 ) alkyl;

each R 23 and R 24 is independently H or (C 1 -C 6 ) alkyl; and

15. The compound of claim 14 , wherein

each R 19 is independently at each occurrence (C 1 -C 6 ) alkyl; and

each R 28 is independently at each occurrence (C 1 -C 6 ) alkyl.

16. The compound of claim 15 , wherein:

R 2 is (C 1 -C 6 ) alkyl, or (C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to two R 8 ;

each R 8 is independently halogen, or —(C 0 -C 4 )-alkylene-(C 6 -C 14 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 9 ; or two R 8 together when on adjacent atoms form a (C 5 -C 6 ) cycloalkyl optionally substituted with one to three R 9 ; and

each R 9 is —(C 0 -C 3 )-alkylene-(C 6 ) aryl.

17. The compound of claim 16 , wherein R 2 is (C 1 -C 6 ) alkyl substituted with one R 8 ; and R 8 is —(C 0 -C 4 )-alkylene-(C 6 -C 14 ) aryl.

18. The compound of claim 17 , wherein

R 6 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, halogen, —NH 2 , —NHC(O)(C 1 -C 6 ) alkyl, (C 6 ) aryl, wherein the alkyl or aryl are optionally substituted with one to three R 13 ;

R 13 is independently (C 1 -C 6 ) alkyl, 5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl and heterocycloalkyl are optionally substituted with one to three R 15 ;

each R 15 is independently (C 1 -C 6 ) alkyl; and

R 7 is H.

19. The compound of claim 18 , wherein R 6 is NHC(O)(C 1 -C 6 ) alkyl.

Assignments (6)

RELEASE OF SECURITY INTEREST Recorded Oct 17, 2023

From: FIRST-CITIZENS BANK & TRUST COMPANY, AS AGENT

To: VALO HEALTH, INC.; VALO HEALTH, LLC

Reel/Frame 065255/0660 →

SECURITY INTEREST Recorded Jul 6, 2023

From: VALO HEALTH, LLC; VALO HEALTH, INC.

To: FIRST-CITIZENS BANK & TRUST COMPANY, AS AGENT

Reel/Frame 064207/0957 →

MERGER Recorded Sep 8, 2021

From: VALO EARLY DISCOVERY, INC.

To: VALO HEALTH, INC.

Reel/Frame 057438/0025 →

CHANGE OF NAME Recorded Sep 16, 2020

From: INTEGRAL EARLY DISCOVERY, INC.

To: VALO EARLY DISCOVERY, INC.

Reel/Frame 053787/0138 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 5, 2020

From: FORMA THERAPEUTICS, INC.

To: INTEGRAL EARLY DISCOVERY, INC.

Reel/Frame 053402/0298 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 16, 2018

From: IOANNIDIS, STEPHANOS; TALBOT, ADAM CHARLES; FOLLOWS, BRUCE; BUCKMELTER, ALEXANDRE JOSEPH; WANG, MINGHUA; CAMPBELL, ANN-MARIE; LANCIA, DAVID R., JR

To: FORMA THERAPEUTICS, INC.

Reel/Frame 047525/0806 →

Continuity (4)

Continuation 15837393 · Dec 11, 2017

Continuation 15015571 · Feb 4, 2016

Provisional Application 62112487 · Feb 5, 2015

Related Publication 20190071421A1 · Mar 7, 2019